Le Xie

Rationale: Semicircular canal occlusion (SCO) is used to treat vestibular vertigo with demonstrated efficacy. This study introduces a novel transcanal endoscopic approach for horizontal SCO to manage vertigo in refractory Meniere’s disease (MD). Patient concerns: Four patients with refractory MD, previously managed conservatively for over 6 months, presented with severe-to-profound hearing loss. Their vertigo symptoms progressively worsened and severely compromised quality of life. Diagnoses: All 4 patients met diagnostic criteria for definite MD with severe-to-profound hearing loss. Interventions: All patients underwent transcanal endoscopic horizontal SCO with a 12-month postoperative follow-up to evaluate clinical outcomes and procedural safety. Outcomes: Postoperative vertigo control was effective, demonstrating significant reductions in both attack frequency and symptom intensity. Subjective tinnitus improved in 1 patient and remained stable in the remaining 3. Hearing thresholds were preserved in all cases without progression. Transient postoperative disequilibrium occurred in 1 patient, resolving spontaneously without complications. Lessons: Transcanal endoscopic horizontal SCO represents a safe, effective, and clinically viable alternative to pharmacologic conservative management for refractory MD with severe-to-profound hearing loss persisting beyond 6 months.

Objectives: In recent years, ear endoscopy has gradually become an important tool in ear surgery. This study further explored its application in ear surgery, to establish a surgical approach for semicircular canal obstruction (SOC) via the ear canal to control vertigo in Meniere's disease. Methods: With the approval of the ethics committee, recruitment started in June 2019. ​Four patients with Meniere's disease who had been treated conservatively for more than six months received SCO via an external ear canal approach under otoendoscopy and were followed for two years after surgery to assess the safety and efficacy of the procedure. Results The control of vertigo after the operation was satisfactory (100%), and the frequency and degree of vertigo were significantly improved. Tinnitus improved in 1 case (25%) and did not progress in the other 3 cases. Hearing loss did not progress in all patients. Postoperative walking instability occurred in 1 patient (25%), and there were no obvious complications. All patients reported significant improvements in their quality of life. Conclusions: SCO via the external auditory canal approach is safe, effective, easy to accept, and an alternative to conservative treatment of Meniere's disease with no actual hearing for more than 6 months.

GJB2 gene mutations are the most common causes of autosomal recessive non-syndromic hereditary deafness. For individuals suffering from severe to profound GJB2-related deafness, cochlear implants have emerged as the sole remedy for auditory improvement. Some previous studies have highlighted the crucial role of preserving cochlear neural components in achieving favorable outcomes after cochlear implantation. Thus, we generated a conditional knockout mouse model (Cx26-CKO) in which Cx26 was completely deleted in the cochlear supporting cells driven by the Sox2 promoter. The Cx26-CKO mice showed severe hearing loss and massive loss of hair cells and Deiter’s cells, which represented the extreme form of human deafness caused by GJB2 gene mutations. In addition, multiple pathological changes in the peripheral auditory nervous system were found, including abnormal innervation, demyelination, and degeneration of spiral ganglion neurons as well as disruption of heminodes in Cx26-CKO mice. These findings provide invaluable insights into the deafness mechanism and the treatment for severe deafness in Cx26-null mice.

Mutations in the GJB2 gene encoding connexin26 (Cx26) protein are one of the most common causes of hereditary deafness. Previous studies have found that different Cx26-null mouse models have severe hearing loss and deformity of the organ of Corti (OC) as well as a reduction in microtubules in pillar cells (PCs). To explore the underlying mechanism of OC deformity caused by Cx26 downregulation further, we established Cx26 knockdown (KD) mouse models at postnatal days (P)0 and P8. The actin filaments contained in the pillar cells of mice in the P0 KD group were reduced by 54.85% and vinculin was increased by 22%, while the outer hair cells (OHCs) showed normal F-actin content. In the P8 KD group, PCs and OHCs of mice also showed almost normal F-actin content. The G-actin/F-actin ratio increased by 38% in the P0 KD group. No significant change was found in the mRNA or protein expression level of G-actin or the cadherin–catenin core complex in the P0 KD group at P6. Moreover, immunofluorescence showed that the intensity of LRRK2 was reduced by 97% in the P0 KD group at P6. Our results indicate that Cx26 is involved in the maturation of the cytoskeleton during the development of the OC at the early postnatal stage. The polymerization of G-actin into F-actin is prevented in Cx26 KD mice.

Auditory neuropathy spectrum disorder (ANSD), also called auditory neuropathy (AN), is a unique type of prelingual hearing impairment. Up to 10% of deaf infants and children are affected by this disease. Mutation of the OTOF gene which encodes otoferlin is the common cause of congenital nonsyndromic ANSD. To date, over 110 mutations have been identified in the OTOF gene according to the Human Gene Mutation Database (HGMD). Here, next-generation sequencing (NGS) revealed that the compound heterozygous mutations c.4748G>A/c.2523+1G>T and c.5248G>C/c.5098G>C of the OTOF gene were present in two Chinese ANSD patients. Each patient had a known pathogenic mutation (c.4748G>A or c.5098G>C) and a novel mutation (c.2523+1G>T or c.5248G>C). Comparative amino acid sequence analysis across different species revealed that the residues at these novel mutation sites are evolutionarily highly conservative. This indicated that the novel mutations were possible causes of the disorder in the patients. Our findings extend the OTOF mutation spectrum and further confirm the role of the OTOF gene in ANSD.

Mutations in the GJB2 gene (which encodes Connexin26 (Cx26)) account for about a quarter of all cases of non-syndromic deafness. Previous studies have indicated that knockout (KO) of Gjb2 gene during early postnatal days can cause outer hair cell (OHC) loss in mouse models. However, the postnatal spatial distribution pattern of Cx26 in different types of supporting cells (SCs) and the role of such distributions for the survival of OHCs is still obscure. In this study, the spatial distribution patterns of Cx26 in SCs were observed, and based on these observations different spatial Cx26-null mouse models were established in order to determine the effect of changes in the spatial distribution of Cx26 in SCs on the survival of OHCs. At postnatal day (P)3, unlike the synchronous expression of Cx26 along both longitudinal and radial boundaries of most types of SCs, Cx26 expression was primarily observed along the longitudinal boundaries of rows of Deiter’s cells (DCs). From P5 to P7, radial expression of Cx26 was gradually observed between adjacent rows of DCs. When Gjb2 gene was knocked out at random in different types of SCs, about 40% of the total DCs lost Cx26 expression and these Cx26-null DCs were distributed randomly in all three rows of DCs. The mice in this randomly Cx26-null group showed normal hearing and no significant OHC loss. When using a longitudinal KO pattern to induce knockout of Gjb2 gene specifically in the third row of DCs, about 33% of the total DCs lost Cx26 expression in this specific longitudinally Cx26-null group. The mice in this group showed late-onset hearing loss and significant OHC loss, however, the morphology of corresponding DCs was slightly altered. In both experimental groups, no substantial DC loss was observed. These results indicate that longitudinal Cx26-based channels are predominant in DCs during P3–P5. The Cx26 expression along rows of DCs might play a key role in the survival of OHCs, but this longitudinal KO pattern in DCs has a limited effect on DC survival or on its postnatal development.

We have synthesized hollow mesoporous silica (HMS) at a zeolitic imidazolate framework (ZIF) capsule that can be used as a drug delivery system for gentamicin (GM). The GM is first loaded into HMS. Then, the outer surface of the GM/HMS is coated with uniformed ZIF nanoparticles (denoted as GM/HMS@ZIF). The GM/HMS@ZIF has been successfully prepared and acts as a capsule for GM. The GM/HMS@ZIF shows a good biocompatibility and a good cellular uptake in House Ear Institute-Organ of Corti 1 (HEI-OC1) cells. The GM is released slowly within 10 h under acidic conditions, which is used to simulate the pH of the endosome and lysosome compartments. The in vivo assay shows that the signal from fluorescein isothiocyanate (FITC) can be observed after 15 days, when the mice were injected with FITC/HMS@ZIF. This opens new opportunities to construct a delivery system for GM via one controlled low dose and sustained release for the therapy of Ménière’s disease.

Mutations in the GJB2 gene [which encodes connexin 26 (Cx26)] are the most common causes of hereditary hearing loss in humans, and previous studies showed postnatal development arrest of the organ of Corti in different Cx26-null mouse models. To explore the pathological changes and the mechanism behind the cochlear abnormalities in these mice further, we established transgenic mouse models by conditional knockdown of cochlear Cx26 at postnatal day (P) 0 and P8. Auditory brainstem responses were recorded and the morphological features in the organ of Corti were analyzed 18 days after Cx26 knockdown. Mice in the P0 knockdown group displayed severe hearing loss at all frequencies, whereas mice in the P8 knockdown group showed nearly normal hearing. In the P8 knockdown group, the organ of Corti displayed normal architecture, and no ultrastructural changes were observed. In the P0 knockdown group, the phalangeal processes of Deiter9s cells did not develop into finger-like structures, and the formation of microtubules in the pillar cells was significantly reduced; moreover, the amount of acetylated α-tubulin was reduced in pillar cells. Our results indicate that Gjb2 participates in postnatal development of the cytoskeleton in pillar cells during structural maturation of the organ of Corti. In P0 knockdown mice, the reduction in microtubules in pillar cells might be responsible for the failure of the tunnel of Corti to open, and the malformed phalangeal processes might negatively affect the supporting framework of the organ of Corti, which would be a new mechanism of Gjb2-related hearing loss.

Connexin26 (Cx26, encoded by GJB2) mutations are the most common cause of non-syndromic deafness. GJB2 is thought to be involved in noise-induced hearing loss (NIHL). However, the role of Cx26 in NIHL is still obscure. To explore the association between Cx26 and NIHL, we established a Cx26 knockdown (KD) mouse model by conditional knockdown of Cx26 at postnatal day 18 (P18), and then we observed the auditory threshold and morphologic changes in these mice with or without noise exposure. The Cx26 KD mice did not exhibit substantial hearing loss and hair cell degeneration, while the Cx26 KD mice with acoustic trauma experienced higher hearing loss than simple noise exposure siblings and nearly had no recovery. Additionally, extensive outer hair cell loss and more severe destruction of the basal organ of Corti were observed in Cx26 KD mice after noise exposure. These data indicate that reduced Cx26 expression in the mature mouse cochlea may increase susceptibility to noise-induced hearing loss and facilitate the cell degeneration in the organ of Corti.