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Objectives: Resonance properties of the nasal and sinus cavities are involved in the individuality of speech. However, detailed information on how alterations in the nasal cavity morphology affect voice quality is lacking. The aim of the present study was to investigate the effects of structural changes in the nasal cavity on voice production by spraying a topical adrenaline solution with a vasoconstrictive effect into the nasal cavity, causing nasal mucosal contraction., Study Design: Prospective., Methods: Overall, 51 adult volunteers were recruited from the Otorhinolaryngology Outpatient Department of the Jikei University Hospital from June to September 2022. Among them, 20 completed acoustic rhinometry and voice recordings before and after adrenaline spraying. The nasal consonant [N] uttered with the mouth completely closed was recorded for 5 seconds. The remaining 31 volunteers completed all auditory experiments. This was conducted to determine whether the changes in voice before and after adrenaline spraying could be discriminated against by the participants., Results: The nasal volume had increased 5 and 10 minutes after spraying compared to that before spraying, reaching a significance at 10 minutes (P = 0.06). It had increased at 2 and 5 cm from the external nostrils compared to that within 3 cm of the external nostrils (P = 0.04). Among the 31 volunteers in the auditory experiments, 30 had a discrimination rate >90%, with a mean of 96.3% (standard error, 3.2). The spectral envelope of the 16 frequency bands varied significantly at 500-Hz increments (P = 0.0006). In particular, changes in the high-frequency bands were larger between 4500 and 6000 Hz., Conclusions: Nasal enlargement with 0.02% topical adrenaline affects the spectral envelope, particularly in the high-frequency bands between 4500 and 6000 Hz, and perceptibly alters the voice., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Voice Foundation. Published by Elsevier Inc. All rights reserved.)

Optic neuritis (ON) is a rare complication of tumor necrosis factor (TNF)-α inhibitors. The autoantibody serostatus, treatment, and outcome of TNF-α inhibitor-associated ON remain unclear. We herein report a 50-year-old woman with ON following adalimumab therapy. The patient presented with decreasing visual acuity of the right eye, quickly diminishing to light perception. Anti-aquaporin-4 (anti-AQP4) and anti-myelin oligodendrocyte glycoprotein antibodies were negative. Adalimumab was discontinued, and intravenous methylprednisolone and intravenous immunoglobulin (IVIg) were administered. However, her visual acuity improved only up to counting fingers. IVIg may be ineffective depending on the pretreatment severity.

Autoantibodies against 3‑hydroxy-3-methylglutaryl-CoA reductase (HMGCR) and the signal recognition particle (SRP) are representative antibodies causing immune-mediated necrotizing myopathies (IMNM), called as anti-HMGCR and anti-SRP myopathies, respectively. Here, we analyzed the differences in routine blood test results between 56 anti-HMGCR and 77 anti-SRP myopathy patients. A higher alanine transaminase (ALT) level and a lower aspartate transaminase (AST)/ALT ratio were observed in anti-HMGCR myopathy patients [ALT, 265.7 ± 213.3 U/L (mean ± standard deviation); AST/ALT ratio, 0.88 ± 0.32] than in anti-SRP-myopathy patients (ALT, 179.3 ± 111.2 U/L, p < 0.05; AST/ALT ratio, 1.28 ± 0.40, p < 0.01). In the active phase, anti-HMGCR myopathy often showed ALT predominance, whereas anti-SRP myopathy often showed AST predominance. In addition, there were differences in erythrocyte sedimentation rate (ESR), total cholesterol (TChol) level, and high-density lipoprotein (HDL) level between anti-HMGCR and anti-SRP myopathies (ESR: HMGCR, 24.4 ± 20.8 mm/1 h; SRP, 35.7 ± 26.7 mm/1 h, p = 0.0334; TChol: HMGCR, 226.7 ± 36.6 mg/dL; SRP, 207.6 ± 40.8 mg/dL, p = 0.0163; HDL: HMGCR, 58.4 ± 13.9 mg/dL; SRP, 46.2 ± 17.3 mg/dL, p < 0.01). Additional studies on the differences in routine blood test results may further reveal the pathomechanisms of IMNM., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021 Elsevier B.V. All rights reserved.)

A 66-year old woman with a 14-year history of rheumatoid arthritis (RA) and uveitis was admitted to our department for evaluation of a mass in the left neck. Fourteen months prior to this admission the patient was started on golimumab. Serum creatine kinase (CK) level was elevated and myositis-specific and -associated antibodies were negative. Manual muscle test showed weakness in the neck flexor, sternocleidomastoid and deltoid muscles. Magnetic resonance imaging (MRI) of the neck, erector muscle of spine, breech, thigh and lower thigh demonstrated high-intensity lesions in the muscles in short-tau inversion recovery images. Electromyography in the right deltoid detected fibrillation potentials. Muscle biopsy from the left neck mass showed granulomatous myositis. Muscle weakness improved and CK levels normalized after discontinuation of golimumab. We report a case of granulomatous myositis under anti-TNF-α treatment for RA.

Objective: To provide evidence that idiopathic inflammatory myopathy (IM) with myasthenia gravis (MG) frequently shows thymoma association and polymyositis (PM) pathology and shares clinicopathologic characteristics with IM induced by immune checkpoint inhibitors (ICIs)., Methods: We analyzed the clinicopathologic features of 10 patients with idiopathic IM and MG identified in 970 consecutive patients with biopsy-proven IM., Results: Seven patients (70%) had thymoma. IM and MG were diagnosed with more than 5-year time difference in 6 thymomatous patients and within 1 year in 1 thymomatous and 3 nonthymomatous patients. Seven thymomatous patients showed rhabdomyolysis-like features with respiratory failure (4/7), dropped head (3/7), cardiac involvement (2/7), and positive anti-acetylcholine receptor (anti-AChR) and anti-titin antibodies (7/7 and 4/6, respectively) but rarely showed ocular symptoms (2/7) or decremental repetitive nerve stimulation (RNS) responses (1/7) at IM diagnosis. Three nonthymomatous patients showed acute cardiorespiratory failure with rhabdomyolysis-like features (1/3), positive anti-AChR and anti-titin antibodies (3/2 and 2/2, respectively), and fluctuating weakness of the skeletal muscle without ocular symptoms (3/3). Muscle pathology showed a PM pathology with infiltration of CD8-positive CD45RA-negative T-lymphocytes (9/9), scattered endomysial programmed cell death 1 (PD-1)-positive cells (9/9), and overexpression of programmed cell death ligand 1 (PD-L1) on the sarcolemma of muscle fibers around the infiltrating PD-1-positive cells (7/9)., Conclusion: Rhabdomyolysis-like features, positive anti-AChR antibody without decremental RNS responses, and PD-L1 overexpression are possible characteristics shared by ICI-induced IM. Frequent thymoma association in patients with idiopathic IM and MG may suggest thymoma-related immunopathogenic mechanisms, including dysregulation of the immune checkpoint pathway.

Background: The morphometric analysis of myelinated nerve fibers of peripheral nerves in cross-sectional optical microscopic images is valuable. Several automated methods for nerve fiber identification and segmentation have been reported. This paper presents a new method that uses a deep learning model of a convolutional neural network (CNN). We tested it for human sural nerve biopsy images., Methods: The method comprises four steps: normalization, clustering segmentation, myelinated nerve fiber identification, and clump splitting. A normalized sample image was separated into individual objects with clustering segmentation. Each object was applied to a CNN deep learning model that labeled myelinated nerve fibers as positive and other structures as negative. Only positives proceeded to the next step. For pretraining the model, 70,000 positive and negative data each from 39 samples were used. The accuracy of the proposed algorithm was evaluated using 10 samples that were not part of the training set. A P-value of <0.05 was considered statistically significant., Results: The total true-positive rate (TPR) for the detection of myelinated fibers was 0.982, and the total false-positive rate was 0.016. The defined total area similarity (AS) and area overlap error of segmented myelin sheaths were 0.967 and 0.068, respectively. In all but one sample, there were no significant differences in estimated morphometric parameters obtained from our method and manual segmentation., Comparison With Existing Methods: The TPR and AS were higher than those obtained using previous methods., Conclusions: High-performance automated identification and segmentation of myelinated nerve fibers were achieved using a deep learning model., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Objective: To determine the clinical features of myositis patients with the histopathologic finding of CD8-positive T cells invading non-necrotic muscle fibers expressing major histocompatibility complex class 1 (CD8-MHC-1 complex), which is shared by polymyositis (PM) and inclusion body myositis (IBM), in relation to the p62 immunostaining pattern of muscle fibers., Methods: All 93 myositis patients with CD8-MHC-1 complex who were referred to our hospital from 1993 to 2015 were classified on the basis of the European Neuromuscular Center (ENMC) diagnostic criteria for IBM (Rose, 2013) or PM (Hoogendijk, 2004) and analyzed., Results: The 93 patients included were 17 patients with PM, 70 patients with IBM, and 6 patients who neither met the criteria for PM nor IBM in terms of muscle weakness distribution (unclassifiable group). For these PM, IBM, and unclassifiable patients, their mean ages at diagnosis were 63, 70, and 64 years; autoimmune disease was present in 7 (41%), 13 (19%), and 4 (67%); hepatitis C virus infection was detected in 0%, 13 (20%), and 2 (33%); and p62 was immunopositive in 0%, 66 (94%), and 2 (33%), respectively. Of the treated patients, 11 of 16 PM patients and 4 of 6 p62-immunonegative patients in the unclassifiable group showed responses to immunotherapy, whereas all 44 patients with IBM and 2 p62-immunopositive patients in the unclassifiable group were unresponsive to immunotherapy., Conclusions: CD8-MHC-1 complex is present in patients with PM, IBM, or unclassifiable group. The data may serve as an argument for a trial of immunosuppressive treatment in p62-immunonegative patients with unclassifiable myositis., (© 2017 American Academy of Neurology.)

Objective: To show cancer association is a risk factor other than statin exposure for anti-3-hydroxy-3-methylglutaryl coenzyme A reductase autoantibody-positive (anti-HMGCR Ab+) myopathy., Methods: We analyzed the clinical features and courses of 33 patients (23 female and 10 male) with anti-HMGCR Ab+ myopathy among 621 consecutive patients with idiopathic inflammatory myopathies., Results: Among the 33 patients, 7 (21%) were statin-exposed and 26 were statin-naive. In relation with cancer, there were 12 patients (statin-exposed, n = 4) with cancers detected within 3 years of myopathy diagnosis (cancer association), 3 patients (all statin-naive) with cancers detected more than 3 years before myopathy diagnosis (cancer history), 10 cancer-free patients followed up for more than 3 years (all statin-naive), and 8 patients without cancer detection but followed up for less than 3 years (statin-exposed, n = 3). Therefore, 12 patients with cancer association (36%) formed a larger group than that of 7 statin-exposed patients (21%). Among 12 patients with cancer association, 92% had cancer detection within 1 year of myopathy diagnosis (after 1.3 years in the remaining patient), 83% had advanced cancers, and 75% died of cancers within 2.7 years. Of interest, 1 patient with cancer history had sustained increase in creatine kinase level over 12 years from cancer removal to the development of weakness., Conclusions: Patients with cancer association formed a large group with poor prognosis in our series of patients with anti-HMGCR Ab+ myopathy. The close synchronous occurrence of cancers and myopathies suggested that cancer association is one of the risk factors for developing anti-HMGCR Ab+ myopathy.

G-protein-coupled receptors (GPCRs) participate in a broad range of physiological functions. A priority for fundamental and clinical research, therefore, is to decipher the function of over 140 remaining orphan GPCRs. The suprachiasmatic nucleus (SCN), the brain's circadian pacemaker, governs daily rhythms in behaviour and physiology. Here we launch the SCN orphan GPCR project to (i) search for murine orphan GPCRs with enriched expression in the SCN, (ii) generate mutant animals deficient in candidate GPCRs, and (iii) analyse the impact on circadian rhythms. We thereby identify Gpr176 as an SCN-enriched orphan GPCR that sets the pace of circadian behaviour. Gpr176 is expressed in a circadian manner by SCN neurons, and molecular characterization reveals that it represses cAMP signalling in an agonist-independent manner. Gpr176 acts independently of, and in parallel to, the Vipr2 GPCR, not through the canonical Gi, but via the unique G-protein subclass Gz.

GPR7, now known as a receptor of neuropeptide B and neuropeptide W, is expressed in neurons of the suprachiasmatic nucleus (SCN), the mammalian circadian center. By the quantitative in situ hybridization, we demonstrated that GPR7 mRNA showed a significant circadian rhythm in the SCN showing a peak at early subjective night in both light-dark and constant dark. We characterized the circadian feature of GPR7-knockout mice, but the period length and the phase-dependent phase shift to light exposure were not disordered in GPR7-knockout mice. Moreover, the food-anticipatory behavior in restricted feeding schedule was observed in this gene-deleted mouse similar to wild-type. These results indicate that the role of GPR7 may be subtle or limited in relation to the circadian clock despite its robust expression in the SCN.

Many human proteins have homopolymeric amino acid (HPAA) tracts, but their physiological functions or cellular effects are not well understood. Previously, we expressed 20 HPAAs in mammalian cells and showed characteristic intracellular localization, in that hydrophobic HPAAs aggregated strongly and caused high cytotoxicity in proportion to their hydrophobicity. In the present study, we investigated the cytotoxicity of these aggregate-prone hydrophobic HPAAs, assuming that the ubiquitin proteasome system is impaired in the same manner as other well-known aggregate-prone polyglutamine-containing proteins. Some highly hydrophobic HPAAs caused a deficiency in the ubiquitin proteasome system and excess endoplasmic reticulum stress, leading to apoptosis. These results indicate that the property of causing excess endoplasmic reticulum stress by proteasome impairment may contribute to the strong cytotoxicity of highly hydrophobic HPAAs, and proteasome impairment and the resulting excess endoplasmic reticulum stress is not a common cytotoxic effect of aggregate-prone proteins such as polyglutamine.