| 1. |
- Li, Hao, et al.
(författare)
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Regeneration in the Auditory Organ in Cuban and African Dwarf Crocodiles (Crocodylus rhombifer and Osteolaemus tetraspis) Can We Learn From the Crocodile How to Restore Our Hearing?
- 2022
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Ingår i: Frontiers in Cell and Developmental Biology. - : Frontiers Media S.A.. - 2296-634X. ; 10
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Tidskriftsartikel (refereegranskat)abstract
- Background: In several non-mammalian species, auditory receptors undergo cell renewal after damage. This has raised hope of finding new options to treat human sensorineural deafness. Uncertainty remains as to the triggering mechanisms and whether hair cells are regenerated even under normal conditions. In the present investigation, we explored the auditory organ in the crocodile to validate possible ongoing natural hair cell regeneration. Materials and Methods: Two male Cuban crocodiles (Crocodylus rhombifer) and an adult male African Dwarf crocodile (Osteolaemus tetraspis) were analyzed using transmission electron microscopy and immunohistochemistry using confocal microscopy. The crocodile ears were fixed in formaldehyde and glutaraldehyde and underwent micro-computed tomography (micro-CT) and 3D reconstruction. The temporal bones were drilled out and decalcified. Results: The crocodile papilla basilaris contained tall (inner) and short (outer) hair cells surrounded by a mosaic of tightly connected supporting cells coupled with gap junctions. Afferent neurons with and without ribbon synapses innervated both hair cell types. Supporting cells occasionally showed signs of trans-differentiation into hair cells. They expressed the MAFA and SOX2 transcription factors. Supporting cells contained organelles that may transfer genetic information between cells, including the efferent nerve fibers during the regeneration process. The tectorial membrane showed signs of being replenished and its architecture being sculpted by extracellular exosome-like proteolysis. Discussion: Crocodilians seem to produce new hair cells during their life span from a range of supporting cells. Imposing efferent nerve fibers may play a role in regeneration and re-innervation of the auditory receptors, possibly triggered by apoptotic signals from wasted hair cells. Intercellular signaling may be accomplished by elaborate gap junction and organelle systems, including neural emperipolesis. Crocodilians seem to restore and sculpt their tectorial membranes throughout their lives.
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| 2. |
- Liu, Wei, et al.
(författare)
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A combined genome-wide association and molecular study of age-related hearing loss in H. sapiens
- 2021
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Ingår i: BMC Medicine. - : BioMed Central (BMC). - 1741-7015. ; 19:1
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Sensorineural hearing loss is one of the most common sensory deficiencies. However, the molecular contribution to age-related hearing loss is not fully elucidated.METHODS: We performed genome-wide association studies (GWAS) for hearing loss-related traits in the UK Biobank (N = 362,396) and selected a high confidence set of ten hearing-associated gene products for staining in human cochlear samples: EYA4, LMX1A, PTK2/FAK, UBE3B, MMP2, SYNJ2, GRM5, TRIOBP, LMO-7, and NOX4.RESULTS: All proteins were found to be expressed in human cochlear structures. Our findings illustrate cochlear structures that mediate mechano-electric transduction of auditory stimuli, neuronal conductance, and neuronal plasticity to be involved in age-related hearing loss.CONCLUSIONS: Our results suggest common genetic variation to influence structural resilience to damage as well as cochlear recovery after trauma, which protect against accumulated damage to cochlear structures and the development of hearing loss over time.
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| 3. |
- Chacko, Lejo Johnson, et al.
(författare)
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Early appearance of key transcription factors influence the spatiotemporal development of the human inner ear
- 2020
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Ingår i: Cell and Tissue Research. - : SPRINGER. - 0302-766X .- 1432-0878. ; 379:3, s. 459-471
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Tidskriftsartikel (refereegranskat)abstract
- Expression patterns of transcription factors leucine-rich repeat-containing G protein-coupled receptor 5 (LGR5), transforming growth factor-beta-activated kinase-1 (TAK1), SRY (sex-determining region Y)-box 2 (SOX2), and GATA binding protein 3 (GATA3) in the developing human fetal inner ear were studied between the gestation weeks 9 and 12. Further development of cochlear apex between gestational weeks 11 and 16 (GW11 and GW16) was examined using transmission electron microscopy. LGR5 was evident in the apical poles of the sensory epithelium of the cochlear duct and the vestibular end organs at GW11. Immunostaining was limited to hair cells of the organ of Corti by GW12. TAK1 was immune positive in inner hair cells of the organ of Corti by GW12 and colocalized with p75 neurotrophic receptor expression. Expression for SOX2 was confined primarily to the supporting cells of utricle at the earliest stage examined at GW9. Intense expression for GATA3 was presented in the cochlear sensory epithelium and spiral ganglia at GW9. Expression of GATA3 was present along the midline of both the utricle and saccule in the zone corresponding to the striolar reversal zone where the hair cell phenotype switches from type I to type II. The spatiotemporal gradient of the development of the organ of Corti was also evident with the apex of the cochlea forming by GW16. It seems that highly specific staining patterns of several transcriptions factors are critical in guiding the genesis of the inner ear over development. Our findings suggest that the spatiotemporal gradient in cochlear development extends at least until gestational week 16.
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| 4. |
- Edvardsson Rasmussen, Jesper, 1984-
(författare)
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Inner ear proteomics and barriers : Clinical and experimental findings
- 2024
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Hearing is important in many aspects of life, including communication, assessing one’s surroundings, entertainment and social interaction. Hearing loss is common and according to the Global Burden of Disease Study, 5% of the global population require hearing rehabilitation (1). Pharmacological treatment options are limited, so understanding cellular mechanisms in the damaged inner ear is crucial for developing novel therapies.In this thesis, the human inner ear proteome in patients with sporadic vestibular schwannoma (VS) and its association with hearing loss were investigated. Ototoxic effects induced by furosemide were also examined, focusing on inner ear barrier function, furosemide sensitive Na-K-Cl co-transporter 1 (NKCC1), Fetuin-A, linked to tumour-associated hearing loss, and Pigment epithelium-derived factor (PEDF), potentially important for blood-endolymph barrier integrity.Translabyrinthine surgery on 35 patients, 32 with VS and three with meningioma, provided samples from perilymph, endolymph, endolymphatic sac tissue, VS biopsies and cerebrospinal fluid (CSF) for proteome analysis. Effects of furosemide on the inner ear barriers were studied in mice using 9.4Tesla MRI, and in guinea pigs using immunohistochemistry and mRNA in situ hybridisation focusing on NKCC1, Fetuin-A, and PEDF.Proteomic analysis revealed consistent sets of proteins in perilymph (91/315) and endolymph (545/1211). The proteomes of perilymph and CSF exhibited specific differences, with proteins unique to each fluid, thereby emphasizing the distinct origin of perilymph separate from CSF. Fetuin-A was inversely related to tumour-associated hearing loss, while patients with severe to profound hearing loss exhibited upregulation of complement factor H-related protein 2 (CFHR2).Furosemide compromised the blood-endolymph barrier, allowing gadolinium contrast into scala media. It affected NKCC1 of type II fibrocytes coinciding with the onset of hearing loss following high-dose furosemide, suggesting early disruption in potassium ion recirculation. Fetuin-A and PEDF were identified in the cochlea at protein and mRNA level. Their staining intensity increased in various cochlear subsites 120 minutes after furosemide administration, indicating their involvement in the cochlear response to the effects of furosemide.In summary, this thesis uncovered significant inter-individual variability in both the perilymph and endolymph proteome, alongside a consistent subset of proteins. Further, associations between hearing loss and proteome changes suggest inflammation as a potential mechanism for hearing degradation caused by vestibular schwannomas. Experimentally, impact of furosemide on blood-inner ear barriers were visualised in vivo and type II fibrocytes were identified as potential initial targets for NKCC1 blockade. Fetuin-A and PEDF were confirmed in several cell types in the cochlea and may increase in response to very high furosemide doses.
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| 5. |
- Edvardsson Rasmussen, Jesper, et al.
(författare)
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The Acute Effects of Furosemide on Na-K-Cl Cotransporter-1, Fetuin-A and Pigment Epithelium-Derived Factor in the Guinea Pig Cochlea
- 2022
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Ingår i: Frontiers in Molecular Neuroscience. - : Frontiers Media S.A.. - 1662-5099. ; 15
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Tidskriftsartikel (refereegranskat)abstract
- Background: Furosemide is a loop diuretic used to treat edema; however, it also targets the Na-K-Cl cotransporter-1 (NKCC1) in the inner ear. In very high doses, furosemide abolishes the endocochlear potential (EP). The aim of the study was to gain a deeper understanding of the temporal course of the acute effects of furosemide in the inner ear, including the protein localization of Fetuin-A and PEDF in guinea pig cochleae. Material and Method: Adult guinea pigs were given an intravenous injection of furosemide in a dose of 100 mg per kg of body weight. The cochleae were studied using immunohistochemistry in controls and at four intervals: 3 min, 30 min, 60 min and 120 min. Also, cochleae of untreated guinea pigs were tested for Fetuin-A and PEDF mRNA using RNAscope (R) technology. Results: At 3 min, NKCC1 staining was abolished in the type II fibrocytes in the spiral ligament, followed by a recovery period of up to 120 min. In the stria vascularis, the lowest staining intensity of NKCC1 presented after 30 min. The spiral ganglion showed a stable staining intensity for the full 120 min. Fetuin-A protein and mRNA were detected in the spiral ganglion type I neurons, inner and outer hair cells, pillar cells, Deiters cells and the stria vascularis. Furosemide induced an increased staining intensity of Fetuin-A at 120 min. PEDF protein and mRNA were found in the spiral ganglia type I neurons, the stria vascularis, and in type I and type II fibrocytes of the spiral ligament. PEDF protein staining intensity was high in the pillar cells in the organ of Corti. Furosemide induced an increased staining intensity of PEDF in type I neurons and pillar cells after 120 min. Conclusion: The results indicate rapid furosemide-induced changes of NKCC1 in the type II fibrocytes. This could be part of the mechanism that causes reduction of the EP within minutes after high dose furosemide injection. Fetuin-A and PEDF are present in many cells of the cochlea and probably increase after furosemide exposure, possibly as an otoprotective response.
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| 6. |
- Frick, Claudia, et al.
(författare)
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Age-Dependency of Neurite Outgrowth in Postnatal Mouse Cochlear Spiral Ganglion Explants
- 2020
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Ingår i: Brain Sciences. - : MDPI. - 2076-3425. ; 10:9
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Tidskriftsartikel (refereegranskat)abstract
- Background: The spatial gap between cochlear implants (CIs) and the auditory nerve limits frequency selectivity as large populations of spiral ganglion neurons (SGNs) are electrically stimulated synchronously. To improve CI performance, a possible strategy is to promote neurite outgrowth toward the CI, thereby allowing a discrete stimulation of small SGN subpopulations. Brain-derived neurotrophic factor (BDNF) is effective to stimulate neurite outgrowth from SGNs.Method: TrkB (tropomyosin receptor kinase B) agonists, BDNF, and five known small-molecule BDNF mimetics were tested for their efficacy in stimulating neurite outgrowth in postnatal SGN explants. To modulate Trk receptor-mediated effects, TrkB and TrkC ligands were scavenged by an excess of recombinant receptor proteins. The pan-Trk inhibitor K252a was used to block Trk receptor actions.Results: THF (7,8,3 '-trihydroxyflavone) partly reproduced the BDNF effect in postnatal day 7 (P7) mouse cochlear spiral ganglion explants (SGEs), but failed to show effectiveness in P4 SGEs. During the same postnatal period, spontaneous and BDNF-stimulated neurite outgrowth increased. The increased neurite outgrowth in P7 SGEs was not caused by the TrkB/TrkC ligands, BDNF and neurotrophin-3 (NT-3).Conclusions: The age-dependency of induction of neurite outgrowth in SGEs was very likely dependent on presently unidentified factors and/or molecular mechanisms which may also be decisive for the age-dependent efficacy of the small-molecule TrkB receptor agonist THF.
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| 7. |
- Hallin, Karin, 1977-, et al.
(författare)
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Auditory brainstem implant pitch discrimination and auditory outcome
- 2022
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Ingår i: ACTA OTO-LARYNGOLOGICA CASE REPORTS. - : Taylor & Francis. - 2377-2484. ; 7:1, s. 39-43
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Tidskriftsartikel (refereegranskat)abstract
- We present a pitch discrimination test performed by five experienced adult auditory brainstem implant (ABI) users with neurofibromatosis type 2 (NF2). The ability to discriminate frequency/pitch from different channels on the implant may be an important factor in improving speech performance. The pitch discrimination ability was evaluated by using a triangle test compared to adjacent contacts and the speech perception was measured by the Swedish three-digit test. The test was easy to perform, and all patients were able to answer reliably, even though it cannot be ruled out that patients used attributes other than pitch to differentiate between sounds. Due to the limited number of patients and small variation in results, no conclusive correlations could be made regarding pitch discrimination and auditory outcome. There was a tendency for poorer ability to discriminate pitch (discrimination of tonotopically adjacent electrodes) at testing to result in poorer speech results.
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| 8. |
- Helpard, Luke, et al.
(författare)
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An Approach for Individualized Cochlear Frequency Mapping Determined From 3D Synchrotron Radiation Phase-Contrast Imaging
- 2021
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Ingår i: IEEE Transactions on Biomedical Engineering. - : Institute of Electrical and Electronics Engineers (IEEE). - 0018-9294 .- 1558-2531. ; 68:12, s. 3602-3611
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Tidskriftsartikel (refereegranskat)abstract
- Objective: Cochlear implants are traditionally programmed to stimulate according to a generalized frequency map, where individual anatomic variability is not considered when selecting the centre frequency of stimulation of each implant electrode. However, high variability in cochlear size and spatial frequency distributions exist among individuals. Generalized cochlear implant frequency maps can result in large pitch perception errors and reduced hearing outcomes for cochlear implant recipients. The objective of this work was to develop an individualized frequency mapping technique for the human cochlea to allow for patient-specific cochlear implant stimulation.Methods: Ten cadaveric human cochleae were scanned using synchrotron radiation phase-contrast imaging (SR-PCI) combined with computed tomography (CT). For each cochlea, ground truth angle-frequency measurements were obtained in three-dimensions using the SR-PCI CT data. Using an approach designed to minimize perceptual error in frequency estimation, an individualized frequency function was determined to relate angular depth to frequency within the cochlea.Results: The individualized frequency mapping function significantly reduced pitch errors in comparison to the current gold standard generalized approach.Conclusion and Significance: This paper presents for the first time a cochlear frequency map which can be individualized using only the angular length of cochleae. This approach can be applied in the clinical setting and has the potential to revolutionize cochlear implant programming for patients worldwide.
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| 9. |
- Helpard, Luke, et al.
(författare)
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Characterization of the human helicotrema : implications for cochlear duct length and frequency mapping
- 2020
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Ingår i: Journal of Otolaryngology - Head & Neck Surgery. - : BMC. - 1916-0216. ; 49
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Tidskriftsartikel (refereegranskat)abstract
- Background: Despite significant anatomical variation amongst patients, cochlear implant frequency-mapping has traditionally followed a patient-independent approach. Basilar membrane (BM) length is required for patient-specific frequency-mapping, however cochlear duct length (CDL) measurements generally extend to the apical tip of the entire cochlea or have no clearly defined end-point. By characterizing the length between the end of the BM and the apical tip of the entire cochlea (helicotrema length), current CDL models can be corrected to obtain the appropriate BM length. Synchrotron radiation phase-contrast imaging has made this analysis possible due to the soft-tissue contrast through the entire cochlear apex.Methods: Helicotrema linear length and helicotrema angular length measurements were performed on synchrotron radiation phase-contrast imaging data of 14 cadaveric human cochleae. On a sub-set of six samples, the CDL to the apical tip of the entire cochlea (CDLTIP) and the BM length (CDLBM) were determined. Regression analysis was performed to assess the relationship between CDLTIP and CDLBM.Results: The mean helicotrema linear length and helicotrema angular length values were 1.6 +/- 0.9 mm and 67.8 +/- 37.9 degrees, respectively. Regression analysis revealed the following relationship between CDLTIP and CDLBM: CDLBM = 0.88(CDLTIP) + 3.71 (R-2 = 0.995).Conclusion: This is the first known study to characterize the length of the helicotrema in the context of CDL measurements. It was determined that the distance between the end of the BM and the tip of the entire cochlea is clinically consequential. A relationship was determined that can predict the BM length of an individual patient based on their respective CDL measured to the apical tip of the cochlea.
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| 10. |
- Helpard, Luke, et al.
(författare)
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Three-Dimensional Modeling and Measurement of the Human Cochlear Hook Region : Considerations for Tonotopic Mapping
- 2021
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Ingår i: Otology and Neurotology. - : Lippincott Williams & Wilkins. - 1531-7129 .- 1537-4505. ; 42:6, s. E658-E665
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Tidskriftsartikel (refereegranskat)abstract
- Hypothesis: Measuring the length of the basilar membrane (BM) in the cochlear hook region will result in improved accuracy of cochlear duct length (CDL) measurements.Background: Cochlear implant pitch mapping is generally performed in a patient independent approach, which has been shown to result in place-pitch mismatches. In order to customize cochlear implant pitch maps, accurate CDL measurements must be obtained. CDL measurements generally begin at the center of the round window (RW) and ignore the basal-most portion of the BM in the hook region. Measuring the size and morphology of the BM in the hook region can improve CDL measurements and our understanding of cochlear tonotopy.Methods: Ten cadaveric human cochleae underwent synchrotron radiation phase-contrast imaging. The length of the BM through the hook region and CDL were measured. Two different CDL measurements were obtained for each sample, with starting points at the center of the RW (CDLRW) and the basal-most tip of the BM (CDLHR). Regression analysis was performed to relate CDLRW to CDLHR. A three-dimensional polynomial model was determined to describe the average BM hook region morphology.Results: The mean CDLRW value was 33.03 ± 1.62 mm, and the mean CDLHR value was 34.68 ± 1.72 mm. The following relationship was determined between CDLRW and CDLHR: CDLHR = 1.06(CDLRW)-0.26 (R2 = 0.99).Conclusion: The length and morphology of the hook region was determined. Current measurements underestimate CDL in the hook region and can be corrected using the results herein.
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