Vestibular hair cells are more prone to damage by excessive acceleration insult in the mouse with KCNQ4 dysfunction.

KCNQ4 is a voltage-gated K+ channel was reported to distribute over the basolateral surface of type 1 vestibular hair cell and/or inner surface of calyx and heminode of the vestibular nerve connected to the type 1 vestibular hair cells of the inner ear. However, the precise localization of KCNQ4 is still controversial and little is known about the vestibular phenotypes caused by KCNQ4 dysfunction or the specific role of KCNQ4 in the vestibular organs. To investigate the role of KCNQ4 in the vestibular organ, 6-g hypergravity stimulation for 24 h, which represents excessive mechanical stimulation of the sensory epithelium, was applied to p.W277S Kcnq4 transgenic mice. KCNQ4 was detected on the inner surface of calyx of the vestibular afferent in transmission electron microscope images with immunogold labelling. Vestibular function decrease was more severe in the Kcnq4p.W277S/p.W277S mice than in the Kcnq4+/+ and Kcnq4+/p.W277S mice after the stimulation. The vestibular function loss was resulted from the loss of type 1 vestibular hair cells, which was possibly caused by increased depolarization duration. Retigabine, a KCNQ activator, prevented hypergravity-induced vestibular dysfunction and hair cell loss. Patients with KCNQ4 mutations also showed abnormal clinical vestibular function tests. These findings suggest that KCNQ4 plays an essential role in calyx and afferent of type 1 vestibular hair cell preserving vestibular function against excessive mechanical stimulation.

Noise induces intercellular Ca 2+ signaling waves and the unfolded protein response in the hearing cochlea.

Exposure to loud noise is a common cause of acquired hearing loss. Disruption of subcellular calcium homeostasis and downstream stress pathways in the endoplasmic reticulum and mitochondria, including the unfolded protein response, have been implicated in the pathophysiology of noise-induced hearing loss. However, studies on the association between calcium homeostasis and stress pathways has been limited due to limited ability to measure calcium dynamics in mature-hearing, noise-exposed mice. We used a genetically encoded calcium indicator mouse model in which GcAMP is expressed specifically in hair cells or supporting cells under control of Myo15Cre or Sox2Cre, respectively. We performed live calcium imaging and UPR gene expression analysis in 8-week-old mice exposed to levels of noise that cause cochlear synaptopathy (98 db SPL) or permanent hearing loss (106 dB SPL). UPR activation occurred immediately after noise exposure and was noise dose-dependent, with the pro-apoptotic pathway upregulated only after 106 dB noise exposure. Spontaneous calcium transients in hair cells and intercellular calcium waves in supporting cells, which are present in neonatal cochleae, were quiescent in mature-hearing cochleae, but re-activated upon noise exposure. 106 dB noise exposure was associated with more persistent and expansive ICS wave activity. These findings demonstrate a strong and dose-dependent association between noise exposure, UPR activation, and changes in calcium homeostasis in hair cells and supporting cells, suggesting that targeting these pathways may be effective to develop treatments for noise-induced hearing loss.

Synaptic ribbon dynamics after noise exposure in the hearing cochlea.

Moderate noise exposure induces cochlear synaptopathy, the loss of afferent ribbon synapses between cochlear hair cells and spiral ganglion neurons, which is associated with functional hearing decline. Prior studies have demonstrated noise-induced changes in the distribution and number of synaptic components, but the dynamic changes that occur after noise exposure have not been directly visualized. Here, we describe a live imaging model using RIBEYE-tagRFP to enable direct observation of pre-synaptic ribbons in mature hearing mouse cochleae after synaptopathic noise exposure. Ribbon number does not change, but noise induces an increase in ribbon volume as well as movement suggesting unanchoring from synaptic tethers. A subgroup of basal ribbons displays concerted motion towards the cochlear nucleus with subsequent migration back to the cell membrane after noise cessation. Understanding the immediate dynamics of synaptic damage after noise exposure may facilitate identification of specific target pathways to treat cochlear synaptopathy.

TMTC4 is a hair cell-specific human deafness gene.

Transmembrane and tetratricopeptide repeat 4 (Tmtc4) is a deafness gene in mice. Tmtc4-KO mice have rapidly progressive postnatal hearing loss due to overactivation of the unfolded protein response (UPR); however, the cellular basis and human relevance of Tmtc4-associated hearing loss in the cochlea was not heretofore appreciated. We created a hair cell-specific conditional KO mouse that phenocopies the constitutive KO with postnatal onset deafness, demonstrating that Tmtc4 is a hair cell-specific deafness gene. Furthermore, we identified a human family in which Tmtc4 variants segregate with adult-onset progressive hearing loss. Lymphoblastoid cells derived from multiple affected and unaffected family members, as well as human embryonic kidney cells engineered to harbor each of the variants, demonstrated that the human Tmtc4 variants confer hypersensitivity of the UPR toward apoptosis. These findings provide evidence that TMTC4 is a deafness gene in humans and further implicate the UPR in progressive hearing loss.

Correlation between serum vitamin D level and benign paroxysmal positional vertigo recurrence.

OBJECTIVE: Benign paroxysmal positional vertigo (BPPV) is the most common cause of dizziness in the general population. BPPV is known to be closely related to the serum vitamin D level. This study aimed to examine the relationship between serum vitamin D levels and BPPV recurrence. METHODS: A retrospective chart review was conducted on 50 patients diagnosed with posterior and lateral canal BPPV. The diagnosis of BPPV was based on the finding of vertigo and nystagmus induced by certain head positions (The Dix-Hallpike maneuver and head roll tests). The patients were classified into BPPV recurrence (Group A) and non-recurrence groups (Group B). Otolith function was assessed by cervical vestibular evoked myogenic potential (cVEMP) and ocular vestibular evoked myogenic potential (oVEMP), and their association with vitamin D levels was evaluated. RESULTS: There were 19 subjects in Group A and 31 in Group B. There were no significant differences in age, sex, cVEMP, and oVEMP between the two groups. The average vitamin D level was 12.9 ± 8.0 ng/mL for Group A and 19.2 ± 8.2 ng/mL for Group B, and the difference between the groups was significant (p = 0.011). In the receiver operating characteristic curve analysis for BPPV recurrence with the best sensitivity and specificity, the optimal cut-off value of total serum vitamin D was determined as 12.74 ng/mL. Furthermore, reclassifying the patients based on the cut-off value showed a significantly higher recurrence rate in the group with a lower serum vitamin D level (70.5% vs. 22.5%, p = 0.007). CONCLUSION: This complex finding highlights the importance of measuring serum vitamin D levels to monitor and evaluate patients at risk of BPPV recurrence.

Association of dietary factors with noise-induced hearing loss in Korean population: A 3-year national cohort study.

Noise-induced hearing loss (NIHL) is a hearing impairment (HI) caused by various clinical factors. Identifying the relationship between NIHL and nutrient consumption could help in reducing the prevalence of hearing loss. The aim of this study was to analyze the relationship between NIHL and dietary factors using data of the Korea National Health and Nutrition Examination survey (KNHANES). The data were collected from The Fifth KNHANES 2010-2012. The survey was taken by a total of 10,850 participants aged 20-65 years. Air conduction audiometry was measured at 500, 1000, 2000, and 4000 Hz in both ears. Metabolic syndrome, noise exposure, alcohol consumption, smoking, income level, marital status, and nutritional intake were evaluated. The differences between non-HI and HI participants in the noise-exposed group showed statistically significant differences in age, sex, marital and smoking status, alcohol consumption, and fasting glucose and triglyceride levels (p<0.05). In a multiple regression analysis of the noise-exposed group, age showed a significant association with HI (OR: 0.604; 95% CI: 0.538-0.678) after adjusting for confounders. In multivariate analysis for dietary factors affecting HI in noise-exposed groups, retinol (OR: 1.356; 95% CI: 1.068-1.722), niacin (OR: 1.5; 95% CI: 1.022-2.201), and carbohydrates (OR: 0.692; 95% CI: 0.486-0.985) showed a significant association with NIHL. Age was identified as the only factor significantly affecting NIHL. When the dietary factors of the noise-exposed group were analyzed, high intake of niacin and retinol and low intake of carbohydrates appeared to reduce the risk of hearing loss.

Comparison of Auditory Outcomes between Inpatient- and Outpatient-Based Treatment in Sudden Sensorineural Hearing Loss.

Objective: The primary treatment for sudden hearing loss is high-dose steroid therapy. In some countries, hospitalization has been taken for granted. Although most countries appear to treat sudden hearing loss on an outpatient basis, some other countries have considered hospitalization as necessary. Only a few studies have been conducted on the effect of hospitalization on hearing outcomes. Therefore, we compared the hearing outcome of inpatient- and outpatient-based treatments to determine whether hospitalization affects the recovery of sudden hearing loss. Methods: We conducted a retrospective case review of patients diagnosed with sudden sensorineural hearing loss (SSNHL). In total, 439 patients with SSNHL were enrolled and categorized as either inpatients (group I) or outpatients (group O). Pure-tone audiometry was initially performed before the treatment and 3 months post-treatment. "Recovery" was defined as a hearing gain of 15 dB HL and a final hearing of better than 25 dB. "No recovery" was defined as an improvement of hearing gain of <15 dB 3 months after treatment. To exclude the effect of the level of pretreatment hearing loss, we divided the patients into three subgroups based on their hearing level: <40 dB, 40−70 dB, and >70 dB. To assess the effect of the treatment modality, the patients were divided into three treatment subgroups: systemic steroids (SS), intratympanic steroids (ITS), and a combination of both (SS and ITS). Results: The pretreatment hearing level was significantly higher in group I (61.5 ± 25.4 dB) than in group O (50.3 ± 23.0 dB; p < 0.05). The hearing gain was significantly higher in group I (33.3 ± 24.4 dB) than in group O (24.0 ± 21.8 dB; p < 0.05). The "Recovery" ratio was significantly higher in group I (70.2%) than in group O (63.1%) (p < 0.05). A repeated measures ANOVA was performed to assess the statistical differences between hospitalization, treatment modalities, and pretreatment subgroups. The inpatient group showed a significant hearing improvement in all SSNHL patients (p < 0.05). There was a significant hearing improvement in the inpatient group with pretreatment hearing <40 and 40−70 dB (p < 0.05). There was no significant difference between the inpatient and outpatient groups in pretreatment hearing >70 dB (p > 0.05). Conclusions: This retrospective study showed that inpatient treatment for sudden hearing loss is more beneficial for hearing improvement than outpatient treatment. The positive effect of inpatient treatment appears to be significant in patients with a pretreatment hearing level of 70 dB or less.