Adult Ear Research Articles

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

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.

Altered expression of genes regulating inflammation and synaptogenesis during regrowth of afferent neurons to cochlear hair cells.

The spiral ganglion neurons constitute the primary connection between auditory hair cells and the brain. The spiral ganglion afferent fibers and their synapse with hair cells do not regenerate to any significant degree in adult mammalian ears after damage. We have investigated gene expression changes after kainate-induced disruption of the synapses in a neonatal cochlear explant model in which peripheral fibers and the afferent synapse do regenerate. We compared gene expression early after damage, during regeneration of the fibers and synapses, and after completion of in vitro regeneration. These analyses revealed a total of 2.5% differentially regulated transcripts (588 out of 24,000) based on a threshold of p<0.005. Inflammatory response genes as well as genes involved in regeneration of neural circuits were upregulated in the spiral ganglion neurons and organ of Corti, where the hair cells reside. Prominent genes upregulated at several time points included genes with roles in neurogenesis (Elavl4 and Sox21), neural outgrowth (Ntrk3 and Ppp1r1c), axonal guidance (Rgmb and Sema7a), synaptogenesis (Nlgn2 and Psd2), and synaptic vesicular function (Syt8 and Syn1). Immunohistochemical and in situ hybridization analysis of genes that had not previously been described in the cochlea confirmed their cochlear expression. The time course of expression of these genes suggests that kainate treatment resulted in a two-phase response in spiral ganglion neurons: an acute response consistent with inflammation, followed by an upregulation of neural regeneration genes. Identification of the genes activated during regeneration of these fibers suggests candidates that could be targeted to enhance regeneration in adult ears.

Sex Characteristics and Distribution of External Ear in Uygur Population of Xinjiang

Objective To analyze the characteristics of the bilateral external ears of Uygur adults by directly observing the morphological characteristics of the external ears of Uygur adults and classifying each feature. The frequency distribution of the characteristics was calculated to provide reference for forensic identification. Methods The 210 cases （75 males and 135 females） of bilateral external ear photos of Uygur adults in Xinjiang that met the inclusion criteria were collected. The frequencies of the features of the external ear were recorded and distinguished between the two sexes and the different sides. The data were statistically analyzed by SPSS 21.0 statistical software. Results The shapes of the external ears of males and females were commonly oblique or rectangular （34.67% of the left external ear of males and 41.33% of the right were oblique; 30.37% of the left and right external ear of females were rectangular）, while triangular ears were the rare variants and the least common. Sex and bilateral differences were observed as regards the form of the helix in the subjects. Normally rolled helix was the most common （58.67% males and 61.48% females for the left ear; 60.00% males and 72.59% females for the right ear）. Wide covering scapha helix was the most rare for the male left ear and flat helix was the most rare for the female right ear. Square and free earlobes were the most common （49.33% males and 62.96% females for the left ear; 40.00% males and 54.81% females for the right ear）, whereas triangular earlobes were rarely seen. Single knob tragus （40.00% males and 37.78% females for the left ear; 37.33% males and 33.33% females for the right ear） and projection type of Darwin's tubercle （50.67% males and 40.00% females for the left ear; 48.00% males and 39.26% females for the right ear） were found to be common. Conclusion The characteristics of the bilateral external ears of male and female Uygur adults have differences, which can be used for forensic identification.

Left Ear Hearing Predicts Functional Activity in the Brains of Patients with Alzheimer's Disease Dementia.

To determine whether central speech processing ability, as measured by hearing in noise, differs between right and left ears in adults with Alzheimer's disease related dementia (AD) as well as whether differences in central speech processing ability correlate with an fMRI-based measurement of global functional brain connectivity. This prospective study was carried out at a tertiary referral center. Patients with an AD diagnosis and pure tone averages 40 dB HL or better were included. They were examined using resting-state fMRI and underwent central audiometric testing using the Dichotic Sentence Identification Test (DSI), the Dichotic Digits Test (DD), and the Synthetic Sentence Identification Test (SS), which test hearing in noise. DSI scores were correlated with resting-state fMRI connectivity between 361 distinct gray matter brain regions of interest (ROIs). Average global connectivity was calculated as mean functional connectivity between an ROI and the other 360 regions, a quantitative marker representing overall functional connectivity in the brain. Sixteen subjects had adequate fMRI and hearing data. The average age was 71.5 years old (±6.0). The average DSI score for the left ear was 40% (±34%) compared to 90% (±10%) in the right ear (P < .001). No difference between ears was noted on the DD. SS does not differentiate between ears, but worsening scores were noted with increasing background noise. Of the fMRI ROIs, 269 of the 361 had multiple comparison corrected significant correlations between global connectivity and DSI of the left ear (P = .004, r = .673), and all 269 showed higher functional connectivity for individuals with higher left DSI score. No correlations between DSI of the right ear and functional connectivity were found. Correlation was noted between left sided DSI and functional connectivity in patients with AD. Auditory input from the left ear was more susceptible to impairment, suggesting that side-specific auditory input may influence central auditory processing.

Effect of stimulation sites on the performance of electromagnetic middle ear implant: A finite element analysis

Electromagnetic middle ear implants (MEIs), which use the mechanical vibration of their implanted transducers to treat hearing loss, have emerged to overcome the limitations of conventional hearing aids. Several reports have indicated that the electromagnetic MEI's performance changed with different stimulation sites of the transducer. The aim of this study was to analyze the influence of the transducers' stimulation sites on the electromagnetic MEIs' performance. To aid this investigation, a human ear finite-element model was developed from micro-CT images of an adult's right ear. The validity of the model was confirmed by comparing the model-derived results with experimental data. Then, stimulation forces, which simulate ideal electromagnetic transducers, were respectively applied at five typical coupling sites: the umbo, incus body, incus long process, the round window, and the stapes. The stimulation sites' influence on the electromagnetic MEI's performance was studied by analyzing their corresponding basilar membrane displacements. The results show that stimulation of the round window with a force produces more cochlear stimulation than equal force stimulation of the umbo, incus body, incus long process and the stapes, though the superiority of the round window depends on its smaller area compared to the stapes footplate. Among the forward stimulation, the stapes is the optimal stimulation site for the electromagnetic transducer regarding its hearing compensation's efficiency. The performance of the umbo stimulation is comparable to that of the incus-long-process stimulation. Driving the incus body is less efficient than stimulating the other forward driving sites. Additional, using the stapes response to evaluate the forward stimulation gives results similar to those deduced by the basilar membrane response; in contrast, for the round-window stimulation, the evaluation result based on the stapes response is prominently less than the one calculated by the basilar membrane response, especially in the mid-high frequency range.

Effect of pulse phase duration on forward masking and spread of excitation in cochlear implant listeners.

Previous cochlear implant (CI) research has shown that at a pulse train with a long pulse phase duration (PPD) requires less current but greater charge to obtain the same loudness as a pulse train with a short PPD. This might result in different excitation patterns between long and short PPDs. At equal loudness, long PPDs might produce greater masking due to greater charge. However, because they require less current, long PPDs may produce a smaller spatial spread of excitation (SOE) compared to short PPDs by evoking a greater neural firing probability within the relatively small current field. To investigate the effects of PPD on excitation patterns, overall masking and SOE were compared for equally loud stimuli with short or long PPD in 10 adult CI ears. Forward masking patterns were measured at relatively soft, medium, and loud presentation levels. Threshold shifts were calculated in terms of percent dynamic range (DR) of the probe. The area under the curve (AUC) of the masking functions was significantly larger for the long PPD than for the short PPD masker. The difference in AUC was proportional to the difference in charge between the short and long PPD maskers. To estimate SOE, the masking patterns were first normalized to the peak masking, and then AUC was calculated. SOE was significantly larger for the short PPD than for the long PPD masker. Thus, at equal loudness, long PPDs produced greater overall masking (possibly due to greater charge) but less SOE (possibly due to less current spread) than did short PPDs. The effect of the interaction between masking and SOE by long PPD stimulation remains to be tested.

Direct Functional Protein Delivery with a Peptide into Neonatal and Adult Mammalian Inner Ear In Vivo

The aim of this study was to study an antimicrobial peptide (AMP), aurein 1.2, which substantially increased protein delivery directly into multiple mammalian inner-ear cell types in vivo. Different concentrations of aurein 1.2 with superpositively charged GFP (+36 GFP) protein fused with Cre recombinase were delivered to postnatal day 1-2 (P1-2) and adult cochleae of Cre reporter transgenic mice with various delivery methods. By cochleostomy at different concentrations of aurein 1.2–+36 GFP (1 μM, 5 μM, 22.5 μM, and 50 μM, respectively), the tdTomato (tdT) expression was observed in outer hair cells (OHCs; 20.77%, 23.02%, 76.36%, and 92.47%, respectively) and inner hair cells (IHCs; 14.90%, 44.50%, 89.59%, and 96.13%, respectively) in the cochlea. The optimal concentration was 22.5 μM with the highest transfection efficiency and the lowest cytotoxicity. Wide-spread tdT signals were detected in the cochlear-supporting cells, utricular-supporting cells, auditory nerve, and spiral ligament in neonatal and adult mice. Compared to cochleostomy, injection through the round window membrane (RWM) also produced highly efficient tdT+ labeled cells with less cell loss. In summary, the peptide aurein 1.2 fused with +36 GFP dramatically expanded the target cells with increased efficiency in direct protein delivery in the inner ear. Aurein 1.2–+36 GFP has the potential to be developed as protein-based therapy in regeneration and genome editing in the mammalian inner ear.

Stem cell-based approaches: Possible route to hearing restoration?

Disabling hearing loss is the most common sensorineural disability worldwide. It affects around 466 million people and its incidence is expected to rise to around 900 million people by 2050, according to World Health Organization estimates. Most cases of hearing impairment are due to the degeneration of hair cells (HCs) in the cochlea, mechano-receptors that transduce incoming sound information into electrical signals that are sent to the brain. Damage to these cells is mainly caused by exposure to aminoglycoside antibiotics and to some anti-cancer drugs such as cisplatin, loud sounds, age, infections and genetic mutations. Hearing deficits may also result from damage to the spiral ganglion neurons that innervate cochlear HCs. Differently from what is observed in avian and non-mammalian species, there is no regeneration of missing sensory cell types in the adult mammalian cochlea, what makes hearing loss an irreversible process. This review summarizes the research that has been conducted with the aim of developing cell-based strategies that lead to sensory cell replacement in the adult cochlea and, ultimately, to hearing restoration. Two main lines of research are discussed, one directed toward the transplantation of exogenous replacement cells into the damaged tissue, and another that aims at reactivating the regenerative potential of putative progenitor cells in the adult inner ear. Results from some of the studies that have been conducted are presented and the advantages and drawbacks of the various approaches discussed.

Yap-lin28a axis targets let7-Wnt pathway to restore progenitors for initiating regeneration.

The sox2 expressing (sox2+) progenitors in adult mammalian inner ear lose the capacity to regenerate while progenitors in the zebrafish lateral line are able to proliferate and regenerate damaged HCs throughout lifetime. To mimic the HC damage in mammals, we have established a zebrafish severe injury model to eliminate both progenitors and HCs. The atoh1a expressing (atoh1a+) HC precursors were the main population that survived post severe injury, and gained sox2 expression to initiate progenitor regeneration. In response to severe injury, yap was activated to upregulate lin28a transcription. Severe-injury-induced progenitor regeneration was disabled in lin28a or yap mutants. In contrary, overexpression of lin28a initiated the recovery of sox2+ progenitors. Mechanistically, microRNA let7 acted downstream of lin28a to activate Wnt pathway for promoting regeneration. Our findings that lin28a is necessary and sufficient to regenerate the exhausted sox2+ progenitors shed light on restoration of progenitors to initiate HC regeneration in mammals.

Can we predict the altered subjective quality assessment of sound after ear canal surgery?

PurposeTo correlate the subjective quality assessment of ear canal acoustics of the participants to the objective measurement of the ear canal acoustics. The objective ear canal acoustics is the frequency-dependent modulation of soundwaves through the ear canal. Our second objective is to design a model to predict the subjective quality of sound based on the altered objective ear canal acoustics.MethodsTo determine the frequency-dependent modulation of the soundwaves the real-ear unaided gain (REUG) of the ear canal is measured. 40 participants with normal hearing were presented six simulated sound fragments representing the acoustic properties of six different ear canals (REUG). These six sound fragments were built based on the difference between these six REUGs and the average REUG of a normal adult ear canal. Subjective sound quality was evaluated using a VAS score and a paired comparison score.ResultsWe found a strong correlation between the objective ear canal acoustics and the subjective assessment of the quality of sound (Spearman’s rho—0.89). Our linear mixed VAS model for individual participants has an intercept of 95.6 and a slope of − 4.2 (p < 0.001). The paired comparison analysis endorsed our findings that an increased difference in REUG is predictive for a decreased quality assessment of ear canal acoustics.ConclusionThere is a strong correlation between the subjective evaluation of ear canal acoustics and the objective quality assessment of ear canal acoustics. Our models show that an increased difference in REUG predicts a decreased quality of ear canal acoustics.

Posterior Semicircular Canal Dehiscence: Case Series and Systematic Review.

To conduct a systematic review of posterior semicircular canal dehiscence (PSCD) and to present a series of patients with PSCD with and without classic third-window symptoms. PubMed, Scopus, and the Cochrane Library from inception until April 2019. Case series of five patients seen in a multidisciplinary, vestibular-focused, neurotology clinic. Inclusion criteria: PSCD studies of symptomatology, diagnostic testing, radiology, and histopathology. non-English articles, reviews, letters, animal studies. Quality evaluated according to Oxford Center for Evidence-Based Medicine criteria and funnel plot via the Stern and Egger method. Two hundred five studies were found, and 58 studies were included. In 47 total patients, sound-induced vertigo, mixed hearing loss, and tinnitus were the most common presenting symptom. A meta-analysis of proportions using eight radiological and histopathological studies revealed an incidence of 0.38% adult ears [95% CI 0.08, 0.89] and 2.16% of adult patients [0.64, 4.54]. The incidence in pediatric patients ranged from 1.3 to 43%. Jugular bulb abnormalities were common. In our case series, four of five patients presented without third-window symptoms, while one had sound- and pressure-induced vertigo. Hearing loss in these patients was not salvageable. PSCD is a rare phenomenon most commonly presenting with third-window type symptoms. However, PSCD might also present with dizziness and hearing loss inconsistent with third-window symptomatology. One should be conscious of potentially poorer prognosis for hearing recovery in these patients.

Reproducing ear-canal reflectance using two measurement techniques in adult ears

Clinical diagnostic applications of ear-canal reflectance have been researched extensively in the literature, however, the measurement uncertainty associated with the conventional measurement technique using an insert ear probe is unknown in human ear canals. Ear-canal reflectance measured using an ear probe is affected by multiple sources of error, including incorrect estimates of the ear-canal cross-sectional area and oblique ear-probe insertions. In this paper, ear-canal reflectance measurements are reproduced in an occluded-ear simulator and in 54 adult ear canals using two different measurement techniques: a conventional ear probe and a two-microphone probe that enables the separation of reverse- and forward-propagating plane waves. The two-microphone probe is inserted directly into test subjects' ear canals, and the two-microphone method is distinguished by not requiring the ear-canal cross-sectional area to calculate the ear-canal reflectance. The results show a reasonable agreement between the two measurement techniques. The paper further examines the influence of oblique ear-probe insertions and the compensation for such oblique insertions, which results in an improved agreement between the two measurement techniques.

Noise-induced hearing loss in zebrafish: investigating structural and functional inner ear damage and recovery

Exposure to continuous moderate noise levels is known to impair the auditory system leading to Noise-Induced Hearing Loss (NIHL) in animals including humans. The mechanism underlying noise-dependent auditory Temporary Threshold Shifts (TTS) is not fully understood. In fact, only limited information is available on vertebrates such as fishes, which share homologous inner ear structures to mammals and have the ability to regenerate hair cells. The zebrafish Danio rerio is a well-established model in hearing research providing an unmatched opportunity to investigate the molecular and physiological mechanisms of NIHL at the sensory receptor level. Here we investigated for the first time the effects of noise exposure on TTS and functional recovery in zebrafish, as well as the associated morphological damage and regeneration of the inner ear saccular hair cells.Adult specimens were exposed for 24h to white noise at various amplitudes (130, 140 and 150 dB re. 1 μPa) and their auditory sensitivity was subsequently measured with the Auditory Evoked Potential (AEP) recording technique. Sensory recovery was tested at different times post-treatment (after 3, 7 and 14 days) and compared to individuals kept under quiet lab conditions. Results revealed noise level-dependent TTS up to 33 dB and increase in response latency. Recovery of hearing function occurred within 7 days for fish exposed to 130 and 140 dB noise levels, while fish subject to 150 dB only returned to baseline thresholds after 14 days. Hearing impairment was accompanied by significant loss of hair cells only at the highest noise treatment. Full regeneration of the sensory tissue (number of hair cell receptors) occurred within 7 days, which was prior to functional recovery.We provide first baseline data of NIHL in zebrafish and validate this species as an effective vertebrate model to investigate the impact of noise exposure on the structure and function of the adult inner ear and its recovery process.

Middle ear functional state in case of pathological changes of nose and throat

Objectives -to compare the functional state of middle ear in adults in case of various pathology of nasal cavity, paranasal sinuses and throat. Material and methods. In 2018-2019 period, 151 patient, aged from 16 to 70 years, was examined by acoustic impedancemetry. The patients reported the subjective satisfactory state of the acoustic organ, but had a pathology of the upper respiratory tract. Results. In the groups, there were no significant differences associated with gender. Most of the patients were of working age. In all study groups, the impaired function of the auditory tube, with various intensity, was registered, although the patients had no hearing complaints. At the same time, the acumetry and tonal threshold audiometry data indicated the normal acuity of hearing. Conclusion. Acute and chronic sinusitis was the most frequent risk factor for middle ear ventilation disorder. A quarter of patients with acute sinusitis, without otological complaints, had type B and C tympanograms. 93.7% of patients, who had undergone the surgical correction of the deviated nasal septum, did not have a middle ear ventilation disorder. Surgical intervention in the nasal cavity and oropharynx leads to a transient dysfunction of the auditory tube, but does not require special treatment due to self-recovery.

Causality-constrained measurements of aural acoustic reflectance and reflection functions.

Causality-constrained procedures are described to measure acoustic pressure reflectance and reflection function (RF) in the ear canal or unknown waveguide, in which reflectance is the Fourier transform of the RF. Reflectance calibration is reformulated to generate causal outputs, with results described for a calibration based on a reflectance waveguide equation to calculate incident pressure and source reflectance in the frequency domain or source RF in the time domain. The viscothermal model RF of each tube is band-limited to the stimulus bandwidth. Results are described in which incident pressure is either known from long-tube measurements or calculated as a calibration output. Calibrations based on constrained nonlinear optimizations are simpler and more accurate when incident pressure is known. Outputs measured by causality-constrained procedures differ at higher frequencies from those using standard procedures with non-causal outputs. Evanescent-mode effects formulated in the time domain and incorporated into frequency-domain calibrations are negligible for long-tube calibrations. Causal reflectance and RFs are evaluated in an adult ear canal and time- and frequency-domain results are contrasted using forward and inverse Fourier transforms. These results contribute to the long-term goals of improving applications to calibrate sound stimuli in the ear canal at high frequencies and diagnose conductive hearing impairments.

Turnover and Activity-Dependent Transcriptional Control of NompC (=TRPN1) in the &lt;i&gt;Drosophila&lt;/i&gt; Ear

Across their lives, biological sensors maintain a near-constant functional output despite a plethora of exogenous and endogenous perturbations. This sensory homeostasis is the product of multiple dynamic equilibria, the breakdown of which contributes to age-dependent sensory decline. The molecular mechanisms of homeostatic maintenance, however, are still poorly understood. The ears of vertebrates and insects are characterised by exquisite sensitivities but also marked functional vulnerabilities. Being under the permanent load of both thermal and acoustic noise, auditory transducer channels are prime examples for the homeostatic challenge. We show that (i) NompC-dependent mechanotransducers in the ear of the fruit fly Drosophila melanogaster undergo a continual turnover with estimated half-lives of ≈ 3h; (ii) a de novo synthesis of NompC can restore transducer function in the adult ears of congenitally deafened flies; (iii) key components of the auditory transduction chain, including NompC, are under activity-dependent transcriptional control, likely forming a transducer-operated gain control system.

Enhancement of in Vitro Developmental Outcome of Cloned Goat Embryos After Epigenetic Modulation of Somatic Cell-Inherited Nuclear Genome with Trichostatin A

Abstract In this study, the effect of trichostatin A (TSA)-mediated epigenomic modulation of nuclear donor cells on the in vitro developmental potential of caprine somatic cell cloned embryos was examined. The enucleated ex vivo-matured oocytes were subzonally injected with adult ear skin-derived fibroblast cells exposed or not exposed to TSA (at a concentration of 50 nM). The experiment was designed on the basis of three different approaches to TSA-dependent modulation of donor cell-descended genome: before being used for somatic cell nuclear transfer/SCNT (Group I); immediately after activation of nuclear-transferred (NT) oocytes (Group II); or combined treatment both before being used for SCNT and after activation of NT oocytes (Group III). In the control Group IV, donor cell nuclei have not been treated with TSA at any stage of the experimental design. In TSA-treated Groups I and II and untreated Group IV, cleavage activities of cloned embryos were at the similar levels (80.6%, 79.8% and 77.1%, respectively). But, significant difference was observed between Groups III and IV (85.3 vs. 77.1%). Moreover, in the experimental Groups I and III, the percentages of cloned embryos that reached the blastocyst stages remarkably increased as compared to those noticed in the control Group IV (31.2% vs. 36.7% vs. 18.9%, respectively). In turn, among embryos assigned to Group II, blastocyst formation rate was only slightly higher than that in the control Group IV, but the differences were not statistically significant (25.8% vs. 18.9%). To sum up, TSA-based epigenomic modulation of somatic cell-inherited nuclear genome gave rise to increased competences of caprine cloned embryos to complete their development to blastocyst stages. In particular, sequential TSA-mediated modulation of both nuclear donor cells and activated NT oocytes led to improvement in the blastocyst yields of cloned goat embryos, which can result from enhanced donor cell nuclear reprogrammability.

Observations of Distortion Product Otoacoustic Emission Components in Adults With Hearing Loss.

Distortion product otoacoustic emissions (DPOAEs) measured in the ear canal are composed of OAEs generated by at least two mechanisms coming from different places in the cochlea. Otoacoustic emission (OAE) models hypothesize that reduction of cochlear gain will differentially impact the components. The purpose of the current experiment was to provide preliminary data about DPOAE components in adults with hearing loss in relation to OAE models and explore whether evaluation of the relative amplitudes of generator and reflection components can enhance identification of hearing loss. DPOAEs were measured from 45 adult ears; 21 had normal hearing (≤15 dB HL) and 24 with mild-to-severe sensorineural hearing loss (>15 dB HL). The higher frequency primary (f2) was swept logarithmically between 1500 and 6000 Hz, and f2/f1 was 1.22. The two equal-level primaries varied from 55 to 75 dB SPL in 5 dB steps. The swept primary procedure permitted the measurement of the amplitude and phase of the DPOAE fine structure and the extraction of the two major components (generator and reflection) by varying the predicted delays of the analysis windows. DPOAE fine structure was reduced or absent in ears with hearing loss. DPOAE generator and reflection components were lower in ears with hearing loss than those with normal hearing, especially for the reflection component. Significant correlations were found between the generator component and hearing threshold but not between reflection levels and hearing threshold. Most ears with normal hearing had both components, but only a small number of ears with hearing loss had both components. The reflection component is not recordable or low in level in ears with hearing loss, explaining the reduced or absent DPOAE fine structure. DPOAE generator components are also lower in level in ears with hearing loss than in ears without hearing loss. In ears that had both measurable generator and reflection components, the relationship between the two did not depend on the presence or absence of hearing loss. Because reflection components are not measurable in many ears with hearing thresholds >15 dB HL, stimuli that evoke other types of reflection emissions, such as stimulus-frequency or long-latency transient-evoked emissions, should be explored in conjunction with DPOAE generator components.

Recurrence of Cholesteatoma - A Retrospective Study Including 1,006 Patients for More than 33 Years.

Introduction Cholesteatomas are benign tumors consisting of skin, and growing inside a retraction pocket in the tympanic membrane. Cholesteatomas can occupy the entirety of the middle ear, and are known for their osteolytic capabilities. Surgery is the only curative treatment for cholesteatomas. Objective To describe the risk of recurrence after first-time surgically-treated middle-ear cholesteatoma (STMEC1) on the island of Funen from 1983 to 2015. Methods Cases of STMEC1 were identified in the Danish National Hospital Register. The medical records were reviewed. Time-to-event analyses were applied. The ears were followed from STMEC1 to a secondary cholesteatoma, emigration, death, or end of follow-up. Results Records from 1,006 patients with STMEC1 were reviewed. A total of 54 patients were submitted to surgery on both ears. The total sample consisted of 1,060 ears with STMEC1; 300 were children's (< 16 years) ears, and 760 were adult's ears. The total observation time was of 12,049 years. The overall estimated proportion with recurrence 5 years after surgery was of 37% in children and of 15% in adults. The older the child was at the first surgery, the risk decreased by 7% per year. In children, canal wall up (CWU) mastoidectomy without obliteration was associated with a hazard ratio for recurrence of 1.9 (95% confidence interval [95%CI]: 1.2–3.0) compared with CWU with obliteration. Conclusion Compared with adults, children were had 2.6 times more risk of recurrence. Procedures performed without mastoidectomy had the lowest risk of recurrence. In children, obliteration was associated with a significantly lower risk of recurrence. However, patients were not randomized regarding the surgical approach; thus, the association between approach and risk of recurrence was likely influenced by confounding factors.

Gene duplication and functional divergence of the zebrafish otospiralin genes.

Otospiralin (OTOSP) is a small protein of unknown function, expressed in fibrocytes of the inner ear and required for normal cochlear auditory function. Despite its conservation from fish to mammals, expression of otospiralin was only investigated in mammals. Here, we report for the first time the expression profile of OTOS orthologous genes in zebrafish (Danio rerio): otospiralin and si:ch73-23l24.1 (designated otospiralin-like). In situ hybridization analyses in zebrafish embryos showed a specific expression of otospiralin-like in notochord (from 14 to 48hpf) and similar expression patterns for otospiralin and otospiralin-like in gut (from 72 to 120hpf), swim bladder (from 96 to 120hpf) and inner ear (at 120hpf). Morpholino knockdown of otospiralin and otospiralin-like showed no strong change of the body structure of the embryos at 5dpf and the inner ear was normally formed. Nevertheless, knockdown embryos showed a reduced number of kinocilia in the lateral crista, indicating that these genes play an important role in kinocilium formation. RT-qPCR revealed that otospiralin is highly expressed in adult zebrafish inner ear comparing to the others analyzed tissues as previously shown for mice. Interestingly, otospiralin-like was not detected in the inner ear which suggests that otospiralin have a more important function in hearing than otospiralin-like. Phylogenetic analysis of otospiralin proteins in vertebrates indicated the presence of two subgroups and supported the functional divergence observed in zebrafish for otospiralin and otospiralin-like genes. This study offers the first insight into the expression of otospiralin and otospiralin-like in zebrafish. Expression data point to an important role for otospiralin in zebrafish hearing and a specific role for otospiralin-like in notochord vacuolization.