Disturbance in the protein landscape of cochlear perilymph in an Alzheimer's disease mouse model.

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 ß (Aß) 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 Aß pathology in the brain to the disturbance of cochlear homeostasis.

An Unusual Case of Eosinophilic Chronic Rhinosinusitis With Concurrent Eosinophilic Otitis Media: Limited Responsiveness to Multiple Antibody Therapies and Subsequent Cochlear Implantation.

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.

Single-cell transcriptomics of human cholesteatoma identifies an activin A-producing osteoclastogenic fibroblast subset inducing bone destruction.

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 ßA. We demonstrate that activin A, a homodimer of inhibin ßA, promotes osteoclast differentiation. Furthermore, the deletion of inhibin ßA /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.

Comparison of the efficacy of the Epley maneuver and repeated Dix-Hallpike tests for eliminating positional nystagmus: A multicenter randomized study.

Background and objectives: Patients with benign paroxysmal positional vertigo of the posterior canal (pc-BPPV) exhibit BPPV fatigue, where the positional nystagmus diminishes with the repeated performance of the Dix-Hallpike test (DHt). BPPV fatigue is thought to be caused by the disintegration of lumps of otoconial debris into smaller parts and can eliminate positional nystagmus within a few minutes [similar to the immediate effect of the Epley maneuver (EM)]. In this study, we aimed to show the non-inferiority of the repeated DHt to the EM for eliminating positional nystagmus after 1 week. Methods: This multicenter, randomized controlled clinical trial was designed based on the CONSORT 2010 guidelines. Patients who had pc-BPPV were recruited and randomly allocated to Group A or Group B. Patients in Group A were treated using the EM, and patients in Group B were treated using repeated DHt. For both groups, head movements were repeated until the positional nystagmus had been eliminated (a maximum of three repetitions). After 1 week, the patients were examined to determine whether the positional nystagmus was still present. The groups were compared in terms of the percentage of patients whose positional nystagmus had been eliminated, with the non-inferiority margin set at 15%. Results: Data for a total of 180 patients were analyzed (90 patients per group). Positional nystagmus had been eliminated in 50.0% of the patients in Group A compared with 47.8% in Group B. The upper limit of the 95% confidence interval for the difference was 14.5%, which was lower than the non-inferiority margin. Discussion: This study showed the non-inferiority of repeated DHt to the EM for eliminating positional nystagmus after 1 week in patients with pc-BPPV and that even the disintegration of otoconial debris alone has a therapeutic effect for pc-BPPV. Disintegrated otoconial debris disappears from the posterior canal because it can be dissolved in the endolymph or returned to the vestibule via activities of daily living. Classification of evidence: This study provides Class II evidence of the non-inferiority of repeated DHt to the EM for eliminating positional nystagmus after 1 week. Registration number: UMIN000016421.

Stratification of patients with Menière's disease based on eye movement videos recorded from the beginning of vertigo attacks and contrast-enhanced MRI findings.

Purpose: 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). Methods: 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 (ss = 91). Patients who obtained no nystagmus videos, who had undergone sac surgery, and those with long examination intervals were excluded (n = 40). Results: 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. Conclusion: 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.

Therapeutic strategy for facial paralysis based on the combined application of Si-based agent and methylcobalamin.

Facial paralysis results in the decline in the generation of facial expressions and is attributed to several causes. Intractable facial paralysis has a poor prognosis, and new treatments are required. Facial paralysis results in the decline in the generation of facial expressions and is attributed to several causes. Reactive oxygen species can inhibit peripheral nerve regeneration after injury. Therefore, the administration of an appropriate antioxidant can promote nerve regeneration. Silicon (Si)-based agents can react with water to generate antioxidant hydrogen. Oral administration of Si-based agents can effectively alleviate symptoms of disease models associated with oxidative stress. Thus, we orally administered a Si-based agent to a facial paralysis model mice to investigate whether promotion of nerve regeneration occurred. The combined administration of methylcobalamin (MeCbl) with the Si-based agent was also investigated. The Si-based agent improved the clinical score evaluation of facial paralysis. Electroneuronography and immunostaining showed that the Si-based agent promoted myelination and recovery of facial nerve function. Furthermore, in the drug-administered group, oxidative stress associated with facial nerve injury was reduced more than that in the non-administered group. The clinical score evaluation, neuroregeneration effect, and reduction of oxidative stress were improved in the combination group compared to the single administration group. The Si-based agent could rapidly improve the disappearance of facial expressions by promoting myelin sheath formation and alleviating oxidative stress. Combination therapy with a Si-based agent and MeCbl should improve the prognosis and treatment of intractable facial paralysis.

Influence of MDR1 gene polymorphism (2677G>T) on expression and function of P-glycoprotein at the blood-brain barrier: utilizing novel P-glycoprotein humanized mice with mutation.

P-glycoprotein, the encoded product of the MDR1 / ABCB1 gene in humans, is expressed in numerous tissues including brain capillary endothelial cells and restricts the distribution of xenobiotics into the brain as an efflux pump. Although a large number of single nucleotide polymorphisms in the MDR1 gene have been identified, the influence of the nonsynonymous 2677G>T/A single nucleotide polymorphism on P-glycoprotein at the blood-brain barrier has remained unclear. In the present study, we developed a novel P-glycoprotein humanized mouse line carrying the 2677G>T mutation by utilizing a mouse artificial chromosome vector constructed by genetic engineering technology and we evaluated the influence of 2677G>T on the expression and function of P-glycoprotein at the blood-brain barrier in vivo . The results of this study showed that the introduction of the 2677G>T mutation does not alter the expression levels of P-glycoprotein protein in the brain capillary fraction. On the other hand, the brain penetration of verapamil, a representative substrate of P-glycoprotein, was increased by the introduction of the 2677G>T mutation. These results suggested that the 2677G>T single nucleotide polymorphism may attenuate the function of P-glycoprotein, resulting in increased brain penetration of P-glycoprotein substrates, without altering the expression levels of P-glycoprotein protein in the blood-brain barrier. This mutant mouse line is a useful model for elucidating the influence of an MDR1 gene single nucleotide polymorphism on the expression and function of P-glycoprotein at the blood-brain barrier.

The effect of cochlear implants on cognitive function in older adults: A prospective, longitudinal 2-year follow-up study.

OBJECTIVES: 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. METHODS: 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. RESULTS: 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. CONCLUSION: 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.

Improved visualization of the chorda tympani nerve using ultra-high-resolution computed tomography.

BACKGROUND: Recognition of the anatomical course of the chorda tympani nerve (CTN) is important for preventing iatrogenic injuries during middle-ear surgery. PURPOSE: This study aims to compare visualization of the CTN using two computed tomography (CT) methods: conventional high-resolution CT (C-HRCT) and ultra-high-resolution CT (U-HRCT). MATERIALS AND METHODS: We performed a retrospective visual assessment of 59 CTNs in normal temporal bones of 54 consecutive patients who underwent both C-HRCT and U-HRCT. After dividing CTN into three anatomical segments (posterior canaliculus, tympanic segment, and anterior canaliculus), two neuroradiologists scored the visualizations on a four-point scale. RESULTS: On C-HRCT, the visual scores of the posterior canaliculus, tympanic segment, and anterior canaliculus were 3.5 ± 0.7, 1.6 ± 0.6, and 3.1 ± 0.7, respectively. The respective values were significantly higher in all segments on U-HRCT: 3.9 ± 0.2, 2.4 ± 0.6, 3.5 ± 0.6 (p < 0.01). Although the difference in scores between methods was greatest for the tympanic segment, the visual score on U-HRCT was lower for the tympanic segment than for the anterior and posterior segments (p < 0.01). CONCLUSION: Ultra-high-resolution CT provides superior visualization of the CTN, especially the tympanic segment.

Daple deficiency causes hearing loss in adult mice by inducing defects in cochlear stereocilia and apical microtubules.

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.

Development of a new method for assessing otolith function in mice using three-dimensional binocular analysis of the otolith-ocular reflex.

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.

Effect of Sitting Position vs. Supine Position With the Head Turned to the Affected Side on Benign Paroxysmal Positional Vertigo Fatigue.

Objective: In benign paroxysmal positional vertigo (BPPV), positional nystagmus becomes generally weaker when the Dix-Hallpike test is repeated. This phenomenon is termed BPPV fatigue. We previously reported that the effect of BPPV fatigue deteriorates over time (i.e., the positional nystagmus is observed again after maintaining a sitting head position). The aim of this study was to investigate whether the effect of BPPV fatigue attenuates after maintaining a supine position with the head turned to the affected side. Methods: Twenty patients with posterior-canal-type BPPV were assigned to two groups. Group A received Dix-Hallpike test, were returned to the sitting position (reverse Dix-Hallpike test) with a sitting head position for 10 min, and then received a second Dix-Hallpike test. Group B received Dix-Hallpike test, were kept in the supine position with the head turned to the affected side for 10 min, and then received reverse Dix-Hallpike test followed by the second Dix-Hallpike test. The maximum slow phase eye velocity (MSPEV) of positional nystagmus induced by the first, reverse, and second Dix-Hallpike test were analyzed. Results: The ratio of MSPEV of the positional nystagmus induced by the second Dix-Hallpike test relative to the first Dix-Hallpike test was significantly smaller in group B than that in group A. There was no difference in the MSPEV of the positional nystagmus induced by the reverse Dix-Hallpike test between group A and B. Conclusions: The effect of BPPV fatigue is continued by maintaining a supine position with the head turned to the affected side, while the effect is weakened by maintaining a sitting head position. On the basis of the most widely accepted theory of the pathophysiology of BPPV fatigue, in which the particles become dispersed along the canal during head movement in the Dix-Hallpike test, we found an inconsistency whereby the dispersed otoconial debris return to a mass during the sitting position but do not return to a mass in the supine position with the head turned to the affected side. Future studies are required to determine the exact pathophysiology of BPPV fatigue. Classification of Evidence: 2b.

Phosphorylation of MYL12 by Myosin Light Chain Kinase Regulates Cellular Shape Changes in Cochlear Hair Cells.

The organ of Corti is an auditory organ located in the cochlea, comprising hair cells (HCs) and other supporting cells. Cellular shape changes of HCs are important for the development of auditory epithelia and hearing function. It was previously observed that HCs and inner sulcus cells (ISCs) demonstrate cellular shape changes similar to the apical constriction of the neural epithelia. Apical constriction is induced via actomyosin cable contraction in the apical junctional complex and necessary for the physiological function of the epithelium. Actomyosin cable contraction is mainly regulated by myosin regulatory light chain (MRLC) phosphorylation by myosin light chain kinase (MLCK). However, MRLC and MLCK isoforms expressed in HCs and ISCs are unknown. Hence, we investigated the expression patterns and roles of MRLCs and MLCKs in HCs. Droplet digital PCR revealed that HCs expressed MYL12A/B and MYL9, which are non-muscle MRLC and smooth muscle MLCK (smMLCK), respectively. Immunofluorescence staining throughout the organ of Corti demonstrated that only MYL12 was expressed in the apical portion of HCs, whereas MYL12 and MYL9 were expressed on ISCs. In addition, purified MYL12B was phosphorylated by smMLCK in vitro, and the harvested HCs contained phosphorylated MYL12. Furthermore, accompanied by the expansion of the cell area of outer HCs, MYL12 phosphorylation was reduced by ML-7, which is an inhibitor of smMLCK. In conclusion, MYL12 phosphorylation by smMLCK contributed to the apical constriction-like cellular shape change of HCs possibly relating to the development of auditory epithelia and hearing function.

Platform posturography of patients with peripheral vestibular dysfunction in the non-acute phase of vertigo.

OBJECTIVE: Posturography (PG) shows various patterns corresponding to a patient's equilibrium condition; however, PG is not useful for the differential diagnosis of peripheral vestibular diseases (PVDs). The aim of this study was to identify parameters of PG that can distinguish between PVDs. METHODS: The differences in PG parameters between PVDs were evaluated retrospectively. Two hundred and two patients with Ménière's disease (MD), 154 patients with benign paroxysmal positional vertigo (BPPV), 20 patients with sudden sensorineural hearing loss with vertigo (SSNHLwV), and 31 patients with vestibular neuritis (VN) underwent PG during the non-acute phase of vertigo, from January 2010 to March 2017. RESULTS: The velocity of body oscillation of BPPV patients with eyes open and closed were significantly faster than those of MD patients with eyes open (p < 0.001) and closed (p = 0.033). The velocity of body oscillation of VN patients with eyes open was significantly faster than that of MD patients with eyes open (p = 0.0083). There were no significant differences among the other PG parameters between PVDs. Although there were significant differences among the velocity with eyes open and closed between males and females (eye open: p = 0.0009, eye close: p < 0.0001), there was no significant difference in the ratio of males to females among PVDs (p = 0.1834). Therefore, the ratio did not influence the difference in velocity among PVDs. Patient age correlated with the velocity with eyes open (p < 0.001) and with eyes closed (p < 0.001). Post-hoc analysis revealed significant differences in patient age, and comparisons of MD and BPPV, MD and SSNHLwV, BPPV and VN, and VN and SSNHLwV. Therefore, we performed multiple regression analysis to determine whether the significant differences in the velocity of body oscillation among PVDs were caused by the difference in age distribution between PVD groups, rather than by differences in the PVDs themselves. There were correlations between age and the velocity of body oscillation with eyes open (p < 0.001) and with eyes closed (p < 0.001). There also were correlations between MD or VN and the velocity of body oscillation with eyes open (p = 0.0194). CONCLUSION: There were significant differences in the velocity of body oscillation with eyes open between MD and VN patients. The difference between MD and VN was significant regardless of the age distribution. To distinguish between MD and VN, the velocity of body oscillation with eyes open is a useful PG index.

Development of Caco-2 cells expressing four CYPs via a mammalian artificial chromosome.

BACKGROUND: 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. RESULTS: 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. CONCLUSIONS: 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.

Prevalence and clinical features of hearing loss caused by EYA4 variants.

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.

Clinical significance of cervical and ocular vestibular evoked myogenic potentials in benign paroxysmal positional vertigo: a meta-analysis.

PURPOSE: As the pathological cause of benign paroxysmal positional vertigo (BPPV), the dislocation or degeneration of otoconia in the utricle and saccule is suggested. Vestibular evoked myogenic potential (VEMP) could reflect otolithic dysfunction due to these etiologies of BPPV. The aim of this study was to validate the clinical significance of cervical (c) and ocular (o) VEMP in BPPV by a meta-analysis of previous articles. METHODS: Articles related to BPPV with data on cVEMP and oVEMP were collected. The following keywords were used to search PubMed and Scopus for English language articles: benign paroxysmal positional vertigo or BPPV and vestibular evoked myogenic potential or VEMP. RESULTS: The p13 latency in cVEMP and n1 latency in oVEMP were slightly but significantly prolonged in BPPV patients compared to control patients. AR in oVEMP of BPPV patients also showed higher value than that of control patients. However, the n23 latency and AR in cVEMP and p1 latency in oVEMP showed no significant difference between BPPV and control patients. Furthermore, latencies in VEMPs also showed no significant difference between an affected and a non-affected ear in BPPV patients. CONCLUSIONS: Our results indicated that otolith dysfunction of BPPVs was detected by latencies in VEMPs, and AR in oVEMP more sensitively reflects the difference between affected and non-affected ears in BPPV patients. The otolith dysfunction of BPPV might be induced by the systemic condition. However, the differences of latencies between BPPV patients and control patients were too small to use VEMPs as a prognostic predictor.

Comprehensive analysis of syndromic hearing loss patients in Japan.

More than 400 syndromes associated with hearing loss and other symptoms have been described, corresponding to 30% of cases of hereditary hearing loss. In this study we aimed to clarify the mutation spectrum of syndromic hearing loss patients in Japan by using next-generation sequencing analysis with a multiple syndromic targeted resequencing panel (36 target genes). We analyzed single nucleotide variants, small insertions, deletions and copy number variations in the target genes. We enrolled 140 patients with any of 14 syndromes (BOR syndrome, Waardenburg syndrome, osteogenesis imperfecta, spondyloepiphyseal dysplasia congenita, Stickler syndrome, CHARGE syndrome, Jervell and Lange-Nielsen syndrome, Pendred syndrome, Klippel-Feil syndrome, Alport syndrome, Norrie disease, Treacher-Collins syndrome, Perrault syndrome and auditory neuropathy with optic atrophy) and identified the causative variants in 56% of the patients. This analysis could identify the causative variants in syndromic hearing loss patients in a short time with a high diagnostic rate. In addition, it was useful for the analysis of the cases who only partially fulfilled the diagnostic criteria.

Osteoclasts Modulate Bone Erosion in Cholesteatoma via RANKL Signaling.

Cholesteatoma starts as a retraction of the tympanic membrane and expands into the middle ear, eroding the surrounding bone and causing hearing loss and other serious complications such as brain abscess and meningitis. Currently, the only effective treatment is complete surgical removal, but the recurrence rate is relatively high. In rheumatoid arthritis (RA), osteoclasts are known to be responsible for bone erosion and undergo differentiation and activation by receptor activator of NF-κB ligand (RANKL), which is secreted by synovial fibroblasts, T cells, and B cells. On the other hand, the mechanism of bone erosion in cholesteatoma is still controversial. In this study, we found that a significantly larger number of osteoclasts were observed on the eroded bone adjacent to cholesteatomas than in unaffected areas, and that fibroblasts in the cholesteatoma perimatrix expressed RANKL. We also investigated upstream transcription factors of RANKL using RNA sequencing results obtained via Ingenuity Pathways Analysis, a tool that identifies relevant targets in molecular biology systems. The concentrations of four candidate factors, namely interleukin-1ß, interleukin-6, tumor necrosis factor α, and prostaglandin E2, were increased in cholesteatomas compared with normal skin. Furthermore, interleukin-1ß was expressed in infiltrating inflammatory cells in the cholesteatoma perimatrix. This is the first report demonstrating that a larger-than-normal number of osteoclasts are present in cholesteatoma, and that the disease involves upregulation of factors related to osteoclast activation. Our study elucidates the molecular basis underlying bone erosion in cholesteatoma.

Neutrophil-to-Lymphocyte Ratio and Platelet-to-Lymphocyte Ratio as Prognostic Hematologic Markers of Bell's Palsy: A Meta-analysis.

OBJECTIVE: Bell's palsy (BP) is the most common cause of unilateral peripheral facial paralysis, and inflammation has been proposed as the main pathological cause. The study aim was to investigate the relationship between hematologic inflammatory markers, including the neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR), and BP. DATA SOURCES: The following key words were used to search PubMed and Scopus for English language articles: Bell's palsy, facial palsy, facial paresis or facial paralysis, neutrophil, lymphocyte, and platelet. STUDY SELECTION: Articles related to BP with NLR or PLR data. DATA EXTRACTION: The data included patient profiles, House-Brackmann score, treatment modality, NLR, and PLR. DATA SYNTHESIS: Seven articles were selected. A random effect model was used to analyze the aggregated data. Six of these articles that included the NLR and two that included the PLR of BP and control patients were analyzed for the difference between BP and control patients. Three articles that included the NLR of the recovery and nonrecovery groups were analyzed for the relationship between NLR and recovery. CONCLUSIONS: The NLR was significantly higher for the BP patients than for the controls. Furthermore, the NLR was significantly lower for the recovery group than for the nonrecovery group. A high NLR was associated with poor prognosis and related to the severity of facial nerve inflammation. There was no significant difference between the PLRs of the BP patients and controls. The NLR, but not the PLR, was found to be a useful prognostic indicator of BP.