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.

＜Editors' Choice＞ Neck pain after cervical laminoplasty is associated with postoperative atrophy of the trapezius muscle.

Cervical laminoplasty is a safe and effective treatment for cervical myelopathy. However, it has a higher frequency of postoperative axial pain than other methods. A variety of causes of postoperative axial pain have been reported, but these have not been fully elucidated. This study aimed to investigate the association between postoperative axial pain and changes in the posterior neck muscles before and after surgery. The study included 93 patients with cervical myelopathy who underwent surgery at our institute between June 2010 and March 2013. The patients with greater preoperative and 1-year postoperative neck pain visual analog scale scores comprised the neck pain group. The cross-sectional area of the cervical posterior extensor muscles and the trapezius muscle were measured by magnetic resonance imaging before and 1 year after surgery at the C3/4, C4/5, and C5/6 levels to compare with neck pain. The total cross-sectional area atrophy rate (C3/C4, C4/C5, and C5/C6) of the trapezius muscle was significantly larger in patients with neck pain (12.8 ± 13.2) than in those without (6.2 ± 14.4; p<0.05). The cross-sectional area atrophy rate of the trapezius muscle at only the C5/6 level was significantly higher in patients with neck pain (16.7 ± 11.7) compared to those without (3.3 ± 14.4; p<0.001). No significant differences were found in the cross-sectional areas of the cervical posterior extensor muscles. Trapezius atrophy, especially at the lower cervical vertebrae, was associated with neck pain after cervical laminoplasty.

Association between Postoperative Neck Pain and Intraoperative Transcranial Motor-Evoked Potential Waveforms of the Trapezius Muscles in Patients with Cervical Myelopathy Who Underwent Cervical Laminoplasty.

STUDY DESIGN: Retrospective study. PURPOSE: Cervical laminoplasty is safe and effective for treating cervical myelopathy but has a higher frequency of postoperative axial pain compared to other methods. Several studies have reported on the causes of postoperative axial pain, but none have fully elucidated them. This study aimed to investigate the association between postoperative neck pain and intraoperative transcranial motor-evoked potential (MEP) waveforms of the trapezius muscles using transcranial MEPs. OVERVIEW OF LITERATURE: Few studies have investigated the association between postoperative neck pain and intraoperative transcranial MEP waveforms of the trapezius muscles in patients with cervical laminoplasty. METHODS: A total of 79 patients with cervical myelopathy who underwent cervical laminoplasty at our facility between June 2010 and March 2013 were included in this study. Intraoperative control and final waveform were evaluated based on the trapezius muscle MEPs by measuring the latency and amplitude. A neck pain group comprised patients with higher neck pain Visual Analog Scale scores from preoperative value to 1 year postoperatively. The cross-sectional areas of the trapezius muscles and the MEP latencies and amplitudes were compared between patients with and without neck pain. RESULTS: The latency and amplitude of the control waveforms were not significantly different between groups. The neck pain group had a significantly shorter final waveform latency (neck pain: 23.6±2.5, no neck pain: 25.8±4.5; p =0.019) and significantly larger amplitude (neck pain: 2,125±1,077, no neck pain: 1,630±966; p =0.041) than the no neck pain group. CONCLUSIONS: Postoperative neck pain was associated with the final waveform latency and amplitude of the trapezius muscle MEPs during cervical laminoplasty. Intraoperative electrophysiological trapezius muscle abnormalities could cause postoperative neck pain.

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.

Spinopelvic Imbalance Is Associated With Increased Sway in the Center of Gravity: Validation of the "Cone of Economy" Concept in Healthy Subjects.

STUDY DESIGN: Cross-sectional study. OBJECTIVES: To investigate the effects of pelvic compensation on standing balance in healthy volunteers. METHODS: The 180 healthy volunteers were recruited at a basic health checkup. The inclusion criteria were: 1) age ≥ 65 years, 2) underwent a whole spine radiograph and stabilometry, 3) well-balanced standing posture with a sagittal vertical axis <50 mm, and 4) a visual analog scale of lower back pain of <20 mm. Based on the pelvic incidence (PI) and lumbar lordosis (LL) mismatch, subjects were divided into harmonious (PI-LL ≤ 10°) or unharmonious (PI-LL > 10°) groups. RESULTS: Participants in the unharmonious group were significantly older compared with the harmonious group (70.2 ± 4.4 vs. 72.0 ± 4.6 years, P < .01). The PI minus LL values were -2.2° ± 7.5° and 16.6° ± 7.0° in the harmonious and unharmonious groups, respectively (P < .001). Anteroposterior LNG/TIME (average center of pressure sway speed) was significantly greater in the unharmonious group with both open and closed eyes (1.04 ± 0.38 cm/s vs. 1.25 ± 0.47 cm/s, P < .001 and 1.22 ± 0.54 cm/s vs. 1.58 ± 0.77 cm/s, P < .001, respectively). Lateral LNG/TIME was significantly greater in the unharmonious group only with closed eyes (1.24 ± 0.54 cm/s vs. 1.47 ± 0.79 cm/s, P = .03). CONCLUSIONS: Healthy elderly subjects with poor spinopelvic harmony had relatively unstable standing balance. The "cone of economy" was demonstrated, showing that unharmonious spinopelvic balance had a non-economic effect on standing.

Surgical outcomes in instrumented surgery for dumbbell type spinal cord tumor -the comparison with non-instrumented surgery for spinal cord tumor.

BACKGROUND: There is little information on outcomes for spinal cord tumor treated surgically with instrumentation. Analysis of surgical outcomes and complications in such cases is needed to develop generalizable conclusions and to help inform patients. METHODS: The subjects were 41 patients treated with instrumentation surgery for dumbbell type tumor resection. Demographic data; tumor histology, level, and location; number of fused vertebra; use of a bilateral or hemilateral screw; operative time; EBL; TcMEP monitoring; lumbar subarachnoid drainage; duration of subfascial drainage; postoperative motor and sensory deficits; CSF leakage, implant-related complications; time for union of fused vertebra; salvage surgeries, and pre-/postoperative McCormick scale were obtained from medical records. Significant factors related to postoperative motor deficits were identified. RESULTS: Postoperative motor deficit occurred in 9 cases (22.0%) and all recovered in 30 days after surgery. CSF leakage at 7 days and 2 years after surgery was subfascial (n = 31, n = 6) and subcutaneous (n = 3, n = 4). Cases with postoperative motor deficits more commonly had lower cervical lesions; those with CSF leakage had longer operative times; and those with delayed union had more use of hemilateral instrumentation. CONCLUSION: In this study in 41 spinal cord tumors treated surgically with instrumentation, the rate of postoperative motor deterioration was 22.0%, and CSF leakage was found in 17.1%.

Laterality of lumbar disc herniation.

BACKGROUND: Lumbar disc herniation (LDH) is most common in men aged 20-40 at the L4/5 level; however, left-right differences have not been reported. Improving our understanding of left- and right-side LDH may facilitate the estimation of mechanical load on intervertebral discs. Here, we assessed left-right differences in LDH via a retrospective analysis of LDH cases. METHODS: Among 10,972 surgical cases of LDH identified in the Nagoya Spine Group database, 2899 in which right- and left-LDH sides were observable in a single vertebral segment were identified (mean age 46.3 ± 16.6 years, 2028 males). The following characteristics of patients with right- and left-LDH were compared: age, LDH level, surgical technique, operative time, blood loss, length of hospital stay, preoperative Japan Orthopaedic Association (JOA) score, and JOA recovery rate. RESULTS: LDH occurred on the right and left sides in 1358 and 1541 patients, respectively, with patients with right-side LDH significantly older than those with left (47.9 ± 16.6 versus 45.0 ± 16.5, respectively; p < 0.001). No between-group differences in sex, age, LDH level, surgical technique, operative time, blood loss, length of hospital stay, preoperative JOA score, or JOA recovery rate were observed. The occurrence of right-side LDH increased with age, occurring in 42.7%, 45.1%, 49.9%, and 54.7% of patients aged 10-29, 30-49, 50-69, and 70-89 years, respectively. CONCLUSION: Left-side LDH was observed more frequently than right; however, right-side LDH incidence increased with age. No significant between-group differences regarding symptoms, treatments, or outcomes were observed.

Paraplegia due to spinal epidural lipoma without spinal dysraphism in an adolescent patient: a case report.

We report the case of a rare lipoma arising in the epidural space of a 14-year-old boy without spinal dysraphism. Lipomas are rare in pediatric soft tissue tumors, accounting for only about 4% of cases. The incidence of an intraspinal epidural lipoma without spinal dysraphism is extremely rare in pediatric patients. In this case, the patient had progressive motor deficits in the lower extremities and difficulty in urination and defecation. Magnetic resonance imaging showed an extradural tumor compressing the spinal cord at the T3-T7 level. Because of the progressive neurological deficits, we performed an emergency surgery. The tumor was completely resected en bloc, and histopathology revealed mature adipose tissue with fibrous septa, diagnosed as atypical lipomatous tumor / well-differentiated liposarcoma. The patient fully recovered and there was no tumor recurrence for 6 years since the surgery. However, re-examination using fluorescence in situ hybridization after 6 years of surgery changed the diagnosis to lipoma as no amplification of murine double-minute type 2 oncogene was observed. In liposarcoma, histopathological diagnosis using fluorescence in situ hybridization is mandatory. Our case illustrates that immunohistochemical diagnosis alone can be misleading. Hence, prompt surgery is required for progressive neuropathy.

Patient factors influencing a delay in diagnosis in pediatric spinal cord tumors.

The diagnosis of pediatric spinal cord tumor is frequently delayed due to the presence of non-specific symptoms. We investigated the factors influencing the delay between the first symptom presentation and the diagnosis for pediatric spinal cord tumor. We retrospectively analyzed 31 patients of age <20 years (18 men, 13 women) who underwent surgery for spinal cord tumor at a single center during 1998-2018. We extracted the relevant data on patients' symptoms, affected spinal location (cervical: C1-7, thoracic: T1-T12, and lumbosacral: L1-S), and tumor anatomical location (extradural, intradural extramedullary, and intramedullary tumor) that could potentially affect the duration of symptom presentation prior to the diagnosis. The most common symptom presented in the patients was pain (n = 22, 71.0 %). Motor symptoms such as paralysis was associated with early diagnosis (P = 0.039). The duration of symptoms prior to diagnosis was found to be significantly longer in patients with spinal tumor in the lumbar-sacral region than in those with the involvement of the cervical and thoracic regions (2.1 ± 1.7 months vs 13.6 ± 12.1 months; P = 0.006 and 2.9 ± 2.2 months vs 13.6 ± 12.1 months; P = 0.012, respectively). Our study results demonstrated that pain was the most common symptom in the examined patients, although it did not affect the delay in diagnosis, whereas the presentation of motor symptoms was helpful in the diagnosis of pediatric spinal cord tumor and the diagnosis could be delayed in lumbar-sacral spinal tumors.

Impact of the hip joint mobility on whole-body sagittal alignment: prospective analysis in case with hip arthroplasty.

PURPOSE: To clarify the impact of restriction of hip extension on radiographic whole-body sagittal alignment with using postoperative changes of radiographical parameters for hip osteoarthritis. METHODS: We prospectively enrolled 68 patients with hip osteoarthritis scheduled for arthroplasty. Variables included manual examination of hip range of motion (H-ROM) and radiographic whole-body sagittal alignment parameters including sagittal vertical axis (SVA), center of acoustic meatus and femoral head offset (CAM-HA), thoracic kyphosis (TK), lumbar lordosis, sacral slope (SS), and knee flexion angle (KF). We divided patients with preoperative hip extension angle < 0 into the extension restriction (ER) + group and ≥ 0 into the ER- group. Differences in H-ROM, radiographic parameters between groups and postoperative changes were comparatively analyzed. RESULTS: Fifty-seven patients (The ER + group included 28 patients and the ER- group included 29 patients.) were available for the analysis. Pre-/postoperative H-ROM were 99.7 ± 24.9/118.1 ± 16.0 degrees (p < .01). Greater increases in SVA (5.4 ± 3.4 vs 3.4 ± 2.8 cm, p = .02) and in CAM-HA (3.9 ± 3.9 vs 2.8 ± 3.4 cm, p = 013) were found in the ER + group versus ER- group. Postoperatively, the ER + group showed an increase in TK (pre-/postoperative: 35.2 ± 9.7/37.4 ± 8.8 degrees, p = .04) and decreases in SS (36.5 ± 9.6/33.7 ± 9.9 degrees, p < .01) and KF (9.5 ± 7.0/6.9 ± 6.0 degrees, p = .02). Postoperative changes in radiographic parameters in the ER- group were not significant. CONCLUSION: Patients with restriction of hip extension showed global spine imbalance, and significant changes in TK, SS, and KF were observed after arthroplasty. The presence of hip joint disorder and H-ROM restriction must be considered when evaluating spinopelvic alignment and whole-body sagittal alignment.

Thoracic myelopathy due to ossification of the posterior longitudinal ligament shown on dynamic MR.

BACKGROUND: Magnetic resonance (MR) and computed tomography (CT) studies combined are the optimal studies for diagnosing thoracic ossification of the posterior longitudinal ligament (OPLL) contributing to myelopathy. Here, we report a 71-year-old female, whose additional dynamic thoracic MR demonstrated transient T6-T9 anterior OPLL with cord compression. CASE DESCRIPTION: A 71-year-old female presented with a progressive myelopathy originally attributed to cervical cord compression resulting in a cervical laminoplasty. However, when she failed to improve postoperatively, a dynamic thoracic MR was performed. On the flexion study, it demonstrated significant although transient T6-T9 anterior thoracic cord compression due to both OPLL and kyphosis. The patient's symptoms resolved following a posterior thoracic fusion alone (i.e., no decompression was warranted). CONCLUSION: Dynamic MR studies (i.e., flexion studies) in addition to the routine MR and CT evaluations should be performed for patients with myelopathy attributed to thoracic OPLL/kyphosis.

Recurrent ossification of the posterior longitudinal ligament in the upper thoracic region 10 years after initial decompression.

BACKGROUND: Posterior decompression surgery consisting of laminoplasty is generally considered be the treatment of choice for upper thoracic OPLL. Here, we describe a patient who, 10 years following a C3-T4 level laminectomy, developed recurrent OPLL at the T2-3 level with kyphosis requiring a posterior fusion. CASE DESCRIPTION: A 64-year-old male with CT documented OPLL at the C3-4, C6-7, and T1-4 levels, originally underwent a cervicothoracic laminectomy with good results. However, 10 years later, when T2-3 OPLL recurred along with kyphosis, he warranted an additional posterior fusion. CONCLUSION: Due to the long-term risks of developing kyphotic deformity/instability, more patients undergoing initial decompressive surgery alone for upper thoracic OPLL should be considered for primary fusions.

Differences in Demographic and Radiographic Characteristics between Patients with Visible and Invisible T1 Slopes on Lateral Cervical Radiographic Images.

INTRODUCTION: The T1 slope is important for cervical surgical planning, and it may be invisible on radiographic images. The prevalence of T1 invisible cases and the differences in demographic and radiographic characteristics between patients whose T1 slopes are visible or invisible remains unexplored. METHODS: This pilot study aimed to evaluate the differences in these characteristics between outpatients whose T1 slopes were visible or invisible on radiographic images. Patients (n = 60) who underwent cervical radiography, whose T1 slope was confirmed clearly, were divided into the visible (V) group and invisible (I) group. The following radiographic parameters were measured: (1) C2-7 sagittal vertical axis (SVA), (2) C2-7 angle in neutral, flexion, and extension positions. RESULTS: Based on the T1 slope visibility, 46.7% of patients were included in group I. The I group had significantly larger C2-7 SVA than the V group for males (p < 0.05). The C2-7 SVA tended to be larger in the I group, without significant difference for females (p = 0.362). DISCUSSION: The mean C2-7 angle in neutral and flexion positions was not significantly different between the V and I groups for either sex. The mean C2-7 angle in the extension position was greater in the V group. The T1 slope was invisible in males with high C2-7 SVA.

Associations Between Neck and Shoulder Pain and Neuropathic Pain in a Middle-aged Community-living Population.

STUDY DESIGN: A cross-sectional study. OBJECTIVE: The present study aimed to investigate the prevalence of NeP in subjects suffering from NSP to reveal the impact of NeP on the health-related QOL (HRQOL) in middle-aged and elderly people with NSP in a health checkup. SUMMARY OF BACKGROUND DATA: No previous studies have established the relationship between NSP and NeP as potential risk factors contributing to a decreased QOL in the general population. METHODS: The present study involved 203 participants (men: 84, women: 119; mean age: 63.3 yr). For each subject, anthro-pometric measurements, physical function examinations, and blood testing were performed. A cut-off score of >0 on the short-form spine painDETECT questionnaire defined the presence of NeP. Subsequently, the NSP (+) subjects were divided into 2 sub-groups: the NeP (+) and NeP (-) groups. For the assessment of QOL, the short form 36 health survey and the EuroQol 5 dimension 5 level version (EQ-5D-5L) tool were used. RESULTS: The study included 100 NSP (+) and 103 NSP (-) subjects. Among the NSP (+) subjects, 46 and 54 subjects were found to be NeP (+) and NeP (-), respectively. For the short form 36 health survey, the multivariate regression analysis revealed that the prevalence of NeP was associated with a lower physical QOL (OR 3.56) and lower mental QOL (OR 4.04). Similarly, the NeP prevalence was found to be the predictor for low QOL scores in EQ-5D-5L (EQ-5D-5L index value <0.875; OR 3.61). CONCLUSION: The prevalence of NeP was reported to be 46.0% in healthy middle-aged and elderly population suffering from NSP, where it was associated with poor HRQOL. Therefore, strategies aimed at alleviating NeP may contribute significantly to the improvement of QOL in middle-aged and elderly people with NSP.Level of Evidence: 2.

Postoperative progression of ligamentum flavum ossification after posterior instrumented surgery for thoracic posterior longitudinal ligament ossification: long-term outcomes during a minimum 10-year follow-up.

OBJECTIVE: The authors sought to investigate clinical and radiological outcomes after thoracic posterior fusion surgery during a minimum of 10 years of follow-up, including postoperative progression of ossification, in patients with thoracic ossification of the posterior longitudinal ligament (T-OPLL). METHODS: The study participants were 34 consecutive patients (15 men, 19 women) with an average age at surgery of 53.6 years (range 36-80 years) who underwent posterior decompression and fusion surgery with instrumentation at the authors' hospital. The minimum follow-up period was 10 years. Estimated blood loss, operative time, pre- and postoperative Japanese Orthopaedic Association (JOA) scores, and JOA score recovery rates were investigated. Dekyphotic changes were evaluated on plain radiographs of thoracic kyphotic angles and fusion levels pre- and postoperatively and 10 years after surgery. The distal junctional angle (DJA) was measured preoperatively and at 10 years after surgery to evaluate distal junctional kyphosis (DJK). Ossification progression at distal intervertebrae was investigated on CT. RESULTS: The Cobb angles at T1-12 were 46.8°, 38.7°, and 42.6°, and those at the fusion level were 39.6°, 31.1°, and 34.1° pre- and postoperatively and at 10 years after surgery, respectively. The changes in the kyphotic angles from pre- to postoperatively and to 10 years after surgery were 8.0° and 7.2° at T1-12 and 8.4° and 7.9° at the fusion level, respectively. The DJA changed from 4.5° postoperatively to 10.9° at 10 years after surgery. There were 11 patients (32.3%) with DJK during follow-up, including 4 (11.8%) with vertebral compression fractures at lower instrumented vertebrae or adjacent vertebrae. Progression of ossification of the ligamentum flavum (OLF) on the caudal side occurred in 8 cases (23.6%), but none had ossification of the posterior longitudinal ligament (OPLL) progression. Cases with OLF progression had a significantly lower rate of DJK (0% vs 38.5%, p < 0.01), a lower DJA (3.4° vs 13.2°, p < 0.01), and a smaller change in DJA at 10 years after surgery (0.8° vs 8.1°, p < 0.01). CONCLUSIONS: Posterior decompression and fusion surgery with instrumentation for T-OPLL was found to be a relatively safe and stable surgical procedure based on the long-term outcomes. Progression of OLF on the caudal side occurred in 23.6% of cases, but cases with OLF progression did not have DJK. Progression of DJK shifts the load in the spinal canal forward and the load on the ligamentum flavum is decreased. This may explain the lack of ossification in cases with DJK.

Relationship of frequency of participation in a physical checkup and physical fitness in middle-aged and elderly people: the Yakumo study.

An annual physical checkup is provided as part of the long-term Yakumo study. The checkup is voluntary and there is variation in the frequency of participation. The aim of this study was to examine relationship of physical fitness with frequency of participation in this checkup. The subjects had all attended at least one annual physical checkup from 2006 to 2018. Data from 1,804 initial checkups were used for analysis. At the checkups, age, gender, height, weight, body mass index (BMI), and bone mineral density (BMD) were recorded, and physical activity was measured. The average number of physical checkups per participant for 13 years was 2.4 (1-13). Daily exercise habits were found to be significantly associated with higher participation in physical checkups. Furthermore, between groups with low (1-5 times; <90th percentile of participants) and high (≥6 times) participation, weight and BMI were significantly higher, and BMD, grip strength, 10-m gait time, back muscle strength, and two-step test were all significantly lower in the group with lower frequency of participation in the checkup. In conclusions, our results show that frequency of participation in a voluntary annual physical checkup is significantly associated with physical fitness in middle-aged and elderly people.