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Background In shoulder arthroplasty, bone resorption around the stem can lead to stem loosening and makes surgery difficult at the time of revision. Proximal bone resorption after reverse shoulder arthroplasty can cause instability because of a decrease of deltoid wrapping effect. As factors of the stem itself, such as stem coating, shape, length, and use of bone cement, may also affect bone resorption, a single-stem model should be used to compare bone resorptions between different pathologies and surgical procedures. However, to date, a few reports have compared these differences in detail using a single-stem model. Therefore, we investigated the prevalence and location of humeral bone resorption in a single-stem model. Methods The study included 100 shoulders that underwent anatomical total shoulder arthroplasty (TSA) or humeral head replacement (HHR) with a single uncemented humeral stem from 2008 to 2018. The patients were 31 men and 69 women. The mean age at surgery was 72.9 years (range, 41-86 years). The patients were divided into three groups: especially, 25, 61, and 14 shoulders received TSA for primary osteoarthritis without rotator cuff tears (TSA group), HHR using an anatomical head with rotator cuff repair for cuff tear arthropathy (CTA) (HHR group), and HHR using a CTA head without rotator cuff repair (CTA group), respectively. Patients were monitored for a mean of 56 months (range, 12-98 months). The location of bone resorption was divided into seven zones as follows: zone 1, greater tuberosity; zone 2, lateral diaphysis; zone 3, lateral diaphysis beyond the deltoid tuberosity; zone 4, tip of the stem; zone 5, medial diaphysis beyond the deltoid tuberosity; zone 6, medial diaphysis; and zone 7, calcar region. The degree of bone resorption was classified from grade 0 to 4. Results Bone resorption of grade 3 or higher was significantly more frequent at the greater tuberosity in the HHR and CTA groups (P Conclusion The state of attachment of the rotator cuff to the greater tuberosity might affect bone resorption at the greater tuberosity, such as the greater tuberosity after shoulder arthroplasty. In cases of shoulder arthroplasty for arthropathy with rotator cuff tear, performing rotator cuff repair might prevent bone resorption. Level of evidence Level IV; Prognosis Study

High-mobility group box 2, a chromatin-associated protein that interacts with deoxyribonucleic acid, is implicated in multiple biological processes, including gene transcription, replication, and repair. High-mobility group box 2 is expressed in several tissues, including the testis; however, its functional role is largely unknown. Here, we elucidated the role of high-mobility group box 2 in spermatogenesis. Paraffin-embedded testicular tissues were obtained from 8-week-old and 1-year-old wild-type and knock-out mice. Testis weight and number of seminiferous tubules were decreased, whereas atrophic tubules were increased in high-mobility group box 2-depleted mice. Immunohistochemistry revealed that atrophic tubules contained Sertoli cells, but not germ cells. Moreover, decreased cell proliferation and increased apoptosis were demonstrated in high-mobility group box 2-depleted mouse testis. To elucidate the cause of tubule atrophy, we examined the expression of androgen and estrogen receptors, and the results indicated aberrant expression of androgen receptor and estrogen receptor alpha in Sertoli and Leydig cells. Southwestern histochemistry detected decreased estrogen response element–binding sites in high-mobility group box 2-depleted mouse testis. High-mobility group box 1, which has highly similar structure and function as high-mobility group box 2, was examined by immunohistochemistry and western blotting, which indicated increased expression in testis. These findings indicate a compensatory increase in high-mobility group box 1 expression in high-mobility group box 2 knock-out mouse testis. In summary, depletion of high-mobility group box 2 induced aberrant expression of androgen receptor and estrogen receptor alpha, leading to decreased germ cell proliferation and increased apoptosis which resulted in focal seminiferous tubule atrophy.

High-mobility group box 2 (HMGB2) is a chromatin-associated protein that is an important regulator of gene transcription, recombination, and repair processes. The functional importance of HMGB2 has been reported in various organs, including the testis, heart, and cartilage. However, its role in the ovary is largely unknown. In this study, ovary tissues from wild-type (WT) and HMGB2-knock-out (KO) mice were examined by histopathological staining and immunohistochemistry. The ovary size and weight were significantly lower in HMGB2-KO mice than in age-matched WT littermates. Histopathological analysis revealed ovarian atrophy and progressive fibrosis in 10-month-old HMGB2-KO mouse ovaries. Compared to age-matched WT mice, the numbers of oocytes and developing follicles were significantly decreased at 2 months of age and were completely depleted at 10 months of age in HMGB2-KO mice. Immunohistochemistry revealed the expression of HMGB2 in the granulosa cells of developing follicles, oocytes, some corpora lutea, and stromal cells. Importantly, HMGB2-positive cells were co-localized with estrogen receptor beta (ERβ), but not ERα. Estrogen response element-binding activity was demonstrated by southwestern histochemistry, and it was decreased in HMGB2-KO mouse ovaries. Cell proliferation activity was also decreased in HMGB2-KO mouse ovaries in parallel with the decreased folliculogenesis. These results indicated that the depletion of HMGB2 induced ovarian atrophy that was characterized by a decreased ovarian size and weight, progressive fibrosis, as well as decreased oocytes and folliculogenesis. In conclusion, we demonstrated the crucial role of HMGB2 in mouse ovarian folliculogenesis through ERβ expression.

We present 2 cases (19- and 40-year-old women) of lumbosacral spinal deformity with sacroiliac joint destruction. Reconstruction surgery using a fibular strut autograft was performed in both patients, and spinal reconstruction and fusion were successfully maintained without bone resorption for at least 7 years.This is the first report of reconstructive surgery using a fibular strut bone graft for lumbosacral deformity with destruction of the sacroiliac joint in patients with neurofibromatosis type 1 (NF-1). These findings suggest that reconstruction with a fibular strut autograft is useful for lumbosacral spinal deformity that includes destruction of the sacroiliac joints in NF-1.

Background Humeral stem loosening has gained attention as it has been identified as a cause of revision surgery in reverse shoulder arthroplasty (RSA). In RSA, humeral stem revision is very difficult if there is humeral bone loss because of stress shielding. Some studies of humeral bone resorption after anatomic shoulder arthroplasty have been published, but there are few detailed reports of humeral bone resorption after RSA. This study aimed to investigate the prevalence of humeral bone resorption after RSA procedures and to evaluate the risk factors for bone resorption. Methods This study included 48 shoulders that underwent RSA with an uncemented humeral stem from July 2014 to May 2017 and were followed up for more than 1 year. The prevalence of humeral bone resorption and risk factors were investigated. Logistic, multiple logistic, and multivariate logistic regression analyses were performed to evaluate the data. Results Grade 0 bone resorption, the most advanced grade, occurred in 8 shoulders (16.7%); grade 1, in 0 (0%); grade 2, in 17 (35.4%); grade 3, in 14 (29.2%); and grade 4, in 9 (18.8%). A high occurrence of bone absorption was observed in zones 1, 2, and 7. Grade 4 bone resorption did not occur in zones 3, 5, and 6. Female sex and an onlay-type stem were significant independent risk factors for grade 4 bone resorption. Conclusions Bone resorption was frequently observed in the greater tuberosity, lateral diaphysis, and calcar region. Significant risk factors included female sex and an onlay-type stem.

Background Avulsion fracture of the medial head of the gastrocnemius muscle is a very rare phenomenon. There are no reports of avulsion fractures associated with multiple ligament injuries before closure of the growth plate. The authors present a case of avulsion fracture of the insertion of the medial head of the gastrocnemius muscle associated with posterior cruciate ligament injury and an avulsion fracture of the medial collateral ligament at the femoral attachment. Case presentation A 15-year-old Japanese boy was injured by contact with another player while playing soccer. He was immediately admitted to the authors’ hospital with knee pain. Radiography and computed tomography revealed an avulsion fracture of the medial collateral ligament at the femoral attachment and an avulsion fracture of the medial head of the gastrocnemius muscle. In examination under anesthesia, the Lachman test was negative and posterior drawer test was positive. Fixation of the avulsion fractures of the medial collateral ligament and medial head of the gastrocnemius was performed 9 days after the injury. After fixation, valgus instability at full extension had disappeared. The knee was immobilized in a brace for 2 weeks postoperatively. One year postoperatively, the posterior drawer test was slightly positive; however, our patient was able to ambulate without pain and returned to sports without feeling instability in his knee. Conclusion A rare case of avulsion fracture of the gastrocnemius muscle combined with multiple ligament injuries before closure of the growth plate is described. A satisfactory result was obtained by fixation of the avulsed bone fragments of the gastrocnemius muscle and medial collateral ligament. The authors believe that avulsion fracture of the medial head of the gastrocnemius muscle associated with posterior cruciate ligament injury should be repaired.

Undifferentiated pleomorphic sarcoma (UPS) is the second most common soft tissue sarcoma. For patients with unresectable or metastatic disease, chemotherapies are considered, but in many cases they are not curative. There is a need to identify specific molecular dysregulations that can be therapeutic targets. We focused on neurotensin receptor 1 (NTSR1), which belongs to the G-protein-coupled receptor. NTSR1 expression was upregulated in specimens from patients with UPS. Real-time polymerase chain reaction showed that expression of NTSR1 messenger RNA was 5- to 7-fold increased in UPS cells compared with myoblasts. Western blot showed a high expression of NTSR1 protein in UPS cell lines. Knockdown of NTSR1 prevented UPS cell proliferation and invasion. We confirmed that SR48692, an inhibitor of NTSR1, exhibited antitumor activities in UPS cells. The combination index showed that SR48692 and standard chemotherapeutic drugs prevented UPS cell proliferation synergistically. Mouse xenograft models showed that SR48692 inhibited extracellular signal-regulated kinase phosphorylation and enhanced the response to standard chemotherapeutic drugs. Inhibition of NTSR1 improved the effect of standard chemotherapeutic drugs for UPS. SR48692 may be a new drug for targeted UPS therapy.

Object: To evaluate the relationship between idiopathic normal-pressure hydrocephalus (iNPH) and lumbar spinal stenosis (LSS).Methods: With the aging of society, the numbers of patients with iNPH and LSS are likely to increase. iNPH and LSS have similar symptoms including gait disturbance and urinary dysfunction. The prevalence of dementia is higher in older adults with LSS. However, the relationship of LSS with iNPH and the prevalence of LSS in patients with iNPH are unknown. In our department between April 2011 and March 2017, 226 patients were diagnosed with iNPH and underwent shunt operation including lumboperitoneal shunts and ventriculoperitoneal shunts. Two spine surgeons evaluated LSS on magnetic resonance imaging of the lumbar spine. Age, sex, body mass index, Timed Up and Go test, Mini Mental State Examination score, and urinary dysfunction were examined before and after surgery for iNPH. Changes in these variables were compared between patients with iNPH without LSS and with iNPH and LSS.Results: In the overall cohort, the median patient age was 78 years and there were 121 males. Among 226 patients with iNPH, 73 (32.3%) had LSS. Neurological symptoms were improved in all patients at final follow-up. The rate of symptom improvement was lower for the iNPH and LSS group compared with the iNPH without LSS group.Conclusions: Surgery to improve gait disturbance might be difficult in patients with iNPH with LSS. When examining patients with iNPH, we should consider the possibility of concomitant LSS.

Most spinal meningiomas arise from the thoracic dura in middle-aged and elderly women. Simpson grade 1 resection is recommended to avoid recurrence. For ventral and ventrolateral tumors, reconstruction after total dural resection is difficult, and spinal fluid leakage is likely. To overcome this concern, Saito et al. developed the technique of resecting the tumor with the inner dural layer, preserving the outer dural layer. Although meningioma rarely recurs, the recurrence period is approximately 8 years postoperatively. No studies have evaluated long-term (> 10-year) outcomes of the Saito method. Here, we report 10 cases of the Saito method with > 10-year follow-up and compare outcomes with those of other standard approaches. Twenty-nine pathology-confirmed meningioma patients underwent surgery in our department, ten with the Saito method. We investigated resection method (dura mater treatment), pathological type, and recurrence and compared pre- and postoperative clinical findings. The median follow-up was 132 months. Recurrence occurred after Simpson grades 3 and 4 resection. Simpson grades 1, 2, and the Saito method resulted in no recurrence. Neurological symptoms improved in all patients at final follow-up. This is the first report of long-term outcomes of the Saito method. The method achieved good neurological improvement with no recurrence in > 10-year follow-up.

Recently, we reported highly active transforming growth factor (TGF)-β and bone morphogenetic protein (BMP) signaling in human chondrosarcoma samples and concurrent downregulation of paternally expressed gene 10 (PEG10). PEG10 expression was suppressed by TGF-β signaling, and PEG10 interfered with the TGF-β and BMP-SMAD pathways in chondrosarcoma cells. However, the roles of PEG10 in bone tumors, including chondrosarcoma, remain unknown. Here, we report that PEG10 promotes SW1353 chondrosarcoma cell growth by preventing TGF-β1-mediated suppression. In contrast, PEG10 knockdown augments the TGF-β1-induced motility of SW1353 cells. Individually, TGF-β1 and PEG10 siRNA increase AKT phosphorylation, whereas an AKT inhibitor, MK2206, mitigates the effect of PEG10 silencing on cell migration. SW1353 cell invasion was enhanced by BMP-6, which was further increased by PEG10 silencing. The effect of siPEG10 was suppressed by inhibitors of matrix metalloproteinase (MMP). BMP-6 induced expression of MMP-1, -3, and -13, and PEG10 lentivirus or PEG10 siRNA downregulated or further upregulated these MMPs, respectively. PEG10 siRNA increased BMP-6-induced phosphorylation of p38 MAPK and AKT, whereas the p38 inhibitor SB203580 and MK2206 diminished SW1353 cell invasion by PEG10 siRNA. SB203580 and MK2206 impeded the enhancing effect of PEG10 siRNA on the BMP-6-induced expression of MMP-1, -3, and -13. Our findings suggest dual functions for PEG10: accelerating cell growth by suppressing TGF-β signaling and inhibiting cell motility and invasion by interfering with TGF-β and BMP signaling via the AKT and p38 pathways, respectively. Thus, PEG10 might be a molecular target for suppressing the aggressive phenotypes of chondrosarcoma cells.

Bacillus Calmette-Guerin (BCG)-associated osteomyelitis is a rare adverse event following BCG vaccination, and there have been no previous reports of BCG-associated cervical spondylitis. Here, we describe the case of a 3-year-old immunocompetent girl who developed BCG-associated cervical spondylitis and was successfully treated by prompt surgical drainage of the abscess and administration of isoniazid and rifampicin for 9 months without sequelae.

Ossification of the posterior longitudinal ligament (OPLL) occurs mainly through endochondral ossification. Although researchers have been attempting to elucidate the pathogenesis of OPLL for many years, it remains unclear which cell types in the ligament have chondrogenic capacity. Furthermore, the contribution of direct bone formation without chondrogenesis remains elusive. To characterize the osteochondrogenic potential of the cells around the ossification area of OPLL, we immunohistochemically evaluated a series of proteins specific to endochondral ossification. We found SOX9/type II collagen-positive chondrocytes in the fibrocartilage area, hypertrophic chondrocytes with type X collagen expression, and osteoblastic cells expressing RUNX2, osterix, and bone sialoprotein in the stromal fibrous area (SFA) between the ossified areas, thereby confirming the concept of an endochondral ossification-like process. In addition, the osteoblastic cells and blood vessel cells in the degenerated ligament, as well as the cells in the SFA outside of the ossified area, expressed both osteoblastic markers and SOX9, suggesting that these cells were bipotential osteochondral progenitor cells. Additionally, we revealed that the blood vessel cells and stromal fibrous cells exhibited bipotential osteochondrogenic features. Our observation suggests that any or all of these osteochondral mesenchymal cells may be initiators of OPLL.

The activation and proliferation of microglia is characteristic of the early stages of brain pathologies. In this study, we aimed to identify a factor that promotes microglial activation and proliferation and examined the in vitro effects on these processes. We cultured microglial cell lines, EOC 2 and SIM-A9, with various growth factors and evaluated cell proliferation, death, and viability. The results showed that only transforming growth factor beta (TGF-&beta, ) caused an increase in the in vitro proliferation of both microglial cell lines. It has been reported that colony-stimulating factor 1 promotes the proliferation of microglia, while TGF-&beta, promotes both proliferation and inhibition of cell death of microglia. However, upon comparing the most effective doses of both (assessed from the proliferation assay), we identified no statistically significant difference between the two factors in terms of cell death, thus, both have a proliferative effect on microglial cells. In addition, a TGF-&beta, receptor 1 inhibitor, galunisertib, caused marked inhibition of proliferation in a dose-dependent manner, indicating that inhibition of TGF-&beta, signalling reduces the proliferation of microglia. Therefore, galunisertib may represent a promising therapeutic agent for the treatment of neurodegenerative diseases via inhibition of nerve injury-induced microglial proliferation, which may result in reduced inflammatory and neuropathic and cancer pain.

Adult bone structural integrity is maintained by remodeling via the coupling of osteoclastic bone resorption and osteoblastic bone formation. Osteocytes or osteoblasts express receptor activator of nuclear factor κ-B ligand (Rankl) or osteoprotegerin (Opg) to promote or inhibit osteoclastogenesis, respectively. Bone morphogenetic protein (BMP) is a potent bone inducer, but its major role in adult bone is to induce osteocytes to upregulate sclerostin (Sost) and increase the Rankl/Opg expression ratio, resulting in promotion of osteoclastogenesis. However, the precise effect of BMP-target gene(s) in osteoblasts on the Rankl/Opg expression ratio remains unclear. In the present study, we identified atonal homolog 8 (Atoh8), which is directly upregulated by the BMP-Smad1 axis in osteoblasts. In vivo, Atoh8 was detected in osteoblasts but not osteocytes in adult mice. Although global Atoh8-knockout mice showed only a mild phenotype in the neonate skeleton, the bone volume was decreased and osteoclasts were increased in the adult phase. Atoh8-null marrow stroma cells were more potent than wild-type cells in inducing osteoclastogenesis in marrow cells. Atoh8 loss in osteoblasts increased Runx2 expression and the Rankl/Opg expression ratio, while Runx2 knockdown normalized the Rankl/Opg expression ratio. Moreover, Atoh8 formed a protein complex with Runx2 to inhibit Runx2 transcriptional activity and decrease the Rankl/Opg expression ratio. These results suggest that bone remodeling is regulated elaborately by BMP signaling; while BMP primarily promotes bone resorption, it simultaneously induces Atoh8 to inhibit Runx2 and reduce the Rankl/Opg expression ratio in osteoblasts, suppressing osteoclastogenesis and preventing excessive BMP-mediated bone resorption.

Background Failure rates after rotator cuff repair remain high in patients with massive tears. Although superior translation of the humeral head has been used to assess the severity of rotator cuff tears, the relevance of anterior migration of the humeral head to clinical outcomes has not been established. The purpose of this study was to investigate the potential role of the T-scale, a measure of the anterolateral translation of the humeral head, as a prognostic factor for rotator cuff repair. Methods One hundred twenty consecutive patients with full-thickness rotator cuff tears underwent primary rotator cuff repair. The T-scale and acromiohumeral interval (AHI) were measured preoperatively on axial computed tomography scans and radiographs, respectively. The correlations of the T-scale and AHI with previously published scores and active forward elevation (FE) were investigated. The outcome of rotator cuff repairs was compared between patients with positive and patients with negative preoperative T-scale values. Results The preoperative T-scale but not AHI correlated significantly with postoperative FE and clinical scores in patients with large to massive tears but not in those with small to medium tears. Postoperative FE and clinical scores were significantly higher in patients with positive T-scale values than in those with negative T-scale values. The relative risk of retear was 2.0 to 7.9 times greater in patients with negative T-scale values. Conclusion Patients with large to massive tears and negative T-scale values had poorer clinical outcomes and higher retear rates. A negative T-scale value represents a useful prognostic factor for considering reverse shoulder arthroplasty in patients at greater risk of retear after rotator cuff repair.

In this study, the efficiency of ionic transport through proton-conducting ceramic electrolytes for energy conversion applications was discussed while considering the energy losses caused by the mixed ionic and electronic conduction and by the ionic transport resistance. It was shown that high energy efficiency cannot be expected with an extremely thin electrolyte because of the significant energy loss due to the internal current leakage. In the case of a fuel cell with a BaZr0.8Y0.2O3−δ electrolyte operating at 873 K, the maximum energy efficiency was estimated to be only 82% when the product of the external current density and the electrolyte thickness was 1.7 × 10−3 A cm−1. The energy efficiency for the ionic transport in BaZr0.8Y0.2O3−δ was compared with those for typical oxide ion conductors, i.e. yttria stabilized zirconia and Ce0.9Gd0.1O1.95−δ, under various fuel cell operating conditions. BaZr0.8Y0.2O3−δ can provide higher energy efficiency than the oxide ion conductors at lower temperatures and under higher current conditions. For the efficient operation of fuel cells using a proton-conducting ceramic as an electrolyte, lower operating temperatures below 873 K is preferable from the viewpoint of energy loss in the electrolyte. The influence of the partial conductivity variation on the energy efficiency was also discussed. It was shown that not only the increase of ionic conductivity but also the decrease of electronic conductivity could improve the energy efficiency if the electrolyte thickness can be optimized. This means that decreasing electronic conductivity as well as increasing proton conductivity can be an effective strategy to develop highly efficient proton conductors for energy conversion applications.

Ossification of the posterior longitudinal ligament (OPLL) of the spine is a common pathological condition that causes intractable myelopathy and radiculopathy, mainly the result of an endochondral ossification-like process. Our previous genome-wide association study identified six susceptibility loci for OPLL, including the cell division cycle 5-like (CDC5L) gene region. Here, we found CDC5L to be expressed in type II collagen-producing chondrocyte-like fibroblasts in human OPLL specimens, as well as in differentiating ATDC5 chondrocytes. Cdc5l siRNA transfection in murine chondrocytes decreased the expression of the early chondrogenic genes Sox9 and Col2a1, diminished the cartilage matrix production, and enhanced the expression of parathyroid-hormone-related protein (a resting chondrocyte marker). We also showed that Cdc5l shRNA suppressed the growth of cultured murine embryonal metatarsal cartilage rudiments and that Cdc5l knockdown suppressed the growth of ATDC5 cells. Fluorescence-activated cell sorting analysis revealed that the G2/M cell cycle transition was blocked; our data showed that Cdc5l siRNA transfection enhanced expression of Wee1, an inhibitor of the G2/M transition. Cdc5l siRNA also decreased the pre-mRNA splicing efficiency of Sox9 and Col2a1 genes in both ATDC5 cells and primary chondrocytes; conversely, loss of Cdc5l resulted in enhanced splicing of Wee1 pre-mRNA. Finally, an RNA-binding protein immunoprecipitation assay revealed that Cdc5l bound directly to these target gene transcripts. Overall, we conclude that Cdc5l promotes both early chondrogenesis and cartilage growth and may play a role in the etiology of OPLL, at least in part by fine-tuning the pre-mRNA splicing of chondrogenic genes and Wee1, thus initiating the endochondral ossification process.

Background Bone resorption around the femoral stem after total hip arthroplasty is a well-known phenomenon. However, only a few studies have evaluated bone resorption after shoulder arthroplasty. This study investigated the prevalence of humeral bone resorption after different shoulder arthroplasty procedures. Methods The study included 147 shoulders that underwent total shoulder arthroplasty (TSA) or humeral head replacement (HHR) with an uncemented humeral stem from November 2008 to May 2015 and were monitored for more than 1 year. The prevalence of humeral bone resorption and risk factors were investigated. Results The most advanced grade of bone resorption, grade 0, occurred in 21 shoulders (14.3%). Grade 1 bone resorption occurred in 10 (6.8%), grade 2 in 28 (19.0%), grade 3 in 61 (41.5%), and grade 4 in 27 (18.4%). High occurrence of bone absorption was observed in zones 1, 2, and 7. Grade 4 bone resorption did not occur in zones 3 and 5. HHR, on-growth type stem coating, and occupation ratio were significant independent risk factors for grade ≥3 bone resorption, whereas female sex and HHR were significant independent risk factors for grade 4. Conclusion Bone resorption was observed in 126 shoulders (85.7%), and full-thickness cortical bone resorption occurred in 27 shoulders (18.4%). Bone resorption was frequently observed at the greater tuberosity, lateral diaphysis, and calcar region (zones 1, 2, and 7). Significant risk factors included female sex, HHR with rotator cuff reconstruction, on-growth type stem coating, and high occupation ratio of the implant.

Objectives: The EFEMP1 gene encoding fibulin-3 is specifically expressed in the superficial zone of articular cartilage. This study examined fibulin-3 expression patterns in joint aging and osteoarthritis (OA) and the role of fibulin-3 in OA pathogenesis. Methods: Immunohistochemical analysis was performed on normal and OA human and mouse knee cartilage. Experimental OA was induced in wild type and fibulin-3-/- mice and OA severity was evaluated by histological scoring. To examine fibulin-3 function, chondrocyte monolayer cultures were transfected with siRNA for quantitative PCR and Western blot analyses. Bone marrow mesenchymal stem cells (MSC) were transduced with EFEMP1 lentivirus and analyzed for chondrogenesis markers. Results: Fibulin-3 was specifically expressed in the SZ of normal cartilage in human and mouse knee joints and declined with aging. Both aging-related OA and experimental OA were significantly more severe in fibulin-3-/- mice compared with wild type mice. Fibulin-3 expression was high in undifferentiated MSC and decreased during chondrogenesis. Suppression of fibulin-3 by siRNA significantly increased SOX9, collagen II and aggrecan in articular chondrocytes, while overexpression of fibulin-3 inhibited chondrogenesis in MSC. Conclusion: Fibulin-3 is specifically expressed in the SZ of articular cartilage and its expression is reduced in aging and OA. Fibulin-3 regulates differentiation of adult progenitor cells and its aging-related decline is an early event in OA pathogenesis. Preventing or restoring aging-associated loss of fibulin-3 in SZ chondrocytes has potential to delay or prevent onset of OA. This article is protected by copyright. All rights reserved.

Tranilast [N-(3′,4′-dimethoxycinnamoyl)-anthranilic acid], initially developed as an antiallergic drug, also exhibits a growth inhibitory effect on various types of cancer. Osteosarcoma is treated mainly with high-dose methotrexate, doxorubicin, cisplatin and ifosfamide; however, 20–30 % of patients cannot be cured of metastatic disease. We investigated whether tranilast enhances the anticancer effects of chemotherapeutic drugs and analyzed its mechanism of action in osteosarcomas. Tranilast inhibited proliferation of HOS, 143B, U2OS and MG-63 osteosarcoma cells in a dose-dependent manner, as well as enhancing the effects of cisplatin and doxorubicin. The average combination index at effect levels for tranilast in combination with cisplatin was 0.57 in HOS, 0.4 in 143B, 0.39 in U2OS and 0.51 in MG-63 cells. Tranilast and cisplatin synergistically inhibited the viability of osteosarcoma cells. In flow cytometric analysis, although tranilast alone did not induce significant apoptosis, the combination of tranilast and cisplatin induced early and late apoptotic cell death. Expression of cleaved caspase-3, cleaved poly(ADP-ribose) polymerase and p-H2AX was enhanced by tranilast in combination with cisplatin. Tranilast alone increased expression of p21 and Bim protein in a dose-dependent manner. Cell cycle analysis using flow cytometry demonstrated that the combination of tranilast and cisplatin increased the number of cells in the G2/M phase. Compared with cisplatin alone, the combination increased levels of phospho-cyclin-dependent kinase 1 (Y15). In the 143B xenograft model, tumor growth was significantly inhibited by combined tranilast and cisplatin compared with the controls, whereas cisplatin alone did not significantly inhibit tumor growth. In conclusion, tranilast has a cytostatic effect on osteosarcoma cells and enhances the effect of anticancer drugs, especially cisplatin. Enhanced sensitivity to cisplatin was mediated by increased apoptosis through G2/M arrest. Since tranilast has been clinically approved and has few adverse effects, clinical trials of osteosarcoma chemotherapy in combination with tranilast are expected.

Background Several authors have reported the occurrence of extraforaminal L5 nerve root compression between lumbosacral transitional vertebrae (LSTV) and sacral ala, but reports on a lesion caused by an intervertebral osteophyte on the ventral and contralateral side of a unilateral abnormality by LSTV are hardly available. Case Description A 67-year-old woman presented with pain along the distribution of the L5 nerve root; straight leg raise test, femoral nerve stretch test, and Kemp test were positive on the left. Following plain radiographs, computerized tomography, magnetic resonance imaging, and selective nerve root block, an osteophyte bridging the L5 and S1 vertebral bodies in the ventral side was identified compressing the L5 nerve root. On account of resistance to conservative therapy and the delicate position of the lesion, surgical treatment was performed by an anterior decompression. Subsequently, the patient attained adequate relief from pain and could walk normally. Conclusion We herein present a very rare case of extraforaminal L5 nerve root compression caused by an intervertebral osteophyte on the ventral and contralateral side of a unilateral abnormality by LSTV, which was managed by anterior decompression.

Purpose: The aim of this study was to investigate the histopathological changes in the humeral head in cuff tear arthropathy (CTA) compared with those in glenohumeral osteoarthritis (OA) and humeral neck fracture, which served as non-cuff tear controls.\nMethods: Twenty-three humeral heads extracted at the time of shoulder prosthesis arthroplasty between June 2014 and July 2015 were evaluated in the present study. The diagnoses included four-part humeral neck fracture (n = 4; average age, 85.0 years), glenohumeral OA (n = 4; average age, 71.0 years), and CTA (n = 15; average age, 73.0 years). The humeral heads were evaluated pathologically by hematoxylin and eosin and Safranin-O staining, and the thickness of the articular cartilage was measured.\nResults: Fibrillation, thinning, and tearing of the cartilage were observed in the superior area of the humeral heads in CTA and glenohumeral OA. In CTA cases, clusters of chondrocytes in the cartilage were observed. Moreover, the thickness of the cartilage layer in the middle of the humeral head was 1.54 ± 0.07, 0.32 ± 0.46, and 2.19 ± 0.50 mm in humeral neck fracture, glenohumeral OA, and CTA, respectively. The cartilage layer in CTA was thicker than that in glenohumeral OA (CTA vs. OA: p < 0.05).\nConclusion: OA changes in the superior area of the humeral heads and thickening of the cartilage layer from the middle to the inferior of the humeral heads were confirmed histopathologically, suggesting that simultaneous mechanical and nutritional factors might be contributing to CTA pathogenesis. The current study provided the better understanding of cartilage damage and thickening in CTA. This will help guide treatment options in the setting of CTA., 論文

Malignant soft-tissue sarcoma resection is associated with a relatively high incidence of surgical site infection (SSI). The known risk factors for SSI following soft-tissue sarcoma resection include tumor size and location, prolonged surgery, and massive blood loss. The geriatric nutritional risk index (GNRI) was used as a tool to help predict the occurrence of SSI after major surgery. We investigated the utility of the GNRI as a predictor of SSI following soft-tissue sarcoma resection. We retrospectively reviewed 152 patients who underwent surgical resection of soft-tissue sarcoma in our institute, and found that the incidence of SSI was 18.4% (28/152). The SSI and non-SSI groups significantly differed regarding surgical time, diameter of the skin incision, maximum tumor diameter, instrumentation, presence of an open wound, preoperative chemotherapy, preoperative C-reactive protein concentration, and GNRI. Binomial logistic regression analysis showed that the risk factors for SSI following soft-tissue sarcoma surgery were male sex, larger skin incision diameter, larger maximum tumor diameter, presence of an open wound, and lower GNRI. Our findings indicate that malnutrition is a risk factor for SSI after soft-tissue sarcoma resection, and suggest that appropriate assessment and intervention for malnutrition may reduce the incidence of SSI.

The treatment of glioblastoma is a critical health issue, owing to its resistance to chemotherapy. The current standard of treatment is surgical resection, followed by adjuvant radiotherapy and temozolomide treatment. Long‑term local treatment of glioblastoma is rarely achieved and the majority of the patients undergo relapse. Resistance to temozolomide emerges from numerous signalling pathways that are altered in glioblastoma, including the Hedgehog signalling pathway. Hence, further research is required to identify effective treatment modalities. We investigated the effect of vismodegib, arsenic trioxide and temozolomide on glioblastoma in vitro and in vivo to apply our findings to the clinical setting. WST‑1 assay revealed that glioblastoma proliferation was inhibited following treatment with these drugs either in single or in combination; this synergistic effect was confirmed by CalcuSyn software. Western blot analysis revealed an increase in the expression of cleaved caspase‑3 and γH2AX. Furthermore, there was marked inhibition and decreased tumour growth in mice that received combination therapy, unlike those that received single agent or vehicle treatment. Our results revealed that the combination of arsenic trioxide/vismodegib and temozolomide may be an attractive therapeutic method for the treatment of glioblastoma.

Study design Retrospective case control study. Objective To investigate whether cervical alignment is related to dysphagia in patients with cervical diffuse idiopathic skeletal hyperostosis (DISH). Summary of background data DISH involves a wide range of ligamentous ossifications, which can cause dysphagia. However, even patients with a high degree of ossification can have only mild dysphagia. Dysphagia results from esophageal compression due to ossification; however, the exact cause of dysphagia is unknown. Methods We reviewed five patients with advanced dysphagia due to anterior cervical hyperostosis who underwent resection (S group), and five patients with mild symptoms who were only monitored (NS group). The patients were evaluated using the Eating Assessment Tool-10 (EAT-10) and plain kinetic radiographs of the cervical spine. The O-C2 angle, M-C angle, C2-7 angle, and C2-6a angle were measured in the flexion, neutral, and extension positions. We compared these parameters in the S group versus the NS group, and compared the pre- and postoperative values in the S group. Results The EAT-10 score indicated a high degree of dysphagia in the S group preoperatively (25 [22-27]) compared with the NS group (1 [1-6]). In the S group, the EAT-10 score significantly decreased postoperatively to 1 (0-1), and improvement of dysphagia was observed. There was a significant difference between the S and NS groups in the ΔC2-7 and ΔC2-6a, and between pre- and postoperative values in the S group. There were no significant changes in O-C2 angle and M-C angle, which are parameters of the superior cervical vertebrae. Conclusion The present results suggest that the restriction of flexion due to cervical spine ankylosis may be one of the reasons for dysphagia in patients with DISH. Level of evidence 4.

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Predicting outcomes in patients with soft tissue sarcoma (STS) is challenging. To improve these predictions, we retrospectively analyzed common nutritional assessment systems, including Glasgow prognostic score (GPS), Geriatric Nutritional Risk Index (GNRI), neutrophil&ndash, lymphocyte ratio (NLR), platelet&ndash, lymphocyte ratio (PLR), and controlling nutritional (CONUT) score against outcomes in 103 patients with STS, of whom 15 (14.6%) died within 1 year of diagnosis. GPS, GNRI, NLR, PLR, and CONUT scores significantly differed between patients who died within one year and patients who lived longer. Binomial logistic regression analysis showed that male sex, older age at diagnosis, higher GPS, higher stage, and unresectable STS were risk factors for death within a year of diagnosis. Overall survival was evaluated by Cox proportional hazards models, which correlated higher NLR, higher PLR, larger maximum diameter of tumor, higher stage, and unresectable STS with poor prognosis. We next examined prognostic factors in the 93 patients with resectable STS, and found male sex, higher GPS, and higher stage were correlated with poor prognosis in these patients. Our findings suggest that GPS, NLR, and PLR are simple predictors of outcome in patients with STS. Nutritional therapies might improve their GPS and prognosis.

Although various surgical procedures have been developed for chronic rotator cuff tear repair, the re-tear rate remains high with severe fat infiltration. However, little is known about the molecular regulation of this process. Mesenchymal stem cells (MSCs) in the intra-muscular space are origin of ectopic fat cells in skeletal muscle. We have previously shown that high-mobility group box 2 (HMGB2), which is a nuclear protein commonly associated with mesenchymal differentiation, is involved in the early articular cartilage degeneration. In this study, we addressed the role of HMGB2 in adipogenesis of MSCs and fat infiltration into skeletal muscles. HMGB2 was highly expressed in undifferentiated MSCs and co-localized with platelet-derived growth factor receptor α (PDGFRA) known as an MSC-specific marker, while their expressions were decreased during adipocytic differentiation. Under the deficiency of HMGB2, the expressions of adipogenesis-related molecules were reduced, and adipogenic differentiation is substantially impaired in MSCs. Moreover, HMGB2+ cells were generated in the muscle belly of rat supraspinatus muscles after rotator cuff transection, and some of these cells expressed PDGFRA in intra-muscular spaces. Thus, our findings suggest that the enhance expression of HMGB2 induces the adipogenesis of MSCs and the fat infiltration into skeletal muscles through the cascade of HMGB2-PDGFRA.