Ergonomics of Various Modalities for Ear Surgery.

Objective: Evaluate ergonomic differences of various modalities for performing middle ear surgery. Study Design: Observational study. Setting: Two academic tertiary care centers. Methods: Attending physicians and residents performing middle ear surgery were photographed intraoperatively. Intraoperative photographs were analyzed using the validated Rapid Upper Limb Assessment (RULA) tool to measure musculoskeletal disease (MSD) risk. Descriptive statistics and significance testing were used to characterize and compare ergonomic differences between surgical modalities. Multivariable ordinal regression was performed to assess factors associated with increased MSD risk, as determined by the final RULA score. Results: Most of our 110 intraoperative photos featured attendings (82.7%) performing combined middle ear surgery and mastoidectomy (60.0%). Body angles and the final RULA score varied significantly among modalities. On subset analysis, microscopic surgery exhibited significantly worse wrist, trunk, and neck angles compared to endoscopic and exoscopic surgery. Exoscopic surgery had significantly lower final RULA scores than both endoscopic and microscopic surgery, indicating significantly lower MSD risk. Microscopic and endoscopic surgery final scores did not vary significantly. In a multivariable ordinal regression of factors associated with increased RULA score, exoscopic surgery had statistically significantly less ergonomic risk relative to microscopic surgery (odds ratio = 0.12, 95% confidence interval = [0.03-0.43]). Conclusion: Exoscopic, endoscopic, and microscopic surgery all featured low ergonomic risk, although exoscopic middle ear surgery demonstrated the lowest risk profile among studied surgical modalities. This demonstrates the importance of using each modality in combination with other ergonomic interventions to provide meaningful musculoskeletal benefits.

Clinical course of five patients definitively diagnosed with idiopathic perilymphatic fistula treated with transcanal endoscopic ear surgery.

Objectives: An idiopathic perilymphatic fistula (PLF) can be difficult to diagnose because patients present with sudden sensorineural hearing loss (SSHL) and/or vestibular symptoms without any preceding events. In such cases, we currently test for cochlin-tomoprotein (CTP) to confirm the diagnosis of idiopathic PLF because CTP is only detected in the perilymph. In this study, we report the clinical course of five patients definitively diagnosed with idiopathic PLF who underwent PLF repair surgery using transcanal endoscopic ear surgery (TEES). Patients and methods: Five patients were initially treated with intratympanic dexamethasone for SSHL, at which time a CTP test was also performed (preoperative CTP test). Due to refractory hearing loss and/or fluctuating disequilibrium, PLF repair surgery using TEES was performed to seal the oval and round windows using connective tissue and fibrin glue. These patients were diagnosed with definite idiopathic PLF based on pre- or intra-operative CTP test results (negative, < 0.4 ng/mL; intermediate, 0.4-< 0.8 ng/mL; and positive, > 0.8 ng/mL). We evaluated pre- and intra-operative CTP values, intraoperative surgical findings via a magnified endoscopic view, and pre- and post-operative changes in averaged hearing level and vestibular symptoms. Results: Pre- and intra-operative CTP values were positive and intermediate in three patients, positive and negative in one patient, and negative and positive in one patient. None of the patients had intraoperative findings consistent with a fistula between the inner and middle ears or leakage of perilymph. Only two patients showed a slight postoperative recovery in hearing. Four patients complained of disequilibrium preoperatively, of whom two had resolution of disequilibrium postoperatively. Conclusion: A positive CTP test confirms PLF in patients without obvious intraoperative findings. The CTP test is considered more sensitive than endoscopic fistula confirmation. We consider that CTP test results are important indicators to decide the surgical indication for idiopathic PLF repair surgery. In our experience with the five cases, two of them showed improvements in both hearing and vestibular symptoms.

The use of basic fibroblast growth factor to treat intractable Bell's palsy administered via transcanal endoscopic ear surgery.

PURPOSE: Facial nerve decompression surgery is an invasive procedure which has hitherto been the main option for patients with severe intractable Bell's palsy which is resistant to drug treatment. We have developed a new salvage treatment for such patients by using minimally invasive transcanal endoscopic ear surgery (TEES) to deliver the biological regenerative agent, basic fibroblast growth factor (bFGF), to the damaged facial nerve. MATERIALS AND METHODS: An endoscopic salvage treatment group was studied prospectively and was made up of severe intractable Bell's palsy patients who did not respond to high dose steroid treatment and had an ENoG value of 5 % or less. This surgery group was retrospectively compared to a similar control group who had received high dose steroid only. RESULTS: Complete recovery to House-Brackmann (HB) Grade I was achieved by 44.8 % of the endoscopic salvage treatment group which was significantly higher than the 21.2 % of the control group at one-year follow up. Patients with an ENoG value of 1 % to 5 % exhibited a significantly higher complete recovery rate of 71.4 % in the endoscopic salvage treatment group than the 28.6 % of the control group. In addition, no complications were observed including hearing loss. CONCLUSIONS: bFGF delivered via TEES shows considerable promise as a new salvage treatment of severe intractable Bell's palsy that is resistant to high dose steroid treatment without the risks presented by facial nerve decompression surgery.

Benefits of High-Dose Corticosteroid and Antiviral Agent Combination Therapy in the Treatment of House-Brackman Grade VI Ramsay Hunt Syndrome.

OBJECTIVE: Few large-scale investigations have been conducted on treatment of House-Brackmann grade VI (HB grade VI) Ramsay Hunt syndrome (RHS) patients. We compared recovery rates among patients receiving a normal-dose corticosteroid (prednisolone [PSL] 60 mg/d) or high-dose corticosteroid (PSL 200 mg/d), both with or without an antiviral agents. Recovery rates were also examined based on the order of presentation of herpetic vesicles versus facial palsy. STUDY DESIGN: Retrospective case review. SETTING: Tertiary referral center. PATIENTS: A total of 128 patients with HB grade VI RHS were treated in our department between 1995 and 2017. These patients were divided into four treatment groups based on corticosteroid dosage and use of an antiviral agent. METHODS: We assessed treatment outcomes for HB grade VI patients together with logistic regression analysis to investigate factors that can impact treatment outcomes, that is, sex, age, days to start of treatment, PSL dosage, and antiviral agent administration. RESULTS: Recovery rates were best in the high-dose corticosteroid group with an antiviral agent (71.1%) in comparison with the normal-dose corticosteroid group with an antiviral agent (60.0%) or high-dose corticosteroid alone (57.1%). Significant factors for treatment outcomes were high-dose corticosteroid administration and early initiation of treatment. A better recovery rate was also found when the herpetic vesicles appeared before facial palsy. CONCLUSION: We showed that a combination of a high-dose corticosteroid and antiviral agent produced the best outcomes for patients with HB grade VI RHS. However, our results were not statistically significant because of small sample size.

A Minority Population of Non-dye-decolorizing Bacillus subtilis enhances the Azo Dye-decolorizing Activity of Enterococcus faecalis.

Microbes live in communities in biological wastewater treatment plants and in the intestines. However, limited information is currently available on the mechanisms by which minority bacterial populations assist other bacteria besides syntrophic relationships as well as on the microbial food web. Therefore, the present study investigated the effects of non-dye-decolorizing Bacillus subtilis strain S4ga at population levels ranging between 0.04 and 4% on the activity of dye-decolorizing Enterococcus faecalis strain T6a1 using a dye decolorization assay. The results obtained revealed that the minority population of B. subtilis S4ga enhanced the dye-decolorizing activity of E. faecalis T6a1, resulting in a shorter lag time and longer active time of dye decolorization. These effects were related to redox potential values rather than O2 concentrations. Comparisons of the extracellular metabolites in individual incubations of E. faecalis T6a1 and B. subtilis S4ga and a co-incubation suggested a mutual relationship through the cross-feeding of specific amino acids (tyrosine, methionine, tryptophan, phenylalanine, valine, and leucine from B. subtilis S4ga to E. faecalis T6a1; glutamine, histidine, aspartic acid, and proline from E. faecalis T6a1 to B. subtilis S4ga). An ana-lysis of intracellular primary metabolites indicated that the arginine deiminase (ADI) pathway, an ATP-producing energy-generating process, was more strongly activated in co-incubated E. faecalis T6a1 than in E. faecalis T6a1 incubated alone. These results suggest that a co-incubation with B. subtilis S4ga promoted ATP production by E. faecalis T6a1 cells and enhanced its dye-decolorizing activity.

The Feasibility and Treatment Results of Transcanal Endoscopic Myringoplasty.

OBJECTIVE: We reported on transcanal endoscopic myringoplasty in 25 cases preliminarily in 2014. Now our number of transcanal endoscopic myringoplasty reached to 209 ears and allowed us to adequately investigate the visibility, necessity of canalplasty, treatment results, and multivariate analysis. STUDY DESIGN: A prospective case series. SETTING: Tertiary referral center. PATIENTS: Transcanal endoscopic myringoplasty was performed on 209 ears in 201 patients between 2011 and 2019 and followed up over 1 year. METHODS: Preoperative endoscopic and microscopic views for the same patient were compared. We examined success rates at 1 year after surgery according to operation type, perforation size, operation side, gender, cause of perforation, and age, and also examined hearing results. Logistic regression analysis was performed to investigate the basic demographic and clinical characteristics of the patients associated with perforation closure. RESULTS: The anterior edge of the preoperative perforation was not visible under microscopy in 14.4% of patients. In contrast, endoscopic views revealed the entire tympanic membrane in one field. However, canalplasty was required in 2.4% of tympanic procedures due to difficulty of manipulation. The overall closure rate for perforations was 90.4%. Logistic regression analysis revealed that age > 11 was the only significant factor associated with perforation closure. The average reduction in air-bone gap was 12.1 dB. CONCLUSION: The endoscopic myringoplasty produced better visualization, the same or better closure rates, and the same or lower complication rates as compared with traditional microscopic techniques.

Multicenter Study of Congenital Middle Ear Anomalies. Report on 246 Ears.

OBJECTIVES/HYPOTHESIS: Congenital middle ear anomalies represent a relatively rare condition. This study aimed to describe the characteristics and the surgical outcomes for patients with middle ear anomalies. METHODS: A multicenter study was conducted of consecutive patients with congenital middle ear anomalies who underwent primary surgical treatment between January 2008 and December 2017. Demographics, surgical procedures, and audiometric data were registered into the institutional database. Hearing changes and postoperative air-bone gap (ABG) were evaluated 1 year after surgery. RESULTS: A total of 246 patients (246 ears) (median age: 14 years, range: 4-75 years old) were included in this study. Anomalies were subdivided using the Teunissen and Cremers classification: 53 ears (22%) were categorized as class I, comprising only stapes ankylosis; 35 ears (14%) as class II, having ossicular chain anomalies with stapes ankylosis; 139 ears (57%) as class III, having ossicular chain anomalies with a mobile stapes-footplate; and 19 ears (8%) as class IV, with aplasia of the oval window. Evaluation of hearing outcomes for 198 ears with more than 1 year of follow-up revealed that good postoperative ABG (≤20 dB) was achieved in 82% of class I, 68% of class II, 74% of class III, and 23% of class IV anomalies. The postoperative ABG in class IV was significantly worse than in class I (P < .001) or class III (P < .01). CONCLUSIONS: This study demonstrated that class III anomalies comprised the majority of middle ear anomalies and surgical outcomes for class IV anomalies are unfavorable. LEVEL OF EVIDENCE: 4 Laryngoscope, 131:E2323-E2328, 2021.

Consistent removal of hair cells in vestibular end organs by time-dependent transtympanic administration of gentamicin in guinea pigs.

BACKGROUND: Vestibular hair cell loss and its role in balance disorders are not yet completely understood due largely to the lack of precise hair cell damage protocols. NEW METHOD: Our damage protocol aims to selectively remove type I hair cells in a way that produces consistent and predictable lesions that can be used for reliable inter-animal and inter-group comparison in balance research. This objective is achieved by transtympanic injection of gentamicin on both the round window membrane and oval window over a fixed time period followed by thorough washing. RESULTS: We achieved nearly total and consistent loss of type I hair cells at 94 % for the crista ampullaris of the lateral semicircular canal (LSC) and 86 % for the utricular macula with negligible loss of type II hair cells at 4% for the crista ampullaris of the LSC and 6% for the utricular macula. While the vestibular function was compromised in the relevant study group, this group had a zero mortality rate with no significant suppression of body weight gain. COMPARISON WITH EXISTING METHODS: Gentamicin is typically administered via intraperitoneal systemic injection or, more recently, transtympanic injection. The intraperitoneal method is simple, but mortality rate is high. The transtympanic injection method produces ototoxic damage but with inconsistent lesion size. This inconsistency prevents reliable comparisons among animals. CONCLUSIONS: This protocol employs a transtympanic injection method which selectively targets type I hair cells for removal in the vestibular epithelia in a time-dependent manner, uniformly damages vestibular function, and causes uniform hair cell loss.

Regenerative Effect of a ROCK Inhibitor, Y-27632, on Excitotoxic Trauma in an Organotypic Culture of the Cochlea.

In the past, most inner ear diseases were thought to start with the impairment of the sensory epithelium of the cochlea before subsequently progressing to secondary neural degeneration. However, recent studies show that loss of primary synapses accompanied by excitotoxic degeneration of peripheral axons is likely to be the underlying pathology in sensorineural hearing loss. Rho-associated coiled-coil containing protein kinase (ROCK) inhibition has been reported to have neuroprotective and regenerative effects on synaptic pathways. Therefore, we analyzed the effect of ROCK inhibition using Y-27632 in a model of peripheral axonal damage in the spiral ganglion neurons created using the glutamate agonists, N-methyl-D-aspartate (NMDA) and kainic acid, to induce excitotoxic trauma in the explanted cochlea. The number of axons projecting to hair cells in the cochlea treated with Y-27632 was significantly greater than those in the cochlea treated only with NMDA + kainic acid. Furthermore, there was a significant increase in synapses between the spiral ganglion and the inner hair cells in the cochlea treated with Y-27632. The findings of this study suggest that ROCK inhibition could be a potential strategy for the regeneration of peripheral axons in the spiral ganglion and synapse formation in the inner hair cells of a cochlea that has sustained excitotoxic injury, which is one of the primary etiologies of inner ear disease.

Real-World Preventive Effects of Suvorexant in Intensive Care Delirium: A Retrospective Cohort Study.

OBJECTIVE: This study aimed to examine the effects of suvorexant on delirium prevention in a real-world setting. Previous studies have demonstrated the efficacy of suvorexant for delirium prevention in limited randomized clinical trial settings; however, its effectiveness in everyday clinical settings remains unknown. METHODS: A single-center, retrospective cohort study was conducted in the intensive care unit of an academic hospital. Patients (aged ≥ 3 years) admitted from January 2016 to December 2018 were eligible if they stayed in the intensive care unit for at least 72 hours. Suvorexant was prescribed by the attending physician for insomnia as part of everyday clinical practice. A Cox proportional hazards regression analysis was conducted on delirium-free survival for suvorexant users, adjusting for delirium-related covariates. As part of routine clinical practice, the Confusion Assessment Method for the Intensive Care Unit was used to detect the existence of delirium at least twice daily throughout the intensive care unit stay. RESULTS: There were 699 patients-84 suvorexant users and 615 suvorexant nonusers. Delirium was detected in 214 patients. Delirium prevalence was significantly lower in suvorexant users than in nonusers (17.9% vs 32.4%, respectively; P = .007). Cox regression analysis revealed a significantly lower hazard ratio (0.472; 95% CI, 0.268-0.832; P = .009) of delirium in suvorexant users than in nonusers. Trazodone also had a preventive effect on delirium (hazard ratio 0.345; 95% CI, 0.149-0.802; P = .013). CONCLUSIONS: The present study extends to real-world settings previous findings that suvorexant is effective for delirium prevention.

The effect of insulin-like growth factor 1 on the recovery of facial nerve function in a guinea pig model of facial palsy.

The efficacy of insulin-like growth factor 1 (IGF-1) in the treatment of peripheral facial nerve palsy was investigated using an animal model. The facial nerve within the temporal bone was exposed and compressed by clamping. The animals were treated with either IGF-1 or saline which was topically administered by a gelatin-based sustained-release hydrogel via an intratemporal route. The recovery from facial nerve palsy was evaluated at 8 weeks postoperatively based on eyelid closure, complete recovery rate, electroneurography and number of axons found on the facial nerve. IGF-1 treatment resulted in significant improvement in the changes of the degree of eyelid closure over the total time period and complete recovery rate. A separate study showed that IGF-1 receptor mRNA was expressed in facial nerves up to 14 days after the nerve-clamping procedure. IGF-1 was thus found to be effective in the treatment of peripheral facial nerve palsy when topically applied using a sustained-release gelatin-based hydrogel via an intratemporal route.

Measurement of the Pediatric and Adult Osseous External Auditory Canal: Implications for Transcanal Endoscopic Ear Surgery.

OBJECTIVE: To develop a method for measuring the diameter of the osseous external auditory canal (OEAC) in pediatric and adult patients. STUDY DESIGN: Retrospective analysis of imaging data from patients with a cholesteatoma who underwent transcanal endoscopic ear surgery (TEES) to remove the cholesteatoma by analyzing preoperative sagittal cone beam computed tomography (CBCT) images using ImageJ. METHODS: Pediatric and adult patients were included who underwent TEES for a cholesteatoma between December 2011 and March 2015 and had available preoperative CBCT scans. Sagittal CT imaging data were analyzed by ImageJ to measure the maximum and minimum Feret diameters along the OEAC. The output data were then analyzed to determine the smallest maximum and smallest minimum Feret diameters for each patient. RESULTS: Fifty-one patients ranging in age from 3 to 83 years old were included in this study. The smallest maximum Feret diameter ranged from 6.5 to 10.1 mm (mean: 8.0 mm) for pediatric patients (<16 years of age) and 6.9 to 15.0 mm (mean: 8.9 mm) for adult patients, while the smallest minimum Feret diameter ranged from 3.6 to 5.9 mm (mean: 5.1 mm) for pediatric patients and 3.4 to 6.4 mm (mean: 5.4 mm) for adult patients. Moreover, the smallest maximum Feret diameters of children were significantly smaller than those of adults. CONCLUSION: We have developed a novel method for measuring the diameter along the OEAC and determining its narrowest site. This method can be incorporated into the preoperative evaluation of patients who are candidates for TEES.

Brain Abscess as a Rare Complication of Primary Extranodal Nasal-type Natural Killer/T-cell Lymphoma.

We present the case of a 58-year-old Japanese woman with a natural killer T (NK/T)-cell lymphoma complicated by brain abscess. NK/T-cell lymphomas represent a rare type of lymphoma derived from either activated NK cells or, rarely, cytotoxic T cells. They are aggressive Epstein-Barr virus (EBV)-associated lymphomas that involve mainly the nasal cavity. Brain abscess associated with primary extranodal nasal-type NK/T-cell lymphoma is extremely uncommon: to our knowledge, this is the first reported case of this lymphoma with brain abscess as the initial clinical manifestation. Endoscopic surgery was performed for definitive diagnosis under intraoperative navigation system. Chemotherapy followed by radiotherapy was performed and was effective: 72 months later the tumor has not recurred. Recommendations of endoscopic management for diagnosis and treatment of this rare neoplasm are discussed.

Facial nerve and chorda tympani schwannomas: Case series, and advantages of using non-rigid registration of post-enhanced 3D-T1 Turbo Field Echo and CT images (TURFECT) in their diagnosis and surgical treatment.

OBJECTIVE: Facial nerve schwannomas (FNSs) and chorda tympani schwannomas are very rare. Diagnosis of these tumors is sometimes difficult, and treatment consensus has not yet been reached. We report here a series of cases of FNS and chorda tympani schwannoma and highlight the usefulness of our newly developed technique of non-rigid registration of post-enhanced 3D-T1 Turbo Field Echo and CT images (TURFECT) in their diagnosis and treatment. METHODS: MRI images were adjusted with the corresponding CT images in terms of angle and position in order to index the anatomical structures. The well-enhanced T1-Gd+ lesions of tumors having good blood flow show up as bright red after color mapping. RESULTS: Between 2014 and 2018, five patients were diagnosed with schwannomas in the temporal bone: three with FNS and two with chorda tympani schwannoma. Gd-enhanced MRI showed only a high-intensity mass, and we could not detect the relationship between tumor-like mass and bone (including the ossicles) by MRI only. In contrast, TURFECT was very useful for diagnosing the precise location, allowing us to decide on an endoscopic surgical plan in some of our cases. An endoscope enabled visualization of the medial wall of the tympanic cavity and the status of the tumors, thus we could successfully perform transcanal endoscopic biopsy and resections. CONCLUSION: TURFECT can be very useful for diagnosis of FNSs and chorda tympani schwannomas and for deciding surgical treatments such as a transcanal endoscopic approach.

Transcanal Endoscopic Ear Surgery for Congenital Middle Ear Anomalies.

OBJECTIVE: To demonstrate the efficacy of transcanal endoscopic ear surgery (TEES) for congenital middle ear anomalies. STUDY DESIGN: Retrospective case review. SETTING: Tertiary referral center. PATIENTS: Twenty-one patients ranging in age from 4 to 62 years old (median: 15 yr) who underwent TEES between 2011 and 2017 were compared with 19 patients ranging in age from 3 to 49 years old (median: 11 yr) who underwent microscopic ear surgery (MES) between 2000 and 2011. INTERVENTION: Ossiculoplasty or stapes surgeries were performed with TEES or MES. TEES was performed using a rigid endoscope with an outer diameter of 2.7-mm coupled with a full high-definition video system. MES was performed via a transcanal approach with a retroauricular incision. MAIN OUTCOME MEASURE: Middle ear anomaly classification, operating time, and hearing outcomes based on the American Academy of Otolaryngology and Head and Neck Surgery criteria were evaluated and compared between the TEES and MES groups. RESULTS: For Teunissen and Cremers class III anomalies, defined as ossicular chain malformations with a mobile stapes footplate, postoperative air-bone gap closure to 10 dB or less was achieved in 50% of the TEES group and 47% of the MES group. Postoperative air-bone gap closure to 20 dB or less was achieved in 86% of the TEES group and 100% of the MES group. No significant difference was found in the operating time between the two groups. All MES procedures required a retroauricular incision. CONCLUSION: Our results indicate that TEES has similar auditory outcomes compared with MES while avoiding a retroauricular incision.

The Prevalence and Clinical Characteristics of TECTA-Associated Autosomal Dominant Hearing Loss.

TECTA is well known as a causative gene for autosomal dominant mid-frequency hearing loss observed in various populations. In this study, we performed next-generation sequencing analysis of a large Japanese hearing loss cohort, including eight hundred and twelve (812) subjects from unrelated autosomal dominant hearing loss families, to estimate the prevalence and phenotype-genotype correlations in patients with TECTA mutations. The prevalence of TECTA mutations in Japanese autosomal dominant sensorineural hearing loss families was found to be 3.2%. With regard to the type of hearing loss, the patients with mutations in the nidogen-like domain or ZA domain of TECTA showed varied audiograms. However, most of the patients with mutations in the ZP domain showed mid-frequency hearing loss. The rate of hearing deterioration in TECTA-associated hearing loss patients and in the normal hearing Japanese control population were the same and regression lines for each group were parallel. We carried out haplotype analysis for four families which had one recurring missense variant, c.5597C>T (p.Thr1866Met). Our results revealed four different haplotypes, suggesting that this mutation occurred independently in each family. In conclusion, TECTA variants represent the second largest cause of autosomal dominant sensorineural hearing loss in Japan. The hearing loss progression observed in the patients with TECTA mutations might reflect presbycusis. The c.5597C>T mutation occurred in a mutational hot spot and is observed in many ethnic populations.

Comprehensive analysis of syndromic hearing loss patients in Japan.

More than 400 syndromes associated with hearing loss and other symptoms have been described, corresponding to 30% of cases of hereditary hearing loss. In this study we aimed to clarify the mutation spectrum of syndromic hearing loss patients in Japan by using next-generation sequencing analysis with a multiple syndromic targeted resequencing panel (36 target genes). We analyzed single nucleotide variants, small insertions, deletions and copy number variations in the target genes. We enrolled 140 patients with any of 14 syndromes (BOR syndrome, Waardenburg syndrome, osteogenesis imperfecta, spondyloepiphyseal dysplasia congenita, Stickler syndrome, CHARGE syndrome, Jervell and Lange-Nielsen syndrome, Pendred syndrome, Klippel-Feil syndrome, Alport syndrome, Norrie disease, Treacher-Collins syndrome, Perrault syndrome and auditory neuropathy with optic atrophy) and identified the causative variants in 56% of the patients. This analysis could identify the causative variants in syndromic hearing loss patients in a short time with a high diagnostic rate. In addition, it was useful for the analysis of the cases who only partially fulfilled the diagnostic criteria.

OTOF mutation analysis with massively parallel DNA sequencing in 2,265 Japanese sensorineural hearing loss patients.

The OTOF gene (Locus: DFNB9), encoding otoferlin, is reported to be one of the major causes of non-syndromic recessive sensorineural hearing loss, and is also reported to be the most common cause of non-syndromic recessive auditory neuropathy spectrum disorder (ANSD). In the present study, we performed OTOF mutation analysis using massively parallel DNA sequencing (MPS). The purpose of this study was to reveal the frequency and precise genetic and clinical background of OTOF-related hearing loss in a large hearing loss population. A total of 2,265 Japanese sensorineural hearing loss (SNHL) patients compatible with autosomal recessive inheritance (including sporadic cases) from 53 otorhinolaryngology departments nationwide participated in this study. The mutation analysis of 68 genes, including the OTOF gene, reported to cause non-syndromic hearing loss was performed using MPS. Thirty-nine out of the 2,265 patients (1.72%) carried homozygous or compound heterozygous mutations in the OTOF gene. It is assumed that the frequency of hearing loss associated with OTOF mutations is about 1.72% of autosomal recessive or sporadic SNHL cases. Hearing level information was available for 32 of 39 patients with biallelic OTOF mutations; 24 of them (75.0%) showed profound hearing loss, 7 (21.9%) showed severe hearing loss and 1 (3.1%) showed mild hearing loss. The hearing level of patients with biallelic OTOF mutations in this study was mostly severe to profound, which is consistent with the results of past reports. Eleven of the 39 patients with biallelic OTOF mutations had been diagnosed with ANSD. The genetic diagnosis of OTOF mutations has significant benefits in terms of clinical decision-making. Patients with OTOF mutations would be good candidates for cochlear implantation; therefore, the detection of OTOF mutations is quite beneficial for patients, especially for those with ANSD.

Expression and localization of diacylglycerol kinase ζ in guinea pig cochlea and its functional implication under noise-exposure stress conditions.

Cochlear hair cells are essential for the mechanotransduction of hearing. Sensorineural hearing loss can be irreversible because hair cells have a minimal ability to repair or regenerate themselves once damaged. In order to develop therapeutic interventions to prevent hair cell loss, it is necessary to understand the signaling pathway operating in cochlear hair cells and its alteration upon damage. Diacylglycerol kinase (DGK) regulates intracellular signal transduction through phosphorylation of lipidic second messenger diacylglycerol. We have previously reported characteristic expression and localization patterns of DGKs in various organs under pathophysiological conditions. Nevertheless, little is known about morphological and functional aspects of this enzyme family in the cochlea. First RT-PCR analysis reveals predominant mRNA expression of DGKα, DGKε and DGKζ. Immunohistochemical analysis shows that DGKζ localizes to the nuclei of inner hair cells (IHCs), outer hair cells (OHCs), supporting cells and spiral ganglion neurons in guinea pig cochlea under normal conditions. It is well known that loud noise exposure induces cochlear damage, thereby resulting in hair cell loss. In particular, OHCs are highly vulnerable to noise exposure than IHCs. We found that after 1 week of noise exposure DGKζ translocates from the nucleus to the cytoplasm in damage-sensitive OHCs and gradually disappears thereafter. In sharp contrast, DGKζ remains to the nucleus in damage-resistant IHCs. These results suggest that DGKζ cytoplasmic translocation is well correlated with cellular damage under noise-exposure stress conditions and is involved in delayed cell death in cochlear outer hair cells.