Tina C. Huang

Oxidative stress-induced apoptosis of cochlear sensory cells: Otoprotective strategies

Apoptosis is an important process, both for normal development of the inner ear and for removal of oxidative‐stress damaged sensory cells from the cochlea. Oxidative‐stressors of auditory sensory cells include: loss of trophic factor support, ischemia‐reperfusion, and ototoxins. Loss of trophic factor support and cisplatin ototoxicity, both initiate the intracellular production of reactive oxygen species and free radicals. The interaction of reactive oxygen species and free radicals with membrane phospholipids of auditory sensory cells creates aldehydic lipid peroxidation products. One of these aldehydes, 4‐hydroxynonenal, functions as a mediator of apoptosis for both auditory neurons and hair cells. We present several approaches for the prevention of auditory sensory loss from reactive oxygen species‐induced apoptosis: 1) preventing the formation of reactive oxygen species; (2) neutralizing the toxic products of membrane lipid peroxidation; and 3) blocking the damaged sensory cells’ apoptotic pathway.

The role of inflammatory mediators in the pathogenesis of otitis media and sequelae.

This review deals with the characteristics of various inflammatory mediators identified in the middle ear during otitis media and in cholesteatoma. The role of each inflammatory mediator in the pathogenesis of otitis media and cholesteatoma has been discussed. Further, the relation of each inflammatory mediator to the pathophysiology of the middle and inner ear along with its mechanisms of pathological change has been described. The mechanisms of hearing loss including sensorineural hearing loss (SNHL) as a sequela of otitis media are also discussed. The passage of inflammatory mediators through the round window membrane into the scala tympani is indicated. In an experimental animal model, an application of cytokines and lipopolysaccharide (LPS), a bacterial toxin, on the round window membrane induced sensorineural hearing loss as identified through auditory brainstem response threshold shifts. An increase in permeability of the blood-labyrinth barrier (BLB) was observed following application of these inflammatory mediators and LPS. The leakage of the blood components into the lateral wall of the cochlea through an increase in BLB permeability appears to be related to the sensorineural hearing loss by hindering K+ recycling through the lateral wall disrupting the ion homeostasis of the endolymph. Further studies on the roles of various inflammatory mediators and bacterial toxins in inducing the sensorineumral hearing loss in otitis media should be pursued.

Calpain inhibitors protect auditory sensory cells from hypoxia and neurotrophin-withdrawal induced apoptosis

Inhibitors of calpain have been shown to protect nerve growth factor (NGF)-deprived ciliary ganglion neurons and hypoxic cortical neurons. Calpains have been identified in the cochlea and are active during ischemic injury. Since apoptosis can be initiated by loss of neurotrophic support, hypoxia, and ototoxins (e.g., cisplatin, CDDP), the role of calpain inhibitors under these conditions was examined in auditory hair cells and neurons. Dissociated spiral ganglion neuron (SGN) cell cultures and organ of Corti explants from P3 rats were used to test the efficacy of calpain inhibitors as otoprotective molecules. Our results indicate that calpain inhibitor I, calpain inhibitor II, and leupeptin all provided significant protection of SGNs against neurotrophin-withdrawal and hypoxia-induced apoptosis. The increase in neuronal survival ranged from 2.16 to 2.31 times greater than in untreated neurotrophin-withdrawn SGN cell cultures. BOC-Asp(Ome)-Fluoromethyl Ketone (B-D-FMK), a general caspase inhibitor, increased neuronal survival 2.16 times more. Neuronal survival rates were from 1.88 to 2.27 times greater than in untreated, hypoxic neurons and hair cell survival rates were from 1.98 to 2.03 times greater than untreated, hypoxic organ of Corti explants. However, protection of auditory hair cells and neurons from CDDP-induced damage (10 and 6 micrograms/ml, respectively) was limited with any of these calpain inhibitors. Apoptotic pathways initiated by neurotrophin-deprivation and ototoxic stress (e.g., CDDP) have been shown to be different. Our results agree with this finding, with neurotrophin-withdrawal and hypoxia, but not CDDP damage-induced apoptosis being calpain-dependent.

A combination antioxidant therapy prevents age-related hearing loss in C57BL/6 mice

OBJECTIVE: Age-related hearing loss (ARHL) is characterized by gradual, progressive sensorineural hearing loss, which impairs communication, lending to clinical depression and social withdrawal. There are currently no effective treatments for ARHL. The purpose of this study is to evaluate the potential of a combination antioxidant therapy in preventing ARHL. STUDY DESIGN: Randomized controlled trial. SETTING: Animal study. SUBJECTS AND METHODS: C57BL/6 mice, a recognized animal model of ARHL, were assigned to one of three groups: early treatment (n = 12), late treatment (n = 9), or control group (n = 9). Treatment groups of mice were fed with a combination agent comprising six antioxidant agents that target four sites within the oxidative pathway: L-cysteine-glutathione mixed disulfide, ribose- cysteine, NW-nitro-L-arginine methyl ester, vitamin B12, folate, and ascorbic acid. Auditory brainstem response (ABR) thresholds were recorded at baseline and every three months following initiation of treatment. RESULTS: Threshold shifts from baseline were decreased in the treatment groups when compared to the control group at all tested frequencies (P < 0.001). The ABR threshold shift at 12 months of age for the control group was 34.7 dB with a 95% confidence interval (CI) of ± 1.6. The mean threshold shifts for the early and late treatment groups were 7.5 dB (±0.87, 95% CI) and 9.2 dB (±1.6, 95% CI). CONCLUSION: Combination antioxidant therapy effectively decreased threshold shifts on ABR within an animal model of ARHL. Combination antioxidant therapy, with further research and investigation, may provide a safe and cost-effective method of preventing presbycusis in the growing elderly population.

Total tympanic membrane reconstruction: AlloDerm versus temporalis fascia.

BACKGROUND AND OBJECTIVE: Patients who require surgery for chronic otitis media with perforation and cholesteatoma frequently provide no residual tympanic membrane that is usable in grafting procedures. A novel technique of total tympanic membrane reconstruction (TTMR) is described that maximizes perforation closure rate in these situations while minimizing mucosalization, incomplete healing, and anterior blunting. The specific aim of this report is to assess the safety and efficacy of TTMR and to compare the results obtained with AlloDerm compared with temporalis fascia as a grafting material. METHODS : The records of 50 patients operated within the years 1999 and the 2004 were reviewed. TTMR with intact canal wall was performed in all cases. Both clinical and audiometric data were analyzed. RESULTS : Overall perforation closure rate was 92%. There was no statistical significance in closure rate when grafting with AlloDerm versus temporalis fascia. A statistically significant shortened healing time was observed with AlloDerm grafting. CONCLUSIONS : TTMR is a highly effective and safe technique.

Remote intraoperative monitoring during cochlear implant surgery is feasible and efficient.

Objectives: Intraoperative testing of cochlear implant devices, establishment of electrical threshold for acoustic reflex, and recording neural responses to electrical stimulation have traditionally required the presence of a cochlear implant audiologist in the operating room. The goal of this study was to determine the feasibility of remote testing to improve time efficiency and reduce cost. Study Design: Prospective. Methods: A standard PC with Tridia VNC software and either Cochlear Corporation or Advanced Bionics Corporation mapping software was configured to perform remote testing. The time required to perform on-site or remote testing was measured. Results: With the availability of the laptop and internet access, there were no geographic restrictions regarding the site of remote testing. Remote testing was time efficient, requiring 9 minutes of audiologists time compared with 93 minutes when the audiologist had to travel to the operating room. Conclusion: Remote testing of the cochlear implant device and patients response to electrical stimulation is technically feasible. It is timesaving, practical, and cost efficient.

Modiolar coiling, electrical thresholds, and speech perception after cochlear implantation using the nucleus contour advance electrode with the advance off stylet technique.

Objective: Perimodiolar electrode arrays were developed in an attempt to improve stimulation of specific neural populations and to decrease electrical thresholds, thereby decreasing power consumption. Postoperative radiographs show that coiling of the arrays is variable. Our previous study explored the relationship between the angle of coiling, threshold levels, and functional outcomes using the Nucleus Contour electrode array. This study compares coiling angle, electrical threshold levels, and speech perception measures with the Nucleus Contour Advance electrode array implanted using the new advance off stylet technique versus the Nucleus Contour electrode array implanted using the standard technique. Study Design: Retrospective review. Setting: University medical center. Patients: Forty-two adults and children with normal cochlear anatomy implanted with the Nucleus CI24RCA electrode using the advance off stylet technique with at least 1-year follow-up. Intervention: Therapeutic. Main Outcome Measures: Computer-aided radiographic analysis of perimodiolar electrode placement, electrical threshold measurements, and speech perception outcome measures at 1 year postimplantation. Results: The degree of modiolar coiling was tighter using the new electrode and technique in comparison with standard insertion technique using the Nucleus Contour electrode array. The tighter coiling tended to result in higher electrical thresholds. Lower speech perception outcome measures tended to correlate with a higher degree of coiling. Conclusion: The Nucleus Contour Advance electrode array combined with the advance off stylet technique resulted in a more consistent perimodiolar position. However, the tighter coiling resulted in statistically significant increased electrical thresholds and decreased speech perception outcomes. This finding may be secondary to multiple factors, not just coiling angle.

Evaluation of the short hybrid electrode in human temporal bones.

Hypothesis: The current hybrid electrode can be inserted without trauma to the temporal bone and, after insertion, assumes a position within the scala tympani near the outer cochlear wall just beneath the basilar membrane. Background: Conservation of residual hearing after cochlear implant electrode insertion requires a special insertion technique and an atraumatic short electrode. This allows electroacoustic stimulation in ears with significant residual hearing. Methods: Human cadaveric temporal bones were implanted with soft surgical technique under fluoroscopic observation. Dehydrated and resin-impregnated bones are dissected. Real-time electrode insertion behavior and electrode position were evaluated. The bones are examined for evidence of insertion-related trauma. Results: No gross trauma was observed in the implanted bones, and the electrode dynamics evaluation revealed smooth scala tympani insertions. Conclusion: Atraumatic insertion of the 10-mm hybrid electrode can be accomplished using an appropriate cochleostomy and insertion technique.

Cochlear Stem Cells/Progenitors and Degenerative Hearing Disorders

Hearing loss (deafness) affects approximately 250 million people globally. The major cause of deafness is loss of hair cells and spiral ganglion neurons due to aging, antibiotic use, noise exposure, and genetic defects. At the present time, there is no effective method for restoration of hearing biologically. Cochlear stem cells/progenitors (CSCs), quiescent in the organ of Corti, are excellent candidates for restoration of cell types in the organ of Corti biologically. However, little is known about the biology of CSCs and developmental cues for CSCs to differentiate into hair cells and neurons at the present time. In this article, we briefly reviewed the isolation of CSCs from the postnatal organ of Corti in mice and their capability to differentiate into hair cells and neurons in vitro under the guidance of a group of growth factors: sonic hedgehog (SHH), epidermal growth factor (EGF), retinoic acid (RA), and brain-derived neurotrophic factor (BDNF), herein termed SERB. The identification of CSCs and their differentiation signals is potentially of clinical importance.

Sudden hearing loss as the presenting symptom of systemic sclerosis.

Objectives: Sudden sensorineural hearing loss (SSHNL) is an emergency in otolaryngology. In most cases, the exact cause cannot be identified, but different immunologic disorders and microvascular events have been suggested to play a role in its pathogenesis. Sudden sensorineural hearing loss can be caused by collagen vascular disorders, but it has rarely been reported as the presenting symptom of these diseases. This case presented with bilateral hearing loss and was finally diagnosed as a systemic sclerosis (SSc) patient. This is the first case of SSc that presented with SSNHL as an initial symptom. Patient: A 65-year-old man presented with bilateral hearing loss. He also complained of generalized fatigue and intermittent paresthesia. Brain imaging and blood tests were negative except for antinuclear antibodies. Administration of high-dose prednisone did not make any improvement. After extensive workup, follow-up, and referral to rheumatologist, the diagnosis of SSc was made. The patients hearing improved after receiving intravenous immunoglobulin along with other symptoms of the disease. Conclusion: This case illustrates the importance of follow-up and appropriate of SSNHL patients with other systemic symptoms.