Spatial heterogeneity of bone marrow endothelial cells unveils a distinct subtype in the epiphysis.

Bone marrow endothelial cells (BMECs) play a key role in bone formation and haematopoiesis. Although recent studies uncovered the cellular taxonomy of stromal compartments in the bone marrow (BM), the complexity of BMECs is not fully characterized. In the present study, using single-cell RNA sequencing, we defined a spatial heterogeneity of BMECs and identified a capillary subtype, termed type S (secondary ossification) endothelial cells (ECs), exclusively existing in the epiphysis. Type S ECs possessed unique phenotypic characteristics in terms of structure, plasticity and gene expression profiles. Genetic experiments showed that type S ECs atypically contributed to the acquisition of bone strength by secreting type I collagen, the most abundant bone matrix component. Moreover, these cells formed a distinct reservoir for haematopoietic stem cells. These findings provide the landscape for the cellular architecture in the BM vasculature and underscore the importance of epiphyseal ECs during bone and haematopoietic development.

Development and validation of machine learning-based predictive model for clinical outcome of decompression surgery for lumbar spinal canal stenosis.

BACKGROUND CONTEXT: Although the results of decompression surgery for lumbar spinal canal stenosis (LSS) are favorable, it is still difficult to predict the postoperative health-related quality of life of patients before surgery. PURPOSE: The purpose of this study was to develop and validate a machine learning model to predict the postoperative outcome of decompression surgery for patients with LSS. STUDY DESIGN/SETTING: A multicentered retrospective study. PATIENT SAMPLE: A total of 848 patients who underwent decompression surgery for LSS at an academic hospital, tertiary center, and private hospital were included (age 71±9 years, 68% male, 91% LSS, level treated 1.8±0.8, operation time 69±37 minutes, blood loss 48±113 mL, and length of hospital stay 12±5 days). OUTCOME MEASURES: Baseline and 2 years postoperative health-related quality of life. METHODS: The subjects were randomly assigned in a 7:3 ratio to a model building cohort and a testing cohort to test the models' accuracy. Twelve predictive algorithms using 68 preoperative factors were used to predict each domain of the Japanese Orthopedic Association Back Pain Evaluation Questionnaire and visual analog scale scores at 2 years postoperatively. The final predictive values were generated using an ensemble of the top five algorithms in prediction accuracy. RESULTS: The correlation coefficients of the top algorithms for each domain established using the preoperative factors were excellent (correlation coefficient: 0.95-0.97 [relative error: 0.06-0.14]). The performance evaluation of each Japanese Orthopedic Association Back Pain Evaluation Questionnaire domain and visual analog scale score by the ensemble of the top five algorithms in the testing cohort was favorable (mean absolute error [MAE] 8.9-17.4, median difference [MD] 8.1-15.6/100 points), with the highest accuracy for mental status (MAE 8.9, MD 8.1) and the lowest for buttock and leg numbness (MAE 1.7, MD 1.6/10 points). A strong linear correlation was observed between the predicted and measured values (linear correlation 0.82-0.89), while 4% to 6% of the subjects had predicted values of greater than±3 standard deviations of the MAE. CONCLUSIONS: We successfully developed a machine learning model to predict the postoperative outcomes of decompression surgery for patients with LSS using patient data from three different institutions in three different settings. Thorough analyses for the subjects with deviations from the actual measured values may further improve the predictive probability of this model.

Coupling of angiogenesis and odontogenesis orchestrates tooth mineralization in mice.

The skeletal system consists of bones and teeth, both of which are hardened via mineralization to support daily physical activity and mastication. The precise mechanism for this process, especially how blood vessels contribute to tissue mineralization, remains incompletely understood. Here, we established an imaging technique to visualize the 3D structure of the tooth vasculature at a single-cell level. Using this technique combined with single-cell RNA sequencing, we identified a unique endothelial subtype specialized to dentinogenesis, a process of tooth mineralization, termed periodontal tip-like endothelial cells. These capillaries exhibit high angiogenic activity and plasticity under the control of odontoblasts; in turn, the capillaries trigger odontoblast maturation. Metabolomic analysis demonstrated that the capillaries perform the phosphate delivery required for dentinogenesis. Taken together, our data identified the fundamental cell-to-cell communications that orchestrate tooth formation, angiogenic-odontogenic coupling, a distinct mechanism compared to the angiogenic-osteogenic coupling in bones. This mechanism contributes to our understanding concerning the functional diversity of organotypic vasculature.

Contribution of lower body segment rotations in various height soccer volley kicking.

We aimed to quantify the contribution of lower body segment rotations in producing foot velocity during the soccer volley kick. Fifteen male experienced university players kicked a soccer ball placed at four height conditions (0, 25, 50 and 75 cm). Their kicking motion was captured at 500 Hz. The effectiveness of lower body segment rotations in producing forward (Ffv) and upward (Fuv) foot velocity were computed and time integrated. Major contributors for Ffv were a) left hip linear velocity, b) knee extension and c) pelvis retroflexion (the pitch rotation). The contribution of a) become smaller as the ball height increased while those of b) and c) did not change significantly. Moreover, the pelvis clockwise rotation (the yaw rotation) showed apparent contribution only for volley kicking (except 0 cm height). Major contributors for Fuv were 1) knee flexion, 2) hip internal rotation, 3) pelvis clockwise rotation (the roll rotation) and 4) hip flexion. The contributions of 1) and 4) become consistently smaller as the ball height increased, while those of 2) and 3) become larger systematically. Soccer volley kicking was found to have unique adaptations of segmental contributions to achieve higher foot position while maintain foot forward velocity.

Clinical Effects of Anterior Cervical Spondylolisthesis on Cervical Spondylotic Myelopathy After Posterior Decompression Surgery: A Retrospective Multicenter Study of 732 Cases.

STUDY DESIGN: Multicenter retrospective study. OBJECTIVES: We aim to investigate features of cervical spondylotic myelopathy (CSM) associated with anterior cervical spondylolisthesis (ACS) during posterior decompression surgery. METHODS: A total of 732 patients with CSM were enrolled, who underwent posterior decompression surgery between July 2011 and November 2015 at 17 institutions. The patients with ACS (group A), defined as an anterior slippage of ≥2 mm on plain radiographs, were compared with those without ACS (group non-A). Also, the characteristics of patients with ACS progression (group P), defined as postoperative worsening of ACS ≥2 mm or newly developed ACS, were investigated. Moreover, kyphosis was defined as C2-C7 angle in neutral position ≤-5°. The Japanese Orthopedic Association (JOA) scoring system was used for clinical evaluation. RESULTS: Group A consisting of 62 patients (8.5%) had worse preoperative clinical status but comparable surgical outcomes to group non-A. Furthermore, ACS was associated with greater age, and the degree of slippage did not affect myelopathy grades. Seventeen patients (2.3%) were observed in group P, and preoperative ACS was a significant predisposing factor for the progression without clinical impact. Among the patients in group A, preoperative cervical kyphosis was a risk factor for lower JOA recovery rate. CONCLUSIONS: Although the presence of ACS increases the risk of postoperative progression, it is not a contraindication for posterior decompression. However, surgeons need to consider the indication of fusion surgery for the patients who have ACS accompanied by kyphosis because of the poor surgical outcomes.

Genetic Deletion of Vascular Endothelial Growth Factor Receptor 2 in Endothelial Cells Leads to Immediate Disruption of Tumor Vessels and Aggravation of Hypoxia.

Vascular endothelial growth factor (VEGF) blockers are used widely in clinics to target various types of human cancer. Although VEGF blockers exert marked tumor suppressive effects, the therapeutic effects can be limited. Moreover, accumulating evidence shows that VEGF acts not just on endothelial cells but also on various nonendothelial cells, including tumor and immune cells, suggesting a need to revisit the bona fide action of VEGF on endothelial cells using specific genetic mouse models. Herein, tamoxifen-inducible endothelial-specific knockout mice lacking VEGF receptor 2 (Vegfr2), the major signal transducer for VEGF, were used. The initial event resulting from cessation of endothelial Vegfr2 signaling was vascular truncation and fragmentation, rather than maturation of abnormalized vessels. Although deletion of endothelial Vegfr2 suppressed intratumor hemorrhage, it enhanced hypoxia in tumor cells and reduced the number of infiltrating cytotoxic T cells, suggesting a profound reduction in intratumor blood flow. In various tissues, deletion of endothelial Vegfr2 induced regression of healthy capillaries in intestinal villi, substantiating intestinal perforation, which is one of the most common adverse effects of VEGF blockade in humans. Overall, the data suggest that some of the known effects of VEGF blockers on tumor vessels are caused by partial cessation of VEGF signaling, or by actions on nonendothelial cells. The results increase the understanding of the mechanisms underlying anti-angiogenic therapy.

Diabetes Does Not Adversely Affect Neurological Recovery and Reduction of Neck Pain After Posterior Decompression Surgery for Cervical Spondylotic Myelopathy: Results From a Retrospective Multicenter Study of 675 Patients.

STUDY DESIGN: Retrospective multicenter study. OBJECTIVE: The aim of this study was to identify the impact of diabetes on surgical outcomes of posterior decompression for cervical spondylotic myelopathy (CSM). SUMMARY OF BACKGROUND DATA: Although some previous studies have reported surgical outcomes of posterior decompression for CSM in diabetic patients, their results were inconsistent. METHODS: We included 675 patients with CSM who underwent posterior decompression. Patients were divided into diabetic (n = 140) and nondiabetic (n = 535) groups according to the diabetic criteria for glucose intolerance. Surgical outcomes as assessed by the Japanese Orthopedic Association (JOA) scores and visual analog scale (VAS) for neck pain were compared between groups. Subsequently, the functional outcomes of diabetic patients were compared between the mild (n = 131) and moderately severe (n = 9) groups. All patients were followed up for at least 1 year after surgery. RESULTS: Compared with the nondiabetic group, the diabetic group showed lower pre- and postoperative JOA scores (P = 0.025 and P = 0.001, respectively) and a lower JOA score recovery rate (RR) (P = 0.009). However, the preoperative-to-postoperative changes in JOA scores in the diabetic and nondiabetic groups were not significantly different (P = 0.988). Pre- and postoperative VAS for neck pain and postoperative reduction of neck pain were comparable between groups (P = 0.976, P = 0.913 and P = 0.688, respectively). Although statistical analysis was not performed due to the small underpowered sample size, functional outcomes assessed by the JOA score RR (43.3 ±â€Š37.1% vs. 45.3 ±â€Š33.9%) and preoperative-to-postoperative changes in JOA scores (3.0 ±â€Š2.2 vs. 2.7 ±â€Š2.5) were similar between the mild and moderately severe diabetes groups. CONCLUSION: CSM patients with diabetes experienced improvements in neurological function and neck pain as a result of posterior decompression to the same extent seen in patients without diabetes.Level of Evidence: 3.

Macrophages fine-tune pupil shape during development.

Tissue macrophages, which are ubiquitously present innate immune cells, play versatile roles in development and organogenesis. During development, macrophages prune transient or unnecessary synapses in neuronal development, and prune blood vessels in vascular development, facilitating appropriate tissue remodeling. In the present study, we identified that macrophages contributed to the development of pupillary morphology. Csf1op/op mutant mice, in which ocular macrophages are nearly absent, exhibited abnormal pupillary edges, with abnormal protrusions of excess iris tissue into the pupillary space. Macrophages located near the pupillary edge engulfed pigmented debris, which likely consisted of unnecessary iris protrusions that emerge during smoothening of the pupillary edge. Indeed, pupillary edge macrophages phenotypically possessed some features of M2 macrophages, consistent with robust tissue engulfment and remodeling activities. Interestingly, protruding irises in Csf1op/op mice were only detected in gaps between regressing blood vessels. Taken together, our findings uncovered a new role for ocular macrophages, demonstrating that this cell population is important for iris pruning during development.

Epithelioid Hemangioma of the Thoracic Spine: A Case Report and Review of the Literature.

Context: Osseous epithelioid hemangioma is uncommon, and reports of epithelioid hemangiomas of the spine are especially rare.Study Design: Case report.Findings: A 43-year-old male was referred to our department with progressive gait disturbance. CT scans showed a lucent mass in the vertebral body at the T3 level. MRI of the thoracic spine showed a strongly enhanced mass compressing the spinal cord. The patient underwent laminectomy from T2 to T4, debulking of the tumor, and posterior fusion from T1 to T5. After the operation, the patient's neurological status improved significantly, and he was able walk without assistance. Histological examination determined that the tumor was an epithelioid hemangioma. The patient was treated with 40 Gy radiation for local control of the tumor. The patient could walk without difficulty 12 months after the surgery.Conclusion: This is a rare example of an epithelioid hemangioma that developed in the thoracic spine and compressed the spinal cord, and was treated successfully.

Hematopoietic insults damage bone marrow niche by activating p53 in vascular endothelial cells.

Hematopoietic stem cells (HSCs) are exposed to various insults such as genotoxic stress, inflammation, and infection, which have a direct effect. These insults deplete, cause a functional decline in, and promote HSC aging and transformation. However, the impact of hematopoietic insults on niche cells remains largely unknown. We have reported previously that p53 is activated in blood vessels by various stresses, including hypoxia, inflammation, and aging, and contributes to tissue dysfunction and metabolic abnormalities. We hypothesized that hematopoietic insults also affect the bone marrow (BM) vascular niche. Here, we demonstrate that p53 becomes activated in BM endothelial cells upon hematopoietic stresses such as irradiation and chemotherapeutic treatments. The conditional activation of p53 in VE-cadherin+ vascular niche cells by deleting Mdm2 induces the expression of p53 target genes specifically in vascular endothelial cells, resulting in the dilation and collapse of vascular endothelial cells and reductions in perivascular mesenchymal stromal cell numbers. Consequently, hematopoietic stem cells (HSCs) fail to maintain dormancy, mobilize to the periphery, and are depleted significantly. Our results indicate that various hematopoietic insults affect HSCs, not only directly, but also indirectly by altering vascular integrity, which is critical for perivascular niche formation and maintenance of HSCs.

Dynamics of submaximal effort soccer instep kicking.

During a soccer match, players are often required to control the ball velocity of a kick. However, little information is available for the fundamental qualities associated with kicking at various effort levels. We aimed to illustrate segmental dynamics of the kicking leg during soccer instep kicking at submaximal efforts. The instep kicking motion of eight experienced university soccer players (height: 172.4 ± 4.6 cm, mass: 63.3 ± 5.2 kg) at 50, 75 and 100% effort levels were recorded by a motion capture system (500 Hz), while resultant ball velocities were monitored using a pair of photocells. Between the three effort levels, kinetic adjustments were clearly identified in both proximal and distal segments with significantly different (large effect sizes) angular impulses due to resultant joint and interaction moments. Also, players tended to hit an off-centre point on the ball using a more medial contact point on the foot and with the foot in a less upright position in lower effort levels. These results suggested that players control their leg swing in a context of a proximal to distal segmental sequential system and add some fine-tuning of the resultant ball velocity by changing the manner of ball impact.

Multifocal primary melanoma of the cervical spinal cord successfully treated by tumorectomy: a case report.

INTRODUCTION: Multifocal primary melanoma of the spine is extremely rare. Here, we report a case of multifocal primary melanoma of the cervical spinal cord. CASE PRESENTATION: A 39-year-old man presented with a 1-year history of numbness of the upper extremities and back. Magnetic resonance imaging of the cervical spine suggested multifocal intradural extramedullary tumors at levels C2 and C4-C5. A diagnostic biopsy revealed a pathological diagnosis of malignant melanoma. Tumorectomy was then performed. The numbness in the patient's upper extremities improved, and he was discharged. As of 2 years after surgery, no signs of local or systemic recurrence have been noted. DISCUSSION: Primary melanoma of the spinal cord usually carries a poor prognosis. However, in this case, the outcome following tumorectomy has been highly favorable. We speculate that this is because the MIB-1 labeling index of the tumors was less than 1%.

Characteristic findings on imaging of cervical spondylolisthesis: Analysis of computed tomography and X-ray photography in 101 spondylolisthesis patients.

INTRODUCTION: The characteristics of cervical spondylolisthesis are not currently fully understood, because of the shortage of reports covering the large population of patients with cervical spondylolisthesis. The purpose of this study was to elucidate the characteristics of cervical spondylolisthesis by examining a relatively large number of cases. METHODS: We analyzed 101 cases with more than 2 mm of vertebral listhesis as determined from X-ray or computed tomography (CT) images among 731 patients who underwent surgery at a single institute. We considered the C2-7 angle, range of motion, and C2-7 sagittal vertical axis on lateral X-ray images. From sagittal CT images, classifications into five grades based on the slipped disc and adjacent caudal levels were made. We examined the orientation of facet joints at the slipped level using axial CT images. RESULTS: Spondylolisthesis was recognized in 101 cases at 124 levels. Anterior and posterior spondylolisthesis were detected in 68 and 40 cases, respectively. Anterior spondylolisthesis developed predominantly at C3 or C4, usually at the level adjacent to the narrowed disc, or at C7, adjacent to the stiffened thoracic spine. The disc height was relatively preserved at the anterior slipped level. Posterior spondylolisthesis developed predominantly at the level of the significantly narrowed disc associated with advanced intervertebral osteoarthritis. At the segment with listhesis in the lower cervical spine, the direction of the facet joint in the axial plane tended to be posteromedial. CONCLUSIONS: Cervical degenerative spondylolisthesis was classified into two types. The first and more common listhesis occurred adjacent to stiffened levels, and anterior slippage was common in this type. The second and less common listhesis occurred within progressively degenerated segments, and posterior slippage was prominent. We have uniquely described the morphological changes in orientation of the cervical facet joints at the slipped level in the transverse plane.

Novel mathematical model to estimate ball impact force in soccer.

To assess ball impact force during soccer kicking is important to quantify from both performance and chronic injury prevention perspectives. We aimed to verify the appropriateness of previous models used to estimate ball impact force and to propose an improved model to better capture the time history of ball impact force. A soccer ball was fired directly onto a force platform (10 kHz) at five realistic kicking ball velocities and ball behaviour was captured by a high-speed camera (5,000 Hz). The time history of ball impact force was estimated using three existing models and two new models. A new mathematical model that took into account a rapid change in ball surface area and heterogeneous ball deformation showed a distinctive advantage to estimate the peak forces and its occurrence times and to reproduce time history of ball impact forces more precisely, thereby reinforcing the possible mechanics of 'footballer's ankle'. Ball impact time was also systematically shortened when ball velocity increases in contrast to practical understanding for producing faster ball velocity, however, the aspect of ball contact time must be considered carefully from practical point of view.