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We developed a novel aerosol-mediated drug delivery system for inner ear therapy by using a silicon-based multiple-Fourier horn nozzle. Intratympanic aerosol (ITA) methylprednisolone (MP) delivery can protect hearing after acoustic trauma. The highest concentration of MP (38.9 ± 5.47 ppm) appeared at 2 h and declined rapidly within 10 h. The concentrations of MP remained at a relatively low level for more than 10 h. Compared to the baseline, the auditory brainstem response (ABR) thresholds shifted markedly at 1 h after noise exposure in all groups (p < 0.05). From the cochleograms, it can be noted that the main lesions encompassed the 2–20 kHz frequency range. Significant differences (p < 0.05) were observed for the range between 5 and 8 kHz in the cell loss of outer hair cells (OHCs). The losses for IHCs were lower than for OHCs. The MP movement in the middle ear was simulated by a convection diffusion equation with a relaxation time. The relaxation time was 0.5 h, and the concentration threshold of MP on the round window membrane (RWM) in the middle ear (C T) was 8900 ppm. Using the unit hydrograph (UH) method, we obtained a proper boundary concentration on the RWM at the cochlea, which resulted in a well-fit concentration. Finally, a linking mechanism between the middle ear and the cochlea was established by the RWM. The adjustable permeability and concentration threshold provide the flexibility to match the peak times and peak values of the concentration on the RWM in the middle ear and the cochlea. [ABSTRACT FROM PUBLISHER]

Mutations in the SLC26A4 gene are a common cause of human hereditary hearing impairment worldwide. Previous studies have demonstrated that different SLC26A4 mutations have different pathogenetic mechanisms. By using a genotype-driven approach, we established a knock-in mouse model (i.e., Slc26a4tm2Dontuh/tm2Dontuh mice) homozygous for the common p.H723R mutation in the East Asian population. To verify the pathogenicity of the p.H723R allele in mice, we further generated mice with compound heterozygous mutations (i.e., Slc26a4tm1Dontuh/tm2Dontuh) by intercrossing Slc26a4+/tm2Dontuh mice with Slc26a4tm1Dontuh/tm1Dontuh mice, which segregated the c.919-2A>G mutation with an abolished Slc26a4 function. Mice were then subjected to audiologic assessments, a battery of vestibular evaluations, inner ear morphological studies, and noise exposure experiments. The results were unexpected; both Slc26a4tm2Dontuh/tm2Dontuh and Slc26a4tm1Dontuh/tm2Dontuh mice showed normal audiovestibular phenotypes and inner ear morphology, and they did not show significantly higher shifts in hearing thresholds after noise exposure than the wild-type mice. The results indicated not only the p.H723R allele was non-pathogenic in mice, but also a single p.H723R allele was sufficient to maintain normal inner ear physiology in heterozygous compound mice. There might be discrepancies in the pathogenicity of specific SLC26A4 mutations in humans and mice; therefore, precautions should be taken when extrapolating the results of animal studies to humans. [ABSTRACT FROM AUTHOR]

Recessive mutations in the SLC26A4 gene are a common cause of hereditary hearing impairment worldwide. Previous studies have demonstrated that different SLC26A4 mutations may have different pathogenetic mechanisms. In the present study, we established a knock-in mouse model (i.e., Slc26a4tm1Dontuh/tm1Dontuh mice) homozygous for the c.919-2A.G mutation, which is a common mutation in East Asians. Mice were then subjected to audiologic assessment, a battery of vestibular evaluations, and inner ear morphological studies. All Slc26a4tm1Dontuh/tm1Dontuh mice revealed profound hearing loss, whereas 46% mice demonstrated pronounced head tilting and circling behaviors. There was a significant difference in the vestibular performance between wild-type and Slc26a4tm1Dontuh/tm1Dontuh mice, especially those exhibiting circling behavior. Inner ear morphological examination of Slc26a4tm1Dontuh/tm1Dontuh mice revealed an enlarged endolymphatic duct, vestibular aqueduct and sac, atrophy of stria vascularis, deformity of otoconia in the vestibular organs, consistent degeneration of cochlear hair cells, and variable degeneration of vestibular hair cells. Audiologic and inner ear morphological features of Slc26a4tm1Dontuh/tm1Dontuh mice were reminiscent of those observed in humans. These features were also similar to those previously reported in both knock-out Slc26a4-/- mice and Slc26a4loop/loop mice with the Slc26a4 p.S408F mutation, albeit the severity of vestibular hair cell degeneration appeared different among the three mouse strains. [ABSTRACT FROM AUTHOR]

Abstract: Cinnabar, a naturally occurring mercuric sulfide (HgS), has long been used in Chinese mineral medicine for more than 2000 years; currently it is still used as a sedative for infants in Asian countries. Since methylmercury is potently ototoxic, whether cinnabar also induces hearing impairment is awaited for delineation. In this study, we attempted to explore the toxic effects of cinnabar on the auditory brainstem response (ABR) system during 2–10 weeks administration at a clinical oral dosage of 10mg/kg/day in mice. The results showed that Hg contents of the brainstem were significantly increased accompanied with gradually progressive abnormality of ABR during 4–10 weeks of cinnabar administration. The progressive increase in hearing thresholds, prolonged absolute and interwave latencies of ABR apparently exhibited a gender difference. Male mice were more sensitive to cinnabar in producing hearing impairment correlated with the biochemical alterations in plasma and brainstem, e.g. an increase of lipid peroxidation (LPO), altered Na+/K+-ATPase activities and decrease of nitric oxide (NO x ) levels. Moreover, accumulation of Hg contents in brainstem with a greater extent was found in male mice. These findings provide important information that the clinical dosage of cinnabar (10mg/kg/day) still exhibited ototoxicity after continuously long-term exposure. The signaling pathway of oxidative stress/Na+–K+-ATPase activities/NO of brainstem (a central auditory regulatory system) probably plays an important role in the toxic mechanisms of cinnabar-induced ototoxicity. The gender difference in cinnabar-induced neurotoxic effects merits further investigation. [Copyright &y& Elsevier]

Accurate epidemiological data on common deafness genes are essential to improve the efficiency and to reduce the cost of molecular diagnosis. They may depend on several factors, including a clear delineation of the source of patients being studied. In the present study, we hypothesize that patients with idiopathic sensorineural hearing loss recruited from different sources might reveal discrepancies in the epidemiological results of genetic screening, because patients from different sources might demonstrate distinct clinical or audiologic features and thus result in biased selection of subjects. To elucidate the relative importance of common deafness genes in Taiwanese and to verify our hypothesis, we conducted a prospective project screening mutations in GJB2, SLC26A4 and mitochondrial 12S rRNA gene in a total of 420 Taiwanese families with idiopathic bilateral sensorineural hearing loss, of which 325 families were recruited from hospitals and 95 from hearing rehabilitation facilities. Allele frequencies of common mutations in these three genes and distributions of the corresponding genotypes were then compared between the two groups. The allele frequencies of mutations in SLC26A4, GJB2 and mitochondrial 12S rRNA in the probands of the 420 families were 14.4, 21.7 and 3.8%, respectively. The allele frequency of SLC26A4 mutations in the hospital group was significantly higher than that in the rehabilitation facility group (16.2 vs. 8.4%, chi(2)-test, p < 0.05), whereas no difference in the frequencies of GJB2 mutations and mitochondrial 12S rRNA mutations was found between the two groups. Distributions of probands classified by SLC26A4 genotypes were also different between the two groups (chi(2)-test, p < 0.05). Accordingly, a discrepancy in the genetic screening results might exist between different sources of idiopathic hearing-impaired patients. Further analysis of audiological results and construction of a logistic regression model showed that different audiological features, namely hearing levels and hearing loss patterns, might be responsible for the unequal distributions of mutations and probands between the hospital and rehabilitation facility groups. [ABSTRACT FROM AUTHOR]

Abstract: Methylmercury (MeHg), a potent neurotoxicant, easily passes through the blood-brain barrier (BBB), accumulates in the brain regions and causes severe irreversible damage. However, the neurotoxic effects and action mechanisms of MeHg are still unclear, especially in low-dose and long-term exposure. In this study, we attempted to explore the toxic effects of low-dose MeHg (0.05mg/kg/day), which was the possible exposed dose by ingestion in MeHg-contaminated areas, on the time course of changes in locomotor activities and auditory brainstem response (ABR) system after administration for 7 consecutive weeks in mice. The results showed that the retention time on the rotating rod (60rpm) was preferentially decreased after 1-week oral administration with MeHg. The locomotor activities parameters of ambulatory distances and stereotype-1 episodes were significantly increased and vertical-plane entries were progressively decreased after MeHg exposure in 3 consecutive weeks. Gradually progressive abnormality of ABR (increase in hearing thresholds, prolonged absolute and interwave latencies) was found during 4–6 weeks administration of MeHg. These impairments correlated with significant Hg accumulation and biochemical alterations in brain regions and/or other tissues, including the increase of lipid peroxidation (LPO) production, influence of Na+/K+-ATPase activities and nitric oxide (NO) levels were found. These findings provide evidence that the signaling of oxidative stress/Na+/K+-ATPase/NO plays a role in the underlying mechanisms of the neurotoxic effects induced by low-dose and long-term exposure of MeHg. [Copyright &y& Elsevier]

The timing of hypoglossal-facial nerve anastomosis is controversial. The present study was performed to clarify the influence of the timing of hypoglossal-facial nerve anastomosis on histological changes in the facial nerve and central nuclei using guinea pigs. The facial nerve was transected first at the labyrinthine portion, and then transected again at the stylomastoid foramen. Hypoglossal-facial nerve anastomosis was carried out immediately or 3 months later. Nerve regeneration and survival of the neurons in the facial and hypoglossal nuclei were evaluated by toluidine blue staining and horseradish peroxidase (HRP). Immediate anastomosis resulted in better nerve regeneration of the facial nerve, but the numbers of surviving neurons in the facial and hypoglossal nuclei were almost the same in both the immediate and delayed anastomosis groups. [ABSTRACT FROM AUTHOR]

Recessive variants of the SLC26A4 gene are globally a common cause of hearing impairment. In the past, cell lines and transgenic mice were widely used to investigate the pathogenicity associated with SLC26A4 variants. However, discrepancies in pathogenicity between humans and cell lines or transgenic mice were documented for some SLC26A4 variants. For instance, the p.C565Y variant, which was reported to be pathogenic in humans, did not exhibit functional pathogenic consequences in cell lines. To address the pathogenicity of p.C565Y, we used a genotype-based approach in which we generated knock-in mice that were heterozygous (Slc26a4+/C565Y), homozygous (Slc26a4C565Y/C565Y), and compound heterozygous (Slc26a4919-2A>G/C565Y) for this variant. Subsequent phenotypic characterization revealed that mice with these genotypes demonstrated normal auditory and vestibular functions, and normal inner-ear morphology and pendrin expression. These findings indicate that the p.C565Y variant is nonpathogenic for mice, and that a single p.C565Y allele is sufficient to maintain normal inner-ear physiology in mice. Our results highlight the differences in pathogenicity associated with certain SLC26A4 variants between transgenic mice and humans, which should be considered when interpreting the results of animal studies for SLC26A4-related deafness. [ABSTRACT FROM AUTHOR]

Excessive levels of reactive oxygen species (ROS) lead to mitochondrial damage and apoptotic cell death in gentamicin-induced ototoxicity. 2,3,4',5-Tetrahydroxystilbene-2-O-β-d-glucoside (THSG), a bioactive constituent, isolated from Polygonum multiflorum Thunb., exhibits numerous biological benefits in treating aging-related diseases by suppressing oxidative damage. However, its protective effect on gentamicin-induced ototoxicity remains unexplored. Therefore, here, we aimed to investigate the otoprotective effect of THSG on gentamicin-induced apoptosis in mouse cochlear UB/OC-2 cells. We evaluated the effect of gentamicin and THSG on the ROS level, superoxide dismutase (SOD) activity, mitochondrial membrane potential, nuclear condensation, and lactate dehydrogenase (LDH) release, and the expression of apoptosis-related proteins was assessed to understand the molecular mechanisms underlying its preventive effects. The findings demonstrated that gentamicin increased ROS generation, LDH release, and promoted apoptotic cell death in UB/OC-2 cells. However, THSG treatment reversed these effects by suppressing ROS production and downregulating the mitochondrial-dependent apoptotic pathway. Additionally, it increased the SOD activity, decreased the expression of apoptosis-related proteins, alleviated the levels of the apoptotic cells, and impaired cytotoxicity. To the best of our knowledge, this is the first study to demonstrate that THSG could be a potential therapeutic option to attenuate gentamicin-induced ototoxicity. [ABSTRACT FROM AUTHOR]

Gap junction protein beta 2 gene (GJB2) mutations are the most frequent cause of hereditary hearing impairment. The recessive c.235delC mutation in the GJB2 gene is the most common mutation causing severe to profound sensorineural hearing loss in the Asian population. The induced pluripotent stem cell (iPSC) line was generated using the integration-free Sendai virus method from peripheral blood mononuclear cells (PBMCs) of a hearing-impaired patient with homozygous GJB2 c.235delC mutation. This cell line may serve as a cellular model for studying the pathogenic mechanisms of deafness caused by GJB2 mutations. [ABSTRACT FROM AUTHOR]

Betel quid is one of the most widely used psychoactive substances, and is consumed by approximately 10% of the world's population. In addition to its carcinogenicity, betel quid has also been reported to affect many organs, including the brain, heart, lungs, gastrointestinal tract, and reproductive organs. As betel quid contains several neurotoxic ingredients, we hypothesize that it also possesses ototoxicity and may lead to sensorineural hearing impairment (SNHI). In this study, we investigated the contribution of betel quid consumption to SNHI in a large clinical cohort, and validated the pathogenetic mechanisms in ex vivo tissue explants. We enrolled a total of 2364 volunteers, and determined their audiologic results based on Z-scores converted from their original frequency-specific hearing thresholds. Using generalized linear regression, we identified a positive correlation between betel quid consumption and the Z-scores across different frequencies. Subsequently, we explored the toxicity of arecoline, the main neuroactive component of betel quid, on tissue explants from murine cochleae. Arecoline reduced cell activity in the explant cultures and induced apoptosis in the hair cells, probably through the effects of oxidative stress. These findings have expanded the potential hazards of betel quid to common neurological disorders, and provide insights into preventive strategies against SNHI caused by neurotoxic substances. [ABSTRACT FROM AUTHOR]

Hereditary hearing impairment (HHI) is a common but heterogeneous clinical entity caused by mutations in a plethora of deafness genes. Research over the past few decades has shown that the genetic epidemiology of HHI varies significantly across populations. In this study, we used different genetic examination strategies to address the genetic causes of HHI in a large Taiwanese cohort composed of >5000 hearing-impaired families. We also analyzed the clinical features associated with specific genetic mutations. Our results demonstrated that next-generation sequencing-based examination strategies could achieve genetic diagnosis in approximately half of the families. Common deafness-associated genes in the Taiwanese patients assessed, in the order of prevalence, included GJB2, SLC26A4, OTOF, MYO15A, and MTRNR1, which were similar to those found in other populations. However, the Taiwanese patients had some unique mutations in these genes. These findings may have important clinical implications for refining molecular diagnostics, facilitating genetic counseling, and enabling precision medicine for the management of HHI. [ABSTRACT FROM AUTHOR]

Objective: To evaluate the feasibility and potential benefits of incorporating genetic and cytomegalovirus (CMV) screenings into the current newborn hearing screening (NHS) programs.Study Design: Newborns were recruited prospectively from a tertiary hospital and a maternity clinic between May 2016 and December 2016 and were subjected to hearing screening, CMV screening, and genetic screening for 4 common mutations in deafness genes (p.V37I and c.235delC of GJB2 gene, c.919-2A>G of SLC26A4 gene, and the mitochondrial m.1555A>G). Infants with homozygous nuclear mutations or homoplasmic/heteroplasmic mitochondrial mutation (referred to as "conclusively positive genotypes") and those who tested positive for CMV received diagnostic audiologic evaluations.Results: Of the total 1716 newborns enrolled, we identified 20 (1.2%) newborns with conclusively positive genotypes on genetic screening, comprising 15 newborns (0.9%) with GJB2 p.V37I/p.V37I and 5 newborns (0.3%) with m.1555A>G. Three (0.2%) newborns tested positive on CMV screening. Twelve of the 20 newborns (60%) with conclusively positive genotypes and all 3 newborns who tested positive for CMV (100%) passed NHS at birth. Diagnostic audiologic evaluations conducted at 3 months confirmed hearing impairment in 6 of the 20 infants (30%) with conclusively positive genotypes.Conclusions: This study confirms the feasibility of performing hearing, genetic, and CMV screenings concurrently in newborns and provides evidence that the incorporation of these screening tests could potentially identify an additional subgroup of infants with impaired hearing that might not be detected by the NHS programs. [ABSTRACT FROM AUTHOR]

Hearing impairment is one of the most common sensory disorders in children, and targeted next-generation sequencing (NGS)-based genetic examinations can assist in its prognostication and management. In 2020, we developed a simplified 30-gene NGS panel from the original 214-gene NGS version based on Taiwanese genetic epidemiology data to increase the accessibility of NGS-based examinations. In this study, we evaluated the diagnostic performance of the 30-gene NGS panel and compared it with that of the original 214-gene NGS panel in patient subgroups with different clinical features. Data on the clinical features, genetic etiologies, audiological profiles, and outcomes were collected from 350 patients who underwent NGS-based genetic examinations for idiopathic bilateral sensorineural hearing impairment between 2020 and 2022. The overall diagnostic yield was 52%, with slight differences in genetic etiology between patients with different degrees of hearing impairment and ages of onset. No significant difference was found in the diagnostic yields between the two panels, regardless of clinical features, except for a lower detection rate of the 30-gene panel in the late-onset group. For patients with negative genetic results, where the causative variant is undetectable on current NGS-based methods, part of the negative results may be due to genes not covered by the panel or yet to be identified. In such cases, the hearing prognosis varies and may decline over time, necessitating appropriate follow-up and consultation. In conclusion, genetic etiologies can serve as references for refining targeted NGS panels with satisfactory diagnostic performance. [ABSTRACT FROM AUTHOR]

Background: Waardenburg syndrome (WS) is a hereditary, genetically heterogeneous disorder characterized by variable presentations of sensorineural hearing impairment and pigmentation anomalies. This study aimed to investigate the clinical features of WS in detail and determine the genetic causes of patients with clinically suspected WS. Methods: A total of 24 patients from 21 Han‐Taiwanese families were enrolled and underwent comprehensive physical and audiological examinations. We applied targeted next‐generation sequencing (NGS) to investigate the potential causative variants in these patients and further validated the candidate variants through Sanger sequencing. Results: We identified 19 causative variants of WS in our cohort. Of these variants, nine were novel and discovered in PAX3, SOX10, EDNRB, and MITF genes, including missense, nonsense, deletion, and splice site variants. Several patients presented with skeletal deformities, hypotonia, megacolon, and neurological disorders that were rarely seen in WS. Conclusion: This study revealed highly phenotypic variability in Taiwanese WS patients and demonstrated that targeted NGS allowed us to clarify the genetic diagnosis and extend the genetic variant spectrum of WS. [ABSTRACT FROM AUTHOR]

Background: Taxifolin is a flavanonol with efficacious cytoprotective properties, such as anti-inflammatory, antioxidant, anticancer, hepatoprotective, and nephroprotective effects. However, the potential protective effects of taxifolin against gentamicin-induced ototoxicity have not been confirmed. In this study, the possible mechanisms underlying the effects of taxifolin on gentamicin-induced death of UB/OC-2 cochlear cells were investigated. Methods: Mouse cochlear UB/OC-2 cells with or without taxifolin pretreatment were exposed to gentamicin, and the effects on cytotoxicity, reactive oxygen species (ROS) production, mitochondrial permeability transition, and apoptotic marker expression were examined using biochemical techniques, flow cytometry, western blotting, and fluorescent staining. Results: Little or no apparent effect of taxifolin on cell viability was observed at concentrations less than 40 μM. Further investigations showed that gentamicin significantly inhibited cell viability in a concentration-dependent manner. Pretreatment with taxifolin attenuated gentamicin-induced lactate dehydrogenase release, as well as cellular cytotoxicity. In addition, taxifolin significantly prevented gentamicin-induced cell damage by decreasing ROS production, stabilizing mitochondrial membrane potential, and downregulating the mitochondrial pathway of apoptosis. Conclusion: In summary, pretreatment with taxifolin is effective for mitigating gentamicin-induced apoptotic cell death mediated by the mitochondrial pathway. Our data suggest that taxifolin provides a new approach to combat gentamicin-induced ototoxicity. [ABSTRACT FROM AUTHOR]

Congenital cytomegalovirus (cCMV) infection is the most prevalent cause of non-genetic sensorineural hearing loss (SNHL) in children. However, the prognostic determinants of SNHL remain unclear. Children with cCMV infection in a tertiary hospital were enrolled. The presence of cCMV-related symptoms at birth, the newborn hearing screening (NHS) results, and the blood viral loads were ascertained. Audiologic outcomes and initial blood viral loads were compared between different groups. Of the 39 children enrolled, 16 developed SNHL. SNHL developed in 60% of children who were initially symptomatic, and in 34.5% of those who were initially asymptomatic with normal hearing or isolated hearing loss, respectively. Failuire in NHS was a reliable tool for early detection of SNHL. The initial viral loads were higher in children who were symptomatic at birth, those who failed NHS, and those who developed SNHL. We observed SNHL deterioration in a patient after CMV DNAemia clearance was achieved, and in another patient with the flare-up of viral load. The presence of cCMV-related symptoms at birth, failure in NHS, and blood viral load might be the prognostic factors for hearing outcomes. Regular audiologic examinations are necessary in all children with cCMV infection even after CMV DNAemia clearance. [ABSTRACT FROM AUTHOR]

Keywords: audit; cochlear implants; communication; diagnosis; genetics; hearing loss; inner ear; outcomes; sensorineural hearing loss EN audit cochlear implants communication diagnosis genetics hearing loss inner ear outcomes sensorineural hearing loss 341 346 6 02/17/22 20220301 NES 220301 Key Points LEOPARD syndrome is a rare hereditary disease characterised by several congenital defects in multiple organs, including sensorineural hearing impairment. The CI outcomes in LEOPARD syndrome patients are influenced by the I PTPN11 i genotypes because different I PTPN11 i mutations confer different pathogenicity on neurocognitive development. Audit, communication, diagnosis, genetics, inner ear, outcomes, sensorineural hearing loss, cochlear implants, hearing loss The authors attributed the unfavourable outcome to the patient's underlying cerebral palsy and late implantation.3 Nierop et al.4 reported another patient with LEOPARD syndrome caused by the I PTPN11 i p.Y279C mutation who received bilateral sequential CI at the ages of 1 years 4 months and 1 years 10 months. [Extracted from the article]

Abstract: To investigate the relationship between plasma reactive oxygen species (ROS) levels and severity of age-related hearing impairment in humans. We recruited 302 adult subjects aged 40–77 years with normal or symmetrical sensorineural hearing loss. The association of plasma ROS levels on pure tone average of low frequencies (PTA-low) and pure tone average of high frequencies (PTA-high) were analyzed. Luminol-dependent chemiluminescence signals, which reflect hydrogen peroxide (H2O2), hypochlorite (HOCl/OCl−) and hydroxyl radicals (•OH) levels, showed significant positive association with PTA-low and PTA-high after adjusting for age, gender, central obesity, systemic diseases, and health-related habits (smoking, drinking, antioxidant intake). Lucigenin-dependent chemiluminescence signals, which mainly reflect superoxide anion (O2•−) levels, showed significant positive association with PTA-low, but not with PTA-high after adjusting for other variables. We concluded that plasma ROS levels were associated with severity of age-related hearing impairment in humans. Various ROS may differently affect auditory dysfunctions. [Copyright &y& Elsevier]

Abstract: Mercury is a well-known toxic metal and potently induces severe neurotoxicological effects, especially in infants and children. The purpose of this study was to explore the underlying mechanisms of neurotoxic effects of mercurial compounds on the different stages of developing mice. Low-doses (the probability of human exposure in mercury-contaminated areas) of methylmercury (MeHg) (M, 0.02mg/kg/day) and mercury chloride (HgCl2) (H, 0.5mg/kg/day) were administered to mice of the following groups: (1) treatment with distilled water for 7 consecutive weeks after weaning (control-vehicle (CV)); exposure to mercurial compounds at different stages; (2) for 7 consecutive weeks after weaning (control-MeHg (CM) and control-HgCl2 (CH)); (3) only during perinatal and weaning stages (MeHg-vehicle (MV) and HgCl-vehicle (HV)); and (4) in all experimental stages (MeHg–MeHg (MM) and HgCl2–HgCl2 (HH)). Results revealed the neurobehavioral defects (increased locomotor activities, motor equilibrium impairment, and auditory dysfunction) that correlated with increasing Hg accumulation in CM and CH groups. However, it revealed a decrease and an increase in locomotor activities in MV and HV groups, respectively; these became more severe in MM and HH groups than in MV and HV groups. Motor equilibrium performance in MV and HV groups remained normal, while that in MM and HH groups was decreased. The most severe auditory defects (altered auditory brainstem response, ABR test) found in MM and HH groups than those in the respective CM and CH, MV and HV, including absolute wave III delays and interwave I–III latencies, which suggested that the irreversible auditory dysfunction caused by mercurial compounds. Furthermore, the alteration of lipid peroxidation (LPO), Na+/K+-ATPase activities, and nitric oxide (NO x ) in the brain tissues contributed to the observed neurobehavioral dysfunction and hearing impairment. These findings provide evidence that fetuses were much more susceptible to the effects of mercurial compounds with regard to inducing severely neurotoxicological injuries as that found in human beings. The signaling of ROS/Na+-K+-ATPase/NO x plays a crucial role in the underlying mechanism for mercurial compound-induced toxic effects in offspring. [Copyright &y& Elsevier]

Abstract: Na+, K+-ATPase and Ca2+-ATPase in the cochlear lateral wall play an important role in maintaining ionic homeostasis and physiologic function of the cochlea. The present study was designed to test whether the changes of Na+, K+-ATPase and Ca2+-ATPase activities of the cochlear lateral wall and the brainstem of guinea pigs after receiving cisplatin for seven consecutive days were correlated with the altered auditory brainstem responses (ABR). Furthermore, whether a chemoprotective agent, d-methionine reversed the increased ABR threshold induced by cisplatin accompanied with the increased ATPase activities was also evaluated. The results obtained showed that cisplatin exposure caused not only a significant increase of threshold but also altered various absolute wave and interwave latencies of ABR. In addition, cisplatin significantly decreased the Na+, K+-ATPase and Ca2+-ATPase activities in the cochlear lateral wall with a good dose–response relationship. Regression analysis indicated that an increase of ABR threshold was well correlated with a decrease of both Na+, K+-ATPase and Ca2+-ATPase activities in the cochlear lateral wall. A chemoprotectant, d-methionine indeed reversed both abnormalities of ABR and ATPase activities in a well correlation function. The selectivity of these observed changes induced by cisplatin and d-methionine was revealed by the findings that cisplatin-treated guinea pigs had normal III–V interwave latency of ABR and no reduction of Na+, K+-ATPase and Ca2+-ATPase specific activities in the brainstem, which is in accordance with the nonpenetrable cisplatin across the blood brain barrier. Taken all together, the present findings suggest that biochemical damage and ionic disturbance may contribute to cisplatin-induced ototoxicity to some extent, which can be reversed by d-methionine. [Copyright &y& Elsevier]

Recessive variants of the SLC26A4 gene are an important cause of hereditary hearing impairment. Several transgenic mice with different Slc26a4 variants have been generated. However, none have recapitulated the auditory phenotypes in humans. Of the SLC26A4 variants identified thus far, the p.T721M variant is of interest, as it appears to confer a more severe pathogenicity than most of the other missense variants, but milder pathogenicity than non-sense and frameshift variants. Using a genotype-driven approach, we established a knock-in mouse model homozygous for p.T721M. To verify the pathogenicity of p.T721M, we generated mice with compound heterozygous variants by intercrossing Slc26a4+/T721M mice with Slc26a4919-2A>G/919-2A>G mice, which segregated the c.919-2A > G variant with abolished Slc26a4 function. We then performed serial audiological assessments, vestibular evaluations, and inner ear morphological studies. Surprisingly, both Slc26a4T721M/T721M and Slc26a4919-2A>G/T721M showed normal audiovestibular functions and inner ear morphology, indicating that p.T721M is non-pathogenic in mice and a single p.T721M allele is sufficient to maintain normal inner ear physiology. The evidence together with previous reports on mouse models with Slc26a4 p.C565Y and p.H723R variants, support our speculation that the absence of audiovestibular phenotypes in these mouse models could be attributed to different protein structures at the C-terminus of human and mouse pendrin. [ABSTRACT FROM AUTHOR]

Congenital cytomegalovirus (cCMV) infection is the leading environmental cause of childhood hearing impairment. However, its significance remains largely undocumented in many regions of the world. The purpose of this study was to investigate the prevalence and clinical features of cCMV infection in East Asia. Neonates born at a municipal hospital in Taipei were prospectively recruited and underwent concurrent hearing and CMV screenings. Those who failed the hearing screening or screened positive for CMV were subjected to a focused audiological and/or virological surveillance. The characteristics of the newborns and their mothers were compared between the CMV-positive and CMV-negative groups. Of the 1,532 newborns who underwent concurrent hearing and CMV screenings, seven (0.46%) were positive for cCMV infection. All seven CMV-positive newborns were asymptomatic at birth, and none of them developed hearing or other symptoms during a follow-up period of 14.4±6.3 months. The mothers of the CMV-positive newborns demonstrated higher gravidity (2.4 ± 1.4 vs. 2.1 ± 1.2) and parity (2.0 ± 1.2 vs. 1.6 ± 0.7) than those in the CMV-negative group; however, the difference did not reach statistical significance. The prevalence of cCMV infection in Taipei newborns was 0.46%, which is slightly lower than that of other populations and that of a previous report in the Taiwanese population. The relatively low prevalence in this study might be attributed to the improved public health system and decreased fertility rate in Taiwan. [ABSTRACT FROM AUTHOR]

Hearing loss is the most prevalent hereditary sensory disorder in children. Approximately 2 in 1000 infants are affected by genetic hearing loss. The PJVK gene, which encodes the pejvakin protein, has been linked to autosomal recessive non-syndromic hearing loss DFNB59. Previous clinical studies have revealed that PJVK mutations might be associated with a wide spectrum of auditory manifestations, ranging from hearing loss of pure cochlear origin to that involving the retrocochlear central auditory pathway. The phenotypic variety makes the pathogenesis of this disease difficult to determine. Similarly, mouse models carrying different Pjvk defects show phenotypic variability and inconsistency. In this study, we generated a knockin mouse model carrying the c.874G > A (p.G292R) variant to model and investigate the auditory and vestibular phenotypes of DFNB59. • A mouse model of DFNB59 with the Pjvk c.874G > A mutation was established by CRISPR/Cas9 approach. • Pjvk c.874G > A mutant mice exhibited progressive hearing loss, with cochlear hair cell and spiral ganglion degeneration. • Vestibular dysfunction with progressive loss of vestibular ganglion neurons was observed in Pjvk c.874G > A mutant mice. [ABSTRACT FROM AUTHOR]

Age-related hearing impairment (ARHI) is a complex neurodegenerative disorder caused by a combination of environmental and genetic factors. We have reported previously that obesity increases the risk for ARHI, and that plasma levels of adiponectin are associated with ARHI. In the present study, we further explored the role of adiponectin in the pathophysiology of ARHI by investigating the genotypes of ADIPOQ and ADIPOR1 , the genes of adiponectin and its type 1 receptor, respectively. A total of 1682 volunteers were enrolled, and their audiological phenotypes were determined according to the z scores converted from their original frequency-specific hearing thresholds. A total of 9 tag-single nucleotide polymorphisms (tagSNPs) in ADIPOQ and 4 tagSNPs in ADIPOR1 were genotyped, and the genotypes were correlated to the audiological phenotypes under the assumption of various inheritance models. Significant associations were identified between certain ADIPOQ tagSNPs and z scores under dominant, codominant, or additive models, whereas no association was identified between ADIPOR1 tagSNPs and z scores. The associations between ADIPOQ tagSNPs and z scores appear to exist only in subjects with specific ADIPOR1 genotypes, indicating an interaction between adiponectin and AdipoR1. Measurement of plasma adiponectin in 736 subjects revealed that ADIPOQ genotypes might exert their effects on hearing levels via modulation of plasma adiponectin levels. Subsequently, we confirmed the expression of AdipoR1 in the inner ear of mice, and demonstrated antiapoptotic effects of adiponectin in cochlear explant cultures. These results provide insights into the physiological function and potential clinical implications of adiponectin against ARHI. [ABSTRACT FROM AUTHOR]

Gradenigo syndrome is a rare but devastating complication of otitis media that involves the petrous apex. Clinically, it is characterized by the triad of suppurative otitis media, deep facial pain, and abducens palsy. Most of the Gradenigo syndrome cases that have been reported in the literature were caused by pyogenic bacteria. In this report, we describe the clinical courses of 4 adults with Gradenigo syndrome who were encountered consecutively at a tertiary referral hospital between 2008 and 2012. Mycobacterium abscessus was confirmed in all 4 cases by culturing the pathological tissues obtained during surgical debridement. To the best of our knowledge, this is the first report documenting infections of nontuberculous mycobacteria (NTM) in Gradenigo syndrome. An NTM infection must be considered in chronic otomastoiditis complicated by Gradenigo syndrome. The definite treatment of Gradenigo syndrome with an NTM infection requires adequate surgical debridement combined with antibiotic treatment for at least 4-6 months. © 2014 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Abstract: This study investigates the photoelectrocatalytic (PEC) property of microporous WO3-loaded TiO2/Ti layer, prepared via micro-arc oxidation (MAO) of Ti plate, followed by sputtering deposition of a thin Pt layer as a Pt-TiO2/Ti electrode. The WO3-loaded TiO2 layer which is associated with a more acidic surface forms many local electrochemical cells on its micro-pores immersed in cationic dye solution. The electrocatalytic (EC) reactions can take place in the local cells by the applied electrons. A low resistivity that is accomplished by MAO technique and by platinization offers an easy path for the electron motions in the Pt-TiO2/Ti electrode. All these features make the EC oxidation of aqueous dye pollutants practically feasible without using counter electrodes and supporting electrolytes. Our experiments demonstrate that, under PEC condition, the Pt-TiO2/Ti shows the highest degradation rate constant of 0.83h−1 at an applied bias of 1.0V and exhibits significantly high PEC and EC oxidation activities at a low applied bias of 0.25V. This is attributable to high anodic currents generated in the Pt-TiO2/Ti even at low bias. The modified microporous electrodes conclusively reveal a very interesting EC property as a two double-sided device that functions the PEC and EC oxidation simultaneously without a need of supporting electrolyte and expensive Pt cathode. [Copyright &y& Elsevier]

Purpose: To report outcomes of the rare disease of squamous cell carcinoma (SCC) of the external auditory canal (EAC) and middle ear treated with surgery and postoperative intensity-modulated radiotherapy (IMRT). Failure patterns related to spatial dose distribution were also analyzed to provide insight into target delineation. Methods and Materials: A retrospective review was conducted of the records of 11 consecutive patients with SCC of the EAC and middle ear who were treated with curative surgery and postoperative IMRT at one institution between January 2007 and February 2010. The prescribed IMRT dose was 60 to 66 Gy at 2 Gy per fraction. Three patients also received concurrent cisplatin-based chemotherapy, and 1 patient received concurrent oral tegafur/uracil. The median follow-up time was 19 months (range, 6–33 months). Results: Four patients had locoregional recurrence, yielding an estimated 2-year locoregional control rate of 70.7%. Among them, 1 patient had persistent disease after treatment, and 3 had marginal recurrence. Distant metastasis occurred in 1 patient after extensive locoregional recurrence, yielding an estimated 2-year distant control rate of 85.7%. The estimated 2-year overall survival was 67.5%. The three cases of marginal recurrence were near the preauricular space and glenoid fossa of the temporomandibular joint, adjacent to the apex of the ear canal and glenoid fossa of the temporomandibular joint, and in the postauricular subcutaneous area and ipsilateral parotid nodes, respectively. Conclusions: Marginal misses should be recognized to improve target delineation. When treating SCC of the EAC and middle ear, care should be taken to cover the glenoid fossa of the temporomandibular joint and periauricular soft tissue. Elective ipsilateral parotid irradiation should be considered. The treatment planning procedure should also be refined to balance subcutaneous soft-tissue dosimetry and toxicity. [ABSTRACT FROM AUTHOR]

Background: Recessive GJB2 variants, the most common genetic cause of hearing loss, may contribute to progressive sensorineural hearing loss (SNHL). The aim of this study is to build a realistic predictive model for GJB2-related SNHL using machine learning to enable personalized medical planning for timely intervention., Method: Patients with SNHL with confirmed biallelic GJB2 variants in a nationwide cohort between 2005 and 2022 were included. Different data preprocessing protocols and computational algorithms were combined to construct a prediction model. We randomly divided the dataset into training, validation, and test sets at a ratio of 72:8:20, and repeated this process ten times to obtain an average result. The performance of the models was evaluated using the mean absolute error (MAE), which refers to the discrepancy between the predicted and actual hearing thresholds., Results: We enrolled 449 patients with 2184 audiograms available for deep learning analysis. SNHL progression was identified in all models and was independent of age, sex, and genotype. The average hearing progression rate was 0.61 dB HL per year. The best MAE for linear regression, multilayer perceptron, long short-term memory, and attention model were 4.42, 4.38, 4.34, and 4.76 dB HL, respectively. The long short-term memory model performed best with an average MAE of 4.34 dB HL and acceptable accuracy for up to 4 years., Conclusions: We have developed a prognostic model that uses machine learning to approximate realistic hearing progression in GJB2-related SNHL, allowing for the design of individualized medical plans, such as recommending the optimal follow-up interval for this population., Competing Interests: Declaration of competing interest The below authors declare the following financial interests/personal relationships which may be considered as potential competing interests., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Aminoglycoside- and cisplatin-induced ototoxicity, which is a significant issue owing to the widespread use of these drugs in clinical practice, involves the entry of aminoglycosides and cisplatin into the endolymph and hair cells via specific channels or transporters, followed by reactive oxygen species (ROS) generation and hair cells apoptosis. Current strategies focalize primarily on interference with downstream ROS effects; however, recent evidence has demonstrated that inhibiting the uptake of aminoglycosides and cisplatin by hair cells is another promising strategy for tackling the upstream drug uptake pathway. With advances in structural biology, the conformations of certain aminoglycoside and cisplatin channels and transporters, such as the mechanoelectrical transduction channel and organic cation transporter-2, have been largely elucidated. These channels and transporters may become potential targets for the introduction of new otoprotective strategies. This review focuses on the strategies for inhibiting ototoxic drugs uptake by auditory hair cells and provides potential targets for recent developments in the field of otoprotection. Molecular dynamics (MD) simulations of these proteins could help identify the molecules that inhibit the uptake of aminoglycosides and cisplatin by hair cells. Integrating upstream drug uptake pathway targets and MD simulations may help dissect molecular mechanisms and develop novel otoprotective strategies for aminoglycoside- and cisplatin-induced ototoxicity., Competing Interests: Conflicts of interest: The authors declare that they have no conflicts of interest related to the subject matter or materials discussed in this article., (Copyright © 2023, the Chinese Medical Association.)

Variants in the gap junction beta-2 ( GJB2 ) gene are the most common cause of hereditary hearing impairment. However, how GJB2 variants lead to local physicochemical and structural changes in the hexameric ion channels of connexin 26 (Cx26), resulting in hearing impairment, remains elusive. In this study, using molecular dynamics (MD) simulations, we showed that detached inner-wall N-terminal "plugs" aggregated to reduce the channel ion flow in a highly prevalent V37I variant in humans. To examine the predictive ability of the computational platform, an artificial mutant, V37M, of which the effect was previously unknown in hearing loss, was created. Microsecond simulations showed that homo-hexameric V37M Cx26 hemichannels had an abnormal affinity between the inner edge and N-termini to block the narrower side of the cone-shaped Cx26, while the most stable hetero-hexameric channels did not. From the perspective of the conformational energetics of WT and variant Cx26 hexamers, we propose that unaffected carriers could result from a conformational predominance of the WT and pore-shrinkage-incapable hetero-hexamers, while mice with homozygous variants can only harbor an unstable and dysfunctional N-termini-blocking V37M homo-hexamer. Consistent with these predictions, homozygous V37M transgenic mice exhibited apparent hearing loss, but not their heterozygous counterparts, indicating a recessive inheritance mode. Reduced channel conductivity was found in Gjb2 V37M/V37M outer sulcus and Claudius cells but not in Gjb2 WT/WT cells. We view that the current computational platform could serve as an assessment tool for the pathogenesis and inheritance of GJB2 -related hearing impairments and other diseases caused by connexin dysfunction., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2023 The Authors.)

Objective: Unilateral sensorineural hearing loss (USNHL) is a condition commonly encountered in otolaryngology clinics. However, its molecular pathogenesis remains unclear. This study aimed to investigate the genetic underpinnings of childhood USNHL and analyze the associated audiological features., Study Design: Retrospective analysis of a prospectively recruited cohort., Setting: Tertiary referral center., Methods: We enrolled 38 children with USNHL between January 1, 2018, and December 31, 2021, and performed physical, audiological, imaging, and congenital cytomegalovirus (cCMV) examinations as well as genetic testing using next-generation sequencing (NGS) targeting 30 deafness genes. The audiological results were compared across different etiologies., Results: Causative genetic variants were identified in 8 (21.1%) patients, including 5 with GJB2 variants, 2 with PAX3 variants, and 1 with the EDNRB variant. GJB2 variants were found to be associated with mild-to-moderate USNHL in various audiogram configurations, whereas PAX3 and EDNRB variants were associated with profound USNHL in flat audiogram configurations. In addition, whole-genome sequencing and extended NGS targeting 213 deafness genes were performed in 2 multiplex families compatible with autosomal recessive inheritance; yet no definite causative variants were identified. Cochlear nerve deficiency and cCMV infection were observed in 9 and 2, respectively, patients without definite genetic diagnoses., Conclusion: Genetic underpinnings can contribute to approximately 20% of childhood USNHL, and different genotypes are associated with various audiological features. These findings highlight the utility of genetic examinations in guiding the diagnosis, counseling, and treatment of USNHL in children., (© 2023 American Academy of Otolaryngology-Head and Neck Surgery Foundation.)

Recessive variants in GJB2 are the most important genetic cause of sensorineural hearing impairment (SNHI) worldwide. Phenotypes vary significantly in GJB2-related SNHI, even in patients with identical variants. For instance, patients homozygous for the GJB2 p.V37I variant, which is highly prevalent in the Asian populations, usually present with mild-to-moderate SNHI; yet severe-to-profound SNHI is occasionally observed in approximately 10% of p.V37I homozygotes. To investigate the genomic underpinnings of the phenotypic variability, we performed next-generation sequencing of GJB2 and other deafness genes in 63 p.V37I homozygotes with extreme phenotypic severities. Additional pathogenic variants of other deafness genes were identified in five of the 35 patients with severe-to-profound SNHI. Furthermore, case-control association analyses were conducted for 30 unrelated p.V37I homozygotes with severe-to-profound SNHI against 28 p.V37I homozygotes with mild-to-moderate SNHI, and 120 population controls from the Taiwan Biobank. The severe-to-profound group exhibited a higher frequency of the crystallin lambda 1 (CRYL1) variant (rs14236), located upstream of GJB2, than the mild-to-moderate and Taiwan Biobank groups. Our results demonstrated that pathogenic variants in other deafness genes and a possible modifier, the CRYL1 rs14236 variant, may contribute to phenotypic variability in GJB2-realted SNHI, highlighting the importance of comprehensive genomic surveys to delineate the genotype-phenotype correlations., Competing Interests: Disclosure Statement None declared., (Copyright © 2023 Association for Molecular Pathology and American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.)

Pathogenic variants of the WFS1 gene can cause recessive-inherited Wolfram syndrome or dominant-inherited Wolfram-like syndrome with optic atrophy and hearing impairment. Using the Sendai virus delivery system, we generated induced pluripotent stem cells from the peripheral blood mononuclear cells of a female patient with the WFS1 pathogenic variant c.2051C > T (p.Ala684Val). The resulting induced pluripotent stem cells exhibited a normal karyotype and pluripotency, as confirmed using immunofluorescence staining, and differentiated into three germ layers in vivo. This cellular model provides a useful platform for investigating the pathogenic mechanisms of both blindness and deafness related to WFS1 variants., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

Rhinosinusitis is common in patients with nasopharyngeal carcinoma (NPC). Our study aimed to explore the role of rhinosinusitis severity in NPC prognosis. Medical records and radiologic examinations of 90 patients with NPC at a single medical center from 2009−2016 were retrospectively analyzed. The Lund−Mackay (L−M) score was obtained for each patient before and after 6 months of treatment. Rhinosinusitis diagnosis was based on L−M scores of ≥4. L−M score differences were calculated as pre-treatment rhinosinusitis (PRRS) minus post-treatment rhinosinusitis (PSRS). L−M score difference was sub-grouped into “L−M scores > 0”, “L−M scores = 0”, and “L−M scores < 0”. Clinical staging of our patients based on the American Joint Committee on Cancer 7th edition were: stage I in nine, stage II in seventeen, stage III in twenty-two, and stage IV in forty-two patients; twenty-seven (30%) patients had died. PRRS incidence was 34.4%, and PSRS was 36.7%. Median of L−M scores difference was 0 (−2.2). L−M score difference was an independent prognostic factor for the overall survival of patients with NPC (p < 0.05). Therefore, worsening rhinosinusitis was a prognostic factor for patients with NPC. Clinicians should consider NPC as a warning sign of poor prognosis during routine follow-ups.

Recessive PJVK mutations that cause a deficiency of pejvakin, a protein expressed in both sensory hair cells and first-order neurons of the inner ear, are an important cause of hereditary hearing impairment. Patients with PJVK mutations garner limited benefits from cochlear implantation; thus, alternative biological therapies may be required to address this clinical difficulty. The synthetic adeno-associated viral vector Anc80L65, with its wide tropism and high transduction efficiency in various inner ear cells, may provide a solution. We delivered the PJVK transgene to the inner ear of Pjvk mutant mice using the synthetic Anc80L65 vector. We observed robust exogenous pejvakin expression in the hair cells and neurons of the cochlea and vestibular organs. Subsequent morphologic and audiologic studies demonstrated significant restoration of spiral ganglion neuron density and hair cells in the cochlea, along with partial recovery of sensorineural hearing impairment. In addition, we observed a recovery of vestibular ganglion neurons and balance function to WT levels. Our study demonstrates the utility of Anc80L65-mediated gene delivery in Pjvk mutant mice and provides insights into the potential of gene therapy for PJVK-related inner ear deficits.

Pathogenic variants of OPA1 have been associated with autosomal dominant optic atrophy (DOA), leading to optic, auditory, and other sensorineural neuropathies and myopathies. Using the Sendai virus delivery system, we generated induced pluripotent stem cells from the peripheral blood mononuclear cells of a female patient with the OPA1 pathogenic variant c.1468T>C (p.Cys490Arg). The resulting induced pluripotent stem cells exhibited a normal karyotype and pluripotency, as confirmed using immunofluorescence staining, and differentiated into three germ layers in vivo. This cellular model is a useful platform for investigating the pathogenic mechanisms of both blindness and deafness related to OPA1 variants., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: Cochlear implants (CIs) are viable treatment options in patients with severe to profound hearing loss. Speech recognition difficulties were reported in some CI recipients even with a good-aided hearing threshold. The aim of this study was to report a mapping strategy based on different target-aided hearing thresholds to achieve optimal speech recognition and maximize functional outcomes. The safety and efficacy of the mapping strategy were also inspected in the article., Methods: This prospective repeated measures study enrolled 20 adult CI recipients with postlingual deafness using the MED-EL CI system. Word and sentence discrimination assessment and administration of a questionnaire pertaining to comfort level were conducted at the end of each session. The electrophysiological features of the CI mapping were recorded., Results: The correlation between audiometry results and word and sentence recognition was not high. CIs performed best at an audiometry threshold between 25 and 35 dB., Conclusion: CI performance with the best perception relies on a balance between minimizing the hearing threshold and maximizing the dynamic range while maintaining an appropriate comfort level, which was achieved when the target hearing threshold was set at 25-35 dB in this study., Competing Interests: Conflicts of interest: The authors declare that they have no conflicts of interest related to the subject matter or materials discussed in this article., (Copyright © 2022, the Chinese Medical Association.)