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We studied the pathological anatomical structures of atypical Wassel Type VI thumb duplication to provide a theoretical basis for surgical treatment. Forty-seven patients with atypical Wassel Type VI thumb duplication were treated. We found that some of cases had an ulnar thumb without an extensor tendon, or without a flexor tendon, or without both. All the ulnar metacarpal bones were abnormal to variable degrees. On-top-plasty is currently the best procedure for the treatment of this type of anomaly. Flexor tendon reconstruction is an important factor in functional reconstruction of the thumb, and keeping the pulley and sheath intact is a key step in flexor tendon reconstruction. Placing the on-top-plasty level at the distal end of the metacarpal or at the proximal phalanx depends on the presence of the flexor tendon. According to the condition of the flexor tendon, the atypical Wassel Type IV duplication can be divided into two types: the absent type and the intact type. Level of evidence: VI

INTRODUCTION: Pemberton osteotomy is a widely used operation in developmental dysplasia of the hip (DDH). The traditional pelvic osteotomy was through outside of the ilium. However, in this study, we performed the pelvic osteotomy through the inner ilium approach. PATIENTS AND METHODS: We retrospectively analyzed 79 patients diagnosed with DDH with open surgery in our hospital from March 2016 to May 2018. There were 39 patients who underwent outside ilium Pemberton osteotomy (PO) and 40 patients who underwent inner “L shaped” ilium Pemberton osteotomy (ILSO). Acetabular index (AI), center–edge angle of Wiberg (CE angle), Severin grading scoring system, postoperative avascular necrosis (AVN) by Kalamchi and McEwen classification, and McKay grading scoring system were used for evaluation. RESULTS: There was no significant difference between the PO group and ILSO group on AI (p = 0.476), CE angles (p = 0.225), avascular necrosis (Kalamchi and McEwen, p = 0.854), and hip function (McKay’s, p = 0.444) on the final follow-up. There were significant differences in X-ray radiation (p

Purpose: Congenital pseudarthrosis of the tibia is a rare disease that is particularly difficult to treat; the most difficult complications include nonunion of the tibia, refracture, and failed surgery. This study aimed to evaluate the efficiency of transposing gastrocnemius flaps for the treatment of congenital pseudarthrosis of the tibia. Methods: Nine patients (aged 6.2 ± 3.6 years) diagnosed with congenital pseudarthrosis of the tibia in our hospital between March 2013 and March 2018 were enrolled. The tibial pseudarthrosis and thickened periosteum were completely removed, and intramedullary nails were used to fix the tibia. Bone harvest from the iliac, mixed with allogenic bone, was filled in the gap created by excision of the pseudarthrosis site and the surrounding periosteum; the gastrocnemius flap was then used to wrap the pseudoarthrosis site. The plaster cast was fixed postoperatively. The tibial union was evaluated via radiograph, and the plaster cast was removed after 12–24 weeks. Patients began walking approximately 12–14 weeks postoperatively. Results: Anatomical reduction was achieved in all the patients; the mean bone healing time was 10.1 ± 2.1 months. Bone nonunion was observed in one patient, and no neurovascular injury or wound infection occurred. Limb length discrepancy was in the range 3.2 ± 1.8 cm at 1 year and 4.7 ± 2.7 cm at 2 years after surgery. Two patients underwent replacement of the intramedullary nail, and eight patients exhibited good functional and radiographic outcomes. Conclusion: This preliminary study proved that using the gastrocnemius muscle flap to cover the pseudarthrosis site was an effective method to promote the tibial union and treat congenital pseudarthrosis of the tibia.

In our previous study, we constructed Schwann cells (SCs) that stably express Simian virus 40 T antigen (SV40T-SCs). SV40T-SCs functions and markers are similar to those of neural crest cells. There we used bone morphogenetic protein 9 (BMP9) to induce SV40T-SCs differentiation in vitro and in vivo and study possible related mechanism. SV40T-SCs differentiation was induced by BMP9 conditioned medium. The lipogenic differentiation of SV40T-SCs was assessed by Oil Red O staining. Alizarin red and Alcian blue staining, and alkaline phosphatase (ALP) assays were used to evaluate the SV40T-SCs osteogenic differentiation. The expression of adipocyte differentiation (c/EBPα and c/EBPβ) and osteoblast differentiation markers (OSX and RUNX2) were detected by quantitative polymerase chain reaction (qPCR). To study possible mechanism related to SV40T-SCs differentiation, the P53 and E2F1 activity were assessed by luciferase reporter plasmid, and Slug and E-cadherin expression by qPCR. In vivo, SV40T-SCs infected by Ad-BMP9 or Ad-GFP were injected under the skin of nude mice. After 4-6 W, the mice were euthanized and subcutaneously mass formed at injecting sites was collected for pathological analysis. After SV40T-SCs were cultured in BMP9 conditioned medium, lipid droplets were formed in the cytoplasm of these cells. Alizarin red and Alcian blue staining were positive, and ALP activity of SV40T-SCs increased significantly. The expression of adipocyte differentiation (c/EBPα and c/EBPβ) and osteoblast differentiation markers (OSX and RUNX2) in SV40T-SCs was upregulated by BMP9. SV40T significantly increased Slug expression and decreased E-cadherin expression. SV40T-SCs infected with Ad-BMP9 were able to differentiate into adipose tissue and form a small bone matrix under the nude mice skin. SV40T-SCs have the ability to differentiate into adipocytes and osteoblasts in vivo and in vitro. SV40T can upregulate the Slug expression and downregulate the E-cadherin expression to produce endothelial-to-mesenchymal transition (EMT). The multidirectional differentiation ability of SV40T-SCs may be related to EMT.

Fracture nonunion is a common and challenging complication. Studies have reported that direct current stimulation can promote fracture healing, but there are reports that there are differences in cell density near positive and negative electrodes during direct current stimulation. The purpose of this study is to explore the effect of direct current positive and negative electrodes on the proliferation of osteoblasts and the effect on fracture healing in vivo. In vitro, MC3T3-E1 cells were stimulated by positive and negative charge to observe cell proliferation, apoptosis and osteogenic factor expression. In vivo, after the model of double toes fracture in New Zealand white rabbits was built, positive and negative charge were respectively connected to Kirschner Wires of fractures. DR examination was performed on Day 1, Day 15 and Day 30 to observe the fracture healing. All rabbits were killed after the last examination, the bone tissue samples were analyzed histologically. The results showed that compared with the control group, after DC stimulation, the number of cells near the positive electrode decreased significantly (P < 0.05), apoptosis increased (P < 0.05), osteocalcin, osteoblast specific gene and osteonectin decreased significantly near the positive electrode (P < 0.05), and increased significantly at the negative electrode (P < 0.05). The fracture at the positive electrode junction of New Zealand white rabbits did not heal. Histomorphological analysis showed that there were more bone trabeculae and calcified bone in the bone tissue sections of the control group and the negative electrode than at the positive electrode. The thickness of bone trabeculae was thick and the connection was good. Positive charge inhibit the cell proliferation of osteoblasts; the fracture site with positive charge is not favor of fracture healing. The positive charge near the fracture site may be a reason for fracture nonunion.

Purpose Approximately 30% of patients with hereditary multiple osteochondromas (HMO) have forearm deformity and dysfunction. The aim of this retrospective study was to review our experience with the surgical treatment of children with HMO and Masada IIb forearm deformities. Methods Data of eight children treated for HMO Masada IIb forearm deformity at our hospital between 2015 and 2019 were collected from the hospital records and retrospectively reviewed. All patients underwent ulnar lengthening by distraction osteogenesis using either the Orthofix or Ilizarov external fixator. Range of movements at the elbow and wrist joints, and forearm supination/pronation, before and after the operation were recorded. Radiographs were evaluated by the Fogel method, and wrist joint function by the Krimmer method. Results Follow-up radiographs showed significant improvement in relative ulnar shortening after treatment (pre-operative 9.23 ± 5.21 mm; post-operative 0.33 ± 4.13 mm). Changes in radial articular angle (pre-operative 33.55° ± 3.88° to 32.78° ± 6.57°) and carpal slip (pre-operative 45.00% ± 19.09%; post-operative 43.13% ± 16.68%) were not significant. Elbow flexion and extension, wrist flexion and extension, ulnar and radial deviation at wrist, and forearm rotation were significantly improved after surgery. Wrist function was graded as excellent in seven patients and as good in one patient. One patient treated with the Ilizarov external fixator had poor radial head reduction. Conclusion Ulnar lengthening with distraction osteogenesis is an effective treatment for HMO Masada IIb deformities. The optimum site for ulnar osteotomy appears to be at the proximal one-third to one-fourth of the ulna.

Background Thumb duplication is a very common congenital malformation. This study describes and compares the phenotypic manifestations of polydactyly between southwest and northeast China. However, previous studies had a limited sample size. Therefore, this study used a large sample. Methods A total of 3549 well-characterized thumb duplication cases were divided into group A (southwest China) and group B (northeast China). Results In group A and group B, the left-to-right ratio was 1:1.5 and 1:1.75, respectively, and the female-to-male ratio was 1:1.5 and 1:1.58, respectively. Conclusions There were no significant differences in gender distribution or the distribution of left and right polydactyly between the two groups, but the distribution of bilateral polydactyly was significantly different.

An optimal surgical approach is required to treat Gartland type III supracondylar humerus fractures (SHFs) in children when open reduction is inevitable, especially in patients with neurovascular injuries. The purposes of this study were to find a better approach for open reduction of Gartland type III SHFs and to achieve anatomic reduction, stable fixation, and good functional and cosmetic outcomes with this approach.

Background: To summarize and analyze the epidemiological characteristics, treatment and corresponding curative effect of triradiate cartilage injury(TCI) in children after trauma, to provide a theoretical basis for early diagnosis and improvement of treatment. Methods: The TCI was classified according to our modified Bucholz classification (type IV and VI were added), and the final curative effect was evaluated with Harris Hip Score and imaging examination during follow-up. Finally, a comprehensive analysis was made by reviewing the cases in the literature combined with the patients in our hospital. Results: A total of 15 cases (18 hips) of triradiate cartilage injuries were collected in our hospital. There was one hip with type I injury, nine hips with type II injury, two hips with type IV injury, one hip with type V injury and five hips with type VI injury. Among the 12 cases with complete follow-up, the bone bridge was found in or around the triradiate cartilage in 8 cases，early fusion of triradiate cartilage occurred in 5 patients, 3 cases had hip dysplasia, 4 cases had a subluxation of the femoral head, and HHS was excellent in 8 cases and good in 4 cases.Conclusion: The early diagnosis of TCI is still a quite challenging issue. Conservative treatment is often the first choice. The overall prognosis of acetabular fractures involving triradiate cartilage is poor. The formation of the bone bridge in triradiate cartilage usually indicates the possibility of premature closure, which may lead to acetabular dysplasia. Level of evidence IV: Retrospective case series

Background: The application of external femoral fixation techniques often causes complications of knee flexion dysfunction. We report on technical modifications in the complications of external femoral fixation leading to knee flexion disorders.Methods: We flexed the knee joint 90 degrees during the operation, and then placed the external fixation nail. A retrospective review was performed for all patients undergoing repair by this technique. Results: A total of 52 children with femoral shaft fractures were included, the flexion of the knee joint measured at the time of discharge was 80 degrees (70-90 degrees) on average; when the external fixation is removed, the knee flexion can reach an average of 95 degrees (90-115 degrees), no children have stiff knees.Conclusion: This technique is simple and easy to implement, and it is worthy of popularization and application in clinical practice.

The Bilhaut-Cloquet technique is the preferred surgical method for thumb polydactyly with symmetrical caliber and osseous components. However, the traditional Bilhaut-Cloquet technique has many esthetic and functional complications. In this study, we aimed to investigate an effective modified Bilhaut-Cloquet procedure for Wassel type IV thumb duplication.The dorsal scar of the thumb was hidden on the ulnar side of the thumb through the flap design. The nail bed was sutured flat by combining the phalangeal bone and nail bed on different planes. The sensory function of the thumb was restored by keeping the ulnar skin of the thumb intact.Our modified Bilhaut-Cloquet procedure did not reduce the mobility of the joints. All patients had relatively rounded fingernails, and no seagull deformity was present. The ulnar side of the palm skin of the thumb remained intact with no scars, maximizing the preservation of the sensory function of the thumb. All the operated children and their parents were satisfied with the esthetic result.We hid the surgical scar by improving the surgical method and reducing the thumb seagull nail deformity, and the influencing of the finger sensation caused by the scar on the finger abdomen. The procedure improved not only the appearance of the reconstructed thumbs but also the sensory function of the thumbs.

Localization of small femur lesions for resection can be challenging and may be associated with the need for significant fluoroscopic imaging and tissue dissection. This study was performed to evaluate the use of a radiopaque localizer grid along with methylene blue staining for resection of small femur lesions in children, and to determine the effectiveness of this effectiveness at reducing radiation exposure and tissue injury.A radiopaque localizer grid was used to identify the body surface site of bone lesions, and then 0.02-0.03 mL of methylene blue was injected into the bone lesions. After skin incision, the blue bone tissue was found and complete lesion resection performed.A radiopaque localizer grid was utilized to plan the point of entry for lesion resection. The average operation time was shorter, and the C-arm was used less frequently, and the incision length was shorter in the grid and methylene blue group compared with the control group.A radiopaque localizer grid is a simple and practical device for efficient localization of the skin entry site, and methylene blue accurately pinpoints bone lesions, reducing radiation exposure and tissue injury.

Traumatic injury to the spinal cord causes permanent loss of function and major personal, social, and economic problems. Cell-based delivery strategies is a promising approach for treating spinal cord injury (SCI). However, the inhospitable microenvironment in the injured spinal cord results in poor cell survival and uncontrolled differentiation of the transplanted stem cells. The combination of a scaffold with cells has been developed with a tendency for achieving greater survival and integration with the host tissue. We investigated the effect of Matrigel combined with neural stem cells (NSCs) in vitro and in vivo. We compared the effect of different types of scaffold on the survival and differentiation of brain-derived NSCs in an in vitro culture. Subsequently, NSCs were transplanted subcutaneously into nude mice to detect graft survival and differentiation in vivo. Finally, phosphate-buffered saline (PBS), Matrigel alone, or Matrigel seeded with NSCs was injected into 48 subacute, clinically relevant rat models of SCI (16 rats per group). Matrigel supported cell survival and differentiation efficiently in vitro and in vivo. SCI rats transplanted with NSCs in Matrigel showed improved behavioral recovery and neuronal and reactive astrocyte marker expression levels compared to PBS- or Matrigel-transplanted rats. Functional repair and neuronal and reactive astrocyte marker expression was slightly improved in the Matrigel-alone group relative to the PBS group, but not statistically significantly. These data suggest that Matrigel is a promising scaffold material for cell transplantation to the injured spinal cord.

Bone morphogenetic proteins (BMPs) are members of the TGF-β superfamily and play a critical role in skeletal development, bone formation and stem cell differentiation. Disruptions in BMP signaling result in a variety of skeletal and extraskeletal anomalies. BMP9 is a poorly characterized member of the BMP family and is among the most osteogenic BMPs, promoting osteoblastic differentiation of mesenchymal stem cells (MSCs) both in vitro and in vivo. Recent findings from various in vivo and molecular studies strongly suggest that the mechanisms governing BMP9-mediated osteoinduction differ from other osteogenic BMPs. Many signaling pathways with diverse functions have been found to play a role in BMP9-mediated osteogenesis. Several of these pathways are also critical in the differentiation of other cell lineages, including adipocytes and chondrocytes. While BMP9 is known to be a potent osteogenic factor, it also influences several other pathways including cancer development, angiogenesis and myogenesis. Although BMP9 has been demonstrated as one of the most osteogenic BMPs, relatively little is known about the specific mechanisms responsible for these effects. BMP9 has demonstrated efficacy in promoting spinal fusion and bony non-union repair in animal models, demonstrating great translational promise. This review aims to summarize our current knowledge of BMP9-mediated osteogenesis by presenting recently completed work which may help us to further elucidate these pathways.

Human mesenchymal stem cells (MSCs) are a heterogeneous subset of nonhematopoietic multipotent stromal stem cells and can differentiate into mesodermal lineage, such as adipocytes, osteocytes, and chondrocytes, as well as ectodermal and endodermal lineages. Human umbilical cord (UC) is one of the most promising sources of MSCs. However, the molecular and cellular characteristics of UC-derived MSCs (UC-MSCs) require extensive investigations, which are hampered by the limited lifespan and the diminished potency over passages. Here, we used the piggyBac transposon-based simian virus 40 T antigen (SV40T) immortalization system and effectively immortalized UC-MSCs, yielding the iUC-MSCs. A vast majority of the immortalized lines are positive for MSC markers but not for hematopoietic markers. The immortalization phenotype of the iUC-MSCs can be effectively reversed by flippase recombinase-induced the removal of SV40T antigen. While possessing long-term proliferation capability, the iUC-MSCs are not tumorigenic in vivo. Upon bone morphogenetic protein 9 (BMP9) stimulation, the iUC-MSC cells effectively differentiate into osteogenic, chondrogenic, and adipogenic lineages both in vitro and in vivo, which is indistinguishable from that of primary UC-MSCs, indicating that the immortalized UC-MSCs possess the characteristics similar to that of their primary counterparts and retain trilineage differentiation potential upon BMP9 stimulation. Therefore, the engineered iUC-MSCs should be a valuable alternative cell source for studying UC-MSC biology and their potential utilities in immunotherapies and regenerative medicine.

Background Context Lung injury is a major cause of respiratory complications following an acute spinal cord injury (ASCI), which are associated with a high mortality rate. Autophagy has been shown to be involved in a variety of lung diseases; however, whether autophagy is activated in the lung following ASCI remains unknown. Purpose The objective of this study was to investigate the induction of autophagy in the lung after ASCI. Study Design This is an experimental animal study of ASCI investigating kinetics of autophagy in the lung following ASCI. Methods One hundred and forty-four rats (N=144) were divided into two groups: (1) a sham (n=72) and (2) an injury group (n=72). Allen's method was used to induce an injury at the level of the 10th thoracic vertebra. Rats were sacrificed at 6, 12, 24, 48, and 72 hours, 1 week, and 2 weeks after surgery. Lung pathology and apoptosis were assessed to determine the level of damage in the lung. LC3, RAB7, P62, and Beclin 1 were used to detect the induction of autophagy. The study was funded by the Natural Science Foundation of China (NSFC,81272172); National Key Specialty Construction of Clinical Projects of China (#2013-544). The funder of the present study had no capacity to influence the scholarly conduct of the research, interpretation of results, or dissemination of study outcomes. Results In the injury group, pathologic changes (i.e., pulmonary congestion, hemorrhage, inflammatory exudation, and alveolar collapse) occurred within the lung tissue within 72 hours after ASCI. Apoptosis of the lung cells gradually increased and peaked 72 hours after ASCI. Within 24 hours of ASCI, LC3 expression decreased, recovered, and gradually increased from 24 hours to 72 hours. As RAB7 decreased, P62 increased, and the ratio of RAB7/LC3 significantly decreased. Conclusions After ASCI, autophagy in the injured lung underwent dynamic changes, as early autophagosome formation decreased and late autophagosomes accumulated; thus, autophagy is in a state of inhibition.

Background Treatment of idiopathic congenital talipes equinovarus (CTEV) is challenging for pediatric orthopedic surgeons. The Ponseti method is an effective protocol for treatment due to its technique of manipulation, casting, and limited surgery. Plaster casting is an essential component of the Ponseti method. In this report, we describe a new brace that was developed for use in the treatment of clubfoot in newborns instead of a plaster cast. Methods This retrospective study was performed in two orthopedic medical centers. Between January 2011 and October 2013, 89 newborns with CTEV (131 ft) underwent corrective treatment using fixation braces in the experiment group (E-group) in our hospital, and 107 newborns with CTEV (141 ft) underwent plaster casting in the control group (C-group) in another medical center. All patients were treated according to the Ponseti method after the application of the inclusion and exclusion criteria. Plaster casts were applied to patients in the C-group. The patients in the E-group received the custom-made polyaxial fixation braces instead of plaster casts. Prospective follow-up was performed for a mean duration of 36 months. The efficacy of the treatment was assessed using Pirani’s scoring system. Chi-squared and independent t tests were used for statistical analyses. Results In the E-group, 85 patients (125 ft) achieved good appearance within 3 months of treatment initiation (average, 1.7 months). Four patients (6 ft) required percutaneous Achilles tenotomy. Seven patients developed sores during treatment because of improper brace application, but all sores healed without scarring with timely treatment. In the C-group, 96 patients (123 ft) achieved good appearance within 3 months of treatment initiation (average, 1.6 months). Eleven patients (18 ft) required percutaneous Achilles tenotomy. Twenty-one feet developed sores during treatment because of plaster cast pressure on the dorsum of the feet. Sixteen sores healed without scarring with timely treatment, and 5 ft had obvious scars. The overall mean Pirani scores 1 year after treatment were 0.26 ± 0.06 in the E-group and 0.25 ± 0.03 in the C-group, and the Pirani scores 3 years after treatment were 0.23 ± 0.05 in the E-group and 0.22 ± 0.03 in the C-group. There were significant differences in the percutaneous Achilles tenotomy and skin sores but no significant difference in the Pirani scores between these two groups. Conclusions Our results showed that the new polyaxial fixation brace used in this study was an effective tool for the corrective treatment of CTEV in newborns. We propose the use of this brace as an alternative treatment for newborns.

The best treatment for medial humeral epicondyle fractures in children has been debated. In case of incarceration of the epicondylar fragment, particularly after elbow dislocation, several materials are used for fixation, including Kirschner wires (K-wires), metallic compression screws, tension band wire, and suture anchors. Herein, we introduce a new fixation material: the absorbable self-reinforced polylactide (SR-PLA) pin. The aim of the study was to prove the feasibility of a new fixation material (absorbable SR-PLA pins) for the treatment of medial epicondyle fracture in children. Thirty-two patients who underwent surgery in our hospital from August 2007 to January 2012 were retrospectively analyzed. The patients were divided into group A (K-wires) and group B (absorbable SR-PLA pin). Group A comprised 11 males and 4 females, aged 8 to 14 years (average, 12.6 years), with 12 patients with elbow dislocation. Group B comprised 13 males and 4 females, aged 7 to 15 years (average, 11.8 years), with 13 patients with elbow dislocation. The same approach was used for all patients by the same team of surgeons, and all the patients were followed up for over 12 months. In all patients, rehabilitation training was started after 3 weeks. The Broberg and Morrey elbow scale was used to evaluate elbow function at follow-up. Four patients from group A developed pin-track infections that gradually resolved after removal of the K-wires, whereas no infections occurred in group B. One patient refractured her humerus after K-wire removal. Using the Broberg and Morrey elbow scale, outcomes in group A were classified as excellent in 5 patients (33.33%), good in 7 patients (46.67%), fair in 2 patients (13.33%), and poor in 1 (0.07%). Group B outcomes were scored as excellent in 12 patients (70.58%), good in 4 (23.53%), and fair in 1 (0.06%) and no patient (0.00%) had a poor outcome. The average Broberg and Morrey score for group A was significantly lower than that for group B (83.27 ± 7.02 vs 95.21 ± 5.04; P = .0238). Absorbable SR-PLA pins can be safely used for medial epicondyle fractures in children. Our results indicate that SR-PLA pins are associated with better short-term functional outcome than K-wires. Level of evidence: III

Osteosarcoma (OS) is the most common primary malignant tumor of bone with a high propensity for lung metastasis. Despite significant advances in surgical techniques and chemotherapeutic regimens over the past few decades, there has been minimal improvement in OS patient survival. There is an urgent need to identify novel antitumor agents to treat human OS. Repurposing the clinically-used drugs represents a rapid and effective approach to the development of new anticancer agents. The anthelmintic drug niclosamide has recently been identified as a potential anticancer agent in human cancers. Here, we investigate if niclosamide can be developed as an anti-OS drug. We find that niclosamide can effectively inhibit OS cell proliferation and survival at low micromolar concentrations. Cell migration and wounding closure are significantly inhibited by niclosamide. Niclosamide induces cell apoptosis and inhibits cell cycle progression in OS cells. Analysis of niclosamide's effect on 11 cancer-related signal pathway reporters reveals that three of them, the E2F1, AP1, and c-Myc-responsive reporters, are significantly inhibited. To a lesser extent, the HIF1α, TCF/LEF, CREB, NFκB, Smad/TGFβ, and Rbpj/Notch pathway reporters are also inhibited, while the NFAT and Wnt/β-catenin reporters are not significantly affected by niclosamide treatment. We demonstrate that the expression of c-Fos, c-Jun. E2F1, and c-Myc in OS cells is effectively inhibited by niclosamide. Furthermore, niclosamide is shown to effectively inhibit tumor growth in a mouse xenograft tumor model of human osteosarcoma cells. Taken together, these results strongly suggest that niclosamide may exert its anticancer activity in OS cells by targeting multiple signaling pathways. Future investigations should be directed to exploring the antitumor activity in clinically relevant OS models and ultimately in clinical trials.

Interferons are a group of small proteins that play key roles in host antiviral innate immunity. Their induction mainly relies on host pattern recognition receptors (PRR). Host PRR for RNA viruses include Toll-like receptors (TLR) and retinoic acid-inducible gene I (RIG-I) like receptors (RLR). Activation of both TLR and RLR pathways can eventually lead to the secretion of type I IFNs, which can modulate both innate and adaptive immune responses against viral pathogens. Because of the important roles of interferons, viruses have evolved multiple strategies to evade host TLR and RLR mediated signaling. This review focuses on the mechanisms of interferon induction and antagonism of the antiviral strategy by RNA viruses.

Osteosarcoma (OS) is the most common primary malignancy of bone and is usually associated with poor prognosis due to its high incidence of metastasis and chemoresistance. Molecular pathogenesis of OS is poorly understood. We previously showed that OS cells are refractory to BMP9-induced osteogenesis and respond favorably to proliferation and tumor growth. Here we investigate if Notch signaling mediates the BMP9-promoted cell proliferation and tumor growth of human osteosarcoma (OS). We find that the expression of Notch1, Notch2, Notch3, DLL1, JAG1 and JAG2 is readily detected in most of the tested OS cell lines. BMP9-promoted OS cell proliferation, migration, and cell cycle S/G2 progression are effectively inhibited by a dominant-negative mutant of Notch1 (dnNotch1) or the γ-secretase inhibitor Compound E (ComE). Furthermore, BMP9-promoted tumor growth and osteolytic lesions in vivo are significantly inhibited by dnNotch1. BMP9 up-regulates the expression of Notch1, Notch3, DLL1, and JAG1 in OS cells. Accordingly, BMP9 stimulation induces a nuclear accumulation of NICD, which is blocked by ComE. Our results demonstrate that BMP9-promoted OS proliferation and tumor growth is at least in part mediated by Notch signaling, suggesting that osteogenic BMPs may function as upstream regulators of Notch signaling in OS tumorigenesis. Thus, pharmacologic intervention of Notch signaling may be explored as a new therapeutic strategy for human OS tumors.

Pre-activation of the retinoid signaling pathway by all-trans retinoic acid facilitates neuronal differentiation of mesenchymal stem cells. Using protein/DNA based screening assays, we identified activator protein 2α as an important downstream target of all-trans retinoic acid. Although all-trans retinoic acid treatment significantly increased activator protein 2α transcriptional activity, it did not affect its expression. Inhibition of activator protein 2α with dominant-negative mutants reduced ATRA-induced differentiation of mesenchymal stem cells into neurons and reversed its associated functional recovery of memory impairment in the cell-based treatment of a hypoxic-ischemic brain damage rat model. Dominant-negative mutants of activator protein 2α inhibited the expression of neuronal markers which were induced by retinoic acid receptor β activation. All-trans retinoic acid treatment increased phosphorylation of activator protein 2α and resulted in its nuclear translocation. This was blocked by siRNA-mediated knockdown of retinoic acid receptor β. Furthermore, we found that retinoic acid receptor β directly interacted with activator protein 2α. In summary, the regulation of all-trans retinoic acid on activator protein 2α transcriptional activity was mediated by activation of retinoic acid receptor β and subsequent phosphorylation and nuclear translocation of activator protein 2α. Our results strongly suggest that activator protein 2α transcriptional activity is essential for all-trans retinoic acid-induced neuronal differentiation of mesenchymal stem cells.

Purpose To evaluate the effectiveness of methylene blue staining during ganglion resection in children, to assess ganglion resection and minimize recurrence. Methods From August 2007 to March 2011, 36 children with dorsal or volar wrist ganglions with an average size of 2 cm (range, 1–4 cm), including 5 recurrent cases, underwent resection performed with intraoperative methylene blue marking of the cyst wall. Results We found recurrence in one patient after 2 years; no obvious complications were observed in any patient. Conclusions Methylene blue staining of the ganglion during resection may be helpful for achieving complete resection. Type of study/level of evidence Therapeutic II.

ObjectiveThe purpose of this study is to compare the outcomes of intramedullary nailing and plate fixation in the treatment of humeral shaft fractures using meta-analysis.MethodsPubMed, MEDLINE, EMBASE, the Cochrane Controlled Clinical Trials Register (CCTR) databases were searched for studies that investigated the efficacy of intramedullary nailing and plate fixation in the management of humeral shaft fractures. Delayed healing rate, nonunion, postoperative infection and radial nerve paralysis were key outcomes of interest. Data were searched within the time period of July 1990 through September 2012. The statistical software RevMan 5.0 was used to analyze the statistical significance of the results.ResultsTotal 459 cases of patients in 10 literature, including 231 cases of plate group and 228 cases of the intramedullary nailing groups were collected. The results of meta-analysis showed that delayed healing rate of humeral shaft fractures was lower in plate fixation compared with intramedullary nailing (RR = 2.64, 95% CI (1.08, 6.49), P 0.05).ConclusionsIn general, the effect size of intramedullary nailing may be comparable to that of plate fixation in the terms of nonunion, postoperative infections, radial nerve paralysis. The only slightly difference was identified in the event of delayed healing rate.

Mesenchymal stem cells (MSCs) are multipotent progenitors and can differentiate into osteogenic, chondrogenic, and adipogenic lineages. Bone morphogenetic proteins (BMPs) play important roles in stem cell proliferation and differentiation. We recently demonstrated that BMP9 is a potent but less understood osteogenic factor. We previously found that BMP9-induced ectopic bone formation is not inhibited by BMP3. Here, we investigate the effect of BMP antagonist noggin on BMP9-induced osteogenic differentiation. BMP antagonists noggin, chording, gremlin, follistatin, and BMP3 are highly expressed in MSCs, while noggin and follistatin are lowly expressed in more differentiated pre-osteoblast C2C12 cells. BMP9-induced osteogenic markers and matrix mineralization are not inhibited by noggin, while noggin blunts BMP2, BMP4, BMP6, and BMP7-induced osteogenic markers and mineralization. Likewise, ectopic bone formation by MSCs transduced with BMP9, but not the other four BMPs, is resistant to noggin inhibition. BMP9-induced nuclear translocation of Smad1/5/8 is not affected by noggin, while noggin blocks BMP2-induced activation of Smad1/5/8 in MSCs. Noggin fails to inhibit BMP9-induced expression of downstream targets in MSCs. Thus, our results strongly suggest that BMP9 may effectively overcome noggin inhibition, which should at least in part contribute to BMP9's potent osteogenic capability in MSCs.

Mesenchymal stem cells (MSCs) are multipotent progenitors, which give rise to several lineages, including bone, cartilage and fat. Epidermal growth factor (EGF) stimulates cell growth, proliferation and differentiation. EGF acts by binding with high affinity to epidermal growth factor receptor (EGFR) on the cell surface and stimulating the intrinsic protein tyrosine kinase activity of its receptor, which initiates a signal transduction cascade causing a variety of biochemical changes within the cell and regulating cell proliferation and differentiation. We have identified BMP9 as one of the most osteogenic BMPs in MSCs. In this study, we investigate if EGF signalling cross-talks with BMP9 and regulates BMP9-induced osteogenic differentiation. We find that EGF potentiates BMP9-induced early and late osteogenic markers of MSCs in vitro, which can be effectively blunted by EGFR inhibitors Gefitinib and Erlotinib or receptor tyrosine kinase inhibitors AG-1478 and AG-494 in a dose- and time-dependent manner. Furthermore, EGF significantly augments BMP9-induced bone formation in the cultured mouse foetal limb explants. In vivo stem cell implantation experiment reveals that exogenous expression of EGF in MSCs can effectively potentiate BMP9-induced ectopic bone formation, yielding larger and more mature bone masses. Interestingly, we find that, while EGF can induce BMP9 expression in MSCs, EGFR expression is directly up-regulated by BMP9 through Smad1/5/8 signalling pathway. Thus, the cross-talk between EGF and BMP9 signalling pathways in MSCs may underline their important roles in regulating osteogenic differentiation. Harnessing the synergy between BMP9 and EGF should be beneficial for enhancing osteogenesis in regenerative medicine.

Background and Aims: Wnt/β-catenin signaling plays important roles in development and cellular processes. The hallmark of canonical Wnt signaling activation is the stabilization of β-catenin protein in cytoplasm and/or nucleus. The stability of β-catenin is the key to its biological functions and is controlled by the phosphorylation of its amino-terminal degradation domain. Aberrant activation of β-catenin signaling has been implicated in the development of human cancers. It has been recently suggested that GSK3βmay play an essential role in regulating global protein turnover. Here, we investigate if the GSK3β phosphorylation site-containing degradation domain of β-catenin is sufficient to destabilize heterologous proteins. Methods and Results: We engineer chimeric proteins by fusing β-catenin degradation domain at the N- and/or C-termini of the enhanced green fluorescent protein (eGFP). In both transient and stable expression experiments, the chimeric GFP proteins exhibit a significantly decreased stability, which can be effectively antagonized by lithium and Wnt1. An activating mutation in the destruction domain significantly stabilizes the fusion protein. Furthermore, GSK3 inhibitor SB-216763 effectively increases the GFP signal of the fusion protein. Conversely, the inhibition of Wnt signaling with tankyrase inhibitor XAV939 results in a decrease in GFP signal of the fusion proteins, while these small molecules have no significant effects on the mutant destruction domain-GFP fusion protein. Conclusion: Our findings strongly suggest that the β-catenin degradation domain may be sufficient to destabilize heterologous proteins in Wnt signaling-dependent manner. It is conceivable that the chimeric GFP proteins may be used as a functional reporter to measure the dynamic status of β-catenin signaling, and to identify potential anticancer drugs that target β-catenin signaling.

Osteosarcoma (OS) is the most common non-hematologic malignant tumor of bone in adults and children. As sarcomas are more common in adolescents and young adults than most other forms of cancer, there are a significant number of years of life lost secondary to these malignancies. OS is associated with a poor prognosis secondary to a high grade at presentation, resistance to chemotherapy and a propensity to metastasize to the lungs. Current OS management involves both chemotherapy and surgery. The incorporation of cytotoxic chemotherapy into therapeutic regimens escalated cure rates from