Tinnitus reduction after active bone-conduction implantation in patients with single-sided deafness: a prospective multicenter study.

PURPOSE: Single-sided deafness (SSD) presents significant challenges for patients, including compromised sound localization, reduced speech recognition, and often, tinnitus. These issues are typically addressed using interventions such as cochlear implantation (CI) and bone conduction implant (BCI). However, evidence regarding the efficacy of BCI in reducing tinnitus in SSD patients remains limited. This study explored the ability of a novel active transcutaneous BCI (Bonebridge BCI602) to alleviate tinnitus in SSD patients. STUDY DESIGN: Prospective cohort multicenter study. SETTING: Tertiary referral hospitals. METHODS: A prospective multicenter study of 30 SSD patients was conducted. The patients were divided into two groups: those with (n = 19) and without (n = 11) tinnitus. Audiometric assessments, subjective questionnaires including the Abbreviated Profile of Hearing Aid Benefit (APHAB) and the Bern Benefit in Single-Sided Deafness (BBSS), and tinnitus evaluations with the Tinnitus Handicap Inventory (THI) and tinnitogram were conducted before and after BCI surgery. RESULTS: THI scores after surgery were significantly reduced in SSD patients with tinnitus. Subjective satisfaction improved in both the tinnitus and non-tinnitus groups; however, the former group exhibited a significantly greater improvement in the APHAB questionnaire score. According to tinnitograms, the loudness of tinnitus decreased, particularly in patients with ipsilateral tinnitus. Patients with residual hearing had greater reductions in their THI scores. However, three patients without residual hearing had a relative worsening of tinnitus after surgery. CONCLUSION: The Bonebridge BCI602 effectively reduced tinnitus in SSD patients, particularly in those with residual hearing. Subjective satisfaction improved in both the tinnitus and non-tinnitus groups. These findings demonstrate the therapeutic potential of BCI for managing SSD and associated tinnitus.

Hemophagocytic lymphohistiocytosis associated with acute otitis media: A case report.

INTRODUCTION: Hemophagocytic lymphohistiocytosis (HLH) is a potentially life-threatening syndrome for which early recognition and treatment are essential for improving outcomes. HLH is characterized by uncontrolled immune activation leading to fever, cytopenias, hepatosplenomegaly, coagulation abnormalities, and elevated typical markers. This condition can be genetic or secondary, with the latter often triggered by infections. Here, we present a unique case of HLH secondary to acute otitis media (AOM), a common ear infection. PATIENT CONCERNS: We describe a 4-year-old boy who initially presented with a high fever and otalgia, later diagnosed with bilateral AOM. Despite antibiotic treatment, his condition deteriorated. DIAGNOSIS: The patient fulfilled diagnostic criteria for HLH. INTERVENTIONS: Aggressive treatment by using combination therapy with immunoglobulins, intravenous steroids (dexamethasone), cyclosporine, and etoposide was performed. OUTCOMES: After 1 month of treatment, improvement in the otologic symptoms was observed, and hematological findings gradually improved and normalized. LESSIONS: The link between AOM and HLH may be associated with inflammatory responses and immunological mechanisms, highlighting the importance of considering HLH in severe infection cases. This case emphasizes the need for prompt diagnosis and management, especially in secondary HLH scenarios, to improve patient outcomes. It is imperative to be aware of the potential correlation between these 2 conditions, and healthcare professionals should consider the likelihood of HLH.

Consensus Statements on the Definition, Classification, and Diagnostic Tests for Tinnitus: A Delphi Study Conducted by the Korean Tinnitus Study Group.

BACKGROUND: Tinnitus is a bothersome condition associated with various symptoms. However, the mechanisms of tinnitus are still uncertain, and a standardized assessment of the diagnostic criteria for tinnitus is required. We aimed to reach a consensus on diagnosing tinnitus with professional experts by conducting a Delphi study with systematic review of the literature. METHODS: Twenty-six experts in managing tinnitus in Korea were recruited, and a two-round modified Delphi study was performed online. The experts evaluated the level of agreement of potential criteria for tinnitus using a scale of 1-9. After the survey, a consensus meeting was held to establish agreement on the results obtained from the Delphi process. Consensus was defined when over 70% of the participants scored 7-9 (agreement) and fewer than 15% scored 1-3 (disagreement). To analyze the responses of the Delphi survey, the content validity ratio and Kendall's coefficient of concordance were evaluated. RESULTS: Consensus was reached for 22 of the 38 statements. For the definition of tinnitus, 10 out of 17 statements reached consensus, with three statements achieving complete agreement including; 1) Tinnitus is a conscious perception of an auditory sensation in the absence of a corresponding external stimulus, 2) Tinnitus can affect one's quality of life, and 3) Tinnitus can be associated with hearing disorders including sensorineural hearing loss, vestibular schwannoma, Meniere's disease, otosclerosis, and others. For the classification of tinnitus, 11 out of 18 statements reached consensus. The participants highly agreed with statements such as; 1) Vascular origin is expected in pulse-synchronous tinnitus, and 2) Tinnitus can be divided into acute or chronic tinnitus. Among three statements on the diagnostic tests for tinnitus only Statement 3, "There are no reliable biomarkers for sensory or emotional factors of tinnitus." reached consensus. All participants agreed to perform pure-tone audiometry and tinnitus questionnaires, including the Tinnitus Handicap Inventory and Tinnitus Questionnaire. CONCLUSION: We used a modified Delphi method to establish a consensus-based definition, a classification, and diagnostic tests for tinnitus. The expert panel reached agreement for several statements, with a high level of consensus. This may provide practical information for clinicians in managing tinnitus.

Efficacy of the Bonebridge BCI602 for Adult Patients with Single-sided Deafness: A Prospective Multicenter Study.

OBJECTIVE: To investigate the safety and efficacy of a novel active transcutaneous bone conduction implant (BCI) device for patients with single-sided deafness (SSD). STUDY DESIGN: Prospective cohort study. SETTING: Tertiary referral hospitals. METHODS: This prospective multicenter study was conducted at 15 institutions nationwide. Thirty adult (aged ≥19 years) SSD patients were recruited. They underwent implantation of an active transcutaneous BCI device (Bonebridge BCI602). Objective outcomes included aided pure-tone thresholds, aided speech discrimination scores (SDSs), and the Hearing in Noise Test (HINT) and sound localization test results. The Bern Benefit in Single-Sided Deafness (BBSS) questionnaire, the Abbreviated Profile of Hearing Aid Benefit (APHAB) questionnaire, and the Tinnitus Handicap Inventory (THI) were used to measure subjective benefits. RESULTS: The mean aided pure-tone threshold was 34.2 (11.3), mean (SD), dB HL at 500 to 4000 Hz. The mean total BBSS score was 27.5 (13.8). All APHAB questionnaire domain scores showed significant improvements: ease of communication, 33.6 (23.2) versus 22.6 (21.3), P = .025; reverberation, 44.8 (16.6) versus 32.8 (15.9), P = .002; background noise, 55.5 (23.6) versus 35.2 (18.1), P < .001; and aversiveness, 36.7 (22.8) versus 25.8 (21.4), P = .028. Moreover, the THI scores were significantly reduced [47.4 (30.1) versus 31.1 (27.0), P = .003]. Congenital SSD was a significant factor of subjective benefit (-11.643; 95% confidence interval: -21.946 to -1.340). CONCLUSION: The BCI602 active transcutaneous BCI device can provide functional hearing gain without any adverse effects and is a feasible option for acquired SSD patients with long-term deafness.

Berberine chloride protects cochlear hair cells from aminoglycoside-induced ototoxicity by reducing the accumulation of mitochondrial reactive oxygen species.

Aminoglycoside, a medicinal category of antibiotics, are used in treatment of Gram-negative bacterial infections. Although they are the most widely-used antibiotics due to their high efficacy and low cost, several main adverse effects have been reported including nephrotoxicity and ototoxicity. Since drug-induced ototoxicity is one of the major etiological causes of acquired hearing loss, we examined cochlear hair cell damages caused by three aminoglycosides (amikacin, kanamycin, and gentamicin), and investigated protective property of an isoquinoline-type alkaloid, Berberine chloride (BC). Berberine, a well-known bioactive compound found from medicinal plants, has been known to have anti-inflammatory, antimicrobial effects. To determine protective effect of BC in aminoglycoside-induced ototoxicity, hair cell damages in aminoglycoside- and/or BC-treated hair cells using ex vivo organotypic culture system of mouse cochlea. Mitochondrial ROS levels and depolarization of mitochondrial membrane potential were analyzed, and TUNEL assay and immunostaining of cleaved caspase-3 were performed to detect apoptosis signals. As the results, it was found that BC significantly prevented aminoglycoside-induced hair cell loss and stereocilia degeneration by inhibiting excessive accumulation of mitochondrial ROS and subsequent loss of mitochondrial membrane potential. It eventually inhibited DNA fragmentation and caspase-3 activation, which were significant for all three aminoglycosides. This study is the first report suggested the preventative effect of BC against aminoglycoside-induced ototoxicity. Our data also suggests a possibility that BC has the potential to exert a protective effect against ototoxicity caused by various ototoxic drugs leading to cellular oxidative stress, not limited to aminoglycoside antibiotics.

Effect of prehydration solution on hearing threshold after chemotherapy in patients with head and neck cancers: a retrospective study.

BACKGROUND: The study aimed to evaluate the effect of prehydration solution on hearing thresholds after cisplatin chemotherapy. METHODS: In this retrospective cohort study, we reviewed the data of patients who underwent ≥3 courses of cisplatin-based chemotherapy for locally advanced head and neck cancers at a tertiary referral center (n=64). The dextrose solution (DW) group (n=26) received 2 L of normal saline and 1 L of 5% dextrose. The Hartmann solution (HS) group (n=38) received 2 L of normal saline and 1 L of HS. Hearing data were measured 1 day before starting the first course of chemotherapy, and again 20 days after the first, second, and third courses of chemotherapy. The severity of hearing loss was evaluated using the Common Terminology Criteria for Adverse Events (CTCAE). RESULTS: Thresholds at all frequencies after chemotherapy were greater in the DW group than in the HS group. The increase in thresholds in 1 to 4 kHz after the third course of chemotherapy was greater in the DW group than in the HS group. CTCAE grades after the second and third courses of chemotherapy were greater in the DW group than in the HS group. Logistic regression showed that the odds ratio for CTCAE grade 3 or 4 after the third course of chemotherapy in the DW group was 4.84 on univariate analysis. CONCLUSION: Prehydration using a solution with salt was associated with a decrease in change in hearing thresholds after cisplatin chemotherapy in patients with head and neck cancers.

Factors Affecting the Extrusion Rate and Complications After Ventilation Tube Insertion: A Multicenter Registry Study on the Effectiveness of Ventilation Tube Insertion in Pediatric Patients With Chronic Otitis Media With Effusion-Part II.

OBJECTIVES: The impacts of ventilation tube (VT) type and effusion composition on the VT extrusion rate and complications in children with otitis media remain unclear. This part II study evaluated the factors affecting the extrusion rate, recurrence rate, and complications of VT insertion. METHODS: A prospective study was conducted between June 2014 and December 2016 (the EVENT study [analysis of the effectiveness of ventilation tube insertion in pediatric patients with chronic otitis media]), with follow-up data collected until the end of 2017. Patients aged <15 years diagnosed with otitis media with effusion who received VT insertion were recruited at 15 tertiary hospitals. The primary outcomes were time to extrusion of VT, time to effusion recurrence, and complications. RESULTS: Data from 401 patients were analyzed. After excluding the. RESULTS: of long-lasting tubes (Paparella type II and T-tubes), silicone tubes (Paparella type I) exhibited a significantly longer extended time to extrusion (mean, 400 days) than titanium tubes (collar-button-type 1.0 mm: mean, 312 days; P<0.001). VT material (hazard ratio [HR], 2.117, 95% confidence interval [CI], 1.254-3.572; P=0.005), age (HR, 3.949; 95% CI, 1.239-12.590; P=0.02), and effusion composition (P=0.005) were significantly associated with the time to recurrence of middle ear effusion. Ears with purulent (mean, 567 days) and glue-like (mean, 588 days) effusions exhibited a shorter time to recurrence than ears with serous (mean, 846 days) or mucoid (mean, 925 days) effusions. The revision VT rates during follow-up were 3.5%, 15.5%, 10.4%, and 38.9% in ears with serous, mucoid, glue-like, and purulent effusions, respectively (P<0.001). The revision surgery rates were higher among patients aged <7 years than among those aged ≥7 years. CONCLUSION: Silicone tubes (Paparella type I) were less prone to early extrusion than titanium 1.0 mm tubes. VT type, patient age, and effusion composition affected the time to recurrence of effusion.

Results of Active Middle Ear Implantation in Patients With Mixed Hearing Loss After Middle Ear Surgery: A Prospective Multicenter Study (the ROMEO Study).

OBJECTIVES: This study was conducted to evaluate the user satisfaction, efficacy, and safety of round window (RW) vibroplasty using the Vibrant Soundbridge (VSB) in patients with persistent mixed hearing loss after mastoidectomy. METHODS: The study included 27 patients (mean age, 58.7 years; age range, 28-76 years; 11 men and 16 women) with mixed hearing loss after mastoidectomy from 15 tertiary referral centers in Korea. The VSB was implanted at the RW. The Korean translation of the Abbreviated Profile of Hearing Aid Benefit (APHAB) questionnaire and the Korean version of the International Outcome Inventory for Hearing Aids (K-IOI-HA) questionnaire were used to evaluate user satisfaction as the primary outcome. The secondary outcome measures were audiological test results and complication rates. RESULTS: The mean scores for ease of communication (61.3% to 29.7% to 30.2%), reverberation (62.1% to 43.1% to 37.4%), and background noise (63.3% to 37.7% to 34.3%) subscales of the APHAB questionnaire significantly decreased after VSB surgery. The mean K-IOI-HA scores at 3 and 6 months after surgery were significantly higher than the mean preoperative score (18.6 to 27.2 to 28.1). The postoperative VSB-aided thresholds were significantly lower than the preoperative unaided and hearing aid (HA)-aided thresholds. There was no significant difference between preoperative unaided, preoperative HA-aided, and postoperative VSB-aided maximum phonetically balanced word-recognition scores. None of the 27 patients experienced a change in postoperative bone conduction pure tone average. One patient developed temporary facial palsy and two developed surgical wound infections. CONCLUSION: RW vibroplasty resulted in improved satisfaction and audiological test results in patients with mixed hearing loss after mastoidectomy, and the complication rate was tolerable.

Protective effect of berberine chloride against cisplatin-induced ototoxicity.

BACKGROUND: Cisplatin (CP) is an effective anticancer drug broadly used for various types of cancers, but it has shown ototoxicity that results from oxidative stress. Berberine has been reported for its anti-oxidative stress suggesting its therapeutic potential for many diseases such as colitis, diabetes, and vascular dementia. OBJECTIVE: Organ of Corti of postnatal day 3 mouse cochlear explants were used to compare hair cells after the treatment with cisplatin alone or with berberine chloride (BC) followed by CP. METHODS: We investigated the potential of the anti-oxidative effect of BC against the cisplatin-induced ototoxicity. We observed a reduced aberrant bundle of stereocilia in hair cells in CP with BC pre-treated group. Caspase-3 immunofluorescence and TUNEL assay supported the hypothesis that BC attenuates the apoptotic signals induced by CP. Reactive oxygen species level in the mitochondria were investigated by MitoSOX Red staining and the mitochondrial membrane potentials were compared by JC-1 assay. RESULTS: BC decreased ROS generation with preserved mitochondrial membrane potentials in mitochondria as well as reduced DNA fragmentation in hair cells. In summary, our data indicate that BC might act as antioxidant against CP by reducing the stress in mitochondria resulting in cell survival. CONCLUSION: Our result suggests the therapeutic potential of BC for prevention of the detrimental effect of CP-induced ototoxicity.

Alterations of functional connectivity in auditory and sensorimotor neural networks: A case report in a patient with cortical deafness after bilateral putaminal hemorrhagic stroke.

RATIONALE: Cortical deafness is a rare auditory dysfunction caused by damage to brain auditory networks. The aim was to report alterations of functional connectivity in intrinsic auditory, motor, and sensory networks in a cortical deafness patient. PATIENT CONCERNS: A 41-year-old woman suffered a right putaminal hemorrhage. Eight years earlier, she had suffered a left putaminal hemorrhage and had minimal sequelae. She had quadriparesis, imbalance, hypoesthesia, and complete hearing loss. DIAGNOSES: She was diagnosed with cortical deafness. After 6 months, resting-state functional magnetic resonance imaging (rs-fMRI) and diffuse tensor imaging (DTI) were performed. DTI revealed that the acoustic radiation was disrupted while the corticospinal tract and somatosensory track were intact using deterministic tracking methods. Furthermore, the patient showed decreased functional connectivity between auditory and sensorimotor networks. INTERVENTIONS: The patient underwent in-patient stroke rehabilitation therapy for 2 months. OUTCOMES: Gait function and ability for activities of daily living were improved. However, complete hearing impairment persisted in 6 months after bilateral putaminal hemorrhagic stroke. LESSONS: Our case report seems to suggest that functional alterations of spontaneous neuronal activity in auditory and sensorimotor networks are related to motor and sensory impairments in a patient with cortical deafness.

Clinical outcomes of otogenic skull base osteomyelitis.

PURPOSE: Skull base osteomyelitis (SBO) is an uncommon and a potentially life-threatening condition if not promptly recognized and properly treated. The aim of our study was to present a 32-case series of patients diagnosed with SBO at a single center. METHODS: In this retrospective study, we reviewed the data of patients diagnosed with otogenic SBO between January 2011 and January 2020. 32 patients were enrolled in the study. SBO diagnosis was based on a combination of symptoms and physical examination, bone scan, brain magnetic resonance imaging, and pathologic examination findings. The following clinical data were collected during the follow-up period: types of antibiotics used, duration of antibiotic treatment, C-reactive protein level, presence of disease control, duration from the onset of symptoms to diagnosis, and patient survival. RESULTS: The mean follow-up period was 11 (1-110) months. The mean duration of antibiotic treatment was 115 (19-223) days. The mean C-reactive protein levels at the time of diagnosis and at the endpoint of follow-up were 3.05 (0.56-18.31) and 0.21 (0.03-33.61) mg/dL, respectively (P < 0.001). Disease control rate was 34.9% at 1-year and 83.7% at 5-year follow-up. Patient survival rate was 90.6% at 1- and 3-year follow-ups. At the endpoint of follow-up, three patients died. The mean durations from the onset of symptoms to diagnosis were 50 (5-360) and 90 (30-480) days in patients with the controlled disease and in those with the uncontrolled disease, respectively, at the endpoint of follow-up (P = 0.043). CONCLUSION: Comprehensive assessment and aggressive treatment of patients exhibiting symptoms suggestive of SBO would help in the rapid diagnosis of otogenic SBO, resulting in an improvement in prognosis.

Comparison of Ossiculoplasty Outcomes Using Different Materials in the Treatment of Chronic Otitis Media.

OBJECTIVE: This study aimed to evaluate success rates after ossicular chain reconstruction using different materials. STUDY DESIGN: Retrospective cohort study. SETTING: Tertiary referral center. PATIENTS: Four hundred forty-three participants who underwent ossiculoplasty at a tertiary medical center were included. INTERVENTION: Ossicular chain reconstruction using five materials: autologous malleus, incus, and cortical bone, as well as Hydroxyapatite (HA) and titanium. MAIN OUTCOME MEASURES: Hearing data were measured 1 day preoperatively and 6 months postoperatively. Successful hearing outcomes were defined by the fulfillment of more than one of the following criteria: postoperative air-bone gap of 20 dB or less, hearing air conduction (AC) gain of 15 dB or more, or postoperative AC hearing less than 30 dB. RESULTS: Preoperative median AC values (95% confidence interval) among participants with malleus, incus, cortical bone, HA, and titanium transplants or prostheses were 50 (39.6-54.6) dB, 51.3 (48.1-51.8) dB, 50 (45.2-52.2) dB, 56.3 (50.9-57.6) dB, and 54.3 (48.5-56.0) dB, respectively (p = 0.092). The success rates in malleus, incus, cortical bone, HA, and titanium were 53.3%, 60.3%, 51.7%, 61.6%, and 69.7%, respectively. Titanium had the highest success rate among the five materials, but the differences between the materials were not statistically significant (p = 0.283). Titanium had highest success rate among the participants with erosive stapes suprastructure or obstructed Eustachian tubes (p = 0.042 for erosive stapes suprastructure and p = 0.010 for obstructed Eustachian tubes). CONCLUSION: Our study demonstrated that titanium prostheses would be a good alternative for ossiculoplasty in cases wherein autologous material is unavailable, especially in association with unfavorable conditions, such as with the presence of cholesteatoma, erosive stapes suprastructure, edematous middle ear mucosa, and obstructed Eustachian tube.

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.

Red cell distribution width is associated with hearing impairment in chronic kidney disease population: a retrospective cross-sectional study.

PURPOSE: Previous studies have shown that inflammatory markers are associated with hearing impairment in participants with inflammatory diseases. Therefore, screening for inflammatory status may have value in predicting the risk of hearing loss (HL) in participants with underlying inflammation. Therefore, red cell distribution width (RDW), an indirect indicator of inflammatory status, was used. The aim of the present study was to evaluate the clinical association between RDW and hearing impairment in a Korean population with chronic kidney disease (CKD). METHODS: In this cross sectional study, a total of 461 participants with estimated glomerular filtration rate (eGFR) < 60 ml/min/1.73 m2 were included. Participants were divided into three tertiles based on their RDW values. The threshold values at 0.5, 1, and 2 kHz were averaged to obtain the Low/Mid-Freq, and the values at 3, 4, and 6 kHz were averaged to obtain the High-Freq. The average hearing threshold (AHT) was calculated as the pure-tone average of the thresholds at 0.5, 1, 2, and 3 kHz. HL was defined as an AHT of > 40 dB. RESULTS: The numbers of participants in the Low, Middle, and High tertiles were 172, 154, and 135, respectively. The AUROCs of RDW and hs-CRP for HL were 0.644 and 0.522, respectively. In the multivariate analysis, the Low/Mid-Freq, High-Freq, and AHT values were lowest in the participants in the Low tertile compared with those in the Middle or High tertiles Multivariate logistic regression analyses showed that participants in the High tertile exhibited 2.32- and 1.78-fold higher odds for HL compared to those of the Low and Middle tertiles, respectively. There were positive associations between RDW and AHT values. CONCLUSION: High RDW was associated with increased odds of hearing impairment in the Korean population with CKD.

KL1333, a derivative of ß-lapachone, protects against cisplatin-induced ototoxicity in mouse cochlear cultures.

Cisplatin (CP) is a chemotherapeutic drug used to treat cancerous solid tumors, but it causes serious side effects, including ototoxicity. The major cause of CP-induced ototoxicity is increased levels of mitochondrial reactive oxygen species (ROS). In this study, we examined the effect of 2-Isopropyl-3H-naphtho(1,2-d)imidazole-4,5-dione (KL1333), a ß-lapachone derivative, on CP-induced ototoxicity using ex vivo organotypic culture system of cochlea. Hair cell damages in CP-treated cochlear explants with or without KL1333 were compared by immunohistochemistry. CP-induced oxidative stress and the preventive effect of KL1333 were analyzed by measuring intracellular ROS levels and depolarization of mitochondrial membrane potential. Activation of apoptosis signaling pathway was detected using TUNEL assay and immunostaining of cleaved caspase-3. As the results, it was found that KL1333 pretreatment significantly decreased stereocilia degeneration and hair cell loss, and prevented an increase in mitochondrial ROS levels in response to CP. Immunohistochemical examinations of cochlear explants revealed greater caspase-3 immunopositivity in the CP group than in controls, while the KL1333 + CP group showed significantly less immunopositivity than the CP group (P < 0.05). Thus, it appeared that KL1333 protected hair cells in the organ of Corti from CP-induced apoptosis by decreasing mitochondrial damages due to the production of mitochondrial ROS. This study is the first report showed the preventive effect of KL1333 against CP-induced ototoxicity. Although further studies should be performed to determine if KL1333 could maintain anticancer effect of CP, our data cautiously suggests that the antioxidant KL1333 can be used as an effective anti-apoptotic agent to prevent ototoxicity caused by CP-induced oxidative stress, and may prove useful in preventing hearing loss caused by CP.

Gene therapy for hereditary hearing loss by SLC26A4 mutations in mice reveals distinct functional roles of pendrin in normal hearing.

Rationale: Mutations of SLC26A4 that abrogate pendrin, expressed in endolymphatic sac, cochlea and vestibule, are known to cause autosomal recessive sensorineural hearing loss with enlargement of the membranous labyrinth. This is the first study to demonstrate the feasibility of gene therapy for pendrin-related hearing loss. Methods: We used a recombinant viral vector to transfect Slc26a4 cDNA into embryonic day 12.5 otocysts of pendrin-deficient knock-out (Slc26a4∆/∆ ) and pendrin-deficient knock-in (Slc26a4tm1Dontuh/tm1Dontuh ) mice. Results: Local gene-delivery resulted in spatially and temporally limited pendrin expression, prevented enlargement, failed to restore vestibular function, but succeeded in the restoration of hearing. Restored hearing phenotypes included normal hearing as well as sudden, fluctuating, and progressive hearing loss. Conclusion: Our study illustrates the feasibility of gene therapy for pendrin-related hearing loss, suggests differences in the requirement of pendrin between the cochlea and the vestibular labyrinth, and documents that insufficient pendrin expression during late embryonal and early postnatal development of the inner ear can cause sudden, fluctuating and progressive hearing loss without obligatory enlargement of the membranous labyrinth.

Evaluating protective and therapeutic effects of alpha-lipoic acid on cisplatin-induced ototoxicity.

Cisplatin, a small platinum-containing molecule, is a widely used, highly effective anticancer drug. However, severe side effects have been found in cancer patients treated with cisplatin, including nephrotoxicity, neurotoxicity, and ototoxicity. These cisplatin-induced side effects can have a major impact on patient quality of life, including social development problems in pediatric patients that develop hearing loss. Previous studies have suggested that the major cause of cisplatin-induced ototoxicity is abnormal accumulation of reactive oxygen species (ROS) and oxidative stress. Alpha-lipoic acid (ALA), one of the most effective antioxidants, is known to be involved in the cellular antioxidant system and may have a protective effect on cisplatin-induced ototoxicity. However, the therapeutic effect of ALA on damaged hearing function and its detailed mechanism of action are not fully understood. This study focused on determining whether ALA has a potential as a protective and/or therapeutic agent for cisplatin-induced ototoxicity. Histological and physiological analyses were performed using cisplatin-treated mouse cochlea and HEI-OC1 culture cells in pre- and post-treatment with ALA in vitro and in vivo. We found that ALA contributes to protecting mitochondrial function by preventing ROS accumulation and inhibiting apoptotic cell death. Importantly, post-treatment with ALA consistently showed an almost equal restorative effect to pretreatment, in vitro and in vivo, supporting the possible use of ALA as a therapeutic agent for cisplatin-induced ototoxicity. This study is the first report on a strong therapeutic potential of ALA to rescue ototoxic hearing loss caused by cisplatin, and our data provide key evidence that ALA may act as a reducing agent for glutathione disulfide to increase glutathione levels on behalf of glutathione reductase. This result was consistent in both cultured cells and the mouse model, which improves the clinical value of ALA for therapy of cisplatin-induced ototoxicity.

Effective PEI-mediated delivery of CRISPR-Cas9 complex for targeted gene therapy.

The-state-of-art CRISPR/Cas9 is one of the most powerful among the approaches being developed to rescue fundamental causes of gene-based inheritable diseases. Several strategies for delivering such genome editing materials have been developed, but the safety, efficacy over time, cost of production, and gene size limitations are still under debate and must be addressed to further improve applications. In this study, we evaluated branched forms of the polyethylenimine (PEI) - branched PEI 25 kDa (BPEI-25K) - and found that it could efficiently deliver CRISPR/Cas9 plasmids. Plasmid DNA expressing both guide RNA and Cas9 to target the Slc26a4 locus was successfully delivered into Neuro2a cells and meditated genome editing within the targeted locus. Our results demonstrated that BPEI-25K is a promising non-viral vector to deliver the CRISPR/Cas9 system in vitro to mediate targeted gene therapy, and these findings contribute to an understanding of CRISPR/Cas9 delivery that may enable development of successful in vivo techniques.

Microbiological Results From Middle Ear Effusion in Pediatric Patients Receiving Ventilation Tube Insertion: Multicenter Registry Study on the Effectiveness of Ventilation Tube Insertion in Pediatric Patients With Chronic Otitis Media With Effusion: Part I.

OBJECTIVES: The aim of this multicenter registry study was to investigate the effectiveness of ventilation tube insertion and the microbiology of otitis media with effusion (OME) in children. This part I study was conducted to evaluate the microbiological profile of children with OME who needed ventilation tube insertion. METHODS: Patients <15 years old who were diagnosed as having OME and received ventilation tube insertion were prospectively enrolled in 16 tertiary hospitals from June 2014 to December 2016. After excluding patients with missing data, the data of 397 patients were analyzed among a total of 433 enrolled patients. The clinical symptoms, findings of the tympanic membrane, hearing level, and microbiological findings were collected. RESULTS: In 103 patients (25.9%), antibiotics were used within 3 weeks before surgery. Ventilation tube insertion was performed in a total of 710 ears (626 in both ears in 313 patients, 55 in the left ear only, and 29 in the right ear only). Culture of middle ear effusion was done in at least one ear in 221 patients (55.7%), and in a total of 346 ears. Only 46 ears (13.3%) showed positive results in middle ear effusion culture. Haemophilus influenzae (17.3%, followed by coagulase-negative Staphylococcus and Staphylococcus auricularis) was the most common bacteria detected. CONCLUSION: H. influenzae was the most commonly found bacteria in middle ear effusion. Relatively low rates of culture positivity were noted in middle ear effusion of patients with OME in Korea.

Exocyst Complex Member EXOC5 Is Required for Survival of Hair Cells and Spiral Ganglion Neurons and Maintenance of Hearing.

The exocyst, an octameric protein complex consisting of Exoc1 through Exoc8, was first determined to regulate exocytosis by targeting vesicles to the plasma membrane in yeast to mice. In addition to this fundamental role, the exocyst complex has been implicated in other cellular processes. In this study, we investigated the role of the exocyst in cochlear development and hearing by targeting EXOC5, a central exocyst component. Deleting Exoc5 in the otic epithelium with widely used Cre lines resulted in early lethality. Thus, we generated two different inner ear-specific Exoc5 knockout models by crossing Gfi1Cre mice with Exoc5f/f mice for hair cell-specific deletion (Gfi1Cre/+;Exoc5f/f) and by in utero delivery of rAAV-iCre into the otocyst of embryonic day 12.5 for deletion throughout the otic epithelium (rAAV2/1-iCre;Exoc5f/f). Gfi1Cre/+;Exoc5f/f mice showed relatively normal hair cell morphology until postnatal day 20, after which hair cells underwent apoptosis accompanied by disorganization of stereociliary bundles, resulting in progressive hearing loss. rAAV2/1-iCre;Exoc5f/f mice exhibited abnormal neurite morphology, followed by apoptotic degeneration of spiral ganglion neurons (SGNs) and hair cells, which led to profound and early-onset hearing loss. These results demonstrate that Exoc5 is essential for the normal development and survival of cochlear hair cells and SGNs, as well as the functional maintenance of hearing.