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Abstract Transforming growth factor-β (TGF-β) signaling plays a significant role in multiple biological processes, including inflammation, immunity, and cell death. However, its specific impact on the cochlea remains unclear. In this study, we aimed to investigate the effects of TGF-β signaling suppression on auditory function and cochlear pathology in mice with kanamycin-induced ototoxicity. Kanamycin and furosemide (KM-FS) were systemically administered to 8-week-old C57/BL6 mice, followed by immediate topical application of a TGF-β receptor inhibitor (TGF-βRI) onto the round window membrane. Results showed significant TGF-β receptor upregulation in spiral ganglion neurons (SGNs) after KM-FA ototoxicity, whereas expression levels in the TGF-βRI treated group remained unchanged. Interestingly, despite no significant change in cochlear TGF-β expression after KM-FS ototoxicity, TGF-βRI treatment resulted in a significant decrease in TGF-β signaling. Regarding auditory function, TGF-βRI treatment offered no therapeutic effects on hearing thresholds and hair cell survival following KM-FS ototoxicity. However, SGN loss and macrophage infiltration were significantly increased with TGF-βRI treatment. These results imply that inhibition of TGF-β signaling after KM-FS ototoxicity promotes cochlear inflammation and SGN degeneration.

Abstract Objective Statins have been reported to improve vascular endothelial function and microcirculation, reduce oxidative stress, and exert anti‐inflammatory and protective effects against inner ear damage. Therefore, this study aimed to investigate the effect of statins on hearing prognosis in patients with idiopathic sudden sensorineural hearing loss (ISSNHL). Methods We reviewed the medical records of 149 patients diagnosed with ISSNHL. Clinical characteristics, hearing thresholds, statin medications, and hematological findings were investigated. First, patients with ISSNHL were assigned to the good and poor outcome groups, and factors influencing their prognosis were analyzed. Furthermore, patients with dyslipidemia were investigated to determine whether statins have therapeutic effects on ISSNHL. Results Significant differences in age (p = .011), days from the onset of ISSNHL to the initiation of treatment (p = .04), and hematological total cholesterol (TC; p = .015) between the good and poor outcome groups were observed. Furthermore, when hearing outcomes were investigated in patients with dyslipidemia, TC was significantly lower in the good outcome group (p = .03). Although no significant therapeutic effects of statins were observed in participants with dyslipidemia, patients in the statin‐treated group were significantly older and experienced more diabetic complications than those in the non‐statin‐treated group. Conclusion Although our study showed that dyslipidemia is a poor prognostic factor for ISSNHL, statins had no significant therapeutic effects on hearing recovery in ISSNHL patients with dyslipidemia. The patients that received statin medications were significantly older and experienced more diabetic complications, which may have affected their hearing prognosis. Level of Evidence Level 4.

Mammalian auditory hair cells transduce sound-evoked traveling waves in the cochlea into nerve stimuli, which are essential for hearing function. Pillar cells located between the inner and outer hair cells are involved in the formation of the tunnel of Corti, which incorporates outer-hair-cell-driven fluid oscillation and basilar membrane movement, leading to the fine-tuned frequency-specific perception of sounds by the inner hair cells. However, the detailed molecular mechanism underlying the development and maintenance of pillar cells remains to be elucidated. In this study, we examined the expression and function of brain-specific angiogenesis inhibitor 3 (Bai3), an adhesion G-protein-coupled receptor, in the cochlea. We found that Bai3 was expressed in hair cells in neonatal mice and pillar cells in adult mice, and, interestingly, Bai3 knockout mice revealed the abnormal formation of pillar cells, with the elevation of the hearing threshold in a frequency-dependent manner. Furthermore, old Bai3 knockout mice showed the degeneration of hair cells and spiral ganglion neurons in the basal turn. The results suggest that Bai3 plays a crucial role in the development and/or maintenance of pillar cells, which, in turn, are necessary for normal hearing function. Our results may contribute to understanding the mechanisms of hearing loss in human patients.

IntroductionSome idiopathic sudden sensorineural hearing loss (ISSHL) cases experience repetitive systemic corticosteroid treatment, but studies focusing on repetitive systemic corticosteroid administration have not been reported. Thus, we investigated the clinical characteristics and usefulness of repetitive systemic corticosteroid treatment in ISSHL cases.MethodsWe reviewed the medical records of 103 patients who received corticosteroids only in our hospital (single-treatment group), and 46 patients who presented at our hospital after receiving corticosteroids in a nearby clinic and were subsequently treated with corticosteroids again in our hospital (repetitive-treatment group). Clinical backgrounds, hearing thresholds, and hearing prognosis were assessed.ResultsThe final hearing outcomes were not different between the two groups. Further, in the repetitive-treatment group, statistical differences were found between the good and poor prognosis groups in the number of days to start corticosteroid administration (p = 0.03), the dose of corticosteroid (p = 0.02), and the duration of corticosteroid administration (p = 0.02) at the previous facility. Multivariate analysis revealed a significant difference in the dose of corticosteroids administered by the previous clinic (p = 0.004).ConclusionThe repetitive systemic corticosteroid administration might play a supplementary role in hearing improvement, and initial sufficient corticosteroid administration would lead to good hearing outcomes in an early phase of ISSHL.

Abstract The purpose of this study was to evaluate the prognostic value of quality of life (QOL) scores acquired not only pre-treatment, but also 1 month after treatment for locoregional control (LRC), distant metastasis-free survival (DMFS), and overall survival (OS) in patients with pharyngeal cancer treated using radiotherapy. Data for 102 patients with naso-, oro-, or hypo-pharyngeal cancer treated between December 2008 and September 2017 were retrospectively analyzed. About 90% of the patients were male. The European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire (QLQ-C30) was used for QOL assessments. Associations between QLQ-C30 scores before and 1 month after treatment and outcomes including LRC, DMFS, and OS were analyzed using Cox proportional hazard models. Median follow-up was 37 months (range, 5–117 months). Three-year LRC, DMFS, and OS rates were 77.8%, 60.0%, and 66.5%, respectively. Pre-treatment emotional functioning and diarrhea at 1 month after treatment were identified as significant predictors of LRC. Pre-treatment global QOL and diarrhea at 1 month after treatment were detected as significant predictors of DMFS. Pre-treatment emotional functioning, pre-treatment appetite loss, and diarrhea at 1 month after treatment were detected as significant predictors of OS. Diarrhea at 1 month after treatment was the most powerful QOL variable for predicting LRC, DMFS and OS. Our study revealed that several QOL scores not only before treatment but also 1 month after treatment correlated with LRC, DMFS and OS. In particular, the diarrhea domain of QOL at 1 month after treatment offered the most powerful prognosticator for pharyngeal cancer patients treated with radiotherapy.

Objective: We aimed to clarify the clinical features and surgical outcomes of descending necrotizing mediastinitis (DNM) to provide a guide for its surgical treatment, focusing on the type of extension and the deployed procedures. Methods: As a joint study of the Japan Broncho-esophagological Society and the Japanese Association for Chest Surgery (JBES1703/JACS1806 study), the clinical data of consecutive patients with DNM who underwent surgical drainage between 2012 and 2016 were collected from 131 participating institutions. The infection limited to the area superior to the carina level was defined as type I; while spreading to the lower mediastinum (LM) as type II. The LM infection limited to the anterior LM, that spread to both the anterior and posterior LM and that limited the posterior LM (type IIC) were further categorized as type IIA, IIB, and IIC, respectively. Results: A total of 225 patients were ultimately eligible. One hundred patients (44.4%) were categorized as type I, whereas 125 patients were type II (56.6%); The number of type IIA, IIB, and IIC cases was 20 (16%), 62 (49.6%) and 43 (34.4%), respectively. Patients with type I and IIC infections more commonly underwent cervical drainage than patients with type IIA and IIB infections (34.3% and 13.4%, respectively). A total of 8 patients died within 30 days (3.6%, type I/II: 1/7). The 5-year overall survival rate was 68.6%. Type II infection was associated with the 90-day mortality (odds ratio, 5.18; P = .045). Conclusions: This study demonstrated a previously unclassified group of lower mediastinal extent that is localized within the posterior mediastinum (type IIC). We proposed a new DNM classification including type IIC mediastinitis.

Abstract Background Patients undergoing hemodialysis (HD) tend to experience hearing loss, including idiopathic sudden sensorineural hearing loss (ISSHL). However, little is known about the relationship between HD and ISSHL. Objective To investigate the effects of HD on the hearing level and the treatment prognosis of ISSHL. Methods We reviewed the medical records of 23 patients with ISSHL receiving HD treatment (HD group) and 101 patients with ISSHL not receiving HD treatment (non‐HD group), and assessed clinical features, results of audiometric tests and blood examination results. Results Statistically significant differences were not observed in pretreatment hearing level and hearing recovery of the ear affected with ISSHL between the two groups (P > .05). Conversely, hearing thresholds in the unaffected ear were statistically different (P

Abstract Hearing loss is associated with cognitive decline and dementia risk. Sensorineural hearing loss suppresses hippocampal neurogenesis, resulting in cognitive decline. However, the underlying mechanism of impaired neurogenesis and the role of microglial activation and stress responses related to hearing loss in the hippocampus remains unknown. Using a conductive hearing loss (CHL) model, we investigated whether a decrease in sound level could induce impairment of hippocampal neurogenesis and examined the differences between unilateral CHL (uCHL) and bilateral CHL (bCHL). To establish the CHL mouse model, ears were unilaterally or bilaterally occluded for five weeks by auditory canal ligation. Although hearing thresholds were significantly increased following CHL, CHL mice exhibited no significant loss of spiral ganglion or hippocampal neurons. Hippocampal neurogenesis was significantly and equally decreased in both sides following uCHL. More severe decreases in hippocampal neurogenesis were observed in both sides in bCHL mice compared with that in uCHL mice. Furthermore, microglial invasion significantly increased following CHL. Serum cortisol levels, which indicate stress response, significantly increased following bCHL. Therefore, auditory deprivation could lead to increased microglial invasion and stress responses and might be a risk factor for hippocampal neurogenesis impairment.

Abstract Background There is increasing evidence that immunotherapy with nivolumab, an anti‐programmed death 1 monoclonal antibody, is effective in the treatment of recurrent or metastatic squamous cell carcinoma of the head and neck (R/M SCCHN). However, the predictive role of hematological inflammatory markers such as neutrophil‐to‐lymphocyte ratio (NLR) and the modified Glasgow prognostic score (mGPS) in patients with R/M SCCHN treated with nivolumab remains unclear. Methods We conducted a multi‐institutional cohort study to evaluate the impact of pretreatment NLR and mGPS on overall survival (OS) and progression‐free survival (PFS) in patients with R/M SCCHN treated with nivolumab in Japan. From 2012 to 2013, 102 patients were eligible, of whom 88 were finally included in the analysis. mGPS was calculated as follows: mGPS of 0, C‐reactive protein (CRP) ≤1.0 mg/dL; 1, CRP > 1.0 mg/dL; and 2, CRP > 1.0 mg/dL and albumin

Abstract Background Disseminated cryptococcosis is a well-characterized complication in immunocompromised patients with cryptococcal pneumonia or meningitis; however, isolated cryptococcal osteomyelitis is a rare entity that occurs in approximately 5% of patients with cryptococcosis. Cryptococcal osteomyelitis in the head and neck region is extremely rare. To the best of our knowledge, no cases of cryptococcal osteomyelitis affecting only the zygomatic bone have been reported to date. Case presentation A 78-year-old man without other comorbidities presented with progressive swelling of the right cheek along with pain and trismus. Clinical examination revealed a tender swelling in the right zygomatic region; the maximal mandibular opening was about 2 cm. Laboratory data showed mildly elevated inflammatory indices (C-reactive protein: 0.45 mg/dL; erythrocyte sedimentation rate: 35 mm/h). Computed tomography showed a 30-mm-diameter lesion at the right zygomatic arch. A part of the lesion has extended to the subcutaneous area of the cheeks with signs of bone destruction and surrounding contrast effects. Histopathological examination of fine-needle aspirate and needle biopsy showed cryptococcus. Furthermore, culture of the aspirate showed growth of Cryptococcus neoformans. No evidence of any other site involvement was observed. Therefore, the patient was diagnosed with isolated cryptococcal osteomyelitis and was initiated on fluconazole therapy. The treatment was effective, and all symptoms were resolved in 4 weeks. Fluconazole therapy was stopped after 6 months. There are no signs of recurrence as of 15-month follow-up. The patient has no cosmetic abnormalities or sequelae. Conclusions Fine-needle aspiration cytology, needle biopsy, and fungal culture were useful for definitive diagnosis. Immunocompetent patients with isolated osteomyelitis may be cured with oral fluconazole alone.

Abstract Background The aim of this study was to explore the relationships between dosimetric parameters of organs at risk and patient-reported outcomes (PRO) after radiotherapy of patients with head and neck cancer. Methods PRO data of 53 patients with head and neck cancer treated with radiotherapy were prospectively collected. These data concerned health-related quality of life (HRQOL) and were collected using the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (QLQ-C30) and head and neck cancer module (QLQ-H&N35). Patients were divided into “severe-deterioration” and “mild-deterioration” groups on the basis of degree of deterioration HRQOL > 6 months after completing treatment. The relationships between HRQOL deteriorations and patient-related or dosimetry-related factors were evaluated. P

Tracheal stenosis is a refractory and recurrent disease induced by excessive cell proliferation within the restricted tracheal space. We investigated the role of extracellular signal-regulated kinase (ERK), which mediates a broad range of intracellular signal transduction processes in tracheal stenosis and the therapeutic effect of the MEK inhibitor which is the upstream kinase of ERK. We histologically analyzed cauterized tracheas to evaluate stenosis using a tracheal stenosis mouse model. Using Western blot, we analyzed the phosphorylation rate of ERK1/2 after cauterization with or without MEK inhibitor. MEK inhibitor was intraperitoneally injected 30 min prior to cauterization (single treatment) or 30 min prior to and 24, 48, 72, and 96 hours after cauterization (daily treatment). We compared the stenosis of non-inhibitor treatment, single treatment, and daily treatment group. We successfully established a novel mouse model of tracheal stenosis. The cauterized trachea increased the rate of stenosis compared with the normal control trachea. The phosphorylation rate of ERK1 and ERK2 was significantly increased at 5 min after the cauterization compared with the normal controls. After 5 min, the rates decreased over time. The daily treatment group had suppressed stenosis compared with the non-inhibitor treatment group. p-ERK1/2 activation after cauterization could play an important role in the tracheal wound healing process. Consecutive inhibition of ERK phosphorylation is a potentially useful therapeutic strategy for tracheal stenosis.

We encountered a rare case of venous malformation located in the parapharyngeal space. The 65-year-old female patient did not have any symptoms, and the malformation was discovered incidentally during a clinical survey. Examination of the oral cavity revealed a mass in the left soft palate. Magnetic resonance imaging showed a well-defined mass in the left parapharyngeal space. Fine needle aspiration cytology suggested no malignancy. Four years after the first visit, she underwent surgery for diagnosis and treatment. We safely removed the mass with a rigid videoendoscope trans-orally. No postoperative complications arose, and she was discharged 7 days after the operation. Histopathological examination identified cavernous hemangioma. Venous malformation (cavernous hemangioma) of the parapharyngeal space is very rare, and few cases of removal under a transoral approach using a rigid endoscope with a flexible tip have been reported. This approach is safe and can be recommended for selected tumors of the parapharyngeal space.

Human neuroglobin (Ngb) is a heme protein expressed in the brain tissue and retina with an important neuroprotective role. However, its molecular mechanism is still under exploration. To gain further insight into this issue, we developed an electrochemical strategy using a facilely prepared nanoporous gold (NPG) electrode. Immobilization of Ngb onto the NPG surface enabled rapid direct electron transfer between Ngb and the electrode, whereas less electrochemical response was generated using a planar gold electrode. Voltammograms recorded using the NPG electrodes gave an E0′ value of −0.170 V (vs. standard hydrogen electrode (SHE)), which is in good agreement with the previously reported values. Furthermore, a heterogeneous electron transfer rate constant of 46 s−1 was obtained, which was larger than the rate constants reported previously. The addition of ferric cytochrome c (Cyt c), a potential redox partner protein of Ngb, increased the cathodic current in the voltammogram, indicating the electron transfer from the reduced (ferrous) Ngb to the ferric Cyt c. In addition, mutational studies demonstrated for the first time that the disulfide bond formation between Cys46 and Cys55 is important for this electron transfer. These results may indicate that ferrous Ngb, in addition to the ferric form, also contributes to the anti-apoptotic properties of Ngb, depending on the disulfide bond formation. Thus, the NPG-based electrochemical system developed in our study is an effective tool for uncovering the molecular basis of Ngb coupled with electron transfer. Keywords: Human neuroglobin, Direct electron transfer, Nanoporous gold, Cytochrome c, Anti-apoptotic

Background: Occupied lesions arising in the parapharyngeal space (PPS) are rare. Among these, venous malformations are particularly rare, and very few case reports have appeared. Methods: Two patients with venous malformations in the PPS were operated on by the same surgeon. Here, we report the patient and tumor characteristics, symptoms, preoperative examinations and diagnoses, treatment plans, intraoperative findings and refinements, histological diagnoses, and postoperative complications, in combination with a review of past reports. Results: The patients were two men aged 37 and 29 years who had persistent swelling and pain in the right parotid region. Imaging showed masses in the prestyloid compartment of the right PPS with maximum diameters of 69 and 54 mm, respectively. Fine needle aspiration cytology (FNAC) showed blood cell components only in both cases and no diagnosis could be made. Both cases were treated with surgery. The facial nerve was identified and preserved, and the soft lesion was removed using a transcervical-parotid approach. Post-operative histological diagnosis was venous malformation in both and no post-operative recurrence was seen. Conclusion: Venous malformations arising in the PPS are clearly distinguishable from major PPS tumors. The preoperative diagnosis and intraoperative refinements reported here were effective in these cases. Keywords: Parapharyngeal space, Venous malformation, Hemangioma, Surgical case

Objective This study aimed to validate new staging of Japanese patients with human papillomavirus-mediated oropharyngeal cancer (HPV + -OPC) and the effectiveness of transoral surgery. Methods Fifty-three patients with HPV + -OPC were classified according to the seventh and eighth editions of the American Joint Committee on Cancer (AJCC) staging, along with assessment of prognosis, smoking and alcohol status, and treatment outcome. Transoral videolaryngoscopic surgery (TOVS) was performed as transoral surgery. Results The 5-year overall survival (OS) rate was 77.3% in all patients. Five-year OS rates of seventh edition staging were as follows: II, 100%; III, 100%; IVa, 75.9%; and IVb and IVc, 0%. Five-year OS rates of the eighth edition clinical staging were as follows: I, 89.3%; II, 88.9%; III, 46.3%; and IV, 0%. In non-smoking and smoking patients with HPV + -OPC, the 5-year OS rates were 90.9% and 70.7%, respectively. TOVS was used for treating 20 smokers with HPV + -OPC (5-year OS: 85.7%), while 12 were treated with chemoradiotherapy (5-year OS: 75.0%). Conclusions The eighth edition of the AJCC determines the prognosis of HPV + -OPC more accurately than the seventh edition in clinical staging. Smokers with HPV + -OPC have a poor prognosis, but TOVS might improve the prognosis.

Various peptides and their derivatives have been reported to exhibit antimicrobial activities. Although these activities have been examined against microorganisms, novel methods have recently emerged for conjugation of the biomaterials to improve their activities. Here, we prepared CKR12-PLGA, in which CKR12 (a mutated fragment of human cathelicidin peptide, LL-37) was conjugated with poly (lactic-co-glycolic) acid (PLGA), and compared the antimicrobial and antifungal activities of the conjugated peptide with those of FK13 (a small fragment of LL-37) and CKR12 alone. The prepared CKR12-PLGA was characterized by dynamic light scattering and measurement of the zeta potential, critical micellar concentration, and antimicrobial activities of the fragments and conjugate. Although CKR12 showed higher antibacterial activities than FK13 against Staphylococcus aureus and Escherichia coli, the antifungal activity of CKR12 was lower than that of FK13. CKR12-PLGA showed higher antibacterial activities against S. aureus and E. coli and higher antifungal activity against Candida albicans compared to those of FK13. Additionally, CKR12-PLGA showed no hemolytic activity in erythrocytes, and scanning and transmission electron microscopy suggested that CKR12-PLGA killed and disrupted the surface structure of microbial cells. Conjugation of antimicrobial peptide fragment analogues was a successful approach for obtaining increased microbial activity with minimized cytotoxicity.

Chiral stationary phases based on chicken alpha 1-acid glycoprotein (cAGP) have been used for enantioseparations of various compounds. However, the chiral binding sites and mechanism have not been clarified yet. Based on chromatographic properties of native and W26-modified cAGP columns and docking simulations of studied compounds into the generated model structure of cAGP, the chiral binding sites were located on cAGP and the chiral binding mechanism was discussed. On cAGP, there existed a binding cavity lined with H25, W26, Y47, R128, T129, D161 and E168, which contribute electrostatic or hydrogen bonding interactions. Benzoin and chlorpheniramine enantiomers interacted with cAGP at almost the same sites a little away from W26, while propranolol enantiomers docked, slightly shifting toward H25 and W26. Furthermore, in addition to hydrophobic interactions, ionic interactions between amino groups of chlorpheniramine enantiomers and a carboxyl group of D161 or E168 played an important role in the chiral recognition, while hydrophobic interactions and hydrogen bonding interactions worked for the chiral recognition of benzoin and propranolol enantiomers.

Auditory nerve fibers synapse onto the cochlear nucleus (CN) and are labeled using the vesicular glutamate transporter-1 (VGLUT-1), whereas non-auditory inputs are labeled using the VGLUT-2. However, the underlying regulatory mechanism of VGLUT expression in the CN remains unknown. We examined whether a sound level decrease, without primary neural damage, induces cellular and VGLUT expression change in the CN, and examined the potential for neural plasticity of the CN using unilateral conductive hearing loss models. We inserted earplugs in 8-week-old mice unilaterally for 4 weeks and subsequently removed them for another 4 weeks. Although the threshold of an auditory brainstem response significantly increased across all tested frequencies following earplug insertion, it completely recovered after earplug removal. Auditory deprivation had no significant impact on spiral ganglion and ventral CN (VCN) neurons’ survival. Conversely, although the cell size and VGLUT-1 expression in the VCN significantly decreased after earplug insertion, VGLUT-2 expression in the granule cell lamina significantly increased. These cell sizes decreased and the alterations in VGLUT-1 and -2 expression almost completely recovered at 1 month after earplug removal. Our results suggested that the cell size and VGLUT expression in the CN have a neuroplasticity capacity, which is regulated by increases and decreases in sound levels. Restoration of the sound levels might partly prevent cell size decrease and maintain VGLUT expression in the CN.