Development of Magnetic Nanosystems with Potential for the Treatment of Inner Ear Pathologies.

Hearing loss (HL) affects more than 5% of the global population, with projections indicating an impact of up to 50% on young individuals in the next years. HL treatments remain limited due to the inner ear's hermeticism. HL often involves inflammatory processes, underscoring the need for enhanced delivery of antiinflammatory agents to the inner ear. Our research focuses on the development of a directed therapy based on magnetic nanoparticles (MNPs). We previously synthesized biocompatible folic acid-coated iron oxide-core nanoparticles (MNPs@FA) as potential carriers for the anti-inflammatory Diclofenac (Dfc). This study aims to incorporate Dfc onto MNPs@FA to facilitate targeted drug delivery to the inner ear. Through optimizing the loading procedure, we achieved optimal loading capacity. Dfc release was studied in the simulated target fluid and the administration vehicle. Complete characterization is also shown. In vitro biocompatibility testing ensured the biosafety of the resulting formulation. Subsequent ex vivo targeting assays on murine cochleae validated the nanosystems' ability to penetrate the round window membrane, one of the main HL therapy barriers. These findings serve as validation before continuing to more complex in vivo studies. Together, the data here presented represent an advancement in addressing unmet medical needs in HL therapy.

Paciente con enfermedad descompresiva del oído interno / Patient with inner ear decompression sickness

Introducción: La enfermedad descompresiva es un síndrome clínico complejo causado por la sobresaturación de gases respiratorios en la sangre y los tejidos, después de una reducción abrupta de la presión ambiental, que puede presentarse como parte de los accidentes de buceo. Dada su baja prevalencia se da a conocer una de sus formas de presentación en los servicios de urgencias, que requiere rapidez en el diagnóstico y conducta terapéutica inmediata. Objetivo: Presentar un caso grave de enfermedad descompresiva del oído interno. Caso clínico: Paciente masculino de 71 años de edad, buzo aficionado y antecedente de un accidente vascular encefálico isquémico hace aproximadamente 1 año. Realizó inmersiones, luego de las cuales comenzó a presentar síntomas como mareos, náuseas, vómitos copiosos, inestabilidad para la marcha y manifestaciones sensitivas en la cara. Horas después de ser evaluado en centro médico de urgencia, sin diagnóstico específico, se trasladó al cuerpo de guardia del hospital, para su valoración por el especialista en medicina subacuática. Conclusiones: La orientación diagnóstica de un paciente con enfermedad descompresiva requiere derivación urgente a un centro de tratamiento de enfermedades disbáricas(AU)

Introduction: Decompression illness is a complex clinical syndrome caused by supersaturation of respiratory gases in the blood and tissues, after an abrupt reduction in environmental pressure, which can occur as part of diving accidents. Given its low prevalence, one of its forms of presentation is revealed in emergency services, which requires speed in diagnosis and immediate therapeutic conduct. Objective: To present a severe case of decompressive disease of the inner ear. Clinical case: 71-year-old male patient, amateur diver, with a history of an ischemic stroke approximately 1 year ago. He performed dives, after which he began to present symptoms such as dizziness, nausea, copious vomiting, unsteadiness in walking, and sensitive manifestations on the face. Hours after being evaluated at the emergency medical center, without a specific diagnosis, he was transferred to the hospital's emergency room, for evaluation by the underwater medicine specialist. Conclusions: The diagnostic orientation of a patient with decompression illness requires urgent referral to a center for the treatment of dysbaric diseases(AU)

Asociación del resultado auditivo final, en pacientes con hipoacusia súbita, a la respuesta a glucocorticoides in vitro / Association of the final hearing result, in patients with sudden hearing loss, to the response to glucocorticoids in vitro

Introducción: La hipoacusia súbita (HS) es poco frecuente y su etiopatogenia no está definida. La terapia con corticoides es de elección en base a recomendaciones de expertos por sus efectos teóricos y no en base a utilidad clínica demostrada. Objetivo: Evaluar si existe correlación entre el resultado auditivo final, de pacientes con HS tratados con corticoides, y la respuesta in vitro de sus leucocitos a corticoides, medida como diferencias en la expresión relativa de genes blanco del receptor de glucocorticoides. Material y Método: Estudio de casos (recuperación total) y controles (no recuperados) de pacientes con HS tratados con corticoides en el Hospital Clínico de la Universidad de Chile, durante 2017-2019. Se obtuvo DNA que fue almacenado en el Biobanco de Tejidos y Fluidos de la Universidad de Chile (BTUCH). Se purificaron y cultivaron leucocitos mononucleares de sangre periférica, expuestos in vitro a hidrocortisona. Se determinó la diferencia en la expresión relativa de genes blanco (IGFBP1, CAT, HSD17B12, APOA2), por Q-RTPCR, entre ambos grupos. Resultados: Se reclutaron 35 pacientes; se incluyeron para análisis 23: 11 casos y 12 controles, con edad promedio de 54,9 y 50,8 años respectivamente, distribución homogénea de sexo. No hubo diferencia estadísticamente significativa en la expresión relativa de los genes blanco, a la exposición in vitro a corticoides, entre ambos grupos. Conclusión: En nuestro estudio, modelo, y sistema de evaluación no se evidenciaron efectos de los corticoides. No podemos descartar que, con un número mayor de pacientes, otros genes blanco u otros protocolos de estudio podrían detectarse diferencias.

Introduction: Sudden hearing loss (SHL) is rare and its etiopathogenesis is still not clear. Corticosteroid therapy is of choice based on expert recommendations due to its theoretical effects and no based on proved clinical efficacy. Objectives: To assess whether there is a correlation between the final auditory outcome of patients with SHL treated with corticosteroids and the in vitro response of their leukocytes to corticosteroids, measured as differences in the relative expression of glucocorticoid receptor target genes. Material and Method: Case-control (total recovery and not recovered respectively) study of patients with SHL treated with corticosteroids at Clinical Hospital Universidad de Chile between 2017 and 2019. DNA was obtained and stored in the Biobanco de Tejidos y Fluidos de la Universidad de Chile (BTUCH). Peripheral blood mononuclear leukocytes were purified and cultured and then exposed to hydrocortisone. The difference in the relative expression of target genes (GFBP1, CAT, HSD17B12, APOA2), by Q-RTPCR was determined. Results: Thirty-five patients were recruited, 24 were included for the analysis: 11 cases and 12 controls, with and average age of 54.9 and 50.,8 years respectively, homogeneous sex distribution. There was no statistically significant difference in the relative expression of the target genes, upon in vitro exposure to corticosteroids, between both groups. Conclusion: In our study, model and evaluation system, no effects of corticosteroids were evidenced. With a larger number of patients, other target genes or other study protocols, we cannot rule out that differences could be detected.

Evaluation of inner ear damage by mastoid drilling with measurement of serum prestin (SLC26A5) levels.

OBJECTIVE: The objective of this study is to demonstrate any inner ear injury caused by drilling in mastoid surgery with prestin, outer hair cell motor protein specific to the cochlea. METHODS: The patients with chronic otitis media requiring mastoidectomy (n = 21) and myringoplasty (n = 21) were included. Serum prestin level obtained from blood samples was measured before surgery and on postoperative days 0, 3, and 7 using Human Prestin (SLC26A5) ELISA Kit. All patients underwent the Pure Tone Audiometry (PTA) test before surgery and on the postoperative 7th day. The drilling time was also recorded for all patients who underwent mastoidectomy. RESULTS: In both mastoidectomy and myringoplasty groups, the postoperative serum prestin levels increased on days 0 and 7 (pday-0 = 0.002, pday-7 = 0.001 and pday-0 = 0.005, pday-7 = 0.001, respectively). There was no significant difference in the serum prestin levels between the two groups, postoperatively. The PTA thresholds at day 7 did not change in either group. A significant decline at 2000 Hz of bone conduction hearing threshold in both groups and a decline at 4000 Hz in the myringoplasty group were found. There was no correlation between the drilling time and the increase of prestin levels in the postoperative day 0, 3, and 7. CONCLUSION: Our results showed that mastoid drilling is not related to a significant inner ear injury. Although the myringoplasty group was not exposed to drill trauma, there was a similar increase in serum prestin levels as the mastoidectomy group. Also, a significant decline at 2000 Hz of bone conduction hearing threshold in both groups and a decline at 4000 Hz in the myringoplasty group were found. These findings suggest that suction and ossicular manipulation trauma can lead to an increase in serum prestin levels and postoperative temporary or permanent SNHL at 2000 and 4000 Hz. LEVEL OF EVIDENCE: Level-4.

Detailed analysis of inner ear malformations in CHARGE syndrome patients - correlation with audiological results and proposal for computed tomography scans evaluation methodology.

OBJECTIVES: The aim was to describe the spectrum of inner ear malformations in CHARGE syndrome and propose a Computed Tomography (CT) detailed scan evaluation methodology. The secondary aim was to correlate the CT findings with hearing thresholds. METHODS: Twenty ears of ten patients diagnosed with CHARGE syndrome were subjected to CT analysis focusing on the inner ear and internal acoustic canal. The protocol used is presented in detail. ASSR results were analyzed and correlated with inner ear malformations. RESULTS: Cochlear hypoplasia type III was the most common malformation found in 12 ears (60%). Cochlear hypoplasia type II, aplasia with a dilated vestibule, and rudimentary otocyst were also identified. In 20%, no cochlear anomaly was found. The lateral Semicircular Canal (SCC) absence affected 100% of ears, the absence of the posterior SCC 95%, and the superior SCC 65%. Better development of cochlea structures and IAC correlated significantly with the lower hearing thresholds. CONCLUSION: This study demonstrated that rudimentary SCC or a complete absence of these SCCs was universally observed in all patients diagnosed with CHARGE syndrome. This finding supports the idea that inner ear anomalies are a hallmark feature of the CHARGE, contributing to its distinct clinical profile. The presence of inner ear malformations has substantial clinical implications. Audiological assessments are crucial for CHARGE syndrome, as hearing loss is common. Early detection of these malformations can guide appropriate interventions, such as hearing aids or cochlear implants, which may significantly improve developmental outcomes and communication for affected individuals. Recognizing inner ear malformations as a diagnostic criterion presents implications beyond clinical diagnosis. A better understanding of these malformations can advance the knowledge of CHARGE pathophysiology. It may also help guide future research into targeted therapies to mitigate the impact of inner ear anomalies on hearing and balance function.

Zebrafish neuromast sensory system: Is it an emerging target to assess environmental pollution impacts?

Environmental pollution poses risks to ecosystems. Among these risks, one finds neurotoxicity and damage to the lateral line structures of fish, such as the neuromast and its hair cells. Zebrafish (Danio rerio) is recommended as model species to be used in ecotoxicological studies and environmental biomonitoring programs aimed at assessing several biomarkers, such as ototoxicity. However, little is known about the history of and knowledge gaps on zebrafish ototoxicity. Thus, the aim of the current study is to review data available in the scientific literature about using zebrafish as animal model to assess neuromast toxicity. It must be done by analyzing the history and publication category, world production, experimental design, developmental stages, chemical classes, neuromasts and hair cell visualization methods, and zebrafish strains. Based on the results, number, survival and fluorescence intensity of neuromasts, and their hair cells, were the parameters oftentimes used to assess ototoxicity in zebrafish. The wild AB strain was the most used one, and it was followed by Tübingen and transgenic strains with GFP markers. DASPEI was the fluorescent dye most often applied as method to visualize neuromasts, and it was followed by Yo-Pro-1 and GFP transgenic lines. Antibiotics, antitumorals, metals, nanoparticles and plant extracts were the most frequent classes of chemicals used in the analyzed studies. Overall, pollutants can harm zebrafish's mechanosensory system, as well as affect their behavior and survival. Results have shown that zebrafish is a suitable model system to assess ototoxicity induced by environmental pollution.

Evaluation of inner ear damage by mastoid drilling with measurement of serum prestin (SLC26A5) levels

Abstract Objective The objective of this study is to demonstrate any inner ear injury caused by drilling in mastoid surgery with prestin, outer hair cell motor protein specific to the cochlea. Methods The patients with chronic otitis media requiring mastoidectomy (n= 21) and myringoplasty (n= 21) were included. Serum prestin level obtained from blood samples was measured before surgery and on postoperative days 0, 3, and 7 using Human Prestin (SLC26A5) ELISA Kit. All patients underwent the Pure Tone Audiometry (PTA) test before surgery and on the postoperative 7th day. The drilling time was also recorded for all patients who underwent mastoidectomy. Results In both mastoidectomy and myringoplasty groups, the postoperative serum prestin levels increased on days 0 and 7 (pday-0 = 0.002, pday-7 = 0.001 and pday-0 = 0.005, pday-7 = 0.001, respectively). There was no significant difference in the serum prestin levels between the two groups, postoperatively. The PTA thresholds at day 7 did not change in either group. A significant decline at 2000 Hz of bone conduction hearing threshold in both groups and a decline at 4000 Hz in the myringoplasty group were found. There was no correlation between the drilling time and the increase of prestin levels in the postoperative day 0, 3, and 7. Conclusion Our results showed that mastoid drilling is not related to a significant inner ear injury. Although the myringoplasty group was not exposed to drill trauma, there was a similar increase in serum prestin levels as the mastoidectomy group. Also, a significant decline at 2000 Hz of bone conduction hearing threshold in both groups and a decline at 4000 Hz in the myringoplasty group were found. These findings suggest that suction and ossicular manipulation trauma can lead to an increase in serum prestin levels and postoperative temporary or permanent SNHL at 2000 and 4000 Hz. Level of evidence: Level-4.

Detailed analysis of inner ear malformations in CHARGE syndrome patients - correlation with audiological results and proposal for computed tomography scans evaluation methodology

Abstract Objectives The aim was to describe the spectrum of inner ear malformations in CHARGE syndrome and propose a Computed Tomography (CT) detailed scan evaluation methodology. The secondary aim was to correlate the CT findings with hearing thresholds. Methods Twenty ears of ten patients diagnosed with CHARGE syndrome were subjected to CT analysis focusing on the inner ear and internal acoustic canal. The protocol used is presented in detail. ASSR results were analyzed and correlated with inner ear malformations. Results Cochlear hypoplasia type III was the most common malformation found in 12 ears (60%). Cochlear hypoplasia type II, aplasia with a dilated vestibule, and rudimentary otocyst were also identified. In 20%, no cochlear anomaly was found. The lateral Semicircular Canal (SCC) absence affected 100% of ears, the absence of the posterior SCC 95%, and the superior SCC 65%. Better development of cochlea structures and IAC correlated significantly with the lower hearing thresholds. Conclusion This study demonstrated that rudimentary SCC or a complete absence of these SCCs was universally observed in all patients diagnosed with CHARGE syndrome. This finding supports the idea that inner ear anomalies are a hallmark feature of the CHARGE, contributing to its distinct clinical profile. The presence of inner ear malformations has substantial clinical implications. Audiological assessments are crucial for CHARGE syndrome, as hearing loss is common. Early detection of these malformations can guide appropriate interventions, such as hearing aids or cochlear implants, which may significantly improve developmental outcomes and communication for affected individuals. Recognizing inner ear malformations as a diagnostic criterion presents implications beyond clinical diagnosis. A better understanding of these malformations can advance the knowledge of CHARGE pathophysiology. It may also help guide future research into targeted therapies to mitigate the impact of inner ear anomalies on hearing and balance function. Level of evidence: 4.

cAMP-Epac1 signaling is activated in DDAVP-induced endolymphatic hydrops of guinea pigs

Abstract Objective To explore whether Cyclic Adenosine Monophosphate (cAMP)-Epac1 signaling is activated in 1-Desamino-8-D-arginine-Vasopressin-induced Endolymphatic Hydrops (DDAVP-induced EH) and to provide new insight for further in-depth study of DDAVP-induced EH. Methods Eighteen healthy, red-eyed guinea pigs (36 ears) weighing 200-350 g were randomly divided into three groups: the control group, which received intraperitoneal injection of sterile saline (same volume as that in the other two groups) for 7 consecutive days; the DDAVP-7d group, which received intraperitoneal injection of 10 mg/mL/kg DDAVP for 7 consecutive days; and the DDAVP-14d group, which received intraperitoneal injection of 10 μg/mL/kg DDAVP for 14 consecutive days. After successful modeling, all animals were sacrificed, and cochlea tissues were collected to detect the mRNA and protein expression of the exchange protein directly activated by cAMP-1 and 2 (Epac1, Epac2), and Repressor Activator Protein-1 (Rap1) by Reverse Transcription (RT)-PCR and western blotting, respectively. Results Compared to the control group, the relative mRNA expression of Epac1, Epac2, Rap1A, and Rap1B in the cochlea tissue of the DDAVP-7d group was significantly higher (p< 0.05), while no significant difference in Rap1 GTPase activating protein (Rap1gap) mRNA expression was found between the two groups. The relative mRNA expression of Epac1, Rap1A, Rap1B, and Rap1gap in the cochlea tissue of the DDAVP-14d group was significantly higher than that of the control group (p< 0.05), while no significant difference in Epac2 mRNA expression was found between the DDAVP-14d and control groups. Comparison between the DDAVP-14d and DDAVP-7d groups showed that the DDAVP-14d group had significantly lower Epac2 and Rap1A (p< 0.05) and higher Rap1gap (p < 0.05) mRNA expression in the cochlea tissue than that of the DDAVP-7d group, while no significant differences in Epac1 and Rap1B mRNA expression were found between the two groups. Western blotting showed that Epac1 protein expression in the cochlea tissue was the highest in the DDAVP-14d group, followed by that in the DDAVP-7d group, and was the lowest in the control group, showing significant differences between groups (p< 0.05); Rap1 protein expression in the cochlea tissue was the highest in the DDAVP-7d group, followed by the DDAVP-14d group, and was the lowest in the control group, showing significant differences between groups (p< 0.05); no significant differences in Epac2 protein expression in the cochlea tissue were found among the three groups. Conclusion DDAVP upregulated Epac1 protein expression in the guinea pig cochlea, leading to activation of the inner ear cAMP-Epac1 signaling pathway. This may be an important mechanism by which DDAVP regulates endolymphatic metabolism to induce EH and affect inner ear function. Oxford Centre for Evidence-Based Medicine 2011 Levels of Evidence Level 5.

cAMP-Epac1 signaling is activated in DDAVP-induced endolymphatic hydrops of guinea pigs.

OBJECTIVE: To explore whether Cyclic Adenosine Monophosphate (cAMP)-Epac1 signaling is activated in 1-Desamino-8-D-arginine-Vasopressin-induced Endolymphatic Hydrops (DDAVP-induced EH) and to provide new insight for further in-depth study of DDAVP-induced EH. METHODS: Eighteen healthy, red-eyed guinea pigs (36 ears) weighing 200-350 g were randomly divided into three groups: the control group, which received intraperitoneal injection of sterile saline (same volume as that in the other two groups) for 7 consecutive days; the DDAVP-7d group, which received intraperitoneal injection of 10 mg/mL/kg DDAVP for 7 consecutive days; and the DDAVP-14d group, which received intraperitoneal injection of 10 µg/mL/kg DDAVP for 14 consecutive days. After successful modeling, all animals were sacrificed, and cochlea tissues were collected to detect the mRNA and protein expression of the exchange protein directly activated by cAMP-1 and 2 (Epac1, Epac2), and Repressor Activator Protein-1 (Rap1) by Reverse Transcription (RT)-PCR and western blotting, respectively. RESULTS: Compared to the control group, the relative mRNA expression of Epac1, Epac2, Rap1A, and Rap1B in the cochlea tissue of the DDAVP-7d group was significantly higher (p <  0.05), while no significant difference in Rap1 GTPase activating protein (Rap1gap) mRNA expression was found between the two groups. The relative mRNA expression of Epac1, Rap1A, Rap1B, and Rap1gap in the cochlea tissue of the DDAVP-14d group was significantly higher than that of the control group (p <  0.05), while no significant difference in Epac2 mRNA expression was found between the DDAVP-14d and control groups. Comparison between the DDAVP-14d and DDAVP-7d groups showed that the DDAVP-14d group had significantly lower Epac2 and Rap1A (p <  0.05) and higher Rap1gap (p < 0.05) mRNA expression in the cochlea tissue than that of the DDAVP-7d group, while no significant differences in Epac1 and Rap1B mRNA expression were found between the two groups. Western blotting showed that Epac1 protein expression in the cochlea tissue was the highest in the DDAVP-14d group, followed by that in the DDAVP-7d group, and was the lowest in the control group, showing significant differences between groups (p <  0.05); Rap1 protein expression in the cochlea tissue was the highest in the DDAVP-7d group, followed by the DDAVP-14d group, and was the lowest in the control group, showing significant differences between groups (p <  0.05); no significant differences in Epac2 protein expression in the cochlea tissue were found among the three groups. CONCLUSION: DDAVP upregulated Epac1 protein expression in the guinea pig cochlea, leading to activation of the inner ear cAMP-Epac1 signaling pathway. This may be an important mechanism by which DDAVP regulates endolymphatic metabolism to induce EH and affect inner ear function. OXFORD CENTRE FOR EVIDENCE-BASED MEDICINE 2011 LEVELS OF EVIDENCE: Level 5.

Audio-vestibular and radiological analysis in Meniere's disease

Abstract Objective: Intravenous gadolinium-enhanced inner ear magnetic resonance imaging (IV Gd-enhanced inner ear MRI) is a new technique for diagnosing Meniere's disease (MD). Vestibular tests have also long been used forMD, but which tests should be included in the oto-neurological test battery remains controversial. The evaluation method to be used to confirm the clinical diagnosis in MD is not clear. This study aimed to examine the results of vestibular tests and IV Gd-enhanced inner ear MRI in individuals diagnosed with unilateral definite Meniere's disease. Methods: IV Gd-enhanced inner ear MRI (Endolymphatic Hydrops [EH] and Perilymphatic Enhancement [PE]), conventional audiometry (0.25-8kHz), video Head Impulse Test (vHIT), cervical Vestibular Evoked Myogenic Potential (cVEMP), air caloric test, and dizziness handicap inventory were applied to 16 adult patients diagnosed with unilateral definite MD. Results: Among the patients with definite MD, EH (cochlear and/or vestibular) was identified in 93.7% and 68.7% of the symptomatic and the asymptomatic ears, respectively. There was a positive correlation between the hearing thresholds at 2, 4, 6 and 8 kHz and the degree of cochlear EH (p < 0.05). PE (cochlear and/or vestibular) was observed in 37.5% of the asymptomatic and symptomatic ears. The sensitivity of the vestibular test battery (vHIT, cVEMP, and caloric test) was 100% and its specificity was 50%, while the sensitivity of the IV Gd-enhanced inner ear MRI (EH and PE together) was 93.8% and the specificity was 81.3%. Conclusion: MRI had higher sensitivity and specificity than the vestibular test battery. PE or vHIT alone was not considered to be reliable in the diagnosis of MD. In suspected MD, the clinical history, hearing tests, and IV Gd-enhanced inner ear MRI are sufficient for diagnosis. If MRI technique is not possible, vestibular tests (caloric test and cVEMP, not vHIT) can provide reliable results when evaluated together.

Audio-vestibular and radiological analysis in Meniere's disease.

OBJECTIVE: Intravenous gadolinium-enhanced inner ear magnetic resonance imaging (IV Gd-enhanced inner ear MRI) is a new technique for diagnosing Meniere's disease (MD). Vestibular tests have also long been used for MD, but which tests should be included in the oto-neurological test battery remains controversial. The evaluation method to be used to confirm the clinical diagnosis in MD is not clear. This study aimed to examine the results of vestibular tests and IV Gd-enhanced inner ear MRI in individuals diagnosed with unilateral definite Meniere's disease. METHODS: IV Gd-enhanced inner ear MRI (Endolymphatic Hydrops [EH] and Perilymphatic Enhancement [PE]), conventional audiometry (0.25-8 kHz), video Head Impulse Test (vHIT), cervical Vestibular Evoked Myogenic Potential (cVEMP), air caloric test, and dizziness handicap inventory were applied to 16 adult patients diagnosed with unilateral definite MD. RESULTS: Among the patients with definite MD, EH (cochlear and/or vestibular) was identified in 93.7% and 68.7% of the symptomatic and the asymptomatic ears, respectively. There was a positive correlation between the hearing thresholds at 2, 4, 6 and 8 kHz and the degree of cochlear EH (p < 0.05). PE (cochlear and/or vestibular) was observed in 37.5% of the asymptomatic and symptomatic ears. The sensitivity of the vestibular test battery (vHIT, cVEMP, and caloric test) was 100% and its specificity was 50%, while the sensitivity of the IV Gd-enhanced inner ear MRI (EH and PE together) was 93.8% and the specificity was 81.3%. CONCLUSION: MRI had higher sensitivity and specificity than the vestibular test battery. PE or vHIT alone was not considered to be reliable in the diagnosis of MD. In suspected MD, the clinical history, hearing tests, and IV Gd-enhanced inner ear MRI are sufficient for diagnosis. If MRI technique is not possible, vestibular tests (caloric test and cVEMP, not vHIT) can provide reliable results when evaluated together.

Auditory and Vestibular Functioning in Individuals with Type-2 Diabetes Mellitus: A Systematic Review

Abstract Introduction Diabetes mellitus is a metabolic disease associated with a rise in the level of blood glucose. Individuals with diabetes mellitus are more likely to develop hearing loss, tinnitus, and dizziness due to macro- and microvascular complications. The extent to which auditory and vestibular functions are impaired in individuals with type-2 diabetes mellitus is still under debate. Objective To systematically review studies focusing on auditory and vestibular functions in individuals with type-2 diabetes mellitus. Data Synthesis A search was conducted in the PubMed, MedlinePlus, Ingenta Connect and Google Scholar databases for articles published until June 2019. A total of 15,980 articles were primarily retrieved, 33 of which were shortlisted based on the inclusion criteria set by the investigators for the systematic review. Out of 33 full-length articles, 26 evaluated the functioning of the auditory system, while 7 evaluated the functioning of the vestibular system. Most studies related to auditory functioning reported a significant effect of type-2 diabetes mellitus on the peripheral auditory system, whereas studies on vestibular functioning reported no significant effect of diabetes mellitus on the functioning of the peripheral vestibular end-organ. Conclusion Overall, the results of various audiological and peripheral vestibular tests reveal distinctive peripheral and/or central auditory and vestibular end-organ impairments in individuals with type-2 diabetes mellitus.

Pharmacological treatment with annexin A1-derived peptide protects against cisplatin-induced hearing loss.

Cisplatin is an antineoplastic agent widely used, and no effective treatments capable of preventing cisplatin-induced ototoxicity and neurotoxicity in humans have yet been identified. This study evaluated the effect of the anti-inflammatory annexin A1 (AnxA1)-derived peptide Ac2-26 in a cisplatin-induced ototoxicity model. Wistar rats received intraperitoneal injections of cisplatin (10 mg/kg/day) for 3 days to induce hearing loss, and Ac2-26 (1 mg/kg) was administered 15 min before cisplatin administration. Control animals received an equal volume of saline. Hearing thresholds were measured by distortion product otoacoustic emissions (DPOAE) before and after treatments. Pharmacological treatment with Ac2-26 protected against cisplatin-induced hearing loss, as evidenced by DPOAE results showing similar signal-noise ratios between the control and Ac2-26-treated groups. These otoprotective effects of Ac2-26 were associated with an increased number of ganglion neurons compared with the untreated cisplatin group. Additionally, Ac2-26 treatment produced reduced immunoreactivity on cleaved caspase 3 and phosphorylated ERK levels in the ganglion neurons, compared to the untreated group, supporting the neuroprotective effects of the Ac2-26. Our results suggest that Ac2-26 has a substantial otoprotective effect in this cisplatin-induced ototoxicity model mediated by neuroprotection and the regulation of the ERK pathway.

Auditory and Vestibular Functioning in Individuals with Type-2 Diabetes Mellitus: A Systematic Review.

Introduction Diabetes mellitus is a metabolic disease associated with a rise in the level of blood glucose. Individuals with diabetes mellitus are more likely to develop hearing loss, tinnitus, and dizziness due to macro- and microvascular complications. The extent to which auditory and vestibular functions are impaired in individuals with type-2 diabetes mellitus is still under debate. Objective To systematically review studies focusing on auditory and vestibular functions in individuals with type-2 diabetes mellitus. Data Synthesis A search was conducted in the PubMed, MedlinePlus, Ingenta Connect and Google Scholar databases for articles published until June 2019. A total of 15,980 articles were primarily retrieved, 33 of which were shortlisted based on the inclusion criteria set by the investigators for the systematic review. Out of 33 full-length articles, 26 evaluated the functioning of the auditory system, while 7 evaluated the functioning of the vestibular system. Most studies related to auditory functioning reported a significant effect of type-2 diabetes mellitus on the peripheral auditory system, whereas studies on vestibular functioning reported no significant effect of diabetes mellitus on the functioning of the peripheral vestibular end-organ. Conclusion Overall, the results of various audiological and peripheral vestibular tests reveal distinctive peripheral and/or central auditory and vestibular end-organ impairments in individuals with type-2 diabetes mellitus.

Otopathologic Abnormalities in CHARGE Syndrome.

OBJECTIVE: To perform an otopathologic analysis of temporal bones (TBs) with CHARGE syndrome. STUDY DESIGN: Otopathologic study of human TB specimens. SETTING: Otopathology laboratories. METHODS: From the otopathology laboratories at the University of Minnesota and Massachusetts Eye and Ear Infirmary, we selected TBs from donors with CHARGE syndrome. These TBs were serially sectioned at a thickness of 20 µm, and every 10th section was stained with hematoxylin and eosin. We performed otopathologic analyses of the external ear, middle ear (middle ear cleft, mucosal lining, ossicles, mastoid, and facial nerve), and inner ear (cochlea, vestibule, internal auditory canal, and cochlear and vestibular nerves). The gathered data were statistically analyzed. RESULTS: Our study included 12 TBs from 6 donors. We found a high prevalence of abnormalities affecting the ears. The most frequent findings were stapes malformation (100%), aberrant course of the facial nerve (100%) with narrow facial recess (50%), sclerotic and hypodeveloped mastoids (50%), cochlear (100%) and vestibular (83.3%) hypoplasia with aplasia of the semicircular canals, hypoplasia and aplasia of the cochlear (66.6%) and vestibular (91.6%) nerves, and narrowing of the bony canal of the cochlear nerve (66.6%). The number of spiral ganglion and Scarpa's ganglion neurons were decreased in all specimens (versus normative data). CONCLUSIONS: In our study, CHARGE syndrome was associated with multiple TB abnormalities that may severely affect audiovestibular function and rehabilitation.

Sordera neurosensorial congénita con malformación de oído interno ligada al X en una familia mexicana / Congenital sensorineural deafness X-linked, with inner ear malformation in a Mexican family

Introducción. Las sorderas o hipoacusias prelinguales son de etiología genética entre el 60 y el 68% de los casos; de estos, del 20 al 40% son malformaciones del oído interno. De los casos de hipoacusia no sindrómica ligada al X se han descrito siete tipos. De las malformaciones de oído interno, la partición coclear incompleta tipo III es la menos frecuente.Objetivo. Presentar el reporte clínico-genético de una familia mexicana, con indi-viduos varones afectados por sordera neurosensorial congénita con malformación de oído interno. Material y Métodos. Se realizó estudio de una familia en la que nueve miembros presentaban sordera. Se estudiaron cuatro de ellos y una madre sin manifestaciones, a través del estudio clínico general por médico genetista, el estudio audiológico (otos-copía y audiometría) por médico audiólogo y el estudio de tomografía computada (TC) por médico radiólogo.Resultados. Los pacientes estudiados presentaron sordera neurosensorial congéni-ta, de severa a profunda bilateral. A través de la TC, se evidenció malformación de oído interno. Tres pacientes presentaron partición coclear incompleta tipo III y un paciente partición incompleta tipo I. Debido al estudio clínico y al árbol genealógico, se definió diagnóstico de hipoacusia neurosensorial no sindrómica ligada al X. La TC de la madre sin manifestaciones no presentó evidencia de malformaciones en oído interno (MOI).Conclusión. El estudio de imagen es fundamental para definir presencia o no de MOI en todos los pacientes con hipoacusia y así poder guiar la terapéutica y el aseso-ramiento genético, así como realizar los estudios moleculares más adecuados

Introduction. The pre-lingual deafness or hearing loss are of genetic cause in be-tween 60% and 68% of cases, among these, between 20% and 40% are malforma-tion of the inner ear. From the non-syndromic hearing loss cases that are linked to the X chromosome, seven types have been described. Among these inner ear malforma-tions, incomplete cochlear partition type III is the less frequent.Objective. Present the clinical genetical report of a Mexican family, with male in-dividuals affected by congenital neurosensory deafness with inner ear malformation.Materials and methodology. A study on a family in which nine members were affected by deafness was done. Four of them, plus a mother without manifestation, were studied through a general clinical study by a geneticist, an audiological study (otoscopy and audiometry) by an audiologist, and a computed tomography (CT) scan by a radiologist.Results. The studied patients presented congenital neurosensory deafness, from se-vere to deep bilateral. Via the CT, the inner ear malformation was made clear. Three of the patients presented incomplete cochlear partition type III and one patient in-complete cochlear partition type I. Due to the clinical study and the family tree, it was diagnosed non-syndromic neurosensory deafness linked to X. The CT of the mother without manifestation did not show evidence of inner ear malformations.Conclusion. The study by image is fundamental to define whether there is or not a presence of inner ear malformations in any patient with heading loss to be able to guide the therapeutics and the genetic counseling, as well as to make more accurate molecular studies

Hearing loss genes reveal patterns of adaptive evolution at the coding and non-coding levels in mammals.

BACKGROUND: Mammals possess unique hearing capacities that differ significantly from those of the rest of the amniotes. In order to gain insights into the evolution of the mammalian inner ear, we aim to identify the set of genetic changes and the evolutionary forces that underlie this process. We hypothesize that genes that impair hearing when mutated in humans or in mice (hearing loss (HL) genes) must play important roles in the development and physiology of the inner ear and may have been targets of selective forces across the evolution of mammals. Additionally, we investigated if these HL genes underwent a human-specific evolutionary process that could underlie the evolution of phenotypic traits that characterize human hearing. RESULTS: We compiled a dataset of HL genes including non-syndromic deafness genes identified by genetic screenings in humans and mice. We found that many genes including those required for the normal function of the inner ear such as LOXHD1, TMC1, OTOF, CDH23, and PCDH15 show strong signatures of positive selection. We also found numerous noncoding accelerated regions in HL genes, and among them, we identified active transcriptional enhancers through functional enhancer assays in transgenic zebrafish. CONCLUSIONS: Our results indicate that the key inner ear genes and regulatory regions underwent adaptive evolution in the basal branch of mammals and along the human-specific branch, suggesting that they could have played an important role in the functional remodeling of the cochlea. Altogether, our data suggest that morphological and functional evolution could be attained through molecular changes affecting both coding and noncoding regulatory regions.

Disección anatómica del oído medio y el oído interno / Middle and inner ear anatomical dissection / Dissecção anatómica do ouvido médio e do ouvido interno

RESUMEN Introducción: El oído medio y el oído interno presentan una compleja constitución anatómica; La disección como método de enseñanza proporciona una comprensión óptima de la configuración tridimensional de sus estructuras debido a su carácter práctico y realista. Se propone un protocolo de disección aislada del oído medio e interno que ofrece una visión amplia de sus estructuras e incorpora esquemas didácticos. Metodología: En tres cadáveres humanos en estado de conservación se delimitaron dos cuadrángulos en la cara _ superior del hueso temporal mediante referentes anatómicos para extraer una estructura paralelepípeda correspondiente a la porción petrosa del hueso temporal, sobre la cual se realizó disección. Resultados: Se creó un protocolo de disección siguiendo esta secuencia: Extracción parcial de la porción petrosa del hueso temporal, visualización del oído medio, exposición de la membrana timpánica y visualización del oído interno. Conclusión: Esta herramienta pedagógica es aplicable al proceso de enseñanza y constituye un recurso cuyo carácter didáctico resulta potencialmente útil para los estudiantes facilitando el aprendizaje activo de los aspectos teóricos y prácticos del oído.

ABSTRACT Introduction: The middle and the inner ear have a complex anatomical constitution. As a traditional teaching method, the dissection provides an optimal knowledge of the three-dimensional configuration of its structures due to its practical and realistic qualities. It proposes a protocol of isolated dissection of the middle and the inner ear offering a broad vision of its structures and incorporates didactic schemes. Materials and Method: We delimited two quadrants in the upper face of the temporal bone of three conserved human corpses by employing anatomical referents to extract a parallelepiped structure that corresponds to the petrous portion of the temporal bone. On this portion, the dissection was performed. Results: we created a dissection protocol following this sequence: The petrous portion of the temporal bone partial removal, middle ear visualization, tympanic membrane exposure and inner ear visualization. Conclusion: This pedagogical instrument is applicable to the process of education and constitutes a resource whose didactic character results potentially useful for the students facilitating the active learning of the theoretical and practical issues of the ear anatomy

RESUMO Introdução: O ouvido médio e interior apresentam uma constituição anatómica complexa; a dissecação como método de ensino proporciona uma compreensão óptima da configuração tridimensional das suas estruturas devido ao seu carácter prático e realista. É proposto um protocolo de dissecção isolada do ouvido médio e interno, que oferece uma visão ampla das suas estruturas e incorpora diagramas didácticos. Metodologia: Em três cadáveres humanos conservados, dois quadrantes foram delimitados na face superior do osso temporal por meio de referências anatómicas, a fim de extrair uma estrutura paralelepipédica correspondente à porção petrosa do osso temporal, sobre a qual foi realizada a dissecação. Resultados: Foi criado um protocolo de dissecação seguindo esta sequência: extracção parcial da porção petrosa do osso temporal, visualização do ouvido médio, exposição da membrana timpánica e visualização do ouvido interno. Conclusão: Esta ferramenta pedagógica é aplicável ao processo de ensino e constitui um recurso cujo carácter didáctico é potencialmente útil para os estudantes, facilitando a aprendizagem activa dos aspectos teóricos e práticos do ouvido.

Cnr2 Is Important for Ribbon Synapse Maturation and Function in Hair Cells and Photoreceptors.

The role of the cannabinoid receptor 2 (CNR2) is still poorly described in sensory epithelia. We found strong cnr2 expression in hair cells (HCs) of the inner ear and the lateral line (LL), a superficial sensory structure in fish. Next, we demonstrated that sensory synapses in HCs were severely perturbed in larvae lacking cnr2. Appearance and distribution of presynaptic ribbons and calcium channels (Cav1.3) were profoundly altered in mutant animals. Clustering of membrane-associated guanylate kinase (MAGUK) in post-synaptic densities (PSDs) was also heavily affected, suggesting a role for cnr2 for maintaining the sensory synapse. Furthermore, vesicular trafficking in HCs was strongly perturbed suggesting a retrograde action of the endocannabinoid system (ECs) via cnr2 that was modulating HC mechanotransduction. We found similar perturbations in retinal ribbon synapses. Finally, we showed that larval swimming behaviors after sound and light stimulations were significantly different in mutant animals. Thus, we propose that cnr2 is critical for the processing of sensory information in the developing larva.