Variants in the EYA4 gene are known to lead to autosomal dominant non-syndromic hereditary hearing loss, DFNA10. To date, 30 variants have been shown to be responsible for hearing loss in a diverse ...set of nationalities. To better understand the clinical characteristics and prevalence of DFNA10, we performed genetic screening for EYA4 mutations in a large cohort of Japanese hearing loss patients. We selected 1,336 autosomal dominant hearing loss patients among 7,408 unrelated Japanese hearing loss probands and performed targeted genome enrichment and massively parallel sequencing of 68 target genes for all patients. Clinical information of cases with mutations in EYA4 was gathered and analyzed from medical charts. Eleven novel EYA4 variants (three frameshift variants, three missense variants, two nonsense variants, one splicing variant, and two single-copy number losses) and two previously reported variants were found in 12 probands (0.90%) among the 1,336 autosomal dominant hearing loss families. The audiometric configuration of truncating variants tends to deteriorate for all frequencies, whereas that of non-truncating variants tends to show high-frequency hearing loss, suggesting a new correlation between genotype and phenotype in DFNA10. The rate of hearing loss progression caused by EYA4 variants was considered to be 0.63 dB/year, as found in this study and previous reports.
The V-shaped arrangement of hair bundles on cochlear hair cells is critical for auditory sensing. However, regulation of hair bundle arrangements has not been fully understood. Recently, defects in ...hair bundle arrangement were reported in postnatal Dishevelled-associating protein (ccdc88c, alias Daple)-deficient mice. In the present study, we found that adult Daple
mice exhibited hearing disturbances over a broad frequency range through auditory brainstem response testing. Consistently, distorted patterns of hair bundles were detected in almost all regions, more typically in the basal region of the cochlear duct. In adult Daple
mice, apical microtubules were irregularly aggregated, and the number of microtubules attached to plasma membranes was decreased. Similar phenotypes were manifested upon nocodazole treatment in a wild type cochlea culture without affecting the microtubule structure of the kinocilium. These results indicate critical role of Daple in hair bundle arrangement through the orchestration of apical microtubule distribution, and thereby in hearing, especially at high frequencies.
Abstract
In the interaural direction, translational linear acceleration is loaded during lateral translational movement and gravitational acceleration is loaded during lateral tilting movement. These ...two types of acceleration induce eye movements via two kinds of otolith-ocular reflexes to compensate for movement and maintain clear vision: horizontal eye movement during translational movement, and torsional eye movement (torsion) during tilting movement. Although the two types of acceleration cannot be discriminated, the two otolith-ocular reflexes can distinguish them effectively. In the current study, we tested whether lateral-eyed mice exhibit both of these otolith-ocular reflexes. In addition, we propose a new index for assessing the otolith-ocular reflex in mice. During lateral translational movement, mice did not show appropriate horizontal eye movement, but exhibited unnecessary vertical torsion-like eye movement that compensated for the angle between the body axis and gravito-inertial acceleration (GIA; i.e., the sum of gravity and inertial force due to movement) by interpreting GIA as gravity. Using the new index (amplitude of vertical component of eye movement)/(angle between body axis and GIA), the mouse otolith-ocular reflex can be assessed without determining whether the otolith-ocular reflex is induced during translational movement or during tilting movement.
Hearing loss is a pivotal risk factor for dementia. It has recently emerged that a disruption in the intercommunication between the cochlea and brain is a key process in the initiation and ...progression of this disease. However, whether the cochlear properties can be influenced by pathological signals associated with dementia remains unclear. In this study, using a mouse model of Alzheimer's disease (AD), we investigated the impacts of the AD-like amyloid β (Aβ) pathology in the brain on the cochlea. Despite little detectable change in the age-related shift of the hearing threshold, we observed quantitative and qualitative alterations in the protein profile in perilymph, an extracellular fluid that fills the path of sound waves in the cochlea. Our findings highlight the potential contribution of Aβ pathology in the brain to the disturbance of cochlear homeostasis.
It is shown that eliminating hearing loss in mid-life may reduce the risk for deterioration in cognitive function. Cochlear implantation (CI) is the only available therapy that can eliminate hearing ...loss in patients who suffer from profound sensorineural hearing loss. This suggests there may be positive effects of hearing level on cognition in older adults following CI. Therefore, the purpose of this study is to clarify whether cognitive function can be improved or maintained using cochlear implants in older adult patients with hearing impairments.
Data for patients that underwent CI surgery for profound bilateral sensorineural hearing loss were collected prospectively. Patients aged 65 years and older were recruited at our university hospital from 2013 to 2017. Twenty-one patients (age range: 65–80 years) were included in this study. The primary outcome measurement was the change in cognitive function three points assessed by Mini-Mental State Examination (MMSE): preoperatively, and at 1 and 2 years after surgery. The secondary outcome measurements were the followings; the Nijmegen Cochlear Implant Questionnaire (NCIQ), the Self-Rating Depression Scale (SDS), and hearing and speech recognition threshold assessment before CI, and 1 and 2 years after CI. Differences in MMSE scores were compared for statistical significance using the Friedman test. The Wilcoxon signed-rank test was used as a post hoc test. Possible correlations between MMSE scores and NCIQ subdomain scores 2 years after surgery were evaluated with Spearman's tests. Statistical significance was defined as a p-value <0.05.
CI recipients showed significant improvement in MMSE scores. This improvement peaked 1 year after CI surgery. The postoperative MMSE score was correlated with the NCIQ speech production score but not with the other five NCIQ subdomains. There was no correlation between MMSE score and speech recognition.
Speech production is important to improve cognitive function after CI, and this improvement peaked 1 year after CI. Although severe or profound hearing loss in older adults worsens the natural course of cognitive function decline, CI has positive impacts on cognitive function even if MMSE scores decrease 1 year after the peak (i.e., 2 years after CI). Talking with others based on hearing is crucial to improve cognitive function. We should encourage older adult patients to take many opportunities to talk with others after CI surgery.
Cholesteatoma, which potentially results from tympanic membrane retraction, is characterized by intractable local bone erosion and subsequent hearing loss and brain abscess formation. However, the ...pathophysiological mechanisms underlying bone destruction remain elusive. Here, we performed a single-cell RNA sequencing analysis on human cholesteatoma samples and identify a pathogenic fibroblast subset characterized by abundant expression of inhibin βA. We demonstrate that activin A, a homodimer of inhibin βA, promotes osteoclast differentiation. Furthermore, the deletion of inhibin βA /activin A in these fibroblasts results in decreased osteoclast differentiation in a murine model of cholesteatoma. Moreover, follistatin, an antagonist of activin A, reduces osteoclastogenesis and resultant bone erosion in cholesteatoma. Collectively, these findings indicate that unique activin A-producing fibroblasts present in human cholesteatoma tissues are accountable for bone destruction via the induction of local osteoclastogenesis, suggesting a potential therapeutic target.
Oral administration is the most common way to deliver drugs to the systemic circulation or target organs. Orally administered drugs are absorbed in the intestine and metabolized in the intestine and ...liver. In the early stages of drug development, it is important to predict first-pass metabolism accurately to select candidate drugs with high bioavailability. The Caco-2 cell line derived from colorectal cancer is widely used as an intestinal model to assess drug membrane permeability. However, because the expression of major drug-metabolizing enzymes, such as cytochrome P450 (CYP), is extremely low in Caco-2 cells, it is difficult to predict intestinal metabolism, which is a significant factor in predicting oral drug bioavailability. Previously, we constructed a mouse artificial chromosome vector carrying the CYP (CYP2C9, CYP2C19, CYP2D6, and CYP3A4) and P450 oxidoreductase (POR) (4CYPs-MAC) genes and increased CYP expression and metabolic activity in HepG2 cells via transfer of this vector. In the current study, to improve the Caco-2 cell assay model by taking metabolism into account, we attempted to increase CYP expression by transferring the 4CYPs-MAC into Caco-2 cells. The Caco-2 cells carrying the 4CYPs-MAC showed higher CYP mRNA expression and activity. In addition, high metabolic activity, availability for permeation test, and the potential to assess drug-drug interactions were confirmed. The established Caco-2 cells with the 4CYPs-MAC are expected to enable more accurate prediction of the absorption and metabolism in the human intestine than parental Caco-2 cells. The mammalian artificial chromosome vector system would provide useful models for drug development.
Eosinophilic chronic rhinosinusitis (ECRS) and eosinophilic otitis media (EOM) are debilitating inflammatory conditions that affect the paranasal sinuses and middle ear, respectively, and are ...characterized by eosinophilic infiltration. This study describes a rare and intricate case of a 65-year-old male patient concurrently afflicted with ECRS, EOM, and bronchial asthma. Despite the systematic administration of corticosteroids and various antibody drugs, the patient's condition remained unimproved, necessitating a cochlear implant for EOM, which is seldom an aggressive intervention. The patient had a history of symptoms dating back to 2005, with notable exacerbations and treatment resistance over the years. Multiple antibody drugs, including anti-IgE, anti-IL-5, and anti-IL-4α antibodies, failed to ameliorate the patient's condition, presenting a significant clinical challenge. Pathological examination revealed marked eosinophilic infiltration and severe fibrosis, suggesting a possible mechanism underlying the poor response to antibody therapy. Cochlear implantation significantly enhanced the patient's communicative abilities. This case highlights the limitations of the current antibody drugs in managing severely intertwined cases of ECRS, EOM, and bronchial asthma, highlighting the need for novel therapeutic strategies. This case also propounds cochlear implantation as an efficacious intervention for refractory EOM with severe sensorineural hearing impairment, extending the spectrum of treatment modalities for such challenging scenarios. This singular case contributes to the growing body of evidence regarding the management of ECRS and EOM, especially against the backdrop of treatment resistance, and can aid clinicians in identifying and navigating similar complex cases in clinical practice.
The aim of this study was to investigate whether the insertion of an implant into the cochlea is accompanied by a deterioration in otolith function. Cervical and ocular vestibular evoked myogenic ...potentials (cVEMP and oVEMP) and linear vestibulo-ocular reflex (lVOR) during eccentric rotation were assessed before and after cochlear implantation (CI) to evaluate otolith function.
Twelve patients with bilateral severe sensorineural hearing loss who had undergone CI surgery in our hospital between May 2016 and November 2017 were included in this study. cVEMP and oVEMP were assessed using the asymmetry ratio (AR), calculated with the following formula: (peak-to-peak amplitude calculated as the sum of the p13 and n23 amplitudes in the non-operated side) − (that in the operated side)/(that in the non-operated side) + (that in the operated side). The ratio of VOR gain during eccentric rotation against VOR gain during center rotation was used to assess lVOR. For eccentric rotation, patients were rotated while displaced from the axis of rotation. At the same time, linear acceleration stimulated the utricle and induced lVOR. All patients underwent cVEMP and oVEMP tests and center and eccentric rotation tests before and about 30days after CI surgery.
Three patients with absent cVEMP responses before surgery were excluded, leaving pre-surgery cVEMP results for 9/12 patients. In five of these patients, the AR of cVEMP increased after CI, indicating that saccular function, as evaluated by cVEMP, did not deteriorate significantly postoperatively. One patient with an absent oVEMP response before CI was excluded, leaving pre-surgery oVEMP results for 11/12 patients. In 10 of these patients, the AR of oVEMP increased after CI surgery, indicating that utricular function, as evaluated by oVEMP, deteriorated significantly postoperatively. However, because the ratio of VOR gain during eccentric rotation against VOR gain during center rotation did not become worse after CI, utricular function, as evaluated by lVOR, did not deteriorate significantly postoperatively. Symptoms of vertigo became worse after CI in two of the 12 patients.
CI does not cause a deterioration in saccular function, as evaluated by cVEMP. Although CI does cause a deterioration in utricular function in oVEMP tests, this is not consistent in lVOR tests. These results indicate that CI causes a slight deterioration in utricular function that is insufficient to cause vertigo or deterioration of lVOR.
Diagnosis of Menière's disease (MD) relies on subjective factors and the patients diagnosed with MD may have heterogeneous pathophysiologies. This study aims to stratify MD patients using two ...objective data, nystagmus videos and contrast-enhanced magnetic resonance imaging (CE-MRI).
This is a retrospective cross-sectional study. According to the Japan Society for Equilibrium Research criteria (c-JSER), adults diagnosed with definite MD and who obtained videos recorded by portable nystagmus recorder immediately following vertigo attacks and underwent CE-MRI of the inner ear were included (
= 91). Patients who obtained no nystagmus videos, who had undergone sac surgery, and those with long examination intervals were excluded (
= 40).
The gender of the subjects was 22 males and 29 females. The age range was 20-82 y, with a median of 54 y. Endolymphatic hydrops (EH) were observed on CE-MRI in 84% (43 patients). Thirty-one patients had unilateral EH. All of them demonstrated EH on the side of the presence of cochlear symptoms. The number of patients who had both nystagmus and EH was 38. Five patients only showed EH and 5 patients only exhibited nystagmus, while 3 patients did not have either. Of the 43 nystagmus records, 32 showed irritative nystagmus immediately after the vertigo episode. The direction of nystagmus later reversed in 44% of cases over 24 h.
Patients were stratified into subgroups based on the presence or absence of EH and nystagmus. The side with cochlear symptoms was consistent with EH. The c-JSER allows for the diagnosis of early-stage MD patients, and it can be used to treat early MD and preserve hearing; however, this approach may also include patients with different pathologies.
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