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Inledning: Helhetssynen på rehabiliteringen efter en CI-operation berörs av många olika aspekter som påverkar livskvaliteten. Vid rehabiliteringen efter att ha opererat in ett cochleaimplantat (CI) är det viktigt att inte bara se till patientens direkta hörselbehov, utan ha en bredare helhetssyn och ta hänsyn till andra behov patienten kan ha. Olika delar i rehabiliteringen efter en CI-operation är teknisk -, medicinsk-, pedagogisk-, psykologisk-, psykosocial-, och samhällelig hörselrehabilitering.   Syfte: Syftet med studien är att undersöka på vilket sätt rehabiliteringsmetoder vid CI-operation sker med utgångspunkt i en helhetssyn på rehabilitering inom audiologisk forskning, samt undersöka hur livskvaliteten påverkas efter CI-operation.   Metod: Examensarbetets syfte och frågeställningar har granskats och besvaras genom en systematisk litteraturstudie.   Resultat: Studier med en helhetssyn på rehabiliteringen som innefattar de sex olika delarna inom hörselrehabilitering saknades. Studiens resultat indikerar att livskvaliteten efter en CI-operation blir avsevärt förbättrad, detta utvärderas med olika självskattningsskalor och rehabiliteringsmetoder.   Slutsatser: Få studier visar prov på ett helhetstänkande enligt den teoretiska beskrivningen av vad en helhetssyn på hörselrehabilitering går ut på. Genom att ha ett helhetstänkande i rehabiliteringen för patienter med CI inkluderas alla olika aspekter som behövs för ett aktivt socialt liv och det emotionella välbefinnandet. Det råder inga tvivel om att livskvaliteten efter en CI-operation ökar.

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Thesis (Ph.D.)--University of Melbourne, Dept. of Otolaryngology (Eye & Ear Hospital), 2006. / Typescript. Includes bibliographical references (leaves 238-253).

Hearing loss or deafness, in its most serious form, affects an estimated 28 million people in America. One of the forms of hearing loss, known as ototoxicity, refers to damage to the ear (-oto) due to xenobiotics. Cisplatin is the most widely used antineoplastic agent in the treatment of various solid tumors. Cisplatin toxicity can lead to severe effects on the kidneys, nervous system and auditory system which significantly reduce the quality of life of cancer patients. While nephrotoxicity could be alleviated by hydration and diuresis, cisplatin-induced ototoxicity is permanent and there is currently no approved treatment for this condition. Previous studies have shown that the generation of reactive oxygen species (ROS) is a critical event that initiates damage to the outer hair cells (OHCs), stria vascularis (SVA) and spiral ganglion cells (SG) of the cochlea, leading to hearing loss after cisplatin treatment. However, the mechanism(s) underlying the transition from ROS generation to the manifestation of ototoxicity is (are) not clearly defined. Recent studies have also implicated inflammatory pathways in cisplatin-induced cell death. Various transcription factors have been linked to the induction of inflammation mediated by cisplatin in the cochlea. Recent study demonstrate that cisplatin activates signal transducer and activator of transcription 1 (STAT1) a transcription factor implicated in inflammation, which mediates damage to utricular hair cell and could also confer cisplatin-induced hearing loss. The aim of this study is to further define a role of STAT1 in cochlear inflammation and in cisplatin-mediated ototoxicity. Based on preliminary data, we hypothesize that STAT1 plays an integral role in cisplatin-mediated inflammation and hearing loss. Our data show that STAT1 couples ROS to the inflammatory process in the cochlea. The major source of ROS appears to be the NOX3 NADPH oxidase system, knockdown of which by short interfering (si)RNA reduces STAT1 activation by cisplatin and alleviates hearing loss. Activation of STAT1 by cisplatin involves phosphorylation of Serine 727 by mitogen activated protein kinases such as extracellular signal regulated kinase (ERK) 1/2 and p38. Knockdown of STAT1 by trans-tympanic administration of siRNA reduces damage to OHCs and protects against cisplatin-induced hearing loss in rats. STAT1 siRNA attenuates the production of inflammatory mediators, such as tumor necrosis factor- α (TNF-α), and reduces the recruitment of inflammatory cells to the cochlea. Furthermore, inhibition of TNF-α by trans-tympanic administration of etanercept, a clinically used TNF-α antagonist, protects against OHC damage and cisplatin-induced hearing loss. These data suggest that targeting STAT1 or the inflammatory genes it regulates could serve as useful strategies for preventing cisplatin-induced hearing loss and improve the overall quality of life of cancer patients.

Cisplatin is a widely used chemotherapeutic drug for the treatment of solid tumors. However, the drug accumulates in the cochlea, and damages inner ear structures, resulting in bilateral andpermanent hearing loss. Previous data from our laboratory indicate that activation of the transient receptor potential vanilloid 1 (TRPV1) receptor (by capsaicin) increases the NOX3 isoform of NADPH oxidase, leading to the generation of reactive oxygen species (ROS) in the cochlea, transient cochlear inflammation and transient hearing loss. We also demonstrated that the transient inflammation was produced by ROS-mediated activation of signal transducer and activator of transcription 1 (STAT1). Surprisingly, over time, this response desensitizes and capsaicin was subsequently able to protect against cisplatin ototoxicity. The goal of this study was to determine the mechanism of otoprotection against cisplatin ototoxicity following the administration of capsaicin. For this study we utilize both an immortalized organ of Corti outer hair cells and rat cochlea. Capsaicin (2.5 µM) increased both Ser727 p-STAT1 and Tyr705 p-STAT3 implicating its role in inflammation. Expression of cannabinoid receptors were observed in UB/OC-1 cells as well as rat outer hair cells (OHCs). However, inhibition of CB2 receptors (by AM630) reduced capsaicin-mediated Tyr705 p-STAT3, but had little effect on Ser727 STAT1. Capsaicin protected UB/OC-1 cells against cisplatin-induced apoptosis. This protection was reversed by CB2 antagonist but potentiated by TRPV1 inhibition. Significant cell death was observed following treatment of UB/OC-1 cells with AM630 alone, underscoring the importance of CB2 receptors in survival of these cells. CB2 agonist, JWH, significantly increased the protective signal, STAT3. Furthermore, capsaicin-mediated protection was reversed by the inhibition of STAT3, implicating STAT3 in otoprotection. In animal studies, oral administration of capsaicin (0.5% solution) induced transient inflammation but led to a long term recovery. Animals pre-treated with oral capsaicin were protected against cisplatin-induced hearing loss as compared to vehicle-treated animals, suggesting protection against hearing loss. Capsaicin increased the expression of both CB1 and CB2 receptors in the organ of Corti, which might confer the long term protective actions of this agent against hearing loss. In rats pretreated with AM630, the protective action of capsaicin was abolished. We conclude that otoprotection mediated by capsaicin is produced by activation of CB receptors in the cochlea which are coupled to both STAT1 and STAT3 activation. However, our data support the conclusion that activation of STAT3 confers the otoprotective action of capsaicin. In contrast, activation of STAT1 by capsaicin could contribute to the transient inflammatory response previously observed in vivo. The net protective action of capsaicin could result from an increase in the STAT3/STAT1 ratio of cells in the cochlea, which antagonizes the ability of cisplatin lower this ratio and promote cell death.

Endocannabinoid (eCB) system is composed of endogenous CB ligands including anandamide (AEA) and 2-Arachidonyl glycerol (2-AG), enzymes involved in their biosynthesis and degradation such as diacylglycerol lipase-α (DAGL- α), and CB receptors. Primarily, there are three types of CB receptors - CB receptor 1(CB1), CB receptor 2 (CB2) and non CB1 non CB2 types of CB receptor (e.g. GPR, TRPV1) and they belong to G-protein (Gi/o) coupled receptors (GPCR) family.CB1 receptors are abundant in the brain where they modulate neuronal activities. On the other hand, CB2 receptors are predominantly expressed in the immune cells and regulate the growth and proliferation of different immune cells and modulate the activities of cytokines network and anti-oxidant machinery in stress conditions. Inflammation plays a central role in hearing loss (HL) caused by different ototoxic insults including anti-neoplastic agents such as cisplatin, aminoglycosides and acoustic trauma. These insults can trigger chronic production of reactive oxygen species (ROS) in regions of cochlea such as organ of Corti, stria vascularis (SVA), spiral ligament (SL) and spiral ganglion neurons (SG). This leads to increased synthesis of pro-inflammatory cytokines, disruption of mitochondrial membrane integrity, activation of DNA damage/repair pathways and activation of pro-apoptotic enzymes. Jeong et al. (2007) have shown that CB2 receptor specific agonist (JWH-015) protects the HEI-OC1 hair cell cultures against cisplatin-induced cytotoxicity in-vitro. The goal of the current study was to examine the distribution and function of CB receptors (mainly CB2) in the cochlea and determine whether activation of these receptors could protect the cochlea by altering the expression of ROS generating proteins, along with pro-inflammatory and pro-apoptotic proteins. This study also investigated whether inhibition of eCB synthesis can causes HL. Aim 1 of the current study investigated the expression of CB receptors in the cochlea using different in-vivo models such as male Wistar rat and knock-in mice with GFP-tagged CB2 receptors, in-vitro models such as organotypic culture of neonatal mouse (C57BL/6) cochlea and University of Bristol organ of Corti (UB/OC1) cells. We show that both CB1 and CB2 receptors are expressed in the outer and the inner hair cells (OHCs and IHCs), SV, SG and supporting cells (SCs) included outer and inner pillar cells. The distribution of DAGL- α was also examined in the male Wistar rats and we found the similar distribution pattern of this enzymes as CB2. DAGL- α catalyzes the hydrolysis of DAG to synthesize 2-AG, which acts as a chief endogenous CB2 ligand. Our initial studies suggested a role of CB2 and not CB1 in protection, leading us to focus on CB2 receptors for subsequent studies. Aim 2 examined the otoprotective role of trans-tympanic application of CB2 specific agonist (JWH-015) against cisplatin-induced hearing loss in male Wistar rats. Activation of CB2 receptors restored cisplatin-induced elevations in ABR thresholds which was significantly reversed by CB2 antagonist AM-630. Pre-treatment with JWH-015 protected against cisplatin-induced loss of hair cell and synaptic ribbons. In-vitro studies in UB/OC-1 cells demonstrated that pre-treatment of JWH-015 modulates the activities of signal transducer and activator of transcription 1 and 3 (STAT1 and STAT3), increases the expression of anti-apoptotic protein Bcl-xL, indicating its role in regulating the apoptosis Activation of CB2 also abrogated cisplatin-induced decrease in Na+/K+ATPase- α in the SV and SL fibrocytes and ameliorated the expression of different pro-inflammatory genes including TRPV1, COX2, NOX3, KIM1, iNOS and TNF- α. We also found that blocking of CB2 by AM630 itself resulted in hearing loss and loss in CB2 receptors, indicating eCB system is tonically active and could be important for physiological function of the cochlea. Indeed, we observed that inhibition of DAGL- α by RHC80267 results in HL. Aim 3 of this current study investigated whether pre-treatment of CB2 agonist will interfere with anti-cancer efficacy of cisplatin against various cancer cell lines head and neck cancer cells (UMSCC10B), and colon cancer cells (HCT116). Our data indicate that JWH-015 did not interfere with cisplatin-induced apoptosis in these cells. Overall, this study provides novel insights into the essential role eCBs plays in protection the cochlea under non-stressed conditions and following exposure to ototoxic agents. It also demonstrates that application of exogenous CB2 agonist (JWH-015) could serve as an effective protective agent against cisplatin ototoxicity These data suggest that localized delivery of CB2 agonists should be studied in human for protection against hearing loss.

TMPRSS3 est une sérine protéase mutée dans les surdités humaines DFNB8/10. Pour déterminer le rôle de cette protéine dans la physiologie cochléaire, nous avons généré puis caractérisé le phénotype auditif d'un modèle murin mimant la pathologie humaine. Les souris mutantes homozygotes sont profondément sourdes, due à une perte rapide et complète des cellules sensorielles cochléaires au moment de leur entrée en fonction. Afin de caractériser les mécanismes moléculaires responsables de la perte de ces cellules, nous avons comparé le protéome de souris sauvages et mutantes par des gels en 2-dimensions. Nous avons ensuite analysé les spots variants par spectrométrie de masse, ce qui nous a permis de reconstruire les réseaux dans lesquels les protéines variantes interviennent. Parmi les réseaux identifiés, nous avons focalisé notre analyse sur celui du canal potassique BK, puisque sa mise en place est concomitante de la dégénérescence des cellules sensorielles. Par des expériences d'immunohistochimie et de patch-clamp, nous avons pu montrer dans les cellules sensorielles de la cochlée, une réduction de l'expression membranaire et de l'activité de ce canal en l'absence de Tmprss3 fonctionnelle. Le résultat original de notre travail est qu'une sérine protéase est capable de réguler le canal potassique BK. / TMPRSS3 is a type II serine protease mutated in human DFNB8/10 deafness. In order to determine the role of this protein in the cochlear physiology, we generated a mutant mice and phenotyped it. We found that homozygous mutant mice are profoundly deaf, due to a rapid and drastic degeneration of cochlear sensory cells at the onset of hearing. In order to decipher the molecular mechanism leading to sensory cells degeneration, we compared the cochlear proteome of wild type and homozygous mice using 2-dimensions gels. Then, we analyzed variant spots using mass spectrometry. Using bioinformatics, we clustered the protein in signaling pathways. We focused on the network centered on BK potassium channel because this channel appears at the onset of hearing, the time when sensory cells degenerate. Using immunohistochemistry and patch-clamp techniques, we were able to show that in the absence of a functional Tmprss3, membranous expression and activity of BK channel are altered in cochlear sensory cells. The original finding of our work is that a serine protease is able to modulate BK potassium channel.

Thesis (Ph.D.)--Boston University / PLEASE NOTE: Boston University Libraries did not receive an Authorization To Manage form for this thesis or dissertation. It is therefore not openly accessible, though it may be available by request. If you are the author or principal advisor of this work and would like to request open access for it, please contact us at open-help@bu.edu. Thank you. / Inner hair cells (IHC) are the primary sensory cells of the mammalian cochlea. They transduce sound energy into a changing receptor potential which stimulates electrical activity in the Type I spiral ganglion cells of the auditory nerve. The auditory information thus encoded leads to the sensation of hearing. This thesis comprises my attempts to elucidate some of the biophysical mechanisms operating in the cochlea by analyzing intracellular recordings from guinea pigs, and to investigate the role these mechanisms play in auditory information processing via conceptual and computational models. Noise in the IHC receptor potential sets limits on the performance of a single cell. The magnitude of the intracellular noise averages 0.3 m V rms. A single IHC will be limited by this noise to: (i) a minimum detectable receptor potential of 0.3 mV (corresponding to about 0 dB SPL), (ii) a channel capacity of 5100 bits/sec, and (iii) a temporal resolution of 42 JLS. I compare these single cell limits to auditory performance as observed in published behavioral studies. The IHC receptor potential is shaped by at least two nonlinear processes: nonlinear transduction and a voltage dependent membrane conductance. I characterized the nonlinear conductance by analyzing recordings made during intracellular current injection. A simple model containing a two-state voltage-gated channel was sufficient to replicate the current-voltage characteristic found in these cells. I investigated the information transfer from inner hair cells to the auditory nerve by comparing the growth of the de receptor potential to the average firing rate in spiral ganglion cells. This comparison suggests that neural units with different thresholds encode different portions of the IHC dynamic range; at conditions well above threshold, low threshold units may be carrying predominantly temporal information while high threshold units may encode the absolute sound level. To help understand the complex behavior of the IHC receptor potential, I developed a computational model for its generation. The model contains gated ion channel descriptions of the nonlinear transducer and membrane conductance. Analysis of the model suggests a possible role for the voltage dependent conductance: efficiently trading sensitivity for temporal resolution as stimulus level increases. / 2031-01-01

The mammalian hearing organ, the cochlea, has a marvelous sensitivity and frequency resolution. Due to passive mechanical properties (e.g. mass, stiffness, damping), sound-induced traveling waves are formed on the basilar membrane (BM), which are longitudinally tuned to different frequencies. In a live cochlea, a phenomenon called cochlear amplification, derived from the mechano-electric transduction of the outer hair cells (OHCs), locally enhances the traveling wave and increases the frequency selectivity. My research during the PhD program was focused on studying the in-vivo mechanical and electrophysiological responses of the cochlea in animal models.In the first set of experiments, the intra-cochlear motion and the OHC-generated local cochlear microphonic (LCM) responses were measured in the base of the gerbil cochlea. We used optical coherence tomography (OCT) to measure the intra-cochlear motion and a tungsten micro-electrode to obtain the LCM responses. We explored the effect of the two types of sound stimuli, single and multi-tone stimuli, to the nonlinear behavior of the LCM and the intra-cochlear motion responses in two frequency bands: a frequency band in which cochlear responses show a nonlinear peak (the best frequency (BF) band) and a frequency range below the large peak (sub-BF band: f < ∼ 0.7 × BF). In the sub-BF band, BM motion had linear growth for both stimulus types, and the motion in the OHC region was mildly nonlinear for single tones, and relatively strongly nonlinear for multi-tones. Sub-BF, the nonlinear character of the LCM was similar to that of the OHC- region motion. In the BF band, the LCM and the intra-cochlear motions all possessed the BF peak nonlinearity. Coupling these observations with previous findings on phasing between OHC force and traveling wave motions, we proposed the following framework for cochlear nonlinearity: The BF-band nonlinearity is an amplifying nonlinearity, in which OHC forces input power into the traveling wave, allowing it to travel further apical to the region where it peaks. The sub-BF nonlinearity is a non- amplifying nonlinearity; it represents OHC electromotility, and saturates due to OHC current saturation, but the OHC forces do not possess the proper phasing to feed power into the traveling wave. In the second set of experiments, we repeated the cochlear measurements as in the first project in the base of guinea pig cochlea. The goal was to compare the degree of nonlinearity and amplification in the LCM and intra-cochlear responses between gerbil and guinea pig. The experimental condition and method were similar to the gerbil study. In the BF band, our observations were similar to our previous measurements in gerbil: a nonlinear peak in LCM responses and in intra- cochlear displacements, and higher motion in the OHC region than the BM. Sub-BF, the responses in the two species were different. In both species the BM motion responses in the sub-BF band was linear and LCM was nonlinear. Sub-BF in the OHC-region, nonlinearity was only observed in a subset of healthy guinea pig cochleae while in gerbil, robust nonlinearity was observed in all healthy cochleae. The differences suggest that gerbils and guinea pigs may employ different mech- anisms for to achieve frequency selectivity. However, it cannot be ruled out that the differences are due to technical measurement differences across the species.