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With the increase in the older population, the number of individuals with age-related hearing loss is also growing explosively. Therefore, there is an urgent need to identify the detailed pathology of age-related hearing loss and develop novel treatment strategies. In this study, we have investigated the audiological physiology and cochlear pathology of advanced-age CBA/CaJ mice, a strain that resists early pathological hearing loss. The subjects were naturally aged close to their lifespan limit (> two years) under normal in vivo conditions. We used 11 CBA/CaJ mice aged between 129 and 138 weeks to establish an aged group. To compare the electrophysiological function and histological changes, a young group was established using 12 young mice aged between 9 and 14 weeks. The loss of outer hair cells peaked at 11.3 kHz, and the greatest synapse loss was observed in the 5.6 kHz region, which was covered by the dominant frequency in the ambient sound. Furthermore, atrophy and microthrombus formation occurred in the stria vascularis, with endolymphatic hydrops observed in the cochlear apical turn. In the spiral ganglion and cochlear nerve, a reduction in the number of cells was accompanied by morphological changes indicative of cell aging. Increased levels of derivative-reactive oxygen metabolites, an oxidative stress marker, were observed in aged mice. These results indicate that age-related hearing loss involves a combined pathology of acoustic cochlear damage, which is potentially associated with chronic sound exposure and metabolic changes owing to mitochondrial dysfunction and oxidative stress accumulation. Accordingly, these two distinct etiologies must be addressed to prevent and treat age-related hearing loss.

Blast exposure can induce various types of hearing impairment, including permanent hearing loss, tinnitus, and hyperacusis. Herein, we conducted a detailed investigation of the cochlear pathophysiology in blast-induced hearing loss in mice using two blasts with different characteristics: a low-frequency dominant blast generated by a shock tube and a high-frequency dominant shock wave generated by laser irradiation (laser-induced shock wave). The pattern of sensorineural hearing loss (SNHL) was low-frequency- and high-frequency-dominant in response to the low- and high-frequency blasts, respectively. Pathological examination revealed that cochlear synaptopathy was the most frequent cochlear pathology after blast exposure, which involved synapse loss in the inner hair cells without hair cell loss, depending on the power spectrum of the blast. This pathological change completely reflected the physiological analysis of wave I amplitude using auditory brainstem responses. Stereociliary bundle disruption in the outer hair cells was also dependent on the blast’s power spectrum. Therefore, we demonstrated that the dominant frequency of the blast power spectrum was the principal factor determining the region of cochlear damage. We believe that the presenting models would be valuable both in blast research and the investigation of various types of hearing loss whose pathogenesis involves cochlear synaptopathy.

Noise-induced hearing loss (NIHL) is one of the most common sensorineural hearing deficits. Recent studies have demonstrated that the pathogenesis of NIHL is closely related to ischemia-reperfusion injury of cochlea, which is caused by blood flow decrease and free radical production due to excessive noise. This suggests that protecting the cochlea from oxidative stress is an effective therapeutic approach for NIHL. NRF2 is a transcriptional activator playing an essential role in the defense mechanism against oxidative stress. To clarify the contribution of NRF2 to cochlear protection, we examined Nrf2 –/– mice for susceptibility to NIHL. Threshold shifts of the auditory brainstem response at 7 days post-exposure were significantly larger in Nrf2 –/– mice than wild-type mice. Treatment with CDDO-Im, a potent NRF2-activating drug, before but not after the noise exposure preserved the integrity of hair cells and improved post-exposure hearing levels in wild-type mice, but not in Nrf2 –/– mice. Therefore, NRF2 activation is effective for NIHL prevention. Consistently, a human NRF2 SNP was significantly associated with impaired sensorineural hearing levels in a cohort subjected to occupational noise exposure. Thus, high NRF2 activity is advantageous for cochlear protection from noise-induced injury and NRF2 is a promising target for NIHL prevention.

Objective Tonsillectomy is an essential surgery and is conducted on both children and adults. However, the risk factors of post‐tonsillectomy hemorrhage for adult patients remain unclear. In this study, we analyzed post‐tonsillectomy hemorrhage in adult patients. Methods We retrospectively analyzed 325 adult patients who underwent a tonsillectomy between 2014 and 2018 in our facilities. Results The average age of this study's population was 31.7 ± 10.5 years (range: 19‐70 years), and 250 (76.9%) patients were male. Overall, post‐tonsillectomy hemorrhage occurred in 71 (21.8%) patients and 5 (1.5%) patients required a second surgery for hemostasis. Post‐tonsillectomy hemorrhage often occurred on postoperative day zero or six. Using multiple logistic regression analysis, current smoking status (odds ratio 3.491; 95% confidence interval 1.813‐6.723), male sex (odds ratio 3.924; 95% confidence interval 1.548‐9.944), and perioperative non‐steroidal anti‐inflammatory drug administration (odds ratio 7.930; 95% confidence interval 1.004‐62.64) were revealed as overall post‐tonsillectomy hemorrhage risk factors. To analyze the hemorrhage period after tonsillectomy, we categorized the post‐tonsillectomy hemorrhage patients into the primary (bleeding within postoperative day one) and secondary hemorrhage (bleeding on or after postoperative day two) groups. The current smoking status and older age were risk factors for primary hemorrhage and the current smoking status and sex (male) were risk factors for secondary hemorrhage. Conclusions In this study, smoking status, sex, and perioperative non‐steroidal anti‐inflammatory drug administration were the clinical risk factors for adult post‐tonsillectomy hemorrhage. Thus, smoking cessation is, at least, mandatory for patients who receive tonsillectomy to avoid post‐tonsillectomy hemorrhage. Level of Evidence 4 Periods and categories of PTH. Among the 71 patients, eight had primary hemorrhage, and 63 had secondary hemorrhage. There were two peaks of frequency on postoperative days 0 and 6.

Objective To reveal the factors affecting the incidence of chorda tympani nerve (CTN) transection during middle ear surgery. Study Design Retrospective case review. Setting Tertiary referral center. Patients We analyzed 232 ears (117 ears with cholesteatoma, 101 ears with chronic otitis media, and 14 ears with otosclerosis) that underwent tympanoplasty or stapes surgery during 2017–2020. Intervention Eighty‐four ears underwent transcanal endoscopic ear surgery (TEES), 103 ears underwent microscopic ear surgery (MES), and 45 ears underwent surgery using both endoscopy and microscopy (Dual). Main Outcome Measure To confirm CTN transection, intraoperative endoscopic/microscopic video images were evaluated. We used the same video images to determine the anatomical variation of the CTN course in the middle ear. Results In 18 ears (7.8%: 6/84 TEES ears [7.1%], 6/103 MES ears [5.8%], and 6/45 Dual ears [13.3%]), the CTN was cut during middle ear surgery. There was no significant difference in CTN transection among groups. In cholesteatoma patients, stapes involvement resulted in a significantly higher CTN transection incidence. CTN anatomical variants such as the “Attached Short type” and “Ultrashort type” showed a significantly higher CTN transection incidence. Conclusion Although endoscopic surgery did not reduce the incidence of CTN transection during middle ear surgery, pathological involvement of the stapes and CTN anatomical variants, such as the “Attached Short type” and “Ultrashort type,” may increase this incidence. Preoperative evaluation of stapes involvement and anatomical location of the CTN course could help identify patients at greater risk for iatrogenic CTN transection. Level of Evidence 4. Although endoscopic surgery did not reduce the incidence of CTN cutting during middle ear surgery, pathological involvement of the stapes and a superior CTN course may increase this incidence. Preoperative evaluation of stapes involvement and anatomical location of the CTN course could help to prevent iatrogenic CTN injuries.

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.

Activator protein‐1 (AP‐1) is a transcriptional factor that regulates the expression of various genes associated with tumor invasion and migration. The purpose of our study was to assess the therapeutic effects of a novel selective AP‐1 inhibitor, T‐5224, in preventing lymph node metastasis in head and neck squamous cell carcinoma (HNSCC) in an orthotopic mouse model. We assessed the effect of T‐5224 on HNSCC cell invasion, migration, proliferation, and MMP activity by carrying out an in vitro study using an invasion assay, scratch assay, WST‐8 assay, and gelatin zymography. We also observed morphological changes in HNSCC cells by time‐lapse microscopy. Furthermore, cervical lymph node metastasis was assessed using an orthotopic tumor model of human oral squamous cell carcinoma cells (HSC‐3‐M3) injected in the tongue of a BALB/c nude mouse. T‐5224 (150 mg/kg) or vehicle was given orally every day for 4 weeks. Animals were killed and assessed for lymph node metastasis by H&E staining of resected lymph nodes. T‐5224 significantly inhibited the invasion, migration, and MMP activity of HNSCC cells in a dose‐dependent manner; there was no significant influence on cell proliferation. The antimetastatic effect of T‐5224 was also confirmed in our animal study. The rate of cervical lymph node metastasis in the model was 40.0% in the T‐5224‐treated group (n = 30) versus 74.1% in the vehicle‐treated group (n = 27; P < 0.05). In conclusion, T‐5224 inhibited the invasion and migration of HNSCC cells in vitro, and prevented lymph node metastasis in head and neck cancer in an animal model. AP‐1 inhibitor T‐5224 prevents lymph node metastasis in head and neck cancer model.

The ear is the organ that is most sensitive to blast overpressure and ear damage is most frequently seen after blast exposure. Blast overpressure to the ear results in sensorineural hearing loss, which is untreatable and is often associated with a decline in the quality of life. In this study, we used a rat model to demonstrate the pathophysiological and structural changes in the inner ear that replicate pure sensorineural hearing loss associated with blast injury using laser-induced shock wave (LISW) without any conductive hearing loss. Our results indicate that threshold elevation of the auditory brainstem response (ABR) after blast exposure was primarily caused by outer hair cell dysfunction induced by stereociliary bundle disruption. The bundle disruption pattern was unique; disturbed stereocilia were mostly observed in the outermost row, whereas those in the inner and middle rows stereocilia remained intact. In addition, the ABR examination showed a reduction in wave I amplitude without elevation of the threshold in the lower energy exposure group. This phenomenon was caused by loss of the synaptic ribbon. This type of hearing dysfunction has recently been described as hidden hearing loss caused by cochlear neuropathy, which is associated with tinnitus or hyperacusis.

Extracellular signal-regulated kinase (ERK) is a member of the family of mitogen-activated protein kinases (MAPKs) and coordinately regulates a multitude of cellular processes. In response to a variety of extracellular stimuli, phosphorylation of both threonine and tyrosine residues activates ERK. Recent evidence indicates that ERK is activated in response to cellular stress such as acoustic trauma. However, the specific role of ERK isoforms in auditory function is not fully understood. Here, we show that the isoform ERK2 plays an important role in regulating hair cell (HC) survival and noise-induced hearing loss (NIHL) in mice (C57BL/6J). We found that conditional knockout mice deficient for Erk2 in the inner ear HCs had hearing comparable to control mice and exhibited no HC loss under normal conditions. However, we found that these knockout mice were more vulnerable to noise and had blunted recovery from NIHL compared to control mice. Furthermore, we observed a significantly lower survival rate of inner hair cells in these mice compared to control mice. Our results indicate that ERK2 plays important roles in the survival of HC in NIHL.

Prophylactic elective neck dissection (ND) with navigation surgery using radioisotope-based sentinel lymph node biopsy (SLNB) is non-inferior to elective ND in terms of survival but has an advantage in postoperative functional disability. We conducted a subgroup analysis to identify predictive factors for false-negative (FN)-SLNB in patients with early oral cavity cancer. This study is a supplementary analysis using the dataset of a previously reported randomized clinical trial on SLN navigation surgery for oral cancers. This study investigated the association of clinical and SLN-related factors with false-negative cases in the SLNB group. From 2011 to 2016, 275 patients were enrolled and randomly assigned to the ND and SLNB study groups, with 134 patients assigned to the SLNB group. In the SLNB group, seven cases with negative SLNs and neck recurrences were judged as FN-SLNBs according to the general definition. The number of detected SLNs with and without adjusting for the propensity score was significantly associated with FNs in the logistic analysis. FN-SLNB was associated with the number of identified SLNs, suggesting the need for careful postoperative monitoring for neck recurrence in patients with one or two identified SLNs after acquiring sufficient experience in the identification technique.