Age-related hearing loss (ARHL) is the most prevalent sensory deficit in the elderly and constitutes the third highest risk factor for dementia. Lifetime noise exposure, genetic predispositions for ...degeneration, and metabolic stress are assumed to be the major causes of ARHL. Both noise-induced and hereditary progressive hearing have been linked to decreased cell surface expression and impaired conductance of the potassium ion channel K
V
7.4 (KCNQ4) in outer hair cells, inspiring future therapies to maintain or prevent the decline of potassium ion channel surface expression to reduce ARHL. In concert with K
V
7.4 in outer hair cells, K
V
7.1 (KCNQ1) in the stria vascularis, calcium-activated potassium channels BK (KCNMA1) and SK2 (KCNN2) in hair cells and efferent fiber synapses, and K
V
3.1 (KCNC1) in the spiral ganglia and ascending auditory circuits share an upregulated expression or subcellular targeting during final differentiation at hearing onset. They also share a distinctive fragility for noise exposure and age-dependent shortfalls in energy supply required for sustained surface expression. Here, we review and discuss the possible contribution of select potassium ion channels in the cochlea and auditory pathway to ARHL. We postulate genes, proteins, or modulators that contribute to sustained ion currents or proper surface expressions of potassium channels under challenging conditions as key for future therapies of ARHL.
Neurotrophins promote neurite outgrowth of auditory neurons and may help closing the gap to cochlear implant (CI) electrodes to enhance electrical hearing. The best concentrations and mix of ...neurotrophins for this nerve regrowth are unknown. Whether electrical stimulation (ES) during outgrowth is beneficial or may direct axons is another open question. Auditory neuron explant cultures of distinct cochlear turns of 6-7 days old mice were cultured for four days. We tested different concentrations and combinations of BDNF and NT-3 and quantified the numbers and lengths of neurites with an advanced automated analysis. A custom-made 24-well electrical stimulator based on two bulk CIs served to test different ES strategies. Quantification of receptors trkB, trkC, p75
, and histological analysis helped to analyze effects. We found 25 ng/mL BDNF to perform best, especially in basal neurons, a negative influence of NT-3 in combined BDNF/NT-3 scenarios, and tonotopic changes in trk and p75
receptor stainings. ES largely impeded neurite outgrowth and glia ensheathment in an amplitude-dependent way. Apical neurons showed slight benefits in neurite numbers and length with ES at 10 and 500 µA. We recommend BDNF as a potent drug to enhance the man-machine interface, but CIs should be better activated after nerve regrowth.
Human stapedius muscle (SM) can be directly and safely accessed via retrofacial approach, opening new approaches to directly measure the electrically evoked stapedius reflex threshold (eSRT). The ...measurement of the SM activity via direct surgical access represents a potential tool for objective eSRT fitting of cochlear implants (CI), increasing the benefit experienced by the CI users and leading to new perspectives in the development of smart implantable neurostimulators. 3D middle-ear reconstructions created after manual segmentation and related SM accessibility metrics were evaluated before the CI surgery for 16 candidates with assessed stapedius reflex. Retrofacial approach to access the SM was performed after facial recess exposure. In cases of poor exposition of SM, the access was performed anteriorly to the FN via drilling of the pyramidal eminence (PE). The total access rate of the SM via both the retrofacial and anterior approach of the FN was 100%. In 81.2% of cases (13/16), the retrofacial approach allowed to access the SM on previously categorized well exposed (8/8), partially exposed (4/5), and wholly concealed (1/3) SM with respect to FN. Following intraoperative evaluation in the remaining 18.8% (3/16), the SM was accessed anteriorly via drilling of the PE. Exposure of SM with respect to the FN and the sigmoid sinus’s prominence was a predictor for the suitable surgical approach. The retrofacial approach offers feasible and reproducible access to the SM belly, opening direct access to electromyographic sensing of the eSRT. Surgical planner tools can quantitatively assist pre-surgical assessment.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Despite the complete embodiment of the stapedius muscle (SM) into the pyramidal eminence, it is possible to safely gain access to the SM belly via a retrofacial approach. This presents a novel ...approach to directly measure the electrically evoked stapedius reflex threshold (eSRT).
Objective fitting of maximum comfortable loudness levels for cochlear implant users can improve the benefit introduced by the device. Sensing SM activity via direct surgical access represents a potential tool for objective eSRT fitting.
Eighteen human temporal bones (TBs) were used. Micro-computed tomography was performed for six TBs. Standard computed tomography for six TBs. Manual 3D-segmentation of the relevant middle and inner ear anatomy was performed on 12 TBs. Mastoidectomy and posterior tympanotomy allowed the access to middle ear of all 18 the TBs. Once identified the mastoidal segment of the facial nerve (FN), the retrofacial access to the SM was drilled.
The total access rate was 72.2%. Only in the first three cases the posterior semi-circular canal was hit. The SM access was identified posterior to the FN at a 4 ± 0.78 mm distance from the stapes' head, almost halfway to the chorda tympani's branching point along the FN direction. The drilling depth to access the SM posterior to the external surface of FN on average was 2 ± 0.30 mm. The exposure took on average of 5 to 8 minutes.
The retrofacial approach seems to offer a feasible and reproducible access to the SM belly opening an avenue to electromyographic sensing of eSRT.
Objectives:
To study the safety and efficacy of continuous intratympanic dexamethasone‐phosphate (Dex‐P) for severe to profound sudden idiopathic sensorineural hearing (ISSHL) or sudden idiopathic ...anacusis after failure of systemic therapy.
Study Design:
Randomized, double‐blind, placebo controlled multicenter trial.
Methods:
Patients with ISSHL and insufficient recovery (mean 4PTA = 97 dB HL) after systemic high dose glucocorticoid therapy received either Dex‐P (4mg/ml) or placebo (NaCl 0.9%) continuously applied for 14 days into the round window niche via a temporarily implanted catheter. For ethical reasons, intratympanic treatment was continued with Dex‐P in all patients for another 14 days after the placebo‐controlled study period. According to a two‐step adaptive study design an interim analysis was performed after inclusion of 23 patients.
Results:
Intention‐to‐treat analysis for the primary outcome criterion (4PTA: 0.5‐3kHz) during the placebo controlled study period (14 days) showed an average hearing improvement in the treatment group of 13.9 dB (SD: 21.3) and in the placebo group of 5.4 dB (SD: 10.4). This difference in hearing improvement between the two groups (mean: 8.4 dB, SD: 17.0, 95% CI: −7.1–24.1) was statistically not significant (p = .26). Of the secondary outcome parameters, the largest benefit of local salvage therapy was found for maximum speech discrimination with an improvement of 24.4% (SD: 32.0) in the treatment and 4.5% (SD: 7.6) in the placebo group (p = 0.07). After a 3 month follow‐up period (i.e. after all patients received intratympanic Dex‐P) hearing improvement in the two groups was very similar. No serious adverse events were observed. Sample size calculation after the interim analysis resulted in stopping of the trial.
Conclusions:
The tendency toward better hearing improvement in the treatment group, the rather conservative inclusion criteria, the limited placebo‐controlled observation period and the absence of serious adverse events supports further investigation local inner ear drug delivery as a first or second line treatment option for ISSHL. Laryngoscope, 119:359–369, 2009
Highlights • Organotypic cochlear spiral ganglion cultures were used. • Neurite outgrowth was quantified after application of neurotrophic factors. • Myelin-induced inhibition was assessed by ...application of myelin-associated proteins. • Combination of TrkB stimulation and ROCK-inhibition overcomes myelin inhibition.
Spread of antimicrobial resistance and shortage of novel antibiotics have led to an urgent need for new antibacterials. Although aminoglycoside antibiotics (AGs) are very potent anti-infectives, ...their use is largely restricted due to serious side-effects, mainly nephrotoxicity and ototoxicity. We evaluated the ototoxicity of various AGs selected from a larger set of AGs on the basis of their strong antibacterial activities against multidrug-resistant clinical isolates of the ESKAPE panel: gentamicin, gentamicin C1a, apramycin, paromomycin and neomycin. Following local round window application, dose-dependent effects of AGs on outer hair cell survival and compound action potentials showed gentamicin C1a and apramycin as the least toxic. Strikingly, although no changes were observed in compound action potential thresholds and outer hair cell survival following treatment with low concentrations of neomycin, gentamicin and paromomycin, the number of inner hair cell synaptic ribbons and the compound action potential amplitudes were reduced. This indication of hidden hearing loss was not observed with gentamicin C1a or apramycin at such concentrations. These findings identify the inner hair cells as the most vulnerable element to AG treatment, indicating that gentamicin C1a and apramycin are promising bases for the development of clinically useful antibiotics.
Abstract
T cell recognition of human leukocyte antigen (HLA)-presented tumor-associated peptides is central for cancer immune surveillance. Mass spectrometry (MS)-based immunopeptidomics represents ...the only unbiased method for the direct identification and characterization of naturally presented tumor-associated peptides, a key prerequisite for the development of T cell-based immunotherapies. This study reports on the implementation of ion mobility separation-based time-of-flight (TOF
IMS
) MS for next-generation immunopeptidomics, enabling high-speed and sensitive detection of HLA-presented peptides. Applying TOF
IMS
-based immunopeptidomics, a novel extensive benign
TOFIMS
dataset was generated from 94 primary benign samples of solid tissue and hematological origin, which enabled the expansion of benign reference immunopeptidome databases with > 150,000 HLA-presented peptides, the refinement of previously described tumor antigens, as well as the identification of frequently presented self antigens and not yet described tumor antigens comprising low abundant mutation-derived neoepitopes that might serve as targets for future cancer immunotherapy development.
Retinitis pigmentosa (RP) is a group of inherited neurodegenerative diseases affecting photoreceptors and causing blindness in humans. Previously, excessive activation of enzymes belonging to the ...poly-ADP-ribose polymerase (PARP) group was shown to be involved in photoreceptor degeneration in the human homologous rd1 mouse model for RP. Since there are at least 16 different PARP isoforms, we investigated the exact relevance of the predominant isoform - PARP1 - for photoreceptor cell death using PARP1 knock-out (KO) mice. In vivo and ex vivo morphological analysis using optic coherence tomography (OCT) and conventional histology revealed no major alterations of retinal phenotype when compared to wild-type (wt). Likewise, retinal function as assessed by electroretinography (ERG) was normal in PARP1 KO animals. We then used retinal explant cultures derived from wt, rd1, and PARP1 KO animals to test their susceptibility to chemically induced photoreceptor degeneration. Since photoreceptor degeneration in the rd1 retina is triggered by a loss-of-function in phosphodiesterase-6 (PDE6), we used selective PDE6 inhibition to emulate the rd1 situation on non-rd1 genotypes. While wt retina subjected to PDE6 inhibition showed massive photoreceptor degeneration comparable to rd1 retina, in the PARP1 KO situation, cell death was robustly reduced. Together, these findings demonstrate that PARP1 activity is in principle dispensable for normal retinal function, but is of major importance for photoreceptor degeneration under pathological conditions. Moreover, our results suggest that PARP dependent cell death or PARthanatos may play a major role in retinal degeneration and highlight the possibility to use specific PARP inhibitors for the treatment of RP.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Age-related hearing loss (ARHL) is the most common sensory impairment mainly caused by degeneration of sensory hair cells in the cochlea with no causal medical treatment available. Auditory function ...and sensory hair cell survival critically depend on the Kv7.4 (KCNQ4) channel, a voltage-gated potassium channel expressed in outer hair cells (OHCs), with its impaired function or reduced activity previously associated with ARHL. Here, we investigated the effect of a potent small-molecule Kv7.4 agonist on ARHL in the senescence-accelerated mouse prone 8 (SAMP8) model. For the first time in vivo, we show that Kv7.4 activation can significantly reduce age-related threshold shifts of auditory brainstem responses as well as OHC loss in the SAMP8 model. Pharmacological activation of Kv7.4 thus holds great potential as a therapeutic approach for ARHL as well as other hearing impairments related to Kv7.4 function.
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