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To compare the concordance of advanced audiologists (AA), junior doctors (JD) and paediatric audiologists (PA) with an Ear, Nose and Throat (ENT) specialist on the diagnosis and management of children with middle ear or hearing concerns.A clinical equivalence (concordance) study.Three AAs, five JDs, three PAs and one ENT specialist asynchronously reported diagnoses and management plans for ten, online paediatric cases consisting of video-otoscopic images and clinical findings.For medical diagnosis, significant agreement with the ENT specialist was observed at moderate and near-perfect levels for two AAs (k = 0.561 and 0.815), moderate levels for four JDs (k = 0.5 to 0.603) and near-perfect level for one PA (k = 0.815). For management decisions, significant agreement with the ENT specialist was observed at substantial (k = 0.636) and near-perfect (k = 0.818) levels for two AAs, and at a moderate level (k = 0.538) for one PA. Within group inter-rater agreement for management plans was substantial for AAs and JDs, and moderate for PAs.For children with middle ear disease or hearing concerns, AAs, JDs and PAs showed similar levels of agreement with an ENT specialist on diagnosis, but AAs were more likely than JDs or PAs to agree with an ENT specialist on management.

Since the discovery of ATP as an extracellular signalling molecule in 1972, purinergic signalling, mediated by extracellular purines and pyrimidines has been identified in virtually all mammalian tissues and is implicated in regulating fundamental cellular processes. In recent years, there has been an increasing focus on the pathophysiology and potential therapeutic interventions based on purinergic signalling. A vast range of compounds targeting purine receptors are in clinical development, and many more are in preclinical studies, which highlights the fast growth in this research field. As a tribute to Professor Geoffrey Burnstock’s legacy in purinergic signalling, we present here a brief review of compounds targeting purine receptors that are in different stages of clinical trials. The review highlights the 50-year journey from basic research on purinergic receptors to clinical applications of therapies targeting purine receptors.

Although higher-order cognitive and lower-order sensorimotor abilities are generally regarded as distinct and studied separately, there is evidence that they not only covary but also that this covariation increases across the lifespan. This pattern has been leveraged in clinical settings where a simple assessment of sensory or motor ability (e.g. hearing, gait speed) can forecast age-related cognitive decline and risk for dementia. However, the brain mechanisms underlying cognitive, sensory, and motor covariation are largely unknown. Here, we examined whether such covariation in midlife reflects variability in common versus distinct neocortical networks using individualized maps of functional topography derived from BOLD fMRI data collected in 769 45-year-old members of a population-representative cohort. Analyses revealed that variability in basic motor but not hearing ability reflected individual differences in the functional topography of neocortical networks typically supporting cognitive ability. These patterns suggest that covariation in motor and cognitive abilities in midlife reflects convergence of function in higher-order neocortical networks and that gait speed may not be simply a measure of physical function but rather an integrative index of nervous system health.

Prior research shows that individuals who have exhibited antisocial behavior are in poorer health than their same-aged peers. A major driver of poor health is aging itself, yet research has not investigated relationships between offending trajectories and biological aging. We tested the hypothesis that individuals following a life-course persistent (LCP) antisocial trajectory show accelerated aging in midlife. Trajectories of antisocial behavior from age 7 to 26 years were studied in the Dunedin Multidisciplinary Health and Development Study, a population-representative birth cohort (N = 1037). Signs of aging were assessed at age 45 years using previously validated measures including biomarkers, clinical tests, and self-reports. First, we tested whether the association between antisocial behavior trajectories and midlife signs of faster aging represented a decline from initial childhood health. We then tested whether decline was attributable to tobacco smoking, antipsychotic medication use, debilitating illnesses in adulthood, adverse exposures in childhood (maltreatment, socioeconomic disadvantage) and adulthood (incarceration), and to childhood self-control difficulties. Study members with a history of antisocial behavior had a significantly faster pace of biological aging by midlife, and this was most evident among individuals following the LCP trajectory (β, 0.22, 95%CI, 0.14, 0.28, p ≤ 0.001). This amounted to 4.3 extra years of biological aging between ages 25–45 years for Study members following the LCP trajectory compared to low-antisocial trajectory individuals. LCP offenders also experienced more midlife difficulties with hearing (β, −0.14, 95%CI, −0.21, −0.08, p ≤ 0.001), balance (β, −0.13, 95%CI, −0.18, −0.06, p ≤ 0.001), gait speed (β, −0.18, 95%CI, −0.24, −0.10, p ≤ 0.001), and cognitive functioning (β, −0.25, 95%CI, −0.31, −0.18, p ≤ 0.001). Associations represented a decline from childhood health. Associations persisted after controlling individually for tobacco smoking, antipsychotic medication use, midlife illnesses, maltreatment, socioeconomic status, incarceration, and childhood self-control difficulties. However, the cumulative effect of these lifestyle characteristics together explained why LCP offenders have a faster Pace of Aging than their peers. While older adults typically age-out of crime, LCP offenders will likely age-into the healthcare system earlier than their chronologically same-aged peers. Preventing young people from offending is likely to have substantial benefits for health, and people engaging in a LCP trajectory of antisocial behaviors might be the most in need of health promotion programs. We offer prevention and intervention strategies to reduce the financial burden of offenders on healthcare systems and improve their wellbeing.

Knowledge of a person’s risk for Alzheimer’s disease and related dementias (ADRDs) is required to triage candidates for preventive interventions, surveillance, and treatment trials. ADRD risk indexes exist for this purpose, but each includes only a subset of known risk factors. Information missing from published indexes could improve risk prediction. In the Dunedin Study of a population-representative New Zealand-based birth cohort followed to midlife (N = 938, 49.5% female), we compared associations of four leading risk indexes with midlife antecedents of ADRD against a novel benchmark index comprised of nearly all known ADRD risk factors, the Dunedin ADRD Risk Benchmark (DunedinARB). Existing indexes included the Cardiovascular Risk Factors, Aging, and Dementia index (CAIDE), LIfestyle for BRAin health index (LIBRA), Australian National University Alzheimer’s Disease Risk Index (ANU-ADRI), and risks selected by the Lancet Commission on Dementia. The Dunedin benchmark was comprised of 48 separate indicators of risk organized into 10 conceptually distinct risk domains. Midlife antecedents of ADRD treated as outcome measures included age-45 measures of brain structural integrity [magnetic resonance imaging-assessed: (i) machine-learning-algorithm-estimated brain age, (ii) log-transformed volume of white matter hyperintensities, and (iii) mean grey matter volume of the hippocampus] and measures of brain functional integrity [(i) objective cognitive function assessed via the Wechsler Adult Intelligence Scale-IV, (ii) subjective problems in everyday cognitive function, and (iii) objective cognitive decline measured as residualized change in cognitive scores from childhood to midlife on matched Weschler Intelligence scales]. All indexes were quantitatively distributed and proved informative about midlife antecedents of ADRD, including algorithm-estimated brain age (β's from 0.16 to 0.22), white matter hyperintensities volume (β's from 0.16 to 0.19), hippocampal volume (β's from −0.08 to −0.11), tested cognitive deficits (β's from −0.36 to −0.49), everyday cognitive problems (β's from 0.14 to 0.38), and longitudinal cognitive decline (β's from −0.18 to −0.26). Existing indexes compared favourably to the comprehensive benchmark in their association with the brain structural integrity measures but were outperformed in their association with the functional integrity measures, particularly subjective cognitive problems and tested cognitive decline. Results indicated that existing indexes could be improved with targeted additions, particularly of measures assessing socioeconomic status, physical and sensory function, epigenetic aging, and subjective overall health. Existing premorbid ADRD risk indexes perform well in identifying linear gradients of risk among members of the general population at midlife, even when they include only a small subset of potential risk factors. They could be improved, however, with targeted additions to more holistically capture the different facets of risk for this multiply determined, age-related disease.

Objective: This study explored cortical auditory evoked potential (CAEPs) elicited by speech sounds in children with unilateral congenital aural atresia (CAA). Design: Twelve children (8 males) age...

Some humans age faster than others. Variation in biological aging can be measured in midlife, but the implications of this variation are poorly understood. We tested associations between midlife biological aging and indicators of future frailty risk in the Dunedin cohort of 1,037 infants born the same year and followed to age 45. Participants’ ‘Pace of Aging’ was quantified by tracking declining function in 19 biomarkers indexing the cardiovascular, metabolic, renal, immune, dental and pulmonary systems across ages 26, 32, 38 and 45 years. At age 45 in 2019, participants with faster Pace of Aging had more cognitive difficulties, signs of advanced brain aging, diminished sensory–motor functions, older appearances and more pessimistic perceptions of aging. People who are aging more rapidly than same-age peers in midlife may prematurely need supports to sustain independence that are usually reserved for older adults. Chronological age does not adequately identify need for such supports. A cohort study tracking 20-year age-related declines in multiple organ systems finds that, already by midlife, those aging fastest showed cognitive declines, signs of brain aging, diminished sensory–motor function and negative views about aging.

Objective To explore the behavioural and functional performance of a group of children with conductive unilateral hearing loss (UHL) due to congenital aural atresia. Method Twelve children aged 7 to 16 years (Mage 10.0, SD 3.1 years) formed the UHL group and 15 age-matched children (Mage 9.5, SD 3.6 years) with normal hearing formed the control group. Auditory skills were assessed using tests of sound localisation, spatial speech perception in noise, and self-ratings of auditory abilities (Listening Inventory for Education; LIFE and Speech, Spatial and Qualities of Hearing scale; SSQ). Results When speech was directed to the good ear, performance was poorer than for normal hearing controls. Sound localisation abilities were impaired in children with UHL. Children with UHL reported higher levels of difficulties in classroom settings compared to children with normal hearing, particularly for activities involving listening in noise and focused listening activities. Older children self-report and parents report difficulties for their children across all SSQ scales. Conclusions Children with UHL showed a wide range of auditory difficulties. As expected, speech recognition in noise differed from controls. Sound localisation abilities were variable; greater variability was seen for right ear hearing losses suggesting that some of these children may have developed compensatory mechanisms. Younger children identified listening difficulties for school situations where focussed auditory attention was needed. Older children and parents reported greatest difficulty for activities requiring perception of the direction, distance, and movement of sound. Higher levels of effort and inability to ignore sounds were reported as major difficulties.

There is growing evidence for a relationship between gut dysbiosis and hearing loss. Inflammatory bowel disease, diet-induced obesity (DIO), and type 2 diabetes have all been linked to hearing loss. Here, we investigated the effect of a chronic high-fat diet (HFD) on the development of inner ear inflammation using a rodent model. Three-week-old CD-1 (Swiss) mice were fed an HFD or a control diet for ten weeks. After ten weeks, mouse cochleae were harvested, and markers of cochlear inflammation were assessed at the protein level using immunohistochemistry and at the gene expression level using quantitative real-time RT-PCR. We identified increased immunoexpression of pro-inflammatory biomarkers in animals on an HFD, including intracellular adhesion molecule 1 (ICAM1), interleukin 6 receptor α (IL6Rα), and toll-like-receptor 2 (TLR2). In addition, increased numbers of ionized calcium-binding adapter molecule 1 (Iba1) positive macrophages were found in the cochlear lateral wall in mice on an HFD. In contrast, gene expression levels of inflammatory markers were not affected by an HFD. The recruitment of macrophages to the cochlea and increased immunoexpression of inflammatory markers in mice fed an HFD provide direct evidence for the association between HFD and cochlear inflammation.

Aim Children with middle ear disease often experience lengthy delays waiting for outpatient paediatric ear nose and throat (ENT) services. This study aimed to investigate whether an alternative service delivery model using audiologists working in an expanded scope of practice reduced waiting times for children to access such services. Methods A total of 131 children consecutively referred to a large ENT outpatient service in Queensland, Australia, for middle ear and hearing concerns were prospectively allocated to either a standard ENT service or an advanced audiology (AA)-led service. Waiting times and attendance rates were collected and compared between the two patient groups. Results The median waiting time from referral to first offered appointment was 96 days for children in the AA-led service versus 417.5 days for children in the standard ENT service. Seventy-nine percent of children in the AA-led service attended their first offered appointment versus 61% in the standard ENT service. For children receiving grommets, the median waiting time from initial referral to grommet insertion was 226 days for children in the AA-led service versus 627 days for children in the standard ENT service. Conclusion The AA-led service was an effective alternative pathway to reduce waiting times for children referred to ENT services with middle ear and hearing concerns.

OBJECTIVES: Expansion of the scopes of practice of allied health practitioners has the potential to improve the efficiency and cost-effectiveness of healthcare, given the identified shortages in medical personnel. Despite numerous examples in other allied health disciplines, this has yet to be applied to pediatric Audiology. This study aimed to investigate the effectiveness and safety of using audiologists with advanced training to independently triage children referred to otolaryngology (ORL) services, and compare the subsequent use of specialist resources, and postoperative grommet care to a standard medical ORL service. DESIGN: One hundred twenty children consecutively referred to a large ORL outpatient service in Queensland, Australia, for middle ear and hearing concerns were prospectively allocated to either the ORL service or Advanced Audiology-led service. Demographic and clinical data were extracted from electronic medical records and compared between the two services. Clinical incidents and adverse events were recorded for the Advanced Audiology-led service. RESULTS: Approximately half of all children referred to ORL for middle ear or hearing concerns were discharged without requiring any treatment, with the remaining half offered surgical treatment. The Advanced Audiology-led model increased the proportion of children assessed by ORL that proceeded to surgery from 57% to 82% compared with the standard medical ORL model. Children followed up by the audiologists after grommet insertion were more likely to be discharged independently and at the first postoperative review appointment compared with the standard medical ORL service. There were no reports of adverse events or long-term bilateral hearing loss after discharge by the Advanced Audiology-led service. CONCLUSIONS: These findings indicate that an Advanced Audiology-led service provides a safe and effective triaging model for the independent management of children not requiring treatment, and children requiring routine postoperative grommet review, and improves the effective use of specialist resource compared with the standard medical ORL service.

Obstructive sleep apnea (OSA) has been linked to multiple co-morbidities, and some research points to a potential relationship between OSA and hearing and balance dysfunction, and the benefits of continuous positive airway pressure (CPAP) treatment.The present study was undertaken as a scoping review of research on OSA and its impact on hearing and balance function in adults and children and whether the treatment of CPAP would affect hearing and balance function.Online databases were used to identify 45 papers published that used hearing and balance assessments concerning OSA and CPAP therapy as a primary outcome. The secondary outcome was the subjective perception through validated questionnaires.Whilst the data on the effect of OSA on middle ear function remains inconclusive, most papers demonstrate an increase in hearing thresholds, an absence of otoacoustic emissions (OAE) and delayed auditory brainstem response (ABR) in adults with OSA. Nystagmus and abnormal vestibular evoked myogenic potentials (VEMPs) were observed in the small number of papers. The positive pressure from CPAP significantly and transiently increases middle ear pressure, however, its effects on other auditory regions and the vestibular system remains inconclusive. Research on hearing and balance function in children with OSA is limited.Narrow assessments of hearing and balance are not sufficient to understand the nature of hearing and balance function in OSA patients and the effect of CPAP therapy. More comprehensive assessments are necessary to observe peripheral and central changes in the auditory and vestibular pathways.

This review aims to provide a conceptual and theoretical overview of the association between gut dysbiosis and hearing loss. Hearing loss is a global health issue; the World Health Organisation (WHO) estimates that 2.5 billion people will be living with some degree of hearing loss by 2050. The aetiology of sensorineural hearing loss (SNHL) is complex and multifactorial, arising from congenital and acquired causes. Recent evidence suggests that impaired gut health may also be a risk factor for SNHL. Inflammatory bowel disease (IBD), type 2 diabetes, diet-induced obesity (DIO), and high-fat diet (HFD) all show links to hearing loss. Previous studies have shown that a HFD can result in microangiopathy, impaired insulin signalling, and oxidative stress in the inner ear. A HFD can also induce pathological shifts in gut microbiota and affect intestinal barrier (IB) integrity, leading to a leaky gut. A leaky gut can result in chronic systemic inflammation, which may affect extraintestinal organs. Here, we postulate that changes in gut microbiota resulting from a chronic HFD and DIO may cause a systemic inflammatory response that can compromise the permeability of the blood–labyrinth barrier (BLB) in the inner ear, thus inducing cochlear inflammation and hearing deficits.

Introduction Hearing is a primary sense that facilitates the development of spoken language, social connection and an appreciation of sounds within the natural world. Hearing loss has multiple adverse effects across the life course. Understanding the worldviews of ear and hearing health in Pacific peoples is crucial to inform responsive and appropriate hearing health and primary healthcare services. Aim To understand the worldviews, knowledge and beliefs held by the Niuean community in Niue towards ear and hearing health, and the use of healthcare methods to contribute to service development. Methods Twenty semi-structured interviews were conducted with Niuean community members. Interviews were audio-recorded, transcribed verbatim, and analysed using thematic analysis methods. Results Niuean people value hearing health as an important way to communicate and connect with each other. They are proactive health seekers, have good knowledge about ear disease and hearing health and use mainstream medicines alongside spiritual practices and traditional remedies to maintain good ear and hearing health. The hospital system is responsive and accessible to the community’s needs, contrasting with Pacific people’s access to hearing health services in New Zealand. Discussion There is a high level of awareness of the importance of hearing health amongst the Niuean community and good accessibility and utilisation of healthcare services. There is potential to implement locally focused ear and hearing health strategies in Niue and conduct hearing health research among the New Zealand-based Niuean community to improve primary healthcare services delivery.

Factors affecting successful listening in older adults and the corresponding electrophysiological signatures are not well understood. The present study investigated age-related differences in attention and temporal processing, as well as differences in the neural activity related to signal degradation during a number comparison task. Participants listened to digits presented in background babble and were tested at two levels of signal clarity, clear and degraded. Behavioral and electrophysiological measures were examined in 30 older and 20 younger neurologically-healthy adults. Relationships between performance on the number comparison task, behavioral measures, and neural activity were used to determine correlates of listening deficits associated with aging. While older participants showed poorer performance overall on all behavioral measures, their scores on the number comparison task were largely predicted (based on regression analyses) by their sensitivity to temporal fine structure cues. Compared to younger participants, older participants required higher signal-to-noise ratios (SNRs) to achieve equivalent performance on the number comparison task. With increasing listening demands, age-related changes were observed in neural processing represented by the early-N1 and later-P3 time windows. Source localization analyses revealed age differences in source activity for the degraded listening condition that was located in the left prefrontal cortex. In addition, this source activity negatively correlated with task performance in the older group. Together, these results suggest that older adults exhibit reallocation of processing resources to complete a demanding listening task. However, this effect was evident only for poorer performing older adults who showed greater posterior to anterior shift in P3 response amplitudes than older adults who were good performers and younger adults. These findings might reflect less efficient recruitment of neural resources that is associated with aging during effortful listening performance.

The advanced audiology-led service is designed to triage and manage children who are referred to Ear Nose and Throat (ENT) outpatient services with middle ear or hearing concerns. This service has resulted in shorter waiting times for children to receive ENT treatment, and improved ENT capacity. The aim of this study was to explore parental satisfaction with the advanced audiology-led ENT service and to determine if there were cultural or process factors affecting satisfaction.Prospective cross-sectional study using a modified Visit-Specific Satisfaction Questionnaire (VSQ-9) survey.One hundred and thirteen parents of children consecutively attending a first appointment in the advanced audiology-led service recruited between October 2016 and October 2017.There were a total of 100 valid responses (rate of 88.5%). The survey showed high levels of satisfaction. Satisfaction scores were significantly higher for items related to interactions with the audiologist compared to items related to waiting times. There were no differences in satisfaction across cultural groups. Parents were equally satisfied with the service whether their child was managed independently by the audiologist or required another appointment for medical input.The advanced audiology-led service had high levels of satisfaction from parents attending with their children.

The sense of hearing enables us to enjoy sounds and music and engage with other people [...]

The inaugural World Report on Hearing was recently published by the World Health Organisation, and outlines the burden of hearing loss, and strategies to overcome this through preventative and public health approaches. Here, we identify barriers to wide-scale adoption, including historic low prioritisation of hearing loss against other public health needs, a lack of a health workforce with relevant training, poor access to assistive technology, and individual and community-level stigma and misunderstanding. Overcoming these barriers will require multi-sector stakeholder collaboration, involving ear and hearing care professionals, patients, communities, industry and policymakers.

Importance Individuals with mental disorders are at an elevated risk of developing chronic age-related physical diseases. However, it is not clear whether psychopathology is also associated with processes of accelerated aging that precede the onset of age-related disease. Objective To test the hypothesis that a history of psychopathology is associated with indicators of accelerated aging at midlife. Design, Setting, and Participants This prospective cohort study was based on the Dunedin Multidisciplinary Health and Development Study, a population-representative birth cohort of 1037 individuals born between April 1, 1972, and March 31, 1973, in Dunedin, New Zealand. Members were followed up to age 45 years (until April 2019). Data were analyzed from January 6 to December 7, 2020. Exposures Mental disorders were assessed in 6 diagnostic assessments from ages 18 to 45 years and transformed through confirmatory factor analysis into continuous measures of general psychopathology (p-factor) and dimensions of internalizing, externalizing, and thought disorders (all standardized to a mean [SD] of 100 [15]). Main Outcomes and Measures Signs of aging (biological pace of aging; declines in sensory, motor, and cognitive functioning; and facial age) were assessed up to age 45 years using previously validated measures including biomarkers, clinical tests, and self-reports. Results Of the original 1037 cohort participants, 997 were still alive at age 45 years, of whom 938 (94%) were assessed (474 men [50.5%]). Participants who had experienced more psychopathology exhibited a faster pace of biological aging (β, 0.27; 95% CI, 0.21-0.33;P Conclusions and Relevance In this cohort study, a history of psychopathology was associated with accelerated aging at midlife, years before the typical onset of age-related diseases. This link is not specific to any particular disorder family but generalizes across disorders. Prevention of psychopathology and monitoring of individuals with mental disorders for signs of accelerated aging may have the potential to reduce health inequalities and extend healthy lives.

Intratympanic injection is a clinically used approach to locally deliver therapeutic molecules to the inner ear. Drug diffusion, at least in part, is presumed to occur through the round window membrane (RWM), one of the two openings to the inner ear. Previous studies in human temporal bones have identified a three-layered structure of the RWM with a thickness of 70–100 μm. This is considerably thicker than the RWM in rodents, which are mostly used to model RWM permeability and assess drug uptake. The sheep has been suggested as a large animal model for inner ear research given the similarities in structure and frequency range for hearing. Here, we report the structure of the sheep RWM. The RWM is anchored within the round window niche (average vertical diameter of 2.1 ± 0.3 mm and horizontal diameter of 2.3 ± 0.4 mm) and has a curvature that leans towards the scala tympani. The centre of the RWM is the thinnest (55–71 μm), with increasing thickness towards the edges (

Objective School hearing screening may mitigate the effects of childhood hearing loss through early identification and intervention. This study provides an overview of existing school hearing screening programs around the world, identifies gaps in the literature, and develops priorities for future research. Data Sources A structured search of the PubMed, Embase, and Cochrane Library databases. Review Methods A total of 65 articles were included according to predefined inclusion criteria. Parameters of interest included age groups screened, audiometric protocols, referral criteria, use of adjunct screening tests, rescreening procedures, hearing loss prevalence, screening test sensitivity and specificity, and loss to follow-up. Conclusions School hearing screening is mandated in few regions worldwide, and there is little accountability regarding whether testing is performed. Screening protocols differ in terms of screening tests included and thresholds used. The most common protocols included a mix of pure tone screening (0.5, 1, 2, and 4 kHz), otoscopy, and tympanometry. Estimates of region-specific disease prevalence were methodologically inaccurate, and rescreening was poorly addressed. Loss to follow-up was also a ubiquitous concern. Implications for Practice There is an urgent need for standardized school hearing screening protocol guidelines globally, which will facilitate more accurate studies of hearing loss prevalence and determination of screening test sensitivity and specificity. In turn, these steps will increase the robustness with which we can study the effects of screening and treatment interventions, and they will support the development of guidelines on the screening, diagnostic, and rehabilitation services needed to reduce the impact of childhood hearing loss.

Aminoglycoside ototoxicity results in permanent loss of the sensory hair cells in the mammalian cochlea. It usually begins at the basal turn causing high-frequency hearing loss. Here we describe previously unreported resistance of hair cells to neomycin ototoxicity in the extreme basal (hook) region of the developing cochlea of the C57BL/6 mouse. Organ of Corti explants from mice at postnatal day 3 were incubated (37 °C, 5% CO2) in normal culture medium for 19.5 h prior to and after exposure to neomycin (1 mM, 3 h). To study neomycin uptake in the hair cells, cochlear explants were incubated with Neomycin Texas-red (NTR) conjugate. As expected, exposure to neomycin significantly reduced the survival of inner (IHC) and outer hair cells (OHC). IHC survival rate was high in the apical segment and low in the basal segment. OHC were well preserved in the apical and hook regions, with substantial OHC loss in the basal segment. The NTR uptake study demonstrated that the high survival rate in the extreme basal turn OHC was associated with low NTR uptake. Treatment with a calcium chelator (BAPTA), which disrupts the opening of mechanoelectrical (MET) transduction channels, abolished or reduced NTR uptake in the hair cells throughout the cochlea. This confirmed the essential role of MET channels in neomycin uptake and implied that the transduction channels could be impaired in the hook region of the developing mouse cochlea, possibly as a result of the cadherin 23 mutation responsible for the progressive deafness in C57BL/6 mice.

Purpose: The present study's objective was to predict the effect of an advanced audiology-led clinic on paediatric ENT outpatient waiting lists in a large secondary public hospital. Methods: A retrospective, single observational study was performed to obtain data on all children referred for semi-urgent or routine ENT outpatient assessment over a six month period. Set criteria were used to calculate the proportion of new ENT referrals that could be eligible for a new advanced audiology-led clinic and the effect this could have on ENT outpatient referrals and capacity. Results: Results indicated that 23% of all semi-urgent and routine paediatric ENT outpatient referrals were eligible for referral to an advanced audiology-led clinic, with 74% of these being from the semi-urgent category. Based on these data, an advanced audiology-led clinic was predicted to increase this facility's ENT outpatient capacity by 77%. Conclusion: In conclusion, the introduction of an advanced audiology-led service could significantly reduce waiting lists and increase capacity in paediatric ENT outpatient services in the public healthcare system.

Objective: To examine cortical auditory evoked potentials (CAEPs) and behavioural measures of spatial speech in noise recognition, sound localization and self-reported perception of hearing...

Our previous studies have shown that the stimulation of A 1 adenosine receptors in the inner ear can mitigate the loss of sensory hair cells and hearing loss caused by exposure to traumatic noise. Here, we focus on the role of adenosine receptors (AR) in the development of noise-induced neural injury in the cochlea using A 1 AR and A 2A AR null mice ( A 1 AR −/− and A 2A AR −/− ). Wildtype (WT) and AR deficient mice were exposed to octave band noise (8–16 kHz, 100 dB SPL) for 2 h to induce cochlear injury and hearing loss. Auditory thresholds and input/output functions were assessed using auditory brainstem responses (ABR) before and two weeks post-exposure. The loss of outer hair cells (OHC), afferent synapses and spiral ganglion neurons (SGN) were assessed by quantitative histology. A 1 AR −/− mice (6–8 weeks old) displayed a high frequency hearing loss (ABR threshold shift and reduced ABR wave I and II amplitudes). This hearing loss was further aggravated by acute noise exposure and exceeded the hearing loss in the WT and A 2A AR −/− mice. All mice experienced the loss of OHC, synaptic ribbons and SGN after noise exposure, but the loss of SGN was significantly higher in A 1 AR −/− mice than in the A 2A AR −/− and WT genotypes. The A 2A AR −/− demonstrated better preservation of OHC and afferent synapses and the minimal loss of SGN after noise exposure. The findings suggest that the loss of A 1 AR expression results in an increased susceptibility to cochlear neural injury and hearing loss, whilst absence of A 2A AR increases cochlear resistance to acoustic trauma.

The primary loss of cochlear glutamatergic afferent nerve synapses due to noise or ageing (cochlear neuropathy) often presents as difficulties in speech discrimination in noisy conditions (hidden hearing loss (HHL)). Currently, there is no treatment for this condition. Our previous studies in mice with genetic deletion of the adenosine A2A receptor (A2AR) have demonstrated better preservation of cochlear afferent synapses and spiral ganglion neurons after noise exposure compared to wildtype mice. This has informed our current targeted approach to cochlear neuroprotection based on pharmacological inhibition of the A2AR. Here, we have used organotypic tissue culture of the Wistar rat cochlea at postnatal day 6 (P6) to model excitotoxic injury induced by N-methyl-d-aspartate (NMDA)/kainic acid (NK) treatment for 2 h. The excitotoxic injury was characterised by a reduction in the density of neural processes immediately after NK treatment and loss of afferent synapses in the presence of intact sensory hair cells. The administration of istradefylline (a clinically approved A2AR antagonist) reduced deafferentation of inner hair cells and improved the survival of afferent synapses after excitotoxic injury. This study thus provides evidence that A2AR inhibition promotes cochlear recovery from excitotoxic injury, and may have implications for the treatment of cochlear neuropathy and prevention of HHL.

ObjectivesHearing loss is one of the most prevalent conditions affecting older people. In addition, there is little known about the factors influencing the uptake of hearing services among underserved communities. Our objective was to identify the barriers to accessing hearing care services among older Pacific Island people in New Zealand.SettingsEligible participants from Auckland City, New Zealand.ParticipantsIndividual face-to-face in-depth interviews were conducted with 36 older Pacific Island people who were experienced hearing difficulties.MethodsA Pacific Island research methodology (Talanoa) and the ‘Health Care Access Barriers’ (HCAB) model, which identifies modifiable barriers to healthcare, was used as a theoretical framework for this research. The interviews were transcribed and analysed using a deductive approach to identify HCAB themes and subthemes experienced by older Pacific Island people.ResultsIdentified themes aligned with HCAB’s themes of financial, structural and cognitive barriers and subthemes described Pacific Island perspectives related to hearing care access in New Zealand. The financial barriers related to the high cost of hearing care and the structural barriers included transportation difficulties, limited family support, preference for community-based services and the absence of hearing care delivered by family doctors. Community norms and attitudes, communication limitations and limited awareness of hearing care services formed cognitive barriers among older Pasifika people in this study.ConclusionWe identified financial, structural and cognitive barriers that dissuaded older Pasifika people from accessing hearing care services. These modifiable barriers need to be eliminated or minimised to enable people to readily receive the hearing care assistance they need. It is essential to improve and develop culturally responsive models of hearing service delivery to ensure equitable access to hearing care, especially for underserved groups such as Pacific Island communities.

The primary loss of cochlear glutamatergic afferent nerve synapses due to noise or ageing (cochlear neuropathy) often presents as difficulties in speech discrimination in noisy conditions (hidden hearing loss (HHL)). Currently, there is no treatment for this condition. Our previous studies in mice with genetic deletion of the adenosine A2A receptor (A2AR) have demonstrated better preservation of cochlear afferent synapses and spiral ganglion neurons after noise exposure compared to wildtype mice. This has informed our current targeted approach to cochlear neuroprotection based on pharmacological inhibition of the A2AR. Here, we have used organotypic tissue culture of the Wistar rat cochlea at postnatal day 6 (P6) to model excitotoxic injury induced by N-methyl-d-aspartate (NMDA)/kainic acid (NK) treatment for 2 h. The excitotoxic injury was characterised by a reduction in the density of neural processes immediately after NK treatment and loss of afferent synapses in the presence of intact sensory hair cells. The administration of istradefylline (a clinically approved A2AR antagonist) reduced deafferentation of inner hair cells and improved the survival of afferent synapses after excitotoxic injury. This study thus provides evidence that A2AR inhibition promotes cochlear recovery from excitotoxic injury, and may have implications for the treatment of cochlear neuropathy and prevention of HHL.

We and others have previously identified signalling pathways associated with the adenosine A1 receptor (A1R) as important regulators of cellular responses to injury in the cochlea. We have shown that the "post-exposure" treatment with adenosine A1R agonists confers partial protection against acoustic trauma and other forms of sensorineural hearing loss (SNHL). The aim of this study was to determine if increasing A1R responsiveness to endogenous adenosine would have the same otoprotective effect. This was achieved by pharmacological targeting of the Regulator of G protein Signalling 4 (RGS4). RGS proteins inhibit signal transduction pathways initiated by G protein-coupled receptors (GPCR) by enhancing GPCR deactivation and receptor desensitisation. A molecular complex between RGS4 and neurabin, an intracellular scaffolding protein expressed in neural and cochlear tissues, is the key negative regulator of A1R activity in the brain. In this study, Wistar rats (6&ndash, 8 weeks) were exposed to traumatic noise (110 dBSPL, 8&ndash, 16 kHz) for 2 h and a small molecule RGS4 inhibitor CCG-4986 was delivered intratympanically in a Poloxamer-407 gel formulation for sustained drug release 24 or 48 h after noise exposure. Intratympanic administration of CCG-4986 48 h after noise exposure attenuated noise-induced permanent auditory threshold shifts by up to 19 dB, whilst the earlier drug administration (24 h) led to even better preservation of auditory thresholds (up to 32 dB). Significant improvement of auditory thresholds and suprathreshold responses was linked to improved survival of sensorineural tissues and afferent synapses in the cochlea. Our studies thus demonstrate that intratympanic administration of CCG-4986 can rescue cochlear injury and hearing loss induced by acoustic overexposure. This research represents a novel paradigm for the treatment of various forms of SNHL based on regulation of GPCR.

Neural activity during early development is known to alter innervation pathways in the central and peripheral nervous systems. We sought to examine how reduced sound-induced sensory activity in the cochlea affected the consolidation of glutamatergic synapses between inner hair cells (IHC) and the primary auditory neurons as these synapses play a primary role in transmitting sound information to the brain. A unilateral conductive hearing loss was induced prior to the onset of sound-mediated stimulation of the sensory hair cells, by rupturing the tympanic membrane and dislocating the auditory ossicles in the left ear of P11 mice. Auditory brainstem responses at P15 and P21 showed a 40-50-dB increase in thresholds for frequencies 8-32kHz in the dislocated ear relative to the control ear. Immunohistochemistry and confocal microscopy were subsequently used to examine the effect of this attenuation of sound stimulation on the expression of RIBEYE, which comprises the presynaptic ribbons, Shank-1, a postsynaptic scaffolding protein, and the GluA2/3 and 4 subunits of postsynaptic AMPA receptors. Our results show that dislocation did not alter the number of pre- or postsynaptic protein puncta. However, dislocation did increase the size of RIBEYE, GluA4, GluA2/3 and Shank-1 puncta, with postsynaptic changes preceding presynaptic changes. Our data suggest that a reduction in sound stimulation during auditory development induces plasticity in the molecular make-up of IHC glutamatergic synapses, but does not affect the number of these synapses. Up-regulation of synaptic proteins with sound attenuation may facilitate a compensatory increase in synaptic transmission due to the reduced sensory stimulation of the IHC.

Kolliker's organ is a transient epithelial structure, comprising a major part of the organ of Corti during pre-hearing stages of development. The auditory system is spontaneously active during development, which serves to retain and refine neural connections. Kolliker's organ is considered a key candidate for generating such spontaneous activity, most likely through purinergic (P2 receptor) signalling and inner hair cell (IHC) activation. Associated with the spontaneous neural activity, ATP released locally by epithelial cells induces rhythmic morphological changes within Kolliker's organ, the purpose of which is not understood. These changes are accompanied by a shift in cellular refractive index, allowing optical detection of this activity in real-time. Using this principle, we investigated the origin of spontaneous morphological activity within Kolliker's organ. Apical turns of Wistar rat cochleae (P9-11) were dissected, and the purinergic involvement was studied following acute tissue exposure to a P2 receptor agonist (ATPγS) and antagonist (suramin). ATPγS induced a sustained darkening throughout Kolliker's organ, reversed by suramin. This effect was most pronounced in the region closest to the inner hair cells, which also displayed the highest frequency of intrinsic morphological events. Additionally, suramin alone induced swelling of this region, suggesting a tight regulation of cell volume by ATP-mediated mechanisms. Histological analysis of cochlear tissues demonstrates the most profound volume changes in the border cell region immediately adjacent to the IHCs. Together, these results underline the role of purinergic signalling in initiating morphological events within Kolliker's organ, and suggest a key involvement of border cells surrounding IHCs in regulating this spontaneous activity. This article is part of a Special Issue entitled .

Permanent high frequency (>4 kHz) sensorineural hearing loss following middle ear surgery occurs in up to 25% of patients. The aetiology of this loss is poorly understood and may involve transmission of supra-physiological forces down the ossicular chain to the cochlea. Investigating the mechanisms of this injury using animal models is challenging, as evaluating cochlear function with evoked potentials is confounded when ossicular manipulation disrupts the normal air conduction (AC) pathway. Bone conduction (BC) using clinical bone vibrators in small animals is limited by poor transducer output at high frequencies sensitive to trauma. The objectives of the present study were firstly to evaluate a novel high frequency bone conduction transducer with evoked auditory potentials in a guinea pig model, and secondly to use this model to investigate the impact of middle ear surgical manipulation on cochlear function. We modified a magnetostrictive device as a high frequency BC transducer and evaluated its performance by comparison with a calibrated AC transducer at frequencies up to 32 kHz using the auditory brainstem response (ABR), compound action potential (CAP) and summating potential (SP). To mimic a middle ear traumatising stimulus, a rotating bur was brought in to contact with the incudomalleal complex and the effect on evoked cochlear potentials was observed. BC-evoked potentials followed the same input-output function pattern as AC potentials for all ABR frequencies. Deterioration in CAP and SP thresholds was observed after ossicular manipulation. It is possible to use high frequency BC to evoke responses from the injury sensitive basal region of the cochlea and so not rely on AC with the potential confounder of conductive hearing loss. Ongoing research explores how these findings evolve over time, and ways in which injury may be reduced and the cochlea protected during middle ear surgery.

Purinergic signaling regulates important physiological processes and the homeostatic response to stress in the cochlea via extracellular nucleosides (adenosine) and nucleotides (ATP, UTP). Using a previously established organotypic culture model, the current study investigated the effect of purinergic P1 (adenosine) and P2 (ATP) receptor activation on the survival of the sensory hair cell population in the cochlea exposed to the ototoxic aminoglycoside neomycin. Organ of Corti explants were obtained from C57BL/6 mice at postnatal day 3 (P3) and maintained in normal culture medium (with or without purine receptor agonists or analogs) for 19.5 h prior to neomycin exposure (1 mM, 3 h) followed by a further incubation for 19.5 h in culture medium. The cochlear explants were then fixed in 4% paraformaldehyde (PFA) and sensory hair cells labeled with Alexa 488-phalloidin. Neomycin induced a substantial loss of the sensory hair cells, mostly in the middle segment of the cochlea. This neomycin-induced ototoxicity was unaffected by the addition of P2 receptor agonists (ATP and UTP) in the culture medium, whilst the addition of their slowly-hydrolyzable analogs (ATPγS, UTPγS) aggravated neomycin-induced sensory hair cell loss. In contrast, the activation of P1 receptors by adenosine or adenosine amine congener (ADAC) conferred partial protection from neomycin ototoxicity. This study demonstrates a pro-survival effect of P1 receptor stimulation, whilst prolonged activation of P2 receptors has an opposite effect. Based on these findings, we postulate that P1 and P2 receptors orchestrate differential responses to cochlear injury and that the balance of these receptors is important for maintaining cochlear homeostasis following ototoxic injury.

In the cochlea, Reissner's membrane separates the scala media endolymphatic compartment that sustains the positive endocochlear potential and ion composition necessary for sound transduction, from the scala vestibuli perilymphatic compartment. It is known that with sustained elevated sound levels, adenosine 5'-triphosphate (ATP) is released into the endolymph and ATP-gated ion channels on the epithelial cells lining the endolymphatic compartment shunt the electrochemical driving force, contributing to protective purinergic hearing adaptation. This study characterises the properties of epithelial cell P2X(2)-type ATP-activated membrane conductance in the mouse Reissner's membrane, which forms a substantial fraction of the scale media surface. The cells were found to express two isoforms (a and b) of the P2X(2) subunit arising from alternative splicing of the messenger RNA (mRNA) transcript that could contribute to the trimeric subunit assembly. The ATP-activated conductance demonstrated both immediate and delayed desensitisation consistent with incorporation of the combination of P2X(2) subunit isoforms. Activation by the ATP analogue 2meSATP had equipotency to ATP, whereas α,β-meATP and adenosine 5'-diphosphate (ADP) were ineffective. Positive allosteric modulation of the P2X(2) channels by protons was profound. This native conductance was blocked by the P2X(2)-selective blocker pyridoxal-phosphate-6-azophenyl-2',4'-disulphonic acid (PPADS) and the conductance was absent in these cells isolated from mice null for the P2rX2 gene encoding the P2X(2) receptor subunit. The activation and desensitisation properties of the Reissner's membrane epithelial cell ATP-gated P2X(2) channels likely contribute to the sensitivity and kinetics of purinergic control of the electrochemical driving force for sound transduction invoked by noise exposure.

To study the changes in behavioural and cortical responses over time in a child with single-sided deafness fitted with a cochlear implant (CI).Cortical auditory evoked potentials (CAEPs) in noise (+5 dB signal-to-noise ratio) were recorded and auditory skills were assessed using tests of sound localization, spatial speech perception in noise, and self-ratings of auditory abilities (Listening inventory for education, LIFE and Speech, spatial and qualities of hearing questionnaire, SSQ parental version). Measures were obtained prior to and after a CI fitting, including one, six, and 12 months after the CI switch on.Spatial speech recognition improved over time. At 12 months post-CI, word recognition scores were similar to those of normal hearing children. Signal-to-noise ratios for sentences decreased (i.e. improved) over time post-CI. Sound localization markedly improved at 12 months post-CI compared to baseline. Self-perception of difficulty scores decreased over time. Parental ratings of hearing abilities improved compared to baseline for all subscales. There were changes in the P1-N1-P2 complex at 12 months post-CI, which were clearer frontally across stimuli. Further research is needed to understand the significance of such changes after CI fitting for single-sided deafness.Although the changes observed could reflect maturational changes, the clinically significant improvement in recognition of speech in noise and improved questionnaire results suggest that the CI was beneficial, consistent with the feedback from the participant.

Objective: To develop and assess use, acceptability and feasibility of an ecological hearing conservation programme for workplaces. Design: A school-based public health hearing preservation education programme (Dangerous Decibels®) was adapted for workplaces using the Multi-level Approach to Community Health (MATCH) Model. The programme was delivered in small manufacturing companies and evaluated using a questionnaire before the training and at one week and two-months after training. Study sample: Workers (n = 56) from five small manufacturing companies were recruited. Results: There was a significant improvement in knowledge, attitudes and behaviour of workers at the intrapersonal level; in behaviour motivation and safety culture at the interpersonal and organisational levels; and an overall improvement in hearing-health behaviour after two months post-intervention. Conclusions: The developed programme offers a simple, interactive and theory-based intervention that is well accepted and effective ...

Noise-induced hearing loss (NIHL) is a global health problem affecting over 5% of the population worldwide. We have shown previously that acute noise-induced cochlear injury can be ameliorated by administration of drugs acting on adenosine receptors in the inner ear, and a selective A1adenosine receptor agonist adenosine amine congener (ADAC) has emerged as a potentially effective treatment for cochlear injury and resulting hearing loss. This study investigated pharmacokinetic properties of ADAC in rat perilymph after systemic (intravenous) administration using a newly developed liquid chromatography-tandem mass spectrometry detection method. The method was developed and validated in accordance with the USA FDA guidelines including accuracy, precision, specificity, and linearity. Perilymph was sampled from the apical turn of the cochlea to prevent contamination with the cerebrospinal fluid. ADAC was detected in cochlear perilymph within two minutes following intravenous administration and remained in perilymph above its minimal effective concentration for at least two hours. The pharmacokinetic pattern of ADAC was significantly altered by exposure to noise, suggesting transient changes in permeability of the blood-labyrinth barrier and/or cochlear blood flow. This study supports ADAC development as a potential clinical otological treatment for acute sensorineural hearing loss caused by exposure to traumatic noise.

Hearing loss from occupational noise exposure is a significant occupational health problem, requiring effective health and safety strategies. Essential to this is an understanding of the noise exposure of workers and the use of hearing protection equipment (HPE). This study reports on data collected in New Zealand. Visits were made to companies in each economic sector. Personal dosimetry was used to assess individual noise exposure of 529 workers. Workers were also interviewed about their use of HPE. Overall, 40.4% of production workers had a daily noise exposure greater than 1 Pa2h, exceeding the New Zealand National Standard for occupational noise exposure without HPE. Of these, 88.5% reported to use HPE when working in noise; however, some observations suggested that workers do not consistently use the devices. These data add to the overall picture of noise exposure of workers in New Zealand and are especially useful in areas where data did not previously exist or were difficult to access.

NADPH oxidases are enzymes that transport electrons across the plasma membrane and generate superoxide radical from molecular oxygen. The current study investigated the expression and distribution of NOX/DUOX members of the NADPH oxidase family (NOX1-5 and DUOX1-2) in the rat cochlea and their regulation in response to noise. Wistar rats (8–10 weeks) were exposed for 24 h to band noise (8–12 kHz) at moderate (100 dB) or traumatic (110 dB) sound pressure levels (SPL). Animals exposed to ambient noise (45–55 dB SPL) served as controls. Immunohistochemistry demonstrated predominant expression of all NOX/DUOX isoforms in the sensory and supporting cells of the organ of Corti, with very limited immunoexpression in the lateral wall tissues and spiral ganglion neurons. Noise exposure induced up-regulation of NOX1 and DUOX2 in the cochlea, whereas NOX3 was down-regulated. A significant reduction in the intensity of NOX3 immunolabeling was observed in the inner sulcus region of the cochlea after exposure to noise. Post-exposure inhibition of NADPH oxidases by Diphenyleneiodonium (DPI), a broadly selective NADPH oxidase inhibitor, mitigated noise-induced hearing loss. Conclusion: Noise-induced up-regulation of NOX1 and DUOX2 could be linked to cochlear injury. In contrast, down-regulation of NOX3 may represent an endogenous protective mechanism to reduce oxidative stress in the noise-exposed cochlea. Inhibition of NADPH oxidases is potentially a novel pathway for therapeutic management of noise-induced hearing loss.

HEARING LOSS FROM injury and disease of the auditory sensory organ, the cochlea, affects a large and increasing proportion of the population (1,2). There is a need to understand the mechanisms of cochlear injury to develop targeted treatments for hearing loss. Cochlear degeneration and the associated hearing loss occur from a great variety of causes including genetic abnormalities, aging, noise exposure, drug ototoxicity (e.g., aminoglycoside antibiotics and anti-cancer drugs), trauma, and infection. Inflammation of the inner ear is thought to be a major contributor to the development of cochlear injury and the concomitant sensorineural hearing loss from many different causes, as well as a consequence of inner ear surgery, for example, cochlear implantation (3). Cochlear inflammation caused by middle or inner ear infections, trauma and noise exposure, has been characterized in animal models (4,5). Treatment with steroids, such as dexamethasone, can mitigate the injury and hearing loss in animals (6). Inflammation is also assumed, rather than diagnosed, in many clinical conditions affecting the inner ear, and steroids are the treatment of choice (6). However, there is scarce direct evidence of inflammation occurring in these clinical conditions and very little evidence of the dynamics of the inflammatory responses in the human inner ear (7,8). Understanding the inflammatory processes, and being able to determine its time course and stages in an individual patient, would aid the diagnosis of the type and location of cochlear injury, and lead to the development of targeted treatments to reduce the deleterious effects of inflammation on the delicate structures of the inner ear. The location of inner ear tissues deep within the temporal bone of the skull is a significant impediment to identifying any disease process in the inner ear. This is particularly an issue when investigating or identifying detrimental processes such as inflammatory disease in the human inner ear. The current knowledge of inner ear inflammation mostly stems from animal studies involving tissue collection and histological or molecular analysis of inflammatory markers, whereas little is known about the progression of inflammatory disease in the living inner ear. Recent developments in MRI offer exciting opportunities for studying structure, function and metabolism of the intact, living cochlea. Visualization of cochlear structures in animals and humans can be achieved with high field strength magnets (9-11) as well as some quantification in animals, but these have been limited to the differentiation and quantification of cochlear fluid compartments, and quantification in terms of relative signal intensity of the uptake of gadolinium based contrast agent (GBCA) in some cochlear fluid spaces (12,13). However, all the studies (10,11,14) to date essentially have been qualitative and, very few have looked at the dynamic changes during cochlear inflammation (7,8). MRI has been used clinically in an attempt to assess cochlear disorders (9-11,14,15), particularly the changes in the dimensions of the fluid compartments associated with Meniere's disease and any changes that may underlie sudden sensorineural hearing loss. For the purpose of this study, the dynamic contrast enhanced-MRI technique and macrophage imaging approach using iron oxide particles are of particular interest. Dynamic contrast enhanced-MRI (DCE-MRI) involves the acquisition of a series of T1-weighted images before and after the injection of a paramagnetic contrast agent. The application of a pharmacokinetic (PK) model to these acquired data permits the calculation of meaningful physiological parameters; namely, the volume transfer rate constant of contrast agent extravasation (Ktrans) and the volume fraction of the extravascular, extracellular space (EES, νe) of the tissue of interest. The original DCE-MRI PK model was described more than 10 years ago (16), and numerous alternate models have been described since (17-24). To date however, quantitative DCE-MRI has not been applied to calculate changes in vascular permeability in the normal or diseased inner ear. Macrophage infiltration may be visualized noninvasively by use of superparamagnetic iron oxide nanoparticles which are taken up by the monocyte-macrophage system (25,26) and predominantly affect the transverse relaxation time. These nanoparticles have found many potential medical applications for the detection of diseases involving an inflammatory response (27) and are seen as having a great potential for the assessment of the therapeutic efficacy of inflammatory diseases developing in the central nervous system (28). To date, one specific type of superparamagnetic iron oxide nanoparticle was reported to facilitate the differentiation between the two cochlear fluids when injected directly into the rat cochlea (29). However, there has been no report of their use for the study of cochlear inflammation. Our approach has been to develop MRI techniques to probe inner ear function and to use specific bio-markers of disease processes to qualitatively and quantitatively define the dynamics (admittedly on the relatively long time scale enabled by MRI) and chronic progression of disease processes in an individual. Here we report the use of DCE-MRI and ultrasmall superparamagnetic iron oxide particles (USPIOs) to quantify changes in vascular permeability and to characterize the recruitment of phagocytic cells into the cochlear tissues in a guinea-pig model of inner ear inflammation. This research also provides a translational pathway for cochlear imaging and development of MR as diagnostic tools for human inner ear diseases.

Oxidative stress has been established as the key mechanism of the cochlear damage underlying noise-induced hearing loss, however, emerging evidence suggests that cochlear inflammation may also be a major contributor. This study aimed to improve our understanding of the cochlear inflammatory response associated with acute and chronic noise exposure. C57BL/6 mice were exposed to acute traumatic noise (100 dBSPL, 8-16 kHz for 24 h) and their cochleae collected at various intervals thereafter, up to 7 days. Using quantitative RT-PCR and immunohistochemistry, changes in expression levels of proinflammatory cytokines (TNF-α, IL-1β), chemokines (CCL2) and cell adhesion molecules (ICAM-1) were studied. All gene transcripts displayed similar dynamics of expression, with an early upregulation at 6 h post-exposure, followed by a second peak at 7 days. ICAM-1 immunoexpression increased significantly in the inferior region of the spiral ligament, peaking 24 h post-exposure. The early expression of proinflammatory mediators likely mediates the recruitment and extravasation of inflammatory cells into the noise-exposed cochlea. The occurrence of the latter expression peak is not clear, but it may be associated with reparative processes initiated in response to cochlear damage. Chronic exposure to moderate noise (90 dBSPL, 8-16 kHz, 2 h/day, up to 4 weeks) also elicited an inflammatory response, reaching a maximum after 2 weeks, suggesting that cochlear damage and hearing loss associated with chronic environmental noise exposure may be linked to inflammatory processes in the cochlea. This study thus provides further insight into the dynamics of the cochlear inflammatory response induced by exposure to acute and chronic noise.