ABSTRACT
OBJECTIVE: This study aimed to determine whether surface-based morphometry of preoperative whole-brain three-dimensional T1-weighted magnetic resonance imaging (MRI) images can predict the clinical outcomes of cochlear implantation. STUDY DESIGN: This was an observational, multicenter study using preoperative MRI data. SETTING: The study was conducted at tertiary care referral centers. PATIENTS: Sixty-four patients with severe to profound hearing loss (≥70 dB bilaterally), who were scheduled for cochlear implant (CI) surgery, were enrolled. The patients included 19 with congenital hearing loss and 45 with acquired hearing loss. INTERVENTIONS: Participants underwent CI surgery. Before surgery, high-resolution three-dimensional T1-weighted brain MRI was performed, and the images were analyzed using FreeSurfer. MAIN OUTCOME MEASURES: The primary outcome was monosyllable audibility under quiet conditions 6 months after surgery. Cortical thickness residuals within 34 regions of interest (ROIs) as per the Desikan-Killiany cortical atlas were calculated based on age and healthy-hearing control regression lines. RESULTS: Rank logistic regression analysis detected significant associations between CI effectiveness and five right hemisphere ROIs and five left hemisphere ROIs. Predictive modeling using the cortical thickness of the right entorhinal cortex and left medial orbitofrontal cortex revealed a significant correlation with speech discrimination ability. This correlation was higher in patients with acquired hearing loss than in those with congenital hearing loss. CONCLUSIONS: Preoperative surface-based morphometry could potentially predict CI outcomes and assist in patient selection and clinical decision making. However, further research with larger, more diverse samples is necessary to confirm these findings and determine their generalizability.
Subject(s)
Cochlear Implantation , Cochlear Implants , Deafness , Hearing Loss, Sensorineural , Hearing Loss , Speech Perception , Humans , Cochlear Implantation/methods , Treatment Outcome , Hearing Loss/surgery , Hearing Loss, Sensorineural/surgery , Deafness/surgeryABSTRACT
Some patients have an atypical form of branchio-oto-renal (BOR) syndrome, which does not satisfy the diagnostic criteria, despite carrying a pathogenic variant (P variant) or a likely pathogenic variant (LP variant) of a causative gene. P/LP variants phenotypic indices have yet to be determined in patients with typical and atypical BOR syndrome. We hypothesized that determining phenotypic and genetic differences between patients with typical and atypical BOR syndrome could inform such indices. Subjects were selected from among patients who underwent genetic testing to identify the cause of hearing loss. Patients were considered atypical when they had two major BOR diagnostic criteria, or two major criteria and one minor criterion; 22 typical and 16 atypical patients from 35 families were included. Genetic analysis of EYA1, SIX1, and SIX5 was conducted by direct sequencing and multiplex ligation-dependent probe amplification. EYA1 P/LP variants were detected in 25% and 86% of atypical and typical patients, respectively. Four EYA1 P/LP variants were novel. Branchial anomaly, inner ear anomaly, and mixed hearing loss were correlated with P/LP variants. Development of refined diagnostic criteria and phenotypic indices for atypical BOR syndrome will assist in effective detection of patients with P/LP variants among those with suspected BOR syndrome.
Subject(s)
Branchio-Oto-Renal Syndrome/genetics , Homeodomain Proteins/genetics , Intracellular Signaling Peptides and Proteins/genetics , Nuclear Proteins/genetics , Phenotype , Protein Tyrosine Phosphatases/genetics , Female , Humans , Male , PedigreeABSTRACT
BACKGROUND: The most reliable head and neck position for cervical vestibular-evoked myogenic potentials (cVEMPs) measurements yet to be determined. AIMS/OBJECTIVES: To assess how four body positions used during clinical recordings of cVEMPs affect cVEMP parameters. MATERIAL AND METHOD: cVEMPs of 10 healthy subjects (26-50 years old) were recorded in four body positions: A. sitting/head rotated; B. supine/head rotated; C. semi-recumbent/head rotated and elevated; D. supine/head elevated. RESULTS: Mean background sternocleidomastoid muscle (SCM) electrical activity was significantly higher in positions C and D than in positions A and B. The latencies of p13 and n23 differed significantly among the four positions. Raw p13-n23 complex amplitude was significantly greater in positions C and D than in A and B. These differences were reduced when amplitudes were corrected by SCM activity. For positions A and B, one and two subjects, respectively, had an abnormal raw asymmetry ratio (AR). After correction, all subjects had normal ARs in all positions. CONCLUSIONS AND SIGNIFICANCE: Body positions in which the head is elevated produce a quicker and larger cVEMP response compared to positions in which the head is not elevated. The difference in ARs among positions can be ignored as long as the correction is made.
Subject(s)
Neck Muscles/physiology , Posture/physiology , Vestibular Evoked Myogenic Potentials , Adult , Female , Healthy Volunteers , Humans , Male , Middle Aged , Reference ValuesABSTRACT
OBJECTIVE: To investigate whether the long-term presence of a patulous Eustachian tube (PET) is associated with sensorineural hearing loss (SNHL). STUDY DESIGN: Retrospective chart review. SETTING: Tertiary referral center. PATIENTS: Ears (nâ=â100) were classified into two groups based on duration of PET symptom(s), i.e., Short (≤3 mo; nâ=â47 ears) and Long (≥48 mo; nâ=â53 ears). Contralateral ears without PET (nâ=â28 ears) were classified as the Contralateral group. MAIN OUTCOME MEASURES: We used ISO 7029 to calculate the hearing thresholds of an age- and sex-matched population at a given frequency. Hearing loss was defined as >25% of these calculated values. RESULTS: At 4âkHz, the Long PET group showed a higher prevalence of hearing loss (47%) at 4âkHz than did the Contralateral (21%) and Short PET (19%) groups (pâ=â0.0280 and 0.0043, respectively). Ears with breathing autophony or a sonotubometric low probe tone level showed a higher prevalence of hearing loss at 4âkHz than those without this symptom or with a high probe tone level (pâ=â0.0329 or 0.0103, respectively). At low frequencies, ≥89% of the ears in all groups showed mild hearing loss. CONCLUSION: Chronic PET was associated with SNHL at 4âkHz. PET patients showed low-frequency hearing loss regardless of disease duration. Further studies are needed to better understand the pathophysiology of SNHL in patients with PET.
Subject(s)
Eustachian Tube , Hearing Loss, Sensorineural , Otitis Media , Eustachian Tube/diagnostic imaging , Hearing , Hearing Loss, Sensorineural/diagnostic imaging , Hearing Loss, Sensorineural/epidemiology , Hearing Loss, Sensorineural/etiology , Humans , Retrospective StudiesABSTRACT
Light-gated ion channels and transporters have been applied to a broad array of excitable cells including neurons, cardiac myocytes, skeletal muscle cells and pancreatic ß-cells in an organism to clarify their physiological and pathological roles. Nonetheless, among nonexcitable cells, only glial cells have been studied in vivo by this approach. Here, by optogenetic stimulation of a different nonexcitable cell type in the cochlea of the inner ear, we induce and control hearing loss. To our knowledge, deafness animal models using optogenetics have not yet been established. Analysis of transgenic mice expressing channelrhodopsin-2 (ChR2) induced by an oligodendrocyte-specific promoter identified this channel in nonglial cells-melanocytes-of an epithelial-like tissue in the cochlea. The membrane potential of these cells underlies a highly positive potential in a K+-rich extracellular solution, endolymph; this electrical property is essential for hearing. Illumination of the cochlea to activate ChR2 and depolarize the melanocytes significantly impaired hearing within a few minutes, accompanied by a reduction in the endolymphatic potential. After cessation of the illumination, the hearing thresholds and potential returned to baseline during several minutes. These responses were replicable multiple times. ChR2 was also expressed in cochlear glial cells surrounding the neuronal components, but slight neural activation caused by the optical stimulation was unlikely to be involved in the hearing impairment. The acute-onset, reversible and repeatable phenotype, which is inaccessible to conventional gene-targeting and pharmacological approaches, seems to at least partially resemble the symptom in a population of patients with sensorineural hearing loss. Taken together, this mouse line may not only broaden applications of optogenetics but also contribute to the progress of translational research on deafness.
ABSTRACT
Identification of the causal effects of specific proteins on recurrent and partially reversible hearing loss has been difficult because of the lack of an animal model that provides reversible gene knockdown. We have developed the transgenic mouse line Actin-tTS::Nkcc1 tetO/tetO for manipulatable expression of the cochlear K+ circulation protein, NKCC1. Nkcc1 transcription was blocked by the binding of a tetracycline-dependent transcriptional silencer to the tetracycline operator sequences inserted upstream of the Nkcc1 translation initiation site. Administration of the tetracycline derivative doxycycline reversibly regulated Nkcc1 knockdown. Progeny from pregnant/lactating mothers fed doxycycline-free chow from embryonic day 0 showed strong suppression of Nkcc1 expression (~90% downregulation) and Nkcc1 null phenotypes at postnatal day 35 (P35). P35 transgenic mice from mothers fed doxycycline-free chow starting at P0 (delivery) showed weaker suppression of Nkcc1 expression (~70% downregulation) and less hearing loss with mild cochlear structural changes. Treatment of these mice at P35 with doxycycline for 2 weeks reactivated Nkcc1 transcription to control levels and improved hearing level at high frequency; i.e., these doxycycline-treated mice exhibited partially reversible hearing loss. Thus, development of the Actin-tTS::Nkcc1 tetO/tetO transgenic mouse line provides a mouse model for the study of variable hearing loss through reversible knockdown of Nkcc1.
Subject(s)
Hearing Loss/pathology , Solute Carrier Family 12, Member 2/genetics , Animals , Anti-Bacterial Agents/pharmacology , Auditory Perception/drug effects , Brain Stem/physiology , Cochlea/drug effects , Cochlea/pathology , Cochlea/ultrastructure , Doxycycline/pharmacology , Gene Expression Regulation/drug effects , Genotype , Hearing Loss/metabolism , In Situ Hybridization , Mice , Mice, Knockout , Organ of Corti/pathology , Phenotype , Repressor Proteins/genetics , Solute Carrier Family 12, Member 2/deficiency , Solute Carrier Family 12, Member 2/metabolismABSTRACT
OBJECTIVES: The purpose of this study was to determine the validity and reliability of a Japanese version of the Khalfa hyperacusis questionnaire (KHQ) and proposed a threshold KHQ score for classifying hyperacusis. METHODS: In total, 112 patients with hyperacusis (group A) and 103 patients without hyperacusis (group B). The patients in group A were further classified into the following subgroups: subjects with hyperacusis as their chief complaint (n = 26, group A1) and subjects with hyperacusis accompanied by chief complaints of tinnitus and/or hearing loss (n = 86, group A2). RESULTS: The average total questionnaire score for patients in group A was 11.8 ± 9.7, which was statistically significantly higher than that of patients in group B, 5.7 ± 4.8. Cronbach's coefficients for internal consistency were high for the total score (0.92). The average total scores for groups A1 and A2 were 18.1 ± 11.1 and 9.9 ± 8.4, respectively, and the difference between the groups was statistically significant. CONCLUSIONS: We developed a Japanese version of the KHQ. It showed high reliability and validity; suggesting its usefulness in clinical practice. We propose that a total KHQ score of 16 is an appropriate cutoff for classifying hyperacusis.
Subject(s)
Hyperacusis/diagnosis , Adult , Aged , Female , Humans , Japan , Male , Middle Aged , Reproducibility of Results , Surveys and QuestionnairesABSTRACT
OBJECTIVE: Evaluating the prevalence of specific gene mutations associated with a certain audiometric configuration facilitates clinical assessment of patients with sensorineural hearing loss (SNHL). WFS1 is responsible for autosomal dominant nonsyndromic deafness 6/14/38 and is the most frequent genetic cause of low-frequency SNHL (LFSNHL); however, the exact prevalence of WFS1 mutations in LFSNHL is unknown. Therefore, we evaluated genetic mutations and clinical features in patients with nonsyndromic bilateral LFSNHL, focusing on the WFS1. STUDY DESIGN: Retrospective case series from 2002 to 2013 at the National Hospital Organization Tokyo Medical Center and collaborating hospitals. METHODS: WFS1, GJB2, and mitochondrial DNA mutation screening was carried out for 74 of 1,007 Japanese probands with bilateral LFSNHL. RESULTS: WFS1 and GJB2 mutations were identified in eight of 74 cases (10.8%). Four cases had heterozygous WFS1 mutations; one case had a heterozygous WFS1 mutation and a heterozygous GJB2 mutation; and three cases had biallelic GJB2 mutations. Three cases with WFS1 mutations were sporadic; two of them were confirmed to be caused by a de novo mutation based on the genetic analysis of their parents. In the case with mutations in both WFS1 and GJB2, a de novo mutation of WFS1 was confirmed in the proband's mother by genetic screening of the mother's parents. CONCLUSION: Genetic screening focusing on LFSNHL has not been conducted. The present study first revealed the prevalence of specific gene mutations. WFS1 autosomal dominant mutations were identified even in sporadic cases. Our results also suggested a mutational hotspot in WFS1. LEVEL OF EVIDENCE: 4. Laryngoscope, 127:E324-E329, 2017.
Subject(s)
Connexins/blood , DNA, Mitochondrial/blood , Hearing Loss, Sensorineural/genetics , Membrane Proteins/blood , Mutation , Age of Onset , Asian People/genetics , Connexin 26 , DNA Mutational Analysis , Female , Genetic Testing , Hearing Loss, Sensorineural/blood , Humans , Infant , Infant, Newborn , Japan , Male , Pedigree , Retrospective StudiesABSTRACT
Few enhancers that target gene expression to inner ear hair cells (HCs) have been identified. Using transgenic analysis of enhanced green fluorescent protein (eGFP) reporter constructs and bioinformatics, we evaluated the control of pou4f3 gene expression, since it is expressed only in HCs within the inner ear and continues to be expressed throughout life. An 8.5-kb genomic DNA fragment 5' to the start codon, containing three regions of high cross-species homology, drove expression in all embryonic and neonatal HCs, and adult vestibular and inner HCs, but not adult outer HCs. Transgenes with 0.4, 0.8, 2.5, or 6.5 kb of 5' DNA did not produce HC expression. However, addition of the region from 6.5 to 7.2 kb produced expression in vestibular HCs and neonatal basal turn outer HCs, which also implicated the region from 7.2 to 8.5 kb in inner and apical outer HC expression. Deletion of the region from 0.4 to 5.5 kb 5' from the 8.5-kb construct did not affect HC expression, further indicating lack of HC regulatory elements. When the region from 1 to 0.4 kb was replaced with the minimal promoter of the Ela1 gene, HC expression was maintained but at a drastically reduced level. Bioinformatics identified regions of highly conserved sequence outside of the 8.5 kb, which contained POU4F3-, GFI1-, and LHX3-binding sites. These regions may be involved in maintaining POU4F3 expression in adult outer HCs. Our results identify separate enhancers at various locations that direct expression to different HC types at different ages and determine that 0.4 kb of upstream sequence determines expression level. These data will assist in the identification of mutations in noncoding, regulatory regions of this deafness gene.
Subject(s)
Ear, Inner/metabolism , Gene Expression Regulation, Developmental/genetics , Hair Cells, Auditory, Inner/metabolism , Homeodomain Proteins/genetics , Transcription Factor Brn-3C/genetics , Animals , Hair Cells, Auditory, Outer/metabolism , Mice, Inbred C57BL , Mice, Transgenic , Promoter Regions, Genetic/genetics , Regulatory Sequences, Nucleic Acid/geneticsABSTRACT
COCH (coagulation factor C homology) encodes cochlin, and certain mutations of COCH cause autosomal dominant nonsyndromic deafness 9 (DFNA9). Hearing loss due to COCH mutation begins in adulthood, and 17 missense mutations and two in-frame mutations have been reported. Studies with animal and cellular models have suggested that the underlying biological mechanism of DFNA9 is the dominant-negative effect of mutated COCH and not haploinsufficiency. However, no human cases of DFNA9 that support this hypothesis have been reported. The proband of the present case was an 18-year-old male with congenital or infantile hearing loss. Targeted next-generation sequencing analysis detected a heterozygous novel frameshift mutation of COCH (c.146dupT, p.C50LfsX8) in the proband, whose hearing loss began earlier than what is typical for DFNA9. His mother also carried the mutation but had normal hearing. Consequently, the mutation was not considered to be the cause of the proband's hearing loss. This family is the first case of a truncating COCH variant and supports the hypothesis that COCH haploinsufficiency is not the cause of hearing loss in humans.
Subject(s)
Extracellular Matrix Proteins/genetics , Frameshift Mutation/genetics , Genetic Predisposition to Disease/genetics , Haploinsufficiency/genetics , Hearing Loss, Sensorineural/genetics , Adolescent , Adult , Humans , Male , Middle Aged , Young AdultABSTRACT
No genes have been discovered for which expression is limited only to inner ear hair cells. This is hardly surprising, since the number of mammalian genes is estimated to be 20-25,000, and each gene typically performs many tasks in various locations. Many genes are expressed in inner ear sensory cells and not in other cells of the labyrinth. However, these genes are also expressed in other locations, often in other sensory or neuronal cell types. How gene transcription is directed specifically to hair cells is unclear. Key transcription factors that act during development can specify cell phenotypes, and the hair cell is no exception. The transcription factor ATOH1 is well known for its ability to transform nonsensory cells of the developing inner ear into hair cells. And yet, ATOH1 also specifies different sensory cells at other locations, neuronal phenotypes in the brain, and epithelial cells in the gut. How it specifies hair cells in the inner ear, but alternate cell types in other locations, is not known. Studies of regulatory DNA and transcription factors are revealing mechanisms that direct gene expression to hair cells, and that determine the hair cell identity. The purpose of this review is to summarize what is known about such gene regulation in this key auditory and vestibular cell type.
Subject(s)
Hair Cells, Auditory, Inner/metabolism , Animals , Basic Helix-Loop-Helix Transcription Factors/genetics , Enhancer Elements, Genetic , Gene Expression Regulation, Developmental , Hair Cells, Auditory, Inner/cytology , Homeodomain Proteins/genetics , Humans , Mice , Mice, Transgenic , Myosin VIIa , Myosins/genetics , Transcription Factor Brn-3C/geneticsABSTRACT
A 36 y/o female presented with the chief complaint of diarrhea and vomiting which had lasted for four days, and with a family history of suicide. The first general examination showed severe dehydration with hyponatremia. After admission, she was diagnosed as having isolated adrenocorticotropic hormone (ACTH) deficiency and mixed connective tissue disease, and the steroid replacement therapy was started with the dose equivalent to 7.5 mg/day of prednisolone (PSL). Three days later, she had right sensorineural hearing loss (SNHL). She was given 40 mg/day PSL in addition to the steroid replacement therapy. On the next day, she developed a persecutory type of paranoid disorder, and then was given psychiatric medication. After tapering off PSL for SNHL, the delusion began to improve with psychiatric medication. Three weeks after the onset of SNHL, her hearing level had partially recovered. Ten months later, she did not show any psychic instability. A family history of psychosis and the present history of malnutrition and connective tissue disease are risk factors of steroid psychosis. It can develop even with 5 mg PSL if the patient has a risk factor. Careful medical history taking and knowledge about the steroid psychosis will prevent the severe side effects associated with steroid treatment.
Subject(s)
Hearing Loss, Sensorineural/drug therapy , Prednisolone/adverse effects , Psychotic Disorders/etiology , Acute Disease , Adult , Female , Hearing Loss, Sensorineural/diagnosis , Humans , Prednisolone/therapeutic use , Psychotic Disorders/drug therapy , Risk Factors , Treatment OutcomeABSTRACT
Transcription factors (TFs) can regulate different sets of genes to determine specific cell types by means of combinatorial codes. We previously identified closely-spaced TF binding motifs located 8.2-8.5 kb 5' to the ATG of the murine Pou4f3 gene, a gene required for late hair cell (HC) differentiation and survival. These motifs, 100% conserved among four mammalian species, include a cluster of E-boxes preferred by TCF3/ATOH1 heterodimers as well as motifs for GATA factors and SP1. We hypothesized that these factors might interact to regulate the Pou4f3 gene and possibly induce a HC phenotype in non-sensory cells of the cochlea. Cochlear sensory epithelium explants were prepared from postnatal day 1.5 transgenic mice in which expression of GFP is driven by 8.5 kb of Pou4f3 5' genomic DNA (Pou4f3/GFP). Electroporation was used to transfect cells of the greater epithelial ridge with multiple plasmids encoding human ATOH1 (hATOH1), hTCF3 (also known as E2A or TEF2), hGATA3, and hSP1. hATOH1 or hTCF3 alone induced Pou4f3/GFP cells but hGATA3 and hSP1 did not. hATOH1 but not hTCF3 induced conversion of greater epithelial ridge cells into Pou4f3/GFP and myosin VIIa double-positive cells. Transfection of hATOH1 in combination with hTCF3 or hGATA3 induced 2-3X more Pou4f3/GFP cells, and similarly enhanced Pou4f3/GFP and myosin VIIa double-positive cells, when compared to hATOH1 alone. Triple or quadruple TF combinations were generally not more effective than double TF combinations except in the middle turn, where co-transfection of hATOH1, hE2A, and hGATA3 was more effective than hATOH1 plus either hTCF3 or hGATA3. The results demonstrate that TFs can cooperate in regulation of the Pou4f3 gene and in the induction of at least one other element of a HC phenotype. Our data further indicate that combinations of TFs can be more effective than individual TFs in the inner ear.
Subject(s)
Basic Helix-Loop-Helix Transcription Factors/genetics , Basic Helix-Loop-Helix Transcription Factors/metabolism , Cochlea/metabolism , Epithelium/metabolism , Gene Expression Regulation, Developmental , Hair Cells, Auditory/metabolism , Homeodomain Proteins/genetics , Myosins/genetics , Transcription Factor Brn-3C/genetics , Animals , Homeodomain Proteins/metabolism , Humans , Mice , Mice, Transgenic , Myosin VIIa , Myosins/metabolism , Transcription Factor Brn-3C/metabolism , TransfectionABSTRACT
HYPOTHESIS: We investigated whether inflammatory biomarkers and stress are involved in the pathophysiology of idiopathic sensorineural hearing loss (ISHL). STUDY DESIGN: Individual cohort study. SETTING: Two tertiary centers. PATIENTS: Forty-three ISHL and 10 non-ISHL patients seen in our ENT departments from 2004 to 2010 within a week from the onset of new symptoms and without steroid administration before visiting our departments. INTERVENTION: Multiple audiologic evaluations, blood tests including leukocyte counts, natural killer cell activity (NKCA), interleukin 6 (IL-6), tumor necrosis factor, high-sensitivity CRP (hCRP), and the General Health Questionnaire were used to evaluate the systemic stress and inflammatory response. MAIN OUTCOME MEASURES: Correlations between biomarkers and ISHL severity and prognosis were evaluated by statistical analysis. RESULTS: In the ISHL patients, a neutrophil count above the reference range was associated with severe hearing loss and poor prognosis, and was accompanied by low NKCA and high IL-6. In the non-ISHL patients, these associations were not present. The abnormal neutrophil count was independent of preexisting vascular diseases. The abnormal counts responded to treatment and decreased into the reference range. CONCLUSION: Neutrophil counts above the reference range of a facility will be a useful indicator of poor prognosis of ISHL. Synchronism of different types of NF-κB activation pathways could be required to cause severe ISHL. An NKCA decrease, an acute neutrophil count increase, and an IL-6 increase can induce NF-κB activation in the cochlea and cause severe ISHL. Further epidemiologic surveys should be conducted to evaluate whether stressful life events increase the risk of severe ISHL onset.
Subject(s)
Hearing Loss, Sensorineural/diagnosis , Hearing Loss, Sudden/diagnosis , Interleukin-6/blood , Tumor Necrosis Factor-alpha/blood , Adult , Aged , Biomarkers/blood , Female , Hearing Loss, Sensorineural/blood , Hearing Loss, Sudden/blood , Humans , Inflammation/blood , Killer Cells, Natural , Leukocyte Count , Male , Middle Aged , Prognosis , Severity of Illness IndexABSTRACT
Hearing impairment can be the cause of serious socio-economic disadvantages. Recent studies have shown inflammatory responses in the inner ear co-occur with various damaging conditions including noise-induced hearing loss. We reported pro-inflammatory cytokine interleukin-6 (IL-6) was induced in the cochlea 6h after noise exposure, but the pathophysiological implications of this are still obscure. To address this issue, we investigated the effects of IL-6 inhibition using the anti-IL-6 receptor antibody (MR16-1). Noise-exposed mice were treated with MR16-1 and evaluated. Improved hearing at 4kHz as measured by auditory brainstem response (ABR) was noted in noise-exposed mice treated with MR16-1. Histological analysis revealed the decrease in spiral ganglion neurons was ameliorated in the MR16-1-treated group, while no significant change was observed in the organ of Corti. Immunohistochemistry for Iba1 and CD45 demonstrated a remarkable reduction of activated cochlear macrophages in spiral ganglions compared to the control group when treated with MR16-1. Thus, MR16-1 had protective effects both functionally and pathologically for the noise-damaged cochlea primarily due to suppression of neuronal loss and presumably through alleviation of inflammatory responses. Anti-inflammatory cytokine therapy including IL-6 blockade would be a feasible novel therapeutic strategy for acute sensory neural hearing loss.
Subject(s)
Antibodies, Monoclonal/therapeutic use , Cochlea/drug effects , Cochlear Diseases/drug therapy , Hearing Loss, Noise-Induced/drug therapy , Interleukin-6/antagonists & inhibitors , Labyrinthitis/drug therapy , Noise/adverse effects , Animals , Cochlea/metabolism , Cochlea/pathology , Cochlear Diseases/etiology , Cochlear Diseases/physiopathology , Evoked Potentials, Auditory, Brain Stem , Hearing Loss, Noise-Induced/physiopathology , Interleukin-6/biosynthesis , Interleukin-6/physiology , Labyrinthitis/pathology , Labyrinthitis/physiopathology , Male , Mice , Mice, Inbred C57BL , Receptors, Interleukin-6/biosynthesis , Receptors, Interleukin-6/immunology , Signal Transduction , Spiral Ganglion/drug effects , Spiral Ganglion/pathologyABSTRACT
Outer hair cell (OHC) loss in the auditory sensory epithelium is a primary cause of noise-induced sensory-neural hearing loss (SNHL). To clarify the participation of glial cells in SNHL, we used an Alexander disease (AxD) mouse model. These transgenic mice harbor the AxD causal mutant of the human glial fibrillary acidic protein (GFAP) under the control of the mouse GFAP promoter. It is thought that GFAP aggregates compromise the function of astrocytes. In the auditory pathway, the formation of GFAP aggregates was observed only in GFAP-positive cells of the cochlear nerve. The presence of GFAP aggregates did not change auditory function at the threshold level. To assess the change in vulnerability to auditory excitotoxicity, both transgenic and control mice were treated with intense noise exposure. Auditory threshold shifts were assessed by auditory brainstem responses (ABR) at 1 and 4 weeks after noise exposure, and OHC damage was analyzed by quantitative histology at 4 weeks after exposure. Transgenic mice showed more severe ABR deficits and OHC damage, suggesting that cochlear nerve glial cells with GFAP aggregates play a role in noise susceptibility. Thus, we should focus more on the roles of cochlear nerve glial cells in SNHL.
Subject(s)
Alexander Disease/metabolism , Cochlear Nerve/metabolism , Glial Fibrillary Acidic Protein/metabolism , Hearing Loss, Sensorineural/metabolism , Neurons, Afferent/metabolism , Organ of Corti/metabolism , Acoustic Stimulation/adverse effects , Alexander Disease/genetics , Alexander Disease/physiopathology , Animals , Astrocytes/metabolism , Astrocytes/pathology , Auditory Threshold/physiology , Cochlear Nerve/pathology , Cochlear Nerve/physiopathology , Disease Models, Animal , Evoked Potentials, Auditory, Brain Stem/physiology , Glial Fibrillary Acidic Protein/genetics , Hearing Loss, Noise-Induced/metabolism , Hearing Loss, Noise-Induced/pathology , Hearing Loss, Noise-Induced/physiopathology , Hearing Loss, Sensorineural/etiology , Hearing Loss, Sensorineural/physiopathology , Inclusion Bodies/genetics , Inclusion Bodies/metabolism , Inclusion Bodies/pathology , Mice , Mice, Inbred C57BL , Mice, Transgenic , Nerve Degeneration/genetics , Nerve Degeneration/metabolism , Nerve Degeneration/physiopathology , Neurons, Afferent/pathology , Noise/adverse effects , Organ of Corti/pathology , Organ of Corti/physiopathologyABSTRACT
Here we report the first case of the development of intracranial solitary plasmacytoma in the inner ear after allogeneic stem cell transplantation (allo-SCT) in a 39-year-old Japanese female with primary plasma cell leukemia (PCL). A point to note is that this is not a case on multiple myeloma but on PCL. She was successfully treated with local irradiation and survived more than 6 years from the time of diagnosis and transplantation. This case elucidates the biology of PCL and stresses the need for an individual approach to the clinical management of patients with plasma cell neoplasm undergoing allo-SCT.
Subject(s)
Ear Neoplasms/etiology , Ear, Inner , Hematopoietic Stem Cell Transplantation/adverse effects , Leukemia, Plasma Cell/surgery , Plasmacytoma/etiology , Adult , Ear Neoplasms/diagnosis , Ear Neoplasms/radiotherapy , Ear, Inner/pathology , Female , Humans , Magnetic Resonance Imaging/methods , Plasmacytoma/diagnosis , Plasmacytoma/radiotherapy , Transplantation, HomologousABSTRACT
Recent studies have showed that inflammatory responses occur in inner ear under various damaging conditions including noise-overstimulation. We evaluated the time-dependent expression of proinflammatory cytokines in noise-exposed rat cochlea. Among several detected cytokines, real-time RT-PCR showed that interleukin-1beta (IL-1beta) and interleukin-6 (IL-6) were significantly induced 3 hr after noise exposure, and quickly downregulated to the basal level. Tumor necrosis factor-alpha (TNF-alpha) was also slightly upregulated immediately after noise exposure. Immunohistochemical analysis showed that IL-6 expression was distinctively induced within the lateral side of the spiral ligament. Sequential expression analysis showed that IL-6 immunoreactivity was initially found in the cytoplasm of lateral wall cells, including Type IV and III fibrocytes, and expanded broader throughout the lateral wall, finally to the stria vascularis. Because of the negative Iba-1 staining, IL-6 expression in the early-phase was not due to macrophage or microglia activation. IL-6 was also detected in spiral ganglion neurons at 12 and 24 hr after noise exposure. Our data demonstrates the production of proinflammatory cytokines, including TNF-alpha, IL-1beta, and IL-6, in early phase of noise overstimulated cochlea. IL-6 expression was observed in the spiral ligament, stria vascularis, and spiral ganglion neurons. These cytokines, produced by the cochlear structure itself in response to noise exposure, may initiate an inflammatory response and have some role in the mechanism of noise-induced cochlear damage.
Subject(s)
Cochlea/injuries , Cochlea/metabolism , Cytokines/biosynthesis , Hearing Loss, Noise-Induced/metabolism , Animals , Blotting, Western , Cochlea/pathology , Evoked Potentials, Auditory, Brain Stem/physiology , Hearing Loss, Noise-Induced/pathology , Immunohistochemistry , Interleukin-1/biosynthesis , Interleukin-6/biosynthesis , Male , Rats , Rats, Sprague-Dawley , Reverse Transcriptase Polymerase Chain Reaction , Tumor Necrosis Factor-alpha/biosynthesisABSTRACT
There is increasing evidence to suggest that the expression of many molecules in the lateral wall of the cochlea plays an important role in noise-induced stress responses. In this study, activation of the nuclear transcription factor nuclear factor-kappa B (NF-kappaB) was investigated in the cochlea of mice treated with intense noise exposure (4 kHz, octave band, 124 dB, for 2 h). The present noise exposure led to remarkable auditory brainstem response threshold shifts and cochlear damage on surface preparations. To assess the effects of noise exposure on NF-kappaB/DNA binding activity in the cochlea, we prepared nuclear extracts from the cochlea at different time points after noise exposure and carried out an electrophoretic mobility shift assay using a probe specific to NF-kappaB. NF-kappaB/DNA binding was significantly enhanced in the cochlea 2-6 h after noise exposure and returned to basal levels after 12 h. Supershift analysis using antibodies against p65 and p50 proteins, which are components of NF-kappaB, demonstrated that enhancement of NF-kappaB/DNA binding was at least in part due to nuclear translocation of p65. An immunohistochemical study also showed that nuclear translocation of both p65 and p50 was observed in the lateral wall after noise exposure and that there may be a possible close association between p65 and enhanced inducible nitric oxide synthase expression. These results suggest that NF-kappaB may have a detrimental role in the response to acoustic overstimulation in the cochlea of mice.
Subject(s)
Acoustic Stimulation , Cell Nucleus/metabolism , Cochlea/metabolism , Cochlea/physiology , NF-kappa B/metabolism , Animals , DNA/metabolism , Data Interpretation, Statistical , Electrophoretic Mobility Shift Assay , Evoked Potentials, Auditory, Brain Stem/physiology , Immunohistochemistry , Male , Mice , Mice, Inbred C57BL , NF-kappa B p50 Subunit/metabolism , Nitric Oxide Synthase Type II/biosynthesis , Nitric Oxide Synthase Type II/genetics , Noise/adverse effects , Protein Transport , Transcription Factor RelA/metabolismABSTRACT
After treatments, several patients with sudden deafness (SD) continued to have symptoms, including hearing loss, tinnitus and dizziness. These unresolved symptoms and their effect on the quality of life (QOL) in SD patients have not been studied. We evaluated QOL using the Hearing handicap inventory (HHIA) and an original questionnaire in SD patients who had been treated more than 6 months prior to the study. Compared to results in bilateral sensorineural hearing were significantly lower in SD patients (p<0.01). In bil SNHL, this score peaked two to 10 years after onset of disease and decreased thereafter. The score peaked more than 10 years after onset of disease in patients with SD. While hearing and test scores were correlated in bil-SNHL, this was not observed in SD. About half of patients were embarrassed by hearing loss and tinnitus after treatment. Among patients who scored more than 44 points on HHIA, all reported hearing loss and tinnitus. When asked about subjective changes in hearing after treatment, 27% believed their hearing had improved, 60% believed there was no change, and 13% believed their hearing had deteriorated. Cases believing deterioration in hearing also had high scores on HHIA. Sequelae of SD may worsen QOL, driving embarrassed patients to visit other medical facilities in to improve their QOL. Even though hearing may not improve after initial treatment in ears affected by SD, informed consent about the clinical course and audiological follow-up should be done.