Hayden Eastwood

Effects of round window dexamethasone on residual hearing in a Guinea pig model of cochlear implantation.

To study electric acoustic stimulation, we have developed a model of guinea pig cochlear implantation via a cochleostomy. Thirty minutes prior to implantation, a hyaluronic acid/carboxymethylcellulose bead, loaded with either dexamethasone or normal saline, was placed upon the round window membrane. Animals that did not receive beads acted as controls. Pure-tone auditory brainstem response thresholds were estimated before and after electrode insertion, and 1 and 4 weeks later. Selected cochlear histology was performed. Results: Dexamethasone could be detected in the cochlea for 24 h after cochlear implantation. Thresholds were elevated across frequencies in all animals immediately after surgery. These thresholds recovered completely at and below 2 kHz, and partially at higher frequencies by 1 week after implantation. At 32 kHz, but not the lower frequencies, the presence of dexamethasone had a significant protective effect upon hearing, which increased in magnitude over time. The protection was greatest in difficult implantations where an intractable resistance to electrode insertion was met. There was a persistent foreign body reaction at the site of implantation of saline-treated implanted ears but not in the dexamethasone-treated implanted ears. Conclusion: Short-term preoperative delivery of dexamethasone through the round window can protect residual hearing during cochlear implantation, especially during technically difficult surgery.

Cellular redox regulation and prooxidant signaling systems: a new perspective on the free radical theory of aging.

Abstract:  The overarching role of coenzyme Q10 in gene regulation, bioenergy formation, cellular redox poise regulation, and hydrogen peroxide formation is presented. Coenzyme Q10 has a central role acting as a prooxidant in the generation of H2O2. Contrary to the dogma that superoxide and H2O2 formation are highly deleterious to cell survival this premise is rejected. Data are discussed that continuous superoxide and hydrogen peroxide formation are essential for normal cell function and that they play a major role in subcellular redox state modulation. It is the prooxidant activity of the so‐called antioxidants that may be responsible for previously claimed benefits for high doses of oxido‐reduction nutritional supplements such as alpha lipoic acid and coenzyme Q10. Oxygen‐free radical formation is essential for the biological function and is not a direct causation of the mammalian aging process; aging is a multisystem stochastic process.

Factors influencing the efficacy of round window dexamethasone protection of residual hearing post-cochlear implant surgery

AIM To protect hearing in an experimental model of cochlear implantation by the application of dexamethasone to the round window prior to surgery. The present study examined the dosage and timing relationships required to optimise the hearing protection. METHODS Dexamethasone or saline (control) was absorbed into a pledget of the carboxymethylcellulose and hyaluronic acid and applied to the round window of the guinea pig prior to cochlear implantation. The treatment groups were 2% w/v dexamethasone for 30, 60 and 120min; 20% dexamethasone applied for 30min. Auditory sensitivity was determined pre-operatively, and at 1 week after surgery, with pure-tone auditory brainstem response audiometry (2-32kHz). Cochlear implantation was performed via a cochleostomy drilled into the basal turn of the cochlea, into which a miniature cochlear implant dummy electrode was inserted using soft-surgery techniques. RESULTS ABR thresholds were elevated after cochlear implantation, maximally at 32kHz and to a lesser extent at lower frequencies. Thresholds were less elevated after dexamethasone treatment, and the hearing protection improved when 2% dexamethasone was applied to the round window for longer periods of time prior to implantation. The time that dexamethasone need be applied to achieve hearing protection could be reduced by increasing the concentration of steroid, with a 20% application for 30min achieving similar levels of protection to a 60min application of 2% dexamethasone. CONCLUSIONS Hearing protection is improved by increasing the time that dexamethasone is applied to the round window prior to cochlear implantation, and the waiting time can be reduced by increasing the steroid concentration. These results suggest that the diffusion dexamethasone through the cochlea is the prime determinant of the extent of hearing protection.

Cellular redox activity of coenzyme Q10: effect of CoQ10 supplementation on human skeletal muscle.

In this paper, we report results obtained from a continuing clinical trial on the effect of coenzyme Q 10 (CoQ 10 ) administration on human vastus lateralis (quadriceps) skeletal muscle. Muscle samples, obtained from aged individuals receiving placebo or CoQ 10 supplementation (300 mg per day for four weeks prior to hip replacement surgery) were analysed for changes in gene and protein expression and in muscle fibre type composition. Microarray analysis (Affymetrix U95A human oligonucleotide array) using a change in gene expression of 1.8-fold or greater as a cutoff point, demonstrated that a total of 115 genes were differentially expressed in six subject comparisons. In the CoQ 10 -treated subjects, 47 genes were up-regulated and 68 down-regulated in comparison with placebo-treated subjects. Restriction fragment differential display analysis showed that over 600 fragments were differentially expressed using a 2.0-fold or greater change in expression as a cutoff point. Proteome analysis revealed that, of the high abundance muscle proteins detected (2086 - 115), the expression of 174 proteins was induced by CoQ 10 while 77 proteins were repressed by CoQ 10 supplementation. Muscle fibre types were also affected by CoQ 10 treatment; CoQ 10 -treated individuals showed a lower proportion of type I (slow twitch) fibres and a higher proportion of type IIb (fast twitch) fibres, compared to age-matched placebo-treated subjects. The data suggests that CoQ 10 treatment can act to influence the fibre type composition towards the fibre type profile generally found in younger individuals. Our results led us to the conclusion that coenzyme Q 10 is a gene regulator and consequently has wide-ranging effects on over-all tissue metabolism. We develop a comprehensive hypothesis that CoQ 10 plays a major role in the determination of membrane potential of many, if not all, sub-cellular membrane systems and that H 2 O 2 arising from the activities of CoQ 10 acts as a second messenger for the modulation of gene expression and cellular metabolism.

Round window delivery of dexamethasone ameliorates local and remote hearing loss produced by cochlear implantation into the second turn of the guinea pig cochlea

Application of dexamethasone to the round window has been shown to ameliorate high frequency hearing loss resulting from the trauma of cochlear implantation in experimental animals, but elucidation of the factors influencing protection of the high frequencies has been confounded by the local trauma from electrode array insertion. In this experiment, a second turn cochleostomy and implantation was performed on guinea pigs, to examine protection in the basal turn without the confounding effect of local trauma, as well as to test the efficacy of hearing protection in the second cochlear turn. The implantation resulted in an increase in hearing thresholds across all frequencies examined (2-32 kHz). Local delivery of dexamethasone to the round window prior to implantation protected hearing across frequencies from 2 to 32 kHz. Auditory thresholds improved over the first week after surgery, and then remained stable for the month of the experiment. The protection of hearing in the basal turn increased with longer periods of drug application prior to implantation. The level of hearing protection in the second turn was similar irrespective of the time that the drug was applied, but was greater when a higher steroid concentration was used. It was concluded that steroids protect hearing in the basal turn of the cochlea even when there was no local trauma. The level of hearing protection in the second turn exceeded that expected from models of steroid diffusion through the cochlea, suggesting that inner ear surgery alters the distribution of dexamethasone within the cochlea.

Human Aging and Global Function of Coenzyme Q10

In this paper, we review two parts of our recent work on human skeletal muscle. The first part mainly describes changes occurring during aging, whereas the second part discusses the functions of coenzyme Q10 (CoQ10), particularly in relation to the aging process. During the lifetime of an individual, mtDNA undergoes a variety of mutation events and rearrangements. These mutations and their consequent bioenergenic decline, together with nuclear DNA damage, contribute to the reduced function of cells and organs, especially in postmitotic tissues. In skeletal muscle, this functional decline can be observed by means of changes with age in fiber type profile and the reduction in the number and size of the muscle fibers. In addition to the functions of coenzyme Q10 as an electron carrier in the respiratory chain and as an antioxidant, CoQ10 has been shown to regulate global gene expression in skeletal muscle. We hypothesize that this regulation is achieved via superoxide formation with H2O2 as a second messenger to the nucleus.

Pre-Operative Intravenous Dexamethasone Prevents Auditory Threshold Shift in a Guinea Pig Model of Cochlear Implantation

Aim: To protect hearing during cochlear implantation with systemic administration of dexamethasone. Methods: Seventeen normal-hearing guinea pigs were randomly allocated to receive an intravenous injection of either normal saline (control), low- (0.2 mg/kg) or high- (2 mg/kg) dose dexamethasone 60 min prior to cochlear implantation. Auditory brainstem response (ABR) threshold shifts (2–32 kHz) were estimated between pre- and 4-week-postoperative levels. Results: ABR threshold shifts (8–32 kHz) observed in control and low-dose steroid groups were significantly reduced in the high-dose steroid group. Conclusions: A single, high-dose injection of intravenous dexamethasone protected hearing during cochlear implantation.

Targeted Therapy of the Inner Ear

Background: There is experimental evidence that targeted delivery of steroids to the inner ear can protect hearing during cochlear implant surgery. The best protection appears to be achieved through pre-treatment of the cochlea, but the time period required for treatment is long compared with the duration of surgery, and needs further optimization. The stability of hearing thresholds is determined over a 3-month period after hearing preservation cochlear implantation. Methods: Adult guinea pigs were implanted with a miniature cochlear implant electrode, and pure tone auditory brainstem response (ABR) thresholds were estimated in response to pure tones of 2–32 kHz immediately after surgery and at 1 week, 1 month and 3 months. Spiral ganglion cell (SGC) densities were estimated from mid-modular histological sections of the cochlea. Thirty minutes prior to implantation, a polymeric sponge (SeprapackTM, Genzyme) was loaded with either a 2% solution of dexamethasone phosphate or normal saline (control) and placed onto the round window. Results: Implantation was associated with an immediate elevation in thresholds across frequencies, with a full recovery below 2 kHz over the next week and a partial recovery of thresholds at higher frequencies. These thresholds remained unchanged for the next 3 months. There was an immediate and sustained reduction in the elevation of thresholds at 32 kHz in dexamethasone-treated animals. SGC densities were greater in steroid-treated animals than controls in the basal turn of the cochlea (at the region of implantation) 3 months after implantation. Conclusion: It is concluded that ABR thresholds remain stable for 3 months after cochlear implantation in the guinea pig, and that local application of steroids to the inner ear prior to implantation is an effective method of preserving SGC populations when there is residual hearing at the time of implantation.

Permanent and transient effects of locally delivered n-acetyl cysteine in a guinea pig model of cochlear implantation.

Protection of residual hearing after cochlear implant surgery can improve the speech and music perception of cochlear implant recipients, particularly in the presence of background noise. Surgical trauma and chronic inflammation are thought to be responsible for a significant proportion of residual hearing loss after surgery. Local delivery of the anti-oxidant precursor n-acetyl cysteine (NAC) to the cochlea via round window 30min prior to surgery, increased the level of residual hearing at 24-32kHz 4weeks post surgery compared to controls. The hearing protection was found in the basal turn near the site of implantation. Coincidentally, the basal turn was also the location that sustained the greatest hearing loss. As well as protecting residual hearing, NAC-treated animals demonstrated a reduction in the chronic inflammatory changes associated with implantation. While these findings indicate that anti-oxidant therapy can be used to reduce the hearing loss associated with surgical trauma, the local delivery of NAC was associated with a transient increase in hearing thresholds, and osseoneogenesis was seen in a greater number of NAC-treated animals. These side-effects would limit its clinical use through local cochlear administration. However, it is not known yet whether these effects would also be produced by other anti-oxidants, or ameliorated by using a different route of administration.

Methylprednisolone Applied Directly to the Round Window Reduces Dizziness after Cochlear Implantation: A Randomized Clinical Trial

This prospective, double-blind controlled, randomized clinical trial of 43 adults showed that topical methylprednisolone applied to the round window during cochlear implantation was effective in protecting inner ear function. Postoperative vestibular disturbance was significantly lower in the steroid group (5%) than the control group (29%). Electrode impedances from the middle portion of the electrode array (electrodes 10–13) were significantly reduced in steroid-treated recipients compared to controls. Hearing and vestibular function analyses were under-powered to detect any drug changes due to limited participant data.