A class of chemical compounds enhances clustering of muscle nicotinic acetylcholine receptor in cultured myogenic cells.

Neuromuscular signal transmission is affected in various diseases including myasthenia gravis, congenital myasthenic syndromes, and sarcopenia. We used an ATF2-luciferase system to monitor the phosphorylation of MuSK in HEK293 cells introduced with MUSK and LRP4 cDNAs to find novel chemical compounds that enhanced agrin-mediated acetylcholine receptor (AChR) clustering. Four compounds with similar chemical structures carrying benzene rings and heterocyclic rings increased the luciferase activities 8- to 30-folds, and two of them showed continuously graded dose dependence. The effects were higher than that of disulfiram, a clinically available aldehyde dehydrogenase inhibitor, which we identified to be the most competent preapproved drug to enhance ATF2-luciferase activity in the same assay system. In C2C12 myotubes, all the compounds increased the area, intensity, length, and number of AChR clusters. Three of the four compounds increased the phosphorylation of MuSK, but not of Dok7, JNK. ERK, or p38. Monitoring cell toxicity using the neurite elongation of NSC34 neuronal cells as a surrogate marker showed that all the compounds had no effects on the neurite elongation up to 1 µM. Extensive docking simulation and binding structure prediction of the four compounds with all available human proteins using AutoDock Vina and DiffDock showed that the four compounds were unlikely to directly bind to MuSK or Dok7, and the exact target remained unknown. The identified compounds are expected to serve as a seed to develop a novel therapeutic agent to treat defective NMJ signal transmission.

Does global spinal alignment affect the use of walking aids after multi-segment spinal fixation for patients with ASD? A multicenter retrospective study.

PURPOSE: This study aimed to clarify the relation between global spinal alignment and the necessity of walking aid use in patients with adult spinal deformity (ASD) and to investigate the impact of spinal fixation on mobility status after surgery. METHODS: In total, 456 older patients with ASD who had multi-segment spinal fixation surgery and were registered in a multi-center database were investigated. Patients under 60 years of age and those unable to walk preoperatively were excluded. Patients were classified by their mobility status into the independent, cane, and walker groups. Comparison analysis was conducted using radiographic spinopelvic parameters and the previously reported global spine balance (GSB) classification. In addition, preoperative and 2 years postoperative mobility statuses were investigated. RESULTS: Of 261 patients analyzed, 66 used walking aids (canes, 46; walkers, 20). Analysis of preoperative radiographical parameters showed increased pelvic incidence and pelvic incidence-lumbar lordosis mismatch in the walker group and increased sagittal vertebral axis in the cane and walker groups versus the independent group. Analysis of GSB classification showed a higher percentage of walker use in those with severe imbalance (grade 3) in the sagittal classification but not in the coronal classification. While postoperative radiographical improvements were noted, there was no significant difference in the use of walking aids before and 2 years after surgery (P = 0.085). CONCLUSION: A significant correlation was found between "sagittal" spinal imbalance and increased reliance on walking aids, particularly walkers. However, the limitation of improvement in postoperative mobility status suggested that multiple factors influence the mobility ability of elderly patients with ASD.

Longitudinal impact of multi-segment spinal fixation surgery on mobility status and clinical outcomes in adult spinal deformity: a multicenter retrospective study.

PURPOSE: To investigate changes in postoperative mobility status in patients with ASD, and the determining factors that influence these changes and their impact on clinical outcomes, including the rate of home discharge and long-term mobility. METHODS: A total of 299 patients with ASD who underwent multi-segment posterior spinal fusion were registered in a multi-center database were investigated. Patient mobility status was assessed using walking aids and classified into five levels (1: independent, 2: cane, 3: walker, 4: assisted, and 5: wheelchair) preoperatively, at discharge, and after 2 years. We determined improvements or declines in the patient's mobility based on changes in the classification levels. The analysis focused on the factors contributing to the deterioration of postoperative mobility. RESULTS: Two years postoperatively, 87% of patients maintained or improved mobility. However, 27% showed decreased mobility status at discharge, associated with a lower rate of home discharge (49% vs. 80% in the maintained mobility group) and limited improvement in mobility status (35% vs. 5%) after 2 years. Notably, postoperative increases in thoracic kyphosis (7.0 ± 12.1 vs. 2.0 ± 12.4°, p = 0.002) and lower lumbar lordosis (4.2 ± 13.1 vs. 1.8 ± 12.6°, p = 0.050) were substantial factors in mobility decline. CONCLUSION: Postoperative mobility often temporarily decreases but generally improves after 2 years. However, an overcorrection in sagittal alignment, evidenced by increased TK, could detrimentally affect patients' mobility status. Transient mobility decline associated with overcorrection may require further rehabilitation or hospitalization. Further studies are required to determine the biomechanical effects of surgical correction on mobility.

Preoperative low Hounsfield units in the lumbar spine are associated with postoperative mechanical complications in adult spinal deformity.

PURPOSE: To determine the most valid bone health parameter to predict mechanical complications (MCs) following surgery for adult spinal deformity (ASD). METHODS: This multicenter study retrospectively examined the records of patients who had undergone fusion of three or more motion segments, including the pelvis, with a minimum two-year follow-up period. Patients with moderate and severe global alignment and proportion scores were included in the study and divided into two groups: those who developed MCs and those who did not. Bone mineral density (BMD) of the lumbar spine and femoral neck was measured using dual-energy X-ray absorptiometry, and Hounsfield units (HUs) were measured in the lumbar spine on computed tomography. Radiographic parameters were evaluated preoperatively, immediately after surgery, and at final follow-up. RESULTS: Of 108 patients, 30 (27.8%) developed MCs, including 26 cases of proximal junctional kyphosis/failure, 2 of distal junctional failure, 6 of rod fracture, and 11 reoperations. HUs were significantly lower in patients who experienced MCs (113.7 ± 41.1) than in those who did not (137.0 ± 46.8; P = 0.02). BMD did not differ significantly between the two groups. The preoperative and two-year postoperative global tilt, as well as the immediately postoperative sagittal vertical axis, were significantly greater in patients who developed MCs than in those who did not (P = 0.02, P < 0.01, and P = 0.01, respectively). CONCLUSION: Patients who experienced MCs following surgery for ASD had lower HUs than those who did not. HUs may therefore be more useful than BMD for predicting MCs following surgery for ASD.

Adenosine triphosphate release inhibitors targeting pannexin1 improve recovery after spinal cord injury.

Traumatic spinal cord injury is characterized by immediate and irreversible tissue loss at the lesion site and secondary tissue damage. Secondary injuries should, in principle, be preventable, although no effective treatment options currently exist for patients with acute spinal cord injury. Traumatized tissues release excessive amounts of adenosine triphosphate and activate the P2X purinoceptor 7/pannexin1 complex, which is associated with secondary injury. We investigated the neuroprotective effects of the blue dye Brilliant Blue FCF, a selective inhibitor of P2X purinoceptor 7/pannexin1 that is approved for use as a food coloring, by comparing it with Brilliant Blue G, a P2X7 purinoceptor antagonist, and carbenoxolone, which attenuates P2X purinoceptor 7/pannexin1 function, in a rat spinal cord injury model. Brilliant Blue FCF administered early after spinal cord injury reduced spinal cord anatomical damage and improved motor recovery without apparent toxicity. Brilliant Blue G had the highest effect on this neurological recovery, with Brilliant Blue FCF and carbenoxolone having comparable improvement. Furthermore, Brilliant Blue FCF administration reduced local astrocytic and microglial activation and neutrophil infiltration, and no differences in these histological effects were observed between compounds. Thus, Brilliant Blue FCF protects spinal cord neurons after spinal cord injury and suppresses local inflammatory responses as well as Brilliant Blue G and carbenoxolone.

Ten-Year Follow-up of Posterior Decompression and Fusion Surgery for Thoracic Ossification of the Posterior Longitudinal Ligament.

BACKGROUND: We evaluated the clinical, functional, and quality of life (QoL) outcomes of surgical treatment of thoracic ossification of the posterior longitudinal ligament (T-OPLL). METHODS: We retrospectively evaluated 51 patients followed for ≥10 years after posterior decompression and corrective fusion surgery for T-OPLL. The data collected included demographics, comorbidities, and pre- and postoperative symptoms. The Japanese Orthopaedic Association (JOA) score, numerical rating scale (NRS) for back and leg pain, and EuroQol-5 Dimension-5 Level (EQ-5D-5L) were used to assess neurological function, pain, and QoL. Imaging evaluations were conducted to assess changes in kyphotic angles and ossification progression. RESULTS: A significant improvement was observed in the JOA score from preoperatively (3.7) to 2 years postoperatively (7.9) (p < 0.05); the score remained stable thereafter. The mean EQ-5D-5L score improved from 0.53 preoperatively to 0.68 at 10 years postoperatively (p < 0.001). NRS scores for back and leg pain decreased from 5.4 to 3.5 and 4.0 to 3.0, respectively, from preoperatively to 10 years (p < 0.001 for both). Radiographic outcomes showed changes in kyphotic angles and ossification areas, with no significant progression after 2 years. Fourteen (27.5%) of the patients experienced postoperative complications. Of these, 8 (15.7%) required reoperation, 6 (11.8%) in the perioperative period and 2 (3.9%) later. Four (7.8%) of the patients underwent additional surgeries for conditions including lumbar spinal canal stenosis and cervical OPLL. Nonetheless, physical function in all cases with postoperative complications or additional surgery remained stable over the decade. CONCLUSIONS: Surgical treatment of T-OPLL is effective in improving neurological function, QoL, and pain management over an extended period. The long-term outcomes of T-OPLL surgery revealed that, although cervical and lumbar spinal lesions led to reoperations, they did not affect QoL, and relative improvement was maintained even after 10 years. LEVEL OF EVIDENCE: Therapeutic Level IV . See Instructions for Authors for a complete description of levels of evidence.

Trabecular Bone Remodeling after Posterior Lumbar Interbody Fusion: Comparison of the Osseointegration in Three-Dimensional Porous Titanium Cages and Polyether-Ether-Ketone Cages.

STUDY DESIGN: Retrospective cohort study. OBJECTIVES: Imaging changes in the vertebral body after posterior lumbar interbody fusion (PLIF) are determined to be trabecular bone remodeling (TBR). This study aimed to investigate the influence of cage materials on TBR and segment stabilization in PLIF by studying image changes. METHODS: This was a retrospective study reviewing 101 cases who underwent one-level PLIF with three-dimensional porous titanium (3DTi) cages (53 patients) or polyether-ether-ketone (PEEK) cages (48 patients). Computed tomography images obtained 3 months, 1 year, and 2 years postoperatively were examined for TBR, vertebral endplate cyst formation as an instability sign, cage subsidence, and clear zone around pedicle screw (CZPS). RESULTS: No significant differences in the TBR-positivity rates were observed between the two cages at 3 months, 1 year, and 2 years postoperatively. However, all 3DTi cage segments that were TBR-positive at 3 months postoperatively showed no CZPS and fewer final instability segments than the TBR-negative segments (0% vs 9%). In contrast, although the PEEK cage segments that were TBR-positive at 3 months postoperatively were not associated with future segmental stabilization, those that were TBR-positive at 1 year postoperatively had fewer final instability segments than the TBR-negative segments (0% vs 33%). CONCLUSIONS: The 3DTi cage segments with TBR 3 months postoperatively showed significant final segmental stabilization, whereas TBR at 1 year rather than 3 months postoperatively was useful in determining final segmental stabilization for the PEEK cage segments. The timing of TBR, a new osseointegration assessment, were associated with the cage material.

Do Postural and Walking Stabilities Change over a Decade by Aging? A Longitudinal Study.

BACKGROUND: Previous studies have demonstrated that the center of gravity (COG) is more unstable in the elderly than in young people. However, it is unclear whether aging itself destabilizes the COG. This study aimed to investigate changes in COG sway and gait kinematics over time by a longitudinal study of middle-aged and elderly adults. METHODS: This study included 198 healthy middle-aged and elderly people who underwent stabilometry at ten-year intervals. The participants' mean age at baseline was 62.9 ± 6.5 years, and 77 (39%) of them were male. The results of stabilometry (mean velocity, sway area, postural sway center in the medial-lateral direction [X center], and postural sway center in the anterior-posterior direction [Y center]), and results of exercise tests (the height-adjusted maximum stride length [HMSL] and the 10 m walk test [10MWT]) were analyzed. The destabilized group with 11 participants, whose mean velocity exceeded 3 cm/s after 10 years, was compared with the stable group with 187 participants, whose mean velocity did not exceed 3 cm/s. RESULTS: Mean velocity increased significantly over ten years (open-eye, from 1.53 ± 0.42 cm to 1.86 ± 0.67 cm, p < 0.001); however, the sway area did not change significantly. X center showed no significant change, whereas Y center showed a significant negative shift (open-eye, from -1.03 ± 1.28 cm to -1.60 ± 1.56 cm, p < 0.001). Although the results of 10MWT and initial HMSL did not differ significantly, the HMSL in the destabilized group at ten years was 0.64, which was significantly smaller than the 0.72 of others (p = 0.019). CONCLUSIONS: The ten-year changes in COG sway in middle-aged and elderly adults were characterized by a significant increase in mean velocity but no significant difference in sway area. Because the destabilized group had significantly smaller HMSL at ten years, instability at the onset of movement is likely to be affected by COG instability.

Obesity Is Associated with Asymptomatic Vertebral Fractures: A Yakumo Study.

(1) Background: Patients with primary vertebral fracture (VF) are at high risk of re-fracture and mortality. However, approximately two-thirds of patients with VFs receive minimal clinical attention. (2) Methods: The current study aimed to investigate the factors associated with asymptomatic VFs in middle-aged and elderly individuals who underwent resident health examinations. (3) Results: The current study included 217 participants aged > 50 years. VFs were diagnosed based on lateral radiographic images using Genant's semiquantitative (SQ) method. The participants were divided into non-VF (N; SQ grade 0) and asymptomatic VF (F; SQ grades 1-3) groups. Data on body composition, blood tests, quality of life measures, and radiographic parameters were assessed. A total of 195 participants were included in the N group (mean age, 64.8 ± 7.8 years), and 22 were in the F group (mean age, 66.1 ± 7.9 years). The F group had a significantly higher body mass index (BMI), body fat percentage (BF%), and proportion of patients with knee osteoarthritis (KOA) than the N group. The F group had a significantly higher knee joint pain visual analog scale (VAS) score and painDETECT score than the N group. Logistic regression analysis showed that BF% was associated with asymptomatic VFs. (4) Conclusions: Middle-aged and elderly individuals with asymptomatic VF presented with high BMIs, BF%, and incidence of KOA.

Automated Detection and Diagnosis of Spinal Schwannomas and Meningiomas Using Deep Learning and Magnetic Resonance Imaging.

Spinal cord tumors are infrequently identified spinal diseases that are often difficult to diagnose even with magnetic resonance imaging (MRI) findings. To minimize the probability of overlooking these tumors and improve diagnostic accuracy, an automatic diagnostic system is needed. We aimed to develop an automated system for detecting and diagnosing spinal schwannomas and meningiomas based on deep learning using You Only Look Once (YOLO) version 4 and MRI. In this retrospective diagnostic accuracy study, the data of 50 patients with spinal schwannomas, 45 patients with meningiomas, and 100 control cases were reviewed, respectively. Sagittal T1-weighted (T1W) and T2-weighted (T2W) images were used for object detection, classification, training, and validation. The object detection and diagnosis system was developed using YOLO version 4. The accuracies of the proposed object detections based on T1W, T2W, and T1W + T2W images were 84.8%, 90.3%, and 93.8%, respectively. The accuracies of the object detection for two spine surgeons were 88.9% and 90.1%, respectively. The accuracies of the proposed diagnoses based on T1W, T2W, and T1W + T2W images were 76.4%, 83.3%, and 84.1%, respectively. The accuracies of the diagnosis for two spine surgeons were 77.4% and 76.1%, respectively. We demonstrated an accurate, automated detection and diagnosis of spinal schwannomas and meningiomas using the developed deep learning-based method based on MRI. This system could be valuable in supporting radiological diagnosis of spinal schwannomas and meningioma, with a potential of reducing the radiologist's overall workload.

Automated Detection of the Thoracic Ossification of the Posterior Longitudinal Ligament Using Deep Learning and Plain Radiographs.

Ossification of the ligaments progresses slowly in the initial stages, and most patients are unaware of the disease until obvious myelopathy symptoms appear. Consequently, treatment and clinical outcomes are not satisfactory. This study is aimed at developing an automated system for the detection of the thoracic ossification of the posterior longitudinal ligament (OPLL) using deep learning and plain radiography. We retrospectively reviewed the data of 146 patients with thoracic OPLL and 150 control cases without thoracic OPLL. Plain lateral thoracic radiographs were used for object detection, training, and validation. Thereafter, an object detection system was developed, and its accuracy was calculated. The performance of the proposed system was compared with that of two spine surgeons. The accuracy of the proposed object detection model based on plain lateral thoracic radiographs was 83.4%, whereas the accuracies of spine surgeons 1 and 2 were 80.4% and 77.4%, respectively. Our findings indicate that our automated system, which uses a deep learning-based method based on plain radiographs, can accurately detect thoracic OPLL. This system has the potential to improve the diagnostic accuracy of thoracic OPLL.