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Determine whether asymmetric hearing loss (AHL) affects postoperative speech outcomes in cochlear implant (CI) patients.Retrospective cohort study.Tertiary care hospital.Adult English-speaking patients with unilateral CIs implanted between 2014 and 2018 were stratified into NonAHL and AHL groups based on preoperative AzBio scores in quiet from the nonimplanted ear (0-50% vs. 51-100%, respectively).CI surgery in the poorer performing ear.Postoperative consonant-nucleusconsonant (CNC) word and AzBio sentence test scores in quiet and/or noise at +5 dB signal-to-noise ratio (SNR).Of 512 patients, 33 non-AHL and 27 AHL patients were included. Average ages were 65.6 and 63.6 years, respectively. As expected, preoperative AzBio scores in quiet from the nonimplanted ear were higher in the AHL group (95% confidence interval [95%CI]: 66.4-76.4%) than the non-AHL group at baseline (95%CI: 12.3-23.6%). In both cohorts, AzBio scores in quiet from the implanted ear improved from baseline, with 24-month scores (95%CI: 73.8 - 84.9%) being higher than preoperative scores (95%CI: 13.2-23.1%). There were also significant differences in AzBio scores in quiet between cohorts overall (p = 0.0120) on mixed model analysis, with the AHL group performing ∼6.4% better than the non-AHL group; however, differences were not significant when scores were stratified by time. In addition, there were no significant differences in CNC in quiet and AzBio scores in noise at +5 dB SNR between cohorts (p = 0.1786 and p = 0.6215, respectively).After CI, patients with AHL can achieve scores on word and sentence tests at least comparable to traditional CI candidates, supporting the expansion of CI candidacy to include patients with AHL.

HYPOTHESIS: Vestibular Schwannoma (VS) can avoid cell death following radiation injury by entering cell cycle arrest and activating RAD51-related DNA repair. BACKGROUND: Although the radiobiology of various cancers is well-studied, the radiobiological effects in VS are poorly understood. In this study, we describe how VS cells enter cell cycle arrest (through p21 expression), activate DNA repair (through RAD51 upregulation), and avoid cell death after radiation-induced double-stranded breaks (DSB) in DNA (as measured by γ-H2AX). METHODS: Primary human VS cells were cultured on 96-well plates and 16-well culture slides at 10,000 cells/well and exposed to either 0 or 18 Gray of radiation. Viability assays were performed at 96 hours in vitro. Immunofluorescence for γ-H2AX, RAD51, and p21 was performed at 6 hours. RESULTS: Radiation (18 Gy) induced the expression of γ-H2AX, p21, and RAD51 in 6 cultured VS, suggesting that irradiated VS acquire DSBs, enter cell cycle arrest, and initiate RAD51 DNA repair to evade cell death. However, viability studies demonstrate variable responses in individual VS cells with 3 of 6 VS showing radiation resistance to 18 Gy. On further analyses, radiation-resistant VS cells expressed significantly more p21 than radiation-responsive tumors. CONCLUSIONS: In response to radiation-induced DNA damage, primary VS cells can enter cell cycle arrest and express RAD51 DNA repair mechanisms to avoid cell death. Radioresistant VS cells may mount a more robust p21 response to ensure sufficient time for DNA repair. Further investigation into DNA repair proteins and cell cycle checkpoints may provide important insight on the radiobiology of VS and mechanisms for resistance.

Background: Vestibular schwannomas (VS) are benign intracranial tumors caused by loss of function of the merlin tumor suppressor. We tested three hypotheses related to radiation, hearing loss (HL), and VS cell survival: (1) radiation causes HL by injuring auditory hair cells (AHC), (2) fractionation reduces radiation-induced HL, and (3) single fraction and equivalent appropriately dosed multi-fractions are equally effective at controlling VS growth. We investigated the effects of single fraction and hypofractionated radiation on hearing thresholds in rats, cell death pathways in rat cochleae, and viability of human merlin-deficient Schwann cells (MD-SC). Methods: Adult rats received cochlear irradiation with single fraction (0 to 18 Gray [Gy]) or hypofractionated radiation. Auditory brainstem response (ABR) testing was performed for 24 weeks. AHC viabilities were determined using immunohistochemistry. Neonatal rat cochleae were harvested after irradiation, and gene- and cell-based assays were conducted. MD-SCs were irradiated, and viability assays and immunofluorescence for DNA damage and cell cycle markers were performed. Results: Radiation caused dose-dependent and progressive HL in rats and AHC losses by promoting expression of apoptosis-associated genes and proteins. When compared to 12 Gy single fraction, hypofractionation caused smaller ABR threshold and pure tone average shifts and was more effective at reducing MD-SC viability. Conclusions: Investigations into the mechanisms of radiation ototoxicity and VS radiobiology will help determine optimal radiation regimens and identify potential therapies to mitigate radiation-induced HL and improve VS tumor control.

Objectives Vestibular schwannomas (VS) are intracranial tumors, which are caused by NF2 gene mutations that lead to loss of merlin protein. A treatment for VS is stereotactic radiosurgery, a form of radiation. To better understand the radiobiology of VS and radiation toxicity to adjacent structures, our main objectives were (1) investigate effects of single fraction (SF) radiation on viability, cytotoxicity, and apoptosis in normal Schwann cells (SCs) and merlin-deficient Schwann cells (MD-SCs) in vitro, and (2) analyze expression of double strand DNA breaks (γ-H2AX) and DNA repair protein Rad51 following irradiation. Study Design This is a basic science study. Setting This study is conducted in a research laboratory. Participants Patients did not participate in this study. Main Outcome Measures In irradiated normal SCs and MD-SCs (0–18 Gy), we measured (1) viability, cytotoxicity, and apoptosis using cell-based assays, and (2) percentage of cells with γ-H2AX and Rad51 on immunofluorescence. Results A high percentage of irradiated MD-SCs expressed γ-H2AX, which may explain the dose-dependent losses in viability in rodent and human cell lines. In comparison, the viabilities of normal SCs were only compromised at higher doses of radiation (>12 Gy, human SCs), which may be related to less Rad51 repair. There were no further reductions in viability in human MD-SCs beyond 9 Gy, suggesting that Conclusion The MD-SCs are more susceptible to radiation than normal SCs, in part through differential expression of γ-H2AX and Rad51. Understanding the radiobiology of MD-SCs and normal SCs is important for optimizing radiation protocols to maximize tumor control while limiting radiation toxicity in VS patients.

Objectives Mesenchymal stem cells (MSCs), classically expanded in culture from bone marrow, are of broad interest to the regenerative medicine community. Human nasal turbinate mesenchymal-like stem cell cultures have also been described, defined by an in vitro phenotype similar to bone marrow MSCs. Nonetheless, the identity in vivo of the cells that give rise to nasal MSC-like cultures remains unclear, and these cells are often suggested to be related to olfactory lineages. Here, we sought to define the in vivo phenotype of human nasal MSC-like cells. Methods Human turbinate tissue samples were used for RNA and immunohistochemical analysis. We also analyzed a recently published single cell RNA-sequencing dataset from adult human olfactory and respiratory mucosa samples from our lab, to focus on cell populations expressing MSC markers. Immunochemistry was performed to stain turbinate sections and nasal MSC cultures for selected markers. Results While there is no single MSC-specific gene, we identified a human nasal mucosal cell population in vivo that uniquely expressed transcripts characteristic of typical MSC cultures, including ENG (CD105), NES, and CD34, and lacked expression of other transcripts associated with surface epithelia. The expression of transcription factors such as SOX17, EBF1, and FOXP1 suggests cells in the MSC-like cluster maintain an ability to direct cell fate, consistent with the behavior of nasal MSC-like cells in vitro. SOX17 was found to be uniformly expressed by nasal MSC cultures, consistent with the in vivo data. Immunohistochemistry of human nasal tissue samples indicated that ENG, CD34, and SOX17 expression localized selectively to cells surrounding blood vessels in the lamina propria. Conclusion Our findings provide evidence that the in vivo origin of nasal MSC-like cultures is likely a vascular or pericyte population, rather than cells related to the olfactory neuronal lineage. Level of evidence NA.

Bone marrow derived-mesenchymal stem cells (BM-MSCs) improve the healing of chronic tympanic membrane perforations (cTMPs) in an animal model.cTMPs generate significant morbidity and reduced quality of life, usually requiring surgical assistance. With growing interest in alternative therapies, we sought to evaluate the effect of BM-MSC-therapy on the healing of cTMPs.Sixty cTMPs were established in C57Bl/6 mice and randomized into four groups: hyaluronate scaffold as graft plus BM-MSCs (n = 19 ears), scaffold plus cell culture media (n = 16), scaffold plus phosphate-buffered saline (PBS, n = 12), and no intervention (n = 13). Hyaluronate scaffolds with or without BM-MSCs were applied on 8-week perforated eardrums. After a blinded assessment of perforation sizes at baseline and 2 weeks after treatment, mean perforation reduction rates (%) were compared. Histology characterization was then performed.Mean perforation size reduction rates were significantly higher for cTMPs that received scaffolds plus BM-MSCs (Student's t test, p = 0.0207, 12.3% [95% CI: 7.8-16.7]) and scaffolds plus cell culture media (p = 0.0477, 11.3% [95% CI: 4.4-18.2]) when compared with no intervention (4.2% [95% CI: 1.2-7.2]). This was not observed when treating eardrums with scaffolds plus PBS (7.3% [95% CI: 2.7-11.9]). On histology, BM-MSC-treated eardrums demonstrated restoration of the trilaminar configuration and reduced inflammatory changes, while other groups developed tissue architecture disorganization and hypercellular infiltrates surrounding the perforation site.BM-MSCs and cell culture media equivalently increased cTMP healing rates. Cell-based therapy conferred a restoration of the trilaminar configuration of the eardrum with relatively compact and organized fibrous layers.

Objective (1) Characterize the distribution of M1 and M2 macrophages in vestibular schwannomas by hearing status. (2) Develop assays to assess monocyte migration and macrophage polarization in cocultures with vestibular schwannoma cells. Study Design Basic and translational science. Setting Tertiary care center. Methods A retrospective chart review of 30 patients with vestibular schwannoma (VS) was performed. Patients were stratified into serviceable and unserviceable hearing groups. Immunohistochemistry for CD80 + M1 and CD163 + M2 macrophages was conducted. Primary VS cultures (n = 4) were developed and cocultured with monocytes. Immunohistochemistry for macrophage markers was performed to assess monocyte migration and macrophage polarization. Results Although tumors associated with unserviceable hearing had higher levels of CD80 and CD163 than those with serviceable hearing, the relationship was only significant with CD163 ( P = .0161). However, CD163 level did not remain a significant predictor variable associated with unserviceable hearing on multivariate analysis when adjusted for other variables. In vitro assays show that VS cells induced monocyte migration and polarization toward CD80 + M1 or CD163 + M2 macrophage phenotypes, with qualitative differences in CD163 + macrophage morphologies between serviceable and unserviceable hearing groups. Conclusion Vestibular schwannomas express varying degrees of CD80 + M1 and CD163 + M2 macrophages. We present evidence that higher expression of CD163 + may contribute to poorer hearing outcomes in patients with VS. We also describe in vitro assays in a proof-of-concept investigation that VS cells can initiate monocyte migration and macrophage polarization. Future investigations are warranted to explore the relationships between tumor, macrophages, secreted cytokines, and hearing outcomes in patients with VS.

Summary Objectives Awake injection medialization laryngoplasty is one of the most common therapeutic procedures done by laryngologists in the office or at the bedside. Complications of injection needle fracture are rarely reported. Methods This is a case report of a 59-year-old male inpatient who developed left vocal fold immobility with significant glottic insufficiency after pneumonectomy for a large left-sided lung cancer. During bedside injection medialization using thyrohyoid approach, the 25 G needle fractured at the hub and was embedded partly in pre-epiglottic space and partly extending over rima glottidis. Results Fractured needle was successfully retrieved at the bedside with an endoscopic biopsy forcep using flexible bronchoscope. Conclusion It is imperative to be aware of rare complications of routine procedures like injection laryngoplasty so they can be managed timely and effectively.

Simple Summary Vestibular schwannomas (VS) are intracranial tumors that originate from the Schwann cells of the vestibulocochlear nerve and cause hearing loss and dizziness. Although radiation therapy is a common treatment for VS, some irradiated tumors do not respond well and continue to grow, requiring additional therapies such as surgery. Little is known about the molecular mechanisms behind the normal response of VS to radiation therapy and why some VS are resistant to radiation. Thus, we aimed to review the current understanding of radiation response and resistance in VS through an in-depth summary of the DNA damage and cell cycle response to ionizing radiation. A better understanding of the radiobiology of VS can help guide future investigations looking at optimal radiation dosing strategies, unique targets for intervention, and novel therapies to improve patient outcomes. Abstract Vestibular schwannomas (VS) are benign tumors arising from cranial nerve VIII that account for 8–10% of all intracranial tumors and are the most common tumors of the cerebellopontine angle. These tumors are typically managed with observation, radiation therapy, or microsurgical resection. Of the VS that are irradiated, there is a subset of tumors that are radioresistant and continue to grow; the mechanisms behind this phenomenon are not fully understood. In this review, the authors summarize how radiation causes cellular and DNA injury that can activate (1) checkpoints in the cell cycle to initiate cell cycle arrest and DNA repair and (2) key events that lead to cell death. In addition, we discuss the current knowledge of VS radiobiology and how it may contribute to clinical outcomes. A better understanding of VS radiobiology can help optimize existing treatment protocols and lead to new therapies to overcome radioresistance.

Objectives: To determine the impact of age, electrode array, and time on impedance patterns in cochlear implant (CI) patients. Methods: A retrospective case review was performed on 98 patients implanted with the CI24RE perimodiolar (PM) and CI422 lateral wall (LW) arrays between 2010 and 2014 to assess impedances at the 1 week and 3-6 month visit after initial stimulation (IS). Results: With respect to age, impedances were higher in young patients compared to older patients in the middle and apical turns. With time, there were significant reductions in impedances across most electrodes. Electrode array type also had a significant impact on impedance measurements with PM and LW arrays having higher impedances in the basal turn and apical turns, respectively. Furthermore, PM arrays demonstrated significantly lower impedances in the middle and apical turn with time, when compared to LW arrays. Conclusions: Age, electrode array, and time can independently affect CI impedances. Moreover, we show that PM arrays may be advantageous to LW arrays, due to demonstrated lower impedances in the middle and apical turns long term. Understanding the impact of impedance on speech discrimination and determining the intracochlear processes that contribute to differences in impedance are future research directions.

Objective To compare the safety and efficacy of manual and powered irrigation of the middle ear using saline or 1% baby shampoo to treat biofilm-forming bacterial middle ear infections. Background Biofilms play a major role in recalcitrant otitis media and are challenging to treat. Many therapeutic strategies have been attempted and the role of topical therapies is still being investigated. Topical irrigation using saline or 1% baby shampoo and the use of a hydrodebrider have been investigated in biofilms involved in chronic rhinosinusitis and their role within the middle ear is yet to be determined. Methods Twenty-two adult chinchillas underwent bilateral trans-bullar inoculation of non-typable biofilm forming Haemophilus influenza followed by unilateral middle ear irrigation 5 days later using saline administered via a powered hydrodebrider or manual irrigation of saline or 1% baby shampoo. Contralateral inoculated ears served as control and were not irrigated. Two days following irrigation, the bullae were harvested and processed for scanning electron microscopy to assess biofilm surface area. Auditory brainstem responses were performed before bacterial inoculation and prior to euthanasia. Results Manual and powered irrigation were effective in reducing the surface area of biofilm when compared to the control group. The hydrodebrider demonstrated to be more effective at eradicating biofilm than manual irrigation, especially in areas of difficult access, such as the ventral portion of the chinchillas' bullae. There was no difference in manual irrigation of saline when compared to 1% baby shampoo. Irrigations either manually or using the hydrodebrider did not affect hearing, the vestibular system or facial function. Conclusion Middle ear biofilms can be treated safely and effectively with rinses using either normal saline or 1% baby shampoo administered manually or with a powered hydrodebrider. Level of evidence NA.

Stereotactic radiosurgery for lateral skull base tumors can cause hearing loss when the cochleae are exposed to high doses of single-fraction radiation. Currently, there are no known nondosimetric preventative treatments for radiation-induced ototoxicity.Intratympanic (IT) dexamethasone (DXM), a synthetic steroid, protects against radiation-induced auditory hair cell (HC) and hearing losses in rats in vivo.Seven rats received radiation (12 Gy) to both cochleae. In irradiated rats and six nonirradiated rats, IT DXM was randomized to one ear, while tympanic puncture without DXM was performed on the contralateral ear. Baseline and 4-week postradiation auditory-evoked potential tests were performed. The cochleae were processed for HC viability.Cochleae exposed to radiation demonstrated more outer HC (OHC) loss in all turns than nonirradiated ears (p 0.05). OHCs were more susceptible to radiation injury than inner HCs in the middle and basal turns (p 0.05). In irradiated cochleae, there was a nonsignificant trend for less OHC loss with IT DXM in the basal turn when compared with placebo. IT DXM did not improve radiation-induced hearing threshold shifts; however, a high rate of tympanic membrane perforations occurred with irradiated ears which may contribute to this finding.Radiation induced loss of OHCs in all turns of the cochlea. IT DXM reduced OHC loss in the basal turn of irradiated ears; however, this finding did not achieve statistical significance. Although IT DXM did not affect radiation-induced hearing threshold shifts in adult rats in vivo, this may be due to a high rate of tympanic membrane perforations.

Olfactory disorders have been regarded in the past with a sense of therapeutic nihilism. However, there have been remarkable advances in chemosensory research over the past several years. The clinical importance of olfactory disorders is well established, and entities such as presbyosmia have gained considerable broad attention. Powerful basic science experimental approaches have revealed aspects of olfactory neuron physiology, olfactory tissue maintenance, and regeneration that provide new potential therapeutic targets for certain forms of olfactory dysfunction. Although many recent advances remain in pre-clinical stages, there is considerable reason for optimism regarding future approaches for treatment of patients with olfactory loss.

ObjectiveTo investigate the effectiveness of scaffold-embedded mesenchymal stem cells (MSCs) as a topical treatment for healing tympanic membrane perforations (TMPs) in a mouse model.Study DesignProspective animal study.SettingExperimental.Subjects and MethodsIn vitro: under sterile conditions, porcine-derived (Gelita-Spon [GS]), hyaluronate-derived (EpiDisc [ED]), and polyvinyl alcohol (PVA) scaffolds were cut into small pieces and cocultured with murine bone marrow–derived MSCs (BM-MSCs) expressing green fluorescent protein (GFP) for 72 hours. The cultures were either analyzed by confocal microscopy or used for subsequent in vivo experiments. In vivo: 26 mice were divided into 3 groups (ie, control [n = 9], GS [n = 8], ED [n = 9]). Under general anesthesia, TMPs of equal sizes were performed bilaterally using a sterile 27-gauge needle under a surgical microscope. The BM-MSCs embedded within GS or ED scaffolds were soaked in phosphate-buffered saline and then topically applied on right TMPs, and scaffold...

The olfactory epithelium (OE) is the peripheral organ for the sense of smell, housing primary sensory neurons that project axons from the nose to the brain. Due to the presence of a basal stem cell niche, the adult mammalian OE is a dynamic tissue capable of replacing neurons following their loss. Nonetheless, certain conditions, such as blunt head trauma, can result in persistent olfactory loss, thought to be due to shearing of olfactory nerve filaments at the skull base, degeneration, and failures in proper regeneration/reinnervation. The identification of new treatment strategies aimed at preventing degeneration of olfactory neurons is, therefore, needed. In considering potential therapies, we have focused on N-acetylcysteine (NAC), a glutathione substrate shown to be neuroprotective, with a record of safe clinical use. Here, we have tested the use of NAC in an animal model of olfactory degeneration. Administered acutely, we found that NAC (100 mg/kg, twice daily) resulted in a reduction of olfactory neuronal loss from the OE of the nose following surgical ablation of the olfactory bulb. At 1 week postlesion, we identified 54 ± 8.1 mature neurons per 0.5 mm epithelium in NAC-treated animals vs. 28 ± 4.2 in vehicle-treated controls (P = 0.02). Furthermore, in an olfactory cell culture model, we have identified significant alterations in the expression of several genes involved in oxidative stress pathways following NAC exposure. Our results provide evidence supporting the potential therapeutic utility for NAC acutely following head trauma-induced olfactory loss. Anat Rec, 303:626-633, 2020. © 2019 American Association for Anatomy.

The benefits of Cochlear implant (CI) technology depend among other factors on the proximity of the electrode array to the spiral ganglion neurons. Laminin, a component of the extracellular matrix, regulates Schwann cell proliferation and survival as well as reorganization of actin fibers within their cytoskeleton, which is necessary for myelination of peripheral axons. In this study we explore the effectiveness of laminin-coated electrodes in promoting neuritic outgrowth from auditory neurons towards the electrode array and the ability to reduce acoustic and electric auditory brainstem response (i.e. aABR and eABR) thresholds. In vitro: Schwann cells and neurites are attracted towards laminin-coated surfaces with longer neuritic processes in laminin-coated dishes compared to uncoated dishes. In vivo: Animals implanted with laminin-coated electrodes experience significant decreases in eABR and aABR thresholds at selected frequencies compared to the results from the uncoated electrodes group. At 1 month post implantation there were a greater number of spiral ganglion neurons and neuritic processes projecting into the scala tympani of animals implanted with laminin-coated electrodes compared to animals with uncoated electrodes. These data suggest that Schwann cells are attracted towards laminin-coated electrodes and promote neuritic outgrowth/ guidance and promote the survival of spiral ganglion neurons following electrode insertion trauma.

Summary: Stem cell-based therapies have been proposed as a strategy to replace damaged tissues, especially in the nervous system. A primary sensory modality, olfaction, is impaired in 12% of the US population, but lacks treatment options. We report here the development of a novel mouse model of inducible hyposmia and demonstrate that purified tissue-specific stem cells delivered intranasally engraft to produce olfactory neurons, achieving recovery of function. Adult mice were rendered hyposmic by conditional deletion of the ciliopathy-related IFT88 gene in the olfactory sensory neuron lineage and following experimentally induced olfactory injury, received either vehicle or stem cell infusion intranasally. Engraftment-derived olfactory neurons were identified histologically, and functional improvements were measured via electrophysiology and behavioral assay. We further explored mechanisms in culture that promote expansion of engraftment-competent adult olfactory basal progenitor cells. These findings provide a basis for translational research on propagating adult tissue-specific sensory progenitor cells and testing their therapeutic potential. : Olfactory sensory losses lack treatment options. The corresponding author and colleagues report the testing of a cellular therapy for olfactory loss. Inducible hyposmia was produced by targeting ciliopathy to the olfactory lineage in mice, and wild-type adult stem cells engrafted to produce functional neurons, assessed using histology, electrophysiology, and behavioral assay. Keywords: olfaction, anosmia, stem cells, neuron, ciliopathy

Chronic tympanic membrane perforations (TMP) can be a source of significant morbidity from hearing loss, recurrent middle ear infections, changes in lifestyle, and risk of cholesteatoma formation. Laboratory experiments of TMP have been fraught by the rapid and high rate of spontaneous healing observed in animal models. There is controversy on the minimal time that perforations in animal models must have in order to be considered chronic TMP and thus have clinical relevance, with authors suggesting time periods of perforation patency of 8-12 weeks. In this article, we sought to create a clinically significant experimental model that could yield a high rate of perforation patency for at least 8 weeks. Animals undergoing acute TMP were exposed to three different experimental situations to delay the healing of the perforation: fractionated radiation, topical lipopolysaccharide application, and a combined dexamethasone and mitomycin C (DXM/MC) solution. In our study, the use of DXM/MC reliably produced TMP lasting at least 8 weeks in 86.48% of the cases without the need to reopen the perforation, infolding the edges of the membrane, or using physical barriers to prevent TMP closure. Histologically, the resulting perforated tympanum showed hyaline changes of the remnant tympanum and hyperkeratosis of the squamous epithelia of the external auditory canal. We believe that this model is reproducible and has potential use in experiments of delayed healing of TMP. Anat Rec, 303:619-625, 2020. © 2019 American Association for Anatomy.

Hypothesis: Dexamethasone (DXM) protects against radiation-induced loss of auditory hair cells (HCs) in rat organ of Corti (OC) explants by reducing levels of oxidative stress and apoptosis. Background: Radiation-induced sensorineural hearing loss (HL) is progressive, dose-dependent, and irreversible. Currently, there are no preventative therapeutic modalities for radiation-induced HL. DXM is a synthetic steroid that can potentially target many of the pathways involved in radiation-induced ototoxicity. Methods: Whole OC explants were dissected from 3-day-old rat cochleae exposed to specific dosages of single-fraction radiation (0, 2, 5, 10, or 20 Gy), were either untreated or treated with DXM (75, 150, 300 μg/mL), and then cultured for 48 or 96 hours. Confocal microscopy for oxidative stress (CellRox, 48 h) and apoptosis (TUNEL assay, 96 h) and fluorescent microscopy for viable HC counts (fluorescein isothiocyanate-phalloidin, 96 h) were performed. Analysis of variance and Tukey post hoc testing were used for statistical analysis. Results: Radiation exposure initiated dose-dependent losses of inner and outer HCs, predominantly in the basal turns of the OC explants. DXM protected against radiation-induced HC losses in a dose-dependent manner. DXM significantly reduced levels of oxidative stress and apoptosis in radiation-injured OC explants (p Conclusions: Radiation-initiated HC losses were dose-dependent in OC explants. DXM treatment protected explant HCs against radiation-initiated losses by decreasing the levels of oxidative stress and apoptosis. DXM may potentially be a therapeutic modality for preventing radiation-induced HL; further in vivo studies are necessary.

Objectives/Hypothesis To evaluate the effectiveness of cochlear measures obtained by high-resolution computed tomography (HRCT) scan in predicting depth of cochlear implant insertion. Study Design Retrospective case review. Methods Patients who underwent cochlear implantation in an academic referral center between 2010 and 2013 were considered. Inclusion criteria included available preoperative HRCT scan and complete operative data. Subjects with labyrinthitis ossificans, cochlear hypoplasia, or major inner ear malformations were excluded. Subsequently, measures of cochlear height in the coronal plane and basal turn width in the axial plane were obtained using electronic calipers of the stored digital HRCT images by a blinded investigator. The insertion was considered deep when the electrode was placed at least 23 mm into the cochlea. Subjects were divided into those who had a deep insertion and those who did not. Regression analyses were done to associate cochlear measures with deep insertion. Results A deep insertion was possible in 25 patients out of 35. There was no statistically significant association between deep insertion and age at implantation, gender, and type of cochleostomy. The mean cochlear height was 6.22 mm (standard deviation [SD] = 0.32 mm) and 5.80 mm (SD = 0.3mm) in subjects with and without deep insertion, respectively (Student t test, P = .0015). Only cochlear height showed an association with deep insertion (logistic regression, P = .0007). For a cochlear height of 6.27 mm, the probability of deep insertion was 0.90. Conclusions Linear measurements of standard CT scans of the cochlea can predict the depth of insertion and may help the selection of the appropriate electrode array preoperatively. Level of Evidence 4. Laryngoscope, 126:1656–1661, 2016

HYPOTHESIS Dexamethasone (DXM) protects against cisplatin-induced auditory hair cell (HC) loss in rat organ of Corti (OC) explants in vitro by reducing levels of oxidative stress and NADPH-Oxidase-3 (NOX-3). BACKGROUND Intratympanic DXM has demonstrated protective effects against cisplatin-induced hearing loss in a few animal studies and one clinical trial. However, levels of protection with intratympanic DXM vary significantly between studies, which may not be a result of the intrinsic properties of DXM but rather reflect the diffusion of DXM into the cochlea. The molecular mechanisms and degree of DXM protection against cisplatin ototoxicity are currently unknown. METHODS OC explants from 3-day-old rats were cultured with no treatment or various concentrations of cisplatin (2, 5, or 10 μM) and DXM (75, 150, or 300 μg/mL) in vitro. HC viability and TUNEL assay were performed after 72 hours in vitro and levels of oxidative stress and NOX-3 were evaluated with confocal microscopy after 48 hours in vitro. Analysis of variance with Tukey's post hoc testing was performed. RESULTS Cisplatin initiated dose-dependent losses of outer HCs (OHCs) in the basal turns of exposed explants (p

Cholesterol granulomas (CGs) are the most common benign lesions of the petrous apex (PA) and have distinct computed tomography (CT) and magnetic resonance imaging (MRI) characteristics. On CT, CGs of the PA (PACG) present as expansile lesions with erosion of bony trabeculae. MRI shows a hyperintense lesion on T1-and T2-weighted images and do not enhance with gadolinium. The objective is to describe the radiographic features of CGs of the skull base that do not arise from the PA. This study is a retrospective review. Three patients were operated on for suspected recurrent endolymphatic sac tumor, intracranial cholesteatoma, and recurrent sphenoid wing meningioma based on CT and MRI findings. Pathology results were consistent with CG in all three cases. All patients had bone erosion on CT. These skull base CGs did not demonstrate similar MRI features. These lesions were hyperintense, iso-to-hyperintense, and hypointense on T1-weighted MRI, respectively. These CGs were hyperintense in two cases and iso-to-hyperintense in one case on T2-weighted MRI. These lesions either demonstrated central or rim enhancement after gadolinium administration. Skull base CGs that do not arise from the PA demonstrate a broad spectrum of radiographic characteristics on MRI that are not typical of PACG.

Hair cells are highly sensitive units that in response to trauma, inflammation, and cochlear implantation activate different signaling pathways leading to hair cell death and hearing impairment. In this chapter we discuss the most recent literature regarding signaling pathways of hair cell loss, mechanisms and inflammatory responses after noise exposure and electrode insertion, and otoprotective strategies that can limit hair cell death and hearing loss.

Objective To compare the safety and efficacy of manual and powered irrigation of the middle ear using saline or 1% baby shampoo to treat biofilm‐forming bacterial middle ear infections. Background Biofilms play a major role in recalcitrant otitis media and are challenging to treat. Many therapeutic strategies have been attempted and the role of topical therapies is still being investigated. Topical irrigation using saline or 1% baby shampoo and the use of a hydrodebrider have been investigated in biofilms involved in chronic rhinosinusitis and their role within the middle ear is yet to be determined. Methods Twenty‐two adult chinchillas underwent bilateral trans‐bullar inoculation of non‐typable biofilm forming Haemophilus influenza followed by unilateral middle ear irrigation 5 days later using saline administered via a powered hydrodebrider or manual irrigation of saline or 1% baby shampoo. Contralateral inoculated ears served as control and were not irrigated. Two days following irrigation, the bullae were harvested and processed for scanning electron microscopy to assess biofilm surface area. Auditory brainstem responses were performed before bacterial inoculation and prior to euthanasia. Results Manual and powered irrigation were effective in reducing the surface area of biofilm when compared to the control group. The hydrodebrider demonstrated to be more effective at eradicating biofilm than manual irrigation, especially in areas of difficult access, such as the ventral portion of the chinchillas' bullae. There was no difference in manual irrigation of saline when compared to 1% baby shampoo. Irrigations either manually or using the hydrodebrider did not affect hearing, the vestibular system or facial function. Conclusion Middle ear biofilms can be treated safely and effectively with rinses using either normal saline or 1% baby shampoo administered manually or with a powered hydrodebrider. Level of Evidence NA.

Alport syndrome is a rare hereditary renal disorder with no etiologic therapy. We found that osteopontin (OPN) is highly expressed in the renal tubules of the Alport mouse and plays a causative pathological role. OPN genetic deletion ameliorated albuminuria, hypertension, tubulointerstitial proliferation, renal apoptosis, and hearing and visual deficits in the Alport mouse. In Alport renal tubules we found extensive cholesterol accumulation and increased protein expression of dynamin-3 (DNM3) and LDL receptor (LDLR) in addition to dysmorphic mitochondria with defective bioenergetics. Increased pathological cholesterol influx was confirmed by a remarkably increased uptake of injected DiI-LDL cholesterol by Alport renal tubules, and by the improved lifespan of the Alport mice when crossed with the Ldlr-/- mice with defective cholesterol influx. Moreover, OPN-deficient Alport mice demonstrated significant reduction of DNM3 and LDLR expression. In human renal epithelial cells, overexpressing DNM3 resulted in elevated LDLR protein expression and defective mitochondrial respiration. Our results suggest a potentially new pathway in Alport pathology where tubular OPN causes DNM3- and LDLR-mediated enhanced cholesterol influx and impaired mitochondrial respiration.

We evaluated the effects of dexamethasone base (DXMb) containing electrode arrays in a guinea pig model of cochlear implantation to determine if eluted DXMb could protect the cochlea against electrode insertion trauma (EIT)-induced: 1) loss of hair cells; 2) disruption of neural elements; 3) increases in hearing thresholds; 4) increased electrical impedance and 5) fibrosis. A guinea pig model of EIT-induced hearing and hair cell losses was used to test silicone electrode arrays that contained either 10%, 1%, 0.1%, or 0% levels of micronized DXMb. These four types of electrode arrays were implanted into the scala tympani via basal turn cochleostomies and left in place for 3 months. Hearing thresholds were determined by ABR and CAP recordings in response to a series of defined pure tone stimuli (i.e. 16-0.5 kHz). Changes in impedance were measured between the implant electrode and a reference electrode. Hair cell counts and neural element integrity were determined by confocal microscopy analyses of stained organ of Corti whole mounts obtained from 90 day post-implantation animals. Fibrosis was measured in Masson trichrome stained cross-sections through the organ of Corti. The results showed that either 10% or 1.0% DXMb eluting electrode arrays protected; hearing thresholds, hair cells, and neural elements against EIT-induced losses and damage. Electrode arrays with 0.1% DXMb only partial protected against EIT-induced hearing loss and damage to the cochlea. Protection of hearing thresholds and organ of Corti sensory elements by electrode-eluted DXMb was still apparent at 3 months post-EIT. All three concentrations of DXMb in the electrode arrays prevented EIT-induced increases in impedance. EIT-initiated fibrosis was significantly reduced within the implanted cochlea of the two DXMb concentrations tested. In conclusion, DXMb eluting electrodes protected the cochlea against long term increases in hearing thresholds, loss of hair cells, damage to neural elements and increases in impedance and fibrosis that result from EIT-initiated damage. The protection achieved by DXMb-eluting electrodes was dose dependent. Establishing a significant level of trauma induced elevation in hearing thresholds was important for the determination of the otoprotective effects of array-eluted DXMb.

Scaffolds are routinely used in the middle ear to provide support after tympanic membrane and ossicular chain reconstruction, to provide hemostasis or to promote tissue regeneration. Its permanence within a body cavity will depend upon several factors, such as the scaffold composition and the surgical procedure to be performed. Autologous grafts (i.e. temporalis fascia, cartilage, perichondrium) are considered the gold standard for tympanic membrane repair. Autologous grafts are associated with donor site morbidity, multiple incisions and increased surgical time. Recently, many alternatives to autologous grafts have become available including allografts (Allo Derm™), xenografts and synthetic materials. Scaffolds can also be characterized by their reabsorption rates and host reaction, and these differences can be exploited to serve different purposes during surgery. While some of these materials have been attributed healing enhancement properties, other materials have been associated with adverse effects, mainly aberrant scarring. A descriptive review of the most commonly used scaffolds in otologic surgery, current research highlights and future applications are discussed. //

To evaluate the effectiveness of cochlear measures obtained by high-resolution computed tomography (HRCT) scan in predicting depth of cochlear implant insertion.Retrospective case review.Patients who underwent cochlear implantation in an academic referral center between 2010 and 2013 were considered. Inclusion criteria included available preoperative HRCT scan and complete operative data. Subjects with labyrinthitis ossificans, cochlear hypoplasia, or major inner ear malformations were excluded. Subsequently, measures of cochlear height in the coronal plane and basal turn width in the axial plane were obtained using electronic calipers of the stored digital HRCT images by a blinded investigator. The insertion was considered deep when the electrode was placed at least 23 mm into the cochlea. Subjects were divided into those who had a deep insertion and those who did not. Regression analyses were done to associate cochlear measures with deep insertion.A deep insertion was possible in 25 patients out of 35. There was no statistically significant association between deep insertion and age at implantation, gender, and type of cochleostomy. The mean cochlear height was 6.22 mm (standard deviation [SD] = 0.32 mm) and 5.80 mm (SD = 0.3mm) in subjects with and without deep insertion, respectively (Student t test, P = .0015). Only cochlear height showed an association with deep insertion (logistic regression, P = .0007). For a cochlear height of 6.27 mm, the probability of deep insertion was 0.90.Linear measurements of standard CT scans of the cochlea can predict the depth of insertion and may help the selection of the appropriate electrode array preoperatively.4. Laryngoscope, 126:1656-1661, 2016.

Conservation of a patient’s residual hearing and prevention of fibrous tissue/new bone formation around an electrode array are some of the major challenges in cochlear implant (CI) surgery. Although it is well known that fibrotic tissue formation around the electrode array can interfere with hearing performance in implanted patients, and that associated intracochlear inflammation can initiate loss of residual hearing, little is known about the molecular and cellular mechanisms that promote this response in the cochlea. In vitro studies in neonatal rats and in vivo studies in adult mice were performed to gain insight into the pro-inflammatory, proliferative, and remodeling phases of pathological wound healing that occur in the cochlea following an electrode analogue insertion. Resident Schwann cells, macrophages/microglia, and fibroblasts had a prominent role in the inflammatory process in the cochlea. Leukocytes were recruited to the cochlea following insertion of a nylon filament in adult mice, where contributed to the inflammatory response. The reparative stages in wound healing are characterized by persistent neuro-inflammation of spiral ganglion neurons and expression of regenerative macrophages in the cochlea. Accordingly, genes involved in extracellular matrix deposition and remodeling were up-regulated in implanted cochleae.Maturation of scar tissue occurs in the remodeling phase of wound healing in the cochlea. Similar to other damaged peripheral nerves, M2 macrophages and de-differentiated Schwann cells were observed in damaged cochleae and may play a role in cell survival and axonal regeneration. In conclusion, the insertion of an electrode analogue into the cochlea is associated with robust early and chronic inflammatory responses characterized by recruitment of leukocytes and expression of pro-inflammatory cytokines that promote intracochlear fibrosis and loss of auditory hair cells and spiral ganglion neurons important for hearing after CI surgery.

International audience; Loss of auditory sensory hair cells (HCs) is the most common cause of hearing loss. This review addresses the signaling pathways that are involved in the programmed and necrotic cell death of auditory HCs that occur in response to ototoxic and traumatic stressor events. The roles of inflammatory processes, oxidative stress, mitochondrial damage, cell death receptors, members of the mitogen-activated protein kinase (MAPK) signal pathway and pro- and anti-cell death members of the Bcl-2 family are explored. The molecular interaction of these signal pathways that initiates the loss of auditory HCs following acoustic trauma is covered and possible therapeutic interventions that may protect these sensory HCs from loss via apoptotic or non-apoptotic cell death are explored.

GelitaSpon gelatin sponge (GS) showed faster reabsorption than gelfoam (GF) in vitro, and GS-packed middle ears resulted in a faster hearing recovery and less inflammation than the ears packed with GF soaked in saline. Soaking GF sponges with boric acid (BA) appeared to offset the inflammatory response of saline-soaked GF, making this inflammatory response comparable to that of GS-packed ears.To describe the reabsorption and inflammatory effects of absorbable gelatin sponge in the middle ear.For in vitro evaluation, GF and GS were used as disks immersed in saline solution or 3% BA and placed in gel. Images were captured with a microscope and processed using image processing Toolbox. For in vivo tests, 16 female albino Sprague Dawley rats were divided into four groups: bulla opening; GF + 0.9% saline; GF + BA; and GS + 0.9% saline. An anterior approach to the right bulla was used for surgery. Preoperative and postoperative auditory brainstem response thresholds were measured.In vitro, there was marked degradation of GF by day 14, while GS showed complete degradation by the third day. In vivo, hearing recovery occurred by day 21. GF produced a more severe inflammatory response, which could be reduced by treating the GF with BA.

Objectives: Evaluate the efficacy of combined antistaphylococcal and anti-pseudomonal preoperative antibiotics for preventing surgical site infections following tympanoplasty with mastoidectomy for contaminated cholesteatoma. Methods: Retrospective chart review of medical records of patients who underwent tympanoplasty with mastoidectomy for cholesteatoma were reviewed. Only cases considered to have contaminated or dirty/infected surgical fields were included. The primary outcome measure was postoperative perichondritis, pinna abscess, periotic cellulitis, and periotic abscess requiring systemic antibiotics or surgical intervention. Results: Charts of 362 patients who underwent tympanoplasty with mastoidectomy were reviewed, and 195 met inclusion criteria. Preoperative antibiotics included single doses of clindamycin and ceftazidime or gentamicin prior to incision. Patients that received no preoperative antibiotics had an infection rate of 11% and those given perioperative antibiotics had a rate of 1% (P = .02). Conclusions: Use of preoperative antibiotics covering both staphylococcus and pseudomonas species appears to be efficacious for the prevention of surgical site infections following tympanoplasty with mastoidectomy for contaminated cholesteatoma.

Objectives:Determine the characteristics of the auditory central gain due to bilateral hearing deprivation, and its relationship with circadian variations as a function of cortical activity.Methods:The study was designed as a prospective observational research, in a national referral center. A total of 28 volunteers ranging between 18 and 30 years old underwent bilateral earplugging with Merocel, previous medical examination, anthropometry, author developed questionnaire, Hamilton anxiety and depression inventory, speech and pure tone audiometry, tympanometry and middle ear reflex (MER), distortion products otoacoustics emissions input/output(DPOAE-I/O), and uncomfortable loudness levels (ULLs) in 0.5-4 kHz. Subjects were randomly divided in 2 groups: Group A, starting at 8:00 am and finishing at 8:00 pm; Group B, starting at 4:00 pm ending at 4:00 am. Serum cortisol levels and audiological test were obtained at the beginning and at the end of the session. A 24-hour free urinary cortisol levels were measu...

Objective: 1) Determine the dissolution pattern of Gelfoam and Invotec with saline and low grade boric acid solution. 2) Measure the effect of both gelatins in animal model hearing in postoperative time. 3) Understand the direct effect of boric acid treated gel in the middle and inner ear.Methods: In vitro, 1 cm2 of Gelfoam and Invotec colored with Congo Red and immersed in saline solution 0.9% and boric acid pH 6.3. Pixel density analysis was performed to determine degradation. Thirty live Sprague-Dawley rats, females of 100 g, were anesthetized with ketamine/xilacine, divided into 5 groups. Preoperatory and postoperatory ABRs were measured. All bullas were processed for histopathology.Results: Invotec dispersion and degradation was 25% sooner than Gelfoam. Boric acid treating resulted in rapid degradation of both gelatins by 18%. Hearing recovery by the Gelfoam group occurred in days 5 and 6, and Invotec treated between days 4 and 5. A shorter period of time of 4 to 5 days in boric acid treated Gelfoam....