Yaodong Xu

Activation of miR-34a/SIRT1/p53 signaling contributes to cochlear hair cell apoptosis: implications for age-related hearing loss

The molecular mechanisms underlying age-related hearing loss are not fully understood, and currently, there is no treatment for this disorder. MicroRNAs have recently been reported to be increasingly associated with age-related diseases and are emerging as promising therapeutic targets. In this study, miR-34a/Sirtuin 1 (SIRT1)/p53 signaling was examined in cochlear hair cells during aging. MiR-34a, p53 acetylation, and apoptosis increased in the cochlea of C57BL/6 mice with aging, whereas an age-related decrease in SIRT1 was observed. In the inner ear HEI-OC1 cell line, miR-34a overexpression inhibited SIRT1, leading to an increase in p53 acetylation and apoptosis. Moreover, miR-34a knockdown increased SIRT1 expression and diminished p53 acetylation, and apoptosis. Additionally, resveratrol, an activator of SIRT1, significantly rescued miR-34a overexpression-induced HEI-OC1 cell death and significantly reduced hearing threshold shifts and hair cell loss in C57BL/6 mice after a 2-month administration. Our results support a link between age-related cochlear hair cell apoptosis and miR-34a/SIRT1/p53 signaling, which may serve as a potential target for age-related hearing loss treatment.

SIRT1 expression in the cochlea and auditory cortex of a mouse model of age-related hearing loss.

SIRT1 is a highly conserved NAD(+)-dependent protein deacetylase known to have protective effects against a variety of age-related diseases. However, there is a lack of information concerning SIRT1 expression in the cochlea and auditory cortex of C57BL/6 mice, a mouse model of age-related hearing loss. Using RT-PCR and immunohistochemistry, we show that SIRT1 is abundantly expressed in the inner hair cells, strial marginal cells, strial intermediate cells, type I and type IV fibrocytes of the spiral ligament and spiral ganglion neurons. In addition, moderate SIRT1 is also detected in the outer hair cells and neurons of the auditory cortex. Associated with elevated hearing thresholds and hair cells loss during aging, there is also a significant reduction of SIRT1 expression in the cochlea and auditory cortex. The expression pattern of SIRT1 in the peripheral and central auditory system suggests that SIRT1 may play an important role in auditory function and therefore may serve as a protective molecule against age-related hearing loss.

The Treatment for Postirradiation Otitis Media With Effusion: A Study of Three Methods

Objective: To explore treatments for postirradiation otitis media with effusion (OME) in patients with nasopharyngeal carcinoma.

Circulating miR-34a levels correlate with age-related hearing loss in mice and humans.

Age-related hearing loss (AHL) is a progressive neurodegenerative disease that is largely silent in its initial stages. There is no sensitive blood biomarker for diagnosis or early detection of AHL. MicroRNAs (miRNAs or miRs) are abundant and highly stable in blood, and have been recently described as powerful circulating biomarkers in a wide range of diseases. In the present study, we identified concordant increases in miR-34a levels in the cochlea, auditory cortex, and plasma of C57BL/6 mice during aging. These increases were accompanied by elevated hearing thresholds and greater loss of hair cells. Levels of miR-34a targets, silent information regulator 1 (SIRT1), B-cell lymphoma-2 (Bcl-2), and E2F transcription factor 3 (E2F3), in the cochlea, auditory cortex, and plasma decreased with aging inversely to miR-34a. Moreover, plasma miR-34a levels were significantly higher in patients with AHL compared with controls who had normal hearing and had a receiver-operating characteristic curve that distinguished AHL patients from controls. However, SIRT1, Bcl-2, and E2F3 showed no correlation with AHL in humans. In summary, circulating miR-34a level may potentially serve as a useful biomarker for early detection of AHL.

Surgical treatment of osteoradionecrosis of the temporal bone in patients with nasopharyngeal carcinoma.

OBJECTIVE To investigate methods of treating diffuse osteoradionecrosis of the temporal bone in cases of nasopharyngeal carcinoma, following radiotherapy. STUDY DESIGN Retrospective. METHODS Fourteen post-irradiation nasopharyngeal carcinoma patients (n = 14 ears) with diffuse osteoradionecrosis received surgical treatment from March 1994 to May 2005. The patients underwent radical mastoidectomy (five ears), extensive radical mastoidectomy (one ear), or radical mastoidectomy and obliteration with local vascularised fascia flaps (eight ears). RESULTS Six ears fully recovered; two ears were still infectious but sequestrum had not re-formed; five ears (50 per cent) still had repeated suppuration and did not epithelialise; and one ear had local re-formation of sequestrum requiring periodic dressing changes. CONCLUSION Diffuse osteoradionecrosis of the temporal bone following radiotherapy for nasopharyngeal carcinoma is difficult to treat surgically. The main objective of surgery is to facilitate drainage and to prevent complications. Radical mastoidectomy and obliteration with local vascularised flaps is an effective method.

Hypoxia-Inducible Factor and Vascular Endothelial Growth Factor Pathway for the Study of Hypoxia in a New Model of Otitis Media with Effusion

The hypoxia-inducible factor and vascular endothelial growth factor (HIF-VEGF) pathway in hypoxic conditions of the middle ear due to dysfunction of the eustachian tube is still unknown, but it is considered as one pathogenetic mechanism in otitis media. This study was designed to investigate the possible involvement of the HIF-VEFG pathway in otitis media with effusion induced by dysfunction of the eustachian tube. We adopted a soft palate approach to obstruct the orifice of the eustachian tube to establish otitis media in a rat model. Auditory evoked brainstem response and tympanometry were used as hearing function tests, hypoxia-related factors were examined by reverse transcriptase polymerase chain reaction (RT-PCR). The expression of hypoxia-related proteins was detected by Western blot and immunostaining. The model of otitis media with effusion was successfully induced by cauterizing the orifice of the eustachian tube. RT-PCR showed up-regulation of hypoxia-related factors in cauterized ears. Western blot and immunostaining showed that the expression of hypoxia-related proteins in cauterized ears was increased. Hypoxia-induced vascular proliferation and an increase in permeability may be one pathogenetic mechanism of otitis media due to dysfunction of the eustachian tube.

Endoscope-assisted partial-superficial parotidectomy through two small skin incisions.

Conclusion. Endoscope-assisted partial-superficial parotidectomy is a feasible method for treatment of benign parotid superficial lobe tumors located at the anterior or the inferior of the auricular lobule. The main advantage of this procedure is that the small operative scar resulted in improved cosmetic results. Objectives. This study evaluated the feasibility of endoscope-assisted partial parotidectomy through two small skin incisions. Patients and methods. Thirty cases with benign parotid superficial lobe tumors with a diameter < 30 mm located at the anterior or the inferior of the auricular lobule underwent endoscope-assisted partial-superficial parotidectomy via retrograde approach through two small skin incisions. Results. All 30 operations were successfully performed endoscopically. All the patients were satisfied with the cosmetic results. Only three patients had transient facial paresis and recovered in 1–2 months. The endoscopic surgery lasted for 106.48±12.62 min. There was no tumor recurrence during the follow-up after 26–50 months.

Effect of the combination of balloon Eustachian tuboplasty and tympanic paracentesis on intractable chronic otitis media with effusion

OBJECTIVE To evaluate the effect of the combination of balloon Eustachian tuboplasty (BET) and tympanic paracentesis (TP) on intractable chronic otitis media with effusion (COME). METHODS Ninety patients with intractable COME were included and randomly assigned to three groups: BET only (30 patients), BET+paracentesis (30 patients), and paracentesis only (30 patients). Otic endoscopic findings and tympanograms were recorded before the surgery and at the month 1, month 3, and month 6 follow-up evaluations. RESULTS Both the BET only and BET+paracentesis groups achieved better outcomes than the paracentesis group. The BET+paracentesis group exhibited better otic endoscopic scores than the BET only group (p<0.05) at 1month post-operation. However, no significant difference was found at month 3 or month 6 post-operation. No significant difference in the tympanograms was observed between these two groups at month 1, month 3, or month 6 post-operation. The otic endoscopic sign scores improved from month 1 to month 6 in the BET only group and from month 1 to month 3 in the BET+paracentesis group. The conversion of type B tympanograms improved from month 1 to month 6 in the BET and BET+paracentesis groups but not in the paracentesis only group. CONCLUSIONS Our results suggested that the combination of BET and TP was effective for intractable COME and can help shorten the recovery period for middle ear effusion.

Surgical treatment of monostotic fibrous dysplasia of the temporal bone: a retrospective analysis.

OBJECTIVE The aim of this study was to analyze the therapeutic effect of external auditory canal stenosis caused by monostotic fibrous dysplasia of the temporal bone by operation. METHODS Seven patients who were finally diagnosed as having monostotic fibrous dysplasia of the temporal bone by temporal bone high-resolution computed tomography (CT) and pathological diagnosis after operation underwent surgical reconstruction of the external auditory canal. The follow-up lasted 2 to 6 years, and it included pure-tone audiometry otoendoscopy, and high-resolution CT of the temporal bone. The hearing recovery and formed external auditory meatus results were retrospectively analyzed. The data were obtained from the Department of Otolaryngology in Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, from April 2003 to September 2008. RESULTS We found 4 ears with combined external auditory canal cholesteatoma intraoperative. The mean pure-tone audiometries (0.5, 1, 2 kHz) and the air-bone gaps for all patients improved after 6 months postoperation. The result was statistically significant. The average air-bone gap was improved, and the external auditory canal restenosis appeared in 1 patient after 4 years. Reconstruction of the external auditory canal was performed in this patient, and no restenosis was found in subsequent 2-year follow-up. All cases were reviewed with CT and otoendoscopy to observe the results and lesion extent, and we found that the lesion was basically stable without significant progress to the periphery major structure. CONCLUSION The monostotic fibrous dysplasia of the temporal bone and its causative external auditory meatus stenosis must be treated as early as possible to recover its patency of external auditory canal to prevent complicated cholesteatoma. Satisfaction results can be obtained from surgical reconstruction of the external auditory canal. We can excise the pathological change of the external auditory canal simply to restore auditory function and eliminate clinical symptoms such as earache, ear muffled sense, and so on. Because the development of lesions was slow during the follow-up, the complete resection of all lesions was not necessary, the external auditory canal restenosis may be operated again, and the prognosis was optimistic.

Cholesterol Granuloma of the Middle Ear in Post-Irradiated Nasopharyngeal Carcinoma Patients

Background/Aims: To evaluate the surgical outcome of tympanoplasty with mastoidectomy for cholesterol granuloma of the middle ear in post-irradiated patients with nasopharyngeal carcinoma (NPC). Methods: Nine post-irradiated NPC patients diagnosed with cholesterol granuloma in a single-sided middle ear were included in this study. The time from radiotherapy termination to surgery ranged from 6 to 14 years (median 9 years). All patients underwent radical tympanoplasty with canal wall down or up mastoidectomy. Results: All the patients with NPC received radiotherapy of 68–75 Gy before surgery. Three ears underwent tympanoplasty with canal wall down mastoidectomy, and 6 ears underwent tympanoplasty with canal wall up mastoidectomy. All the patients were followed up for at least 2 years. Seven ears (77.8%) had an intact tympanic membrane and 2 ears developed re-perforation of the eardrum 3 months after surgery, but otorrhea decreased significantly. All these patients reported improved quality of life after surgery. Before the operation, the pure tone averages (0.25, 0.5, 1, 2 kHz) were 90.5 dB and the air-bone gaps (0.5, 1, 2 kHz) were 45.8 dB (vs. 62.3 and 25.5 dB, respectively, at 6 months after the operation). Conclusions: Most post-irradiated NPC patients with cholesterol granuloma of the middle ear benefit from this surgery. Chronic otitis media caused by radiotherapy is not a contraindication to tympanoplasty.