Hao Xiong

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.

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.

The Diagnostic Value of Narrow-Band Imaging for the Detection of Nasopharyngeal Carcinoma

Objectives: To evaluate the diagnostic value of narrow-band imaging (NBI) for the detection of nasopharyngeal carcinoma (NPC). Study Design: Prospective study. Setting: Tertiary medical center. Subjects and Methods: Between December 2009 and June 2010, a total of 1,854 patients were examined by means of an electronic nasopharyngolaryngoscope equipped with conventional white light (WL) and an NBI system. The sensitivity, specificity and positive/negative predictive values for detecting NPC were calculated and compared. Results: Of these patients, 62 cases (3.34%) were pathologically confirmed as NPC. The sensitivity, specificity, positive predictive value and negative predictive value for detecting NPC significantly increased from 90.3, 75.4, 11.3 and 99.6% with WL up to 100, 99.2, 81.6 and 100% with NBI, respectively. Conclusion: Our findings suggested that NBI endoscopy might serve as an ideal tool in the detection of NPC.

The characteristic and changes of the event-related potentials (ERP) and brain topographic maps before and after treatment with rTMS in subjective tinnitus patients.

Objectives To compare the event-related potentials (ERPs) and brain topographic maps characteristic and change in normal controls and subjective tinnitus patients before and after repetitive transcranial magnetic stimulation (rTMS) treatment. Methods and Participants The ERPs and brain topographic maps elicited by target stimulus were compared before and after 1-week treatment with rTMS in 20 subjective tinnitus patients and 16 healthy controls. Results Before rTMS, target stimulus elicited a larger N1 component than the standard stimuli (repeating sounds)in control group but not in tinnitus patients. Instead, the tinnitus group pre-treatment exhibited larger amplitude of N1 in response to standard stimuli than to deviant stimuli. Furthermore tinnitus patients had smaller mismatch negativity (MMN) and late discriminative negativity (LDN)component at Fz compared with the control group. After rTMS treatment, tinnitus patients showed increased N1 response to deviant stimuli and larger MMN and LDN compared with pre-treatment. The topographic maps for the tinnitus group before rTMS -treatment demonstrated global asymmetry between the left and right cerebral hemispheres with more negative activities in left side and more positive activities in right side. In contrast, the brain topographic maps for patients after rTMS-treatment and controls seem roughly symmetrical. The ERP amplitudes and brain topographic maps in post-treatment patient group showed no significant difference with those in controls. Conclusions The characterical changes in ERP and brain topographic maps in tinnitus patients maybe related with the electrophysiological mechanism of tinnitus induction and development. It can be used as an objective biomarker for the evaluation of auditory central in subjective tinnitus patients. These findings support the notion that rTMS treatment in tinnitus patients may exert a beneficial effect.

Efficacy of balloon dilation in the treatment of symptomatic Eustachian tube dysfunction: One year follow-up study

PURPOSEnEustachian tube balloon dilation (ETBD) has been recently described as feasible treatment for patients with refractory Eustachian tube dysfunction (ETD). The aim of this study was to evaluate the efficacy of ETBD in the treatment of symptomatic Eustachian tube dysfunction (SETD) by subjective and objective analysis.nnnMATERIALS AND METHODSnForty patients who underwent ETBD were included in the study. Subjects inclusion criteria were as follows: symptoms of ETD (aural fullness predominantly, with or without otalgia, muffle hearing and tinnitus), normal tympanic membrane, type A or C tympanograms, and without a history of any middle ear diseases. Main outcomes including subjective improvement, otoscopy, pure-tone audiometry, impedance audiometry, R-value in tubomanometry (TMM) at three pressure measurements (30, 40, and 50 mbar), Eustachian Tube Score (ETS) and the ability to perform a Valsalva maneuver were assessed preoperatively, 1 week, 3 months and 12 months postoperatively.nnnRESULTSnAll cases were dilated successfully. A significant effect of treatment was documented when measuring subjective improvement, impedance audiometry, R-value in TMM, ETS and the ability to perform a Valsalva maneuver 1 week, 3 months and 12 month postoperatively. Subjective symptoms were not relieved only in one patient. The overall success rate for all patients was 98%.nnnCONCLUSIONSnETBD can provide both short- and long-term benefits to those who are diagnosed SETD and refractory to medical management. SETD might be an optimal indication for ETBD in the treatment of ETD.

A comparison of inner ear imaging features at different time points of sudden sensorineural hearing loss with three-dimensional fluid-attenuated inversion recovery magnetic resonance imaging

AbstractnIt has been reported that about half of patients with sudden sensorineural hearing loss (SSNHL) show high signals in the affected inner ear on three-dimensional, fluid-attenuated inversion recovery magnetic resonance imaging (3D-FLAIR MRI). These signals may reflect minor hemorrhage or an increased concentration of protein in the inner ear, which has passed through blood vessels with increased permeability. Our objective was to compare the positive ratio of the high signal in affected inner ears at different time points to determine the suitable imaging time point for 3D-FLAIR MRI in SSNHL. 3D-FLAIR MRI images were taken at three times, precontrast and approximately 10xa0min and 4xa0h after intravenous injection of a single dose of gadodiamide (Gd) (0.1xa0mmol/kg), in 46 patients with SNHL. We compared the positive findings of the high signals in the inner ear of patients with SNHL as well as the signal intensity ratio (SIR) between the affected cochleae and unaffected cochleae at three time points. The positive ratios of the high signals in the affected inner ear at the time points of precontrast and 10xa0min and 4xa0h after the intravenous Gd injection were 26.1, 32.6, and 41.3xa0%, respectively. The high signal intensity ratios of affected inner ears at the three time points were 1.28, 1.31, and 1.48, respectively. The difference between the positive ratios precontrast and at 10xa0min after the intravenous Gd injection was statistically significant (Pxa0=xa00.006); the differences between the positive ratios at 4xa0h after the intravenous Gd injection and precontrast and between the ratios at 4xa0h and 10xa0min after the intravenous Gd injection were not statistically significant. The time effects of the median value of SIR were not significant (Pxa0=xa00.064). We do not recommend 4xa0h after intravenous Gd injection as a time point to image the inner ear in SNHL. We believe that imaging precontrast and at 10xa0min after the intravenous Gd injection are suitable time points.

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

OBJECTIVEnTo evaluate the effect of the combination of balloon Eustachian tuboplasty (BET) and tympanic paracentesis (TP) on intractable chronic otitis media with effusion (COME).nnnMETHODSnNinety 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.nnnRESULTSnBoth 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.nnnCONCLUSIONSnOur 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.

NMDA receptors are involved in the regulation of BMP4-mediated survival in rat cochlear epithelial cells.

Bone morphogenic protein (BMP4) and the N-methyl-d-aspartic acid (NMDA) receptor both participate in the regulation of cochlear sensory epithelial cell survival. However, whether the NMDA receptor is involved in the BMP4 pathway has not been fully elucidated in rat cochlear sensory epithelial cells. Here, we show that after 3 days of culture with exogenous BMP4, the number of surviving cells in the treated group was less than that in the control group. The apoptosis rate was higher and the percentage of cells in S-phase was lower in the experimental group than in other control group. When the cells were cultured with noggin for 3 days, the results were opposite of those observed with BMP4. When BMP4-treated cells were supplemented with APV for 3 days, the number of viable cells and the percentage of those in S-phase were greater compared to the BMP4-only group. Additionally, the apoptosis rate was lower in the BMP4+APV cells than in the cells cultured with BMP4 only. Meanwhile, the number of NR2B-positive cells, as revealed by the NR2B mRNA and protein levels, was greater in the BMP4 group than in the control group. These results suggest that BMP4 may affect the expression of NR2B, thus playing a role in regulating the survival of cochlear epithelial cells.

TLR4 drives the pathogenesis of acquired cholesteatoma by promoting local inflammation and bone destruction.

Acquired cholesteatoma is a chronic inflammatory disease characterized by both hyperkeratinized squamous epithelial overgrowth and bone destruction. Toll-like receptor (TLR) activation and subsequent inflammatory cytokine production are closely associated with inflammatory bone disease. However, the expression and function of TLRs in cholesteatoma remain unclear.We observed inflammatory cell infiltration of the matrix and prematrix of human acquired cholesteatoma, as well as dramatically increased expression of TLR4 and the pro-inflammatory cytokines TNF-α and IL-1β. TLR2 exhibited an up-regulation that was not statistically significant. TLR4 expression in human acquired cholesteatoma correlated with disease severity; the number of TLR4-positive cells increased with an increased degree of cholesteatoma, invasion, bone destruction, and hearing loss. Moreover, TLR4 deficiency was protective against experimental acquired cholesteatoma-driven bone destruction and hearing loss, as it reduced local TNF-α and IL-1β expression and impaired osteoclast formation by decreasing expression of the osteoclast effectors receptor activator of nuclear factor (NF)-κB ligand (RANKL) and tartrate-resistant acid phosphatase (TRAP). TLR2 deficiency did not relieve disease severity, inflammatory responses, or osteoclast formation. Moreover, neither TLR2 nor TLR4 deficiency had an effect on antimicrobial peptides, inducible iNOS,BD-2 expression or bacterial clearance. Therefore, TLR4 may promote cholesteatoma-induced bone destruction and deafness by enhancing inflammatory responses and osteoclastogenesis.