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Frontiers in Neuroscience 2024Subjective tinnitus, the perception of sound without an external acoustic source, is often subsequent to noise-induced hearing loss or ototoxic medications. The...
INTRODUCTION
Subjective tinnitus, the perception of sound without an external acoustic source, is often subsequent to noise-induced hearing loss or ototoxic medications. The condition is believed to result from neuroplastic alterations in the auditory centers, characterized by heightened spontaneous neural activities and increased synchrony due to an imbalance between excitation and inhibition. However, the role of the thalamic reticular nucleus (TRN), a structure composed exclusively of GABAergic neurons involved in thalamocortical oscillations, in the pathogenesis of tinnitus remains largely unexplored.
METHODS
We induced tinnitus in mice using sodium salicylate and assessed tinnitus-like behaviors using the Gap Pre-Pulse Inhibition of the Acoustic Startle (GPIAS) paradigm. We utilized combined viral tracing techniques to identify the neural circuitry involved and employed immunofluorescence and confocal imaging to determine cell types and activated neurons.
RESULTS
Salicylate-treated mice exhibited tinnitus-like behaviors. Our tracing clearly delineated the inputs and outputs of the auditory-specific TRN. We discovered that chemogenetic activation of the auditory TRN significantly reduced the salicylate-evoked rise in c-Fos expression in the auditory cortex.
DISCUSSION
This finding posits the TRN as a potential modulatory target for tinnitus treatment. Furthermore, the mapped sensory inputs to the auditory TRN suggest possibilities for employing optogenetic or sensory stimulations to manipulate thalamocortical activities. The precise mapping of the auditory TRN-mediated neural pathways offers a promising avenue for designing targeted interventions to alleviate tinnitus symptoms.
PubMed: 38629053
DOI: 10.3389/fnins.2024.1368816 -
Journal of the Association For Research... Jun 2024Cisplatin is a low-cost clinical anti-tumor drug widely used to treat solid tumors. However, its use could damage cochlear hair cells, leading to irreversible hearing...
PURPOSE
Cisplatin is a low-cost clinical anti-tumor drug widely used to treat solid tumors. However, its use could damage cochlear hair cells, leading to irreversible hearing loss. Currently, there appears one drug approved in clinic only used for reducing ototoxicity associated with cisplatin in pediatric patients, which needs to further explore other candidate drugs.
METHODS
Here, by screening 1967 FDA-approved drugs to protect cochlear hair cell line (HEI-OC1) from cisplatin damage, we found that Tedizolid Phosphate (Ted), a drug indicated for the treatment of acute infections, had the best protective effect. Further, we evaluated the protective effect of Ted against ototoxicity in mouse cochlear explants, zebrafish, and adult mice. The mechanism of action of Ted was further explored using RNA sequencing analysis and verified. Meanwhile, we also observed the effect of Ted on the anti-tumor effect of cisplatin.
RESULTS
Ted had a strong protective effect on hair cell (HC) loss induced by cisplatin in zebrafish and mouse cochlear explants. In addition, when administered systemically, it protected mice from cisplatin-induced hearing loss. Moreover, antitumor studies showed that Ted had no effect on the antitumor activity of cisplatin both in vitro and in vivo. RNA sequencing analysis showed that the otoprotective effect of Ted was mainly achieved by inhibiting phosphorylation of ERK. Consistently, ERK activator aggravated the damage of cisplatin to HCs.
CONCLUSION
Collectively, these results showed that FDA-approved Ted protected HCs from cisplatin-induced HC loss by inhibiting ERK phosphorylation, indicating its potential as a candidate for preventing cisplatin ototoxicity in clinical settings.
Topics: Animals; Cisplatin; Zebrafish; Mice; Hearing Loss; Oxazoles; Organophosphates; Antineoplastic Agents; United States Food and Drug Administration; Drug Approval; Hair Cells, Auditory; United States; Ototoxicity; Humans
PubMed: 38622383
DOI: 10.1007/s10162-024-00945-2 -
Otolaryngology--head and Neck Surgery :... Apr 2024To explore whether there is an association between serious mental illness (SMI) and hearing loss (HL) among US Hispanic adults.
OBJECTIVE
To explore whether there is an association between serious mental illness (SMI) and hearing loss (HL) among US Hispanic adults.
STUDY DESIGN AND SETTING
Cross-sectional epidemiological study (Hispanic Community Health Study), including multicentered US volunteers.
METHODS
Multivariable linear regressions were conducted to study the association between SMI and HL. Adjustments were made for potential confounders including age, sex, education, vascular disease (hypertension or diabetes mellitus), and cognition. SMI was defined by (1) antipsychotic medication classification and (2) the use of at least 1 antipsychotic medication specifically used to treat SMI in clinical psychiatric practice. HL was measured by pure tone audiometry.
RESULTS
A total of 7581 subjects had complete data. The mean age was 55.2 years (SD = 7.5 years) and the mean pure tone average in the better ear was 16.8 dB (SD = 10.7 dB). A total of 194 (2.6%) subjects were taking a HCHS-defined antipsychotic and 98 (1.3%) were taking at least 1 antipsychotic specifically used to treat SMI. On multivariable regression, use of HCHS's classified antipsychotics was associated with 3.75 dB worse hearing (95% confidence interval [CI] = 2.36-5.13, P < .001) and use of antipsychotics specific for SMI was associated with 4.49 dB worse hearing (95% CI = 2.56-6.43, P < .001) compared to those not using antipsychotics.
CONCLUSION
SMI, as defined by either the use of HCHS-defined antipsychotics or the use of antipsychotic medication specific for SMI, is associated with worse hearing, controlling for potential confounders. Whether SMI contributes to HL, antipsychotic medication (through ototoxicity) contributes to HL, or whether HL contributes to SMI is unknown and warrants further investigation.
PubMed: 38606639
DOI: 10.1002/ohn.763 -
Journal of Investigative Medicine : the... Apr 2024Cisplatin use is often limited by its ototoxic side effects, which can lead to irreversible hearing loss. Preventing cisplatin-induced ototoxicity is crucial to improve...
Cisplatin use is often limited by its ototoxic side effects, which can lead to irreversible hearing loss. Preventing cisplatin-induced ototoxicity is crucial to improve patient outcomes. Fluoxetine and fluvoxamine, both selective serotonin reuptake inhibitors antidepressants, inhibit the NLR pyrin domain-containing protein 3 inflammasome, a potential therapeutic target for preventing ototoxicity. However, human studies have not evaluated if these antidepressants may protect against cisplatin-induced ototoxicity. The object of this study is to assess the association between fluoxetine or fluvoxamine use and incidence of hearing loss or tinnitus in a large cohort of patients receiving cisplatin chemotherapy. We use a retrospective cohort study within the U.S. Department of Veterans Affairs healthcare system. Adult patients with cancer who received cisplatin chemotherapy between 2000 and 2023 are included. Incidence of ototoxicity, defined by international classification of diseases revision 9-CM or international classification of diseases revision 10-CM diagnoses of hearing loss or tinnitus is compared between concurrent use of fluoxetine or fluvoxamine and cisplatin alone. A total of 20,552 patients were included. Of those, 489 received cisplatin and fluoxetine or fluvoxamine. After propensity score adjustment, the hazard of ototoxicity was lower in the group receiving fluoxetine or fluvoxamine compared to the group receiving cisplatin alone (HR = 0.62, 95% CI = (0.41-0.94)). Fluoxetine or fluvoxamine use may be associated with a reduced risk of cisplatin-induced ototoxicity. Randomized clinical trials are needed to confirm these findings and establish the efficacy of the medications in ototoxicity prevention. Further research is also warranted to investigate the potential mechanisms underlying this protective effect.
PubMed: 38597272
DOI: 10.1177/10815589241247796 -
Cancer Discovery Apr 2024Childhood cancer survivorship studies generate comprehensive datasets comprising demographic, diagnosis, treatment, outcome, and genomic data from survivors. To broadly...
Childhood cancer survivorship studies generate comprehensive datasets comprising demographic, diagnosis, treatment, outcome, and genomic data from survivors. To broadly share this data, we created the St. Jude Survivorship Portal (https://survivorship.stjude.cloud), the first data portal for sharing, analyzing, and visualizing pediatric cancer survivorship data. Over 1,600 phenotypic variables and 400 million genetic variants from over 7,700 childhood cancer survivors can be explored on this free, open-access portal. Summary statistics of variables are computed on-the-fly and visualized through interactive and customizable charts. Survivor cohorts can be customized and/or divided into groups for comparative analysis. Users can also seamlessly perform cumulative incidence and regression analyses on the stored survivorship data. Using the portal, we explored the ototoxic effects of platinum-based chemotherapy, uncovered a novel association between mental health, age, and limb amputation, and discovered a novel haplotype in MAGI3 strongly associated with cardiomyopathy specifically in survivors of African ancestry.
PubMed: 38593228
DOI: 10.1158/2159-8290.CD-23-1441 -
HNO Jun 2024For preoperative skin antisepsis, alcohol-containing iodine solutions and octenidine are suitable. For wound antisepsis, polyhexanide and hypochlorous acid (HOCL) are... (Review)
Review
For preoperative skin antisepsis, alcohol-containing iodine solutions and octenidine are suitable. For wound antisepsis, polyhexanide and hypochlorous acid (HOCL) are also available, but only PVP-iodine and HOCL can be applied to cartilage. Chlorhexidine should only be used as mouth- and bodywash for Staphylococcus aureus (MRSA) decolonization. For the many other throat antiseptics, evidence of clinical efficacy is lacking. For decolonization of the nares, polyhexanide and octenidine are available as nasal gels, but these are inferior to mupirocin for MRSA decolonization. PVP-iodine and HOCL are safe to use for nasal irrigation, but only HOCL has proven effective to improve symptoms of chronic rhinosinusitis. All antiseptics exhibit a certain ototoxicity. With an intact eardrum, acetic acid-containing eardrops can be used to prevent and treat external otitis and myringitis. When the eardrum is perforated, only alcohol-free PVP-iodine and HOCL may be used.
Topics: Humans; Anti-Infective Agents, Local; Otolaryngology; Otorhinolaryngologic Diseases
PubMed: 38592477
DOI: 10.1007/s00106-024-01456-5 -
Audiology & Neuro-otology Apr 2024The objective of this study was to identify and clinically characterize patients treated in an Otoneurology Unit who experienced vestibular ototoxicity as a result of...
INTRODUCTION
The objective of this study was to identify and clinically characterize patients treated in an Otoneurology Unit who experienced vestibular ototoxicity as a result of using aminoglycoside ear drops during outbreaks of superinfection in chronic otitis media.
MATERIAL AND METHODS
An observational retrospective study was conducted, including patients with perforated eardrums who developed vestibular ototoxicity within the past ten years following the application of topical ear aminoglycosides in a tertiary referral center. The study encompassed the assessment of the clinical presentation, treatment, quality of life, and evolution after treatment of the identified individuals.
RESULTS
During the study period, six patients, aged between 33 and 71 years, developed vestibular ototoxicity following the use of topical aminoglycoside drops due infection flares in chronic otitis media. All cases involved the use of gentamicin. Two cases were unilateral, and four were unilateral. The onset of symptoms occurred within one to four weeks of using the drops, resulting in all patients experiencing instability without vertigo attacks. After discontinuing the drops and undergoing vestibular rehabilitation, four patients experienced sequelae, with two patients (both with bilateral vestibular hypofunction) suffering significant impairment in their quality of life.
CONCLUSIONS
Conclusion: Vestibular ototoxicity due to the topical application of aminoglycosides during acute exacerbations of chronic otitis media is a rare occurrence. However, given its potential for severe consequences and the fact that we are still encountering patients with this condition, healthcare professionals should explore alternative antibacterial agents that offer similar efficacy.
PubMed: 38588647
DOI: 10.1159/000538756 -
The Science of the Total Environment Jun 2024Until now, bacteria able to degrade, 3,3'-iminodipropionitrile (IDPN), a neurotoxin that destroys vestibular hair cells, causing ototoxicity, culminating in irreversible...
Until now, bacteria able to degrade, 3,3'-iminodipropionitrile (IDPN), a neurotoxin that destroys vestibular hair cells, causing ototoxicity, culminating in irreversible movement disorders, had never been isolated. The aim of this study was to isolate a novel IDPN-biodegrading microorganism and characterize its metabolic pathway. Enrichment was performed by inoculating activated sludge from a wastewater treatment bioreactor that treated IDPN-contaminated wastewater in M9 salt medium, with IDPN as the sole carbon source. A bacterial strain with a spherical morphology that could grow at high concentrations was isolated on a solid medium. Growth of the isolated strain followed the Monod kinetic model. Based on the 16S rRNA gene, the isolate was Paracoccus communis. Whole-genome sequencing revealed that the isolated P. communis possessed the expected full metabolic pathway for IDPN biodegradation. Transcriptome analyses confirmed the overexpression of the gene encoding hydantoinase/oxoprolinase during the exponential growth phase under IDPN-fed conditions, suggesting that the enzyme involved in cleaving the imine bond of IDPN may promote IDPN biodegradation. Additionally, the newly discovered P. communis isolate seems to metabolize IDPN through cleavage of the imine bond in IDPN via nitrilase, nitrile hydratase, and amidase reactions. Overall, this study lays the foundation for the application of IDPN-metabolizing bacteria in the remediation of IDPN-contaminated environments.
Topics: Nitriles; Bioreactors; Wastewater; Biodegradation, Environmental; Paracoccus; Waste Disposal, Fluid; Water Pollutants, Chemical; RNA, Ribosomal, 16S
PubMed: 38580115
DOI: 10.1016/j.scitotenv.2024.172099 -
Journal of Pharmaceutical Policy and... 2024Early detection, monitoring, and managing adverse events (AEs) are crucial in optimising treatment for multidrug-resistant tuberculosis (MDR-TB) patients.
BACKGROUND
Early detection, monitoring, and managing adverse events (AEs) are crucial in optimising treatment for multidrug-resistant tuberculosis (MDR-TB) patients.
OBJECTIVES
To investigate the incidence, factors, management, and impact of AEs on treatment outcomes in MDR-TB patients.
METHODS
This study reviewed the medical records of 275 MDR-TB patients at Fatimah Jinnah Institute of Chest Diseases in Quetta, Pakistan. Patient information was collected using a designed data collection form. Mann-Whitney and Kruskal-Wallis tests examined the difference in AEs occurrences based on patients' characteristics. Multiple binary logistic regression identified factors associated with unsuccessful outcomes, with statistical significance set at a -value < 0.05.
RESULTS
Almost all patients (99.6%) experienced at-least one AE (median = 4/patient, interquartile range:3-6). The most common were GI disturbance (95.3%), arthralgia (80.4%), body pain and headache (61.8%), ototoxicity (61.4%), psychiatric disturbance (44%), hypokalaemia (40.4%), dermatological reactions (26.2%) and hypothyroidism (21.5%). AEs led to treatment modification in 7.3% patients. Educated patients, those with a history of TB treatment, previous use and resistance to any second-line drug had significantly higher number of AEs. A total of 64.0% were declared cured, 3.6% completed treatment, 19.6% died and 12.7.9% were lost to follow-up. Patients' age of 41-60(OR = 9.225) and >60 years(OR = 23.481), baseline body weight of 31-60 kg(OR = 0.180), urban residence(OR = 0.296), and experiencing ototoxicity (OR = 0.258) and hypothyroidism (OR = 0.136) were significantly associated with unsuccessful treatment outcomes.
CONCLUSION
AEs were highly prevalent but did not negatively impact treatment outcomes. Patients at higher risk of developing AEs and unsuccessful outcomes should receive special attention for its early management.
PubMed: 38572376
DOI: 10.1080/20523211.2024.2332878 -
Scientific Reports Apr 2024Nobiletin, a citrus polymethoxy flavonoid with antiapoptotic and antioxidative properties, could safeguard against cisplatin-induced nephrotoxicity and neurotoxicity....
Nobiletin, a citrus polymethoxy flavonoid with antiapoptotic and antioxidative properties, could safeguard against cisplatin-induced nephrotoxicity and neurotoxicity. Cisplatin, as the pioneer of anti-cancer drug, the severe ototoxicity limits its clinical applications, while the effect of nobiletin on cisplatin-induced ototoxicity has not been identified. The current study investigated the alleviating effect of nobiletin on cisplatin-induced ototoxicity and the underlying mechanisms. Apoptosis and ROS formation were evaluated using the CCK-8 assay, Western blotting, and immunofluorescence, indicating that nobiletin attenuated cisplatin-induced apoptosis and oxidative stress. LC3B and SQSTM1/p62 were determined by Western blotting, qPCR, and immunofluorescence, indicating that nobiletin significantly activated autophagy. Nobiletin promoted the nuclear translocation of NRF2 and the transcription of its target genes, including Hmox1, Nqo1, and ferroptosis markers (Gpx4, Slc7a11, Fth, and Ftl), thereby inhibiting ferroptosis. Furthermore, RNA sequencing analysis verified that autophagy, ferroptosis, and the NRF2 signaling pathway served as crucial points for the protection of nobiletin against ototoxicity caused by cisplatin. Collectively, these results indicated, for the first time, that nobiletin alleviated cisplatin-elicited ototoxicity through suppressing apoptosis and oxidative stress, which were attributed to the activation of autophagy and the inhibition of NRF2/GPX4-mediated ferroptosis. Our study suggested that nobiletin could be a prospective agent for preventing cisplatin-induced hearing loss.
Topics: Humans; Cisplatin; NF-E2-Related Factor 2; Ototoxicity; Ferroptosis; Prospective Studies; Phospholipid Hydroperoxide Glutathione Peroxidase; Autophagy; Flavones
PubMed: 38570541
DOI: 10.1038/s41598-024-55614-4