Masaaki Teranishi

Visualization of Endolymphatic Hydrops in Patients With Meniere's Disease†

Objective: Recently, there have been many reports of intratympanic gentamicin therapy for the treatment of intractable Menieres disease. Intratympanic administration of steroids has also been used to treat sudden sensorineural hearing loss. We attempted to visualize how the intratympanically administered drug enters the inner ear.

Free radical-induced megamitochondria formation and apoptosis.

Pathophysiological meaning and the mechanism of the formation of megamitochondria (MG) induced under physiological and pathological conditions remain obscure. We now provide evidence suggesting that the MG formation may be a prerequisite for free radical-mediated apoptosis. MG were detected in primary cultured rat hepatocytes, rat liver cell lines RL-34 and IAR-20 and kidney cell line Cos-1 treated for 22 h with various chemicals known to generate free radicals: hydrazine, chloramphenicol, methyl-glyoxal-bis-guanylhydrazone, indomethacin, H2O2, and erythromycin using a fluorescent dye Mito Tracker Red CMXRos (CMXRos) for confocal laser microscopy and also by electron microscopy. Remarkable elevations of the intracellular level of reactive oxygen species (ROS), monitored by staining of cells with a fluorescent dye carboxy-H2-DCFDA, were detected before MG were formed. Prolongation of the incubation time with various chemicals, specified above, for 36 h or longer has induced distinct structural changes of the cell, which characterize apoptosis: condensation of nuclei, the formation of apoptotic bodies, and the ladder formation. Cells treated with the chemicals for 22 h were arrested in G1 phase, and apoptotic sub-G1 populations then became gradually increased. The membrane potential of MG induced by chloramphenicol detected by CMXRos for flow cytometry was found to be decreased compared to that of mitochondria in control cells. Rates of the generation of H2O2 and O2- from MG isolated from the liver of rats treated with chloramphenicol or hydrazine were found to be lower than those of mitochondria of the liver of control animals. We suggest, based on the present results together with our previous findings, that the formation of MG may be an adaptive process at a subcellular level to unfavorable environments: when cells are exposed to excess amounts of free radicals mitochondria become enlarged decreasing the rate of oxygen consumption. Decreases in the oxygen consumption of MG may result in decreases in the rate of ROS production as shown in the present study. This will at the same time result in decreases in ATP production from MG. If cells are exposed to a large amount of free radicals beyond a certain period of time, lowered intracellular levels of ATP may result in apoptotic changes of the cell.

Grading of endolymphatic hydrops using magnetic resonance imaging

Conclusion: Grading of endolymphatic hydrops in the vestibule and the cochlea using magnetic resonance imaging (MRI) is proposed (2008 Nagoya scale). Objective: To standardize the evaluation of endolymphatic hydrops in both the vestibule and the cochlea using MRI. Patients and methods: The endolymphatic space was evaluated after intratympanic gadolinium injection using three-dimensional fluid attenuated (3D-FLAIR) MRI and three-dimensional real inversion recovery (3D-real IR) MRI. Results: A simple three-stage grading system was acceptable for hydrops in both the vestibule and the cochlea: none, mild, and significant. In the vestibule, the grading was determined by the ratio of the area of endolymphatic space to the vestibular fluid space (sum of the endolymphatic and perilymphatic spaces). Patients with no hydrops have a ratio of one-third or less, those with mild hydrops have between one-third and a half, and those with significant hydrops have a ratio of more than 50%. In the cochlea, patients classified as having no hydrops show no displacement of Reissners membrane; those with mild hydrops show displacement of Reissners membrane but the area of the endolymphatic space does not exceed the area of the scala vestibuli; and in those with significant hydrops the area of the endolymphatic space exceeds the area of the scala vestibuli.

Three-dimensional fluid-attenuated inversion recovery magnetic resonance imaging findings and prognosis in sudden sensorineural hearing loss.

Objectives/Hypothesis: Three‐dimensional fluid‐attenuated inversion recovery (3D‐FLAIR) magnetic resonance imaging (MRI) has recently been developed to detect high concentrations of protein or hemorrhage. We have previously reported that 50% of patients with sudden sensorineural hearing loss (SNHL) show high signals in the affected inner ear on 3D‐FLAIR MRI. However, the relationship between 3D‐FLAIR findings and hearing prognosis is unclear. Our objective was to evaluate the relationship between the results of 3D‐FLAIR MRI at 3 Tesla and prognosis in sudden SNHL.

Opposite effects of microtubule-stabilizing and microtubule-destabilizing drugs on biogenesis of mitochondria in mammalian cells.

Distribution of mitochondria as well as other intracellular organelles in mammalian cells is regulated by interphase microtubules. Here, we demonstrate a role of microtubules in the mitochondrial biogenesis using various microtubule-active drugs and human osteosarcoma cell line 143B cells and rat liver-derived RL-34 cells. Depolymerization of microtubules by nocodazole or colchicine, as well as 2-methoxyestradiol, a natural estrogen metabolite, arrested asynchronously cultured cells in G(2)/M phase of cell cycle and at the same time inhibited the mitochondrial mass increase and mtDNA replication. These drugs also inhibited the mitochondrial mass increase in the cells that were synchronized in cell cycle, which should occur during G(1) to G(2) phase progression in normal conditions. However, stabilization of microtubules by taxol did not affect the proliferation of mitochondria during the cell cycle, yet a prolonged incubation of cells with taxol induced an abnormal accumulation of mitochondria in cells arrested in G(2)/M phase of cell cycle. Taxol-induced accumulation of mitochondria was not only demonstrated by mitochondria-specific fluorescent dyes but also evidenced by the examination of cells transfected with yellow fluorescent protein fused with mitochondrial targeting sequence from subunit VIII of human cytochrome c oxidase (pEYFP) and by enhanced mtDNA replication. Two subpopulations of mitochondria were detected in taxol-treated cells: mitochondria with high Delta(psi)(m), detectable either by Mito Tracker Red CMXRos or by Green FM, and those with low Delta(psi)(m), detectable only by Green FM. However, taxol-induced increases in the mitochondrial mass and in the level of acetylated (alpha)-tubulin were abrogated by a co-treatment with taxol and nocodazole or taxol and colchicine. These data strongly suggest that interphase microtubules may be essential for the regulation of mitochondrial biogenesis in mammalian cells.

Vestibular and Cochlear Toxicity of Aminoglycosides - A review

Recently, there have been many reports describing the efficacy of intratympanic aminoglycoside injection for the treatment of intractable vertigo in patients with Ménières disease. However, the number of injections and the amount of drug injected varies, with concomitant variation in the side-effect of hearing deterioration. To identify drugs that are more selectively vestibulotoxic, we have reviewed the ototoxicity of aminoglycosides, focusing on differences between vestibulo- and cochleotoxicity. At present, the basis for the different effects of each drug is unknown. The mechanisms of vestibulo- and cochleotoxicity are deemed worthy of further study.Recently, there have been many reports describing the efficacy of intratympanic aminoglycoside injection for the treatment of intractable vertigo in patients with Ménières disease. However, the number of injections and the amount of drug injected varies, with concomitant variation in the side-effect of hearing deterioration. To identify drugs that are more selectively vestibulotoxic, we have reviewed the ototoxicity of aminoglycosides, focusing on differences between vestibulo- and cochleotoxicity. At present, the basis for the different effects of each drug is unknown. The mechanisms of vestibulo- and cochleotoxicity are deemed worthy of further study.

Individual Differences in the Permeability of the Round Window: Evaluating the Movement of Intratympanic Gadolinium Into the Inner Ear

Objective: Many recent studies have reported on intratympanic gentamicin therapy for the treatment of intractable Ménières disease. Intratympanic administration of steroids has also been used to treat sudden sensorineural hearing loss. These intratympanic drug therapies are based on the assumption that the drug administered intratympanically enters the inner ear through the round window membrane. We used magnetic resonance imaging (MRI) to evaluate whether and how intratympanically administered gadolinium (Gd) enters the inner ear. Methods: GD hydrate was injected intratympanically through the tympanic membrane using a 23-G needle into 61 ears of 55 patients with inner ear diseases. The injected Gd was diluted 8-fold in saline for injection into 58 ears and 16-fold for 3 ears. Three-dimensional fluid-attenuated inversion recovery (3D-FLAIR) imaging was performed using a 3-Tesla MRI unit 1 day after the intratympanic injection. Results: In 53 of 61 ears, the Gd-containing inner ear was detected well as a high signal on 3D-FLAIR imaging. However, Gd was not visible in 2 ears with Ménières disease and in 1 ear with profound deafness. The concentration of Gd in the perilymph was lower in 4 ears with Ménières disease and 1 ear with delayed endolymphatic hydrops than after intratympanic administration of the 16-fold Gd dilution. Conclusion: Round window permeability was absent in 5% of ears, and 13% of ears had poor round window permeability. These results should be considered when planning intratympanic drug administration therapy to treat inner ear diseases.

Effects of α-tocopherol on cisplatin-induced ototoxicity in guinea pigs

Abstract Cisplatin (CDDP), an antitumor agent widely used in the treatment of head and neck cancers, has dose-limiting side effects such as ototoxicity and nephrotoxicity. Recently, evidence has been accumulated to demonstrate that these side effects are closely related to oxidative stress. In the present study, we attempted to suppress CDDP-induced ototoxicity and nephrotoxicity in guinea pigs by administering α-tocopherol, a naturally occurring antioxidant. Hartley albino guinea pigs (250∼300 g) were treated with CDDP (4 mg/kg intraperitoneally (I.P.)) for 3 days in the presence and absence of α-tocopherol (50 mg/kg I.P.) injection for 6 days. The combined treatment of animals with α-tocopherol distinctly improved the CDDP-induced side effects. These were: loss of Preyer’s reflex at high frequencies; distinct elevation of auditory brain stem response threshold at 16 kHz; increased lipid peroxidation in the cochlea determined by the malondialdehyde–thiobarbituric acid method; substantial losses of outer hair cells in the basal and second turns of the cochlea; fragmentation of nuclear DNA detected by the TUNEL method in cochlear hair cells and cells in the stria vascularis; and increases in serum BUN and Cr. These results strongly suggest that α-tocopherol suppresses CDDP-induced ototoxicity and nephrotoxicity via the suppression of the increased production of reactive oxygen species.

Thirty-year trends in sudden deafness from four nationwide epidemiological surveys in Japan.

Conclusions. The estimated annual number of patients with sudden deafness treated in Japan has increased during the last 30 years, especially in the elderly population. Hypertension and diabetes mellitus could contribute to the etiology of this disorder. Objectives. To investigate the epidemiological trends of sudden deafness in Japan over the past 30 years by analyzing data from national surveys. Materials and methods. Nationwide epidemiological surveys on sudden deafness were conducted four times by the Research Committee of the Ministry of Health and Welfare in Japan. The first, second, third, and fourth surveys were performed in 1972, 1987, 1993, and 2001, respectively. Results. The estimated annual numbers of patients with sudden deafness treated in Japan were 4000 in 1972; 16 700 in 1987; 24 000 in 1993, and 35 000 in 2001.The average ages of patients at onset were 39.1, 45.4, 49.3, and 51.3 years, respectively. Thus, both the number of patients and the average age of patients with sudden deafness have increased during the past 30 years. Patients with sudden deafness in the fourth survey exhibited hypertension and diabetes mellitus more frequently than did patients in the first survey; this trend was particularly noticeable among elderly patients.

Endolymphatic hydrops revealed by intravenous gadolinium injection in patients with Ménière's disease

CONCLUSION Visualization of endolymphatic hydrops became possible after intravenous gadolinium (Gd) injection in patients with Ménières disease. OBJECTIVE To visualize endolymphatic hydrops after intravenous Gd injection. METHODS Gd (gadoteridol; 0.2 mmol/kg) was injected intravenously in three patients with unilateral Ménières disease. We performed three-dimensional fluid attenuated inversion recovery (3D-FLAIR) and three-dimensional real inversion recovery (3D-real IR) magnetic resonance imaging (MRI) 4 h after the injection using a 3-Tesla MRI unit. We used a 32-channel array coil to obtain a high signal-to-noise ratio. RESULTS Endolymphatic hydrops was observed in the ears of patients with Ménières disease. However, Gd concentration in the perilymph was lower compared with that obtained after intratympanic Gd injection.