Daniel Bodmer

A new implantable middle ear hearing device for mixed hearing loss: A feasibility study in human temporal bones

Hypothesis: To assess the feasibility of a new, active middle ear device in temporal bones (TB). Background: This device is designed for patients with mixed hearing loss subsequent to chronic middle ear infection, surgery, or trauma. This Bell-Vibroplasty is built from a VIBRANT MED-EL Vibrant Soundbridge and a Kurz Bell titanium partial ossicular replacement prosthesis. Methods: In three fresh TBs, healthy and reconstructed middle ears were analyzed by means of laser Doppler interferometry. The sound transmission properties of a partial ossicular replacement prosthesis and a passive and an active Bell-Vibroplasty were compared with healthy middle ear function. Results: The measurements provided reliable results with small standard deviations and good signal-to-noise ratios. The performance levels of the partial ossicular replacement prosthesis and of the passive Bell-Vibroplasty were comparable with that of healthy middle ear function. The activated Bell-Vibroplasty provided linear function and a flat frequency response within the measured frequency range (500 Hz-8 kHz), with peak deviations of less than 10 dB. The maximum output of the Bell-Vibroplasty was equivalent to 125-dB sound pressure level. Conclusion: Bell-Vibroplasty is feasible in TBs. Bell-Vibroplasty performance in TBs is sufficient to allow for a clinical trial as a next step.

NF-kappaB-dependent apoptotic hair cell death in the auditory system

Hair cells are the most vulnerable elements in the inner ear and their degeneration is the most common cause of hearing loss. In the last few years progress has been made in uncovering the molecular mechanisms involved in hair cell damage and death. However, little is known about factors important for hair cell survival. Recently, it has been demonstrated that the transcription factor NF-kappaB is required for survival of immature auditory hair cells in vitro. Here we used DNA microarray technology to explore NF-kappaB downstream events in organ of Corti explants of postnatal day-5 Sprague-Dawley rats which were exposed to a cell-permeable NF-kappaB-inhibitory peptide. Gene expression was analyzed using DNA microarray technology. Genes were selected on the basis of comparative analysis, which reliably distinguished the NF-kappaB inhibitor-treated samples from control samples. Interestingly, among the up-regulated genes was the gene coding for the regulatory subunit of phosphatidylinositol 3-kinase. Moreover, inhibition of the phosphatidylinositol 3-kinase signaling pathway in organ of Corti explants exposed to the NF-kappaB inhibitor reduced caspase-3 activation. These data link NF-kappaB-dependent hair cell death to phosphatidylinositol 3-kinase signaling.

The Effect of Erythropoietin on Gentamicin‐Induced Auditory Hair Cell Loss

Objective/Hypothesis: Mammalian auditory hair cells that are unable to regenerate and various agents, including gentamicin, can irreversibly damage the hair cells. Erythropoietin, known as the primary regulator of erythropoiesis, exerts also neuroprotective effects by binding to its receptor. We tested whether erythropoietin can protect the hair cells from gentamicin‐induced damage.

Early gene expression in the organ of Corti exposed to gentamicin

Studies have demonstrated different pathogenetic key factors in gentamicin-induced hair cell death. The production of reactive oxygen species (ROS), as well as apoptosis-related genes, play a critical role. However, a coordinated large-scale investigation of gene expression in the organ of Corti (OC) exposed to gentamicin has not yet been conducted. Here we used DNA microarray technology to compare the expression profile of OC exposed to gentamicin to the expression profile of untreated OC. The OCs of Sprague Dawley rats were dissected and the basal turns were cultured. Two-thirds of the explants were then exposed to l00 microM gentamicin, for 4 and 8 h, while one-third of the explants remained in culture medium alone. Gene expression was analyzed using DNA microarray technology and the dChip software package. Based on the results, the 4-h time-point was chosen for further analysis. In these assays, out of 8800 genes, 12 genes were identified on the basis of differential expression in the OC exposed to gentamicin vs. control OC. The identity of these genes suggests that the response of the OC to the gentamicin challenge involves down-regulation of specific gene families in order to alleviate ROS and N-methyl-D-aspartate (NMDA) receptor-mediated cellular stress.

Promyelocytic leukemia zinc finger protein localizes to the cochlear outer hair cells and interacts with prestin, the outer hair cell motor protein.

Hair cells in the auditory sensory organ are specialized mechanoreceptors common to mammalian and non-mammalian species. The mammalian cochlear outer hair cells (OHC) possess a distinct motile property, dubbed membrane-based electromotility, that enhances the receptor function. This electromotility is believed to be the basis of cochlear amplification that increases sensitivity of the mammalian ear to sound. Prestin, a unique voltage-sensitive motor molecule localized in the lateral membrane of OHC, is presumably responsible for OHC electromotility. It has been documented that prestin null-animals lack electromotility and suffer from approximately 50 dB loss of hearing sensitivity. To identify proteins that interact with prestin we carried out a yeast two-hybrid library screen using the C-terminal intracellular domain of prestin as bait. Seven bait-dependent prey clones were identified independently. Further analysis revealed that they encode partially over-lapping regions of a single protein: a transcriptional repressor, promyleocytic leukemia zinc finger protein (PLZF). PLZF encodes a POZ/domain Kruppel-type zinc finger transcription factor reported to have pro-apoptotic and anti-proliferative activity. The interaction between endogenous prestin and PLZF proteins in the cochlea was confirmed by co-immunoprecipitation using organ of Corti lysates. Furthermore, immunohistochemical studies strongly suggest that PLZF co-localizes with prestin near the lateral membrane of cochlear OHC. The physiological significance of this interaction remains to be explored.

Alteration of activator protein 1 DNA binding activity in gentamicin-induced hair cell degeneration

Sensorineural hearing loss is often associated with damage of cochlear hair cells and/or of the neurons of the auditory pathway. This damage can result from a variety of causes, e.g. genetic disorders, aging, exposure to certain drugs such as aminoglycosides, infectious disease and intense sound overexposure. Intracellular events that mediate aspects of aminoglycoside-mediated damage to hair cells have been partially unraveled. Several independent research groups have demonstrated a crucial role of mitogen-activated protein kinase signaling in aminoglycoside-induced ototoxicity. Mitogen-activated protein kinases are important mediators of signal transduction from the cell surface to the nucleus. Jun N-terminal kinases, members of the mitogen-activated protein kinase family, are strongly activated in cell culture conditions by stress inducing stimuli, including ultraviolet light, heat shock and tumor necrosis factor; therefore they are also referred to as stress-activated protein kinases. In hair cells aminoglycoside treatment was shown to activate the Jun N-terminal kinase signaling pathway. Activation of Jun N-terminal kinase leads to phosphorylation and thereby activation of transcription factors and consequently to altered gene expression. There are many nuclear Jun N-terminal kinase substrates including c-Jun, ATF-2, and Elk-1 proteins. One of the downstream targets of Jun N-terminal kinase is the transcription factor activating protein-1. Activating protein-1 is a dimeric complex composed of members of the Fos and Jun proteins. A variety of different stimuli is known to induce activating protein-1 activity. Induction of activating protein-1 is thought to play a central role in reprogramming gene expression in response to external stimuli. In this study we have analyzed the effect of gentamicin treatment on the downstream targets of Jun N-terminal kinase. Our results demonstrate that gentamicin treatment of explants of organ of Corti results in increased activating protein-1 binding activity. The main component of these activating protein-1 complexes is the c-Fos protein. Moreover, we show that the activating protein-1 induction is transient and occurs exclusively in hair cells of rat organ of Corti explants.

Qualitative case studies of five cochlear implant recipients' experience with music

Abstract Cochlear implantation has revolutionized the management of those who suffer from severe-to-profound hearing loss because many patients now achieve excellent speech understanding with objective testing. Nevertheless, speech understanding in noisy conditions and music appreciation remain significant challenges to cochlear implant (CI) users. Music appreciation is an extremely complex experience that is difficult to quantify through a conventional outcome study. This paper aims at documenting the experience of five CI patients with regard to music appreciation using qualitative techniques. This information was obtained through a semi-structured interview process. The interviews were then transcribed and analysed using a constant comparative method of qualitative description. The results together with medical case records were used to identify emerging themes. The common themes that evolved were: musical background, the experience of receiving the implant, current experience with music, attention, musical prediction ability, internal hearing, hedonic vs. critical listening, determination, and timbre perception. By documenting their experiences in this manner, novel insights into the patient perspective are provided that are unique to the literature. These descriptions will aid clinicians and researchers who work in the area of cochlear implantation to better understand the needs of their patients.

Nogo in the Mammalian Cochlea

Hypothesis: Different members of the Nogo system are expressed in the mammalian cochlea. Background: The protein Nogo has gained a lot of attention during the last couple of years because it inhibits neurite outgrowth in the adult central nervous system. In contrast to the central nervous system, very little is known regarding the expression and possible function of the Nogo system within the inner ear. Methods: Using reverse-transcriptase-polymerase chain reaction and immunohistochemistry, we analyzed for the expression of members of the Nogo system within the cochlea. In addition, we determined hearing levels of Nogo A knockout and wild-type mice with auditory brainstem response audiometry. Results: In this study, we demonstrate the expression of Nogo A, B, C, and of Nogo receptor mRNA in the organ of Corti, spiral ganglion, and stria vascularis. Immunohistochemistry revealed that Nogo A and Nogo receptor localize to the spiral ganglion neurons. Interestingly, Nogo A expression was also observed in the outer and inner hair cells of the organ of Corti. As revealed by light microscopy, deletion of Nogo A does not alter cochlear microanatomy. We have assessed hearing levels in 10-month old wild-type and Nogo A knockout mice, and thereby, we could not detect any differences between these 2 groups. Conclusion: Different members of the Nogo family are expressed in the mammalian cochlea. Deletion of Nogo A does not alter cochlea microanatomy or hearing levels compared with wild-type mice.