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Purpose: This study aimed to investigate the clinical outcomes of and risk factors for post-operative onset lateral hinge fracture (LHF) following medial opening-wedge distal tibial tuberosity osteotomy (DTO). Methods: A total of 68 patients who underwent DTO were stratified into non-LHF and post-operative onset LHF groups. The groups were compared in terms of radiographic parameters, including the hip–knee–ankle (HKA) angle, and were clinically evaluated using the Knee Society Score (KSS) and 2011KSS. Multiple logistic regression analysis was performed to identify risk factors for post-operative onset LHF. Results: The non-LHF and post-operative onset LHF groups included 53 and 15 patients, respectively. The post-operative HKA angle was significantly smaller (valgus) in the post-operative onset LHF group than in the non-LHF group (P ​= ​0.005). Knee and function scores were significantly lower in the post-operative onset LHF group than the non-LHF group at 6 months (P ​= ​0.002 for each comparison). All 2011KSS subscores were significantly lower in the post-operative onset LHF group than the non-LHF group at 6 months (P ​= ​0.001, 0.010, 0.013, and 0.013, respectively). Post-operative HKA angle was a risk factor for post-operative onset LHF (odds ratio ​= ​0.589, 95% confidence interval 0.392–0.886; P ​= ​0.011). Conclusions: Post-operative weight bearing may be delayed to prevent post-operative onset LHF, especially in patients with post-operative large valgus knee alignment.

Background: This study aimed to evaluate bone union of the tibial tuberosity in patients undergoing medial opening wedge distal tibial tuberosity osteotomy (OWDTO). It was hypothesized that bone union of the tibial tuberosity could be associated with lateral hinge fractures (LHFs), but not thickness of the tibial tuberosity osteotomy. Methods: Data of 61 consecutive patients who underwent OWDTO were retrospectively reviewed. Radiographic parameters of the lower limb and LHFs were evaluated. Thickness of the tibial tuberosity osteotomy and bone union of the tibial tuberosity were assessed at 1, 2, 3, 4, and 5 cm distal to the most proximal part of the tibial tuberosity on computed tomography. Bone union was assessed. Factors related to bone union of the tibial tuberosity were analyzed. Results: There were 13 postoperative onset LHFs: all healed with conservative treatments within 6 months after surgery. The total score of bone union of the tibial tuberosity was 8.4 ± 2.1 points, which correlated with age, postoperative medial proximal tibial angle (MPTA), correction angle, and postoperative onset LHF (r = 0.307, 0.388, 0.275, and −0.624, respectively; p = 0.016, 0.002, 0.033, and

Purpose: This prospective multicenter study investigated the implant fixation of a cementless cup in primary total hip arthroplasty (THA) for osteoarthritis (OA) secondary to developmental dysplasia of the hip (DDH) in Japanese patients. Methods: Ten hospitals in Japan were enrolled in this study. The cohort comprised 267 hips in 228 Japanese patients who underwent primary THA for OA secondary to DDH. An acetabular cup with advanced in-growth, GRIPTION™ coating, was used in all patients. Mean age at surgery was 66.9 (range 45–89) years, and 201 patients (239 hips) were female. Of these patients, 89.1 ​% (238/267) was Crowe group I. Radiolucent lines around the cup, osteolysis, cup migration, grafted bone status, and clinical scores were evaluated preoperatively and at 6 months, 1 year, and 2 years postoperatively. Adverse events were evaluated throughout the study. Implant survivorship was assessed using the Kaplan–Meier method. Results: Nine hips had radiolucent lines ≥2 ​mm that resolved by 6 months. All cups showed bone in-growth and no cups loosened. At 2 years, the bone grafts had remodeled and incorporated in 68 ​% (43/63) of hips. There were four systemic and five surgical site events, and one procedure-related dislocation. The survivorship with cup revision as the endpoint was 99.6 ​% (95 ​% confidence interval, 97.3–99.9). All clinical scores were improved at 2 years compared with preoperatively (p ​

Abstract Background Meningioma is the second most common intradural extramedullary tumor, following schwannoma. Meningioma is primarily categorized as benign World Health Organization grade 1, but clear cell meningioma is grade 2 of the intermediate malignant category. Clear cell meningiomas are rare, accounting for less than 1% of all meningioma tumors. There is no previous report of multiple intraspinal clear cell meningiomas without dural attachment. Case presentation A 27-year-old Asian male patient presented with lower right extremity pain, and had undergone tumor resection for intracranial clear cell meningioma 7 years previously, with re-resection and radiotherapy for local tumor recurrence at our hospital’s department of neurosurgery being carried out 4 years previously. No recurrence was observed since then. Preoperative lumbar magnetic resonance imaging showed two tumors at the L1 and L4 levels, both mimicking schwannoma with well-defined margins, no dural tail sign and homogeneous internal contrast. Intraoperative findings on tumor resection showed two tumors contiguous with the right L2 and L5 roots, which were not attached to the dura mater, similar to a schwannoma. After gross total resection, the postoperative pathology revealed no nuclear SMARCE1 antibody staining. The patient was diagnosed with clear cell meningioma. The patient’s postoperative course went well, with no symptoms of nerve dropout and no recurrence 2 years after surgery. In this case, both lumbar lesions were well demarcated and spherical in shape, occurring with single roots. Tumor characteristics suggested a primary rather than a metastatic lesion. Clear cell meningioma is characterized by a SMARCE1 mutation and is different from other types of meningiomas. Conclusion To the best of our knowledge, this is the first report of multiple intraspinal clear cell meningiomas without dural attachment at the lumbar spine after resection of intracranial clear cell meningioma. We speculate that the two tumors were de novo lesions on the basis of the features of the tumors, although they were detected 7 years after the resection of intracranial clear cell meningioma.

Abstract Dupuytren’s contracture, a superficial dermal fibrosis, causes flexion contracture of the affected finger, impairing hand function. Specific single-nucleotide polymorphisms within genes in the Wnt signalling pathway are associated with the disease. However, the precise role of Wnt signalling dysregulation in the onset and progression of Dupuytren’s contracture remains unclear. Here, using a fibrosis mouse model and clinical samples of human Dupuytren’s contractures, we demonstrate that the activation of Wnt/β-catenin signalling in Tppp3-positive cells in the dermis of the paw is associated with the development of fibrosis. Fibrosis development and progression via Wnt/β-catenin signalling are closely related to stromal cell–macrophage interactions, and Wnt/β-catenin signalling activation in Tppp3-positive stromal cells causes M2 macrophage infiltration via chemokine Cxcl14, resulting in the formation of a TGF-β-expressing fibrotic niche. Inhibition of Cxcl14 mitigates fibrosis by decreasing macrophage infiltration. These findings suggest that Cxcl14-mediated stromal cell–macrophage interaction is a promising therapeutic target for Wnt/β-catenin-induced fibrosis.

Background: An association has been reported between rotator cuff tear and inflammation. We hypothesized that blood flow in the anterior humeral circumflex artery would reflect synovial inflammation in the shoulder. This study aimed to clarify the association of blood flow in the anterior humeral circumflex artery with synovial inflammation and shoulder pain in patients with rotator cuff tears. Methods: In this prospective, cross-sectional study, tissue samples from the synovium in the rotator interval were obtained from 33 patients undergoing arthroscopic rotator cuff repair. Reverse transcription-polymerase chain reaction and real-time polymerase chain reaction were performed to determine the messenger RNA expression of inflammatory mediators, growth factors, and matrix metalloproteinases. Additional tissue samples were fixed for histologic evaluation. Before surgery, we measured the peak systolic velocity in the anterior humeral circumflex artery using pulse Doppler ultrasonography. Results: The peak systolic velocity in the anterior humeral circumflex artery was positively correlated with the messenger RNA expression of interleukin 1β, interleukin 8, and matrix metalloproteinase 3 genes (r = 0.49, P = .004; r = 0.55, P = .001; and r = 0.39, P = .026, respectively), as well as histologic synovitis scores (r = 0.48, P = .005). Additionally, it was significantly higher in patients with resting pain than in those without resting pain (P = .048). Conclusion: The peak systolic velocity in the anterior humeral circumflex artery is associated with the severity of synovial inflammation. Our results suggest that assessing the peak systolic velocity in the anterior humeral circumflex artery is useful for evaluating the severity of synovial inflammation.

Abstract Developmental dysplasia of the hip (DDH) is characterized by anatomical abnormalities of the hip joint, ranging from mild acetabular dysplasia to hip subluxation and eventually dislocation. The mechanism underlying the cartilage degeneration of the hip joints exposed to reduced dynamic loads due to hip dislocation remains unknown. We established a rodent hip dislocation (disarticulation; DA) model of DDH (DA-DDH rats and mice) by swaddling. Expression levels of periostin (Postn) and catabolic factors, such as interleukin-6 (IL-6) and matrix metalloproteinase 3 (Mmp3), increased and those of chondrogenic markers decreased in the acetabular cartilage of the DA-DDH models. Postn induced IL-6 and Mmp3 expression in chondrocytes through integrin αVβ3, focal adhesion kinase, Src, and nuclear factor-κB (NF-κB) signaling. The microgravity environment created by a random positioning machine induced Postn expression in chondrocytes through signal transducer and activator of transcription 3 (STAT3) signaling. IL-6 stimulated Postn expression via STAT3 signaling. Furthermore, cartilage degeneration was suppressed in the acetabulum of Postn −/− DA-DDH mice compared with that in the acetabulum of wild type DA-DDH mice. In summary, reduced dynamic loads due to hip dislocation induced acetabular cartilage degeneration via IL-6 and MMP3 through STAT3/periostin/NF-κB signaling in the rodent DA-DDH models.

Abstract Background Lubricin, a proteoglycan encoded by the PRG4 gene, is synthesised by superficial zone (SFZ) chondrocytes and synovial cells. It reduces friction between joints and allows smooth sliding of tendons. Although lubricin has been shown to be effective against osteoarthritis and synovitis in animals, its clinical application remains untested. In this study, we aimed to induce lubricin-expressing cells from pluripotent stem cells (iPSCs) and applied them locally via cell transplantation. Methods To generate iPSCs, OCT3/4, SOX2, KLF4, and L-MYC were transduced into fibroblasts derived from Prg4-mRFP1 transgenic mice. We established a protocol for the differentiation of iPSC-derived Prg4-mRFP1-positive cells and characterised their mRNA expression profile. Finally, we injected Prg4-mRFP1-positive cells into the paratenon, surrounding the Achilles tendons and knee joints of severe combined immunodeficient mice and assessed lubricin expression. Result Wnt3a, activin A, TGF-β1, and bFGF were applied to induce the differentiation of iPSC-derived Prg4-mRFP1-positive cells. Markers related to SFZ chondrocytes and fibroblast-like synovial cells (FLSs) were expressed during differentiation. RNA-sequencing indicated that iPSC-derived Prg4-mRFP1-positive cells manifested expression profiles typical of SFZ chondrocytes and FLSs. Transplanted iPSC-derived Prg4-mRFP1-positive cells survived around the Achilles tendons and in knee joints. Conclusions The present study describes a protocol for the differentiation of iPSC-derived Prg4-positive cells with characteristics of SFZ chondrocytes and FLSs. Transplantation of lubricin-expressing cells offers promise as a therapy against arthritis and synovitis.

Intramembranous and endochondral bone formation have been considered to be independent processes mediated by independent stem cells. Here the authors show that periosteal stem cells participate in both types of bone formation, supporting endochondral formation by producing Ihh.

Study Design Cross-sectional observational study. Purpose To examine whether pelvic rotation as a compensatory mechanism for sagittal imbalance is related to quality of life (QOL). Overview of Literature Poor sagittal alignment is associated with compensatory pelvic retroversion and decreased QOL. Whether the compensatory pelvic tilt (PT) influences QOL is unclear. Methods Overall, 134 subjects aged ≥20 years with lower back pain were included (104 females; mean age, 70±9.8 years). Sagittal vertical alignment (SVA) and PT were analyzed radiographically. Patients were stratified into three groups based on SVA values: good alignment (group G), intermediate alignment (group I), and poor sagittal alignment (group P). Patients in group I were further categorized into two groups: low PT and high PT. The Japanese Orthopaedic Association Back Pain Evaluation Questionnaire (JOABPEQ) was used for clinical assessment, and the scores were compared between groups. Results As SVA increased, PT and lumbar lordosis (LL) increased and decreased, respectively. PT and LL differed significantly between groups G and P (p

Abstract Frontotemporal dementia (FTD) is a heterogeneous clinical disorder characterized by progressive abnormalities in behavior, executive functions, personality, language and/or motricity. A neuropathological subtype of FTD, frontotemporal lobar degeneration (FTLD)-FET, is characterized by protein aggregates consisting of the RNA-binding protein fused in sarcoma (FUS). The cause of FTLD-FET is not well understood and there is a lack of genetic evidence to aid in the investigation of mechanisms of the disease. The goal of this study was to identify genetic variants contributing to FTLD-FET and to investigate their effects on FUS pathology. We performed whole-exome sequencing on a 50-year-old FTLD patient with ubiquitin and FUS-positive neuronal inclusions and unaffected parents, and identified a de novo postzygotic nonsense variant in the NCDN gene encoding Neurochondrin (NCDN), NM_014284.3:c.1206G > A, p.(Trp402*). The variant was associated with a ~ 31% reduction in full-length protein levels in the patient’s brain, suggesting that this mutation leads to NCDN haploinsufficiency. We examined the effects of NCDN haploinsufficiency on FUS and found that depleting primary cortical neurons of NCDN causes a reduction in the total number of FUS-positive cytoplasmic granules. Moreover, we found that these granules were significantly larger and more highly enriched with FUS. We then examined the effects of a loss of FUS function on NCDN in neurons and found that depleting cells of FUS leads to a decrease in NCDN protein and mRNA levels. Our study identifies the NCDN protein as a likely contributor of FTLD-FET pathophysiology. Moreover, we provide evidence for a negative feedback loop of toxicity between NCDN and FUS, where loss of NCDN alters FUS cytoplasmic dynamics, which in turn has an impact on NCDN expression.

Arthrodesis is a reliable surgical procedure for treating thumb carpometacarpal osteoarthritis. However, the most frequent and problematic complication of arthrodesis is nonunion. Although postarthrodesis-related nonunion is a common complication, the indications and results of revision procedures for this pathological condition have not been well documented. A 59-year-old man underwent arthrodesis for thumb carpometacarpal osteoarthritis, which resulted in painful nonunion 7 months after the surgery. We performed revision surgery for this pathological condition, using first dorsal metacarpal artery-pedicled second metacarpal vascularized bone graft. This method resulted in successful bone union and pain relief. First dorsal metacarpal artery-pedicled second metacarpal vascularized bone grafting could be an alternative method for nonunion, which is a common complication after thumb carpometacarpal arthrodesis.

Objectives The mechanism underlying neuropathic pain (NP) in osteoarthritis (OA) of the knee is not completely understood. This study aimed to investigate whether possible NP in patients with knee OA undergoing knee surgery is associated with specific radiological findings. Methods This study included 197 patients who underwent knee surgery for symptomatic knee OA. Clinical evaluation was performed using the Central Sensitization Inventory (CSI), Western Ontario and McMaster Universities Arthritis Index (WOMAC), and PainDETECT questionnaire. Radiological evaluation was performed using the hip-knee-ankle (HKA) angle, posterior tibial slope (PTS), varus and valgus laxities, and magnetic resonance imaging OA Knee Score (MOAKS). Radiological findings were compared between patients with possible and unlikely NP. Logistic regression analysis was performed to identify the predictive factors for NP. Results There were 163 and 34 patients with unlikely NP and with possible NP, respectively. The percentage of patients with CSI score ≥ 40 was significantly higher in the possible NP group than in the unlikely NP group (17.6% vs. 6.1%). Patients with possible NP had worse WOMAC scores than patients with unlikely NP. There were no significant positive associations between the possible NP and radiological findings in knee OA. Regression analysis showed no predictive factors for possible NP. Conclusions Possible NP is not associated with specific radiological findings in knee OA. Patients with possible NP may mediate CS and experience more severe symptoms, including decreased knee function and lower quality of life, than patients with unlikely NP.

Abstract Background Ectopic gas in the graft is occasionally encountered upon follow-up computed tomography (CT) after anterior cervical corpectomy and fusion (ACCF). However, most cases lack inflammatory responses and manifestations of infection. Although the clinical significance of ectopic gas in the graft has not yet been established, to the best of our knowledge, no previous studies have described ectopic gas in the graft after ACCF. This study evaluated ectopic gas in the fibular graft upon follow-up CT after ACCF. Methods We reviewed 112 patients who underwent ACCF and follow-up CT, with a minimum follow-up period of 3 years. CT images were retrospectively reviewed to confirm the presence of ectopic gas in the graft and bone fusion. Bone fusion was defined as follows: mobility less than 2 mm between spinous processes on the flection-extension radiograph or a bone bridge on CT images. Results Of the 112 patients, 30 (27%) patients had ectopic gas in the fibular grafts. Among them, ectopic gas was initially observed 3 months after surgery (early onset) in 23 (77%) patients and 6 months after surgery (late-onset) in the remaining seven (23%) patients. Upon the latest follow-up CT, ectopic gas more frequently remained in late-onset (4/7, 57%) rather than in early-onset (3/23, 13%) cases (p = 0.033). Bone fusion was not observed when CT images exhibited ectopic gas in the graft, whereas ectopic gas was not observed when CT images exhibited bone fusion. Conclusion Ectopic gas in the fibular graft was observed at both early and late-onset after ACCF; late-onset gas remained significantly. The remaining gas was strongly associated with pseudoarthrosis; therefore, pseudoarthrosis should be considered when ectopic gas in the graft is observed on CT images.

Nakamura et al. used expression studies to identify an enrichment of Zfhx4 in cartilage and revealed through global gene knock-down that it is required for proper endochondral ossification in mice. They further demonstrated a physical and genetic interaction between Zfhx4 and Osterix, which is of interest to the field of transcriptional regulation of mammalian endochondral ossification.

Backgrounds: For the surgical treatment of lumbar canal stenosis (LCS) due to spinal epidural lipomatosis (SEL), several studies have reported direct decompression, including fat debulking. However, none of these studies have mentioned indirect decompression for SEL. Here we report two cases in which indirect decompression with lateral interbody fusion (LIF) was effective in treating LCS due to SEL. Case description: Case 1 involves a 71-year-old male with LCS due to SEL at the L3/4 and L4/5 levels without a history of steroid usage. Case 2 involves a 60-year-old male with LCS due to SEL at the L2/3, L3/4, and L4/5 levels, who had been medicated with prednisolone (2.5 mg/day) and methotrexate (6 mg/week) for the treatment of remitting seronegative symmetrical synovitis with pitting edema syndrome. After oblique lateral interbody fusion and posterior fusion with percutaneous pedicle screw, the patients’ symptoms disappeared immediately. Postoperative magnetic resonance imaging showed that the epidural fat had been successfully stretched, and the dura was decompressed. Conclusions: Indirect decompression with LIF could be a new surgical option for treating LCS due to SEL.

How transcription factors regulate cell fates in native tissues is unclear. Here, the authors report that differential chromatin binding of NKX2-1 determines opposing alveolar cell fates in the murine lung, showing loss of YAP/TAZ directs NKX2-1 to alternative binding sites leading to cell fate conversion.

Background: Degenerative greater tuberosity (GT) changes are often associated with rotator cuff tears. However, little is known about the impact of GT morphology on surgical outcomes. The aim of this study was to examine the relationship between clinical and radiological outcomes, after rotator cuff repair, and GT morphology. Methods: We retrospectively investigated shoulders that underwent arthroscopic repair of nontraumatic full-thickness supra-/infraspinatus tears. The exclusion criteria were a lack of either radiographs or magnetic resonance images, revision surgery, partial repair, complications such as infection or dislocation, and follow-up < 2 years. GT morphology on radiographs was classified into 5 groups: normal, sclerosis, bone spur, roughness, and femoralization. The acromiohumeral interval (AHI) was measured on anteroposterior radiographs. Fatty degeneration of the cuff muscles was evaluated using the global fatty degeneration index (GFDI). Postoperative cuff integrity was classified using Sugaya's classification at 2 years after surgery. Clinical outcomes were assessed preoperatively and at postoperative 2 years with the Japanese Orthopaedic Association score and the University of California, Los Angeles shoulder rating scale. Results: The study included 220 shoulders in 212 patients (104 men and 108 women), with a mean age of 66 years (range 43-85). The mean follow-up period was 28 months (range, 24-60 months). Seven shoulders (3.2%) were classified as normal, 65 (29.5%) as sclerosis, 55 (25.0%) as bone spur, 78 (34.5%) as roughness, and 15 (6.8%) as femoralization. The preoperative AHI, in the roughness and femoralization groups, was significantly smaller than that in the sclerosis (P

Abstract Background Changes in gait speed are required in various situations and can be achieved by changing stride length, cadence, or both. Differences in strategies for increasing gait speed may have different effects on hip joint and physical function. The purpose of this study was to determine the effects of strategies for increasing gait speed on hip pain, physical function, and changes in hip loading during gait in patients with hip osteoarthritis (OA). We hypothesized that patients who increase gait speed mainly by increasing cadence would have lesser hip pain, a higher physical function, and a lower rate of increase in hip moments with increasing gait speed. Methods Forty-seven patients with secondary hip OA (age, 48.3 ± 11.0 years) were included. Gait speed, stride length, cadence, and peak and impulse of the hip moments were measured during gait at self-selected normal and fast gait speeds. The patients were classified as types S (with mainly increasing stride length, n = 11 [23.4%]), C (with mainly increasing cadence, n = 23 [48.9%]), and SC (with increasing stride length and cadence, n = 13 [27.7%]) according to whether they used changes in stride length and/or cadence to transition from normal to fast gait. Hip pain, physical function, and hip moment changes during gait were compared between types. Results The physical function was higher in types C (38.0 ± 8.8, P = 0.018) and SC (40.6 ± 8.5, P = 0.015) than in type S (28.2 ± 7.8), even after adjustment for age and minimum joint space width. Hip pain was not significantly different between types. The robustness of these results was confirmed with sensitivity analysis. The rates of increases in peak external hip adduction (P = 0.003) and internal rotation moments (P = 0.009) were lower in type C than in type SC. Conclusions Type C tended to suppress the increase in hip moments during fast gait. Types C and SC, which included increased cadence, maintained higher physical function levels than type S. Encouraging the use of cadence-increasing strategy may be useful for reducing hip loading and maintaining physical function in patients with hip OA.

Abstract Background We investigated the mid-term clinical and radiological results of total hip arthroplasty (THA) using a three-dimensional (3D) porous titanium cup and analyzed the micromotion at the interface of the cup using subject-specific finite element (FE) analysis. Methods We evaluated 73 hips of 65 patients (6 men and 59 women; mean age at the time of surgery, 62.2 years; range, 45–86 years) who had undergone THA using a 3D porous titanium cup. Clinical evaluations were performed using the Japanese Orthopaedic Association (JOA) hip score system. We assessed the fixation of the acetabular component based on the presence of radiolucent lines and cup migration using anteroposterior radiographs. Subject-specific FE models were constructed from computed tomography data. Results The JOA score improved from a preoperative mean of 52.2 (range, 23–82) to a mean of 87.8 (range, 71–100) at the final follow-up. None of the patients underwent revisions during the follow-up period. Radiolucent lines were observed in 26 cases (35.6%) and frequently appeared at DeLee and Charnley Zone 3. Following the FE analysis, the micromotion at DeLee and Charnley Zone 3 was significantly larger than that at Zone 2. Furthermore, micromotion was large in the groups in which radiolucent lines appeared at Zone 3. Conclusions The mid-term clinical outcome of THA using a 3D porous titanium cup was excellent. However, radiolucent lines frequently appeared at DeLee and Charnley Zone 3. FE analysis indicated that micromotion was large at the same site, strongly suggesting that it contributes to the emergence of radiolucent lines. The 3D porous titanium cups are useful in THA, and with improvements focused on micromotion, we anticipate better long-term outcomes.

Background: Difference in the clinical course and outcomes between simultaneous- and staged-bilateral medial opening wedge high tibial osteotomies (OWHTOs) over time was unknown. The study hypothesis was that patients who underwent simultaneous-bilateral OWHTO (SMBO) have a more rapid improvement in knee function than those who underwent staged-bilateral OWHTO (STBO) due to difference in the change of lower limb alignment between SMBO and STBO. Methods: The records of 56 knees in 28 patients who underwent either SMBO (n = 28) or STBO (n = 28) were retrospectively analysed. The time course data of weight-bearing line percentage (%WBL), joint line convergence angle (JLCA), and Knee Society Score were compared between the two procedures. Results: Hospitalisation for SMBO was longer than that for STBO by 1 week. No significant difference was observed in %WBL between the two procedures. The JLCA was significantly lower with SMBO than with the first-stage surgery of STBO (P

Abstract TAR DNA-binding protein of 43 kDa (TDP-43) is a major component of intracellular aggregates formed in brains of the patients with frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS), which are correctively referred to as TDP-43 proteinopathies. A link between Ataxin-2 (ATXN2) and TDP-43 proteinopathies was established when intermediate CAG repeat expansions of ATXN2 gene were found to be associated with ALS and it was shown that ATXN2 modifies TDP-43 toxicity. Although ATXN2’s contribution to TDP-43 proteinopathies has been mostly studied in ALS, recent studies have shown that intermediate repeat expansions of ATXN2 also influence the phenotype of FTLD by an unknown mechanism. To address this issue, we immunohistochemically and biochemically analyzed the intracellular dynamics of ATXN2 in brains of normal controls and FTLD-TDP cases. The immunohistochemical studies revealed that ATXN2 localized in the neuronal cytoplasm and proximal dendrites, and expressed widely and uniformly in normal human brains. A semi-quantitative immunofluorescent analysis of normal brains revealed that the cytoplasmic ATXN2 strongly associates with ribosomal protein S6 and poly-A binding protein 1 and partially overlaps with the endoplasmic reticulum marker Calnexin, suggesting a major role of ATXN2 in protein synthesis. The results of immunohistochemical and biochemical analyses of brains from FTLD-TDP cases showed the colocalization of ATXN2 and phosphorylated TDP-43 in the dystrophic neurites and the neuronal cytoplasmic inclusions in the hippocampal region, and a significant reduction of ATXN2 protein compared to controls. These results suggest that ATXN2 is involved in the pathological process of FTLD-TDP. It remains to be clarified whether reduced ATXN2 expression induces neurodegeneration by impairing protein synthesis or plays a neuroprotective role by attenuating the toxicity of TDP-43 aggregates in FTLD-TDP and other TDP-43 proteinopathies.

The authors reported a 58-year-old male who suffered from severe low back pain due to kyphoscoliosis associated with congenital contractural arachnodactyly (CCA), a subset of Marfan syndrome. Posterior spinal corrective fusion surgery from T8 to the pelvis with pedicle subtraction osteotomy at L4 was conducted. Because of long upper extremities due to CCA, we had no choice but to keep his shoulders abducted 90°, horizontal flexed 30°, and elbow flexed 120° with the conventional arm table during the surgery. Immediately after the surgery, he complained of numbness on the lateral aspect of his right forearm, difficulty of elbow flexion, and supination. Postoperative upper arm magnetic resonance imaging revealed evidence of coracobrachialis, brachialis, and biceps brachii myositis resulted from denervation by musculocutaneous nerve. We diagnosed his symptoms as postoperative isolated musculocutaneous neuropathy (MCNP) based on physical and radiological findings. Weakness and numbness began to be resolved 1.5 months after the surgery. Active motion of the elbow started to recover two months after the surgery and completely recovered six months postoperatively. The potential cause of our patient’s pathology was regarded to be intraoperative malposition of the abnormal long arms. In conclusion, we reported a case of isolated MCNP after thoracolumbar spine surgery under prone position, which is extremely rare and not well known among surgeons. Therefore, spine surgeons should take care of arm position and joint angle even though prone surgery to prevent MCNP, particularly in the patient with long arm span because of Marfanoid.

The growth plates are cartilage tissues found at both ends of developing bones, and vital proliferation and differentiation of growth plate chondrocytes are primarily responsible for bone growth. C-type natriuretic peptide (CNP) stimulates bone growth by activating natriuretic peptide receptor 2 (NPR2) which is equipped with guanylate cyclase on the cytoplasmic side, but its signaling pathway is unclear in growth plate chondrocytes. We previously reported that transient receptor potential melastatin-like 7 (TRPM7) channels mediate intermissive Ca2+ influx in growth plate chondrocytes, leading to activation of Ca2+/calmodulin-dependent protein kinase II (CaMKII) for promoting bone growth. In this report, we provide evidence from experiments using mutant mice, indicating a functional link between CNP and TRPM7 channels. Our pharmacological data suggest that CNP-evoked NPR2 activation elevates cellular cGMP content and stimulates big-conductance Ca2+-dependent K+ (BK) channels as a substrate for cGMP-dependent protein kinase (PKG). BK channel-induced hyperpolarization likely enhances the driving force of TRPM7-mediated Ca2+ entry and seems to accordingly activate CaMKII. Indeed, ex vivo organ culture analysis indicates that CNP-facilitated bone growth is abolished by chondrocyte-specific Trpm7 gene ablation. The defined CNP signaling pathway, the NPR2-PKG-BK channel–TRPM7 channel–CaMKII axis, likely pinpoints promising target proteins for developing new therapeutic treatments for divergent growth disorders.

Abstract Background A larger daily cumulative hip loading, which is the product of the external hip adduction moment (HAM) impulse during gait and the number of steps per day has been identified as a factor associated with the progression of secondary hip osteoarthritis (OA). The cause of the increased HAM impulse in patients with hip OA has not been identified. The purpose of this study was to identify the gait parameters associated with HAM impulse during gait in patients with secondary hip OA. Methods Fifty-five patients (age 22–65 years) with mild-to-moderate secondary hip OA participated in this cross-sectional study. The HAM impulse during gait was measured using a three-dimensional gait analysis system. To identify the gait parameters associated with HAM impulse, hierarchical multiple regression analysis was performed. The first model (basic model) included body weight and stance phase duration. The second models included gait parameters (gait speed; ground reaction force [GRF] in frontal plane; and hip, pelvic, and trunk angle in frontal plane) and hip pain in addition to the basic model. Results Body weight and stance phase duration explained 61% of the variance in HAM impulse. In the second model, which took into account body weight and stance phase duration, hip adduction angle (9.4%), pelvic tilt (6.5%), and trunk lean (3.2%) in addition to GRF explained the variance in the HAM impulse. Whereas larger hip adduction angle and pelvic tilt toward the swing limb were associated with a larger HAM impulse, larger trunk lean toward the stance limb was associated with smaller HAM impulse. Conclusion In patients with excessive hip adduction and pelvic tilt toward the swing limb during gait, gait modification may contribute to the reduction of hip joint loading.

The EWS-ATF1 fusion gene causes clear cell sarcoma (CCS). Here, the authors show that the downstream effects of EWS-ATF1 expression are strictly context dependent, and reveal the cell of origin for CCS to be Tppp3-expressing cells in peripheral nerves.

Objective In this study, we aimed to elucidate the relationship between the duration from diagnosis to femoral head collapse and the collapse rate among patients with pre-collapse osteonecrosis of the femoral head (ONFH). Methods In this retrospective, observational, multicenter study, we analyzed 268 patients diagnosed with ONFH and classified them using the Japanese Investigation Committee classification. The primary endpoint was duration from the time of diagnosis to femoral head collapse for each type of ONFH. Results The 12-, 24-, and 36-month collapse rates among participants were 0%, 0%, and 0% for type A, respectively; 0%, 2.0%, and 10.8% for type B, respectively; 25.5%, 40.8%, and 48.5% for type C-1, respectively; and 57.4%, 70.3%, and 76.7% for type C-2 ONFH, respectively. A comparison of unilateral and bilateral ONFH, using Kaplan–Meier survival curves demonstrated similar collapse rates. Conclusions The lowest collapse rate was observed for ONFH type A, followed by types B, C-1, and C-2. Additionally, a direct association was observed between the collapse rate and location of the osteonecrotic lesion on the weight-bearing surface.

Background: Although many complications of the spinal implant have been reported previously, to the best of our knowledge, this is the first report on a delayed implant complication of the ilium, leading to buttock pain and aggravated scoliosis. Case description: A 78-year-old woman underwent transforaminal lumbar interbody fusion with pedicle screws at the L4–L5 level at another institution. Preoperative symptoms, left leg pain, disappeared soon after surgery. However, 6 months post surgery, she experienced severe pain in her left buttock and sacroiliac joint area, which was treated only at our pain clinic. Based on our initial consultation 5 years after the operation, her plain radiography findings showed a 29° convex left-sided scoliosis spanning from the L1–L5. Computed tomography scan revealed apparent iliac bone erosion at the point of contact with the left-side screw head and rod at L5. The patient had painful scoliosis owing to implant irritation. Soon after the removal of the left implant, the pain was relieved and the degree of scoliosis decreased to 17°. Conclusion: This study reports the presence of an unexpected complication caused by pedicle screw fixation at the L4–L5 level. Although the implant was far from the iliac bone, at the L4–L5 fusion, it could cause erosion of the bone after the progression of L3–L4 and L5–S1 disk degeneration and aggravate scoliosis. Neurosurgeons should be aware that patients may present with buttock pain and unprecedented scoliosis by hardware irritation.

Aim: Spinal cord injury in elderly populations has increased in recent years. This study aimed to investigate the pathology, severity, efficacy of the surgery, and complications of cervical spinal cord injury in extremely elderly patients aged >80 years. Methods: Sixty-three patients who underwent surgical treatment for cervical spinal cord injury were enrolled in this retrospective multicenter study. Forty patients were aged

Summary: Evidence regarding intraductal papillary neoplasm of the bile duct (IPNB) as a type of precancerous lesion of cholangiocarcinoma is limited. Moreover, a reproducible in vivo model is lacking, and IPNB pathogenesis remains unclear. Here, we use a doxycycline-inducible tetracycline (Tet)-on mice model to control fibroblast growth factor 10 (FGF10) expression, which regulates branching and tubule formation. FGF10-induced IPNB mimics the multifocal and divergent human IPNB phenotypes via the FGF10-FGF receptor 2 (FGFR2)-RAS-extracellular-signal-regulated kinase (ERK) signaling pathway. A paracrine/autocrine growth factor is sufficient to initiate and maintain IPNB originating from the peribiliary glands, including biliary stem/progenitor cells. With KrasG12D, p53, or p16 mutations or both, Fgf10-induced IPNB shows stepwise carcinogenesis, causing associated invasive carcinoma. Fgf10-induced papillary changes and progression are suppressed by the inhibition of the FGF10-FGFR2-RAS-ERK signaling pathway, demonstrating that the signal is a therapeutic target for IPNB and associated carcinoma.

Introduction. Purely chondral injuries of the knee are relatively rare, and no consensus exists on the appropriate treatment in such cases. We describe two adolescent patients with chondral injury of the knee who were successfully treated by osteochondral peg fixation. Patients, Concerns, and Clinical Findings. In case 1, a 14-year-old boy presented with complaints of right knee pain after landing on his leg while playing basketball. Radiography and computerized tomography revealed no abnormalities. However, magnetic resonance imaging revealed a chondral defect in his lateral femoral condyle and a loose chondral fragment measuring 6.5 cm2. In case 2, a 12-year-old boy presented with complaints of left knee pain after a rotational injury while playing baseball. Similar to case 1, magnetic resonance imaging revealed a chondral defect in his lateral femoral condyle and a loose chondral fragment measuring 3.0 cm2. Primary Diagnosis, Interventions, and Outcomes. The two patients were treated by surgical fixation using osteochondral pegs, which were harvested from the femoral condyle. After a year, postoperative computerized tomography and magnetic resonance imaging showed union of the chondral fragment with the osteochondral pegs and surrounding tissue. In both cases, the Lysholm score was 100 points at the final follow-up more than 2 years after surgery. Conclusion. The findings reported herein suggest that osteochondral peg fixation is a feasible treatment option for chondral injury of the knee, with satisfactory outcomes.

Study DesignRetrospective study.PurposeThe purpose of this study was to investigate the influence of sagittal alignment of the strut graft on graft subsidence and clinical outcomes after anterior cervical corpectomy and fusion (ACCF).Overview of LiteratureACCF is a common technique for the treatment of various cervical pathologies. Although graft subsidence sometimes occurs after ACCF, it is one cause for poor clinical results. Malalignment of the strut graft is probably one of the factors associated with graft subsidence. However, to the best of our knowledge, no prior reports have demonstrated correlations between the alignment of the strut graft and clinical outcomes.MethodsWe evaluated 56 patients (33 men and 23 women; mean age, 59 years; range, 33–84 years; 45 with cervical spondylotic myelopathy and 11 with ossification of the posterior longitudinal ligament) who underwent one- or two-level ACCF with an autogenous fibular strut graft and anterior plating. The Japanese Orthopaedic Association (JOA) score recovery ratio for cervical spondylotic myelopathy was used to evaluate clinical outcomes. The JOA score and lateral radiograms were evaluated 1 week and 1 year postoperatively. Patients were divided into two groups (a straight group [group I] and an oblique group [group Z]) based on radiographic assessment of the sagittal alignment of the strut graft.ResultsGroup I showed a significantly greater JOA score recovery ratio (p

We report the case of a wound complication that was reconstructed by reverse lateral arm flap after excision of heterotopic ossification (HO) of the elbow in a patient with severe burns. Careful attention should be paid to wound complication and HO recurrence in patients undergoing surgical treatment for elbow HO following burn injury. Keywords: Burn, Heterotopic ossification, Elbow, Complication

Recent studies using defined transcription factors to convert skin fibroblasts into chondrocytes have raised the question of whether osteo-chondroprogenitors expressing SOX9 and RUNX2 could also be generated during the course of the reprogramming process. Here, we demonstrated that doxycycline-inducible expression of reprogramming factors (KLF4 [K] and c-MYC [M]) for 6 days were sufficient to convert murine fibroblasts into SOX9+/RUNX2+ cellular aggregates and together with SOX9 (S) promoted the conversion efficiency when cultured in a defined stem cell medium, mTeSR. KMS-reprogrammed cells possess gene expression profiles akin to those of native osteo-chondroprogenitors with elevated osteogenic properties and can differentiate into osteoblasts and chondrocytes in vitro, but form bone tissue upon transplantation under the skin and in the fracture site of mouse tibia. Altogether, we provide a reprogramming strategy to enable efficient derivation of osteo-chondrogenic cells that may hold promise for cell replacement therapy not limited to cartilage but also for bone tissues.

Abstract In 2006, mutations in the granulin gene were identified in patients with familial Frontotemporal Lobar Degeneration. Granulin transcript haploinsufficiency has been proposed as a disease mechanism that leads to the loss of functional progranulin protein. Granulin mutations were initially found in tau-negative patients, though recent findings indicate that these mutations are associated with other neurodegenerative disorders with tau pathology, including Alzheimer’s disease and corticobasal degeneration. Moreover, a reduction in progranulin in tau transgenic mice is associated with increasing tau accumulation. To investigate the influence of a decline in progranulin protein on other forms of neurodegenerative-related protein accumulation, human granulin mutation cases were investigated by histochemical and biochemical analyses. Results showed a neuronal and glial tau accumulation in granulin mutation cases. Tau staining revealed neuronal pretangle forms and glial tau in both astrocytes and oligodendrocytes. Furthermore, phosphorylated α-synuclein-positive structures were also found in oligodendrocytes and the neuropil. Immunoblot analysis of fresh frozen brain tissues revealed that tau was present in the sarkosyl-insoluble fraction, and composed of three- and four-repeat tau isoforms, resembling Alzheimer’s disease. Our data suggest that progranulin reduction might be the cause of multiple proteinopathies due to the accelerating accumulation of abnormal proteins including TDP-43 proteinopathy, tauopathy and α-synucleinopathy.

Purpose: To compare patient subjective satisfaction between medial opening-wedge high tibial osteotomy (HTO) and total knee arthroplasty (TKA). Methods: This study enrolled 110 knees, including comprising 49 knees in the HTO group, and 61 knees in the TKA group. We assessed the overall satisfaction using a three-point questionnaire. The satisfaction questionnaire included three questions: (1) How satisfied are you with the results of your knee surgery? (2) How satisfied are you with your most recent knee surgery for reducing your pain? and (3) How satisfied are you with your most recent knee surgery for improving your ability to perform functions? Furthermore, we assessed knee pain and function by using the Knee Society Function Score (KSS) and Knee Injury and Osteoarthritis Outcome Score (KOOS) systems. Results: Overall, 93.8% of patients from the HTO group and 95.1% from the TKA group indicated subjective satisfaction (very satisfied and satisfied) with their surgeries. For pain relief, the HTO group showed significantly better outcomes for overall satisfaction ( p = 0.04 in walking on a flat surface and p = 0.02 in going upstairs or downstairs). For restored function, the HTO group scored significantly better on ascending stairs than the TKA group ( p = 0.007). Functional outcomes using the KSS scoring system did not show significant differences between the two groups. The KOOS pain score was significantly higher in the TKA group (89.9 ± 6.4) than in the HTO group (80.3 ± 12.5). Conclusion: HTO and TKA have comparable outcomes with respect to overall patient satisfaction. Level of evidence: Level III, therapeutic case series.

Summary: In higher vertebrates, cephalic neural crest cells (NCCs) form craniofacial skeleton by differentiating into chondrocytes and osteoblasts. A subpopulation of cephalic NCCs, cardiac NCCs (CNCCs), migrates to the heart. However, CNCCs mostly do not yield skeletogenic derivatives, and the molecular mechanisms of this fate restriction remain elusive. We identify a disintegrin and metalloprotease 19 (Adam19) as a position-specific fate regulator of NCCs. Adam19-depleted mice abnormally form NCC-derived cartilage in their hearts through the upregulation of Sox9 levels in CNCCs. Moreover, NCC-lineage-specific Sox9-overexpressing mice recapitulate CNCC chondrogenesis. In vitro experiments show that Adam19 mediates the cleavage of bone morphogenic protein (BMP) type I receptor Alk2 (Acvr1), whereas pharmacogenetic approaches reveal that Adam19 inhibits CNCC chondrogenesis by suppressing the BMP-Sox9 cascade, presumably through processing Alk2. These findings suggest a metalloprotease-dependent mechanism attenuating cellular responsiveness to BMP ligands, which is essential for both the positional restriction of NCC skeletogenesis and normal heart development. : Arai et al. show that metalloprotease Adam19 is essential for proper differentiation of cardiac neural crest cells (CNCCs) in murine embryogenesis. Adam19 suppresses the response of CNCCs to bone morphogenic protein by cleaving its receptor Alk2, thus restricting CNCC skeletogenic potential and preventing cartilage formation in the heart. Keywords: cardiac neural crest cells, a disintegrin and metalloprotease 19, bone morphogenic protein, skeletogenesis, Sox9, Alk2

Purpose: Tranexamic acid (TXA) is a commonly used compound that reduces postoperative blood loss. Periarticular injection of TXA is a recently reported procedure with some advantages such as cost-effectiveness and the ease of performance over an intravenous or topical administration. However, its association with functional recovery remains unclear. This study aimed to examine the effect of periarticular injection of TXA on early postoperative recovery of knee functionality after total knee arthroplasty (TKA). Methods: Eighty-four patients who underwent primary unilateral TKA from February 2013 to August 2016 were classified into two groups based on whether they received TXA injection (44 cases each in the TXA and control groups). Patients in the TXA group received periarticular injection of TXA (1000 mg) just prior to incision closure. Ten-meter walk test (s), pain visual analog scale, knee extension muscle force (N), range of motion (ROM) (maximum flexion angle, maximum extension angle, and motion arc), and blood loss (mL) were assessed. Results: The maximum flexion angle and maximal extension angle on postoperative day (POD) 4, POD7, POD10, and POD14 in the TXA group were significantly larger than those in the control group. The postoperative drained blood in the TXA group was significantly less than that of the control group (543.9 ± 464.3 mL and 814.9 ± 481.4 mL, respectively, p < 0.05). No significant difference was observed in the other parameters at any time point. Conclusion: Periarticular injection of TXA significantly promotes early recovery of knee ROM after TKA. Level of Evidence: Level IV, therapeutic case series.

Rupture of the flexor tendons is a rare complication following distal radius malunion after nonoperative management. This article presents 2 cases of delayed flexor tendon ruptures following malunited distal radius fracture and discusses the characteristics, operative management, and outcomes of this rare complication by reviewing the previous literature. Our analysis demonstrate that surgical reconstruction of ruptured tendons provides good outcomes when the number of tendon ruptures is small. If multiple tendon ruptures are present, surgical outcomes may be poor despite surgical reconstruction. Osseous surgery would be necessary to prevent additional tendon ruptures; however, less invasive and simple surgeries arrowing early rehabilitation would be preferable. Keywords: Distal radius fracture, Malunion, Nonoperative treatment, Flexor tendon rupture, Complication

Rela is a transcription factor shown to have seemingly contradictory roles in anabolism and catabolism of cartilage. Here the authors find that Rela prevents chondrocyte apoptosis and that homozygous knockout causes accelerated osteoarthritis in adults, whereas heterozygous knockout suppresses osteoarthritis by maintaining wild-type effects on apoptosis but inhibiting catabolic gene expression.

EWS-FLI1, a multi-functional fusion oncogene, is exclusively detected in Ewing sarcomas. However, previous studies reported that rare varieties of osteosarcomas also harbor EWS-ETS family fusion. Here, using the doxycycline-inducible EWS-FLI1 system, we established an EWS-FLI1-dependent osteosarcoma model from murine bone marrow stromal cells. We revealed that the withdrawal of EWS-FLI1 expression enhances the osteogenic differentiation of sarcoma cells, leading to mature bone formation. Taking advantage of induced pluripotent stem cell (iPSC) technology, we also show that sarcoma-derived iPSCs with cancer-related genetic abnormalities exhibited an impaired differentiation program of osteogenic lineage irrespective of the EWS-FLI1 expression. Finally, we demonstrate that EWS-FLI1 contributed to secondary sarcoma development from the sarcoma iPSCs after osteogenic differentiation. These findings demonstrate that modulating cellular differentiation is a fundamental principle of EWS-FLI1-induced osteosarcoma development. This in vitro cancer model using sarcoma iPSCs should provide a unique platform for dissecting relationships between the cancer genome and cellular differentiation.

After acute kidney injury (AKI), surviving cells within the nephron proliferate and repair. We identify Sox9 as an acute epithelial stress response in renal regeneration. Translational profiling after AKI revealed a rapid upregulation of Sox9 within proximal tubule (PT) cells, the nephron cell type most vulnerable to AKI. Descendants of Sox9+ cells generate the bulk of the nephron during development and regenerate functional PT epithelium after AKI-induced reactivation of Sox9 after renal injury. After restoration of renal function post-AKI, persistent Sox9 expression highlights regions of unresolved damage within injured nephrons. Inactivation of Sox9 in PT cells pre-injury indicates that Sox9 is required for the normal course of post-AKI recovery. These findings link Sox9 to cell intrinsic mechanisms regulating development and repair of the mammalian nephron.

Study DesignRetrospective study.PurposeTo assess treatment outcomes of snowboarding-related spinal and spinal cord injuries.Overview of LiteratureSnowboarding-related spinal or spinal cord injury have a great impact on social and sporting activities.MethodsA retrospective review of 19 cases of surgically treated snowboard-related injury was done. Analyzed parameters included site of injury, type of fracture, peri- and postoperative complications, pre- and postoperative neurological status, activities of daily living, and participation in sports activities at the final follow-up.ResultsThe major site of injury was the thoracolumbar junction caused by fracture-dislocation (13/19 cases). The remaining 6 cases had cervical spine injuries. Over 60% of the patients had Frankel A and B paralysis. All patients were surgically treated by posterior fusion with instrumentation. Five underwent additional anterior fusion. Surgical outcome was restoration of ambulatory capacity in 12 patients (63.2%). Ultimately, 15 patients (78.9%) could return to work. Patients with complete paralysis upon admission showed reduced ambulatory capacity compared to those with incomplete paralysis. None of the patients again participated in any sports activities, including snowboarding.ConclusionsSnowboarding-related spinal or spinal cord injury has a great impact on social as well as sports activities. It is necessary to enhance promotion of injury prevention emphasizing the snowboarders' responsibility code.

TDP-43 is the major component protein of ubiquitin-positive inclusions in brains of patients with frontotemporal lobar degeneration (FTLD-TDP) or amyotrophic lateral sclerosis (ALS). Here, we report the characterization of prion-like properties of aggregated TDP-43 prepared from diseased brains. When insoluble TDP-43 from ALS or FTLD-TDP brains was introduced as seeds into SH-SY5Y cells expressing TDP-43, phosphorylated and ubiquitinated TDP-43 was aggregated in a self-templating manner. Immunoblot analyses revealed that the C-terminal fragments of insoluble TDP-43 characteristic of each disease type acted as seeds, inducing seed-dependent aggregation of TDP-43 in these cells. The seeding ability of insoluble TDP-43 was unaffected by proteinase treatment but was abrogated by formic acid. One subtype of TDP-43 aggregate was resistant to boiling treatment. The insoluble fraction from cells harboring TDP-43 aggregates could also trigger intracellular TDP-43 aggregation. These results indicate that insoluble TDP-43 has prion-like properties that may play a role in the progression of TDP-43 proteinopathy.

Tissue reconstruction in vitro can provide, if successful, a refined and simple system to analyze the underlying mechanisms that drive the morphogenesis and maintain the ordered structure. We have recently succeeded in reconstruction of seminiferous cord-like and tubule-like structures using 3-D re-aggregate culture of dissociated testicular cells. In testis formation, endothelial cells that migrated from mesonephroi to embryonic gonads have been shown to be critical for development of testis cords, but how endothelial cells contribute to testis cord formation remains unknown. To decipher the roles of endothelial and peritubular cells in the reconstruction of cord-like and tubule-like structures, we investigated the behavior of CD34+ endothelial and p75+ cells, and peritubular myoid cells (PTMCs) in 3-D re-aggregate cultures of testicular cells. The results showed that these 3 types of cells had the capacity of re-aggregation on their own and with each other, and of segregation into 3 layers in a re-aggregate, which were very similar to interstitial and peritubular tissues in vivo. Observation of behaviors of fluorescent Sertoli cells and other non-fluorescent types of cells using testes from Sox9-EGFP transgenic mice showed dynamic cell movement and segregation in re-aggregate cultures. Cultures of testicular cells deprived of interstitial and peritubular cells resulted in dysmorphic structures, but re-addition of them restored tubule-like structures. Purified CD34+ cells in culture differentiated into p75+ cells and PTMCs. These results indicate that CD34+ cells differentiate into p75+ cells, which then differentiate into PTMCs. TGFβ signaling inhibitors, SB431542 and ALK5i, disturbed the reconstruction of cord-like and tubule-like structures, and the latter compromised re-construction of interstitial-like and peritubular-like structures, as well as the proliferation of CD34+, p75+, PTMCs, and Sertoli cells, and their movement and differentiation. These results indicate that CD34+ cells and signaling through ALK5 play pivotal roles in the morphogenesis of interstitial-like, peritubular-like and cord-like structures.

We describe a case of suprascapular nerve entrapment caused by protrusion of an intraosseous ganglion of the glenoid into the spinoglenoid notch. A 47-year-old man with left shoulder pain developed an intraosseous cyst in the left glenoid, which came into contact with the suprascapular nerve. The area at which the patient experienced spontaneous shoulder pain was innervated by the suprascapular nerve, and 1% xylocaine injection into the spinoglenoid notch under ultrasonographic guidance relieved the pain. Therefore, we concluded that the protrusion of an intraosseous cyst of the glenoid into the spinoglenoid notch was a cause of the pain, and performed curettage. Consequently, the shoulder pain was resolved promptly without suprascapular nerve complications, and the cyst was histologically diagnosed as an intraosseous ganglion. This case demonstrated that the intraosseous ganglion of the glenoid was a benign lesion but could be a cause of suprascapular nerve entrapment syndrome. Curettage is a useful treatment option for a ganglion inside bone and very close to the suprascapular nerve.

Summary The membrane-anchored metalloproteinase-regulator RECK has been characterized as a tumor suppressor. Here we report that mice with reduced Reck-expression show limb abnormalities including right-dominant, forelimb-specific defects in postaxial skeletal elements. The forelimb buds of low-Reck mutants have an altered dorsal ectoderm with reduced Wnt7a and Igf2 expression, and hypotrophy in two signaling centers (i.e., ZPA and AER) that are essential for limb outgrowth and patterning. Reck is abundantly expressed in the anterior mesenchyme in normal limb buds; mesenchyme-specific Reck inactivation recapitulates the low-Reck phenotype; and some teratogens downregulate Reck in mesenchymal cells. Our findings illustrate a role for Reck in the mesenchymal-epithelial interactions essential for mammalian development.

Soft tissue metastases of prostate cancer to other sites are extremely rare, and, to our best knowledge, there have been no reports of metastasis to soft tissue of the hand. A 63-year-old man was diagnosed with prostatic cancer. During treatment, bone and soft tissue metastases to the right hand, appearing in the first web space, were observed. The tumor was resected, along with both the first and second metacarpal bones. The thumb was reconstructed by pollicization of the remaining index finger, enabling the patient to use the pollicized thumb for activities of daily living. This is the first case report of prostate cancer metastasizing to the soft tissue in hand. After wide resection, pollicization was able to reconstruct a functional hand and thumb.

Mild discolouration of the articular cartilage is known to gradually occur during aging. However, pathological tissue pigmentation is occasionally induced under several specific conditions. In the present case, we performed total knee replacement in a patient with recurrent haemarthrosis. However, during the operation, we observed severe black colouration of the knee articular cartilage, due to the deposition of hemosiderin and lipofuscin. To our knowledge, this is the first report of severe cartilage pigmentation, due to hemosiderin and lipofuscin deposition in articular cartilage.