Umbilical Cord Mesenchymal Stromal Cell-Derived Exosomes Rescue the Loss of Outer Hair Cells and Repair Cochlear Damage in Cisplatin-Injected Mice.

Umbilical cord-derived mesenchymal stromal cells (UCMSCs) have potential applications in regenerative medicine. UCMSCs have been demonstrated to repair tissue damage in many inflammatory and degenerative diseases. We have previously shown that UCMSC exosomes reduce nerve injury-induced pain in rats. In this study, we characterized UCMSC exosomes using RNA sequencing and proteomic analyses and investigated their protective effects on cisplatin-induced hearing loss in mice. Two independent experiments were designed to investigate the protective effects on cisplatin-induced hearing loss in mice: (i) chronic intraperitoneal cisplatin administration (4 mg/kg) once per day for 5 consecutive days and intraperitoneal UCMSC exosome (1.2 µg/µL) injection at the same time point; and (ii) UCMSC exosome (1.2 µg/µL) injection through a round window niche 3 days after chronic cisplatin administration. Our data suggest that UCMSC exosomes exert protective effects in vivo. The post-traumatic administration of UCMSC exosomes significantly improved hearing loss and rescued the loss of cochlear hair cells in mice receiving chronic cisplatin injection. Neuropathological gene panel analyses further revealed the UCMSC exosomes treatment led to beneficial changes in the expression levels of many genes in the cochlear tissues of cisplatin-injected mice. In conclusion, UCMSC exosomes exerted protective effects in treating ototoxicity-induced hearing loss by promoting tissue remodeling and repair.

Intracochlear tPA infusion may reduce fibrosis caused by cochlear implantation surgery.

BACKGROUND: Experiments show that the extent of ongoing fibrotic change within the cochlea can be determined by the volume and pattern of bleeding within the first 24 h following cochlear implantation. Tissue-type plasminogen activator (tPA) is effective at reducing thrombus volume when administered both within and external to the systemic circulation. AIMS/OBJECTIVES: To determine if tPA delivered into the scala tympani immediately following implantation will reduce thrombus volume within the lower basal turn of the cochlea. MATERIALS AND METHODS: Guinea pigs were implanted with either 'soft' or 'hard' arrays and administered tPA or saline via an intra-cochlear infusion immediately after implantation. Hearing was checked prior to, and 2 weeks after implantation. Cochleae were then harvested and imaged. RESULTS: Animals implanted with 'soft' arrays had 4.2% less tissue response compared with animals implanted with 'hard' arrays. In animals receiving 'soft' arrays, tPA reduced the volume of tissue response (measured by the percentage of the lower basal turn of the scala tympani occupied by tissue response) compared with saline. CONCLUSIONS AND SIGNIFICANCE: tPA may be effective in reducing the overall volume of tissue response in routine 'soft' cochlear implantation and may have a greater effect in the event of significant surgical trauma.

Effects of lifetime noise exposure on the middle-age human auditory brainstem response, tinnitus and speech-in-noise intelligibility.

Recent animal studies have shown that the synapses between inner hair cells and the dendrites of the spiral ganglion cells they innervate are the elements in the cochlea most vulnerable to excessive noise exposure. Particularly in rodents, several studies have concluded that exposure to high level octave-band noise for 2 h leads to an irreversible loss of around 50% of synaptic ribbons, leaving audiometric hearing thresholds unaltered. Cochlear synaptopathy following noise exposure is hypothesized to degrade the neural encoding of sounds at the subcortical level, which would help explain certain listening-in-noise difficulties reported by some subjects with otherwise 'normal' hearing. In response to this peripheral damage, increased gain of central stages of the auditory system has been observed across several species of mammals, particularly in association with tinnitus. The auditory brainstem response (ABR) wave I amplitude and waves I-V amplitude ratio have been suggested as non-invasive indicators of cochlear synaptopathy and central gain activation respectively, but the evidence for these hearing disorders in humans is inconclusive. In this study, we evaluated the influence of lifetime noise exposure (LNE) on the human ABR and on speech-in-noise intelligibility performance in a large cohort of adults aged 29 to 55. Despite large inter-subject variability, results showed a moderate, but statistically significant, negative correlation between the ABR wave I amplitude and LNE, consistent with cochlear synaptopathy. The results also showed (a) that central gain mechanisms observed in animal studies might also occur in humans, in which higher stages of the auditory pathway appear to compensate for reduced input from the cochlea; (b) that tinnitus was associated with activation of central gain mechanisms; (c) that relevant cognitive and subcortical factors influence speech-in-noise intelligibility, in particular, longer ABR waves I-V interpeak latencies were associated with poorer performance in understanding speech in noise when central gain mechanisms were active; and (d) absence of a significant relationship between LNE and tinnitus, central gain activation or speech-in-noise performance. Although this study supports the possible existence of cochlear synaptopathy in humans, the great degree of variability, the lack of uniformity in central gain activation and the significant involvement of attention in speech-in-noise performance suggests that noise-induced cochlear synaptopathy is, at most, one of several factors that play a role in humans' speech-in-noise performance.

Ozone Prevents Cochlear Damage From Ischemia-Reperfusion Injury in Guinea Pigs.

The cochlea is an end organ, which is metabolically dependent on a nutrient and oxygen supply to maintain its normal physiological function. Cochlear ischemia and reperfusion (IR) injury is considered one of the most important causes of human idiopathic sudden sensorineural hearing loss. The aim of the present study was to study the efficacy of ozone therapy against cochlear damage caused by IR injury and to investigate the potential clinical use of this treatment for sudden deafness. Twenty-eight guinea pigs were randomized into four groups. The sham group (S) (n = 7) was administered physiological saline intraperitoneally (i.p.) for 7 days. The ozone group (O) (n = 7) was administered 1 mg/kg of ozone i.p. for 7 days. In the IR + O group (n = 7), 1 mg/kg of ozone was administered i.p. for 7 days before IR injury. On the eighth day, the IR + O group was subjected to cochlear ischemia for 15 min by occluding the bilateral vertebral artery and vein with a nontraumatic clamp and then reperfusion for 2 h. The IR group was subjected to cochlear IR injury. After the IR procedure, the guinea pigs were sacrificed on the same day. In a general histological evaluation, cochlear and spiral ganglionic tissues were examined with a light microscope, and apoptotic cells were counted by terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) staining. The apoptotic index (AI) was then calculated. Blood samples were sent for analyses of superoxide dismutase (SOD), glutathione peroxidase (GSH-Px), catalase, malondialdehyde (MDA), the total oxidant score (TOS), and total antioxidant capacity (TAC). Data were evaluated statistically using the Kruskal-Wallis test. The AI was highest in the IR group. The AI of the IR + O group was lower than that of the IR group. The biochemical antioxidant parameters SOD and GSH-Px and the TAC values were highest in the O group and lowest in the IR group. The MDA level and TOS were highest in the IR group and lowest in the O group. Controlled ozone administration stimulated endogenous antioxidant defense systems, thereby helping the body to combat IR injury. Although this study revealed a statistically significant decrease in cochlear IR damage following ozone therapy, further studies will be necessary to explain the protective mechanisms of ozone therapy in cochlear IR injury.

[Hirudotherapy in the treatment of peripheral cochleovestibular disorders of vascular origin].

Basic therapy of peripheral cochleovestibular disorders of vascular origin consists of the rational combination of medicamentous and non-medicamentous treatments that collectively ensure positive clinical results. The use of hirudotherapy for the management of peripheral cochleovestibular disorders resulted in the substantial decrease of ear noise and the maintenance of the tendency toward further improvement of cochlear and vestibular functions.

Hyperacusis in Williams syndrome: characteristics and associated neuroaudiologic abnormalities.

BACKGROUND: Hyperacusis and phonophobia are common, debilitating symptoms in Williams syndrome (WS), yet little is known about their underlying audiologic and neurologic processes. METHODS: The mothers of 49 subjects with WS were asked to complete the Hyperacusis Screening Questionnaire. Subjects with reported hyperacusis and sufficient developmental capacity underwent comprehensive audiological and brain auditory evoked response (BAER) testing. Findings were compared with those from pair-matched typically developing control subjects. RESULTS: Forty-one of the 49 children with WS (84%) had hyperacusis of moderate to severe degree, which began in infancy. Of these, 21 (mean age 15.8 +/- 5.5 years) were quantitatively tested. Subjects with WS reported discomfort at sound intensities on average 20 dB lower than control subjects. Pure-tone audiometry and distortion products otoacoustic emission test revealed a high-frequency cochlear hearing loss. An absence of ipsilateral acoustic reflex responses to maximum stimulation was significantly more common in the subjects with WS than controls. On BAER testing, the WS group had a significant prolongation in wave I latency. CONCLUSIONS: Hyperacusis in Williams syndrome (WS) is associated with a high-frequency hearing loss resembling the configuration of noise-induced hearing loss. The hyperacusis and hearing loss in WS may stem from a deficiency in the acoustic reflex resulting from auditory nerve dysfunction. Additional mechanisms that may mediate hyperacusis in WS and should be evaluated in future studies include recruitment, malformation of the facial canal, and haploinsufficiency of the elastin gene.

Transient otoacoustic emissions in children with chronic renal failure.

This study was conducted on 34 children with chronic renal failure: 27 on regular haemodialysis and seven on conservative treatment. Twenty normal healthy children served as controls. They were subjected to clinical examination including otoscopic examination, basic audiological assessment and transient otoacoustic emission testing (TOAE). Four patients had a conductive hearing loss and five had a bilateral moderately severe high frequency sensory neural hearing loss. TOAE testing was carried out for the rest whose ears displayed normal hearing. No response (fail) was obtained in 8% of them but in none of the controls and a partial pass response in 38% versus 10% of controls (P < 0.001). Cochlear dysfunction was significant only at low frequency levels. The mean overall echo-level and reproducibility were significantly lower in patients than in controls. The same holds true for the subgroup of patients on haemodialysis but not for those on conservative treatment. The overall echo-levels did not correlate with serum urea, creatinine, sodium or potassium.

[Endaural reflex diagnosis of cochleovestibular dysfunctions in patients with vascular brain diseases]. / Endoaural'naia refleksodiagnostika kokhleovestibuliarnykh disfunktsii u bol'nykh s sosudistymi zabolevaniiami golovnogo mozga.

The analysis of electrical conductivity of acupuncture points was performed in 225 patients with cochleovestibular dysfunctions against a background of cerebrovascular pathology. Original highly sensitive express-method with application of special registering device was proposed for endaural reflex diagnosis. The system was elaborated for interpretation of examination's results. It permitted either to confirm or to define more precisely both the location (side and level) and the stage of cochleovestibular damage.

Modulation of cochlear responses in the guinea pig by low-frequency, phase-shifted maskers following noise trauma.

Low-frequency acoustic biasing using an intensive phase-shifted, low-frequency masker was studied according to its ability to determine disorders of cochlear micromechanics following noise trauma in the guinea pig as animal model. Statistical analyses proved that this technique allowed electrophysiological differentiation of controls versus groups with different degrees of experimentally induced threshold shifts. To substantiate group differences an intensity of at least 70 dB SPL was required for the 52 Hz masker and the difference in relation to the test-tone intensity had to be +/- 10 or +/- 20 dB SPL. The noise-traumatized cochlea could be identified by means of a threshold shift for the 5 microV pseudothreshold, a low modulation span of the compound action potential amplitude (< 25-50 microV frequency dependent), and reduced positive summating potential amplitude with negative non-modulating values within the different measurement phases for 1 and 2 kHz stimulation.

[Evoked otoacoustic emissions in noise-induced hearing loss]. / Le otoemissioni acustiche evocate nella ipoacusia da trauma acustico cronico.

The Authors evaluated patterns of click-evoked otoacoustic emissions (EOE) in a group of 184 patients exposed to noise in their working environment. The aim of the study was to detect changes in EOE patterns in this group compared to the EOE of healthy subjects. The clinical history of each subject was recorded and otoscopy, pure tone audiogram and impedance tests (tympanometry, stapedial reflex threshold) were carried out in all patients. Noise-induced hearing loss found in 97 patients, unilateral sensorineural hearing loss in 17, other hearing disorders in 24 and normal auditory threshold in 46. EOE recording was carried out in the group of patients with noise-induced hearing loss (97), in the group with normal threshold (46) and in a control group of 15 healthy subjects. EOE recording was obtained using the ILO 88 Otodynamic Analyzer. We introduce a probe into the external ear canal using a non-linear click stimulus (intensity at approximately 85 dB spl) at a 20/sec. rate with a 20 msec. window. Normal EOE were found in the control group. Abnormal EOE were found in 79 cases (81%) of the noise-induced hearing loss group, and in 22 (48%) of the normal threshold group. These data show that noise-exposed subjects have alterations of EOE such as threshold shift missing frequency bands, even in absence of an auditory threshold shift. When EOE were present, the frequency spectrum often showed lack of emissions at high frequencies. This study confirms that cochlear exposure to noise may produce significant alterations of EOE and that this test may be considered highly sensitive in detecting early cochlear damage in chronic acoustic trauma. Therefore, EOE may be used in screening and follow-up of high risk populations such as noise-exposed subjects.

The choice of ABR click polarity and amplitude variables in multiple sclerosis patients.

Evoked brainstem responses (ABR) to 75 dB nHL condensation (C), rarefaction (R), and alternating (A = C+R) clicks were investigated in healthy subjects and in patients with multiple sclerosis. A new wave IV-V 'shape ratio' (SR IV-V) was most sensitive. SR IV-V correlated most strongly with clinical MS classification, and seemed to be rather specific for retrocochlear dysfunction. Wave IV-V amplitude was also more sensitive than the common IV-V amplitude ratio. The variability of latencies and interpeak latencies was lower in ABR to A clicks than in ABR to either R or to C clicks. In patients, fewer subcomponents were found in ABR to A than in ABR to R and C clicks. ABR to A clicks were on the average slightly more sensitive than either C or R click ABR. Our results suggest that both A-mode ABR and the 'dispersion' variable SR IV-V can be used without significant problems in the diagnosis of brainstem demyelination. A test protocol which requires ABR to both C and R clicks to be abnormal, will, however, be less sensitive, though probably more specific.