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The Journal of Biological Chemistry Jun 2024Hearing crucially depends on cochlear ion homeostasis as evident from deafness elicited by mutations in various genes encoding cation or anion channels and transporters....
Hearing crucially depends on cochlear ion homeostasis as evident from deafness elicited by mutations in various genes encoding cation or anion channels and transporters. Ablation of ClC‑K/barttin chloride channels causes deafness by interfering with the positive electrical potential of the endolymph, but roles of other anion channels in the inner ear have not been studied. Here we report the intracochlear distribution of all five LRRC8 subunits of VRAC, a volume-regulated anion channel that transports chloride, metabolites, and drugs such as the ototoxic anti-cancer drug cisplatin, and explore its physiological role by ablating its subunits. Sensory hair cells express all LRRC8 isoforms, whereas only LRRC8A, D and E were found in the potassium-secreting epithelium of the stria vascularis. Cochlear disruption of the essential LRRC8A subunit, or combined ablation of LRRC8D and E, resulted in cochlear degeneration and congenital deafness of Lrrc8a mice. It was associated with a progressive degeneration of the organ of Corti and its innervating spiral ganglion. Like disruption of ClC-K/barttin, loss of VRAC severely reduced the endocochlear potential. However, the mechanism underlying this reduction seems different. Disruption of VRAC, but not ClC-K/barttin, led to an almost complete loss of Kir4.1 (KCNJ10), a strial K channel crucial for the generation of the endocochlear potential. The strong downregulation of Kir4.1 might be secondary to a loss of VRAC-mediated transport of metabolites regulating inner ear redox potential such as glutathione. Our study extends the knowledge of the role of cochlear ion transport in hearing and ototoxicity.
PubMed: 38838775
DOI: 10.1016/j.jbc.2024.107436 -
BioRxiv : the Preprint Server For... May 2024Our ability to hear and maintain balance relies on the proper functioning of inner ear sensory hair cells, which translate mechanical stimuli into electrical signals via...
Our ability to hear and maintain balance relies on the proper functioning of inner ear sensory hair cells, which translate mechanical stimuli into electrical signals via mechano-electrical transducer (MET) channels, composed of TMC1/2 proteins. However, the therapeutic use of ototoxic drugs, such as aminoglycosides and cisplatin, which can enter hair cells through MET channels, often leads to profound auditory and vestibular dysfunction. Despite extensive research on otoprotective compounds targeting MET channels, our understanding of how small molecule modulators interact with these channels remains limited, hampering the discovery of novel compounds. Here, we propose a structure-based screening approach, integrating 3D-pharmacophore modeling, molecular simulations, and experimental validation. Our pipeline successfully identified several novel compounds and FDA-approved drugs that reduced dye uptake in cultured cochlear explants, indicating MET modulation activity. Molecular docking and free-energy estimations for binding allowed us to identify three potential drug binding sites within the channel pore, phospholipids, and key amino acids involved in modulator interactions. We also identified shared ligand-binding features between TMC and structurally related TMEM16 protein families, providing novel insights into their distinct inhibition, while potentially guiding the rational design of MET-channel-specific modulators. Our pipeline offers a broad application to discover small molecule modulators for a wide spectrum of mechanosensitive ion channels.
PubMed: 38826329
DOI: 10.1101/2024.03.05.583611 -
Otolaryngology--head and Neck Surgery :... Jun 2024Establishing the cause of hearing loss (HL) is important and rewarding, though not without its challenges. While our ability to identify the etiology for HL has...
OBJECTIVE
Establishing the cause of hearing loss (HL) is important and rewarding, though not without its challenges. While our ability to identify the etiology for HL has improved with advances in scientific knowledge, a significant proportion of cases remain of unknown etiology. Recent protocol changes within the NHS Genomic Medicine Service support the utilization of the HL gene panel test, rather than individual gene tests. In light of these changes, determining the yield of these more extensive panel tests is important in informing future practice.
STUDY DESIGN
Retrospective study.
SETTING
The Cochlear Implant (CI) Department at Great Ormond Street Hospital (GOSH).
METHODS
Four hundred seventy-six children with profound HL were identified from a database of referrals to the GOSH CI Department. Data on etiology of HL including genetic diagnosis was collected from hospital notes on an electronic patient records system and hospital genetics database.
RESULTS
We identified a positive result in 163/476 (34%) cases through the gene panel test, representing an additional 19% yield to current level 1 investigations. Genetic HL, including both syndromic (including those not covered by the HL gene panel) and nonsyndromic (209/476, 44%) was the most common etiology in our cohort. Perinatal, intrauterine, ototoxicity, meningitis, and encephalitis categories altogether comprised 97/476 (20%) cases.
CONCLUSION
Gene panel testing provides significant additional yield over current level 1 investigations which include GJB2 testing only. This has far-reaching implications for how we optimize investigations into HL in children and counsel families, and for future early interventions.
PubMed: 38822754
DOI: 10.1002/ohn.838 -
Pediatrics and Neonatology May 2024We conducted a nationwide population-based case-control study to analyse potential predisposing factors for hearing loss (HL) that present during the fetal, perinatal,...
BACKGROUND
We conducted a nationwide population-based case-control study to analyse potential predisposing factors for hearing loss (HL) that present during the fetal, perinatal, and postnatal periods in prematurely born children.
METHODS
This study enrolled 21,576 children born at < 37 weeks of gestation; 3,596 with HL and 17,980 with normal hearing born between 2002 and 2015, matched for sex, age at diagnosis, and enrollment time. Data were abstracted from the concatenation of three nationwide databases for overall risk factors till the diagnosis of HL.
RESULTS
Maternal HL, maternal diabetes, particularly type 1 diabetes mellitus, and at or before 32 weeks of gestation were the major obstetric risk factors for HL. Prematurely born children who were born via cesarean section and received a combination of antenatal steroids and magnesium sulfate exhibited a significantly reduced risk of developing HL. Ear malformation was a critical predictor for HL. The major postnatal risk factors included seizure and ototoxic drugs use. Premature infants diagnosed with more than 1 diagnosis of bronchopulmonary dysplasia, necrotizing enterocolitis, and intracerebral hemorrhage were at an increased risk of developing HL. Congenital CMV infection and recurrent acute otitis were also independent postnatal factors for HL in prematurely born children.
CONCLUSION
To reduce the incidence of childhood HL in prematurely born children, aggressive management of premature birth-related consequences and treatable causes and longitudinal audiological follow-up with early detection and adequate intervention are crucial.
PubMed: 38811322
DOI: 10.1016/j.pedneo.2024.04.006 -
Ear and Hearing May 2024To date, there is no international standard on how to use distortion-product otoacoustic emissions (DPOAEs) in serial measurements to accurately detect changes in the...
OBJECTIVES
To date, there is no international standard on how to use distortion-product otoacoustic emissions (DPOAEs) in serial measurements to accurately detect changes in the function of the cochlear amplifier due, for example, to ototoxic therapies, occupational noise, or the development of regenerative therapies. The use of clinically established standard DPOAE protocols for serial monitoring programs appears to be hampered by multiple factors, including probe placement and calibration effects, signal-processing complexities associated with multiple sites of emission generation as well as suboptimal selection of stimulus parameters.
DESIGN
Pulsed DPOAEs were measured seven times within 3 months for f2 = 1 to 14 kHz and L2 = 25 to 80 dB SPL in 20 ears of 10 healthy participants with normal hearing (mean age = 32.1 ± 9.7 years). L1 values were computed from individual optimal-path parameters derived from the corresponding individual DPOAE level map in the first test session. Three different DPOAE metrics for evaluating the functional state of the cochlear amplifier were investigated with respect to their test-retest reliability: (1) the interference-free, nonlinear-distortion component level (LOD), (2) the time course of the DPOAE-envelope levels, LDP(t), and (3) the squared, zero-lag correlation coefficient () between the time courses of the DPOAE-envelope pressures, pDP(t), measured in two sessions. The latter two metrics include the two main DPOAE components and their state of interference.
RESULTS
Collated over all sessions and frequencies, the median absolute difference for LOD was 1.93 dB and for LDP(t) was 2.52 dB; the median of was 0.988. For the low (f2 = 1 to 3 kHz), mid (f2 = 4 to 9 kHz), and high (f2 = 10 to 14 kHz) frequency ranges, the test-retest reliability of LOD increased with increasing signal to noise ratio (SNR).
CONCLUSIONS
On the basis of the knowledge gained from this study on the test-retest reliability of pulsed DPOAE signals and the current literature, we propose a DPOAE protocol for future serial monitoring applications that takes into account the following factors: (1) separation of DPOAE components, (2) use of individually optimal stimulus parameters, (3) SNR of at least 15 dB, (4) accurate pressure calibration, (5) consideration of frequency- and level-dependent test-retest reliabilities and corresponding reference ranges, and (6) stimulus levels L2 that are as low as possible with sufficient SNR to capture the nonlinear functional state of the cochlear amplifier operating at its highest gain.
PubMed: 38809242
DOI: 10.1097/AUD.0000000000001522 -
Otolaryngologia Polska = the Polish... Jun 2024<b><br>Introduction:</b> Immune checkpoint inhibitors (ICIs) and T-cell therapies are a modern, well-established cancer treatment. The priority of... (Review)
Review
<b><br>Introduction:</b> Immune checkpoint inhibitors (ICIs) and T-cell therapies are a modern, well-established cancer treatment. The priority of oncological treatment is to cure cancer. However, treatment-related toxicities, i.e. immune-related adverse events (irAEs), continue to emerge and are not that well understood yet. ICIs can cause profound, multiple, and diverse irAEs - the sequelae of unknown mechanisms. One of the organs susceptible to collateral damage is the hearing organ. Complications related to hearing, tinnitus, and balance disorders are extremely burdensome and significantly impair many aspects of the quality of life of patients and survivors.</br> <b><br>Aim:</b> The aim of the work is to review the literature in the area of ototoxicity of ICIs.</br> <b><br>Materials and method:</b> A systematic search of the Web of Science, PubMed, and Embase databases for studies published until 1 March 2022 was conducted.</br> <b><br>Results:</b> Reported clinical symptoms ranged from sudden bilateral hearing loss and imbalance to mild hearing loss or tinnitus with preserved hearing. It was found that the median time from ICI initiation to hearing loss development was 3 months. The hearing impairment was secondary to bilateral sensorineural hearing loss in the majority of patients (>60%), and at least one other irAE accompanied the hearing loss in 2/3 of patients. Hearing loss significantly improved in 45.7% of the patients.</br> <b><br>Conclusions:</b> The majority of cases of ICI-related hearing loss presented in the literature were reversible. Therefore, it is important to develop and implement routine therapeutic algorithms. Further research is needed to define the true prevalence of ICI-related hearing loss, optimal diagnostics, and management.</br>.
Topics: Humans; Immune Checkpoint Inhibitors; Ototoxicity; Male; Female; Hearing Loss; Neoplasms; Middle Aged
PubMed: 38808639
DOI: No ID Found -
Radiotherapy and Oncology : Journal of... May 2024To identify dosimetric predictive factors of sensorineural hearing loss (SNHL) in children after cranial radiation therapy (RT) in a single institution using dosimetric...
PURPOSE
To identify dosimetric predictive factors of sensorineural hearing loss (SNHL) in children after cranial radiation therapy (RT) in a single institution using dosimetric data from the French National Registry PediaRT.
METHODS AND MATERIALS
Complete audiological follow-up data were available for 44 children treated with cranial RT between 2014 and 2021 at our institution. The median age at the time of RT initiation was 9 years (range: 2-17 years). No children presented with hearing loss prior to treatment. SNHL was defined as a Chang ototoxicity grade ≥ 1a or higher.
RESULTS
Median audiometric follow-up duration was 51 months. Seven children (16 %) developed SNHL with a median time to occurrence of 33 months (range, 18-46 months). The estimated SNHL cumulative rate at 2 years post-RT was 4,5% ± 3,1% and at 5 years was 21 % ± 7.2 %. Multiple Cox regression models showed that the association of the age at radiotherapy and the dosimetric values to the inner ear canal and cochlea were the most significant predictive factors of SNHL occurrence. No child who received less than 35 Gy on average to both cochleae (n = 26) suffered from SNHL, whereas the 5-year SNHL cumulative incidence for the children who received greater than or equal to 35 Gy on average to either cochlea (n = 18) was 51.8 % ± 15.1 %.
CONCLUSION
Doses received by the inner ear canal and cochlea, associated with the age at RT initiation, are the main predictive factors for radiation-induced SNHL. A median dose to either cochlea over 35 Gy significantly increases the risk of SNHL and justify close audiometric monitoring to detect and equip hearing loss at an early stage.
PubMed: 38806115
DOI: 10.1016/j.radonc.2024.110346 -
HNO May 2024To date, there is no consensus on how to standardize the assessment of ototoxicity in serial measurements. For the diagnosis of damage to the cochlear amplifier,...
BACKGROUND
To date, there is no consensus on how to standardize the assessment of ototoxicity in serial measurements. For the diagnosis of damage to the cochlear amplifier, measurement methods are required that have the highest possible test-retest reliability and validity for detecting persistent damage. Estimated distortion-product thresholds (L) based on short-pulse distortion-product otoacoustic emission (DPOAE) level maps use individually optimal DPOAE stimulus levels and allow reliable quantitative estimation of cochlea-related hearing loss.
MATERIALS AND METHODS
Hearing thresholds were estimated objectively using L and subjectively using modified Békésy tracking audiometry (L). Recordings were performed seven times within three months at 14 frequencies (f = 1-14 kHz) in 20 ears (PTA < 20 dB HL). Reconstruction of the DPOAE growth behavior as a function of the stimulus levels L, L was performed on the basis of 21 DPOAE amplitudes. A numerical fit of a nonlinear mathematical function to the three-dimensional DPOAE growth function yielded L for each stimulus frequency. For the combined analysis, probability distributions of hearing thresholds (L, L), DPOAE levels (L), and combinations thereof were determined.
RESULTS
L and L each exhibited a test-retest reliability with a median of absolute differences (AD) of 3.2 dB and 3.3 dB, respectively. Combining L, L, and L into a single parameter yielded a significantly smaller median AD of 2.0 dB.
CONCLUSION
It is expected that an analysis paradigm based on a combination of L, suprathreshold L, and fine-structure-reduced L would achieve higher test performance (sensitivity and specificity), allowing reliable detection of pathological or regenerative changes in the outer hair cells.
PubMed: 38801424
DOI: 10.1007/s00106-024-01477-0 -
Toxicology in Vitro : An International... May 2024Cisplatin is an effective chemotherapeutic agent; however, ototoxicity is one of its negative effects that greatly limits the use of cisplatin in clinical settings....
Cisplatin is an effective chemotherapeutic agent; however, ototoxicity is one of its negative effects that greatly limits the use of cisplatin in clinical settings. Previous research has shown that the most important process cisplatin damage to inner ear cells, such as hair cells (HCs), is the excessive production and accumulation of ROS. Schisandrin B (SchB), is a low-toxicity, inexpensive, naturally occurring antioxidant with a variety of pharmacological effects. Therefore, the potential antioxidant effects of SchB may be useful for cisplatin ototoxicity treatment. In this study, the effects of SchB on cochlear hair cell viability, ROS levels, and expression of apoptosis-related molecules were evaluated by CCK-8, immunofluorescence, flow cytometry, and qRT-PCR, as well as auditory brainstem response (ABR) and dysmorphic product otoacoustic emission (DPOAE) tests to assess the effects on inner ear function. The results showed that SchB treatment increased cell survival, prevented apoptosis, and reduced cisplatin-induced ROS formation. SchB treatment reduced the loss of cochlear HCs caused by cisplatin in exosome culture. In addition, SchB treatment attenuated cisplatin-induced hearing loss and HC loss in mice. This study demonstrates the ability of SchB to inhibit cochlear hair cell apoptosis and ROS generation and shows its potential therapeutic effect on cisplatin ototoxicity.
PubMed: 38789064
DOI: 10.1016/j.tiv.2024.105852 -
The Cochrane Database of Systematic... May 2024Acute heart failure (AHF) is new onset of, or a sudden worsening of, chronic heart failure characterised by congestion in about 95% of cases or end-organ hypoperfusion... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Acute heart failure (AHF) is new onset of, or a sudden worsening of, chronic heart failure characterised by congestion in about 95% of cases or end-organ hypoperfusion in 5% of cases. Treatment often requires urgent escalation of diuretic therapy, mainly through hospitalisation. This Cochrane review evaluated the efficacy of intravenous loop diuretics strategies in treating AHF in individuals with New York Heart Association (NYHA) classification III or IV and fluid overload.
OBJECTIVES
To assess the effects of intravenous continuous infusion versus bolus injection of loop diuretics for the initial treatment of acute heart failure in adults.
SEARCH METHODS
We identified trials through systematic searches of bibliographic databases and in clinical trials registers including CENTRAL, MEDLINE, Embase, CPCI-S on the Web of Science, ClinicalTrials.gov, the World Health Organization (WHO) International Clinical Trials Registry platform (ICTRP), and the European Union Trials register. We conducted reference checking and citation searching, and contacted study authors to identify additional studies. The latest search was performed on 29 February 2024.
SELECTION CRITERIA
We included randomised controlled trials (RCTs) involving adults with AHF, NYHA classification III or IV, regardless of aetiology or ejection fraction, where trials compared intravenous continuous infusion of loop diuretics with intermittent bolus injection in AHF. We excluded trials with chronic stable heart failure, cardiogenic shock, renal artery stenosis, or end-stage renal disease. Additionally, we excluded studies combining loop diuretics with hypertonic saline, inotropes, vasoactive medications, or renal replacement therapy and trials where diuretic dosing was protocol-driven to achieve a target urine output, due to confounding factors.
DATA COLLECTION AND ANALYSIS
Two review authors independently screened papers for inclusion and reviewed full-texts. Outcomes included weight loss, all-cause mortality, length of hospital stay, readmission following discharge, and occurrence of acute kidney injury. We performed risk of bias assessment and meta-analysis where data permitted and assessed certainty of the evidence.
MAIN RESULTS
The review included seven RCTs, spanning 32 hospitals in seven countries in North America, Europe, and Asia. Data collection ranged from eight months to six years. Following exclusion of participants in subgroups with confounding treatments and different clinical settings, 681 participants were eligible for review. These additional study characteristics, coupled with our strict inclusion and exclusion criteria, improve the applicability of the body of the evidence as they reflect real-world clinical practice. Meta-analysis was feasible for net weight loss, all-cause mortality, length of hospital stay, readmission, and acute kidney injury. Literature review and narrative analysis explored daily fluid balance; cardiovascular mortality; B-type natriuretic peptide (BNP) change; N-terminal-proBNP change; and adverse incidents such as ototoxicity, hypotension, and electrolyte imbalances. Risk of bias assessment revealed two studies with low overall risk, four with some concerns, and one with high risk. All sensitivity analyses excluded trials at high risk of bias. Only narrative analysis was conducted for 'daily fluid balance' due to diverse data presentation methods across two studies (169 participants, the evidence was very uncertain about the effect). Results of narrative analysis varied. For instance, one study reported higher daily fluid balance within the first 24 hours in the continuous infusion group compared to the bolus injection group, whereas there was no difference in fluid balance beyond this time point. Continuous intravenous infusion of loop diuretics may result in mean net weight loss of 0.86 kg more than bolus injection of loop diuretics, but the evidence is very uncertain (mean difference (MD) 0.86 kg, 95% confidence interval (CI) 0.44 to 1.28; 5 trials, 497 participants; P < 0.001, I = 21%; very low-certainty evidence). Importantly, sensitivity analysis excluding trials with high risk of bias showed there was insufficient evidence for a difference in bodyweight loss between groups (MD 0.70 kg, 95% CI -0.06 to 1.46; 3 trials, 378 participants; P = 0.07, I = 0%). There may be little to no difference in all-cause mortality between continuous infusion and bolus injection (risk ratio (RR) 1.53, 95% CI 0.81 to 2.90; 5 trials, 530 participants; P = 0.19, I = 4%; low-certainty evidence). Despite sensitivity analysis, the direction of the evidence remained unchanged. No trials measured cardiovascular mortality. There may be little to no difference in the length of hospital stay between continuous infusion and bolus injection of loop diuretics, but the evidence is very uncertain (MD -1.10 days, 95% CI -4.84 to 2.64; 4 trials, 211 participants; P = 0.57, I = 88%; very low-certainty evidence). Sensitivity analysis improved heterogeneity; however, the direction of the evidence remained unchanged. There may be little to no difference in the readmission to hospital between continuous infusion and bolus injection of loop diuretics (RR 0.85, 95% CI 0.63 to 1.16; 3 trials, 400 participants; P = 0.31, I = 0%; low-certainty evidence). Sensitivity analysis continued to show insufficient evidence for a difference in the readmission to hospital between groups. There may be little to no difference in the occurrence of acute kidney injury as an adverse event between continuous infusion and bolus injection of intravenous loop diuretics (RR 1.02, 95% CI 0.70 to 1.49; 3 trials, 491 participants; P = 0.92, I = 0%; low-certainty evidence). Sensitivity analysis continued to show that continuous infusion may make little to no difference on the occurrence of acute kidney injury as an adverse events compared to the bolus injection of intravenous loop diuretics.
AUTHORS' CONCLUSIONS
Analysis of available data comparing two delivery methods of diuretics in acute heart failure found that the current data are insufficient to show superiority of one strategy intervention over the other. Our findings were based on trials meeting stringent inclusion and exclusion criteria to ensure validity. Despite previous reviews suggesting advantages of continuous infusion over bolus injections, our review found insufficient evidence to support or refute this. However, our review, which excluded trials with clinical confounders and RCTs with high risk of bias, offers the most robust conclusion to date.
Topics: Adult; Aged; Humans; Acute Disease; Bias; Cause of Death; Heart Failure; Infusions, Intravenous; Injections, Intravenous; Length of Stay; Randomized Controlled Trials as Topic; Sodium Potassium Chloride Symporter Inhibitors
PubMed: 38775253
DOI: 10.1002/14651858.CD014811.pub2