Sporadic inclusion body myositis-derived myotube culture revealed muscle cell-autonomous expression profiles.

Sporadic inclusion body myositis (sIBM) is a muscle disease in older people and is characterized by inflammatory cell invasion into intact muscle fibers and rimmed vacuoles. The pathomechanism of sIBM is not fully elucidated yet, and controversy exists as to whether sIBM is a primary autoimmune disease or a degenerative muscle disease with secondary inflammation. Previously, we established a method of collecting CD56-positive myoblasts from human skeletal muscle biopsy samples. We hypothesized that the myoblasts derived from these patients are useful to see the cell-autonomous pathomechanism of sIBM. With these resources, myoblasts were differentiated into myotubes, and the expression profiles of cell-autonomous pathology of sIBM were analyzed. Myoblasts from three sIBM cases and six controls were differentiated into myotubes. In the RNA-sequencing analysis of these "myotube" samples, 104 differentially expressed genes (DEGs) were found to be significantly upregulated by more than twofold in sIBM, and 13 DEGs were downregulated by less than twofold. For muscle biopsy samples, a comparative analysis was conducted to determine the extent to which "biopsy" and "myotube" samples differed. Fifty-three DEGs were extracted of which 32 (60%) had opposite directions of expression change (e.g., increased in biopsy vs decreased in myotube). Apolipoprotein E (apoE) and transmembrane protein 8C (TMEM8C or MYMK) were commonly upregulated in muscle biopsies and myotubes from sIBM. ApoE and myogenin protein levels were upregulated in sIBM. Given that enrichment analysis also captured changes in muscle contraction and development, the triggering of muscle atrophy signaling and abnormal muscle differentiation via MYMK or myogenin may be involved in the pathogenesis of sIBM. The presence of DEGs in sIBM suggests that the myotubes formed from sIBM-derived myoblasts revealed the existence of muscle cell-autonomous degeneration in sIBM. The catalog of DEGs will be an important resource for future studies on the pathogenesis of sIBM focusing on primary muscle degeneration.

Dynamic cortical and tractography atlases of proactive and reactive alpha and high-gamma activities.

Alpha waves-posterior dominant rhythms at 8-12 Hz reactive to eye opening and closure-are among the most fundamental EEG findings in clinical practice and research since Hans Berger first documented them in the early 20th century. Yet, the exact network dynamics of alpha waves in regard to eye movements remains unknown. High-gamma activity at 70-110 Hz is also reactive to eye movements and a summary measure of local cortical activation supporting sensorimotor or cognitive function. We aimed to build the first-ever brain atlases directly visualizing the network dynamics of eye movement-related alpha and high-gamma modulations, at cortical and white matter levels. We studied 28 patients (age: 5-20 years) who underwent intracranial EEG and electro-oculography recordings. We measured alpha and high-gamma modulations at 2167 electrode sites outside the seizure onset zone, interictal spike-generating areas and MRI-visible structural lesions. Dynamic tractography animated white matter streamlines modulated significantly and simultaneously beyond chance, on a millisecond scale. Before eye-closure onset, significant alpha augmentation occurred at the occipital and frontal cortices. After eye-closure onset, alpha-based functional connectivity was strengthened, while high gamma-based connectivity was weakened extensively in both intra-hemispheric and inter-hemispheric pathways involving the central visual areas. The inferior fronto-occipital fasciculus supported the strengthened alpha co-augmentation-based functional connectivity between occipital and frontal lobe regions, whereas the posterior corpus callosum supported the inter-hemispheric functional connectivity between the occipital lobes. After eye-opening offset, significant high-gamma augmentation and alpha attenuation occurred at occipital, fusiform and inferior parietal cortices. High gamma co-augmentation-based functional connectivity was strengthened, whereas alpha-based connectivity was weakened in the posterior inter-hemispheric and intra-hemispheric white matter pathways involving central and peripheral visual areas. Our results do not support the notion that eye closure-related alpha augmentation uniformly reflects feedforward or feedback rhythms propagating from lower to higher order visual cortex, or vice versa. Rather, proactive and reactive alpha waves involve extensive, distinct white matter networks that include the frontal lobe cortices, along with low- and high-order visual areas. High-gamma co-attenuation coupled to alpha co-augmentation in shared brain circuitry after eye closure supports the notion of an idling role for alpha waves during eye closure. These normative dynamic tractography atlases may improve understanding of the significance of EEG alpha waves in assessing the functional integrity of brain networks in clinical practice; they also may help elucidate the effects of eye movements on task-related brain network measures observed in cognitive neuroscience research.

Diagnosis and Treatment of Brown Tumor in the Femur Induced by Parathyroid Carcinoma: A Case Report.

Brown tumors are rare destructive bone lesions caused by hyperparathyroidism. As their clinical symptoms, radiographic findings, and laboratory results closely mimic those of metastatic tumors or multiple myeloma, the diagnosis may often be mistaken. We report a case of a 61-year-old woman with brown tumors in both femurs due to parathyroid carcinoma. The patient presented with multiple osteolytic lesions that caused pain in the right thigh. Whole-body computed tomography (CT), including the neck, suspected a parathyroid tumor, and a biopsy of the bone lesion revealed no malignancy. Following parathyroidectomy, she was diagnosed with a brown tumor with hyperparathyroidism due to a very rare parathyroid carcinoma. Although the right femoral lesion was indicated as an impending fracture, conservative treatment was performed because of the instability of her general condition after parathyroidectomy and her wishes. Bone remodeling of the right femur progressed, and the patient was ambulatory; however, 9 months postoperatively, the patient fell, developed a pathological fracture, and underwent internal fixation. When multiple osteolytic bone lesions are present, CT imaging of the neck should be performed to determine the possibility of a brown tumor due to parathyroid disease. Bone lesions of brown tumors are known to be naturally cured after treatment for hyperparathyroidism. However, when the lesion of a brown tumor in the femur is an impending fracture, prophylactic internal fixation is recommended aggressively if the patient's general condition permits.

Assessing the Utility of 18F-Fluorodeoxyglucose Positron Emission Tomography in the Differential Diagnosis Between Spinal Schwannomas and Meningiomas.

Objective The advantage of 18F-fluorodeoxyglucose-positron emission tomography (FDG-PET) for the differential diagnosis of schwannoma and meningioma remains unclear. The purpose of this study was to compare the maximum standardized uptake value (SUVmax) with computed tomography (CT) and magnetic resonance imaging (MRI) findings and assess its utility in the differential diagnosis of schwannomas and meningiomas. Methods This study included 42 patients who underwent surgery and had pathological diagnoses of schwannomas (S group) or meningiomas (M group). Multivariate logistic regression analyses were conducted using meningioma prevalence as the dependent variable, and confounders were selected from those with p-values <0.05, including calcification, dural tail sign, tumor volume, and SUVmax at each spinal level as independent variables. Results The SUVmax of the spinal canal type at the level of the cervical vertebrae was significantly higher in the M group (4.6 ± 0.8) than in the S group (2.7 ± 1.4; P = 0.017). Multivariate logistic regression analysis showed that the dural tail sign was significantly associated with differential diagnosis between the S and M groups (odds ratio [OR], 0.851; 95% confidence interval [CI], 0.704-1.031, p<0.001). Conclusions The dural tail sign on MRI, but not the SUVmax of FDG-PET, was the most useful for the differential diagnosis between schwannomas and meningiomas.

Spontaneous modulations of high-frequency cortical activity.

OBJECTIVE: We clarified the clinical and mechanistic significance of physiological modulations of high-frequency broadband cortical activity associated with spontaneous saccadic eye movements during a resting state. METHODS: We studied 30 patients who underwent epilepsy surgery following extraoperative electrocorticography and electrooculography recordings. We determined whether high-gamma activity at 70-110 Hz preceding saccade onset would predict upcoming ocular behaviors. We assessed how accurately the model incorporating saccade-related high-gamma modulations would localize the primary visual cortex defined by electrical stimulation. RESULTS: The dynamic atlas demonstrated transient high-gamma suppression in the striatal cortex before saccade onset and high-gamma augmentation subsequently involving the widespread posterior brain regions. More intense striatal high-gamma suppression predicted the upcoming saccade directed to the ipsilateral side and lasting longer in duration. The bagged-tree-ensemble model demonstrated that intense saccade-related high-gamma modulations localized the visual cortex with an accuracy of 95%. CONCLUSIONS: We successfully animated the neural dynamics supporting saccadic suppression, a principal mechanism minimizing the perception of blurred vision during rapid eye movements. The primary visual cortex per se may prepare actively in advance for massive image motion expected during upcoming prolonged saccades. SIGNIFICANCE: Measuring saccade-related electrocorticographic signals may help localize the visual cortex and avoid misperceiving physiological high-frequency activity as epileptogenic.

Distinction between benign and malignant soft tissue tumors based on an ultrasonographic evaluation of vascularity and elasticity.

The initial diagnostic distinction between benign and malignant soft tissue tumors is critical for decisions regarding the appropriate course of treatment. The current study aimed to evaluate the vascularity and elasticity of soft tissue tumors by superb microvascular imaging and shear wave elastography using ultrasonography (US), to determine their usefulness in distinguishing malignant soft tissue tumors, and to further establish the diagnostic accuracy and usefulness of a scoring system (SS) based on these evaluations. The present study used 167 lesions of soft tissue tumors examined by US prior to biopsy, surgery and pathological tissue diagnosis. The vascularity index (VI) and the maximal shear velocity (MSV), as indices of vascularity and elasticity respectively, were evaluated using US. The tumor size and depth were also evaluated via magnetic resonance imaging (MRI). Based on the odds ratio of these parameters determined by multivariate logistic regression analysis, an original SS was established to identify the malignancy of soft tissue tumors. VI and MSV exhibited significantly high values for malignant tumors. Tumor size was also significantly larger for malignant than benign tumors. The areas under the curves (AUCs) of the receiver operating characteristic analysis for VI, MSV and tumor size were 0.75, 0.84 and 0.69, respectively, indicating that these methods were effective for the diagnosis of malignancy. An original SS consisting of VI, MSV and tumor size, excluding tumor depth, was established, and revealed an AUC value of 0.90, with 93.6% sensitivity and 79.2% specificity for malignancy distinction. US evaluation of vascularity and elasticity was an effective technique to distinguish malignant soft tissue tumors, and the current SS based on US evaluations including tumor size via MRI demonstrated a high diagnostic accuracy for malignant soft tissue tumors.

Childhood-onset cerebellar ataxia in Japan: A questionnaire-based survey.

OBJECTIVE: The diagnosis of childhood-onset cerebellar ataxia (CA) is often challenging due to variations in symptoms and etiologies. Despite the known regional differences in the prevalence of etiologies underlying CA, the frequency and characteristics of CA in Japan remain unclear. We conducted a questionnaire-based survey to identify the clinical characteristics of childhood-onset CA in the Japanese population. MATERIALS AND METHODS: Questionnaires were sent to 1,103 board-certified pediatric neurologists in Japan from 2016 to 2017. The primary survey requested the number of patients with CA under care, and the follow-up secondary questionnaire requested additional clinical characteristics of the patients. RESULTS: The primary survey obtained 578 responses (response rate, 52.4%) on 385 patients with CA, including 171 diagnosed and 214 undiagnosed cases (diagnostic rate, 44.4%). The most frequent etiology was dentatorubropallidoluysian atrophy (DRPLA), followed by mitochondrial disorders and encephalitis. The secondary survey obtained the clinical characteristics of 252 cases (119 diagnosed and 133 undiagnosed cases). Multiple logistic regression analysis revealed that a younger age at onset, hearing issues, and short stature were associated with a higher risk of remaining undiagnosed with CA in Japan. CONCLUSIONS: The diagnostic rate of childhood-onset CA in the current study was comparable to those reported in other countries. The high prevalence of autosomal dominant ataxia, especially DRPLA, was a signature of CA in Japan. These data offer insights into the characteristics of childhood-onset CA in the Japanese population.

Aberrant axon branching via Fos-B dysregulation in FUS-ALS motor neurons.

BACKGROUND: The characteristic structure of motor neurons (MNs), particularly of the long axons, becomes damaged in the early stages of amyotrophic lateral sclerosis (ALS). However, the molecular pathophysiology of axonal degeneration remains to be fully elucidated. METHOD: Two sets of isogenic human-induced pluripotent stem cell (hiPSCs)-derived MNs possessing the single amino acid difference (p.H517D) in the fused in sarcoma (FUS) were constructed. By combining MN reporter lentivirus, MN specific phenotype was analyzed. Moreover, RNA profiling of isolated axons were conducted by applying the microfluidic devices that enable axon bundles to be produced for omics analysis. The relationship between the target gene, which was identified as a pathological candidate in ALS with RNA-sequencing, and the MN phenotype was confirmed by intervention with si-RNA or overexpression to hiPSCs-derived MNs and even in vivo. The commonality was further confirmed with other ALS-causative mutant hiPSCs-derived MNs and human pathology. FINDINGS: We identified aberrant increasing of axon branchings in FUS-mutant hiPSCs-derived MN axons compared with isogenic controls as a novel phenotype. We identified increased level of Fos-B mRNA, the binding target of FUS, in FUS-mutant MNs. While Fos-B reduction using si-RNA or an inhibitor ameliorated the observed aberrant axon branching, Fos-B overexpression resulted in aberrant axon branching even in vivo. The commonality of those phenotypes was further confirmed with other ALS causative mutation than FUS. INTERPRETATION: Analyzing the axonal fraction of hiPSC-derived MNs using microfluidic devices revealed that Fos-B is a key regulator of FUS-mutant axon branching. FUND: Japan Agency for Medical Research and development; Japanese Ministry of Education, Culture, Sports, Science and Technology Clinical Research, Innovation and Education Center, Tohoku University Hospital; Japan Intractable Diseases (Nanbyo) Research Foundation; the Kanae Foundation for the Promotion of Medical Science; and "Inochi-no-Iro" ALS research grant.

The updated retrospective questionnaire study of sporadic inclusion body myositis in Japan.

BACKGROUND: Sporadic inclusion body myositis (sIBM) is the most prevalent muscle disease in elderly people, affecting the daily activities. sIBM is progressive with unknown cause and without effective treatment. In 2015, sIBM was classified as an intractable disease by the Japanese government, and the treatment cost was partly covered by the government. This study aimed to examine the changes in the number of patients with sIBM over the last 10 years and to elucidate the cross-sectional profile of Japanese patients with sIBM. METHODS: The number of sIBM patients was estimated through a reply-paid postcard questionnaire for attending physicians. Only patients diagnosed as "definite" or "probable" sIBM by clinical and biopsy sIBM criteria were included in this study (Lancet Neurol 6:620-631, 2007, Neuromuscul Disord 23:1044-1055, 2013). Additionally, a registered self-administered questionnaire was also sent to 106 patients who agreed to reply via their attending physician, between November 2016 and March 2017. RESULTS: The number of patients diagnosed with sIBM for each 5-year period was 286 and 384 in 2011 and 2016, respectively. Inability to stand-up, cane-dependent gait, inability to open a plastic bottle, choking on food ingestion, and being wheelchair-bound should be included as sIBM milestones. Eight patients were positive for anti-hepatitis C virus antibody; three of them were administered interferon before sIBM onset. Steroids were administered to 33 patients (31.1%) and intravenous immunoglobulin to 46 patients (43.4%). From 2016 to 2017, total of 70 patients applied for the designated incurable disease medical expenses subsidy program. Although the treatment cost was partly covered by the government, many patients expressed psychological/mental and financial anxieties. CONCLUSIONS: We determined the cross-sectional profile of Japanese patients with sIBM. Continuous support and prospective surveys are warranted.

Aberrant astrocytic expression of chondroitin sulfate proteoglycan receptors in a rat model of amyotrophic lateral sclerosis.

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease. Progressive and systemic loss of motor neurons with gliosis in the central nervous system (CNS) is a neuropathological hallmark of ALS. Chondroitin sulfate proteoglycans (CSPGs) are the major components of the extracellular matrix of the mammalian CNS, and they inhibit axonal regeneration physically by participating to form the glial scar. Recently, protein tyrosine phosphatase sigma (PTPσ) and leukocyte common antigen-related protein were discovered as CSPG receptors that play roles in inhibiting regeneration. Here we examined the expression of CSPG receptors in transgenic female rats overexpressing an ALS-linked mutant cytosolic Cu/Zn superoxide dismutase gene (SOD1). In contrast to controls, multiple immunofluorescence analyses revealed aberrant expression of CSPG receptors dominantly in reactive astrocytes, while PTPσ expression in neurons decreased in the spinal ventral horns of ALS transgenic rats. The aberrant and progressive astrocytic expression of CSPG receptors and reactive astrocytes themselves may be therapeutic targets for reconstructing a regeneration-supportive microenvironment under neurodegenerative conditions such as ALS.

[Case of cardiac tamponade during the treatment of acute cerebral infarction].

A 59-year-old man was admitted to our hospital because of sudden weakness in his left foot. He had been treated for lung cancer by chemotherapy and irradiation 3 years earlier. Brain magnetic resonance (MR) imaging revealed multiple acute cerebral infarctions in the area of the right anterior cerebral artery. MR angiography (MRA) revealed that the right anterior cerebral artery was patent, with slight irregularity in the A3 portion. He was treated by administration of aspirin (200 mg/day) and a continuous intravenous unfragmented heparin infusion (10,000 IU/day). Four days after admission, he developed dyspnea. Chest computed tomography (CT) performed 5 days after admission revealed both a marked pericardial effusion and a pleural effusion. Emergency pericardiocentesis was therefore performed. While 1,000 ml of bloody pericardial effusion were aspirated, his dyspnea ameliorated dramatically. Histological examination of the pericardial effusion revealed infiltration of lung adenocarcinoma cells in the pericardium. Intracranial 3D-CT angiography revealed the pearl and string sign in the right anterior cerebral artery 6 days after admission. Anterior cerebral artery dissection was diagnosed as the cause of his cerebral infarction. It is important to recognize the possibility of cardiac tamponade as an uncommon complication of the treatment for acute cerebral infarction.