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.

Neurologic recovery following laminectomy and tumor resection of a pediatric cervical synovial osteochondromatosis causing paralysis.

PURPOSE: To report the surgical outcome of synovial osteochondromatosis, a rare tumor of the cervical spine, in a 6-year-old boy. METHODS: A 6-year-old boy presented with muscle weakness in the right deltoid (2) and biceps (4) during a manual muscle test. Magnetic resonance imaging showed a 3 × 2 × 1.5 cm mass within the spinal canal at the C4-6 level, compressing the cervical spinal cord from the right side. Computed tomography revealed hyperintense areas within the tumor and ballooning of the right C4-5 and C5-6 facet joints. RESULTS: After a biopsy confirmed the absence of malignancy, a gross total resection was performed. The pathological diagnosis of synovial osteochondromatosis was established. Postoperatively, muscle weakness improved fully in the manual muscle test, and there were no neurological findings after 3 months. However, the patient is under careful follow-up owing to the detection of a regrowth site within the right C4-5 and C5-6 intervertebral foramen 2 years postoperatively. CONCLUSIONS: Synovial osteochondromatosis of the cervical spine in children is rare, and this is the first report of its regrowth after surgery. Synovial osteochondromatosis should be included in the differential diagnosis of pediatric cervical spine tumors.

Reduction of sleep bruxism events according to contingent electrical stimulus intensity.

BACKGROUND: Although biofeedback with contingent electrical stimulation (CES) has demonstrated the reduction effect on sleep bruxism (SB), the relationship between the actual applied CES intensity and efficacy remains uncertain. OBJECTIVE: This study aimed to investigate whether the reduction of bruxism events and jaw muscle symptoms could vary according to the intensity of CES and in probable sleep bruxers. METHODS: Twenty probable sleep bruxers were initially screened for bruxer confirmation based on a 2-week recording of SB events with a portable electromyography recorder (BUTLER®GrindCare®, GC4). A 3-week recording was conducted without CES using a GC4, followed by another 3-week recording with CES. At baseline and before and after the CES (+) session, clinical muscle symptoms were assessed using a 0-10 numerical rating scale (NRS). The relationships between the actual applied CES intensity and the number of SB events/hour, as well as the NRS of clinical muscle symptoms, were analysed. RESULTS: The actual applied CES intensity was positively correlated with the reduction rate of the number of SB events/hour (R = .643, p = .002), as well as with the reduction rate of NRS for pain, unpleasantness, fatigue, tension and stiffness (R > .500, p < .011). CONCLUSION: Higher CES elicited a more robust reduction in SB events and clinical muscle symptoms, in probable bruxers. Prior to selecting CES biofeedback as a management option for SB, it would be beneficial to assess the tolerance threshold of CES in each bruxer in order to predict the effectiveness of CES in probable sleep bruxers.

Metabolic syndrome reduces spinal range of motion: The Yakumo study.

BACKGROUND: Excess visceral fat can accumulate owing to lack of exercise. The relationship between metabolic syndrome (MetS) and spinal range of motion (ROM) is not clear. The purpose of this study was to investigate the relationship between MetS and spinal alignment and ROM. METHODS: Orthopedic evaluation was prospectively performed in 544 participants. The participants were classified into two groups on the basis of the Japanese-specific MetS criteria proposed by the Japanese Committee of the Criteria for MetS (JCCMS). Lower back pain (LBP), knee joint pain with the visual analog scale (VAS), Kellgren-Lawrence (K-L) grade for knee osteoarthritis, body mass index (BMI), and spinal alignment and ROM were evaluated. RESULTS: Forty-four (8.1%) were diagnosed as having MetS. The prevalence rate of K-L grade 4 in the MetS group was significantly higher than that in the non-MetS group (p < 0.05). When sex, age, and BMI were evaluated as covariates, there were significant differences in the VAS score for knee pain (non-MetS group vs MetS group: 13.7 vs 23.3, p < 0.05), L1-S1 flexion spinal ROM (44.1° vs 38.1°, p < 0.001), flexion spinal inclination angle (SIA) ROM (107.6° vs 99.3°, p < 0.01), and SIA ROM (135.4° vs 124.0°, p < 0.05). CONCLUSIONS: Knee pain increased and flexion spinal ROM decreased significantly in the MetS group as compared with non-MetS group. Systemic factors associated with MetS may have a specific impact on spinal ROM while promoting knee osteoarthrosis and increased knee pain.

Evaluation of masticatory performance by motion capture analysis of jaw movement.

BACKGROUND: The assessment of masticatory performance (MP) is conducted in hospitals, but is difficult to perform in nursing facilities that lack specialists in dysphagia. To select the appropriate food textures in nursing practice, a simple method of evaluating the MP should be developed. OBJECTIVE: The purpose of this study was to investigate motion parameters that influence MP by motion capture analysis of maxillofacial movement on chewing gummy jelly in healthy adults. METHODS: The subjects were 50 healthy adults. The state of chewing gummy jelly was photographed using a high-speed camera. Simultaneously, we evaluated the amount of glucose extracted (AGE) obtained with gummy jelly as a reference value for MP. The subjects were divided into two groups: normal and low masticatory groups (NG and LG, respectively) based on the AGE. The cycle of mastication was classified into three phases: closing phase (CP), transition phase (TP) and opening phase (OP) through motion capture analysis of the video photographed. Parameters of jaw movement and their associations with the AGE were examined. RESULTS: The transition phase rate (TR) and opening phase rate (OR) were correlated with the AGE. Furthermore, the TR in the NG was significantly higher than in the LG, whereas the OR was significantly lower than in the LG. The age, TR and opening velocity were significant independent variables. CONCLUSION: Motion capture technology facilitated the analysis of jaw movement. The results suggested that MP can be evaluated by analysing the TP and OP rates.

Effect of ageing and tooth loss on sensory function of alveolar mucosa.

BACKGROUND: Maintaining quality of life of elderly denture wearers is one of the most crucial tasks for dentists in the super-aged society. Although external mechanical load on removable dentures has been investigated to minimise a risk of soreness caused by dentures, sensory perception of the alveolar mucosa remains obscure. OBJECTIVES: This study aimed to investigate effect of ageing and tooth loss in sensory function on the alveolar mucosa for deep understanding of the characteristics of pain sensitivity in edentulous individuals. METHODS: Eighteen edentulous participants (ED), as well as 18 age-matched dentate participants (EC) and 18 young dentate participants (YC), participated in this study. Tactile detection threshold (TDT) and pain threshold (PT) were measured with von Frey filaments (0.125-512 mN). Mechanical pain sensitivity (MPS) after a 2-sec application of 1 kg palpation was assessed with a 0-50-100 Numerical Rating Scale (NRS) (0: no pain, 50: slight pain and 100: the worst pain imaginable). Furthermore, entropy scores of TDT, PT and NRS on MPS were calculated. RESULTS: In both maxilla and mandible, EC showed significantly higher TDT and PT, compared with YC, whereas ED showed significantly lower TDT and PT, compared with EC. NRS on MPS in ED was significantly higher than that in EC. The entropy scores of all the outcome parameters showed no significant difference between groups. CONCLUSION: Both ageing and tooth loss can alter tactile and pain perception in the oral mucosa. This suggests that it might be beneficial to assess sensory function of the alveolar mucosa in edentulous patients clinically in prior to denture fabrication.

Primary cervical decompression surgery may improve lumbar symptoms in patients with tandem spinal stenosis.

PURPOSE: Tandem spinal stenosis (TSS) refers to coexisting lumbar and cervical canal stenosis. Evidence regarding whether cervical decompression improves lumbar symptoms in TSS is insufficient. Therefore, we determined the effectiveness of cervical decompression surgery for patients with lumbar spinal stenosis (LSS) and cervical spinal stenosis. METHODS: The records of 64 patients with TSS experiencing lumbar symptoms who underwent cervical decompression surgery between April 2013 and July 2017 at a single institution were retrospectively reviewed. We categorized patients into the Non-improved (n = 20), Relapsed (n = 30), and Maintained-improvement (n = 14) groups according to the presence or absence of improvement and relapse in lower limb symptoms in TSS following cervical decompression surgeries. RESULTS: Of 64 patients, 44 (69%) showed improved lower limb or low back symptoms, with 14 (22%) patients maintaining improvement. The preoperative cervical myelopathy-Japanese Orthopedic Association score and the preoperative number of steps determined using the 10-s step test were significantly lower in the Non-improved group than in the Maintained-improvement group. Receiver operating characteristic curve of preoperative 10-s step test results revealed 12 steps as a predictor for maintained improvement. CONCLUSION: The improvement of LSS symptoms following cervical decompression surgeries may be associated with the severity of cervical myelopathy as determined in clinical findings rather than in imaging findings. Patients with TSS having a 10-s step test result of < 12 steps were more likely to experience a relapse of lower limb symptoms following cervical decompression surgeries.

Overcoming locomotive syndrome: The Yakumo Study.

OBJECTIVES: Improvement of life expectancy is increasingly important with the aging of society. The aim of the study was to compare physical performance in elderly people in two 3-year periods (2001-2003) and (2016-2018). METHODS: The participants were healthy Japanese elderly adults who attended public health check-ups in Yakumo. Results for 10 m gait time, two-step test, back muscle strength, and grip strength were examined prospectively for participants in 2001-2003 (Group A: n = 488) and 2016-2018 (Group B: n = 309) by gender and age (65-74 and 75-84 years). RESULTS: There were significant differences between Groups A and B for 10 m gait time (age 65-74: male: 5.6 vs. 5.2 s, female: 6.3 vs. 5.5 s; age 75-84: male: 6.1 vs. 5.5 s, female: 6.7 vs. 5.8 s; all p < .05) and two-step test (age 65-74: male: 1.41 vs. 1.48, female: 1.35 vs. 1.44; age 75-84: male: 1.32 vs. 1.41, female: 1.30 vs. 1.38; all p < .05), but not for back muscle strength or grip strength. CONCLUSION: Our results suggest a phenomenon of 'overcoming locomotive syndrome', in which physical performance changed by aging, including motor functions such as 10 m gait time and two-step test, has improved in the current population compared with a similar population from 15 years ago.

Impact of pelvic incidence on lumbar osteophyte formation and disc degeneration in middle-aged and elderly people in a prospective cross-sectional cohort.

PURPOSE: Pelvic incidence (PI) is unique to each individual and does not change throughout life. High PI is related to lumbar spondylolisthesis, but associations of PI with lumbar osteophyte formation and disc degeneration are unclear. The objective was to evaluate relationships of PI with lumbar osteophyte formation and disc degeneration, as well as spinal sagittal alignment and geriatric diseases, in middle-aged and elderly people. METHODS: A total of 1002 volunteers (male: 434, female: 568, average age: 63.5) were prospectively examined for lumbar osteophyte formation (Nathan class ≥ 2) and disc degeneration (disc score ≥ 3). High (PI > 51, n = 501) and low (PI ≤ 51, n = 501) PI groups were defined. Clinical factors, frailty, sarcopenia, and physical quality of life (QOL) were compared between these groups, and risk factors for lumbar osteophyte formation and disc degeneration were identified in multivariate logistic regression analysis. RESULTS: Physical QOL was poorer in people with lumbar osteophyte formation (54.8%) and disc degeneration (33.6%). Age, male gender, spinal parameters including PI, bone mineral density, back muscle strength, and gait ability differed significantly between the groups, whereas frailty and sarcopenia were not significantly different. Low PI, low lumbar lordosis, elder age, male gender, high BMI, and weak back muscle strength were significant risk factors for lumbar osteophyte formation and disc degeneration. CONCLUSIONS: Low PI was identified as a risk factor for lumbar osteophyte formation and disc degeneration, both of which reduce physical QOL in middle-aged and elderly people. These slides can be retrieved under Electronic Supplementary Material.

Age-related changes in upper and lower cervical alignment and range of motion: normative data of 600 asymptomatic individuals.

PURPOSE: To identify age-related changes and the relationship between upper and lower cervical sagittal alignment and the range of motion (ROM). METHODS: A total of 600 asymptomatic volunteers were enrolled. There were 50 males and 50 females in each decade of life between the third and the eighth. The O-C2 angle and the C2-7 angle were measured using the neutral radiographs of the cervical spine. ROM was assessed by measuring the difference in alignment in the neutral, flexion, and extension positions. RESULTS: The mean O-C2 angle in the neutral position was 14.0° lordotic. The mean ROM of the O-C2 angle was 23.1°. The mean C2-7 angle in the neutral position was 14.3° lordotic. The mean ROM of the C2-7 angle was 56.0°. The O-C2 angle was 16.1° in the third decade and gradually decreased to 11.4° in the eighth decade. There were no significant age-related changes in the ROM of the O-C2 angle. The C2-7 angle was 7.2° in the third decade and gradually increased to 20.8° in the eighth decade, and the ROM gradually decreased with increasing age. Significant negative correlation was observed between O-C2 angle and C2-7 angle. CONCLUSION: The O-C2 angle gradually decreased and the C2-7 angle increased with age. The ROM of the O-C2 angle did not change, but the ROM of the C2-7 angle decreased with age. The upper and lower cervical spine showed different age-related changes.

Relationship between lumbopelvic discordance and locomotive syndrome in a middle-aged community-living population: The Yakumo study.

BACKGROUND: Locomotive syndrome (LS) affects the quality and activities of daily living. Although spinal sagittal balance influences LS, no report elucidated the relationship between LS risk and lumbopelvic discordance. This study aimed to investigate the relationship between lumbopelvic discordance and LS in a middle-aged community. METHODS: The subjects (n = 135) were divided into three groups based on the LS risk stage, which was evaluated through spinopelvic sagittal alignment and lumbopelvic mismatch prevalence (Pelvic incidence-Lumbar lordosis >10°:PI-LL mismatch).Then, the subjects were divided into two groups (lumbopelvic matched and mismatched groups) and analyzed based on the demographic data, physical test, stabilometry, and body pain using the visual analog scale. RESULTS: There were 76, 37 and 22 subjects in stages 0, 1, and 2, respectively. The pelvic incidence-lumbar lordosis (PI-LL) mismatched group had a higher prevalence in LS risk stage 2 than in LS risk stage 0. The prevalence of PI-LL mismatch was significantly different among the groups. Post hoc test revealed the differences in spinopelvic alignment among the stages. In each LS risk stage, the degree of PI-LL was significantly higher in stage 2 than that in stages 0 and 1. On comparing the PI-LL matched (n = 67) and mismatched groups (n = 68) with a stabilometer, the envelopment area tracing by the movement of the center of pressure and locus length/second was greater in the PI-LL mismatched group than that in the PI-LL matched group with/without eyes opened. CONCLUSIONS: The prevalence of LS risk stage 2 was more frequently observed in the PI-LL mismatched group. The degree of PI-LL was evaluated through the LS risk stages. Physical dysfunction in the PI-LL mismatched group was related to trunk imbalance based on stabilometry. These findings will help manage LS and PI-LL mismatched subjects.

The relationship between sarcopenia and oral sarcopenia in elderly people.

BACKGROUND: Sarcopenia in the oral region, including the tongue, leads to declined swallowing function and dysphagia. Muscle mass and strength, and motor function in the oral region have not been examined together, and the relationship between generalised and oral sarcopenia remains unclear. OBJECTIVE(S): The purpose of this study is to clarify the relationship between generalised sarcopenia and oral sarcopenia in the elderly in order to facilitate the establishment of a method for assessing oral sarcopenia. METHODS: A total of 54 elderly persons participated in this study. We examined the skeletal muscle mass index (SMI), grip strength (GS) and walking speed (WS) as the index of generalised sarcopenia, and the cross-sectional area of the geniohyoid muscle (CSG), tongue pressure (TP) and oral diadochokinesis (ODK) as the index of oral sarcopenia. RESULTS: We found a moderate correlation between CSG and SMI, a weak correlation between GS and TP, and a moderate correlation between WS and ODK. CSG, TP and ODK were significantly smaller in the sarcopenia group than in the non-sarcopenia group. By multiple regression analysis, SMI and TP were significantly associated with CSG. ODK, BMI and CSG were significantly associated with TP. WS and SMI were significantly associated with ODK. CONCLUSION: CSG, TP and ODK were confirmed as endpoints of oral sarcopenia. All endpoints of oral sarcopenia were influenced by those of generalised sarcopenia.

Functional computed tomography scanning for evaluating fusion status after anterior cervical decompression fusion.

INTRODUCTION: Nonunion is a major complication of anterior cervical fusion that causes poor outcomes and occasionally requires additional operative intervention. The purpose of this study is to evaluate the accuracy of functional computed tomography (CT) scanning for determining fusion status after anterior cervical fusion by comparing with functional radiographs. MATERIALS AND METHODS: The fusion status in 59 patients treated by anterior cervical fusion was assessed by functional radiography and functional CT scanning at 6 and 12 months after surgery. Fusion rates and clinical symptoms were evaluated. Fusion on functional radiography was defined as less than 2 mm of motion between adjacent spinous processes and a particular bony trabeculation on functional CT; fusion was defined as nonexistence of a clear zone or a gas pattern and a particular bone connection on reconstructed sagittal-view images. RESULTS: Functional radiographs demonstrated solid fusion in 83.9% at 6 months and 91.1% at 12 months postoperatively; functional CT showed solid fusion in 55.3 and 78.6%, respectively. The fusion rate detected on functional CT images was significantly lower than that on functional radiographs at each period. At 6 months postoperatively, patients with incomplete union on functional CT were more likely to have neck pain than those who had complete union on functional CT. (46.2 vs 13.3%, P < 0.05) CONCLUSION: Functional CT can detect nonunion more clearly than functional radiography. At 6 months postoperatively, patients with incomplete union on functional CT images were likely to have more neck pain. Functional CT may allow accurate detection of symptomatic nonunion after anterior cervical fusion.

Treatment outcomes of intradiscal steroid injection/selective nerve root block for 161 patients with cervical radiculopathy.

Patients with cervical radiculopathy (CR) were treated with intradiscal injection of steroids (IDIS) and/or selective nerve root block (SNRB) at our hospital. We retrospectively report the outcomes of these nonsurgical treatments for CR. 161 patients who were followed up for >2months were enrolled in this study. Patients' clinical manifestations were classified as arm pain, arm numbness, neck and/or scapular pain, and arm paralysis. Improvement in each manifestation was classified as "disappeared," "improved," "poor," or "worsened." Responses of "disappeared" or "improved" manifestations suggested treatment effectiveness. Final clinical outcomes were evaluated using the Odom criteria. Changes in herniated disc size were evaluated by comparing the initial and final MRI scans. On the basis of these changes, the patients were divided into regression, no-change, or progression groups. We investigated the relationship between the Odom criteria and changes observed on MRI. Effectiveness rates were 89% for arm pain, 77% for arm numbness, 82% for neck and/or scapular pain, and 76% for arm paralysis. In total, 91 patients underwent repeated MRI. In 56 patients (62%), the size of the herniated disc decreased, but 31 patients (34%) exhibited no change in disc size. The regression group showed significantly better Odom criteria results than the no-change group. In conclusion, IDIS and SNRB for CR are not widely performed. However, other extremely effective therapies that can rapidly improve neuralgia should be considered before surgery.

Calcitriol ameliorates motor deficits and prolongs survival of Chrne-deficient mouse, a model for congenital myasthenic syndrome, by inducing Rspo2.

Signal transduction at the neuromuscular junction (NMJ) is compromised in a diverse array of diseases including congenital myasthenic syndromes (CMS). Germline mutations in CHRNE encoding the acetylcholine receptor (AChR) ε subunit are the most common cause of CMS. An active form of vitamin D, calcitriol, binds to vitamin D receptor (VDR) and regulates gene expressions. We found that calcitriol enhanced MuSK phosphorylation, AChR clustering, and myotube twitching in co-cultured C2C12 myotubes and NSC34 motor neurons. RNA-seq analysis of co-cultured cells showed that calcitriol increased the expressions of Rspo2, Rapsn, and Dusp6. ChIP-seq of VDR revealed that VDR binds to a region approximately 15 â€‹kbp upstream to Rspo2. Biallelic deletion of the VDR-binding site of Rspo2 by CRISPR/Cas9 in C2C12 myoblasts/myotubes nullified the calcitriol-mediated induction of Rspo2 expression and MuSK phosphorylation. We generated Chrne knockout (Chrne KO) mouse by CRISPR/Cas9. Intraperitoneal administration of calcitriol markedly increased the number of AChR clusters, as well as the area, the intensity, and the number of synaptophysin-positive synaptic vesicles, in Chrne KO mice. In addition, calcitriol ameliorated motor deficits and prolonged survival of Chrne KO mice. In the skeletal muscle, calcitriol increased the gene expressions of Rspo2, Rapsn, and Dusp6. We propose that calcitriol is a potential therapeutic agent for CMS and other diseases with defective neuromuscular signal transmission.

Successful endoscopic submucosal dissection of colorectal lipoma with an overlying adenoma.

We report the case of a 65-year-old woman whose colonoscopy revealed a soft submucosal tumor approximately 7 cm in diameter in the ascending colon with an overlying flat lesion. The tumor was diagnosed as a lipoma with an overlying adenoma. Endoscopic submucosal dissection (ESD) was performed. Pathological examination revealed that the epithelium was a low-grade tubulovillous adenoma, while the submucosal yellow tumor was a lipoma. ESD appears to be a safe and effective treatment for colorectal lipomas overlying lipomas with colorectal adenomas.