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https://www.mdpi.com/1660-4601/16/18/3428

Effect of Specific Retinoic Acid Receptor Agonists on Noise-Induced Hearing Loss
by Sang Hyun Kwak 1,Gi-Sung Nam 2,Seong Hoon Bae 1 andJinsei Jung 1,*OrcID
1
Department of Otorhinolaryngology, Yonsei University College of Medicine, Seoul 03722, Korea
2
Department of Otorhinolaryngology, Chonbuk National University College of Medicine, Jeonju 54907, Korea
*
Author to whom correspondence should be addressed.
Int. J. Environ. Res. Public Health 2019, 16(18), 3428; https://doi.org/10.3390/ijerph16183428
Received: 3 July 2019 / Revised: 10 September 2019 / Accepted: 11 September 2019 / Published: 16 September 2019
(This article belongs to the Special Issue Environmental Exposures and Hearing Loss)

https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0221713

https://www.ncbi.nlm.nih.gov/pubmed/31498809?dopt=Abstract

A systematic review and network meta-analysis of existing pharmacologic therapies in patients with idiopathic sudden sensorineural hearing loss.

PLoS One. 2019;14(9):e0221713

Authors: Ahmadzai N, Kilty S, Cheng W, Esmaeilisaraji L, Wolfe D, Bonaparte JP, Schramm D, Fitzpatrick E, Lin V, Skidmore B, Moher D, Hutton B

Abstract

BACKGROUND: Hearing loss is one of the leading causes of disability worldwide. Patients with hearing loss experience impaired quality of life, as well as emotional and financial consequences that affect both themselves and their families. Idiopathic sudden sensorineural hearing loss (ISSNHL) is a common but difficult to treat condition that has a sudden onset of ≤ 72 hour associated with various etiologies, with the majority of cases being idiopathic. There exists a wide range of therapeutic options, however, the uncertainty surrounding their comparative efficacy and safety makes selection of treatment difficult. This systematic review and network meta-analysis (NMA) assessed the relative effects of competing treatments for management of ISSNHL.

METHODS: A protocol for this review was registered with PROSPERO (CRD42017073756). A detailed search of MEDLINE, Embase and the Cochrane Library from inception to February 8th, 2018 was carried out by an experienced information specialist. Grey literature was also searched. Screening full-text records, and risk of bias assessment were carried out independently by two reviewers, and disagreements were resolved through consensus or third party adjudication, while data was collected by one reviewer and verified by a second reviewer. Bayesian network meta-analyses (NMA) were performed to inform comparisons between interventions for a priori specified outcomes that included pure tone average (PTA) improvement and hearing recovery.

RESULTS: The search identified a total of 1,138 citations, of which 613 remained for review after removal of duplicates. Of these, 23 publications describing 19 unique studies (total sample size of 1,527) met our a priori eligibility criteria, that were assessed to be at unclear or high risk of bias on several domains. We identified data on several interventions for ISSNHL therapy and were able to construct treatment networks consisting of six intervention groups that included placebo; intratympanic (IT) steroid; IT plus systemic steroid; per oral (PO) steroid; intravenous (IV) steroid; and IV plus PO steroid for our NMAs. IT plus systemic steroids demonstrated the largest difference in PTA improvement compared to placebo (25.85 dB, 95% CrI 7.18-40.58), followed by IV plus PO steroids (22.06 dB, 95% CrI 1.24-39.17), IT steroids (18.24 dB, 95% CrI 3.00-29.81). We observed that the difference of PTA improvement between each intervention and placebo diminished over time, attributed to spontaneous recovery. The binary outcomes of hearing recovery demonstrated similar relative ordering of interventions but were less sensitive than PTA improvement to capture the significant differences between interventions and placebo.

CONCLUSION: Unclear to high risk of bias trials rated IT plus systemic steroid treatment as the best among the six interventions compared, and all active treatments were better than placebo in improving PTA. However, it should be noted that certain comparisons were based on indirect evidence only or few studies of small sample size, and analyses were unable to control for steroid type and dosage. Given these limitations, further data originating from methodologically sound and rigorous trials with adequate reporting are needed to confirm our findings.

PMID: 31498809 [PubMed – in process]

https://journals.lww.com/otology-neurotology/Abstract/publishahead/High_Dose_of_Intratympanic_Steroids_for_Sudden.96374.aspx

https://www.ncbi.nlm.nih.gov/pubmed/31498293?dopt=Abstract

High Dose of Intratympanic Steroids for Sudden Sensorineural Hearing Loss Salvage.

Otol Neurotol. 2019 Sep 06;:

Authors: Taha A, Shlamkovitch N, Abu-Eta R, Yeheskeli E, Muallem-Kalmovich L, Gavriel H, Pitaro J

Abstract

OBJECTIVE: Intratympanic (IT) steroid administration for sudden sensorineural hearing loss is offered as salvage to patients who failed systemic steroid treatment. Our objective was to study the audiometric and clinical outcomes of patients given salvage therapy with high-dose IT steroids instilled via ventilation tube.

STUDY DESIGN: Retrospective case review.

SETTING: Academic secondary medical center.

PATIENTS: One hundred three patients >18 years of age with sudden sensorineural hearing loss who failed systemic steroids and received IT treatment between 2010 and 2018.

INTERVENTION: Following ventilation tube insertion, 1 ml of 10 mg/ml dexamethasone was instilled, twice daily, for 7 days.

OUTCOME MEASURES: Hearing assessment immediately before and after treatment. Tinnitus and vertigo complaints and risk factors were also retrieved.

RESULTS: Tinnitus had improved in 53 (52%) patients, vertigo in 4 (4%), and aural fullness sensation in 56 (55%) (p < 0.001, p = 0.344, p < 0.001, respectively). The mean pure-tone threshold difference across frequencies following treatment was between 0 and 6 dB. A significant improvement was observed at 250, 500, 1000 Hz (p < 0.001 in all), and at 2000 Hz (p = 0.035). No significant difference was found at 4000 and 8000 Hz (p = 0.055, p = 0.983 respectively). Mean pure-tone average improvement of 4.5 dB was detected in 61 (59%) patients (p = 0.001). The mean speech discrimination score improved by 7% (p = 0.001). Four (22%) diabetic and nine (20%) hypertensive patients had pure-tone average ≥10 dB improvement (p = 0.759, p = 0.852 respectively). CONCLUSION: Although more than half of the patients improved clinically, the significance of the slight audiometric improvement should be weighed against the treatment protocol's complications. PMID: 31498293 [PubMed - as supplied by publisher]

https://www.tandfonline.com/doi/abs/10.1080/00016489.2019.1654130?journalCode=ioto20

https://www.ncbi.nlm.nih.gov/pubmed/31486693?dopt=Abstract

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Authors: Lee SH, Lyu AR, Shin SA, Jeong SH, Lee SA, Park MJ, Park YH

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Glucocorticoid (GC) is a steroid hormone secreted from the adrenal cortex in response to stress, which acts by binding to cytoplasmic glucocorticoid receptors (GRs). Dexamethasone (DEX) is a synthetic GC exhibiting immunosuppressive effects in both human and rodent models of hearing loss. While clinical evidence has shown the effectiveness of DEX for treatment of various inner ear diseases, its mechanisms of action and the optimal timing of treatment are not well understood. In the present study, intergroup comparisons were conducted based on the time point of treatment with DEX: (1) pretreatment; (2) posttreatment; and (3) pre&post-noise. The pre&post DEX treatment group showed a significant improvement in threshold shift at 1 day post-noise exposure as compared to the TTS (transient threshold shift)-only group at 8 and 16 kHz. Both TTS and PTS (permanent threshold shift) significantly reduced cochlear GR mRNA expression and increased serum corticosterone and cochlear inflammatory cytokines. The pre&post DEX treatment group showed a significant decrease in serum corticosterone level as compared to other DEX treatment groups and TTS-treated group at 3 days after acoustic trauma. Our results suggest that the timing of DEX administration differentially modulates systemic steroid levels, GR expression and cochlear cytokine expression.

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Three Cases of Sudden Sensorineural Hearing Loss with Complete Recovery by Korean Medical Treatment

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PKHD1L1 is a coat protein of hair-cell stereocilia and is required for normal hearing.

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The bundle of stereocilia on inner ear hair cells responds to subnanometer deflections produced by sound or head movement. Stereocilia are interconnected by a variety of links and also carry an electron-dense surface coat. The coat may contribute to stereocilia adhesion or protect from stereocilia fusion, but its molecular identity remains unknown. From a database of hair-cell-enriched translated proteins, we identify Polycystic Kidney and Hepatic Disease 1-Like 1 (PKHD1L1), a large, mostly extracellular protein of 4249 amino acids with a single transmembrane domain. Using serial immunogold scanning electron microscopy, we show that PKHD1L1 is expressed at the tips of stereocilia, especially in the high-frequency regions of the cochlea. PKHD1L1-deficient mice lack the surface coat at the upper but not lower regions of stereocilia, and they develop progressive hearing loss. We conclude that PKHD1L1 is a component of the surface coat and is required for normal hearing in mice.

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Rare KCNQ4 variants found in public databases underlie impaired channel activity that may contribute to hearing impairment.

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KCNQ4 is frequently mutated in autosomal dominant non-syndromic hearing loss (NSHL), a typically late-onset, initially high-frequency loss that progresses over time (DFNA2). Most KCNQ4 mutations linked to hearing loss are clustered around the pore region of the protein and lead to loss of KCNQ4-mediated potassium currents. To understand the contribution of KCNQ4 variants to NSHL, we surveyed public databases and found 17 loss-of-function and six missense KCNQ4 variants affecting amino acids around the pore region. The missense variants have not been reported as pathogenic and are present at a low frequency (minor allele frequency < 0.0005) in the population. We examined the functional impact of these variants, which, interestingly, induced a reduction in potassium channel activity without altering expression or trafficking of the channel protein, being functionally similar to DFNA2-associated KCNQ4 mutations. Therefore, these variants may be risk factors for late-onset hearing loss, and individuals harboring any one of these variants may develop hearing loss during adulthood. Reduced channel activity could be rescued by KCNQ activators, suggesting the possibility of medical intervention. These findings indicate that KCNQ4 variants may contribute more to late-onset NSHL than expected, and therefore, genetic screening for this gene is important for the prevention and treatment of NSHL. PMID: 31434872 [PubMed - in process]

https://www.sciencedirect.com/science/article/pii/S0378595519301893?via%3Dihub

https://www.ncbi.nlm.nih.gov/pubmed/31493568?dopt=Abstract

Cochlear histopathology in human genetic hearing loss: State of the science and future prospects.

Hear Res. 2019 Aug 19;382:107785

Authors: Bommakanti K, Iyer JS, Stankovic KM

Abstract

Sensorineural hearing loss (SNHL) is an extraordinarily common disability, affecting 466 million people across the globe. Half of these incidents are attributed to genetic mutations that disrupt the structure and function of the cochlea. The human cochlea’s interior cannot be imaged or biopsied without damaging hearing; thus, everything known about the morphologic correlates of hereditary human deafness comes from histopathologic studies conducted in either cadaveric human temporal bone specimens or animal models of genetic deafness. The purpose of the present review is to a) summarize the findings from all published histopathologic studies conducted in human temporal bones with known SNHL-causing genetic mutations, and b) compare the reported phenotypes of human vs. mouse SNHL caused by the same genetic mutation. The fact that human temporal bone histopathologic analysis has been reported for only 22 of the nearly 200 identified deafness-causing genes suggests a great need for alternative and improved techniques for studying human hereditary deafness; in light of this, the present review concludes with a summary of promising future directions, specifically in the fields of high resolution cochlear imaging, intracochlear fluid biopsy, and gene therapy.

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https://www.termedia.pl/Hearing-regeneration-and-regenerative-medicine-present-and-future-approaches,19,36991,1,1.html

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Hearing regeneration and regenerative medicine: present and future approaches.

Arch Med Sci. 2019 Jul;15(4):957-967

Authors: Nacher-Soler G, Garrido JM, Rodríguez-Serrano F

Abstract

More than 5% of the world population lives with a hearing impairment. The main factors responsible for hearing degeneration are ototoxic drugs, aging, continued exposure to excessive noise and infections. The pool of adult stem cells in the inner ear drops dramatically after birth, and therefore an endogenous cellular source for regeneration is absent. Hearing loss can emerge after the degeneration of different cochlear components, so there are multiple targets to be reached, such as hair cells (HCs), spiral ganglion neurons (SGNs), supporting cells (SCs) and ribbon synapses. Important discoveries in the hearing regeneration field have been reported regarding stem cell transplantation, migration and survival; genetic systems for cell fate monitoring; and stem cell differentiation to HCs, SGNs and SCs using adult stem cells, embryonic stem cells and induced pluripotent stem cells. Moreover, some molecular mediators that affect the establishment of functional synapses have been identified. In this review, we will focus on reporting the state of the art in the regenerative medicine field for hearing recovery. Stem cell research has enabled remarkable advances in regeneration, particularly in neuronal cells and synapses. Despite the progress achieved, there are certain issues that need a deeper development to improve the results already obtained, or to develop new approaches aiming for the clinical application.

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Avenanthramide-C prevents noise- and drug-induced hearing loss while protecting auditory hair cells from oxidative stress.

Cell Death Discov. 2019;5:115

Authors: Umugire A, Lee S, Kim D, Choi M, Kim HS, Cho HH

Abstract

Noise exposure or ototoxic drugs instigate various types of damage to the cochlea, resulting in hearing loss (HL). While the incidence of HL is growing continuously, there are, so far, no adequate drugs to prevent or treat HL. Avenanthramide (AVN), a natural product extracted from oats, has been reported to possess anti-oxidant/inflammatory properties, and protect several types of cells. In this study, we investigated whether AVN-C can protect auditory hair cells, and preserve hearing from noise trauma and ototoxic drugs. Wild-type C57BL/6 mice were used to generate several HL models. Serum and perilymphatic fluid samples were analyzed using mass spectrophotometry to detect AVN-C. AVN-C crossed the blood-labyrinth barrier, and was detected in the perilymph after systemic injection. Pretreatment by AVN-C 24โ€‰h before exposure to temporary threshold shift noise contributed to the preserving hearing. Moreover, in the case of permanent threshold shift, AVN-C provided significant protection from noise. AVN-C also strongly protected against deterioration in hearing due to kanamycin and furosemide (Kโ€‰+โ€‰F). According to the results of our scanning electron microscopy analysis, many outer hair cells (OHCs) were destroyed by noise trauma, while AVN-C prevented these losses. OHC loss due to Kโ€‰+โ€‰F was even more severe, even affecting the apex. Strikingly, AVN-C treatment maintained OHCs at a level comparable to normal cochlea. AVN-C reduced the dichlorofluorescin (DCF)-positive population in gentamicin-treated HEI-OC1 in vitro. The expressions of TNF-a, BAK, IL-1b, and Bcl-2 were attenuated by AVN-C, revealing its antioxidant effects. The results of this study show that AVN-C crosses the blood-labyrinth barrier and provide a significant protection against noise- and drug-induced ototoxicity. Hence, AVN-C is a good candidate for future therapy aimed at protecting against sensorineural HL.

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https://www.ncbi.nlm.nih.gov/pubmed/31285299?dopt=Abstract

Divergent auditory-nerve encoding deficits between two common etiologies of sensorineural hearing loss.

J Neurosci. 2019 Jul 08;:

Authors: Henry KS, Sayles M, Hickox AE, Heinz MG

Abstract

Speech intelligibility can vary dramatically between individuals with similar clinically defined severity of hearing loss based on the audiogram. These perceptual differences, despite equal audiometric-threshold elevation, are often assumed to reflect central-processing variations. Here, we compared peripheral-processing in auditory-nerve fibers of male chinchillas between two prevalent hearing-loss etiologies: metabolic hearing loss (MHL) and noise-induced hearing loss (NIHL). MHL results from age-related reduction of the endocochlear potential due to atrophy of the stria vascularis. MHL in the present study was induced using furosemide, which provides a validated model of age-related MHL in young animals by reversibly inhibiting the endocochlear potential. Effects of MHL on peripheral processing were assessed using Wiener-kernel (system-identification) analyses of single auditory-nerve fiber responses to broadband noise, for direct comparison to previously published auditory-nerve responses from animals with NIHL. Wiener-kernel analyses show that even mild NIHL causes grossly abnormal coding of low-frequency stimulus components. In contrast, for MHL the same abnormal coding was only observed with moderate-severe loss. For equal sensitivity loss, coding impairment was substantially less severe with MHL than with NIHL, probably due to greater preservation of the tip-to-tail ratio of cochlear frequency tuning with MHL compared to NIHL rather than different intrinsic auditory-nerve properties. Differences in peripheral neural coding between these two pathologies [sbond] the more severe of which, NIHL, is preventable [sbond] likely contribute to individual speech-perception differences. Our results underscore the need to minimize noise overexposure and for strategies to personalize diagnosis and treatment for individuals with sensorineural hearing loss.SIGNIFICANCE STATEMENTDifferences in speech perception ability between individuals with similar clinically defined severity of hearing loss are often assumed to reflect central neural processing differences. Here, we demonstrate for the first time that peripheral neural processing of complex sounds differs dramatically between the two most common etiologies of hearing loss. Greater processing impairment with noise-induced compared to an age-related (metabolic) hearing-loss etiology may explain heightened speech-perception difficulties in people overexposed to loud environments. These results highlight the need for public policies to prevent noise-induced hearing loss – an entirely avoidable hearing-loss etiology – and for personalized strategies to diagnose and treat sensorineural hearing loss.

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Sex differences in hearing: Probing the role of estrogen signaling.

J Acoust Soc Am. 2019 Jun;145(6):3656

Authors: Shuster BZ, Depireux DA, Mong JA, Hertzano R

Abstract

Hearing loss is the most common form of sensory impairment in humans, with an anticipated rise in incidence as the result of recreational noise exposures. Hearing loss is also the second most common health issue afflicting military veterans. Currently, there are no approved therapeutics to treat sensorineural hearing loss in humans. While hearing loss affects both men and women, sexual dimorphism is documented with respect to peripheral and central auditory physiology, as well as susceptibility to age-related and noise-induced hearing loss. Physiological differences between the sexes are often hormone-driven, and an increasing body of literature demonstrates that the hormone estrogen and its related signaling pathways may in part, modulate the aforementioned differences in hearing. From a mechanistic perspective, understanding the underpinnings of the hormonal modulation of hearing may lead to the development of therapeutics for age related and noise induced hearing loss. Here the authors review a number of studies that range from human populations to animal models, which have begun to provide a framework for understanding the functional role of estrogen signaling in hearing, particularly in normal and aberrant peripheral auditory physiology.

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BMC Res Notes. 2019 May 23;12(1):283

Authors: Mohammed SH, Shab-Bidar S, Abuzerr S, Habtewold TD, Alizadeh S, Djafarian K

Abstract

OBJECTIVE: Evidence shows that anemic individuals are at a higher risk of hearing loss. However, there is no systematic review and meta-analysis study. Thus, we aimed to meta-analyze the existing evidence on the association of iron deficiency anemia (IDA) with sensorineural hearing loss (SNHL). We searched PubMed, MEDLINE, Embase, Scopus, and Google Scholar from inception through October 30, 2017, for studies done on the association of the IDA with SNHL. Pooled odds ratio (OR) was calculated by random effect meta-analysis method. Heterogeneity was assessed by I2 metrics.

RESULT: Four studies, covering a total of 344,080 adults and children, were included. The odds of SNHL was higher by 55% in individuals with IDA, compared with individuals without IDA (OR = 1.55, 95% CI 1.17-2.06; P = 0.03). The age-specific ORs were 1.36 (95% CI 1.15-1.61; P = 0.27) and 3.67 (95% CI 1.72-7.84) for adults and children, respectively. IDA may be a contributing factor to hearing loss. Further studies are warranted, including whether IDA treatment reduces the risk of hearing loss. Meanwhile, hearing loss screening in anemic individuals, or vice versa, may represent an important consideration. PROSPERO registration CRD42017082108.

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https://www.ncbi.nlm.nih.gov/pubmed/31083073?dopt=Abstract

Hearing Protection, Restoration, and Regeneration: An Overview of Emerging Therapeutics for Inner Ear and Central Hearing Disorders.

Otol Neurotol

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Hearing Protection, Restoration, and Regeneration: An Overview of Emerging Therapeutics for Inner Ear and Central Hearing Disorders.

Otol Neurotol. 2019 Jun;40(5):559-570

Authors: Schilder AGM, Su MP, Blackshaw H, Lustig L, Staecker H, Lenarz T, Safieddine S, Gomes-Santos CS, Holme R, Warnecke A

Abstract

OBJECTIVE: To provide an overview of biotechnology and pharmaceutical companies active in the field of inner ear and central hearing disorders and their therapeutic approaches.

METHODS: Scientific and grey literature was searched using broad search terms to identify companies and their hearing-related therapeutic approaches. For each approach its lead indication, product, therapeutic modality, target, mechanism of action and current phase of clinical development was collated.

RESULTS: A total of 43 biotechnology and pharmaceutical companies have been identified that are developing therapeutics for inner ear and central hearing disorders. Their therapeutics include drug-, cell- and gene-based approaches to prevent hearing loss or its progression, restore hearing, and regenerate the inner ear. Their therapeutic targets and specific mechanisms of action are wide-ranging, reflecting the complexity of the hearing pathways and the diversity of mechanisms underlying inner ear disorders. While none of the novel products under investigation have yet made it to the clinical market, and a large proportion are still at preclinical phase, many therapeutics have already entered clinical testing with more expected to do so in the next few years.

CONCLUSION: A wide range of novel therapeutics targeting different hearing, balance and tinnitus pathways, and patient populations are approaching the clinical domain. It is important that clinicians involved in the care of patients with hearing loss prepare for what may become a radically different approach to the management of hearing disorders, and develop a true understanding of the new therapies’ mechanisms of action, applications, and indications.

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Adv Exp Med Biol. 2019;1130:93-107

Authors: Liu W, Wang X, Wang M, Wang H

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In the auditory system, the primary sensory neurons, spiral ganglion neurons (SGNs), transmit complex acoustic information from hair cells to the second-order sensory neurons in the cochlear nucleus for sound processing, thus building the initial bridge between the physical world of sound and the perception of that sound. Cochlear SGN loss causes irreversible hearing impairment because this type of neural cell cannot regenerate. A better understanding of the molecular mechanisms of formation, structure, degeneration, and protection of SGNs will help to design potential therapeutic strategies for preservation and replacement of them in the cochlear implant recipient. In this review, we described and summarized the following about SGNs: (1) their cell biology and their peripheral and central connections, (2) mechanisms of their neuronal damage and their protection, and (3) the neural and synaptic mechanism of auditory neuropathy and current options for hearing rehabilitation from auditory neuropathy. The updates of the research progress and the significant issues on these topics were discussed.

PMID: 30915703 [PubMed – indexed for MEDLINE]