Akinori Kashio

Ocular vestibular-evoked myogenic potentials (oVEMPs) require extraocular muscles but not facial or cochlear nerve activity

OBJECTIVES Cervical vestibular evoked myogenic potentials (cVEMPs) have been found to be useful for clinical testing of vestibular function. Recently, investigators showed that short-latency, initially negative surface EMG potentials can be recorded around the extraocular muscles (oVEMPs) in response to air-conducted sound (ACS), bone-conducted vibration (BCV), and head taps. Although these evoked potentials, which are located around the eyes, most likely originate primarily from the otolith-ocular pathway, the possibility of contamination by other nerve activities cannot be completely eliminated. The purpose of the present study was to clarify the origin of oVEMPs by examining these possibilities using clinical findings. METHODS Twelve healthy subjects and 15 patients were enrolled. Of the 15 patients, 3 patients had undergone exenteration of the unilateral intraorbital contents, one had undergone exenteration of the right eyeball with preservation of extraocular muscles, 5 had facial palsy, and 6 had profound hearing loss. ACS and/or BCV were used in these subjects. RESULTS Exenteration of the unilateral intraorbital contents resulted in absence of myogenic potentials on the affected side. On the other hand, exenteration of the eyeball with preservation of extraocular muscles did not have a major impact on the responses. There were no significant differences in the waveforms between healthy subjects and patients with facial palsy or profound hearing loss. CONCLUSIONS The results suggested that short-latency, initially negative evoked potentials recorded below the eyes are not affected by cochlear or facial nerve activities and are dependent on the presence of extraocular muscles. SIGNIFICANCE This study provides the evidence that oVEMPs originate from exraocular muscles activated through the vestibulo-ocular pathway.

Micellization of cisplatin (NC-6004) reduces its ototoxicity in guinea pigs

Nanocarriers potentially reduce or prevent chemotherapy-induced side effects, facilitating the translation of nanocarrier formulation into the clinic. To date, organ-specific toxicity by nanocarriers remains to be clarified. Here, we studied the potential of polymeric micelle nanocarriers to prevent the ototoxicity, which is a common side effect of high-dose cisplatin (CDDP) therapy. In this study, we evaluated the ototoxicity of CDDP-incorporating polymeric micelles (NC-6004) in guinea pigs in comparison with that of cisplatin. Their auditory brainstem responses (ABRs) to 2, 6, 12, 20, and 30kHz sound stimulation were measured before and 5 days after the drug administration. Groups treated with NC-6004 showed no apparent ABR threshold shifts, whereas groups treated with CDDP showed dose-dependent threshold shifts particularly at the higher frequencies. Consistent with the ABR results, groups treated with NC-6004 showed excellent hair-cell preservation, whereas groups treated with CDDP exhibited significant hair-cell loss (P<0.05). Synchrotron radiation-induced X-ray fluorescence spectrometry imaging demonstrated that the platinum distribution and concentration in the organ of Corti were significantly reduced (P<0.01) in guinea pigs treated with NC-6004 compared with guinea pigs treated with CDDP. These findings indicate that micellization of CDDP reduces its ototoxicity by circumventing the vulnerable cells in the inner ear.

Methimazole-induced cell death in rat olfactory receptor neurons occurs via apoptosis triggered through mitochondrial cytochrome c-mediated caspase-3 activation pathway.

The administration of methimazole is known to induce cell death in rat olfactory receptor neurons (ORNs). We investigated whether this injury occurs via apoptosis or through necrosis and whether it involves the extrinsic or intrinsic pathway. Rats were intraperitoneally injected with vehicle (control) or 300 mg/kg methimazole. The experimental animals were also administered vehicle or a caspase‐3 or caspase‐9 inhibitor 30 min earlier. The administration of methimazole induced cell death predominantly in the mature ORNs and partially reduced olfactory sensitivity in the rats; the injured cells were TUNEL‐positive and showed a nuclear staining pattern. This insult induced cytochrome c release from the mitochondria and a significant increase in the immunoreactivity of activated caspase‐3 and caspase‐9 as well as that of cleaved poly‐ADP‐ribose‐polymerase; in addition, it caused a significant increase in the fluorogenic activity of caspase‐3 and caspase‐9. However, it did not affect the immunoreactivity of activated caspase‐8 or the fluorogenic activity of caspase‐8. Pretreatment with a caspase‐3 or caspase‐9 inhibitor nearly completely prevented the morphologic, biochemical, and functional changes induced by methimazole. These findings suggest strongly that methimazole‐induced cell death in rat ORNs is predominantly apoptosis; moreover, the majority of this apoptotic cell death is triggered through mitochondrial cytochrome c‐mediated caspase‐3 activation pathway, and both caspase‐3 and caspase‐9 inhibitors can prevent methimazole‐induced cell death in the ORNs.

Analysis of vestibular testing in patients with vestibular schwannoma based on the nerve of origin, the localization, and the size of the tumor.

Objectives: We aimed to analyze the factors influencing caloric response and vestibular evoked myogenic potential (VEMP) in vestibular schwannoma. Subjects: The subjects comprised 130 patients with unilateral vestibular schwannoma pathologically diagnosed by surgery. Method: Caloric response and the amplitude and latency of VEMP were measured and analyzed based on the nerve of origin, localization, and size of the tumor. The tumors were classified into 3 types based on localization: intracanalicular, intermediate, and medial; and into 4 grades based on size: 9 mm or less, 10 to 19 mm, 20 to 29 mm, and 30 mm or greater. Results: Abnormal rates of caloric response and VEMP in patients with tumors arising from the superior vestibular nerve were not significantly different from those in patients with tumors of the inferior vestibular nerve. In the intermediate and medial type-but not in the intracanalicular type-a significant difference in tumor size was observed between patients with normal caloric response and those with canal paresis as also between patients with normal VEMP and those with abnormal VEMP. In patients with tumors that maximally measured 10 to 19 mm or of the intermediate type, the p- and n-wave latencies of VEMP were significantly prolonged compared with those in the normal opposite ear. Conclusion: 1) The nerve of origin of tumors cannot be predicted based on caloric response and VEMP. 2) In the intermediate and medial types, caloric response and the VEMP amplitude are significantly diminished in association with an increase in tumor size. 3) Prolonged VEMP latencies seem to be not only caused by tumor compression to the brainstem or vestibular spinal tract but also by tumor compression isolated to the inferior vestibular nerve.

A protein derived from the fusion of TAT peptide and FNK, a Bcl-xL derivative, prevents cochlear hair cell death from aminoglycoside ototoxicity in vivo

We constructed a powerful artificial cytoprotective protein, FNK, from an antiapoptotic member of the BCL‐2 family, Bcl‐xL. To test the efficacy of FNK in protecting cochlear hair cells (HCs) from aminoglycoside‐induced cell death in vivo, we fused FNK with protein transduction domain, TAT, of the HIV/Tat protein to construct a fusion protein of TAT‐FNK. We demonstrated that, after an intraperitoneal administration to guinea pigs, TAT‐myc‐FNK protein was diffusely distributed in the cochlea, most prominently in the HCs and supporting cells, followed by the spiral ganglion cells, 3 hr after the injection. We next demonstrated that TAT‐FNK attenuated cochlear damage induced by an ototoxic combination of kanamycin sulfate (KM) and ethacrynic acid (EA) administered at 2 different dosages: 400 mg/kg KM + 50 mg/kg EA and 200 mg/kg KM + 40 mg/kg EA. TAT‐FNK or vehicle was intraperitoneally injected from 3 hr before through 5 hr after inducing the ototoxic insults, 14 days after which auditory brainstem response (ABR) and HC loss were evaluated. In comparison with vehicle‐administered controls, the TAT‐FNK protein significantly attenuated ototoxic drug‐induced ABR threshold shifts and the extent of HC death at either dosage. The TAT‐FNK protein also significantly reduced the amount of cleaved poly‐(ADP‐ribose) polymerase‐positive HCs 8 hr after the ototoxic insults compared with that in the vehicle‐administered controls. These findings indicate that systemically administered TAT‐FNK was successfully delivered to the guinea pig cochlea and effectively prevented apoptotic cell death of the cochlear HCs induced by KM and EA.

Effect of vitamin C depletion on age-related hearing loss in SMP30/GNL knockout mice

Using senescence marker protein 30 (SMP30)/gluconolactonase (GNL) knockout (KO) mice, which cannot synthesize vitamin C (VC), we examined whether modulating VC level affects age-related hearing loss (AHL). KO and wild-type (WT) C57BL/6 mice were given water containing 1.5 g/L VC [VC(+)] or 37.5mg/L VC [VC(-)]. At 10 months of age, KO VC(-) mice showed significant reduction in VC level in the inner ear, plasma, and liver, increase in auditory brainstem response (ABR) thresholds, and decrease in the number of spiral ganglion cells compared to WT VC(-), WT VC(+), and KO VC(+) mice. There were no differences in VC level in the inner ear, ABR thresholds, or the number of spiral ganglion cells among WT VC(-), WT VC(+), and KO VC(+) mice. These findings suggest that VC depletion can accelerate AHL but that supplementing VC may not increase VC level in the inner ear or slow AHL in mice.

Hydrogen in drinking water attenuates noise-induced hearing loss in guinea pigs

It has been shown that molecular hydrogen acts as a therapeutic and preventive antioxidant by selectively reducing the hydroxyl radical, the most cytotoxic of the reactive oxygen species. In the present study, we tested the hypothesis that acoustic damage in guinea pigs can be attenuated by the consumption of molecular hydrogen. Guinea pigs received normal water or hydrogen-rich water for 14 days before they were exposed to 115 dB SPL 4-kHz octave band noise for 3h. Animals in each group underwent measurements for auditory brainstem response (ABR) or distortion-product otoacoustic emissions (DPOAEs) before the treatment (baseline) and immediately, 1, 3, 7, and 14 days after noise exposure. The ABR thresholds at 2 and 4 kHz were significantly better on post-noise days 1, 3, and 14 in hydrogen-treated animals when compared to the normal water-treated controls. Compared to the controls, the hydrogen-treated animals showed greater amplitude of DPOAE input/output growth functions during the recovery process, with statistical significance detected on post-noise days 3 and 7. These findings suggest that hydrogen can facilitate the recovery of hair cell function and attenuate noise-induced temporary hearing loss.

Age-Related Hearing Loss in Mn-SOD Heterozygous Knockout Mice

Age-related hearing loss (AHL) reduces the quality of life for many elderly individuals. Manganese superoxide dismutase (Mn-SOD), one of the antioxidant enzymes acting within the mitochondria, plays a crucial role in scavenging reactive oxygen species (ROS). To determine whether reduction in Mn-SOD accelerates AHL, we evaluated auditory function in Mn-SOD heterozygous knockout (HET) mice and their littermate wild-type (WT) C57BL/6 mice by means of auditory brainstem response (ABR). Mean ABR thresholds were significantly increased at 16 months when compared to those at 4 months in both WT and HET mice, but they did not significantly differ between them at either age. The extent of hair cell loss, spiral ganglion cell density, and thickness of the stria vascularis also did not differ between WT and HET mice at either age. At 16 months, immunoreactivity of 8-hydroxydeoxyguanosine was significantly greater in the SGC and SV in HET mice compared to WT mice, but that of 4-hydroxynonenal did not differ between them. These findings suggest that, although decrease of Mn-SOD by half may increase oxidative stress in the cochlea to some extent, it may not be sufficient to accelerate age-related cochlear damage under physiological aging process.

Effect of Corticosteroids or Diuretics in Low-Tone Sensorineural Hearing Loss

Objectives: We retrospectively analyzed 225 patients with acute low-tone sensorineural hearing loss (ALSHL), comparing the effectiveness of corticosteroid and diuretic therapy, and also determining the factors affecting hearing recovery. Design: Retrospective clinical record review. Methods: Multivariate logistic regression analysis. Results: Analyses identified unfavorable factors such as aging, late initiation of treatment, and pretreatment pure-tone hearing thresholds at three lower frequencies adding up to 95 dB and more. Multivariate logistic regression analysis indicated a significantly greater improvement in hearing in patients treated with corticosteroids at high initial and total doses than in those treated with vitamin B12 and ATP without adding corticosteroids. In 145 patients treated with corticosteroids, multivariate logistic regression analysis showed a trend toward greater improvement with high initial and total doses than with low doses. Conclusion: Corticosteroids should be changed from low to high doses within 7 days after onset of ALSHL, if low doses are failing.

Carhart Notch 2-kHz Bone Conduction Threshold Dip A Nondefinitive Predictor of Stapes Fixation in Conductive Hearing Loss With Normal Tympanic Membrane

OBJECTIVE To evaluate the significance of the Carhart notch (a 2-kHz bone conduction threshold dip [2KBD]) in the diagnosis of stapes fixation by comparing its incidence among ears with various ossicular chain abnormalities. DESIGN Retrospective study. SETTING University hospital. PATIENTS A total of 153 ears among 127 consecutive patients with a congenital ossicular anomaly or otosclerosis. MAIN OUTCOME MEASURES The 2KBD depth was defined as the threshold at 2 kHz minus the mean of thresholds at 1 and 4 kHz. The presence of 2KBD (depth, ≥10 dB), 2KBD depth, relationship between 2KBD depth and air-bone gap, and 2-kHz bone conduction recovery after operation were evaluated in a stapes fixation group (which included cases of otosclerosis and congenital stapes fixation), an incudostapedial joint detachment group, and a malleus or incus fixation group. RESULTS A 2KBD was present in 32 of 102 stapes fixation ears (31.4%), 5 of 19 incudostapedial joint detachment ears (26.3%), and 6 of 20 malleus or incus fixation ears (30.0%) (12 ears had other diagnoses). The mean (SD) 2KBD depths were 17.3 (5.2) dB in the stapes fixation group, 18.5 (2.2) dB in the incudostapedial joint detachment group, and 16.3 (2.1) dB in the malleus or incus fixation group. No statistically significant differences were noted among these 3 groups. No correlation was noted between 2KBD depth and air-bone gap extent. Recovery of 2-kHz bone conduction threshold in the stapes fixation group was less than that in the other 2 groups. CONCLUSION Incidence of 2KBD was similar among the stapes fixation, incudostapedial joint detachment, and malleus or incus fixation groups, implying that 2KBD is not a useful predictor of stapes fixation.