Elevated Auditory Brainstem Response Thresholds Research Articles

Tissue‐specific calibration of extracellular matrix material properties by transforming growth factor‐β and Runx2 in bone is required for hearing

Physical cues, such as extracellular matrix stiffness, direct cell differentiation and support tissue-specific function. Perturbation of these cues underlies diverse pathologies, including osteoarthritis, cardiovascular disease and cancer. However, the molecular mechanisms that establish tissue-specific material properties and link them to healthy tissue function are unknown. We show that Runx2, a key lineage-specific transcription factor, regulates the material properties of bone matrix through the same transforming growth factor-β (TGFβ)-responsive pathway that controls osteoblast differentiation. Deregulated TGFβ or Runx2 function compromises the distinctly hard cochlear bone matrix and causes hearing loss, as seen in human cleidocranial dysplasia. In Runx2+/⁻ mice, inhibition of TGFβ signalling rescues both the material properties of the defective matrix, and hearing. This study elucidates the unknown cause of hearing loss in cleidocranial dysplasia, and demonstrates that a molecular pathway controlling cell differentiation also defines material properties of extracellular matrix. Furthermore, our results suggest that the careful regulation of these properties is essential for healthy tissue function.

Unmyelinated auditory type I spiral ganglion neurons in congenic Ly5.1 mice

With the exception of humans, the somata of type I spiral ganglion neurons (SGNs) of most mammalian species are heavily myelinated. In an earlier study, we used Ly5.1 congenic mice as transplant recipients to investigate the role of hematopoietic stem cells in the adult mouse inner ear. An unanticipated finding was that a large percentage of the SGNs in this strain were unmyelinated. Further characterization of the auditory phenotype of young adult Ly5.1 mice in the present study revealed several unusual characteristics, including 1) large aggregates of unmyelinated SGNs in the apical and middle turns, 2) symmetrical junction-like contacts between the unmyelinated neurons, 3) abnormal expression patterns for CNPase and connexin 29 in the SGN clusters, 4) reduced SGN density in the basal cochlea without a corresponding loss of sensory hair cells, 5) significantly delayed auditory brainstem response (ABR) wave I latencies at low and middle frequencies compared with control mice with similar ABR threshold, and 6) elevated ABR thresholds and deceased wave I amplitudes at high frequencies. Taken together, these data suggest a defect in Schwann cells that leads to incomplete myelinization of SGNs during cochlear development. The Ly5.1 mouse strain appears to be the only rodent model so far identified with a high degree of the "human-like" feature of unmyelinated SGNs that aggregate into neural clusters. Thus, this strain may provide a suitable animal platform for modeling human auditory information processing such as synchronous neural activity and other auditory response properties.

Protective effects of Salvia miltiorrhiza against cisplatin-induced ototoxicity in guinea pigs

Objective The aim of the study was to investigate the protective effects of Salvia miltiorrhiza (SM) against cisplatin-induced ototoxicity in guinea pigs. Methods Thirty-nine guinea pigs were randomly divided into 3 groups. The first group (control group) received physiologic saline by intraperitoneal (i.p.) injection for 5 days. The second group (cisplatin group) was treated with cisplatin (2 mg/kg per day, i.p. injection) for 5 days. The third group (SM group) was given SM (8 g/kg per day, i.p. injection) for 2 days and then was given SM (8 g/kg per day, i.p. injection) and cisplatin (2 mg/kg per day, i.p. injection) for 5 days. Auditory brain stem response (ABR) and cochlea blood flow measurement were used to evaluate cochlea function. The structures of cochlea were observed by light microscope, scanning electron microscope, transmission electron microscope (TEM), and immunohistochemical examination. Results Cisplatin could cause severe acoustic damages including significant elevation of ABR threshold, substantial losses of outer hair cells and inner hair cells, and severe damage on the stria vascularis and spiral ganglion cells (SGCs). Although in SM group, the increased tendency of threshold was milder than that in cisplatin group. The damages in cochlea and stria vascularis were also less severe than those in cisplatin group. The expression of induced nitric oxide synthase in the cochlea and SGC in SM group was lower than that in cisplatin group. Conclusions Salvia miltiorrhiza can significantly reduce the cisplatin-induced side effects.

Risk factors for elevation of ABR threshold in NICU-treated infants

Objective Several risk factors for hearing impairment among infants treated in the neonatal intensive care unit (NICU) have been reported, but there have been few studies that show the correlation strength between the risk factors in NICU-treated infants and hearing impairment in childhood. The aim of this study was to clarify the relationship between risk factors in NICU-treated infants and a deteriolation of auditory brainstem response (ABR) threshold in their childhood. Methods One hundred one NICU-treated infants with ABR threshold of 50 dBnHL or more underwent 2nd ABR test at 20 months after delivery. Multiple regression analysis was performed with ABR threshold change as an objective variable and risk factors as explanatory variables. Results Two ABR tests of the 101 infants resulted in that 7 showed an elevation of ABR threshold by 20 dB, 70 showed a drop of ABR threshold by 20 dB, and 24 showed no significant change. Multiple regression analysis revealed that the factors contributing to the elevation of ABR threshold were congenital diaphragmatic hernia, severe respiratory disease, and a high C-reactive protein (CRP) level. Conclusions In the infants treated in NICU, an incidence of ABR threshold of 50 dBnHL or more was 9.0%, and 6.9% of the infants with the ABR threshold abnormality showed a significant elevation of ABR threshold in their childhood. Factors significantly related to an elevation of ABR threshold were a history of congenital diaphragmatic hernia, severe respiratory disease, and elevation of CRP. In infants with such factors, periodical examination of hearing is required.

Postnatal impairments of auditory acuity and neural transmission times induced by maternal iron deficiency

Iron deficiency (ID) is believed to affect central nervous system (CNS) on several aspects such as myelinogenesis, neurotransmitter synthesis and brain fatty acid metabolism. While most findings in humans investigated ID during post natal periods, our study aimed to evaluate consequences of moderate maternal ID on CNS development in guinea pig offspring. We used auditory brainstem response (ABR) to assess neurophysiologic auditory function and neural transmission times (NTT). Females were fed an iron sufficient (IS) or deficient (ID) diet during the gestation and lactation periods. ID appeared in the third trimester of pregnancy for the ID group. On post natal day 9 (PND9), an IS diet was introduced to wean offspring from both groups. ABR was measured on PND24 using descending intensities and various frequencies (2 to 32 kHz). ID pups had significantly elevated ABR thresholds (hearing loss) at 2, 16 and 32 kHz. NTT seemed to demonstrate shorter inter peak latencies for offspring born to ID dams. A delay in the appearance of the first neural nucleus is likely to be the explanation, whereas later relays did not differ among the two groups. Our study demonstrates that a moderate maternal ID adversely impairs the auditory functions of pups born to ID females. These results suggest that maternal ID may alter the CNS myelinogenesis in the progeny. Support: Canadian Institutes of Health Research and the Canada Research Chairs.

Geranylgeranylacetone ameliorates acute cochlear damage caused by 3-nitropropionic acid

3-Nitropropionic acid (3-NP) induces hearing loss by impairing mitochondrial energy generation. Geranylgeranylacetone (GGA) is known to protect the cochlea from various injuries. The present study was designed to investigate the protective effect of GGA against acute 3-NP-induced damage to the cochlear mitochondria. Female Hartley guinea pigs were divided into 4 groups. The 3-NP vehicle was injected to control animals and in animals receiving GGA alone, only GGA was administered for 7 days. 3-NP (500 mM, 4 μl) was administered with (animals receiving both GGA and 3-NP) or without (animals receiving 3-NP alone) GGA pretreatment (800 mg/kg, 7 days). The auditory brainstem response (ABR) was recorded at click and at 8, 16 and 32 kHz before and after injection, respectively. After cochlear harvest, hematoxylin/eosin staining and immunohistochemistry for anti-HSP70 antibody were done. 3-NP exposure resulted in elevated ABR thresholds that exceeded the maximum recording limit, while GGA pretreatment before 3-NP exposure led to a significant decrease in hearing threshold shift. Histological analysis of above former group revealed loss of type II fibrocytes in the spiral ligament, hair cells in the organ of Corti, stellate fibrocytes in the spiral limbus and spiral ganglion cells, while in above latter group, these cells were preserved. Control animals revealed weak HSP70 expression in the nuclei of some supporting cells (pillar cells, Deiters’ cells and Hensen's cells) and interdental cells. Animals receiving GGA alone showed strong HSP70 expression in the same area as in control animals, while animals receiving both GGA and 3-NP demonstrated slightly decreased HSP70 expression in that area. These results suggest that GGA may protect the cochlea against acute injury resulting from mitochondrial dysfunction.

Developmental Exposure to PCBs, MeHg, or Both: Long-Term Effects on Auditory Function

BackgroundDevelopmental exposure to polychlorinated biphenyls (PCBs) or methylmercury (MeHg) can result in a variety of neurotoxic effects, including long-term auditory deficits. However, little is known about the effects of combined exposure to PCBs and MeHg on auditory function.ObjectiveWe developmentally exposed rats to PCBs and/or MeHg and assessed auditory function in adulthood to determine the effects of exposure to these contaminants individually and in combination.MethodsWe exposed female Long-Evans rats to 1 or 3 mg/kg PCB in corn oil, 1.5 or 4.5 ppm MeHg in drinking water, or combined exposure to 1 mg/kg PCB + 1.5 ppm MeHg or 3 mg/kg PCB + 4.5 ppm MeHg. Controls received corn oil vehicle and unadulterated water. Dosing began 28 days before breeding and continued until weaning at postnatal day (PND) 21. Auditory function of the offspring was assessed at approximately PND 200 by measuring distortion product otoacoustic emissions (DPOAEs) and auditory brainstem responses (ABRs).ResultsGroups exposed to PCBs alone had attenuated DPOAE amplitudes, elevated DPOAE thresholds, and elevated ABR thresholds compared with controls. Groups exposed to MeHg alone did not differ from controls. Unexpectedly, the effects of PCB exposure appeared to be attenuated by coexposure to MeHg.ConclusionDevelopmental exposure to PCBs can result in permanent hearing deficits, and the changes in DPOAE amplitudes and thresholds suggest a cochlear site of action. Coexposure to MeHg appeared to attenuate the PCB-related deficits, but the mechanism for this unexpected interaction remains to be determined.

A Mouse Model for Degeneration of the Spiral Ligament

Previous studies have indicated the importance of the spiral ligament (SL) in the pathogenesis of sensorineural hearing loss. The aim of this study was to establish a mouse model for SL degeneration as the basis for the development of new strategies for SL regeneration. We injected 3-nitropropionic acid (3-NP), an inhibitor of succinate dehydrogenase, at various concentrations into the posterior semicircular canal of adult C57BL/6 mice. Saline-injected animals were used as controls. Auditory function was monitored by measurements of auditory brain stem responses (ABRs). On postoperative day 14, cochlear specimens were obtained after the measurement of the endocochlear potential (EP). Animals that were injected with 5 or 10 mM 3-NP showed a massive elevation of ABR thresholds along with extensive degeneration of the cochleae. Cochleae injected with 1 mM 3-NP exhibited selective degeneration of the SL fibrocytes but alterations in EP levels and ABR thresholds were not of sufficient magnitude to allow for testing functional recovery after therapeutic interventions. Animals injected with 3 mM 3-NP showed a reduction of around 50% in the EP along with a significant loss of SL fibrocytes, although degeneration of spiral ganglion neurons and hair cells was still present in certain regions. These findings indicate that cochleae injected with 3 mM 3-NP may be useful in investigations designed to test the feasibility of new therapeutic manipulations for functional SL regeneration.

Evaluating the ototoxicity of topical piperacillin–tazobactam

With the increased use of ototopical ciprofloxacin solution, newly evolved bacterial fluoroquinolone resistance has also become more of a problem. The emergence of ciprofloxacin-resistant Pseudomonas aeruginosa (CRPA) has created a new therapeutic challenge in otology. We evaluated the ototoxicity of topical fortified piperacillin-tazobactam solution by performing experiments in young male albino guinea pigs (weight, 250-300 g each). Antimicrobial assay by direct contact test using scanning electron microscope was performed. Twenty guinea pigs (250-300 g) were treated with fortified piperacillin-tazobactam solution. In experimental group 1 (n=10), a gelfoam ball impregnated with 120 microl of fortified piperacillin-tazobactam was implanted on the round window membrane by a posterior approach. In experimental group 2 (n=10), 20 microl of fortified piperacillin-tazobactam was injected into the middle ear cavity via silicone tube with a small hole placed in the superior aspect of the bulla by drilling. The drug application through the tube was performed for 7 consecutive days. In control group (n=5), a gelfoam ball impregnated with 120 microl of gentamicin solution (80 mg/2 ml) was implanted on the round window membrane. The fortified piperacillin-tazobactam 20 microl treated CRPAs showed destruction of their cell membrane in antimicrobial assay by direct contact test. No significant difference in the mean auditory brainstem response (ABR) thresholds before and after drug administration was found for the experimental group. However, significant elevation of the mean ABR thresholds was found for the control group. In experimental group, scanning electron microscopy showed almost normal sterociliary arrangements and surface structure on the inner and outer hair cells. However, significant destruction of outer hair cells was identified in control group. This present study's data suggests that fortified piperacillin-tazobactam solution can be effectively used for topically treating CRPA otorrhea in those patients who suffer with chronic suppurative otitis media.

Abnormal neurological responses in young adult offspring caused by excess omega-3 fatty acid (fish oil) consumption by the mother during pregnancy and lactation

Consuming omega-3 fatty acids (ω-3 FA) during pregnancy and lactation benefits fetal and infant brain development and might reduce the severity of preterm births by prolonging pregnancy. However, diets that are relatively rich in ω-3 FA can adversely affect fetal and infant development and the auditory brainstem response (ABR), a measure of brain development and sensory function. We previously examined the offspring of female rats fed excessive, adequate or deficient amounts of ω-3 FA during pregnancy and lactation. The 24-day-old offspring in the Excess group, compared to the Control group, had postnatal growth retardation and poor hearing acuity and prolonged neural transmission times as evidenced by the ABR. The Deficient group was intermediate. The current study followed these offspring to see if these poor outcomes persisted into young adulthood. Based on prior findings, we hypothesized that the Excess and Deficient offspring would “catch-up” to the Control offspring by young adulthood. Female Wistar rats received one of the three diet conditions from day 1 of pregnancy through lactation. The three diets were the Control ω-3 FA condition (ω-3/ω-6 ratio ~ 0.14), the Excess ω-3 FA condition (ω-3/ω-6 ratio ~ 14.0) and Deficient ω-3 FA condition (ω-3/ω-6 ratio ~ 0% ratio). The Control diet contained 7% soybean oil; whereas the Deficient and Excess ω-3 FA diets contained 7% safflower oil and 7% fish oil, respectively. One male and female offspring per litter were ABR-tested as young adults using tone pip stimuli of 2, 4, 8 and 16 kHz. The postnatal growth retardation and prolonged neural transmission times in the Excess and Deficient pups had dissipated by young adulthood. In contrast, the Excess group had elevated ABR thresholds (hearing loss) at all tone pip frequencies in comparison to the Control and Deficient groups. The Deficient group had worse ABR thresholds than the Control group in response to the 8 kHz tone pips only. The Excess group also had ABR amplitude–intensity profiles suggestive of hyperacusis. These results are consistent with the Barker hypothesis concerning the fetal and neonatal origins of adult diseases. Thus, consuming diets that are excessively rich or deficient in ω-3 FA during pregnancy and lactation seems inadvisable because of risks for long-lasting adverse effects on brain development and sensory function.

Age-related auditory pathology in the CBA/J mouse

Commercially obtained aged male CBA/J mice presented a complex pattern of hearing loss and morphological changes. A significant threshold shift in auditory brainstem responses (ABR) occurred at 3 months of age at 4 kHz without apparent loss of hair cells, rising slowly at later ages accompanied by loss of apical hair cells. A delayed high-frequency deficit started at 24 kHz around the age of 12 months. At 20–26 months, threshold shifts at 12 and 24 kHz and the accompanying hair cell loss at the base of the cochlea were highly variable with some animals appearing almost normal and others showing large deficits. Spiral ganglion cells degenerated by 18 months in all regions of the cochlea, with cell density reduced by approximately 25%. There was no degeneration of the stria vascularis and the endocochlear potential remained stable from 3 to 25 months of age regardless of whether the animals had normal or highly elevated ABR thresholds. The slow high-frequency hearing loss combined with a modest reduction of ganglion cell density and an unchanged endocochlear potential suggest sensorineural presbycusis. The superimposed early hearing loss at low frequencies, which is not seen in animals bred in-house, may complicate the use of these animals as a presbycusis model.

Early Sensorineural Hearing Loss in Ob/Ob Mouse, an Animal Model of Type 2 Diabetes

ObjectivesThere have been many studies on the relationship between diabetes mellitus and presbycusis. Microangiopathy and neuropathy that's caused by chronic hyperglycemia may lead to damage to the inner ear. Several clinical studies on humans and animal studies have been performed to investigate the association between diabetes and hearing loss, however, this relationship is still a matter of debate. We investigated the association of diabetes and sensorineural hearing loss in an animal model of type-2 diabetes and obesity (the ob/ob mouse [OM]).MethodsThe auditory brainstem response (ABR) thresholds were obtained in the OM and the wild type mice (C57BL/6J mice) up to 25 weeks after birth. After the animals were sacrificed, their cochleae were retrieved and then subjected to histopathologic observations.ResultsThe OM exhibited significantly elevated ABR thresholds at 21 weeks of age, yet the C57BL/6J mice exhibited no significant change until 25 weeks of age. On the histological findings, outer hair cell degeneration and loss of spiral ganglion cells were observed in the middle and basal turns of the OM. On the contrary, no degenerative change was observed until 25 weeks of age in the C57BL/6J mice.ConclusionThis study suggests that chronic hyperglycemia and obesity may lead to early sensorineural hearing loss.

Reduced auditory acuity in rat pups from excess and deficient omega-3 fatty acid consumption by the mother

Consumption of the nutrients omega-3 fatty acids (ω-3 FA) during pregnancy and lactation is considered beneficial to fetal and infant development. It may also reduce the incidence and severity of preterm births by prolonging gestational length. However several recent human and animal studies have reported that over-supplementation with ω-3 FA, especially in the form of fish oil, can have adverse effects on fetal and infant development and the auditory brainstem response (ABR). Our goal was to assess further the effects of ω-3 FA excess and deficiency during pregnancy and lactation on the offspring's auditory acuity as evidenced by their ABR thresholds. Female Wistar rats were given diets that were either deficient, adequate (control) or excess in ω-3 FA from day 1 of pregnancy through lactation. The offspring were ABR-tested at the postnatal age of 24 days. The rat pups in the Excess treatment condition had significantly elevated (worse) ABR thresholds, postnatal growth restriction, and a trend for increased postnatal mortality in comparison to the Control group. The Deficient group was intermediate. In conclusion, excess or deficient amounts of ω-3 FA during pregnancy and lactation in the laboratory rat adversely affected the offspring's auditory acuity. Postnatal thriving was also adversely affected. Consuming or administering large or inadequate amounts of ω-3 FA during pregnancy and lactation seems inadvisable because of the potential for adverse effects on infant development.

Transient infantile auditory neuropathy and its clinical implications

Auditory neuropathy (AN) has been a well-accepted clinical entity during the last years. Though we are able to diagnose AN reliably, little is known concerning its epidemiology, etiology and prognosis. This study is aimed at presenting a particular characteristic of the disease, namely its potential transient behaviour, observed in a group of high risk neonates suffering from AN. The ensuing clinical implications are underlined. From 1995 to 2004, 1150 high risk (HR) neonates were subjected consecutively to audiological evaluation by auditory brain stem responses (ABR), participating in a targeted hearing screening program for HR neonates. All neonates with ABR threshold >40 dBnHL and middle ear free from disease underwent otoacoustic emissions (OAEs) testing as well. Children with elevated ABR thresholds were scheduled for re-examination after 4-6 months. Only infants demonstrating considerably elevated thresholds (>70 dBnHL), absent or atypical ABR in combination with normal OAEs were considered as suffering from AN. One hundred and seventy-seven neonates showed elevated ABR thresholds (15.4%). Seventy-nine of them demonstrated ABR thresholds >or=75 dBnHL, absent or strongly atypical waveforms at maximum test intensity and among them 25 displayed findings consistent with AN. Follow-up examination revealed a resolution of AN in 13 out of 20 infants retested, that is a restoration of ABR to normal and typical OAEs recordings. Using multiple logistic regression, we found that low birth weight may represent a reliable predictor for clinical recovery of AN infants. This article bring to light the temporary character that AN could show in HR neonates and especially in those with low birth weight. Based on the results of our study, the higher the birth weight, the less likely it is for neonates to recover from AN. From a practical point of view, these findings suggest that hearing screening protocols for HR neonates should be revised in both their methodology and time of application. Finally, the decision for amplification or cochlear implantation in HR infants with AN should be made very carefully and well after the 6th month of age, since the maturation process may still be in progress.

AAV-Mediated Delivery of the Caspase Inhibitor XIAP Protects Against Cisplatin Ototoxicity

Delivery of the gene encoding X-linked inhibitor of apoptosis (XIAP) using an adeno-associated viral (AAV) vector can protect against cisplatin-mediated ototoxicity. Cisplatin is a widely used chemotherapeutic agent with significant ototoxic side effects. One possible mechanism of toxicity is apoptotic death of many cochlear cell types. Acute treatment with inhibitors of caspases- enzymes critical for apoptosis- has been shown to prevent hearing loss in vivo, but is too short-acting for therapeutic use. Gene therapy provides a specific and chronic means of delivering potential therapeutic gents. Introducing an anti-apoptotic gene into the cochlea could provide long-term prophylaxis against the ototoxic effects of cisplatin. Two groups of rats were treated with unilateral injection into the round window of AAV harboring a gene encoding either XIAP or green fluorescent protein (GFP). After at least two months of gene expression, auditory-brainstem-response (ABR) threshold shifts and outer-hair-cell (OHC) number were measured in these two groups of animals after 72-hour treatment with cisplatin. Consistent with previous reports, uninjected and AAV.GFP-injected ears displayed profound ABR threshold elevations and OHC loss after cisplatin treatment. Ears that had been injected with AAV encoding XIAP, however, were significantly protected from these effects: cisplatin-induced ABR-threshold shift and hair-cell loss were attenuated by as much as 78% and 45%, respectively, when compared with contralateral (untreated) ears. XIAP delivery to the cochlea can protect against the audiometric changes and hair-cell loss associated with cisplatin ototoxicity. The efficacy, specificity, and duration of the protective effects make this a potentially attractive therapeutic paradigm.

Cochlear Protection by Local Insulin-Like Growth Factor-1 Application Using Biodegradable Hydrogel

The aim of this experimental study was to examine the potential of local recombinant human insulin-like growth factor-1 (rhIGF-1) application through a biodegradable hydrogel for the treatment of cochleae. A hydrogel immersed with rhIGF-1 was placed on the round window membrane of Sprague-Dawley rats while a hydrogel immersed with physiological saline was applied to control animals. On day 3 after drug application, the animals were exposed to white noise at 120 dB sound pressure level (SPL) for 2 hours. Cochlear function was monitored using measurements of auditory brain stem responses (ABRs) at frequencies of 8, 16, and 32 kHz. The temporal bones were collected 7 or 30 days after noise exposure and the loss of hair cells was quantitatively analyzed. Local rhIGF-1 treatment significantly reduced the elevation of ABR thresholds on days 7 and 30 after noise exposure. Histologic analysis revealed that local rhIGF-1 treatment significantly prohibited the loss of outer hair cells. These findings demonstrate that local IGF-1 application through the biodegradable hydrogel has the potential for protection of cochleae from noise trauma.

Prevalence of auditory neuropathy/synaptopathy in a population of children with profound hearing loss

To examine the prevalence of auditory neuropathy/synaptopathy (AN/AS) in a cohort of children with profound hearing loss. From 1997 until 2004, 5190 children, aged 1-15 years, whose hearing ability was uncertain or who had risk factors for hearing impairment were investigated with subjective and objective hearing tests. Three thousand four hundred and fifteen from these children were screened for AN/AS using pure-tone audiometry, impedance measurement, transient evoked otoacoustic emissions (TEOAE) and click-evoked auditory brainstem responses (ABR). From 3415 patients who participated in an ABR and TEOAE assessment, 379 children showed absent or elevated (> or = 80 dB nHL) ABR thresholds. Within this group we found 32 cases with evidence of AN/AS via visible TEOAE and/or cochlear microphonics (CM) coupled with absent ABR. In the remaining 3036 children, AN/AS, could be ruled out by means of detectable ABR-thresholds and coherent findings in pure-tone audiometry and TEOAE assessment. This results in a prevalence of AN/AS of 0.94% within the group at risk for hearing loss, compared to 8.44% among profoundly hearing impaired children. This study shows that AN/AS is a common finding in the population of hearing impaired infants. In the majority of our AN/AS children (50%, n=16), an early audiological diagnosis was made under the age of 12 months. Therefore, clinicians and other health care professionals should generally be sensitised for AN/AS in infants, so that an appropriate treatment can promptly be initiated. Further research on clinical and pathophysiological aspects is necessary to better identify and manage patients suffering from AN/AS.

A comparison of vestibular and auditory phenotypes in inbred mouse strains

The purposes of this research were to quantify gravity receptor function in inbred mouse strains and compare vestibular and auditory function for strain- and age-matched animals. Vestibular evoked potentials (VsEPs) were collected for 19 inbred strains at ages from 35 to 389 days old. On average, C57BL/6J (35 to 190 days), BALB/cByJ, C3H/HeSnJ, CBA/J, and young LP/J mice had VsEP thresholds comparable to normal. Elevated VsEP thresholds were found for elderly C57BL/6J, NOD.NONH2 kb, BUB/BnJ, A/J, DBA/2J, NOD/LtJ, A/WySnJ, MRL/MpJ, A/HeJ, CAST/Ei, SJL/J, elderly LP/J, and CE/J. These results suggest that otolithic function varies among inbred strains and several strains displayed gravity receptor deficits by 90 days old. Auditory brainstem response (ABR) thresholds were compared to VsEP thresholds for 14 age-matched strains. C57BL/6J mice (up to 190 days) showed normal VsEPs with normal to mildly elevated ABR thresholds. Four strains (BUB/BnJ, NOD/LtJ, A/J, elderly LP/J) had significant hearing loss and elevated VsEP thresholds. Four strains (DBA/2J, A/WySnJ, NOD.NONH2 kb, A/HeJ) had elevated VsEP thresholds (including absent VsEPs) with mild to moderate elevations in ABR thresholds. Three strains (MRL/MpJ, Ce/J, SJL/J) had significant vestibular loss with no concomitant hearing loss. These results suggest that functional change in one sensory system does not obligate change in the other. We hypothesize that genes responsible for early onset hearing loss may affect otolithic function, yet the time course of functional change may vary. In addition, some genetic mutations may produce primarily gravity receptor deficits. Potential genes responsible for selective gravity receptor impairment demonstrated herein remain to be identified.

Geranylgeranylacetone, a heat shock protein inducer, prevents acoustic injury in the guinea pig

Geranylgeranylacetone (GGA) used widely as anti-ulcer agent is accepted as an inducer of the heat shock proteins (Hsps) at gastric mucosa, liver, heart, and brain. However, there have been no reports that GGA could induce Hsps in the cochlea leading up to the oto-protection. The purpose of the present study was to investigate whether single oral dose of GGA could induce Hsps at cochlea and oral administration had protective effect to the cochlea against noise trauma. We used Hartley guinea pigs and investigated the expression of Hsp70, 40, and 27 in cochlea by Western blot analysis. To evaluate cochlear function, we assessed thresholds of the auditory brain stem response (ABR). For histological assessment, we observed the sensory epithelium using surface preparation technique. GGA (600 mg/kg) or vehicle was given orally to animals. Western blot analysis showed that the expressions of Hsp 70, 40, and 27 were increased 24–48 h after administration of single dose of GGA, whereas there was less expression in the animals given vehicle. In the animals given GGA once a day for a week before sound exposure (130 dB SPL octave band noise with a center frequency of 4 kHz) for 3 h, their ABR threshold elevations were lowered significantly. In addition, significantly fewer defects were observed on outer hair cells of organ of Corti in the animals treated by GGA than those of the animals without GGA. This result shows that pretreatment by GGA have a potential to prevent cochlea damage against the intense noise.

Effects of Alcohol and Noise on Temporary Threshold Shift in Guinea Pigs

The purpose of this study was to investigate the effects of concomitant exposure to noise and alcohol on the auditory thresholds. Twenty-four guinea pigs were equally divided into three groups: the acute intoxication group, the chronic intoxication group and the control group. Animals in the acute group received single intraperitoneal injections of ethanol (2 g/kg). In the chronic group, alcohol was administered via drinking water (10%, v/v) over a 60-day period. All animals were exposed to a white noise at the intensity of 105 dB A for 30 min. Auditory brainstem response (ABR) thresholds and distortion product otoacoustic emission (DPOAE) levels were measured before, immediately after noise exposure and also 1, 2, and 7 days following exposure. The results showed: first, acute alcohol injection caused a significant, temporary elevation of ABR threshold (4.8 dB in average), while chronic alcohol treatment did not change auditory threshold significantly. Second, noise exposure induced a mean threshold shift of 15.4– 19.7 dB. ABR threshold returned to normal 2 days after exposure. Both acute and chronic alcohol treatment did not alter the magnitude and time course of recovery of the temporary threshold shift (TTS). Third, the mean DPOAE amplitudes decreased at most frequencies following acute injection of alcohol. However, the differences did not reach statistical significance. Fourth, the mean DPOAE levels dropped 3.4–9.6 dB in all groups after noise exposure and returned to normal 1 day to 2 days after noise. There were no significant differences in the amount of DPOAE suppression after noise between the three groups. In summary, we have found that acute and chronic treatment of alcohol in combination with noise did not significantly exacerbate TTS or decrease DPOAE amplitudes relative to noise exposure alone.