L-Ergothioneine slows the progression of age-related hearing loss in CBA/CaJ mice.

The naturally occurring amino acid, l-ergothioneine (EGT), has immense potential as a therapeutic, having shown promise in the treatment of other disease models, including neurological disorders. EGT is naturally uptaken into cells via its specific receptor, OCTN1, to be utilized by cells as an antioxidant and anti-inflammatory. In our current study, EGT was administered over a period of 6 months to 25-26-month-old CBA/CaJ mice as a possible treatment for age-related hearing loss (ARHL), since presbycusis has been linked to higher levels of cochlear oxidative stress, apoptosis, and chronic inflammation. Results from the current study indicate that EGT can prevent aging declines of some key features of ARHL. However, we found a distinct sex difference for the response to the treatments, for hearing - Auditory Brainstem Responses (ABRs) and Distortion Product Otoacoustic Emissions (DPOAEs). Males exhibited lower threshold declines in both low dose (LD) and high dose (HD) test groups throughout the testing period and did not display some of the characteristic aging declines in hearing seen in Control animals. In contrast, female mice did not show any therapeutic effects with either treatment dose. Further confirming this sex difference, EGT levels in whole blood sampling throughout the testing period showed greater uptake of EGT in males compared to females. Additionally, RT-PCR results from three tissue types of the inner ear confirmed EGT activity in the cochlea in both males and females. Males and females exhibited significant differences in biomarkers related to apoptosis (Cas-3), inflammation (TNF-a), oxidative stress (SOD2), and mitochondrial health (PGC1a).These changes were more prominent in males as compared to females, especially in stria vascularis tissue. Taken together, these findings suggest that EGT has the potential to be a naturally derived therapeutic for slowing down the progression of ARHL, and possibly other neurodegenerative diseases. EGT, while effective in the treatment of some features of presbycusis in aging males, could also be modified into a general prophylaxis for other age-related disorders where treatment protocols would include eating a larger proportion of EGT-rich foods or supplements. Lastly, the sex difference discovered here, needs further investigation to see if therapeutic conditions can be developed where aging females show better responsiveness to EGT.

Bile Acid Application in Cell-Targeting for Molecular Receptors in Relation to Hearing: A Comprehensive Review.

Bile acids play important roles in the human body, and changes in their pool can be used as markers for various liver pathologies. In addition to their functional effects in modulating inflammatory responses and cellular survivability, the unconjugated or conjugated, secondary, or primary nature of bile acids accounts for their various ligand effects. The common hydrophilic bile acids have been used successfully as local treatment to resolve drug-induced cell damage or to ameliorate hearing loss. From various literature references, bile acids show concentration and tissue-dependent effects. Some hydrophobic bile acids act as ligands modulating vitamin D receptors, muscarinic receptors, and calcium-activated potassium channels, important proteins in the inner ear system. Currently, there are limited resources investigating the therapeutic effects of bile acid on hearing loss and little to no information on detecting bile acids in the remote ear system, let alone baseline bile acid levels and their prevalence in healthy and disease conditions. This review presents both hydrophilic and hydrophobic human bile acids and their tissue-specific effects in modulating cellular integrity, thus considering the possible effects and extended therapeutic applicability of bile acids to the inner ear tissue.

In vivo real-time imaging reveals megalin as the aminoglycoside gentamicin transporter into cochlea whose inhibition is otoprotective.

Aminoglycosides (AGs) are commonly used antibiotics that cause deafness through the irreversible loss of cochlear sensory hair cells (HCs). How AGs enter the cochlea and then target HCs remains unresolved. Here, we performed time-lapse multicellular imaging of cochlea in live adult hearing mice via a chemo-mechanical cochleostomy. The in vivo tracking revealed that systemically administered Texas Red-labeled gentamicin (GTTR) enters the cochlea via the stria vascularis and then HCs selectively. GTTR uptake into HCs was completely abolished in transmembrane channel-like protein 1 (TMC1) knockout mice, indicating mechanotransducer channel-dependent AG uptake. Blockage of megalin, the candidate AG transporter in the stria vascularis, by binding competitor cilastatin prevented GTTR accumulation in HCs. Furthermore, cilastatin treatment markedly reduced AG-induced HC degeneration and hearing loss in vivo. Together, our in vivo real-time tracking of megalin-dependent AG transport across the blood-labyrinth barrier identifies new therapeutic targets for preventing AG-induced ototoxicity.

Complications and prognosis associated with intra-tympanic steroid injection to treat sudden sensorineural hearing impairment.

PURPOSE: The purpose of this study was to measure the incidence of complications in sudden sensorineural hearing loss (SSNHL) patients treated with intra-tympanic steroid injection (ITSI) and compare hearing recovery rates. MATERIALS AND METHODS: 123 patients with unilateral SSNHL receiving ITSIs were included in this study. Post-ITSI complications were documented including otalgia, dysgeusia, vertigo (duration>1 h), and persistent eardrum perforation. The pain intensity was evaluated with visual analog scale (VAS). Hearing was measured before ITSI and at 1 month after the final ITSI. We compared our patients' hearing threshold between presence and absence of different complications. RESULTS: 47.2% patients experienced post-injection otalgia with the average VAS score 3.2 (range 2-6). Five (4.1%) and six (4.9%) patients exhibited vertigo and persistent eardrum perforations, respectively. The patients were divided into three groups based on the absence of complications and the presence of vertigo and eardrum perforation. The hearing threshold improvements did not differ significantly among the three groups (p = 0.366). Although the difference was not significant (p = 0.664), the proportion of patients experiencing post-ITSI vertigo who were on contemporaneous oral steroids was lower than the proportion of non-vertigo patients on such steroids. CONCLUSION: The incidences of otalgia, vertigo, and persistent eardrum perforation in SSNHL patients treated with ITSI were 47.2%, 4.1% and 4.9%, respectively. We found no association between concurrent oral steroid use and the incidence of post-ITSI eardrum perforation or vertigo. Although statistical significance was lacking, patients who did not take contemporaneous oral steroids may have a higher rate of prolonged post-ITSI vertigo.

A BK channel-targeted peptide induces age-dependent improvement in behavioral and neural sound representation.

Recent evidence suggests that modulation of the large-conductance, calcium-activated potassium (BK) channel regulates auditory processing in the brain. Because ion channel expression often changes during aging, this could be a factor in age-related hearing loss. The current study explored how the novel BK channel modulator LS3 shapes central auditory processing in young and old adult mice. In vivo extracellular recordings in the auditory midbrain demonstrated that LS3 differentially modulates neural processing along the tonotopic axis. Though sound-evoked activity was reduced in the mid and ventral tonotopic regions, LS3 enhanced excitatory drive and sound-evoked responses for some neurons in the dorsal, low-frequency region. Behavioral assessment using acoustic reflex modification audiometry indicated improved tone salience following systemic LS3 administration. Moderation of these responses with aging correlated with an age-related decline in BK channel expression. These findings suggest that targeting the BK channel enhances responsivity to tonal sounds, providing the potential to improve hearing acuity and treat hearing loss.

Thymoquinone ameliorates age-related hearing loss in C57BL/6J mice by modulating Sirt1 activity and Bak1 expression.

Age-related hearing loss (AHL) is the most common sensory disorder of aged population. Currently, one of the most important sources of experimental medicine for AHL is medicinal plants. This study performed the first investigation of the effect of thymoquinone (TQ), a potent antioxidant, on AHL. Here, we used inbred C57BL/6J mice (B6 mice) as a successful experimental model of the early onset of AHL. The behavioral assessment of hearing revealed that the injection of a high dose of TQ (40 mg/kg; TQ40) significantly improved the auditory sensitivity of B6 mice at all tested frequencies (8, 16 and 22 kHz). Histological sections of cochlea from B6 mice injected with a low dose (20 mg/kg; TQ20) and high dose showed relatively less degenerative signs in the modiolus, hair cells and spiral ligaments, the main constituents of the cochlea. In addition, TQ40 completely restored the normal pattern of hair cells in B6 mice, as shown in scanning electron micrographs. Our data indicated that TQ20 and TQ40 reduced levels of Bak1-mediated apoptosis in the cochlea of B6 mice. Interestingly, the level of Sirt1, a positive regulator of autophagy, was significantly increased in B6 mice administered TQ40. In conclusion, TQ relieves the symptoms of AHL by downregulating Bak1 and activating Sirt1 in the cochlea of B6 mice.

Efficacy of middle-ear packing in success of type 1 tympanoplasty: a prospective randomised study.

OBJECTIVE: A prospective randomised study was undertaken to compare the results of type 1 tympanoplasty with and without middle-ear packing with gelfoam. METHOD: Eighty patients undergoing type 1 tympanoplasty were randomised into two groups according to packing in the middle ear: with gelfoam and without gelfoam. The data in terms of graft uptake rate, hearing gain and subjective improvement were analysed at one and three months. RESULTS: The graft uptake rate between both groups did not show a statistically significant difference. There was conductive hearing loss in the gelfoam group in the early post-operative period. Subjectively, patients were more comfortable with respect to heaviness and hearing gain than in the non-gelfoam group. CONCLUSION: Gelfoam use in middle-ear packing is not an essential step and causes more discomfort in patients during the early post-operative period. It should be a surgeon's choice to use it when and where it is necessary.

Modulation of NAD+ biosynthesis activates SIRT1 and resists cisplatin-induced ototoxicity.

Cisplatin, the most widely used platinum-based anticancer drug, often causes progressive and irreversible sensorineural hearing loss in cancer patients. However, the precise mechanism underlying cisplatin-associated ototoxicity is still unclear. Nicotinamide adenine dinucleotide (NAD+), a co-substrate for the sirtuin family and PARPs, has emerged as a potent therapeutic molecular target in various diseases. In our investigates, we observed that NAD+ level was changed in the cochlear explants of mice treated with cisplatin. Supplementation of a specific inhibitor (TES-1025) of α-amino-ß-carboxymuconate-ε-semialdehyde decarboxylase (ACMSD), a rate-limiting enzyme of NAD+de novo synthesis pathway, promoted SIRT1 activity, increased mtDNA contents and enhanced AMPK expression, thus significantly reducing hair cells loss and deformation. The protection was blocked by EX527, a specific SIRT1 inhibitor. Meanwhile, the use of NMN, a precursor of NAD+ salvage synthesis pathway, had shown beneficial effect on hair cell under cisplatin administration, effectively suppressing PARP1. In vivo experiments confirmed the hair cell protection of NAD+ modulators in cisplatin treated mice and zebrafish. In conclusion, we demonstrated that modulation of NAD+ biosynthesis via the de novo synthesis pathway and the salvage synthesis pathway could both prevent ototoxicity of cisplatin. These results suggested that direct modulation of cellular NAD+ levels could be a promising therapeutic approach for protection of hearing from cisplatin-induced ototoxicity.

Osteoporosis, bisphosphonate use, and risk of moderate or worse hearing loss in women.

BACKGROUND: Osteoporosis and low bone density (LBD) may be associated with higher risk of hearing loss, but findings are inconsistent and longitudinal data are scarce. Bisphosphonates may influence risk, but the relation has not been studied in humans. We longitudinally investigated associations of osteoporosis and LBD, bisphosphonate use, vertebral fracture (VF), hip fracture (HF), and risk of self-reported moderate or worse hearing loss. DESIGN: Longitudinal cohort study. SETTING: The Nurses' Health Study (NHS) (1982-2016) and Nurses' Health Study II (NHS II) (1995-2017). PARTICIPANTS: Participants included 60,821 NHS women, aged 36-61 years at baseline, and 83,078 NHS II women, aged 31-48 years at baseline (total n = 143,899). MEASUREMENTS: Information on osteoporosis, LBD, bisphosphonate use, VF, HF, and hearing status was obtained from validated biennial questionnaires. In a subcohort (n = 3749), objective hearing thresholds were obtained by audiometry. Multivariable-adjusted Cox proportional hazards models were used to examine independent associations between osteoporosis (NHS), osteoporosis/LBD (NHS II), and risk of hearing loss. RESULTS: The multivariable-adjusted relative risk (MVRR, 95% confidence interval) of moderate or worse hearing loss was higher among women with osteoporosis or LBD in both cohorts. In NHS, compared with women without osteoporosis, the MVRR was 1.14 (1.09, 1.19) among women with osteoporosis; in NHS II, the MVRR was 1.30 (1.21, 1.40) among women with osteoporosis/LBD. The magnitude of the elevated risk was similar among women who did and did not use bisphosphonates. VF was associated with higher risk (NHS: 1.31 [1.16, 1.49]; NHS II: 1.39 [1.13, 1.71]), but HF was not (NHS: 1.00 [0.86, 1.16];NHS II: 1.15 [0.75,1.74]). Among participants with audiometric measurements, compared with women without osteoporosis/LBD, the mean multivariable-adjusted hearing thresholds were higher (i.e., worse) among those with osteoporosis/LBD who used bisphosphonates. CONCLUSION: Osteoporosis and LBD may be important contributors to aging-related hearing loss. Among women with osteoporosis, the risk of hearing loss was not influenced by bisphosphonate use.

The relationship between chronic exposure to arsenic through drinking water and hearing function in exposed population aged 10-49 years: A cross-sectional study.

It has been documented that arsenic has a potential risk to human health and identified as a risk factor for hearing impairment. However, there are few studies that confirm the ototoxic effect of arsenic, especially on the human auditory system. Therefore, the current study was conducted to investigate the correlation between auditory thresholds at different frequencies (0.25, 0.5, 1, 2, 4 and 8 kHz) and arsenic levels in drinking water samples. A total of 240 people, divided into two equal groups: exposed and reference, were selected for the auditory tests. It should be noted that, at frequencies from 0.25 to 1 kHz, no hearing loss was observed in the both groups. Based on the results, no significant correlations (p > 0.05) were found between hearing thresholds and confounding variables including gender and BMI. However, smoking and age are known to be the main variables for hearing loss in univariate regression analysis. In the case of age, the hearing loss risk in the older participants was increased compared with the younger participants (4 kHz (OR =1.09; 95% CI: 1.04, 1.13) and 8 kHz (OR =1.12; 95% CI: 1.06, 1.18)). Smoking habits had significant associations with hearing loss risk at 4 kHz (OR = 3.48; 95% CI: 1.47, 8.22) and 8 kHz (OR = 3.01; 95% CI: 1.14, 7.95). The multivariate regression analysis showed that age, smoking status, and exposure to arsenic were significantly associated with increased risk of hearing loss. Moreover, no statistically significant correlation (p˃0.05) was observed between arsenic exposure and hearing loss in the logistic regression model compared to the reference group. These outcomes suggest that further investigation and cohort studies with a larger number of participants should be conducted to find an association between arsenic exposure and hearing loss in general population.

Comparison of 2 Different Intratympanic Methylprednisolone Injection Schedules in Combination With Intravenous Dexamethasone for Unilateral Sudden Sensorineural Hearing Loss.

Sudden sensorineural hearing loss is a common otologic disease in clinic. Systemic and intratympanic steroid treatment have been proved to be effective, but the regimens vary from center to center. The purpose of the study is to analyze the effects of the combined application of intravenous dexamethasone and intratympanic methylprednisolone injection in different time strategies for the treatment of unilateral sudden sensorineural hearing loss. A retrospective chart review was performed for the period from March 2016 to June 2018 at our Department of Otorhinolaryngology-Head and Neck Surgery. A total number of 61 patients who met the academy criteria for unilateral sudden hearing loss were included and grouped based on the time to introduce intratympanic methylprednisolone. All the patients received intravenous dexamethasone 10 mg once daily for 5 days, followed 5 mg once daily for the next 7 days. Intratympanic methylprednisolone (40 mg) was injected every other day 4 times into all patients. This regimen was commenced on day 1 in group 1 and on day 6 in group 2. The pre and posttreatment pure-tone audiograms were analyzed. Sixty-one patients met our inclusion criteria. No significant differences were observed between patients' demographics or pretreatment hearing thresholds. In the 3 months posttreatment pure-tone audiogram assessment, the mean hearing threshold improvement were similar between groups with no frequency specificity. The curative rate in both groups were similar and satisfying. Two patients with diabetes mellitus had persistent small perforations. Some patients had other transient discomfort that disappeared before discharge. The different timing of initiation of intratympanic methylprednisolone injection does not significantly affect the outcome of the treatment for sudden sensorineural hearing loss. Thus, we suggest that intratympanic steroid injection should not be applied as a first-line method except for patients who do not respond early to systemic steroid therapy.

Prophylactic nimodipine treatment improves hearing outcome after vestibular schwannoma surgery in men: a subgroup analysis of a randomized multicenter phase III trial.

A 2016 published randomized multicenter phase III trial of prophylactic nimodipine treatment in vestibular schwannoma surgery showed only a tendency for higher hearing preservation rates in the treatment group. Gender was not included in statistical analysis at that time. A retrospective analysis of the trial considering gender, preoperative hearing, and nimodipine treatment was performed. The treatment group received parenteral nimodipine from the day before surgery until the seventh postoperative day. The control group was not treated prophylactically. Cochlear nerve function was determined by pure-tone audiometry with speech discrimination preoperatively, during in-patient care, and 1 year after surgery and classified according to the Gardner-Robertson grading scale (GR). Logistic regression analysis showed a statistically significant effect for higher hearing preservation rates (pre- and postoperative GR 1-4) in 40 men comparing the treatment (n = 21) and the control (n = 19) groups (p = 0.028), but not in 54 women comparing 27 women in both groups (p = 0.077). The results were also statistically significant for preservation of postoperative hearing with pre- and postoperative GR 1-3 (p = 0.024). There were no differences in tumor sizes between the treatment and the control groups in men, whereas statistically significant larger tumors were observed in the female treatment group compared with the female control group. Prophylactic nimodipine is safe, and an effect for hearing preservation in 40 men with preoperative hearing ability of GR 1-4 was shown in this retrospective investigation. The imbalance in tumor size with larger tumors in females of the treatment group may falsely suggest a gender-related effect. Further investigations are recommended to clarify whether gender has impact on nimodipine's efficacy.

Glucocorticoid and Breviscapine Combination Therapy Versus Glucocorticoid Alone on Sudden Sensorineural Hearing Loss in Patients with Different Audiometric Curves.

INTRODUCTION: We aimed to retrospectively analyze the therapeutic outcomes of using glucocorticoid combined with a vasodilator, breviscapine, versus glucocorticoid alone in patients with sudden sensorineural hearing loss (SSNHL) and to explore the impact on different audiometric curves. METHODS: Data from 154 patients were collected between January 2017 and December 2018. Patients received treatments of either glucocorticoid combined with breviscapine (GC + Bre) or glucocorticoid alone (GC). These two groups were stratified into low frequencies SSNHL (LF-SSNHL), high frequencies SSNHL (HF-SSNHL), all frequencies SSNHL (AF-SSNHL), and total deafness SSNHL (TD-SSNHL) subgroups according to their corresponding audiograms. The hearing level was evaluated by pure tone audiometry, and hearing recovery was calculated by comparing the pure tone average (PTA) at pretreatment and 4 weeks after therapy. RESULTS: Hearing recovery was significantly greater for GC + Bre than GC-only treatment in the AF-SSNHL and TD-SSNHL subgroups (P < 0.05) and to a lesser extent in the LF-SSNHL and HF-SSNHL subgroups (P > 0.05). Logistic regression analysis also showed a favorable outcome for SSNHL in the GC + Bre group (odds ratio 2.848, P < 0.05). CONCLUSION: Treating SSNHL using glucocorticoid combined with breviscapine could be more beneficial than using glucocorticoid alone, especially for patients with AF-SSNHL and TD-SSNHL. TRIAL REGISTRATION NUMBER: ChiCTR18000170072.

Pharmacologic and surgical therapies for patients with Meniere's disease: A systematic review and network meta-analysis.

BACKGROUND: Meniere's disease (MD) is a chronic condition of the inner ear consisting of symptoms that include vertigo attacks, fluctuating sensorineural hearing loss, tinnitus and aural fullness. Despite availability of various interventions, there is uncertainty surrounding their relative efficacy, thus making it difficult to select the appropriate treatments for MD. The objective of this systematic review was to assess the relative effects of the available pharmacologic and surgical interventions in patients with MD with regard to vertigo and other key patient outcomes based on data from randomized clinical trials (RCTs). METHODS: Our published protocol registered with PROSPERO (CRD42019119129) provides details on eligibility criteria and methods. We searched various databases including MEDLINE, Embase and the Cochrane Library from inception to December 10th, 2018. Screening at citation and full-text levels and risk of bias assessment were performed by two independent reviewers in duplicate, with discrepancies resolved by consensus or third-party adjudication. Bayesian network meta-analyses (NMA) were performed for hearing change and vertigo control outcomes, along with pairwise meta-analyses for these and additional outcomes. RESULTS: We identified 2,889 unique citations, that yielded 23 relevant publications describing 18 unique RCTs (n = 1,231 patients). Overall, risk-of bias appraisal suggested the evidence base to be at unclear or high risk of bias. Amongst pharmacologics, we constructed treatment networks of five intervention groups that included placebo, intratympanic (IT) gentamicin, oral high-dose betahistine, IT steroid and IT steroid plus high-dose betahistine for NMAs of hearing change (improvement or deterioration) and complete vertigo control. IT steroid plus high-dose betahistine was associated with the largest difference in hearing improvement compared to placebo, followed by high-dose betahistine and IT steroid (though 95% credible intervals failed to rule out the possibility of no difference), while IT gentamicin was worse than IT steroid. The NMA of complete vertigo control suggested IT gentamicin was associated with the highest probability of achieving better complete vertigo control compared to placebo, followed by IT steroid plus high-dose betahistine. Only two studies related to surgical interventions were found, and data suggested no statistically significant difference in hearing changes between endolymphatic duct blockage (EDB) versus endolymphatic sac decompression (ESD), and ESD with or without steroid injection. One trial reported that 96.5% of patients in EDB group compared to 37.5% of the patients in ESD group achieved complete vertigo control 24 months after surgery (p = 0.002). CONCLUSION: To achieve both hearing preservation and vertigo control, the best treatment option among the pharmacologic interventions compared may be IT steroid plus high-dose betahistine, considering that IT gentamicin may have good performance to control vertigo but may be detrimental to hearing preservation with high cumulative dosage and short interval between injections. However, IT steroid plus high-dose betahistine has not been compared in head-to-head trials against other interventions except for IT steroid alone in one trial, thus future trials that compare it with other interventions will help establish comparative effectiveness with direct evidence.

Usefulness of current candidate genetic markers to identify childhood cancer patients at risk for platinum-induced ototoxicity: Results of the European PanCareLIFE cohort study.

BACKGROUND: Irreversible sensorineural hearing loss is a common side effect of platinum treatment with the potential to significantly impair the neurocognitive, social and educational development of childhood cancer survivors. Genetic association studies suggest a genetic predisposition for cisplatin-induced ototoxicity. Among other candidate genes, thiopurine methyltransferase (TPMT) is considered a critical gene for susceptibility to cisplatin-induced hearing loss in a pharmacogenetic guideline. The aim of this cross-sectional cohort study was to confirm the genetic associations in a large pan-European population and to evaluate the diagnostic accuracy of the genetic markers. METHODS: Eligibility criteria required patients to be aged less than 19 years at the start of chemotherapy, which had to include cisplatin and/or carboplatin. Patients were assigned to three phenotype categories: no, minor and clinically relevant hearing loss. Fourteen variants in eleven candidate genes (ABCC3, OTOS, TPMT, SLC22A2, NFE2L2, SLC16A5, LRP2, GSTP1, SOD2, WFS1 and ACYP2) were investigated. Multinomial logistic regression was performed to model the relationship between genetic predictors and platinum ototoxicity, adjusting for clinical risk factors. Additionally, measures of the diagnostic accuracy of the genetic markers were determined. RESULTS: 900 patients were included in this study. In the multinomial logistic regression, significant unique contributions were found from SLC22A2 rs316019, the age at the start of platinum treatment, cranial radiation and the interaction term [platinum compound]∗[cumulative dose of cisplatin]. The predictive performance of the genetic markers was poor compared with the clinical risk factors. CONCLUSIONS: PanCareLIFE is the largest study of cisplatin-induced ototoxicity to date and confirmed a role for the polyspecific organic cation transporter SLC22A2. However, the predictive value of the current genetic candidate markers for clinical use is negligible, which puts the value of clinical factors for risk assessment of cisplatin-induced ototoxicity back into the foreground.

Loss of Cochlear Ribbon Synapse Is a Critical Contributor to Chronic Salicylate Sodium Treatment-Induced Tinnitus without Change Hearing Threshold.

Tinnitus is a common auditory disease worldwide; it is estimated that more than 10% of all individuals experience this hearing disorder during their lifetime. Tinnitus is sometimes accompanied by hearing loss. However, hearing loss is not acquired in some other tinnitus generations. In this study, we injected adult rats with salicylate sodium (SS) (200 mg/kg/day for 10 days) and found no significant hearing threshold changes at 2, 4, 8, 12, 14, 16, 20, or 24 kHz (all p > 0.05). Tinnitus was confirmed in the treated rats via Behaviour Testing of Acoustic Startle Response (ASR) and Gap Prepulse Inhibition Test of Acoustic Startle Reflex (GPIAS). A immunostaining study showed that there is significant loss of anti-CtBP2 puncta (a marker of cochlear inner hair cell (HC) ribbon synapses) in treated animals in apical, middle, and basal turns (all p < 0.05). The ABR wave I amplitudes were significantly reduced at 4, 8, 12, 14, 16, and 20 kHz (all p < 0.05). No significant losses of outer HCs, inner HCs, or HC cilia were observed (all p > 0.05). Thus, our study suggests that loss of cochlear inner HC ribbon synapse after SS exposure is a contributor to the development of tinnitus without changing hearing threshold.

Direct Delivery of Antisense Oligonucleotides to the Middle and Inner Ear Improves Hearing and Balance in Usher Mice.

Usher syndrome is a syndromic form of hereditary hearing impairment that includes sensorineural hearing loss and delayed-onset retinitis pigmentosa (RP). Type 1 Usher syndrome (USH1) is characterized by congenital profound sensorineural hearing impairment and vestibular areflexia, with adolescent-onset RP. Systemic treatment with antisense oligonucleotides (ASOs) targeting the human USH1C c.216G>A splicing mutation in a knockin mouse model of USH1 restores hearing and balance. Herein, we explore the effect of delivering ASOs locally to the ear to treat hearing and vestibular dysfunction associated with Usher syndrome. Three localized delivery strategies were investigated in USH1C mice: inner ear injection, trans-tympanic membrane injection, and topical tympanic membrane application. We demonstrate, for the first time, that ASOs delivered directly to the ear correct Ush1c expression in inner ear tissue, improve cochlear hair cell transduction currents, restore vestibular afferent irregularity, spontaneous firing rate, and sensitivity to head rotation, and successfully recover hearing thresholds and balance behaviors in USH1C mice. We conclude that local delivery of ASOs to the middle and inner ear reach hair cells and can rescue both hearing and balance. These results also demonstrate the therapeutic potential of ASOs to treat hearing and balance deficits associated with Usher syndrome and other ear diseases.

Gap Detection Deficits in Chinchillas with Selective Carboplatin-Induced Inner Hair Cell Loss.

Temporal resolution is essential for processing complex auditory information such as speech. In hearing impaired persons, temporal resolution, often assessed by detection of brief gaps in continuous sound stimuli, is typically poorer than in individuals with normal hearing. At low stimulus presentation levels, hearing impaired individuals perform poorly but the deficits are greatly reduced when the sensation level of the stimuli are adjusted to match their normal hearing peers. In the present study, we evaluated the effect of selective inner hair cell loss on gap detection in chinchillas treated with carboplatin, an anticancer drug that selectively damages inner hair cells and afferents in this species. Treatment with carboplatin-induced inner hair cell loss of ~ 70 % but had little effect on audiometric thresholds in quiet and produced no evidence of outer hair cell loss. In contrast, selective inner hair cell loss had a significant effect on gap detection ability across a wide range of presentation levels. These results suggest that gap detection tasks are more sensitive to inner hair cell pathology than audiometric thresholds.

The Outcome of Prompt Concomitant Single-Dose High-Concentration Intratympanic and Tapered Low-Dose Oral Systemic Corticosteroid Treatment for Sudden Deafness.

OBJECTIVES: To investigate the efficacy of prompt concomitant corticosteroid treatment with single application of high-concentration intratympanic (IT) dexamethasone and tapered low-dose systemic methylprednisolone of an idiopathic sudden sensorineural hearing loss (ISSNHL). MATERIALS AND METHODS: Between September 2017 and September 2019, 86 adult patients met the criteria for the diagnosis of ISSNHL at baseline evaluation. The patients received immediate concomitant treatment with single high-concentration (24 mg/mL) IT dexamethasone and low-dose (48 mg) oral methylprednisolone for 1 week followed by tapered doses. Improvement in pure-tone average (PTA) and word recognition score (WRS) was determined after 1 and 6 months. RESULTS: A total of 63 patients met the requirements for the analysis. PTA improved in 71% and WRS improved in 59% of patients with ISSNHL. PTA and WRS were statistically significantly different at different time points during the intervention (p<0.0005). Hearing improved in all measured frequencies from 125 to 8000 Hz until the second follow-up. In 65.4% of patients with tinnitus, the WRS has improved compared with 27.3% without tinnitus (p<0.05). In 69.2% of patients without vertigo, the WRS has improved compared with 41.7% with vertigo (p<0.05). CONCLUSION: Prompt concomitant single high-concentration IT and low-dose systemic corticosteroid treatment is efficient in recovering hearing loss and speech discrimination in ISSNHL. Tinnitus positively predicts hearing outcome. Vertigo negatively predicts speech discrimination recovery.

Intratympanic steroid injection for sudden sensorineural hearing loss: Impact of injection interval on therapeutic efficacy.

OBJECTIVE: To compare the effect of injection time intervals of intratympanic (IT) dexamethasone (DEX) in patients with idiopathic sudden sensorineural hearing loss (ISSNHL). METHODS: Seventy-five adults with ISSNHL were grouped into four groups according to the IT DEX interval. In addition to concurrent oral steroid medication for two weeks, patients received IT DEX injections every 1, 2, 3, and four days, respectively. (Group 1, Group 2, Group 3, and Group 4). We evaluated the treatment outcomes according to modified criteria from "Clinical Practice Guideline: Sudden Hearing Loss" of the American Academy of Otolaryngology-Head and Neck Surgery (AAOHNS) to justify treatment success. RESULTS: There were no significant differences in demographic and baseline audiometric data. The mean of pure tone audiometry (PTA) and speech discrimination score (SDSs) were significantly improved after oral steroid and IT DEX treatment in all four groups. Group 1 showed significantly higher improvement than Group 4 in PTA after treatment. There was a significantly higher complete recovery (CR) rate in Group 1 than Group 4. CONCLUSION: We found a statistically significant difference in the complete hearing recovery rate and audiometric results (PTA) between the group with a daily interval of injections and the group with a four-day time interval. Therefore, daily time intervals in intratympanic steroid injection may be considered as an option for better improvement of hearing in patients with ISSNHL.