Dysbiosis and Staphylococcus aureus Colonization Drives Inflammation in Atopic Dermatitis.

Staphylococcus aureus skin colonization is universal in atopic dermatitis and common in cancer patients treated with epidermal growth factor receptor inhibitors. However, the causal relationship of dysbiosis and eczema has yet to be clarified. Herein, we demonstrate that Adam17(fl/fl)Sox9-(Cre) mice, generated to model ADAM17-deficiency in human, developed eczematous dermatitis with naturally occurring dysbiosis, similar to that observed in atopic dermatitis. Corynebacterium mastitidis, S. aureus, and Corynebacterium bovis sequentially emerged during the onset of eczematous dermatitis, and antibiotics specific for these bacterial species almost completely reversed dysbiosis and eliminated skin inflammation. Whereas S. aureus prominently drove eczema formation, C. bovis induced robust T helper 2 cell responses. Langerhans cells were required for eliciting immune responses against S. aureus inoculation. These results characterize differential contributions of dysbiotic flora during eczema formation, and highlight the microbiota-host immunity axis as a possible target for future therapeutics in eczematous dermatitis.

Surgical management of omega deformity in a patient with neurofibromatosis type 1: a case report.

PURPOSE: To describe the surgical treatment in a patient with a partial omega deformity in the thoracic spine with neurofibromatosis type 1. METHODS: The patient was a 55-year-old man with an omega deformity, which is defined as a curvature in which the end vertebra is positioned at the level of, above, or below the apical vertebra (i.e., a horizontal line bisecting it). We performed halo gravity traction (HGT) for 7 weeks, followed by posterior spinal instrumented nearly equal in situ fusion from T2-L5 with three femoral head allografts and a local bone autograft. We avoided reconstruction of the thoracic anterior spine because of his severe pulmonary dysfunction. RESULTS: HGT improved the % vital capacity from 32.5 to 43.5%, and improved the Cobb angle of the kyphosis from > 180° before traction to 144° after traction. The Cobb angle of kyphosis and scoliosis changed from > 180° preoperatively to 155° and 146°, respectively, postoperatively, and 167° and 156°, respectively, at final follow-up. His postoperative respiratory function deteriorated transiently due to bilateral pleural effusions and compressive atelectasis, which was successfully treated with a frequent change of position and nasal high flow for 1 week. At final follow-up, his pulmonary function improved from 0.86 to 1.04 L in VC, and from 32.5 to 37.9% in %VC. However, there was no overall improvement in preoperative distress following surgery, although his modified Borg scale improved from 3 preoperatively to 0.5 postoperatively. One month after discharge, he felt worsening respiratory distress (SpO2:75%) and was readmitted for pulmonary hypertension for 2 months. He was improved by non-invasive positive pressure ventilation (biphasic positive airway pressure) for 1 week, medication and daily lung physiotherapy. Thereafter, he has been receiving permanent daytime (0.5 L/min) and nighttime (2 L/min) oxygen therapy at home. A solid arthrodesis through the fusion area was confirmed on computed tomography. However, the kyphosis correction loss was 12° (i.e., 155°-167°), while the scoliosis correction loss was 10° (i.e., 146°-156°) at 2 years of recovery. CONCLUSIONS: We suggest that nearly equal in situ fusion is a valid option for preventing further deformity deterioration and avoiding fatal complications.

Restricted kinematically aligned total knee arthroplasty with an anatomically designed implant can restore constitutional coronal lower limb alignment.

PURPOSE: Restricted kinematically aligned total knee arthroplasty (rKA-TKA) may not restore the constitutional varus alignment in most patients with knee osteoarthritis. This study aimed to investigate (1) the extent to which constitutional lower limb alignment can be restored by rKA-TKA using an anatomically designed implant and (2) which lower limb alignment parameters are associated with patient-reported outcome measures (PROMs). METHODS: This study included 60 patients who underwent rKA-TKA using an anatomically designed implant. Radiographic alignment parameters, including mechanical lateral distal femoral angle (mLDFA), medial proximal tibial angle (MPTA), coronal hip-knee-ankle angle (HKA), coronal joint line obliquity (JLO), posterior tibial slope (PTS), single-leg standing knee flexion angle (KFA), sagittal JLO, and arithmetic HKA (aHKA), were evaluated preoperatively and postoperatively. The Western Ontario and McMaster Universities Arthritis Index (WOMAC) was used for clinical evaluation. RESULTS: The mLDFA, MPTA, and aHKA showed no significant differences before and after surgery. Coronal HKA and PTS have significantly changed from 8.1 ± 8.7° and 9.9 ± 8.6° preoperatively to 3.5 ± 3.1° and 2.5 ± 2.0° postoperatively, respectively (p < 0.001 for each comparison). The postoperative WOMAC total score was significantly correlated with the KFA (r = 0.4063, p = 0.0034) and sagittal JLO (r = -0.3435, p = 0.0157). Postoperative KFA is a causal factor for the increased postoperative WOMAC total score (r = 1.416, 95% confidence interval: 0.491-2.342, p = 0.003). CONCLUSION: rKA-TKA using an anatomically designed implant can restore constitutional coronal lower limb alignment, while postoperative KFA and sagittal JLO were associated with poor PROMs. Care should be taken for the postoperative KFA because it is a risk factor for poor PROMs. LEVEL OF EVIDENCE: Level III, case-control study.

Minimally invasive arthroscopy-assisted arthrodesis for thumb carpometacarpal osteoarthritis.

INTRODUCTION: Arthrodesis is a reliable surgical procedure for treatment of thumb carpometacarpal (CMC) osteoarthritis that provides hand strength and pain relief. Locking plate fixation is a common technique that provides rigid fixation and a high rate of bone union; however, it requires extensive surgical exploration of the first metacarpal and trapezium. Here, we report the surgical outcome of minimally invasive arthroscopy-assisted thumb CMC arthrodesis that preserves soft tissue supplying the blood flow to the bones. MATERIALS AND METHODS: Nine thumbs of nine patients who underwent arthroscopy-assisted thumb CMC arthrodesis were retrospectively analysed (mean postoperative follow-up, 19.7 months). We investigated the time from surgery to bone union, grip strength, pinch strength (pulp and key), range of motion (ROM) of the thumb, visual analogue scale (VAS) score for pain, Disabilities of Arm, Shoulder, and Hand (DASH) score, and Hand20 questionnaire score preoperatively and at the final follow-up. RESULTS: Bone union was observed in eight of the nine patients. The mean time to bone union was 2.9 months (range 8 weeks-9 months). Although grip strength changed from 24.0 kg preoperatively to 25.8 kg at the final follow-up (not significant), the pulp pinch strength and key pinch strength significantly increased from 2.3 kg and 3.7 kg preoperatively to 3.8 kg and 5.6 kg at the final follow-up, respectively. No significant change occurred in the thumb ROM. The DASH score, Hand20 questionnaire score, and VAS score for pain significantly improved from 29.8, 42.2, and 78.4 preoperatively to 12.4, 11.2, and 13.2 at the final follow-up, respectively. Non-union was observed in one patient. No other complications were observed. CONCLUSIONS: Arthroscopy-assisted arthrodesis is a valuable procedure for thumb CMC osteoarthritis. However, the learning curve for this procedure must be overcome before the operative time can be shortened and successful bone union and satisfactory outcomes achieved.

Identifying Muscle Function-based Phenotypes Associated With Radiographic Progression of Secondary Hip Osteoarthritis.

OBJECTIVE: The purposes of our study were to (1) identify muscle function-based clinical phenotypes in patients with hip osteoarthritis (OA) and (2) determine the association between those phenotypes and radiographic progression of hip OA. DESIGN: Prospective cohort study. SETTING: Clinical biomechanics laboratory of a university. PARTICIPANTS: Fifty women patients with mild-to-moderate secondary hip OA (N=50) were recruited from the orthopedic department of a single institution. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Two-step cluster analyses were performed to classify the patients, using hip flexion, extension, abduction, and external/internal rotation muscle strength (cluster analysis 1); relative hip muscle strength to total hip strength (ie, hip muscle strength balance; cluster analysis 2); and both hip muscle strength and muscle strength balance (cluster analysis 3) as variables. The association between the phenotype and hip OA progression over 12 months (indicated by joint space width [JSW] >0.5 mm) was investigated by logistic regression analyses. Hip joint morphology, hip pain, gait speed, physical activity, Harris hip score, and SF-36 scores were compared between the phenotypes. RESULTS: Radiographic progression of hip OA was observed in 42% of the patients. The patients were classified into 2 phenotypes in each of the 3 cluster analyses. The solution in cluster analyses 1 and 3 was similar, and high-function and low-function phenotypes were identified; however, no association was found between the phenotypes and hip OA progression. The phenotype 2-1 (high-risk phenotype) extracted in cluster analysis 2, which had relative muscle weakness in hip flexion and internal rotation, was associated with subsequent hip OA progression, even after adjusting for age and minimum JSW at baseline (adjusted odds ratio [95% confidence interval], 3.60 [1.07-12.05]; P=.039). CONCLUSION: As preliminary findings, the phenotype based on hip muscle strength balance, rather than hip muscle strength, may be associated with hip OA progression.

Possible association of limbic tau pathology with psychosis or behavioral disturbances: Studies of two autopsied psychiatric patients.

Tauopathies, including Alzheimer's disease and primary age-related tauopathy (PART), present heterogeneous clinico-pathological phenotypes that include dementia, aphasia, motor neuron diseases, and psychiatric symptoms. PART is neuropathologically characterized by the presence of neurofibrillary tangles in limbic regions without significant Aß deposition, but its clinical features have not yet been fully established. Here, we present two patients with distinct psychosis and behavioral symptoms. At autopsy, these patients showed tau pathologies that could not be classified as typical PART, although PART-like neurofibrillary tangles were present in limbic regions. Clinically, both patients were admitted to mental hospitals due to severe delusions or other neuropsychiatric/behavioral symptoms. The first case presented with hallucination, delusion, and apathy at age 70, and died of pancreatic cancer at age 75. He had neuronal cytoplasmic inclusions with selective accumulation of 3Rtau in the striatum and thorn-shaped astrocytes in the amygdala. The second case, who presented with abnormal behaviors such as wandering, agitation and disinhibition, exhibited limbic neurodegeneration with massive 4R tau-positive oligodendroglial inclusions in the medial temporal white matter. His age at onset was 73, and the duration of disease was 15 years. These findings support the notion that distinct limbic tau pathology with concomitant degeneration of the related neural circuits might induce specific psychosis and behavioral symptoms. This underlines the importance of neuropathological evaluation for both clinical education and practice in the fields of neuropathology and neuropsychiatry.

Redundant and additive functions of the four Lef/Tcf transcription factors in lung epithelial progenitors.

In multicellular organisms, paralogs from gene duplication survive purifying selection by evolving tissue-specific expression and function. Whether this genetic redundancy is also selected for within a single cell type is unclear for multimember paralogs, as exemplified by the four obligatory Lef/Tcf transcription factors of canonical Wnt signaling, mainly due to the complex genetics involved. Using the developing mouse lung as a model system, we generate two quadruple conditional knockouts, four triple mutants, and various combinations of double mutants, showing that the four Lef/Tcf genes function redundantly in the presence of at least two Lef/Tcf paralogs, but additively upon losing additional paralogs to specify and maintain lung epithelial progenitors. Prelung-specification, pan-epithelial double knockouts have no lung phenotype; triple knockouts have varying phenotypes, including defective branching and tracheoesophageal fistulas; and the quadruple knockout barely forms a lung, resembling the Ctnnb1 mutant. Postlung-specification deletion of all four Lef/Tcf genes leads to branching defects, down-regulation of progenitor genes, premature alveolar differentiation, and derepression of gastrointestinal genes, again phenocopying the corresponding Ctnnb1 mutant. Our study supports a monotonic, positive signaling relationship between CTNNB1 and Lef/Tcf in lung epithelial progenitors as opposed to reported repressor functions of Lef/Tcf, and represents a thorough in vivo analysis of cell-type-specific genetic redundancy among the four Lef/Tcf paralogs.

Joint gap produced by manual stress is dependent on the surgeon's experience and is smaller in flexion in robotic-assisted total knee arthroplasty.

PURPOSE: This study aimed to retrospectively investigate (1) the reproducibility of gap measurements by manual stress using the Z-shaped retractor depending on the surgeon's experience with this maneuver and (2) the consistency of the gap distraction force produced by manual stress throughout the range of motion (ROM) in the robotic-assisted total knee arthroplasty (TKA). It was hypothesized that the joint gap produced by manual stress is not reproducible depending on the surgeon's experience, and the distraction force applied by manual stress throughout the ROM is not constant. METHODS: Medial and lateral joint gaps were obtained throughout the ROM by manual stress or a tensioner by two surgeons with different levels of experience in robotic-assisted TKA. The association between the differences in gap measurement by the two surgeons and the preoperative radiographic parameters, including the hip-knee-ankle (HKA) angle and absolute and relative varus/valgus laxities were analyzed. RESULTS: The experienced surgeon produced significantly greater gaps than the inexperienced surgeon from 0° to 100° flexion, with a mean difference of 0.35 ± 0.12 mm in the medial gap (p < 0.0001), and from 10° to 120° flexion with a mean difference of 0.57 ± 0.13 mm in the lateral gap (p < 0.0001). The tensioner produced a significantly greater medial gap from 70° to 110° flexion with a mean difference of 0.32 ± 0.01 mm in the medial gap (p < 0.0001) and from 0° to 110° flexion with a mean difference of 1.12 ± 0.26 mm in the lateral gap (p < 0.0001). The differences in gap distance by manual stress between experienced and inexperienced surgeons were moderately correlated with the HKA angle in the lateral gap (r = 0.40, p = 0.01). The gap differences due to manual stress and a tensioner showed moderate negative correlation with the HKA angle in the medial gap (r = - 0.50, p = 0.001) and weak negative correlation with the absolute valgus laxity in the lateral gap (r = - 0.35, p = 0.03). CONCLUSIONS: The joint distraction force by manual stress may differ depending on the surgeon's experience and tended to be smaller in deep flexion; therefore, the flexion gap may be underestimated. Surgeons should determine implant positioning considering gap balance by manual stress, taking into account these characteristics of the manual stress maneuver. LEVEL OF EVIDENCE: Level III, retrospective cohort study.

The malignant transformation of osteoid osteoma in the cervical spine to high-grade osteosarcoma: a case report and review of literature.

PURPOSE: Osteoid osteoma occasionally occur in the spine, but their malignant transformation is not common. We present an extremely rare case of the malignant transformation of an osteoid osteoma to high-grade osteosarcoma that formed in the pedicle and spread to the lateral mass of the cervical spine. CASE PRESENTATION: We report the case of an 18-year-old man who suffered from neck pain as an initial symptom. The size of the radiolucent lesion was 12 mm in diameter at the time of diagnosis. Intralesional tumour resection and autologous bone grafting were performed. The remaining tumour grew gradually for 40 months after the surgery; therefore, the tumour had grown rapidly till 51 months after the initial diagnosis. At this stage, the tumour size was approximately 6-fold larger than the initial size, and resulted in progressive paraplegia. A biopsy revealed that the tumour had transformed into a high-grade osteosarcoma. Heavy charged particle irradiation was performed to control tumour growth. CONCLUSIONS: There is a possibility of malignant transformation of osteoid osteoma. Patients with osteoid osteoma or osteoblastoma should be carefully observed, especially for recurrent tumours after an intralesional resection.

Current status and future prospects of the Japanese orthopaedic association national registry (JOANR), Japan's first national registry of orthopaedic surgery.

The Japanese Orthopaedic Association National Registry (JOANR) is Japan's first national registry of orthopaedic surgery, which has been developed after having been selected for the Project for Developing a Database of Clinical Outcome approved by the Health Policy Bureau of the Ministry of Health, Labour and Welfare. Its architecture has two levels of registration, one being the basic items of surgical procedure, disease, information on surgeons, surgery-related information, and outcome, and the other being detailed items in the affiliated registries of partner medical associations. It has a number of features, including the facts that, because it handles medical data, which constitute special care-required personal information, data processing is conducted entirely in a cloud environment with the imposition of high-level data security measures; registration of the implant data required to assess implant performance has been automated via a bar code reader app; and the system structure enables flexible collaboration with the registries of partner associations. JOANR registration is a requirement for accreditation as a core institution or partner institution under the board certification system, and the total number of cases registered during the first year of operation (2020) was 899,421 registered by 2,247 institutions, providing real-world evidence concerning orthopaedic surgery.

Bcl2l1 Deficiency in Osteoblasts Reduces the Trabecular Bone Due to Enhanced Osteoclastogenesis Likely through Osteoblast Apoptosis.

Bcl2l1 (Bcl-XL) belongs to the Bcl-2 family, Bcl2 and Bcl2-XL are major anti-apoptotic proteins, and the apoptosis of osteoblasts is a key event for bone homeostasis. As the functions of Bcl2l1 in osteoblasts and bone homeostasis remain unclear, we generated osteoblast-specific Bcl2l1-deficient (Bcl2l1fl/flCre) mice using 2.3-kb Col1a1 Cre. Trabecular bone volume and the trabecular number were lower in Bcl2l1fl/flCre mice of both sexes than in Bcl2l1fl/fl mice. In bone histomorphometric analysis, osteoclast parameters were increased in Bcl2l1fl/flCre mice, whereas osteoblast parameters and the bone formation rate were similar to those in Bcl2l1fl/fl mice. TUNEL-positive osteoblastic cells and serum TRAP5b levels were increased in Bcl2l1fl/flCre mice. The deletion of Bcl2l1 in osteoblasts induced Tnfsf11 expression, whereas the overexpression of Bcl-XL had no effect. In a co-culture of Bcl2l1-deficient primary osteoblasts and wild-type bone-marrow-derived monocyte/macrophage lineage cells, the numbers of multinucleated TRAP-positive cells and resorption pits increased. Furthermore, serum deprivation or the deletion of Bcl2l1 in primary osteoblasts increased apoptosis and ATP levels in the medium. Therefore, the reduction in trabecular bone in Bcl2l1fl/flCre mice may be due to enhanced bone resorption through osteoblast apoptosis and the release of ATP from apoptotic osteoblasts, and Bcl2l1 may inhibit bone resorption by preventing osteoblast apoptosis.

Trapeziectomy with ligament reconstruction and tendon interposition arthroplasty continuously improves hand functions up to 5-year postoperatively.

INTRODUCTION: Trapeziectomy with ligament reconstruction and tendon interposition (LRTI) arthroplasty is a reliable surgical procedure for the treatment of thumb carpometacarpal osteoarthritis, which provides good long-term outcomes. However, it remains unclear when the greatest benefit of this procedure can be obtained, and how long these benefits will continue. Therefore, we investigated the middle- to long-term advantages of this procedure by analysing the chronological changes in clinical outcomes by following the same patients from 1 year to a median 5 years after trapeziectomy with LRTI. MATERIALS AND METHODS: Sixteen thumbs that completed consecutive clinical and radiographic evaluations preoperatively, 1 year, 2 years, 3 years, and median 5 years (range 4-8 years) after trapeziectomy with LRTI were included in this study. We investigated grip strength, pinch strength, range of motion (ROM) of the thumb, a visual analogue scale for pain, Disabilities of Arm, Shoulder and Hand (DASH) score, Hand20 questionnaire score, trapezial space height, and trapezial space ratio at every time point. RESULTS: Hand strength (grip, pulp, and lateral pinch), palmar abduction, DASH score, and Hand20 questionnaire score were improved at 1 year postoperatively while the radial abduction showed significant improvement at the final follow-up. Moreover, pulp pinch strength, DASH score, and Hand20 questionnaire score continued to improve significantly from 1 year postoperatively to the final follow-up. Conversely, trapezial space height and ratio continuously decreased up to the final follow-up. CONCLUSIONS: Trapeziectomy with LRTI consecutively improved the pinch strength, ROM of the thumb, DASH score, and Hand20 questionnaire score up to 5 years postoperatively. It also maintained the improvement of the other clinical outcomes up to 5 years postoperatively except for radiological findings.

Requirement for scleraxis in the recruitment of mesenchymal progenitors during embryonic tendon elongation.

The transcription factor scleraxis (Scx) is required for tendon development; however, the function of Scx is not fully understood. Although Scx is expressed by all tendon progenitors and cells, only long tendons are disrupted in the Scx-/- mutant; short tendons appear normal and the ability of muscle to attach to skeleton is not affected. We recently demonstrated that long tendons are formed in two stages: first, by muscle anchoring to skeleton via a short tendon anlage; and second, by rapid elongation of the tendon in parallel with skeletal growth. Through lineage tracing, we extend these observations to all long tendons and show that tendon elongation is fueled by recruitment of new mesenchymal progenitors. Conditional loss of Scx in mesenchymal progenitors did not affect the first stage of anchoring; however, new cells were not recruited during elongation and long tendon formation was impaired. Interestingly, for tenocyte recruitment, Scx expression was required only in the recruited cells and not in the recruiting tendon. The phenotype of Scx mutants can thus be understood as a failure of tendon cell recruitment during tendon elongation.

Deletion of Tfam in Prx1-Cre expressing limb mesenchyme results in spontaneous bone fractures.

INTRODUCTION: Osteoblasts require substantial amounts of energy to synthesize the bone matrix and coordinate skeleton mineralization. This study analyzed the effects of mitochondrial dysfunction on bone formation, nano-organization of collagen and apatite, and the resultant mechanical function in mouse limbs. MATERIALS AND METHODS: Limb mesenchyme-specific Tfam knockout (Tfamf/f;Prx1-Cre: Tfam-cKO) mice were analyzed morphologically and histologically, and gene expressions in the limb bones were assessed by in situ hybridization, qPCR, and RNA sequencing (RNA-seq). Moreover, we analyzed the mitochondrial function of osteoblasts in Tfam-cKO mice using mitochondrial membrane potential assay and transmission electron microscopy (TEM). We investigated the pathogenesis of spontaneous bone fractures using immunohistochemical analysis, TEM, birefringence analyzer, microbeam X-ray diffractometer and nanoindentation. RESULTS: Forelimbs in Tfam-cKO mice were significantly shortened from birth, and spontaneous fractures occurred after birth, resulting in severe limb deformities. Histological and RNA-seq analyses showed that bone hypoplasia with a decrease in matrix mineralization was apparent, and the expression of type I collagen and osteocalcin was decreased in osteoblasts of Tfam-cKO mice, although Runx2 expression was unchanged. Decreased type I collagen deposition and mineralization in the matrix of limb bones in Tfam-cKO mice were associated with marked mitochondrial dysfunction. Tfam-cKO mice bone showed a significantly lower Young's modulus and hardness due to poor apatite orientation which is resulted from decreased osteocalcin expression. CONCLUSION: Mice with limb mesenchyme-specific Tfam deletions exhibited spontaneous limb bone fractures, resulting in severe limb deformities. Bone fragility was caused by poor apatite orientation owing to impaired osteoblast differentiation and maturation.

Transcriptional control of lung alveolar type 1 cell development and maintenance by NK homeobox 2-1.

The extraordinarily thin alveolar type 1 (AT1) cell constitutes nearly the entire gas exchange surface and allows passive diffusion of oxygen into the blood stream. Despite such an essential role, the transcriptional network controlling AT1 cells remains unclear. Using cell-specific knockout mouse models, genomic profiling, and 3D imaging, we found that NK homeobox 2-1 (Nkx2-1) is expressed in AT1 cells and is required for the development and maintenance of AT1 cells. Without Nkx2-1, developing AT1 cells lose 3 defining features-molecular markers, expansive morphology, and cellular quiescence-leading to alveolar simplification and lethality. NKX2-1 is also cell-autonomously required for the same 3 defining features in mature AT1 cells. Intriguingly, Nkx2-1 mutant AT1 cells activate gastrointestinal (GI) genes and form dense microvilli-like structures apically. Single-cell RNA-seq supports a linear transformation of Nkx2-1 mutant AT1 cells toward a GI fate. Whole lung ChIP-seq shows NKX2-1 binding to 68% of genes that are down-regulated upon Nkx2-1 deletion, including 93% of known AT1 genes, but near-background binding to up-regulated genes. Our results place NKX2-1 at the top of the AT1 cell transcriptional hierarchy and demonstrate remarkable plasticity of an otherwise terminally differentiated cell type.

Arid1a is essential for intestinal stem cells through Sox9 regulation.

Inactivating mutations of Arid1a, a subunit of the Switch/sucrose nonfermentable chromatin remodeling complex, have been reported in multiple human cancers. Intestinal deletion of Arid1a has been reported to induce colorectal cancer in mice; however, its functional role in intestinal homeostasis remains unclear. We investigated the functional role of Arid1a in intestinal homeostasis in mice. We found that intestinal deletion of Arid1a results in loss of intestinal stem cells (ISCs), decreased Paneth and goblet cells, disorganized crypt-villous structures, and increased apoptosis in adult mice. Spheroids did not develop from intestinal epithelial cells deficient for Arid1a Lineage-tracing experiments revealed that Arid1a deletion in Lgr5+ ISCs leads to impaired self-renewal of Lgr5+ ISCs but does not perturb intestinal homeostasis. The Wnt signaling pathway, including Wnt agonists, receptors, and target genes, was strikingly down-regulated in Arid1a-deficient intestines. We found that Arid1a directly binds to the Sox9 promoter to support its expression. Remarkably, overexpression of Sox9 in intestinal epithelial cells abrogated the above phenotypes, although Sox9 overexpression in intestinal epithelial cells did not restore the expression levels of Wnt agonist and receptor genes. Furthermore, Sox9 overexpression permitted development of spheroids from Arid1a-deficient intestinal epithelial cells. In addition, deletion of Arid1a concomitant with Sox9 overexpression in Lgr5+ ISCs restores self-renewal in Arid1a-deleted Lgr5+ ISCs. These results indicate that Arid1a is indispensable for the maintenance of ISCs and intestinal homeostasis in mice. Mechanistically, this is mainly mediated by Sox9. Our data provide insights into the molecular mechanisms underlying maintenance of ISCs and intestinal homeostasis.

Spontaneous morphological remodelling of the O-C1 joint after posterior fusion for occipitocervical dislocation.

BACKGROUND: Traumatic occipitocervical dislocation (OCD) occurs due to fatal high-energy injury. Modern screw-based constructs enable successful reduction and stabilisation. In view of this, there are no previous reports on the spontaneous remodelling of the O-C1 joint after posterior fusion. We report the first case of postoperative spontaneous remodelling and stabilisation of the O-C1 joint after traumatic OCD.Case description: A 9-year-old girl suffered from traumatic OCD, accompanied by complete rupture of the O-C1-C2 ligamentous complex. Halo-vest fixation, and subsequently posterior fusion surgery from the occipital bone to C2, with autologous iliac crest bone graft and an allograft were performed. However, we could not achieve complete reduction of the O-C1 joint during surgery owing to extremely severe instability.Postoperative X-ray and computed tomography scan showed incomplete reduction of the O-C1 joint. Insufficient congruity of the O-C1 joint persisted. Afterwards, gradual spontaneous remodelling of the O-C1 joint occurred, both anteriorly and posteriorly 3 months postoperatively. Solid union was achieved 6 months postoperatively. Two years later, bilateral O-C1 joints in the patient were completely reformed and restabilised by incredible vigorous remodelling. Insufficient reduction and persisting poor joint congruence after surgery for OCD was probably restabilised by further spontaneous remodelling of articular morphology in such a young patient. CONCLUSIONS: Postoperative spontaneous remodelling of the O-C1 joint after posterior reconstruction for OCD may occur in young patients. Incomplete reduction of the O-C1 joint during surgery may be acceptable due to the possibility of postoperative bone remodelling and restabilisation.

Medial proximal tibial angle at the posterior tibial plateau represents the pre-arthritic constitutional medial proximal tibial angle in anterior cruciate ligament-intact, advanced osteoarthritis of the knee.

PURPOSE: In kinematically aligned total knee arthroplasty (TKA), it is necessary to infer the pre-arthritic constitutional medial proximal tibial angle (MPTA) in advanced osteoarthritis (OA) of the knee with bone loss. The aim of this study was to investigate whether MPTA at the posterior tibial plateau represents the pre-arthritic constitutional MPTA in anterior cruciate ligament (ACL)-intact, advanced OA knees. It was hypothesized that MPTA at the posterior tibial plateau represents the pre-arthritic constitutional MPTA of ACL-intact, advanced knee OA. METHODS: One hundred varus, anterior cruciate ligament (ACL)-intact, advanced OA knees were analysed. The hip-knee-ankle (HKA) angle and MPTA were assessed on computed radiography (CR) and MPTAs at the anterior, middle, and posterior part of the tibial plateau were assessed on computed tomography (CT) images. The association between these parameters was also analysed. RESULTS: CR images showed an HKA angle of 172.4 ± 4.1° and MPTA of 84.3 ± 2.5°. CT images showed different MPTAs in the three regions, ranging from 83.9 ± 2.4° to 85.9 ± 2.8°. The middle MPTA was the lowest at 83.9 ± 2.4°. HKA angle correlated with the middle MPTA (r = 0.3355, 95% confidence interval [CI] 0.1489-0.4991, p = 0.0006) and ΔMPTA (Middle-Posterior) (r = 0.5128, 95% CI 0.3518-0.6443, p < 0.0001). CONCLUSION: The MPTA at the posterior tibial plateau represents the pre-arthritic constitutional MPTA in ACL-intact, advanced OA knees. LEVEL OF EVIDENCE: III, retrospective cohort study.

Fracture of the tibial tubercle does not affect clinical outcomes in medial opening wedge high tibial osteotomy with distal tibial tubercle osteotomy.

PURPOSE: To investigate whether tibial tubercle fracture affected clinical outcomes and bony union in medial opening wedge high tibial osteotomy with distal tibial tubercle osteotomy (DTO) and to determine the anatomical risk factors for tibial tubercle fracture. MATERIALS AND METHODS: All patients who underwent DTO were retrospectively reviewed, and 104 successive patients were included. The Knee Society Score and complications including tibial tubercle fracture were recorded. On radiographs and computed tomography scans, the length, thickness, width, height, and bony union of the osteotomized tibial tubercle and the posterior tibial slope were statistically analysed. RESULTS: Fracture of the tibial tubercle occurred intraoperatively in 11 patients (10.6%) and in the postoperative period in 1 (1.0%). The case of postoperative fracture showed non-union. There was no significant difference in the Knee Society Score between the non-fracture and fracture groups. There were significant differences in the posterior tibial slope and the height of the tibial tubercle between the groups (p < 0.0001 for each comparison). The logistic regression analysis showed that the height of the tibial tubercle was associated with a higher risk of the fracture of the tibial tubercle (p < 0.01; OR, 1.548; 95% CI, 1.149-2.085). However, there were no significant differences in the bony union rate of the tibial tubercle at 6 months after surgery between the groups. CONCLUSIONS: Tibial tubercle fracture did not affect the clinical outcome and bony union in spite of the relatively high occurrence rate. Anatomical risk factors for the fractures was a lower tibial tubercle position. LEVEL OF EVIDENCE: Level IV.

Loss of Mob1a/b in mice results in chondrodysplasia due to YAP1/TAZ-TEAD-dependent repression of SOX9.

Hippo signaling is modulated in response to cell density, external mechanical forces, and rigidity of the extracellular matrix (ECM). The Mps one binder kinase activator (MOB) adaptor proteins are core components of Hippo signaling and influence Yes-associated protein 1 (YAP1) and transcriptional co-activator with PDZ-binding motif (TAZ), which are potent transcriptional regulators. YAP1/TAZ are key contributors to cartilage and bone development but the molecular mechanisms by which the Hippo pathway controls chondrogenesis are largely unknown. Cartilage is rich in ECM and also subject to strong external forces - two upstream factors regulating Hippo signaling. Chondrogenesis and endochondral ossification are tightly controlled by growth factors, morphogens, hormones, and transcriptional factors that engage in crosstalk with Hippo-YAP1/TAZ signaling. Here, we generated tamoxifen-inducible, chondrocyte-specific Mob1a/b-deficient mice and show that hyperactivation of endogenous YAP1/TAZ impairs chondrocyte proliferation and differentiation/maturation, leading to chondrodysplasia. These defects were linked to suppression of SOX9, a master regulator of chondrogenesis, the expression of which is mediated by TEAD transcription factors. Our data indicate that a MOB1-dependent YAP1/TAZ-TEAD complex functions as a transcriptional repressor of SOX9 and thereby negatively regulates chondrogenesis.