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Glutathione Ester Protects Against Hydroxynonenal-Induced Loss of Auditory Hair Cells
Otolaryngology– Head and Neck Surgery Volume 133 Number 2
AM
Long-Term Complications of Bone-Anchored Hearing Aids: Fourteen-Year Follow-Up Khaled H. Badran, AFRCSI DO-HNS (presenter); Dan K. Bunstone; Arvind Arya, MD; Ranganathan Suryanarayanan; Robert Temple; Neil Mackinnon Chester United Kingdom; Chester United Kingdom; Chester United Kingdom; Chester United Kingdom; Chester United Kingdom; Chester United Kingdom
Objective: The Merseyside bone-anchored hearing aid (BAHA) program began in 1991, and by 2004, a total of 152 patients had been fitted with such aids. We wish to present our series with respect to complications that have occurred over this time in this developing technique. Methods: Retrospective review of patients operative records and postoperative follow up. Results: 152 patients underwent a total of 162 procedures. Intraoperatively, the only complication was bleeding at the puncture site (n ⫽ 5). Postoperative complications encountered included primary bleeding (n ⫽ 2), severe skin reaction [granulation] (n ⫽ 8), thickening or overgrowth of skin and soft tissue requiring excision (n ⫽ 12), failure to achieve osseointegration requiring fitting a new screw (n ⫽ 28), graft necrosis requiring revision (n ⫽ 1), and recurrent pain from the abutment site (n ⫽ 7). Re-grafting was necessary in 4 patients while bone drilling was required in 2 patients. Sixteen patients (11%) abandoned the BAHA following failure to achieve osseointegration (n ⫽ 4), dissatisfaction with the aid (n ⫽ 6), intolerable pain at the site of abutment (n ⫽ 4), uncontrolled hair growth around the abutment (n ⫽ 1), and recurrent skin infections (n ⫽ 1). In 12 patients the BAHA was surgically removed. The median interval of failure to achieve osseointegration was 8.4 months, and in 46% of the times within 6 months of the operation. In total, 53 patients underwent revision surgery at some stage during their rehabilitation (35%) Conclusion: The surgeon should be aware of potential long-term complications of BAHA before embarking on this relatively new technique. An adequate preoperative evaluation of patients is essential. Significance: Our study shows that despite being relatively simple technique, BAHA patients require long term follow up in order to assess any possible complications which may occur several years after the initial operation. Support: No grants 9:12
AM
Effect of Dexamethasone on Nitric Oxide-Induced Hearing Loss Andrew S Florea, MD (presenter); Jeffrey Smit, MD; Aron Depew, MD; Ryan Gaines; Choong Won Lee, MD; Seong-Kook Park, MD; Ernest John, PhD; Timothy T K Jung, MD PhD Loma Linda CA; Loma Linda CA; Loma Linda CA; Loma Linda CA; Riverside CA; Loma Linda CA; Loma Linda CA; Loma Linda CA
Objective: Intra-tympanic dexamethasone has been shown previously to be efficacious in the treatment of hearing loss caused by many different factors such as otitis media, noise induced and sudden hearing loss. In our previous studies, it was noted that nitric oxide (NO) releasing compound, Snitroso-N-acetylpenicillamine (SNAP) and peroxynitrite releasing compound, 3-morpholinosydnonimine (SIN-1), caused significant hearing loss, when applied to the round window membrane (RWM) in a chinchilla animal model. The purpose of this study was to determine whether dexamethasone can limit the hearing loss caused by exogenous NO (SNAP and SIN-1). Methods: After obtaining initial hearing thresholds using ABR, the SNAP, SIN-1, or dexamethasone-SNAP were placed on the RWM, and baseline ABR hearing thresholds as well as post-application ABR hearing thresholds were obtained at one, two, four and eight hour intervals. Dexamethasone in the dexamethasone-SNAP groups was applied one hour prior to SNAP application on RWM. Results: Three groups were studied: SNAP, SIN-1, and dexamethasone-SNAP. SNAP treated animals (n ⫽ 9) developed a mean hearing loss of 53.9 ⫾5.8 dB at 8 hours postapplication. SIN-1 treated animals (n ⫽ 9) developed a mean hearing loss of 44.6 ⫾ 4.9 dB at 8 hours post-application. Dexamethasone-SNAP treated animals developed a mean hearing loss of 18.3 ⫾1.7dB at 8 hours post-application. The difference between the Dexamethasone-SNAP treated animals and the SNAP and SIN-1 treated animals began to be significant at 4 hours post-application and continued to remain significant through 8 hours post-application. Distortion product otoacoustic emission (DPOAE) measurements suggest the same trends. Conclusion: These findings suggest that dexamethasone can prevent hearing loss induced by exogenous nitric oxide. Significance: Corticosteroids such as dexamethasone can be used to prevent hearing loss caused by free radical compounds, nitric oxide.
9:20
AM
Glutathione Ester Protects Against HydroxynonenalInduced Loss of Auditory Hair Cells Jose W. Ruiz, III, MD (presenter); Jose E Guzman, MD; Marek Polak, PhD; Adrien A Eshraghi, MD, MSc; Thomas J Balkany, MD; Thomas R Van De Water, PhD Miami FL; Miami FL; Miami FL; Miami FL; Miami FL; Miami FL
Objective: Test the ability of glutathione monoethyl ester (GSHe) to protect auditory hair cells against the ototoxic effects of 4-hydroxy-2,3-nonenal (HNE). Methods: Organ of Corti explants were either untreated or treated with one of a series of four concentrations of GSHe for one day, then exposed to HNE. Counts of FITC-phalloidin
TUESDAY
9:04
Research Forum—Tuesday P85
Research Forum—Tuesday
labeled hair cells determined both HNE ototoxicity and GSHe otoprotection. Results: HNE was toxic to hair cells at physiologically relevant levels, e.g. 400 micromoles, and GSHe provided a significant level of protection against HNE ototoxicity (p less than 0.05) at all levels tested, i.e. 1.6 to 9.3 millimoles. Conclusion: GSHe protects auditory hair cells from damage and loss initiated by a naturally occurring ototoxic molecule, i.e. HNE (a byproduct of oxidative stress). Significance: Treatment with GSHe may be an effective therapy to protect the cochlea against the adverse effects of traumas (e.g. electrode insertion) that generate oxidative stress. 9:36
AM
Acoustic Trauma in Monocyte Chemoattractant Protein-1/Chemokine Receptor-2 Knockout Mice Nathan B. Sautter, MD (presenter); Richard Ransohoff, MD; Keiko Hirose, MD Cleveland Heights OH; Cleveland OH; Shaker Heights OH
Objective: Although the effects of acoustic trauma on the inner ear have been well studied, little is known about the inflammatory process that is known to occur in the cochlea following acoustic injury. Cells resembling microglia and macrophages have been observed within the mouse cochlea following acoustic trauma. It is unknown whether this inflammatory process is ultimately harmful or beneficial to cochlear function. We plan to determine the effects of inhibiting this process. Methods: We are studying the effect of impaired monocyte chemotaxis and activation in genetically modified mice following exposure to damaging noise levels. The chemokine receptor/ligand combination of CCR-2 (chemokine receptor-2) and MCP-1 (monocyte chemoattractant protein-1) is the most powerful and validated effector of monocyte chemotaxis into the central and peripheral nervous systems. MCP-1 and CCR-2 knockout mice, aged 8-10 weeks, were exposed to 112 dB SPL for 2 hours in a noise-insulated sound booth. Functional outcomes were quantified using ABR threshold shift analysis at several survival points following the initial injury. Systematic histological and immunohistochemical analysis of the cochlea was performed to assess cellular damage and characterize the inflammatory cell population. Results: No distinct impairment of monocyte migration has been detected at this time with the CCR2 phenotype. This research project is currently ongoing. Conclusion: Further studies need to be completed before we can conclude the role of MCP-1/CCR2 in monocyte migration in the mouse cochlea. Significance: Noise-induced hearing loss is the most common preventable cause of hearing loss in the United States
and is one of the most frequent causes of workplace injury, resulting in extensive social, economic and quality of life issues. Although inflammation is known to occur within the inner ear following exposure to damaging noise levels, little is known about this inflammatory process. Modification of this inflammatory process may result in greater hearing preservation following acoustic injury.
9:44
AM
Morphometric Study of Cochlear Innervation in a Mouse Model of Presbycusis Sofia Stamataki, MD (presenter); Mohamed Lehar, MD; Yu Saito; Alejandro Rivas, MD; David K Ryugo, PhD; Howard W Francis, MD Baltimore MD; Baltimore MD; Baltimore MD; Baltimore MD; Baltimore MD; Baltimore MD
Objective: Presbycusis is one of the most common and disabling manifestations of cochlear disorders. Age related dysfunction, however, is not entirely explained by sensory and neural pathology seen with the light microscope. The encoding properties of auditory nerve fibers mediate the perception of sound and are linked to the ultrastructure of nerve terminals and their synapses with inner hair cells. We have conducted a morphometric study of afferent innervation in the C57BL/6J mouse, an animal model of presbycusis, with the objective of identifying pathologies the afferent nerve ending and IHC interface that might underlie age-related hearing loss. Methods: Cochleae of three 2-3 month old mice with normal ABR threshold and one 8 month old mouse with mild threshold shift were prepared for examination by a transmission electron microscope (TEM). Serial alternate sections of the IHC at the 16 kHz location were collected, aligned and consequently reconstructed in 3-dimensions. We evaluated the number and size of afferent nerve ending and the morphometry of their synapses. Results: There was no apparent difference in mean terminal number, size, mitochondrial content synapses and presynaptic bodies between the older animal and the three younger animals. However there was an increase in number of folded endings in animals older than 2 months that was not related to hearing loss. Conclusion: Mild age-related hearing loss does not appear to be associated with structural changes at the afferent synapse. The appearance of folded morphology may represent an early precursor of age-related hearing loss. Examinations of additional animals with larger thresholds shifts will be used to further test our hypothesis Significance: A detailed description of changes of the ultrastructure of nerve terminals and their synapses with IHC’s enhance our understanding of the pathophysiology of
TUESDAY
P86
Otolaryngology– Head and Neck Surgery August 2005
AM
Long-Term Complications of Bone-Anchored Hearing Aids: Fourteen-Year Follow-Up Khaled H. Badran, AFRCSI DO-HNS (presenter); Dan K. Bunstone; Arvind Arya, MD; Ranganathan Suryanarayanan; Robert Temple; Neil Mackinnon Chester United Kingdom; Chester United Kingdom; Chester United Kingdom; Chester United Kingdom; Chester United Kingdom; Chester United Kingdom
Objective: The Merseyside bone-anchored hearing aid (BAHA) program began in 1991, and by 2004, a total of 152 patients had been fitted with such aids. We wish to present our series with respect to complications that have occurred over this time in this developing technique. Methods: Retrospective review of patients operative records and postoperative follow up. Results: 152 patients underwent a total of 162 procedures. Intraoperatively, the only complication was bleeding at the puncture site (n ⫽ 5). Postoperative complications encountered included primary bleeding (n ⫽ 2), severe skin reaction [granulation] (n ⫽ 8), thickening or overgrowth of skin and soft tissue requiring excision (n ⫽ 12), failure to achieve osseointegration requiring fitting a new screw (n ⫽ 28), graft necrosis requiring revision (n ⫽ 1), and recurrent pain from the abutment site (n ⫽ 7). Re-grafting was necessary in 4 patients while bone drilling was required in 2 patients. Sixteen patients (11%) abandoned the BAHA following failure to achieve osseointegration (n ⫽ 4), dissatisfaction with the aid (n ⫽ 6), intolerable pain at the site of abutment (n ⫽ 4), uncontrolled hair growth around the abutment (n ⫽ 1), and recurrent skin infections (n ⫽ 1). In 12 patients the BAHA was surgically removed. The median interval of failure to achieve osseointegration was 8.4 months, and in 46% of the times within 6 months of the operation. In total, 53 patients underwent revision surgery at some stage during their rehabilitation (35%) Conclusion: The surgeon should be aware of potential long-term complications of BAHA before embarking on this relatively new technique. An adequate preoperative evaluation of patients is essential. Significance: Our study shows that despite being relatively simple technique, BAHA patients require long term follow up in order to assess any possible complications which may occur several years after the initial operation. Support: No grants 9:12
AM
Effect of Dexamethasone on Nitric Oxide-Induced Hearing Loss Andrew S Florea, MD (presenter); Jeffrey Smit, MD; Aron Depew, MD; Ryan Gaines; Choong Won Lee, MD; Seong-Kook Park, MD; Ernest John, PhD; Timothy T K Jung, MD PhD Loma Linda CA; Loma Linda CA; Loma Linda CA; Loma Linda CA; Riverside CA; Loma Linda CA; Loma Linda CA; Loma Linda CA
Objective: Intra-tympanic dexamethasone has been shown previously to be efficacious in the treatment of hearing loss caused by many different factors such as otitis media, noise induced and sudden hearing loss. In our previous studies, it was noted that nitric oxide (NO) releasing compound, Snitroso-N-acetylpenicillamine (SNAP) and peroxynitrite releasing compound, 3-morpholinosydnonimine (SIN-1), caused significant hearing loss, when applied to the round window membrane (RWM) in a chinchilla animal model. The purpose of this study was to determine whether dexamethasone can limit the hearing loss caused by exogenous NO (SNAP and SIN-1). Methods: After obtaining initial hearing thresholds using ABR, the SNAP, SIN-1, or dexamethasone-SNAP were placed on the RWM, and baseline ABR hearing thresholds as well as post-application ABR hearing thresholds were obtained at one, two, four and eight hour intervals. Dexamethasone in the dexamethasone-SNAP groups was applied one hour prior to SNAP application on RWM. Results: Three groups were studied: SNAP, SIN-1, and dexamethasone-SNAP. SNAP treated animals (n ⫽ 9) developed a mean hearing loss of 53.9 ⫾5.8 dB at 8 hours postapplication. SIN-1 treated animals (n ⫽ 9) developed a mean hearing loss of 44.6 ⫾ 4.9 dB at 8 hours post-application. Dexamethasone-SNAP treated animals developed a mean hearing loss of 18.3 ⫾1.7dB at 8 hours post-application. The difference between the Dexamethasone-SNAP treated animals and the SNAP and SIN-1 treated animals began to be significant at 4 hours post-application and continued to remain significant through 8 hours post-application. Distortion product otoacoustic emission (DPOAE) measurements suggest the same trends. Conclusion: These findings suggest that dexamethasone can prevent hearing loss induced by exogenous nitric oxide. Significance: Corticosteroids such as dexamethasone can be used to prevent hearing loss caused by free radical compounds, nitric oxide.
9:20
AM
Glutathione Ester Protects Against HydroxynonenalInduced Loss of Auditory Hair Cells Jose W. Ruiz, III, MD (presenter); Jose E Guzman, MD; Marek Polak, PhD; Adrien A Eshraghi, MD, MSc; Thomas J Balkany, MD; Thomas R Van De Water, PhD Miami FL; Miami FL; Miami FL; Miami FL; Miami FL; Miami FL
Objective: Test the ability of glutathione monoethyl ester (GSHe) to protect auditory hair cells against the ototoxic effects of 4-hydroxy-2,3-nonenal (HNE). Methods: Organ of Corti explants were either untreated or treated with one of a series of four concentrations of GSHe for one day, then exposed to HNE. Counts of FITC-phalloidin
TUESDAY
9:04
Research Forum—Tuesday P85
Research Forum—Tuesday
labeled hair cells determined both HNE ototoxicity and GSHe otoprotection. Results: HNE was toxic to hair cells at physiologically relevant levels, e.g. 400 micromoles, and GSHe provided a significant level of protection against HNE ototoxicity (p less than 0.05) at all levels tested, i.e. 1.6 to 9.3 millimoles. Conclusion: GSHe protects auditory hair cells from damage and loss initiated by a naturally occurring ototoxic molecule, i.e. HNE (a byproduct of oxidative stress). Significance: Treatment with GSHe may be an effective therapy to protect the cochlea against the adverse effects of traumas (e.g. electrode insertion) that generate oxidative stress. 9:36
AM
Acoustic Trauma in Monocyte Chemoattractant Protein-1/Chemokine Receptor-2 Knockout Mice Nathan B. Sautter, MD (presenter); Richard Ransohoff, MD; Keiko Hirose, MD Cleveland Heights OH; Cleveland OH; Shaker Heights OH
Objective: Although the effects of acoustic trauma on the inner ear have been well studied, little is known about the inflammatory process that is known to occur in the cochlea following acoustic injury. Cells resembling microglia and macrophages have been observed within the mouse cochlea following acoustic trauma. It is unknown whether this inflammatory process is ultimately harmful or beneficial to cochlear function. We plan to determine the effects of inhibiting this process. Methods: We are studying the effect of impaired monocyte chemotaxis and activation in genetically modified mice following exposure to damaging noise levels. The chemokine receptor/ligand combination of CCR-2 (chemokine receptor-2) and MCP-1 (monocyte chemoattractant protein-1) is the most powerful and validated effector of monocyte chemotaxis into the central and peripheral nervous systems. MCP-1 and CCR-2 knockout mice, aged 8-10 weeks, were exposed to 112 dB SPL for 2 hours in a noise-insulated sound booth. Functional outcomes were quantified using ABR threshold shift analysis at several survival points following the initial injury. Systematic histological and immunohistochemical analysis of the cochlea was performed to assess cellular damage and characterize the inflammatory cell population. Results: No distinct impairment of monocyte migration has been detected at this time with the CCR2 phenotype. This research project is currently ongoing. Conclusion: Further studies need to be completed before we can conclude the role of MCP-1/CCR2 in monocyte migration in the mouse cochlea. Significance: Noise-induced hearing loss is the most common preventable cause of hearing loss in the United States
and is one of the most frequent causes of workplace injury, resulting in extensive social, economic and quality of life issues. Although inflammation is known to occur within the inner ear following exposure to damaging noise levels, little is known about this inflammatory process. Modification of this inflammatory process may result in greater hearing preservation following acoustic injury.
9:44
AM
Morphometric Study of Cochlear Innervation in a Mouse Model of Presbycusis Sofia Stamataki, MD (presenter); Mohamed Lehar, MD; Yu Saito; Alejandro Rivas, MD; David K Ryugo, PhD; Howard W Francis, MD Baltimore MD; Baltimore MD; Baltimore MD; Baltimore MD; Baltimore MD; Baltimore MD
Objective: Presbycusis is one of the most common and disabling manifestations of cochlear disorders. Age related dysfunction, however, is not entirely explained by sensory and neural pathology seen with the light microscope. The encoding properties of auditory nerve fibers mediate the perception of sound and are linked to the ultrastructure of nerve terminals and their synapses with inner hair cells. We have conducted a morphometric study of afferent innervation in the C57BL/6J mouse, an animal model of presbycusis, with the objective of identifying pathologies the afferent nerve ending and IHC interface that might underlie age-related hearing loss. Methods: Cochleae of three 2-3 month old mice with normal ABR threshold and one 8 month old mouse with mild threshold shift were prepared for examination by a transmission electron microscope (TEM). Serial alternate sections of the IHC at the 16 kHz location were collected, aligned and consequently reconstructed in 3-dimensions. We evaluated the number and size of afferent nerve ending and the morphometry of their synapses. Results: There was no apparent difference in mean terminal number, size, mitochondrial content synapses and presynaptic bodies between the older animal and the three younger animals. However there was an increase in number of folded endings in animals older than 2 months that was not related to hearing loss. Conclusion: Mild age-related hearing loss does not appear to be associated with structural changes at the afferent synapse. The appearance of folded morphology may represent an early precursor of age-related hearing loss. Examinations of additional animals with larger thresholds shifts will be used to further test our hypothesis Significance: A detailed description of changes of the ultrastructure of nerve terminals and their synapses with IHC’s enhance our understanding of the pathophysiology of
TUESDAY
P86
Otolaryngology– Head and Neck Surgery August 2005