Publications by authors named "Hinrich Staecker"

98 Publications

Evaluating Neurotrophin Signaling Using MicroRNA Perilymph Profiling in Cochlear Implant Patients With and Without Residual Hearing.

Otol Neurotol 2021 May 10. Epub 2021 May 10.

Department of Otolaryngology Head and Neck Surgery, Washington University School of Medicine in St. Louis, St. Louis, Missouri Department of Otolaryngology Head and Neck Surgery, University of Kansas School of Medicine, Kansas City, Kansas Department of Otolaryngology, Medizinische Hochschule Hannover, Hannover Cluster of Excellence "Hearing4all" of the German Research Foundation (EXC 1077), Germany.

Hypothesis: MicroRNAs predicted to regulate neurotrophin signaling can be found in human perilymph.

Background: Animal and human temporal bone studies suggest that spiral ganglion health can affect cochlear implant (CI) outcomes. Neurotrophins have been identified as a key factor in the maintenance of spiral ganglion health. Changes in miRNAs may regulate neurotrophin signaling and may reflect neurotrophin expression levels.

Methods: Perilymph sampling was carried out in 18 patients undergoing cochlear implantation or stapedotomy. Expression of miRNAs in perilymph was evaluated using an Agilent miRNA gene chip. Using ingenuity pathway analysis (IPA) software, miRNAs targeting neurotrophin signaling pathway genes present in a cochlear cDNA library were annotated. Expression levels of miRNAs in perilymph were correlated to the patients' preoperative pure-tone average.

Results: Expression of mRNAs coding for neurotrophins and their receptors were identified in tissue obtained from normal human cochlea during skull base surgery. We identified miRNAs predicted to regulate these signaling cascades, including miR-1207-5p, miR-4651, miR-103-3p, miR-100-5p, miR-221-3p, miR-200-3p. There was a correlation between poor preoperative hearing and lower expression of miR-1207 (predicted to regulate NTR3) and miR-4651 (predicted to regulate NTR2). Additionally, miR-3960, miR-4481, and miR-675 showed significant differences in expression level when comparing mild and profound hearing loss patients.

Conclusions: Expression of some miRNAs that are predicted to regulate neurotrophin signaling in the perilymph of cochlear implant patients vary with the patient's level of residual hearing. These miRNAs may serve as biomarkers for changes in neurotrophin signaling.
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http://dx.doi.org/10.1097/MAO.0000000000003182DOI Listing
May 2021

Two-phase survey on the frequency of use and safety of MRI for hearing implant recipients.

Eur Arch Otorhinolaryngol 2021 Mar 31. Epub 2021 Mar 31.

Vienna Medical University-General Hospital AKH, Vienna, Austria.

Purpose: Magnetic resonance imaging (MRI) is often used to visualize and diagnose soft tissues. Hearing implant (HI) recipients are likely to require at least one MRI scan during their lifetime. However, the MRI scanner can interact with the implant magnet, resulting in complications for the HI recipient. This survey, which was conducted in two phases, aimed to evaluate the safety and performance of MRI scans for individuals with a HI manufactured by MED-EL (MED-EL GmbH, Innsbruck, Austria).

Methods: A survey was developed and distributed in two phases to HEARRING clinics to obtain information about the use of MRI for recipients of MED-EL devices. Phase 1 focused on how often MRI is used in diagnostic imaging of the head region of the cochlear implant (CI) recipients. Phase 2 collected safety information about MRI scans performed on HI recipients.

Results: 106 of the 126 MRI scans reported in this survey were performed at a field strength of 1.5 T, on HI recipients who wore the SYNCHRONY CI or SYNCHRONY ABI. The head and spine were the most frequently imaged regions. 123 of the 126 scans were performed without any complications; two HI recipients experienced discomfort/pain. One recipient required reimplantation after an MRI was performed using a scanner that had not been approved for that implant. There was only one case that required surgical removal of the implant to reduce the imaging artefact.

Conclusion: Individuals with either a SYNCHRONY CI or SYNCHRONY ABI from MED-EL can safely undergo a 1.5 T MRI when it is performed according to the manufacturer's safety policies and procedures.
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http://dx.doi.org/10.1007/s00405-020-06525-3DOI Listing
March 2021

Re-evaluating aminoglycoside ototoxicity.

Authors:
Hinrich Staecker

J Cyst Fibros 2021 Jan;20(1)

Department of Otolaryngology Head and Neck Surgery, University of Kansas Health System.

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http://dx.doi.org/10.1016/j.jcf.2021.01.003DOI Listing
January 2021

Supervised machine learning for automated classification of human Wharton's Jelly cells and mechanosensory hair cells.

PLoS One 2021 8;16(1):e0245234. Epub 2021 Jan 8.

Department of Plastic Surgery, University of Kansas Medical Center, Kansas City, KS, United States of America.

Tissue engineering and gene therapy strategies offer new ways to repair permanent damage to mechanosensory hair cells (MHCs) by differentiating human Wharton's Jelly cells (HWJCs). Conventionally, these strategies require the classification of each cell as differentiated or undifferentiated. Automated classification tools, however, may serve as a novel method to rapidly classify these cells. In this paper, images from previous work, where HWJCs were differentiated into MHC-like cells, were examined. Various cell features were extracted from these images, and those which were pertinent to classification were identified. Different machine learning models were then developed, some using all extracted data and some using only certain features. To evaluate model performance, the area under the curve (AUC) of the receiver operating characteristic curve was primarily used. This paper found that limiting algorithms to certain features consistently improved performance. The top performing model, a voting classifier model consisting of two logistic regressions, a support vector machine, and a random forest classifier, obtained an AUC of 0.9638. Ultimately, this paper illustrates the viability of a novel machine learning pipeline to automate the classification of undifferentiated and differentiated cells. In the future, this research could aid in automated strategies that determine the viability of MHC-like cells after differentiation.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0245234PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7793269PMC
May 2021

Extracellular vesicles from human multipotent stromal cells protect against hearing loss after noise trauma in vivo.

Clin Transl Med 2020 Dec;10(8):e262

GMP Unit, Spinal Cord Injury and Tissue Regeneration Centre Salzburg (SCI-TReCS), Paracelsus Medical University (PMU), Salzburg, Austria.

The lack of approved anti-inflammatory and neuroprotective therapies in otology has been acknowledged in the last decades and recent approaches are heralding a new era in the field. Extracellular vesicles (EVs) derived from human multipotent (mesenchymal) stromal cells (MSC) can be enriched in vesicular secretome fractions, which have been shown to exert effects (eg, neuroprotection and immunomodulation) of their parental cells. Hence, MSC-derived EVs may serve as novel drug candidates for several inner ear diseases. Here, we provide first evidence of a strong neuroprotective potential of human stromal cell-derived EVs on inner ear physiology. In vitro, MSC-EV preparations exerted immunomodulatory activity on T cells and microglial cells. Moreover, local application of MSC-EVs to the inner ear significantly attenuated hearing loss and protected auditory hair cells from noise-induced trauma in vivo. Thus, EVs derived from the vesicular secretome of human MSC may represent a next-generation biological drug that can exert protective therapeutic effects in a complex and nonregenerating organ like the inner ear.
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http://dx.doi.org/10.1002/ctm2.262DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7752163PMC
December 2020

Internal Auditory Canal Diverticula in Children: A Congenital Variant.

Laryngoscope 2021 05 17;131(5):E1683-E1687. Epub 2020 Nov 17.

Department of Otolaryngology- Head and Neck Surgery, Children's Mercy Kansas City, Kansas City, Missouri, U.S.A.

Objectives/hypothesis: Internal auditory diverticula in adults have been found to exist independent of otosclerosis, and in the presence of otosclerosis. We sought to determine the prevalence of internal auditory canal (IAC) diverticula in a pediatric cohort, to assess whether IAC diverticula are a risk factor for hearing loss, and the co-occurrence of otic capsule hypoattenuation.

Study Design: Retrospective review.

Methods: A single-site retrospective review of high-resolution temporal bones computed tomography (CT) scans including the presence and size of diverticula and hypoattenuation of the otic capsule. Demographic, imaging, and audiometric data were collected and descriptively analyzed. Bivariate analysis of collected variables was conducted. Comparisons between sides in unilateral cases were also performed.

Results: 16/600 (2.7%; 95% CI [2.0%, 3.4%]) were found to have IAC diverticula. Six were bilateral. Thirty-one patients (5.2%) were found to have hypoattenuation of the otic capsule. There were no coincident cases of IAC diverticulum and hypoattenuation of the otic capsule. There was no association between the presence of IAC diverticula and age (P = .13). In six patients with unilateral diverticula, pure tone average (P = .42), and word recognition (P = .27) scores were not significantly different when compared to the normal, contralateral side.

Conclusions: The prevalence of IAC diverticula in children is lower than the prevalence in adults. IAC diverticula in children likely represent congenital variants of temporal bone anatomy. Similar to adult populations, there is evidence that IAC diverticula in children are likely not an independent risk factor for hearing loss.

Level Of Evidence: 4 Laryngoscope, 131:E1683-E1687, 2021.
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http://dx.doi.org/10.1002/lary.29278DOI Listing
May 2021

Expression pattern of brain-derived neurotrophic factor and its associated receptors: Implications for exogenous neurotrophin application.

Hear Res 2020 Oct 21:108098. Epub 2020 Oct 21.

Department of Otorhinolaryngology, Head and Neck Surgery, Hannover Medical School, Hannover, Germany; Cluster of Excellence "Hearing4all" of the German Research Foundation (EXC 2177/1).

The application of neurotrophins such as brain-derived neurotrophic factor (BDNF) is a promising pharmacological approach in cochlear implant research. Several in vitro and in vivo studies demonstrated that treatment with neurotrophins support the spiral ganglion neuron (SGN) survival and the synapses. Of the more than 40 companies that are working in the field of inner ear therapeutics, only one company is currently advancing BDNF towards clinical translation. Thus, there are no approved clinical therapies with neurotrophins, their precursors or neurotrophin-like substances. For a better understanding of the mechanisms of BDNF in the inner ear, we analysed the expression of mature BDNF (mBDNF), its pro-form proBDNF and their respective receptors the low affinity p75 neurotrophin receptor (p75NTR) and the neurotrophic receptor tyrosine kinase 2 (NTRK2). In the adult murine inner ear, mBDNF is expressed in the inner and outer hair cells (IHC and OHC) of the organ of Corti and in the spiral ganglion of the Rosenthal's canal, whereas proBDNF is only detected in the supporting cells below the OHC. The corresponding receptors NTRK2 and p75NTR are expressed in the spiral ganglion whereof p75NTR is stronger expressed. For more insights in the effects of mBDNF and proBDNF on inner ear specific cells, we treated primary dissociated SGN with different concentrations of mBDNF and proBDNF alone and in combination. Interestingly, treatment with proBDNF is not toxic for SGN but simultaneously not protective. However, combined treatment of mBDNF and proBDNF maintained and perhaps slightly increased the protective effect of mBDNF. Thus, the mixture of mBDNF and proBDNF could be the new direction for the development of BDNF-based therapeutics in cochlear implantation and could represent more precisely the natural environment.
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http://dx.doi.org/10.1016/j.heares.2020.108098DOI Listing
October 2020

MicroRNA Profiling as a Methodology to Diagnose Ménière's Disease: Potential Application of Machine Learning.

Otolaryngol Head Neck Surg 2021 02 14;164(2):399-406. Epub 2020 Jul 14.

Department of Otolaryngology-Head and Neck Surgery, School of Medicine, University of Kansas, Kansas City, Kansas, USA.

Objective: Diagnosis and treatment of Ménière's disease remains a significant challenge because of our inability to understand what is occurring on a molecular level. MicroRNA (miRNA) perilymph profiling is a safe methodology and may serve as a "liquid biopsy" equivalent. We used machine learning (ML) to evaluate miRNA expression profiles of various inner ear pathologies to predict diagnosis of Ménière's disease.

Study Design: Prospective cohort study.

Setting: Tertiary academic hospital.

Subjects And Methods: Perilymph was collected during labyrinthectomy (Ménière's disease, n = 5), stapedotomy (otosclerosis, n = 5), and cochlear implantation (sensorineural hearing loss [SNHL], n = 9). miRNA was isolated and analyzed with the Affymetrix miRNA 4.0 array. Various ML classification models were evaluated with an 80/20 train/test split and cross-validation. Permutation feature importance was performed to understand miRNAs that were critical to the classification models.

Results: In terms of miRNA profiles for conductive hearing loss versus Ménière's, 4 models were able to differentiate and identify the 2 disease classes with 100% accuracy. The top-performing models used the same miRNAs in their decision classification model but with different weighted values. All candidate models for SNHL versus Ménière's performed significantly worse, with the best models achieving 66% accuracy. Ménière's models showed unique features distinct from SNHL.

Conclusions: We can use ML to build Ménière's-specific prediction models using miRNA profile alone. However, ML models were less accurate in predicting SNHL from Ménière's, likely from overlap of miRNA biomarkers. The power of this technique is that it identifies biomarkers without knowledge of the pathophysiology, potentially leading to identification of novel biomarkers and diagnostic tests.
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http://dx.doi.org/10.1177/0194599820940649DOI Listing
February 2021

The reliability of hearing implants: report on the type and incidence of cochlear implant failures.

Cochlear Implants Int 2020 07 10;21(4):228-237. Epub 2020 Mar 10.

Instituto de ORL, Av Ambrosio Olmos 754, Córdoba, Argentina.

This study presents the data collected through a database on the type and incidence of cochlear implant device failures and major complications and quantifies the risk of failures across time based on the Association for the Advancement of Medical Instrumentation (AAMI) CI86:2017 standard. Information on reliability of MED-EL cochlear implants was collected from the MED-EL complaint database between 2003 and2013. Explants were categorized and device reliability was calculated according to the AAMI CI86:2017 standard principles. Data were collected for 11662 devices (5462 children, 6200 adults). The mean duration of follow up was 46.16 months. The total failure rate for all devices and all subjects was 2.41%. Medical related explants (MRE) were significantly worse for children than for adults with the ceramic implants, C40+ ( = 0.008) and PULSAR ( = 0.020). Device failure explants (DFE) were significantly worse for children than for adults with all four devices in the study, the C40+ ( < 0.001), PULSAR ( < 0.001), SONATA ( < 0.001), and CONCERTO ( = 0.023). The mean annual failure rate for all subjects and devices was 0.63% (1.03% for children, 0.28% for adults). The mean annual failure rate was 0.90% for the C40+; 0.57% for the PULSAR; 0.46% for the SONATA; and 0.39% for the CONCERTO. Compared to adults, children had significantly worse MRE and DFE due to a higher risk of head trauma and more vulnerable skull anatomy. Further, the authors conclude that the AAMI standard will ensure a more comprehensive and transparent evaluation of cochlear implant reliability in the future.
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http://dx.doi.org/10.1080/14670100.2020.1735678DOI Listing
July 2020

Hearing Preservation Following Repeated Adenovector Delivery.

Anat Rec (Hoboken) 2020 03 8;303(3):600-607. Epub 2020 Jan 8.

Department of Otolaryngology Head and Neck Surgery, University of Kansas School of Medicine, Kansas City, Kansas.

Factors influencing the damage to the inner ear can include the surgical approach used for vector delivery, the volume of vector used, the buffer that the vector is suspended in as well as the host response to the vector capsid and vector genes that are transferred. We evaluated the effect of Ad5 capsid adenovectors on hearing function after delivery to the perilymph of adult C57Bl/6 mice. Hearing was evaluated before surgery and 3 days post-surgery by auditory brain stem response (ABR) and distortion product otoacoustic emissions (DPOAE). A second group of mice underwent repeated delivery of adenovector two times to determine if a preliminary exposure to an Ad vector could induce an inflammatory response leading to further loss. The first adenovector (Ad.11D.LacZ) was delivered to the posterior semicircular canal or via round window. In the second surgery, a second adenovector (Ad.11D.gfp) was delivered to the horizontal semicircular canal. The functional outcome was tested prior, 7 days post first vector delivery, and 3 days post second vector delivery via ABR and DPOAE. Dual delivery via the semicircular canals resulted in preservation of hearing suggesting that pre-exposure to Ad5 capsid does not predispose to hearing loss. Delivery to the round window resulted in hearing loss that was worsened after the second vector delivery, suggesting that delivery route and prior injury to the inner ear rather than the repetition of delivery predisposes to further hearing loss. Anat Rec, 303:600-607, 2020. © 2019 American Association for Anatomy.
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http://dx.doi.org/10.1002/ar.24347DOI Listing
March 2020

Early Onset Region and Cell Specific Alterations of Doublecortin Expression in the CNS of Animals with Sound Damage Induced Hearing Loss.

IBRO Rep 2019 Dec 6;7:129-140. Epub 2019 Nov 6.

Department of Otolaryngology- Head and Neck Surgery, University of Kansas Medical Center, 3901 Rainbow Blvd, Kansas City, KS 66160, United States.

Sound damage induced hearing loss has been shown to elicit changes in auditory and non-auditory brain regions. A protein critical for neuronal migration and brain development, doublecortin (DCX), has been used as a marker of central nervous system (CNS) neuroplasticity. DCX is expressed in unipolar brush cells (UBCs) of the dorsal cochlear nucleus (DCN), cerebellar parafloccular lobe (PFL) and neuronal precursor cells in the sub-granular zone of the hippocampal dentate gyrus (DG). Sound damage induced hearing loss has been shown to differentially impact DCX expression months later. To identify earlier alterations in DCX expression, we utilized immunohistochemistry to detect DCX protein in three brain regions (DCN, PFL, DG) approximately one month following unilateral sound damage. Auditory brainstem response was used to measure hearing loss. Unilateral hearing loss was evident in all sound damaged animals. Hearing loss related decreases in DCX expression were evident bilaterally in the DG while hearing loss related increases in DCX expression were evident bilaterally in the PFL. No changes to DCX expression were evident in the auditory DCN. Gap detection was used to assess whether this sound damage paradigm induced tinnitus-like behavior. However, results obtained from this behavioral test as used here were inconclusive and are presented here only as a guide to others wishing to design similar studies.
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http://dx.doi.org/10.1016/j.ibror.2019.10.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6906648PMC
December 2019

Postoperative Opioid Use and Pain Management Following Otologic and Neurotologic Surgery.

Ann Otol Rhinol Laryngol 2020 Feb 18;129(2):175-180. Epub 2019 Oct 18.

Department of Otolaryngology-Head and Neck Surgery, University of Kansas School of Medicine, Kansas City, KS, USA.

Objectives: The topic of prescription opioid overuse remains a growing concern in the United States. Our objective is to provide insight into pain perception and opioid use based on a patient cohort undergoing common otologic and neurotologic surgeries.

Study Design: Prospective observational study with patient questionnaire.

Setting: Single academic medical center.

Subjects And Methods: Adult patients undergoing otologic and neurotologic procedures by two fellowship trained neurotologists between June and November of 2018 were included in this study. During first postoperative follow-up, participants completed a questionnaire assessing perceived postoperative pain and its impact on quality of life, pain management techniques, and extent of prescription opioid use.

Results: A total of 47 patients met inclusion and exclusion criteria. The median pain score was 3 out of 10 (Interquartile Range [IQR] = 2-6) with no significant gender differences ( = .92). Patients were prescribed a median of 15.0 (IQR = 10.0-15.0) tablets of opioid pain medication postoperatively, but only used a median of 4.0 (IQR = 1.0-11.5) tablets at the time of first follow-up. Measured quality of life areas included sleep, physical activity, work, and mood. Sleep was most commonly affected, with 69.4% of patients noting disturbances.

Conclusions: This study suggests that practitioners may over-estimate the need for opioid pain medication following otologic and neurotologic surgery. It also demonstrates the need for ongoing patient education regarding opioid risks, alternatives, and measures to prevent diversion.
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http://dx.doi.org/10.1177/0003489419883296DOI Listing
February 2020

The Size of Internal Auditory Canal Diverticula Is Unrelated to Degree of Hearing Loss.

Laryngoscope 2020 04 24;130(4):1011-1015. Epub 2019 Jun 24.

the Department of Otolaryngology Head and Neck Surgery, University of Kansas School of Medicine, Kansas City, Kansas.

Objectives: To explore the relationship between hearing loss and the internal auditory canal (IAC) diverticula. To determine whether diverticula exist within or medial to the otic capsule and the prevalence in a control population.

Methods: Retrospective review of adult patients with radiologic evidence of an IAC diverticulum, no evidence of otosclerosis, and audiometric testing. Analyzed degree of hearing loss and width, length, height, and volume of diverticulum. Hounsfield unit (HU) measurements lateral and medial to the diverticulum.

Results: Pure tone average (PTA), air-bone gap, and WRS (word recognition score) did not correlate with length, width, height, and volume of the diverticula. In patients with a unilateral diverticulum, there was no difference in mean PTA or WRS when comparing the diverticulum and nondiverticulum sides. Mean HU lateral to the diverticulum (2104 HU) was found to be significantly higher than medial to the diverticulum (1818 HU). There is a 5.6% prevalence of IAC diverticula in patients who underwent high-resolution computed tomography (CT) scans for chronic sinusitis (control group).

Conclusion: These data support the notion that hearing loss in this population is a product of sampling bias. The size of IAC diverticula does not correlate with the degree of hearing loss, and there is no statistically significant association between sensorineural hearing loss (SNHL) and the presence of an IAC diverticulum. IAC diverticula may exist medial to, rather than within, the otic capsule given the significant difference in mean HUs medial and lateral to the diverticula.

Level Of Evidence: 4 Laryngoscope, 130:1011-1015, 2020.
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http://dx.doi.org/10.1002/lary.28155DOI Listing
April 2020

Utility of Perilymph microRNA Sampling for Identification of Active Gene Expression Pathways in Otosclerosis.

Otol Neurotol 2019 07;40(6):710-719

Department of Otolaryngology, Head & Neck Surgery, The University of Kansas Medical Center, Kansas City, Kansas.

Hypothesis: Profiling of microRNA (miRNA) within perilymph samples collected at the time of stapedectomy can be used to identify active gene expression pathways in otosclerosis as compared with controls.

Background: miRNAs are small non-coding RNAs that effect gene expression by post-transcription regulation and silencing. Perilymph sampling allows for a novel way to collect material actively involved in the disease process.

Methods: Perilymph was collected at time of stapedectomy, underwent a microarray analysis, and significantly expressed miRNAs were correlated to known bone morphology pathways using a cochlear transcriptome library. To determine miRNA related specifically to otosclerosis, cochlear implant controls were used for statistical analysis.

Results: A total of 321 significantly expressed miRNAs were identified within the four otosclerosis perilymph samples. miRNAs associated with 23 genes involved in bone morphology pathways were significantly expressed. A significant difference in the otosclerotic samples as compared with control was noted in miRNA expression regulating HMGA2, ITGB3, SMO, CCND1, TP53, TP63, and RBL2 gene pathways. No significant difference was noted in miRNAs expression associated with ACE, RELN, COL1A1, and COL1A2 genes which were previously correlated with otosclerosis.

Conclusions: Perilymph miRNA profiling obtained at the time of stapedectomy consistently identifies differentially expressed genes compared with controls. Perilymph miRNA sampling with cochlear transcriptome library cross-referencing can be successfully used to identify active gene expression pathways in otosclerosis.
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http://dx.doi.org/10.1097/MAO.0000000000002243DOI Listing
July 2019

Histopathologic Characteristics of Internal Auditory Canal Diverticula.

Otol Neurotol 2019 07;40(6):e653-e656

House Ear Institute.

Hypothesis: We hypothesize that internal auditory canal (IAC) diverticula occur independent of otosclerosis as demonstrated by temporal bone histopathology.

Background: Diverticula at the anterior-inferior aspect of the IAC have been described histologically in the setting of cavitary otosclerosis. Recent radiographic studies show the prevalence of IAC diverticula that is higher than what can be accounted for by cavitary otosclerosis alone.

Methods: We examined hematoxylin and eosin temporal bone histopathology slides with otosclerosis involving the IAC. We also examined bones from normal hearing subjects with normal histologic findings. Temporal bones were included if donors were more than 18 years of age at time of death and adequate horizontal cuts were available to evaluate the area of interest.

Results: IAC diverticula were found in 33 of 47 (70%) temporal bones with IAC otosclerosis and in 5 of 20 (25%) normal temporal bones. The difference in mean pure tone averages (PTA) in the normal temporal bones with (PTA 7.3 ± 7) and without (PTA 8 ± 2) diverticula was not statistically significant (p = 0.86).

Conclusion: IAC diverticula which have been previously demonstrated to occur in the setting of cavitary otosclerosis can also occur independent from otosclerosis. Subjects with diverticula but without other temporal bone pathology have normal hearing thresholds.
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http://dx.doi.org/10.1097/MAO.0000000000002256DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6565456PMC
July 2019

Efficacy and Safety of AM-111 in the Treatment of Acute Unilateral Sudden Deafness-A Double-blind, Randomized, Placebo-controlled Phase 3 Study.

Otol Neurotol 2019 06;40(5):584-594

Auris Medical AG, Basel, Switzerland.

Objective: To confirm the efficacy and safety of AM-111 (brimapitide), a cell-penetrating c-Jun N-terminal Kinase (JNK) inhibitor, in patients suffering from severe to profound acute unilateral idiopathic sudden sensorineural hearing loss (ISSNHL).

Study Design: Prospective, double-blind, randomized, placebo-controlled phase 3 study with follow-up visits on Days 3, 7, 28, and 91.

Setting: Fifty-one European and Asian sites (tertiary referral centers, private ENT practices).

Patients: Two hundred fifty-six patients aged 18 to 65 years presenting within 72 hours following ISSNHL onset with mean hearing loss ≥ 40 dB and mean threshold ≥ 60 dB at the 3 worst affected contiguous test frequencies.

Interventions: Single-dose intratympanic injection of AM-111 (0.4 or 0.8 mg/ml) or placebo; oral prednisolone as reserve therapy if hearing improvement < 10 dB at Day 7.

Main Outcome Measures: Hearing improvement to Day 28 was the primary efficacy endpoint; complete hearing recovery, frequency of reserve therapy used, complete tinnitus remission, improvement in word recognition were secondary endpoints. Safety was evaluated by the frequency of clinically relevant hearing deterioration and adverse events.

Results: While the primary efficacy endpoint was not met in the overall study population, post-hoc analysis showed a clinically relevant and nominally significant treatment effect for AM-111 0.4 mg/ml in patients with profound ISSNHL. The study drug and the administration procedure were well tolerated.

Conclusions: AM-111 provides effective otoprotection in case of profound ISSNHL. Activation of the JNK stress kinase, AM-111's pharmacologic target, seems to set in only following pronounced acute cochlear injury associated with large hearing threshold shifts.
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http://dx.doi.org/10.1097/MAO.0000000000002229DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6553962PMC
June 2019

Hearing Protection, Restoration, and Regeneration: An Overview of Emerging Therapeutics for Inner Ear and Central Hearing Disorders.

Otol Neurotol 2019 06;40(5):559-570

Department of Otolaryngology Head and Neck Surgery, Hannover Medical School, Hannover.

Objective: To provide an overview of biotechnology and pharmaceutical companies active in the field of inner ear and central hearing disorders and their therapeutic approaches.

Methods: Scientific and grey literature was searched using broad search terms to identify companies and their hearing-related therapeutic approaches. For each approach its lead indication, product, therapeutic modality, target, mechanism of action and current phase of clinical development was collated.

Results: A total of 43 biotechnology and pharmaceutical companies have been identified that are developing therapeutics for inner ear and central hearing disorders. Their therapeutics include drug-, cell- and gene-based approaches to prevent hearing loss or its progression, restore hearing, and regenerate the inner ear. Their therapeutic targets and specific mechanisms of action are wide-ranging, reflecting the complexity of the hearing pathways and the diversity of mechanisms underlying inner ear disorders. While none of the novel products under investigation have yet made it to the clinical market, and a large proportion are still at preclinical phase, many therapeutics have already entered clinical testing with more expected to do so in the next few years.

Conclusion: A wide range of novel therapeutics targeting different hearing, balance and tinnitus pathways, and patient populations are approaching the clinical domain. It is important that clinicians involved in the care of patients with hearing loss prepare for what may become a radically different approach to the management of hearing disorders, and develop a true understanding of the new therapies' mechanisms of action, applications, and indications.
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http://dx.doi.org/10.1097/MAO.0000000000002194DOI Listing
June 2019

Detection of BDNF-Related Proteins in Human Perilymph in Patients With Hearing Loss.

Front Neurosci 2019 26;13:214. Epub 2019 Mar 26.

Department of Otolaryngology, Hannover Medical School, Hanover, Germany.

The outcome of cochlear implantation depends on multiple variables including the underlying health of the cochlea. Brain derived neurotrophic factor (BDNF) has been shown to support spiral ganglion neurons and to improve implant function in animal models. Whether endogenous BDNF or BDNF-regulated proteins can be used as biomarkers to predict cochlear health and implant outcome has not been investigated yet. Gene expression of BDNF and downstream signaling molecules were identified in tissue of human cochleae obtained from normal hearing patients ( = 3) during skull base surgeries. Based on the gene expression data, bioinformatic analysis was utilized to predict the regulation of proteins by BDNF. The presence of proteins corresponding to these genes was investigated in perilymph ( = 41) obtained from hearing-impaired patients ( = 38) during cochlear implantation or skull base surgery for removal of vestibular schwannoma by nanoscale liquid chromatography coupled to tandem mass spectrometry (nano LC-MS/MS). Analyzed by mass spectrometry were 41 perilymph samples despite three patients undergoing bilateral cochlear implantation. These particular BDNF regulated proteins were not detectable in any of the perilymph samples. Subsequently, targeted analysis of the perilymph proteome data with Ingenuity Pathway Analysis (IPA) identified further proteins in human perilymph that could be regulated by BDNF. These BDNF regulated proteins were correlated to the presence of residual hearing (RH) prior to implantation and to the performance data with the cochlear implant after 1 year. There was overall a decreased level of expression of BDNF-regulated proteins in profoundly hearing-impaired patients compared to patients with some RH. Phospholipid transfer protein was positively correlated to the preoperative hearing level of the patients. Our data show that combination of gene expression arrays and bioinformatic analysis can aid in the prediction of downstream signaling proteins related to the BDNF pathway. Proteomic analysis of perilymph may help to identify the presence or absence of these molecules in the diseased organ. The impact of such prediction algorithms on diagnosis and treatment needs to be established in further studies.
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http://dx.doi.org/10.3389/fnins.2019.00214DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6445295PMC
March 2019

High-Resolution Computed Tomography of the Inner Ear: Effect of Otosclerosis on Cochlear Aqueduct Dimensions.

Ann Otol Rhinol Laryngol 2019 Aug 11;128(8):749-754. Epub 2019 Apr 11.

1 Department of Otolaryngology, Head & Neck Surgery, The University of Kansas Medical Center, Kansas City, Kansas, USA.

Objectives: The cochlear aqueduct is a bony duct connecting the scala tympani with the subarachnoid space. Given the pathophysiology of otosclerosis, including bone resorption and new bone deposition, we hypothesize that the cochlear aqueduct in otosclerotic ears is narrowed.

Methods: A retrospective review of patients with otosclerosis who have undergone high-resolution computed tomography (HRCT) of the temporal bone was completed. The control cohort included 20 patients with the diagnosis of noise-induced hearing loss, without the diagnosis of otosclerosis. Uniform measurements of cochlear aqueduct dimensions were performed using the axial plane.

Results: The otosclerosis cohort included 25 males and 52 females with mean age of 52.2 ± 17.6 years. The control group included 10 males and 10 females with mean age of 64.0 ± 18.5 years. The mean cochlear aqueduct length, width mid canal, aperture base, aperture widest diameter, and funnel diameter in millimeters were 12.19 ± 1.66, 0.68 ± 0.28, 4.21 ± 1.67, 3.23 ± 1.47, and 2.70 ± 1.05 in the ears with otosclerotic foci and 11.57 ± 1.66, 0.69 ± 0.29, 2.56 ± 1.59, 2.77 ± 1.67, and 2.58 ± 1.03 in control group, respectively. Statistical difference was seen in length of cochlear aqueduct, aperture base, and aperture widest diameters ( = .017, <.001, .007).

Conclusions: The length of the cochlear aqueduct and the funnel width are statistically longer in the otosclerotic population compared to control. The width of the cochlear aqueduct is not statistically different.
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http://dx.doi.org/10.1177/0003489419842579DOI Listing
August 2019

Using Machine Learning to Predict Sensorineural Hearing Loss Based on Perilymph Micro RNA Expression Profile.

Sci Rep 2019 03 4;9(1):3393. Epub 2019 Mar 4.

University of Kansas School of Medicine, Department of Otolaryngology-Head and Neck Surgery, Kansas City, KS, USA.

Hearing loss (HL) is the most common neurodegenerative disease worldwide. Despite its prevalence, clinical testing does not yield a cell or molecular based identification of the underlying etiology of hearing loss making development of pharmacological or molecular treatments challenging. A key to improving the diagnosis of inner ear disorders is the development of reliable biomarkers for different inner ear diseases. Analysis of microRNAs (miRNA) in tissue and body fluid samples has gained significant momentum as a diagnostic tool for a wide variety of diseases. In previous work, we have shown that miRNA profiling in inner ear perilymph is feasible and may demonstrate distinctive miRNA expression profiles unique to different diseases. A first step in developing miRNAs as biomarkers for inner ear disease is linking patterns of miRNA expression in perilymph to clinically available metrics. Using machine learning (ML), we demonstrate we can build disease specific algorithms that predict the presence of sensorineural hearing loss using only miRNA expression profiles. This methodology not only affords the opportunity to understand what is occurring on a molecular level, but may offer an approach to diagnosing patients with active inner ear disease.
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http://dx.doi.org/10.1038/s41598-019-40192-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6399453PMC
March 2019

Magnetic resonance imaging with cochlear implants and auditory brainstem implants: Are we truly practicing MRI safety?

Laryngoscope 2019 02 9;129(2):482-489. Epub 2018 Nov 9.

Department of Otolaryngology-Head and Neck Surgery, University of Kansas School of Medicine, Kansas City, Kansas, U.S.A.

Objective: Our objective is to evaluate the safety in patients with cochlear implants (CIs) and auditory brainstem implants (ABI) undergoing 1.5 Tesla (T) magnetic resonance imaging (MRI). Secondly, we want to raise awareness on CI and MRI safety, and advocate for continued improvement and advancement to minimize morbidity for our CI patients.

Methods: Retrospective case series from 2006 to 2018 at a single tertiary academic center. Data was collected on patients with CI or auditory brainstem implants undergoing MRI. Outcomes collected include demographic data, age at time of MRI, MRI characteristics, complications, CI manufacturer, and image quality.

Results: Eighteen patients with CI or ABI collectively underwent a total of 62 MRI scans. Five of 15 (33%) CI patients with magnet had complications: five total of 24 MRI scans (21%). Two patients had magnet removal prior to 29 MRI scans without complications. Four of five MRI-related complications were equipped with a U.S. Food and Drug Administration-approved head wrap. Three of five required a trip to the operating room to explore and reposition the CI magnet; two could not complete MRI secondary to pain. Of the complications, two were Cochlear (Sydney, Australia), two Advanced Bionics (Valencia, CA), and one MED-EL (Innsbruck, Austria). Synchrony model (MED-EL) had 0 of seven complications, with a total of 19 MRI scans, which features a freely rotating and self-aligning magnet.

Conclusion: Our series offers a diverse number of CI manufacturers and is in accordance with other literature that CI MRI-related adverse events are occurring at an unacceptable frequency. We can promote CI MRI safety through our institutions' MRI CI patient protocols, raise awareness that diagnostic MRI benefits must outweigh CI-related complications, and advocate for continued industry technological innovation.

Level Of Evidence: 4 Laryngoscope, 129:482-489, 2019.
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http://dx.doi.org/10.1002/lary.27516DOI Listing
February 2019

Atypical Form of Cervicofacial Actinomycosis Involving the Skull Base and Temporal Bone.

Ann Otol Rhinol Laryngol 2019 Feb 29;128(2):152-156. Epub 2018 Oct 29.

1 Department of Otolaryngology-Head and Neck Surgery, University of Kansas Health System, Kansas City, KS, USA.

Background:: Cervicofacial actinomycosis is an uncommon indolent infection caused by Actinomyces spp that typically affects individuals with innate or adaptive immunodeficiencies. Soft tissues of the face and neck are most commonly involved. Actinomyces osteomyelitis is uncommon; involvement of the skull base and temporal bone is exceedingly rare. The authors present a unique case of refractory cervicofacial actinomycosis with development of skull base and temporal bone osteomyelitis in an otherwise healthy individual.

Methods:: Case report with literature review.

Results:: A 69-year-old man presented with a soft tissue infection, culture positive for Actinomyces, over the right maxilla. Previous unsuccessful treatment included local debridement and 6 weeks of intravenous ceftriaxone. He was subsequently treated with conservative debridement and a prolonged course of intravenous followed by oral antibiotic. However, he eventually required multiple procedures, including maxillectomy, pterygopalatine fossa debridement, and a radical mastoidectomy to clear his disease. Postoperatively he was gradually transitioned off intravenous antibiotics.

Conclusions:: Cervicofacial actinomycosis involves soft tissue surrounding the facial skeleton and oral cavity and is typically associated with a history of mucosal trauma, surgery, or immunodeficiency. The patient was appropriately treated but experienced disease progression and escalation of therapy. Although actinomycosis is typically not an aggressive bacterial infection, this case illustrates the need for prompt recognition of persistent disease and earlier surgical intervention in cases of recalcitrant cervicofacial actinomycosis. Chronic actinomycosis has the potential for significant morbidity.
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http://dx.doi.org/10.1177/0003489418808541DOI Listing
February 2019

Tinnitus perception in patients after vagal nerve stimulator implantation for epilepsy.

Am J Otolaryngol 2018 Sep - Oct;39(5):599-602. Epub 2018 Jul 11.

Department of Otolaryngology, Head & Neck Surgery, The University of Kansas Medical Center, Kansas City, KS, USA.

Purpose: Vagal nerve stimulation in conjunction with sound therapy has been proposed as a treatment for subjective tinnitus. The purpose of this study is to retrospectively review the effect of VNS on perception of tinnitus in epilepsy patients. We explore the incidence of tinnitus and its perceived reduction in patients requiring implantation of VNS for medically refractory seizures.

Materials And Methods: A phone survey was conducted in adult patients with prior VNS implantation. A questionnaire including the visual analog scale (VAS) of tinnitus loudness was used to determine the presence and severity of tinnitus.

Results: Out of the 56 patients who had completed the phone survey, 20 (35%) reported the presence of pre-operative tinnitus. The tinnitus positive group was significantly older (p = 0.019). Of the 20 pre-operative tinnitus positive patients, all patients continued to have tinnitus post-operatively. Four (20%) noted no changes in VAS of tinnitus loudness while 16 (80%) had at least a one-point decrease. The mean difference between pre- and post-operative VAS of loudness was 2.05, with a standard deviation of 1.84 and this was statistically significant (p < 0.001).

Conclusions: In this study, we evaluate the potential of vagal nerve stimulation to alter the perception of tinnitus in patients with refractory epilepsy. Eighty percent of patients noted some level of subjective tinnitus improvement after VNS implantation. Given this finding, there may be a potential additional benefit to the use of VNS in patients with epilepsy.
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http://dx.doi.org/10.1016/j.amjoto.2018.07.009DOI Listing
January 2019

Microenvironmental support for cell delivery to the inner ear.

Hear Res 2018 10 21;368:109-122. Epub 2018 Jun 21.

Department of Otorhinolaryngology, Head and Neck Surgery, Hannover Medical School, Carl Neuberg-Str. 1, 30625 Hannover, Germany; Cluster of Excellence "Hearing4all" of the German Research Foundation, Germany. Electronic address:

Transplantation of mesenchymal stromal cells (MSC) presents a promising approach not only for the replacement of lost or degenerated cells in diseased organs but also for local drug delivery. It can potentially be used to enhance the safety and efficacy of inner ear surgeries such as cochlear implantation. Options for enhancing the effects of MSC therapy include modulating cell behaviour with customized bio-matrixes or modulating their behaviour by ex vivo transfection of the cells with a variety of genes. In this study, we demonstrate that MSC delivered to the inner ear of guinea pigs or to decellularized cochleae preferentially bind to areas of high heparin concentration. This presents an opportunity for modulating cell behaviour ex vivo. We evaluated the effect of carboxymethylglucose sulfate (Cacicol), a heparan sulfate analogue on spiral ganglion cells and MSC and demonstrated support of neuronal survival and support of stem cell proliferation.
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http://dx.doi.org/10.1016/j.heares.2018.06.015DOI Listing
October 2018

Hypertrophic Pachymeningitis of the Internal Auditory Canal: A Rare Case of Unilateral Sudden Sensorineural Hearing Loss.

Ann Otol Rhinol Laryngol 2018 Sep 25;127(9):649-652. Epub 2018 Jun 25.

1 University of Kansas Department of Otolaryngology-Head and Neck Surgery, Kansas City, Kansas, USA.

Objectives: To describe and increase awareness of a rare cause of unilateral sudden sensorineural hearing loss.

Methods: Case report and literature review.

Results: We present a 66-year-old female who suffered left-sided sudden sensorineural hearing loss and dizziness. Diagnostic magnetic resonance imaging (MRI) did not reveal masses or lesions along the eighth cranial nerve or in the inner ear. Upon eventual referral to neurotology clinic, hypertrophic pachymeningitis of her left internal auditory canal and adjacent middle and posterior fossa dura were identified. The ensuing laboratory workup for autoimmune and infectious etiology revealed mild elevation of ACE 93 (9-67) but otherwise normal results.

Conclusions: Idiopathic hypertrophic pachymeningitis is a diagnosis of exclusion. Neoplastic, infectious, and autoimmune causes must be ruled out. The prevailing treatment for this condition is high-dose corticosteroids. This entity should be considered when evaluating MRI scans obtained in the setting of sudden sensorineural hearing loss.
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http://dx.doi.org/10.1177/0003489418784051DOI Listing
September 2018

Methionine Sulfoxide Reductase A Knockout Mice Show Progressive Hearing Loss and Sensitivity to Acoustic Trauma.

Audiol Neurootol 2018 21;23(1):20-31. Epub 2018 Jun 21.

Department of Hearing and Speech, School of Health Professions, University of Kansas Medical Center, Kansas City, Kansas, USA.

Methionine sulfoxide reductases (MsrA and MsrB) protect the biological activity of proteins from oxidative modifications to methionine residues and are important for protecting against the pathological effects of neurodegenerative diseases. In the current study, we characterized the auditory phenotype of the MsrA knockout mouse. Young MsrA knockout mice showed small high-frequency threshold elevations for auditory brainstem response and distortion product otoacoustic emission compared to those of wild-type mice, which progressively worsened in older MsrA knockout mice. MsrA knockout mice showed an increased sensitivity to noise at young and older ages, suggesting that MsrA is part of a mechanism that protects the cochlea from acoustic damage. MsrA mRNA in the cochlea was increased following acoustic stimulation. Finally, expression of mRNA MsrB1 was compromised at 6 months old, but not in younger MsrA knockout mice (compared to controls). The identification of MsrA in the cochlea as a protective mediator from both early onset hearing loss and acoustic trauma expands our understanding of the pathways that may induce protection from acoustic trauma and foster further studies on how to prevent the damaging effect of noise exposure through Msr-based therapy.
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http://dx.doi.org/10.1159/000488276DOI Listing
May 2019

Petrous Apex Pneumatization: Influence on Postoperative Cerebellopontine Angle Tumor Cerebrospinal Fluid Fistula.

Ann Otol Rhinol Laryngol 2018 Sep 21;127(9):604-607. Epub 2018 Jun 21.

1 University of Kansas Department of Otolaryngology-Head and Neck Surgery, Kansas City, Kansas, USA.

Objective: Multiple investigators have sought to identify risk factors for cerebrospinal fluid (CSF) leak following cerebellopontine angle (CPA) tumor resection. We evaluated whether pneumatization of the petrous apex (PA) is a risk factor for CSF fistula.

Method: We conducted a retrospective chart review at 2 major tertiary academic institutions undergoing CPA tumor resection and analyzed their respective head or temporal computed tomography (CT) scans if available.

Results: A total of 91 cases were identified; 51 (64%) demonstrated PA pneumatization, and a total of 17 CSF leaks were identified. We discovered higher rates of CSF leak (25.0% vs 13.7%; P = .273) and CSF rhinorrhea (15.0% vs 5.9%; P = .174) in patients with PA pneumatization compared to those without PA pneumatization.

Conclusions: Isolated PA pneumatization may be a risk factor and communication pathway for CSF fistula. Further studies will need to be broadened across multiple institutions to draw any additional and stronger conclusions.
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http://dx.doi.org/10.1177/0003489418781934DOI Listing
September 2018

Feasibility of microRNA profiling in human inner ear perilymph.

Neuroreport 2018 08;29(11):894-901

Departments of Otolaryngology Head and Neck Surgery.

Hearing loss is common and caused by a wide range of molecular and cellular pathologies. Current diagnosis of hearing loss depends on a combination of physiologic testing, patient history, and in some cases genetic testing. Currently, no biopsy or equivalent procedure exists to diagnose inner ear disorders. MicroRNAs (miRNA) are short ribonucleic acids that regulate a variety of cellular processes. They have been found to be reliable markers for a variety of disease processes. In particular, a variety of miRNAs that are markers for neurodegenerative disease have been identified in cerebrospinal fluid. The aim of this study was to determine whether miRNAs could be identified in human perilymph potentially leading to the development of biomarkers for inner ear disease. Prospective sampling of human perilymph and its analysis were carried out. Patients undergoing surgery in which the inner ear is opened as part of the procedure (cochlear implantation, stapedectomy, labyrinthectomy) were recruited. A total of 2-5 μl of perilymph was collected and analyzed using Affymetrix GeneChip miRNA 4.0 microarrays. MiRNA common to all sampling approaches were selected. Analysis of miRNAs was carried out by evaluating miRNA targets in a cochlear transcriptome library using the Ingenuity Pathway Analysis software package. MiRNAs could be isolated from the perilymph of all patients. Evaluation of miRNAs shows the presence of miRNA populations that are predicted to interact with genes expressed in the inner ear. Additional analysis of miRNA populations shows that perilymph miRNAs could be linked to pathways associated with hearing disorders. Sampling of human perilymph is feasible and can potentially identify miRNAs associated with hearing disorders.
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http://dx.doi.org/10.1097/WNR.0000000000001049DOI Listing
August 2018

Alginate Ototoxicity in the Mouse Model.

Otolaryngol Head Neck Surg 2018 10 15;159(4):733-738. Epub 2018 May 15.

1 Department of Otolaryngology, University of Kansas Medical Center, Kansas City, Kansas, USA.

Objective To determine whether alginate exposure to the round window of the mouse causes any measurable ototoxicity. Study Design Prospective animal study. Setting Basic science laboratory affiliated with a tertiary care university medical center. Subjects and Methods After Institutional Animal Care and Use Committee approval, 5 adult mice were obtained and underwent bullostomy and round window niche application of alginate. Auditory brainstem response (ABR) tests were completed at baseline prior to the procedure and also 5, 14, and 30 days postprocedure. Results were compared. At termination of procedure, the mice were sacrificed with harvest of the cochleae, which were viewed under histologic section. Results There were no significant increases in ABR thresholds in any of the test animals at all test periods after alginate exposure compared to baseline. There were also no observable behavioral changes after the procedure to indicate vestibular dysfunction. Cochlear sectioning revealed no evidence of histologic damage. Conclusion Exposure of alginate to the round window does not cause any obvious ototoxicity in the mouse model. Further clinical trials will be needed to elucidate the effect of alginate in the human middle ear.
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http://dx.doi.org/10.1177/0194599818775951DOI Listing
October 2018