[Study on gene therapy for DPOAE and ABR threshold changes in adult Otof-/- mice].

Objective:This study aims to analyze the threshold changes in distortion product otoacoustic emissions（DPOAE） and auditory brainstem response（ABR） in adult Otof-/- mice before and after gene therapy, evaluating its effectiveness and exploring methods for assessing hearing recovery post-treatment. Methods:At the age of 4 weeks, adult Otof-/- mice received an inner ear injection of a therapeutic agent containing intein-mediated recombination of the OTOF gene, delivered via dual AAV vectors through the round window membrane（RWM）. Immunofluorescence staining assessed the proportion of inner ear hair cells with restored otoferlin expression and the number of synapses.Statistical analysis was performed to compare the DPOAE and ABR thresholds before and after the treatment. Results:AAV-PHP. eB demonstrates high transduction efficiency in inner ear hair cells. The therapeutic regimen corrected hearing loss in adult Otof-/- mice without impacting auditory function in wild-type mice. The changes in DPOAE and ABR thresholds after gene therapy are significantly correlated at 16 kHz. Post-treatment,a slight increase in DPOAE was observeds,followed by a recovery trend at 2 months post-treatment. Conclusion:Gene therapy significantly restored hearing in adult Otof-/- mice, though the surgical delivery may cause transient hearing damage. Precise and gentle surgical techniques are essential to maximize gene therapy's efficacy.

Analysis of the vestibular aqueduct development on the risk for suffering from idiopathic sudden sensorineural hearing loss.

OBJECTIVE: Large vestibular aqueduct syndrome (LVAS) is one of the etiology of hearing loss. Clinically, we observed that the VA size of patients with idiopathic sudden sensorineural hearing loss (ISSNHL) did not meet the diagnostic criteria of VA enlargement, but there were individual variations. Through this study, we want to understand the VA development and explore its risk for suffering from ISSNHL. METHODS: 74 patients with ISSNHL were retrospectively reviewed in our department from June 2018 to September 2021. Meanwhile, 57 people with no ear diseases were randomly selected as the control group. All their clinical information were systematically collected. The axial thin-slice CT images of temporal bone were used to observe and measure the VA in ISSNHL and controls. ISSNHL were classified as different types and grades according to pure tone audiometry and the degree of hearing loss, respectively. Logistic regression analysis was adopted to evaluate the risk factors of different types and grades of ISSNHL. RESULTS: The operculum morphology could be funnel-shaped, tubular and invisible, but they had no statistical difference in the morbidity of ISSNHL. The operculum width of the affected sides in the case group was significantly wider than that of the matched sides in the control group (0.84±0.35mm vs 0.68±0.34mm, p=0.009), but the midpoint width had no statistical difference (p=0.447). The operculum width was an independent risk factor for the total hearing loss type (p=0.036, OR=4.49, 95% CI=1.10-18.29), moderate (p=0.013, OR=17.62, 95% CI=1.82-170.95) and profound (p=0.031, OR=4.50, 95% CI=1.14-17.67) grade of ISSNHL. Hypertension was an independent risk factor for the severe grade (p=0.004, OR=12.44, 95% CI=2.19-70.64) of ISSNHL. Both the operculum width (p=0.048, OR=7.14, 95% CI=1.02-50.26) and hypertension (p=0.014, OR=6.73, 95% CI=1.46-30.97) were the risk factors for the flat type of ISSNHL. The midpoint width of the VA, gender, age, diabetes mellitus, hyperlipidemia, and plasma fibrinogen concentration had no significant effect on the risk for suffering from ISSNHL. CONCLUSION: The development of the VA operculum is a risk factor for some types and grades of ISSNHL. Hypertension remained a risk factor for ISSNHL.

Melatonin Attenuates Cisplatin-Induced Ototoxicity via Regulating the Cell Apoptosis of the Inner Ear.

Objective: The mechanism of ototoxicity caused by cisplatin is currently unclear, and the induced apoptosis may play an important role in inner ear injury. Melatonin has high antioxidant and antiapoptotic effects. This study is aimed at clarifying the protective effect on the inner ear and the underlying mechanism of melatonin. Design: The mice and HEI-OC1 cells were randomly separated into four groups: control group, cisplatin group, melatonin group, and cisplatin exposure after melatonin pretreatment group. Place and Duration of the Study. From September 2018 to September 2021, all experiments were completed at the Second Hospital of Shandong University. And the study was approved by the Ethics Committee of the Second Hospital of Shandong University (KYLL-2020 (KJ) A-0191). Methodology. Mice were pretreated with peritoneal injection of melatonin prior to the application of cisplatin. Auditory Brainstem Response (ABR) test was performed before and after treatment, then the temporal bones were collected for histology investigation. HEI-OC1 cells were pretreated with melatonin before adding cisplatin. The apoptosis of HEI-OC1 cells was observed by MTS, TUNEL, and flow cytometry, respectively. Moreover, the mRNA expression of apoptosis-related factors was detected by qRT-PCR. Results: ABR and morphological analysis showed that cisplatin caused damage to the function and structure of the inner ear. MTS, TUNEL, and flow cytometry showed that the application of cisplatin caused a significant increase in the apoptosis level of HEI-OC1 cells, and melatonin pretreatment reduced this damage. Moreover, melatonin pretreatment reversed the mRNA expression changes of apoptosis-related factors induced by cisplatin. Conclusions: Apoptosis is involved in the inner ear dysfunction caused by cisplatin. Melatonin reduces the ototoxicity of cisplatin by regulating the induced apoptosis response.

MiR-142-5p directly targets cyclin-dependent kinase 5-mediated upregulation of the inflammatory process in acquired middle ear cholesteatoma.

MicroRNAs (miRNAs) play important roles in the regulation of cell proliferation, differentiation, apoptosis, and inflammatory responses. MiR-142-5p is an important inflammation-associated miRNA, whose abnormal expression has been associated with a variety of inflammation-related diseases. However, the role and signaling pathways targeted by miR-142-5p in acquired middle ear cholesteatoma (AMEC) have not been fully elucidated. Cyclin-dependent kinase 5 (CDK5), a special member of the CDK family compared with classic cyclins that plays a critical role in the inflammatory response. In this study, we investigated the roles of miR-142-5p and CDK5 in inflammatory responses in AMEC. Our results revealed that the expression of miR-142-5p was significantly reduced in AMEC, and was negatively correlated with the expression of CDK5 (r=-0.5451). We also found that miR-142-5p can inhibit CDK5 expression by directly target 3' untranslated region (UTR) of CDK5. Additionally, our findings indicated that the increased expression of CDK5 induces the secretion of inflammatory cytokines. In order to further confirm the involvement of miR-142-5p in the regulation of the inflammatory response in AMEC through its inhibitory effect on CDK5 expression, we studied the inflammatory response in HaCaT cells transfected with small interfering RNA against CDK5 (si-CDK5) and a miR-142-5p inhibitor. The results confirmed that miR-142-5p regulates the inflammatory response in AMEC by downregulating CDK5. In summary, miR-142-5p directly inhibits the CDK5-mediated upregulation of inflammatory cytokines in AMEC, which makes it a potential therapeutic target in this disease.

TFIIB-related factor 2 regulates glucose-regulated protein 78 expression in acquired middle ear cholesteatoma.

Acquired middle ear cholesteatoma leads to hearing loss, ear discharge, ear pain, and more serious intracranial complications. However, there is still no effective treatment other than surgery. TFIIB-related factor 2 (BRF2) acted as a redox sensor overexpressing in oxidative stress which linked endoplasmic reticulum (ER) stress, while glucose-regulated protein 78 (GRP78) was a biomarker of ER stress in cancer, atherosclerosis and inflammation. In our study, we investigated the roles of BRF2 and GRP78 in acquired middle ear cholesteatoma. Our results revealed that the expression of BRF2 was significant increased in acquired middle ear cholesteatoma, and which was positively correlated with the expression of GRP78. In addition, BRF2 and GRP78 showed colocalization in epithelium of acquired middle ear cholesteatomas and HaCaT cells. Prolongation of LPS stimulation in HaCaT cells escalated the expression of BRF2 and GRP78. To confirm the role of BRF2 and GRP78, we transfected si-BRF2 into HaCaT cells. All results indicated that BRF2 expression positively regulates the expression of GRP78 and may participate in the pathogenesis of acquire middle ear cholesteatoma.

Analysis of the developmental trajectory and influencing factors of auditory and speech functions after cochlear implantation in Mandarin Chinese speaking children.

Background: The auditory and speech development of the children with cochlear implants (CIs) are influenced by many factors.Objective: To study the developmental trajectory and influencing factors of auditory and speech functions for the Mandarin Chinese speaking children with CIs.Material and methods: The children with CIs undergoing rehabilitation in the same institution from June 2016 to June 2019 were followed up. Their closed monosyllables and disyllables recognition rate, closed average language age, categories of auditory performance (CAP) and speech intelligibility rating (SIR) were evaluated at 0, 1, 3, 6, 12 and 24 months of rehabilitation. The results were analyzed by SPSS 23.0.Results: 49 children were followed up for 1 year, 29 children for 2 years. The evaluated indicators of auditory and speech functions were improved with the prolongation of rehabilitation and influenced by the age of cochlear implantation, the use of hearing aids before surgery, guardian's educational degree, the relationship between guardian and child.Conclusions and significance: The auditory and speech functions of the children with CIs were improved significantly with the prolongation of rehabilitation and influenced by many factors, which can help us to predict the effect of CI more accurately and develop an individualized rehabilitation program.

The variation of superior semicircular canal bone thickness in relation to age and gender.

BACKGROUND: Superior semicircular canal dehiscence syndrome (SSCD) is a current diagnosis that is due to a loss of bone covering the superior semicircular canal (SSC). This results in pressure-/sound- induced vertigo and oscillopsia. OBJECTIVE: To find the variation of the thickness of the bone that covers the Superior Semicircular Canal with relation to age and gender among the Chinese descents. MATERIALS AND METHODS: Three hundred and eleven temporal bone Cone Beam Computed Tomography (CBCT) images of patients who attended Otology clinic at Second Hospital of Shandong University from January, 2017 to April, 2018 were retrospectively studied. The images were reconstructed in the line of Poschl and the thinnest area of the bone covering the SSC was taken. RESULTS: We included 172 (55.31%) females and 139 (44.69%) males. Mean age was 41 years. Overall mean difference in thickness was found to be -0.0210. There was no significant difference between the female and male bone thickness (p = .7113). With age the mean difference was 0.0801 (p = .1557) which was not statistically significant. CONCLUSION AND SIGNIFICANCE: There was no significant change in bone thickness with advancing age. CBCT is the best method of assessing SSCD.

Comparison of electrode position between round window and cochleostomy inserting approaches among young children: a cone-beam computed tomography study.

BACKGROUND: As the two most commonly used approaches for cochlear implants (CIs), the round-window insertion (RWI) and cochleostomy are still controversial about which approach is optimal. The lack of visual observation methods makes it difficult to compare the electrode position between them. OBJECTIVES: To evaluate and compare the electrode position between RWI and cochleostomy approaches for CI among young children. MATERIALS AND METHODS: Twenty-four patients (16 male, 8 female) accepting CI and temporal cone-beam computed tomography (CBCT) scan post-operation in our hospital from January 2016 to July 2017 were analyzed retrospectively. Operative notes and images were used to identify the surgical technique. Mainly depending on the round-window exposure, 15 cochleae were performed with RWI and 11 performed with cochleostomy. RESULTS: Mean age, 2.4 (range 0.8-7) years. The CBCT images showed that all the electrode arrays were located in scala tympani. There were no significantly statistical differences in the distance between electrode contacts and modiolus (EMI), intracochlear insertion length and the angle of electrode arrays at the insertion site of the cochlea. CONCLUSIONS AND SIGNIFICANCE: Both approaches could insert electrodes into scala tympani satisfactorily. As electrodes and cochlear structures could be clearly visualized, CBCT can be applied to assess the electrode position reliably.