GJB2 c.35del variant up-regulates GJA1 gene expression and affects differentiation of human stem cells.

Pathogenic DNA alterations in GJB2 are present in nearly half of non-syndromic hearing loss cases with autosomal recessive inheritance. The most frequent variant in GJB2 causing non-syndromic hearing loss is the frameshifting c.35del. GJB2 encodes Cx26, a protein of the connexin family that assembles hemichannels and gap junctions. The expression of paralogous proteins is believed to compensate for the loss of function of specific connexins. As Cx26 has been involved in cell differentiation in distinct tissues, we employed stem cells derived from human exfoliated deciduous teeth (SHEDs), homozygous for the c.35del variant, to assess GJB2 roles in stem cell differentiation and the relationship between its loss of function and the expression of paralogous genes. Primary SHED cultures from patients and control individuals were compared. SHEDs from patients had significantly less GJB2 mRNA and increased amount of GJA1 (Cx43), but not GJB6 (Cx30) or GJB3 (Cx31) mRNA. In addition, they presented higher induced differentiation to adipocytes and osteocytes but lower chondrocyte differentiation. Our results suggest that GJA1 increased expression may be involved in functional compensation for GJB2 loss of function in human stem cells, and it may explain changes in differentiation properties observed in SHEDs with and without the c.35del variant.

White noise effect on listening effort among patients with chronic tinnitus and normal hearing thresholds

Abstract Objective This study investigated the effects of WN on LE in subjects with chronic tinnitus and normal hearing thresholds. The study was a prospective, non-randomized, before-and-after, intra-participant intervention. Methods Twenty-five subjects performed the following tests: conventional and high-frequency audiometry, acuphenometry, screening questionnaires for depression and anxiety symptoms, Tinnitus Handicap Inventory (THI), Montreal Cognitive Assessment, and high WM test from the Working Memory Assessment Battery, Federal University of Minas Gerais (WMAB) as the LE measure in two conditions: No Added Noise (NAN) and with Added Noise (AN). Results Seventeen participants (68%) performed better on AN condition. Data analysis revealed a 45% improvement in the WMAB total span count on AN setting, with a significant p value (p = 0.001). Conclusion The subgroup of participants without traces of anxiety symptoms, up to mild traces of depressive symptoms, having unilateral tinnitus, and a THI level up to grade 2, had improved WM performance in the presence of WN, which suggests a release of cognitive resources and less auditory effort under these combined conditions. Evidence level 4.

Generation of four induced pluripotent stem cells lines from PBMC of the DFNA58 family members: Two hearing-impaired duplication carriers (USPi006-A e USPi007-A) and two normal-hearing noncarriers (USPi004-A and USPi005-A).

The DFNA58 locus contains a genomic duplication involving three protein-coding genes (CNRIP1, PLEK, and PPP3R1's exon 1) and other uncharacterized lncRNA genes (LOC101927723, LOC107985892 and LOC102724389). To clarify the role of these genes in hearing and precisely determine their role in hearing loss, four iPSC lines were generated from two carriers and two noncarriers of the duplication.

Translation and validation of the Tinnitus Primary Function Questionnaire into Brazilian Portuguese

Abstract Objective: In this study, the Tinnitus Primary Function Questionnaire was translated, culturally adapted and validated for Brazilian Portuguese. Methods: This study was carried out in two stages. First, a prospective study of translation and cultural adaptation was carried out with a group of 20 patients. The questionnaire was translated, revised and back-translated from Portuguese into English. Subsequently, a retrospective study was carried out with 1,095 patients, 18 months after the first stage. The validation and reliability of the Tinnitus Primary Function Questionnaire was verified by comparing its results with the results of the Tinnitus Handicap Inventory. Results: The interclass correlation coefficient of the behavioral aspects ranged from 0.82 to 0.90 and the total score was 0.93, while Cronbach's alpha was >0.94 for the total score during the test-retest application. To validate the questionnaire, a database was used, which consisted of 1,095 patients submitted to tinnitus assessment using the Tinnitus Primary Function Questionnaire and Tinnitus Handicap Inventory simultaneously. Patients were enrolled from 14 Brazilian states (46% female), with a mean age of 58 years. The reliability of the Tinnitus Primary Function Questionnaire was tested during validation for the four different evaluated behavioral aspects, and the results were significantly high for all aspects and the total score. To validate the Tinnitus Primary Function Questionnaire, the results of the total Tinnitus Primary Function Questionnaire and Tinnitus Handicap Inventory scores were compared using Pearson's product-moment correlation test. The results indicate a high correlation between the two questionnaires (r = 0.84; p < 0.001; 95% CI 0.82-0.85). Conclusion: The data from the Tinnitus Primary Function Questionnaire showed a high correlation with those of the Tinnitus Handicap Inventory. This indicates that the Portuguese version of the Tinnitus Primary Function Questionnaire can be adopted as a valuable tool in the clinical evaluation of patients with tinnitus. Level of Evidence: 2C.

Hearing aid effectiveness on patients with chronic tinnitus and associated hearing loss

Abstract Objective: Our study aimed to measure the effectiveness of using HA in reducing the disturbance caused by tinnitus. Methods: Study was designed as a within-subjects clinical trial. Nineteen patients with chronic tinnitus and untreated sensorineural hearing loss were under counseling, HA fitting and 6 months follow-up. Tinnitus assessment was performed with Tinnitus Handicap Inventory (THI), Visual Analog Scale (VAS), pitch and loudness matching, and Minimum Masking Level measurements (MML). Results: following 6 months of HA use, a reduction in reported tinnitus and hearing handicap scales scores was observed both statistically and clinically. The pitch and loudness matching, as well as MML at the baseline and final evaluation were compared. MML's thresholds reduced significantly after 6 months of HA use. Conclusion: Our study has provided evidence that HA fitting is a valuable treatment strategy for chronic tinnitus relief and associated hearing loss subtype of patient. Level of evidence: 3.

Translation, Cultural Adaptation and Validation to Brazilian Portuguese of the Tinnitus Functional Index Questionnaire

Abstract Introduction Tinnitus affects a large portion of the world's population. There are several questionnaires being used for the evaluation of the severity of tinnitus and its impact in quality of life; however, they do not measure treatment-related changes. So, a new self-reported questionnaire was developed, the Tinnitus Functional Index (TFI), which has been translated into several languages. Objective To perform the translation, cultural adaptation and validation of the TFI questionnaire for Brazilian Portuguese. Method This is a multicenter project divided into two stages: translation and cultural adaptation; and validation and reliability. For the validation, the Brazilian Portuguese version of the TFI was correlated with the Tinnitus Handicap Inventory (THI) domains for tinnitus and quality of life and was evaluated by the Spearman ρ test. The reliability and internal consistency were evaluated by the Cronbach α test. Result The Brazilian version of the TFI was obtained through an initial translation process, synthesis of translations, backtranslation and evaluation by a committee of experts. This version was then applied in 88 patients complaining of tinnitus from speech therapy and otorhinolaryngology outpatient clinics of the three school clinics. The Brazilian version presented high reliability, as evidenced by the Cronbach α value (α = 0.870), and strong correlation (rho = 0.760 and p = 0.000). Conclusion The high reliability found in the results demonstrates that the Brazilian Portuguese version of the TFI is a valid and reliable instrument to evaluate the severity and impact of tinnitus on quality of life and changes related to its treatment.

Translation, Cultural Adaptation and Validation to Brazilian Portuguese of the Tinnitus Functional Index Questionnaire.

Introduction Tinnitus affects a large portion of the world's population. There are several questionnaires being used for the evaluation of the severity of tinnitus and its impact in quality of life; however, they do not measure treatment-related changes. So, a new self-reported questionnaire was developed, the Tinnitus Functional Index (TFI), which has been translated into several languages. Objective To perform the translation, cultural adaptation and validation of the TFI questionnaire for Brazilian Portuguese. Method This is a multicenter project divided into two stages: translation and cultural adaptation; and validation and reliability. For the validation, the Brazilian Portuguese version of the TFI was correlated with the Tinnitus Handicap Inventory (THI) domains for tinnitus and quality of life and was evaluated by the Spearman ρ test. The reliability and internal consistency were evaluated by the Cronbach α test. Result The Brazilian version of the TFI was obtained through an initial translation process, synthesis of translations, backtranslation and evaluation by a committee of experts. This version was then applied in 88 patients complaining of tinnitus from speech therapy and otorhinolaryngology outpatient clinics of the three school clinics. The Brazilian version presented high reliability, as evidenced by the Cronbach α value (α = 0.870), and strong correlation (rho = 0.760 and p = 0.000). Conclusion The high reliability found in the results demonstrates that the Brazilian Portuguese version of the TFI is a valid and reliable instrument to evaluate the severity and impact of tinnitus on quality of life and changes related to its treatment.

Translation and validation of the Tinnitus Primary Function Questionnaire into Brazilian Portuguese.

OBJECTIVE: In this study, the Tinnitus Primary Function Questionnaire was translated, culturally adapted and validated for Brazilian Portuguese. METHODS: This study was carried out in two stages. First, a prospective study of translation and cultural adaptation was carried out with a group of 20 patients. The questionnaire was translated, revised and back-translated from Portuguese into English. Subsequently, a retrospective study was carried out with 1,095 patients, 18 months after the first stage. The validation and reliability of the Tinnitus Primary Function Questionnaire was verified by comparing its results with the results of the Tinnitus Handicap Inventory. RESULTS: The interclass correlation coefficient of the behavioral aspects ranged from 0.82 to 0.90 and the total score was 0.93, while Cronbach's alpha was >0.94 for the total score during the test-retest application. To validate the questionnaire, a database was used, which consisted of 1,095 patients submitted to tinnitus assessment using the Tinnitus Primary Function Questionnaire and Tinnitus Handicap Inventory simultaneously. Patients were enrolled from 14 Brazilian states (46% female), with a mean age of 58 years. The reliability of the Tinnitus Primary Function Questionnaire was tested during validation for the four different evaluated behavioral aspects, and the results were significantly high for all aspects and the total score. To validate the Tinnitus Primary Function Questionnaire, the results of the total Tinnitus Primary Function Questionnaire and Tinnitus Handicap Inventory scores were compared using Pearson's product-moment correlation test. The results indicate a high correlation between the two questionnaires (r=0.84; p<0.001; 95% CI 0.82-0.85). CONCLUSION: The data from the Tinnitus Primary Function Questionnaire showed a high correlation with those of the Tinnitus Handicap Inventory. This indicates that the Portuguese version of the Tinnitus Primary Function Questionnaire can be adopted as a valuable tool in the clinical evaluation of patients with tinnitus. LEVEL OF EVIDENCE: 2C.

Hearing aid effectiveness on patients with chronic tinnitus and associated hearing loss.

OBJECTIVE: Our study aimed to measure the effectiveness of using HA in reducing the disturbance caused by tinnitus. METHODS: Study was designed as a within-subjects clinical trial. Nineteen patients with chronic tinnitus and untreated sensorineural hearing loss were under counseling, HA fitting and 6 months follow-up. Tinnitus assessment was performed with Tinnitus Handicap Inventory (THI), Visual Analog Scale (VAS), pitch and loudness matching, and Minimum Masking Level measurements (MML). RESULTS: following 6 months of HA use, a reduction in reported tinnitus and hearing handicap scales scores was observed both statistically and clinically. The pitch and loudness matching, as well as MML at the baseline and final evaluation were compared. MML's thresholds reduced significantly after 6 months of HA use. CONCLUSION: Our study has provided evidence that HA fitting is a valuable treatment strategy for chronic tinnitus relief and associated hearing loss subtype of patient.

Effectiveness of Dry Needling in Bothersome Chronic Tinnitus in Patients with Myofascial Trigger Points

Abstract Introduction Therapeutic dry needling (DN) is effective in reducing the discomfort of chronic somatosensory tinnitus in patients with myofascial trigger points (MTP)s. Objective To evaluate the efficacy of DN in chronic somatosensory tinnitus discomfort in patients with MTP. Methods Placebo-controlled paired trial that included 16 patients with a diagnosis of somatosensory chronic tinnitus and with the presence of at least one active or latent MTP. Treatment was performed in two phases: (1) four sessions (one session per week for four consecutive weeks) of placebo DN and (2) four sessions of therapeutic DN with a gap (washout) of 15 days between these phases. Results The Tinnitus Handicap Inventory (THI) variable and its emotional domain had a statistically significant reduction in therapeutic DN when compared with placebo DN (p= 0.024 and p = 0.011, respectively). The tinnitus visual analogic scale (VAS) signaled a reduction in tinnitus discomfort when compared with moments before and after therapeutic DN (p< 0.05). Conclusion The therapeutic DN technique for MTP in patients with chronic tinnitus of somatosensory origin proved effective in reducing symptom discomfort, as measured by the THI (total score) and its emotional domain when compared with placebo DN.

Effectiveness of Dry Needling in Bothersome Chronic Tinnitus in Patients with Myofascial Trigger Points.

Introduction Therapeutic dry needling (DN) is effective in reducing the discomfort of chronic somatosensory tinnitus in patients with myofascial trigger points (MTP)s. Objective To evaluate the efficacy of DN in chronic somatosensory tinnitus discomfort in patients with MTP. Methods Placebo-controlled paired trial that included 16 patients with a diagnosis of somatosensory chronic tinnitus and with the presence of at least one active or latent MTP. Treatment was performed in two phases: (1) four sessions (one session per week for four consecutive weeks) of placebo DN and (2) four sessions of therapeutic DN with a gap (washout) of 15 days between these phases. Results The Tinnitus Handicap Inventory (THI) variable and its emotional domain had a statistically significant reduction in therapeutic DN when compared with placebo DN ( p = 0.024 and p = 0.011, respectively). The tinnitus visual analogic scale (VAS) signaled a reduction in tinnitus discomfort when compared with moments before and after therapeutic DN ( p < 0.05). Conclusion The therapeutic DN technique for MTP in patients with chronic tinnitus of somatosensory origin proved effective in reducing symptom discomfort, as measured by the THI (total score) and its emotional domain when compared with placebo DN.

Evaluating the efficacy of hearing aids for tinnitus therapy - A Positron emission tomography study.

Brain imaging studies have revealed neural changes in chronic tinnitus patients that are not restricted to auditory brain areas; rather, the engagement of limbic system structures, attention and memory networks are has been noted. Hearing aids (HA) provide compensation for comorbid hearing loss and may decrease tinnitus-related perception and annoyance. Using resting state positron emission tomography our goal was to analyze metabolic and functional brain changes after six months of effective HA use by patients with chronic tinnitus and associated sensorineural hearing loss. 33 age and hearing loss matched participants with mild/moderate hearing loss were enrolled in this study: 19 with tinnitus, and 14 without tinnitus. Participants with tinnitus of more than 6 months with moderate/severe Tinnitus Handicap Inventory (THI) and Visual Analogue Scale (VAS) scores composed the tinnitus group. A full factorial 2X2 ANOVA was conducted for imaging analysis, with group (tinnitus and controls) and time point (pre-intervention and post-intervention) as factors. Six months after HA fitting, tinnitus scores reduced statistically and clinically. Analysis revealed increased glycolytic metabolism in the left orbitofrontal cortex, right temporal lobe and right hippocampus, and reduced glycolytic metabolism in the left cerebellum and inferior parietal lobe within the tinnitus group. The hearing loss control group showed no significant metabolic changes in the analysis. Parsing out the contribution of tinnitus independent of hearing loss, allowed us to identify areas implicated in declines in tinnitus handicap as a result of the intervention. Brain regions implicated in the present study may be part of chronic tinnitus-specific network.

Molecular and genetic characterization of a large Brazilian cohort presenting hearing loss.

Hearing loss is one of the most common sensory defects, affecting 5.5% of the worldwide population and significantly impacting health and social life. It is mainly attributed to genetic causes, but their relative contribution reflects the geographical region's socio-economic development. Extreme genetic heterogeneity with hundreds of deafness genes involved poses challenges for molecular diagnosis. Here we report the investigation of 542 hearing-impaired subjects from all Brazilian regions to search for genetic causes. Biallelic GJB2/GJB6 causative variants were identified in 12.9% (the lowest frequency was found in the Northern region, 7.7%), 0.4% carried GJB2 dominant variants, and 0.6% had the m.1555A > G variant (one aminoglycoside-related). In addition, other genetic screenings, employed in selected probands according to clinical presentation and presumptive inheritance patterns, identified causative variants in 2.4%. Ear malformations and auditory neuropathy were diagnosed in 10.8% and 3.5% of probands, respectively. In 3.8% of prelingual/perilingual cases, Waardenburg syndrome was clinically diagnosed, and in 71.4%, these diagnoses were confirmed with pathogenic variants revealed; seven out of them were novel, including one CNV. All these genetic screening strategies revealed causative variants in 16.2% of the cases. Based on causative variants in the molecular diagnosis and genealogy analyses, a probable genetic etiology was found in ~ 50% of the cases. The present study highlights the relevance of GJB2/GJB6 as a cause of hearing loss in all Brazilian regions and the importance of screening unselected samples for estimating frequencies. Moreover, when a comprehensive screening is not available, molecular diagnosis can be enhanced by selecting probands for specific screenings.

NCOA3 identified as a new candidate to explain autosomal dominant progressive hearing loss.

Hearing loss is a frequent sensory impairment in humans and genetic factors account for an elevated fraction of the cases. We have investigated a large family of five generations, with 15 reported individuals presenting non-syndromic, sensorineural, bilateral and progressive hearing loss, segregating as an autosomal dominant condition. Linkage analysis, using SNP-array and selected microsatellites, identified a region of near 13 cM in chromosome 20 as the best candidate to harbour the causative mutation. After exome sequencing and filtering of variants, only one predicted deleterious variant in the NCOA3 gene (NM_181659, c.2810C > G; p.Ser937Cys) fit in with our linkage data. RT-PCR, immunostaining and in situ hybridization showed expression of ncoa3 in the inner ear of mice and zebrafish. We generated a stable homozygous zebrafish mutant line using the CRISPR/Cas9 system. ncoa3-/- did not display any major morphological abnormalities in the ear, however, anterior macular hair cells showed altered orientation. Surprisingly, chondrocytes forming the ear cartilage showed abnormal behaviour in ncoa3-/-, detaching from their location, invading the ear canal and blocking the cristae. Adult mutants displayed accumulation of denser material wrapping the otoliths of ncoa3-/- and increased bone mineral density. Altered zebrafish swimming behaviour corroborates a potential role of ncoa3 in hearing loss. In conclusion, we identified a potential candidate gene to explain hereditary hearing loss, and our functional analyses suggest subtle and abnormal skeletal behaviour as mechanisms involved in the pathogenesis of progressive sensory function impairment.

A rare genomic duplication in 2p14 underlies autosomal dominant hearing loss DFNA58.

Here we define a ~200 Kb genomic duplication in 2p14 as the genetic signature that segregates with postlingual progressive sensorineural autosomal dominant hearing loss (HL) in 20 affected individuals from the DFNA58 family, first reported in 2009. The duplication includes two entire genes, PLEK and CNRIP1, and the first exon of PPP3R1 (protein coding), in addition to four uncharacterized long non-coding (lnc) RNA genes and part of a novel protein-coding gene. Quantitative analysis of mRNA expression in blood samples revealed selective overexpression of CNRIP1 and of two lncRNA genes (LOC107985892 and LOC102724389) in all affected members tested, but not in unaffected ones. Qualitative analysis of mRNA expression identified also fusion transcripts involving parts of PPP3R1, CNRIP1 and an intergenic region between PLEK and CNRIP1, in the blood of all carriers of the duplication, but were heterogeneous in nature. By in situ hybridization and immunofluorescence, we showed that Cnrip1, Plek and Ppp3r1 genes are all expressed in the adult mouse cochlea including the spiral ganglion neurons, suggesting changes in expression levels of these genes in the hearing organ could underlie the DFNA58 form of deafness. Our study highlights the value of studying rare genomic events leading to HL, such as copy number variations. Further studies will be required to determine which of these genes, either coding proteins or non-coding RNAs, is or are responsible for DFNA58 HL.

Neurotology: definitions and evidence-based therapies - Results of the I Brazilian Forum of Neurotology / Otoneurologia: definições e terapias baseadas em evidências - Resultados do I Fórum Brasileiro de Otoneurologia

Abstract Introduction: Neurotology is a rapidly expanding field of knowledge. The study of the vestibular system has advanced so much that even basic definitions, such as the meaning of vestibular symptoms, have only recently been standardized. Objective: To present a review of the main subjects of neurotology, including concepts, diagnosis and treatment of Neurotology, defining current scientific evidence to facilitate decision-making and to point out the most evidence-lacking areas to stimulate further new research. Methods: This text is the result of the I Brazilian Forum of Neurotology, which brought together the foremost Brazilian researchers in this area for a literature review. In all, there will be three review papers to be published. This first review will address definitions and therapies, the second one will address diagnostic tools, and the third will define the main diseases diagnoses. Each author performed a bibliographic search in the LILACS, SciELO, PubMed and MEDLINE databases on a given subject. The text was then submitted to the other Forum participants for a period of 30 days for analysis. A special chapter, on the definition of vestibular symptoms, was translated by an official translation service, and equally submitted to the other stages of the process. There was then a in-person meeting in which all the texts were orally presented, and there was a discussion among the participants to define a consensual text for each chapter. The consensual texts were then submitted to a final review by four professors of neurotology disciplines from three Brazilian universities and finally concluded. Based on the full text, available on the website of the Brazilian Association of Otorhinolaryngology and Cervical-Facial Surgery, this summary version was written as a review article. Result: The text presents the official translation into Portuguese of the definition of vestibular symptoms proposed by the Bárány Society and brings together the main scientific evidence for each of the main existing therapies for neurotological diseases. Conclusion: This text rationally grouped the main topics of knowledge regarding the definitions and therapies of Neurotology, allowing the reader a broad view of the approach of neurotological patients based on scientific evidence and national experience, which should assist them in clinical decision-making, and show the most evidence-lacking topics to stimulate further study.

Resumo Introdução: A otoneurologia é uma área de conhecimento que tem se expandido muito rapidamente. O estudo do sistema vestibular tem avançado tanto que mesmo definições básicas, como o significado dos sintomas vestibulares, foram apenas recentemente padronizadas. Objetivo: Apresentar uma revisão dos principais assuntos da otoneurologia, inclusive conceitos, diagnóstico e tratamento da otoneurologia, definir a evidência científica atual para facilitar a tomada de decisões e demonstrar as áreas mais carentes de evidência para estimular novas pesquisas. Método: Este texto é fruto do I Fórum Brasileiro de Otoneurologia, que reuniu os principais pesquisadores brasileiros dessa área para uma revisão da literatura. Serão feitos três trabalhos de revisão a serem publicados. Este primeiro abordou as definições e as terapias, o segundo abordará as ferramentas diagnósticas e o terceiro definirá os principais diagnósticos. Cada autor fez um levantamento bibliográfico na base de dados da Lilacs, SciELO, Pubmed e Medline de um determinado assunto. O seu texto foi então submetido aos demais participantes do Fórum por 30 dias para análise. Um capítulo especial, da definição dos sintomas vestibulares, foi traduzido por serviço de tradução oficial e igualmente submetido às demais etapas do processo. Houve então uma reunião presencial em que todos os textos foram apresentados oralmente e houve uma discussão entre os participantes para a definição de um texto consensual para cada capítulo. Os textos consensuais foram então submetidos a uma revisão final por quatro professores de otoneurologia de três universidades brasileiras e, por fim, finalizado. A partir do texto completo, publicado no site da Associação Brasileira de Otorrinolaringologia e Cirurgia Cérvico-Facial, foi escrita esta versão-resumo como artigo de revisão. Resultado: O texto apresenta a tradução oficial para o português da definição dos sintomas vestibulares propostos pela Barany Society e agrupa as principais evidências científicas para cada um das principais terapias existentes para as doenças otoneurológicas. Conclusão: Este texto agrupou de forma racional os principais tópicos de conhecimento a respeito das definições e terapias da otoneurologia, permite ao leitor uma visão ampla da abordagem dos pacientes otoneurológicos baseada em evidências científicas e experiência nacional, que deverá auxiliá-lo na tomada de decisões clínicas, e mostra os assuntos mais carentes de evidência para estimular novos estudos.

Neurotology: definitions and evidence-based therapies - Results of the I Brazilian Forum of Neurotology.

INTRODUCTION: Neurotology is a rapidly expanding field of knowledge. The study of the vestibular system has advanced so much that even basic definitions, such as the meaning of vestibular symptoms, have only recently been standardized. OBJECTIVE: To present a review of the main subjects of neurotology, including concepts, diagnosis and treatment of Neurotology, defining current scientific evidence to facilitate decision-making and to point out the most evidence-lacking areas to stimulate further new research. METHODS: This text is the result of the I Brazilian Forum of Neurotology, which brought together the foremost Brazilian researchers in this area for a literature review. In all, there will be three review papers to be published. This first review will address definitions and therapies, the second one will address diagnostic tools, and the third will define the main diseases diagnoses. Each author performed a bibliographic search in the LILACS, SciELO, PubMed and MEDLINE databases on a given subject. The text was then submitted to the other Forum participants for a period of 30 days for analysis. A special chapter, on the definition of vestibular symptoms, was translated by an official translation service, and equally submitted to the other stages of the process. There was then a in-person meeting in which all the texts were orally presented, and there was a discussion among the participants to define a consensual text for each chapter. The consensual texts were then submitted to a final review by four professors of neurotology disciplines from three Brazilian universities and finally concluded. Based on the full text, available on the website of the Brazilian Association of Otorhinolaryngology and Cervical-Facial Surgery, this summary version was written as a review article. RESULT: The text presents the official translation into Portuguese of the definition of vestibular symptoms proposed by the Bárány Society and brings together the main scientific evidence for each of the main existing therapies for neurotological diseases. CONCLUSION: This text rationally grouped the main topics of knowledge regarding the definitions and therapies of Neurotology, allowing the reader a broad view of the approach of neurotological patients based on scientific evidence and national experience, which should assist them in clinical decision-making, and show the most evidence-lacking topics to stimulate further study.

Stem-cell therapy for hearing loss: are we there yet? / Terapia com células-tronco para perda auditiva: já chegamos lá?

Abstract Introduction: Mammalian hair cells and auditory neurons do not show regenerative capacity. Hence, damage to these cell types is permanent and leads to hearing loss. However, there is no treatment that re-establishes auditory function. Regenerative therapies using stem cells represent a promising alternative. Objective: This article aims to review the current literature about the main types of stem cells with potential for application in cell therapy for sensorineural hearing loss, the most relevant experiments already performed in animals, as well as the advances that have been recently made in the field. Methods: Research included the databases PubMed/MEDLINE, Web of Science, Science Direct and SciELO, as well as gray literature. Search strategy included the following main terms: "stem cells", "hair cells" and "auditory neurons". Additionally, the main terms were combined with the following secondary terms: "mesenchymal", "iPS", "inner ear", "auditory". The research was conducted independently by three researchers. Results: Differentiation of stem cells into hair cells and auditory neurons has a high success rate, reaching up to 82% for the first and 100% for the latter. Remarkably, these differentiated cells are able to interact with hair cells and auditory neurons of cochlear explants through formation of new synapses. When transplanted into the cochlea of animals with hearing loss, auditory restoration has been documented to date only in deafferented animals. Conclusion: Advances have been more prominent in cases of auditory neuropathy, since partial improvement of auditory nerve conditions through cell-based therapy may increase the number of patients who can successfully receive cochlear implants.

Resumo Introdução: Nos mamíferos, as células ciliadas e os neurônios auditivos não apresentam capacidade regenerativa. Assim, os danos a esses tipos celulares são permanentes e levam à perda auditiva. Contudo, como não há tratamento que restabeleça a função auditiva, as terapias regenerativas utilizando células-tronco representam uma alternativa promissora. Objetivo: Este artigo tem como objetivo revisar a literatura atual sobre os principais tipos de células-tronco com potencial para aplicação em terapia celular para perda auditiva sensorioneural, os experimentos mais relevantes já realizados em animais, bem como os avanços obtidos recentemente nessa área. Método: As pesquisas incluíram as bases de dados PubMed/MEDLINE, Web of Science, Science Direct e SciELO, além da literatura cinza. A estratégia de busca incluiu os seguintes termos principais: "stem cells", "hair cells" e "auditory neurons". Além disso, os termos principais foram combinados com os seguintes termos secundários: "mesenchymal", "iPS", "inner ear" e "auditory". A pesquisa foi realizada de forma independente por três pesquisadores. Resultados: A diferenciação de células-tronco em células ciliadas e neurônios auditivos têm alta taxa de sucesso, chegando a 82% para o primeiro caso e 100% para o segundo. Notavelmente, essas células diferenciadas são capazes de interagir com células ciliadas e neurônios auditivos de explantes cocleares através da formação de novas sinapses. Quando transplantadas para a cóclea de animais com perda auditiva, a restauração da função auditiva foi observada, até o momento, apenas em animais com ablação do VIII nervo craniano. Conclusão: Os avanços têm sido mais proeminentes em casos de neuropatia auditiva. A melhora parcial das condições do nervo auditivo por meio de terapia baseada em células-tronco pode aumentar o número de pacientes candidatos a receber implantes cocleares com sucesso.

Stem-cell therapy for hearing loss: are we there yet?

INTRODUCTION: Mammalian hair cells and auditory neurons do not show regenerative capacity. Hence, damage to these cell types is permanent and leads to hearing loss. However, there is no treatment that re-establishes auditory function. Regenerative therapies using stem cells represent a promising alternative. OBJECTIVE: This article aims to review the current literature about the main types of stem cells with potential for application in cell therapy for sensorineural hearing loss, the most relevant experiments already performed in animals, as well as the advances that have been recently made in the field. METHODS: Research included the databases PubMed/MEDLINE, Web of Science, Science Direct and SciELO, as well as gray literature. Search strategy included the following main terms: "stem cells", "hair cells" and "auditory neurons". Additionally, the main terms were combined with the following secondary terms: "mesenchymal", "iPS", "inner ear", "auditory". The research was conducted independently by three researchers. RESULTS: Differentiation of stem cells into hair cells and auditory neurons has a high success rate, reaching up to 82% for the first and 100% for the latter. Remarkably, these differentiated cells are able to interact with hair cells and auditory neurons of cochlear explants through formation of new synapses. When transplanted into the cochlea of animals with hearing loss, auditory restoration has been documented to date only in deafferented animals. CONCLUSION: Advances have been more prominent in cases of auditory neuropathy, since partial improvement of auditory nerve conditions through cell-based therapy may increase the number of patients who can successfully receive cochlear implants.