Potential treatments for genetic hearing loss in humans: current conundrums.

Genetic defects are a major cause of hearing loss in newborns. Consequently, hearing loss has a profound negative impact on human daily living. Numerous causative genes for genetic hearing loss have been identified. However, presently, there are no truly curative treatments for this condition. There have been several recent reports on successful treatments in mice using embryonic gene therapy, neonatal gene therapy and neonatal antisense oligonucleotide therapy. Herein, we describe state-of-the-art research on genetic hearing loss treatment through gene therapy and discuss the obstacles to overcome in curative treatments of genetic hearing loss in humans.

PAF- and histamine-receptor antagonists lessen allergen-induced hearing impairment in guinea pigs.

We have demonstrated degranulation of mast cells in the endolymphatic sac as well as an increase in audiological threshold shift in the experimental animal models following antigen provocation. Mast cells, however, release such chemical mediators as histamine, platelet activating factor (PAF), and leukotriene due to an antigen-antibody reaction on the cell surface. The aim of this study was to clarify the major chemical mediators responsible for hearing impairment in the animal models following antigen provocation. Guinea pigs were actively sensitized with DNP-Ascaris and provoked with an injection of DNP-BSA. A significant audiological threshold shift was observed at 1, 10, 24, and 72 h following challenge with allergen. The peak shift was at 10 h; all changes were reversed after 7 days. This threshold shift was abolished by prior injection of either a histamine- or PAF-receptor antagonist to allergen, but not of a leukotriene-receptor antagonist. Results suggest that histamine and PAF are involved in the hearing impairment induced by allergen exposure in the guinea pig.

Neuro-otologic abnormalities in myelopathy associated with human T-cell lymphotropic virus type 1.

Auditory testing (pure tone audiometry, auditory brain stem response), and vestibular tests (eye tracking test, optokinetic pattern test, and caloric test) were performed to define neuro-otologic abnormalities in myelopathy associated with human T-cell lymphotropic virus type 1. Of the eight patients tested, seven showed sensorineural hearing loss and one showed mixed hearing loss on pure tone audiometry. The auditory brain stem responses of five patients showed increases of the I-III and I-V interpeak latencies. Two patients showed fast superimposed saccadic movements on the smooth pursuit test, and one other patient showed canal paresis on the caloric test. These findings suggest both the presence of neuro-otologic abnormality and involvement of the brain stem in myelopathy associated with human T-cell lymphotropic virus type 1.

Muscarinic acetylcholine receptors on human lymphocytes in patients with Menière's disease.

To investigate patients with Menière's disease and the association of cholinergic hyperreactivity, we performed muscarinic acetylcholine receptor assay using peripheral blood lymphocytes from patients with Menière's disease and non-dizzy, non-allergic control subjects. Cholinergic receptor maximal bindings (Bmax) and dissociation constants (Kd) were compared between the two groups, indicating the number and the affinities of the receptors, respectively. The receptor Bmax value in Meniére's patients during the remission state (108.6 +/- 51.2 fmol/l x 10(6) lymphocytes) was higher than that in normal controls (45.8 +/- 9.2 fmol/l x 10(6) lymphocytes) (p < 0.01). Furthermore, during an exacerbated state, Bmax was increased significantly (223.7 +/- 90.2 fmol/l x 10(6) lymphocytes) compared to the remission state (p < 0.01). In contrast, Kd values for the receptor did not differ between the two groups. These results suggest that patients with Menière's disease have cholinergic hyperreactivity, which may be further upregulated during a state of exacerbation due to an increase in the number of cholinergic receptors.

The effects of histamine and its antagonists on the cochlear microphonic and the compound action potential of the guinea pig.

OBJECT: we studied the effects of histamine, the H1 receptor antagonist pyrilamine, and the H2 receptor antagonist cimetidine on the cochlear potential of guinea pigs (cochlear microphonic, CM; compound action potential, CAP). METHODS: histamine was applied into the cochlear perilymph at three different dosages (10 microM, 50 microM or 10 mM). Pyrilamine and cimetidine were applied at 50 microM each. RESULTS: histamine increased the CAP at 10 and 50 microM without any significant effects on the CM. The effects of histamine at 50 microM were suppressed by the 50-microM of pyrilamine and cimetidine. At 10 mM of histamine, CAP and CM amplitudes were significantly decreased. CONCLUSION: in low concentrations, histamine may act as an extracellular signal on inner hair cells (IHCs) or it may stimulate the afferent nerve by binding to their H1 and H2 receptors. A possible explanation for the inhibitory effects of histamine at 10-mM dosage was apparently found in that the effects of the high concentration may be supraphysiological; and furthermore, there is a difference in the mechanism by which histamine exerts its effects mediated by the histamine receptors on the cochlea.

Neurologic and otologic findings in Fisher's syndrome.

We performed neurologic and otologic examinations in 14 patients with Fisher's syndrome to determine whether its manifestations inducing acute ophthaloplegia, ataxia and areflexia may involve the auditory and vestibular systems. Tests included pure tone audiometry, auditory brainstem response, observations of nystagmus, smooth pursuit test, saccade test, optokinetic nystagmus test, and the caloric test. One patient showed downbeat nystagmus and lateral gaze nystagmus without restriction of eye movement, two patients showed dysmetria on saccades without restriction of eye movement, and three patients showed superimposed saccadic eye movement on smooth pursuit without lateral gaze nystagmus. The abnormalities in those six cases could not be explained by solely muscular weakness, but also appeared to involve the central oculomotor system. In the other patients, nystagmus could be explained by muscular weakness alone. Additionally, three patients, including two patients with dysmetria on saccades, showed a unilateral diminished response to caloric testing with no severe restriction of eye movements. In evaluating the auditory brainstem response of these three patients, one patient, who showed abnormality on the saccade and caloric tests, showed an elongation of wave I latencies and of wave I-III interpeak latencies at both ears, and one other patient showed an elongation of wave III-V interpeak latencies at both ears. This disorder may involve the peripheral and central auditory systems as well as the peripheral vestibular system.

Evaluation of brain and head and neck tumors with 4D contrast-enhanced MR angiography at 3T.

BACKGROUND AND PURPOSE: Systematic assessment of brain and head and neck tumors with 4D-CE-MRA at 3T has not been investigated. The purpose of this study was to test the hypothesis that 4D-CE-MRA at 3T can replace DSA in the identification of feeding arteries and tumor stain to plan interventional procedures in hypervascular brain and head and neck tumors. MATERIALS AND METHODS: Fifteen consecutive patients with brain and head and neck tumors underwent 4D-CE-MRA at 3T and DSA. 4D-CE-MRA combined randomly segmented central k-space ordering, keyhole imaging, SENSE, and half-Fourier imaging. We obtained 30 dynamic scans every 1.9 seconds at an acquired spatial resolution of 0.9 × 0.9 × 1.5 mm; the matrix was 256 × 256. Two independent observers inspected the 4D-CE-MRA images for the main arterial feeders and tumor stain. Interobserver and intermodality agreement was assessed by κ statistics. RESULTS: For 4D-CE-MRA, the interobserver agreement was fair with respect to the main arterial feeders and very good for the degree of tumor stain (κ = 0.28 and 0.87, respectively). Intermodality agreement was moderate for the main arterial feeders (κ = 0.45) and good for the tumor stain (κ = 0.74). CONCLUSIONS: Although 4D-CE-MRA may be useful for evaluating tumor stain in hypervascular brain and head and neck tumors, it is not able to replace DSA in planning interventional procedures.

Initial steroid hormone dose in the treatment of idiopathic sudden deafness.

OBJECTIVE: The purpose of this study was to clarify whether higher doses of steroids improve the prognosis of idiopathic sensorineural hearing loss (ISHL) and the suitable dose of steroid hormone. STUDY DESIGN: The study was a retrospective statistical analysis. SETTING: This study was performed at the Department of Otolaryngology, Head Neck Surgery, Kumamoto University School of Medicine. PATIENTS: Two hundred fifty patients with ISHL were analyzed in this study. They were divided into two groups: those receiving less than a specified daily dose of steroid and those receiving a daily dose greater than or equal to the specified dose. INTERVENTIONS: The patients received systemic steroid therapy combined with adenosine triphosphate, vitamins, diuretics, vasodilators, hyperbaric oxygen therapy, stellate ganglion block, or volume expander. MAIN OUTCOME MEASURES: The correlation between the initial dose of steroid hormone and the improvement rate was analyzed. RESULT: Spearman's correlation coefficients and partial correlation coefficients between the initial dose and the prognosis were all significantly negative. On the other hand, the correlations between the initial dose and the prognosis were positive in the group receiving <30 mg/day, whereas they were negative in the group receiving > or =30 mg/day, although these correlations were not significant. CONCLUSION: The general use of steroid hormone to treat ISHL is not recommended. Furthermore, if steroid hormone is used for treatment, the use of <30 mg/day of prednisolone is preferable.

Recurrent hearing impairment and nystagmus induced by repeated antigen exposure in actively sensitized guinea pigs.

Although many studies have suggested a relation between allergy and Ménière's disease, the pathophysiology of this condition remains controversial. The aim of this study was to clarify whether an anaphylactic reaction in the inner ear can disturb hearing and equilibrium, and whether such disturbances recur in response to repeated anaphylactic reactions. Increases in audiological threshold, nystagmus, and endolymphatic hydrops were observed in response to a single exposure to antigen administered to actively sensitized guinea pigs. The increase in audiological threshold was maximal 10 h after antigen challenge (p < 0.005) and returned to the baseline level after 7 days. Nystagmus and the increase in audiological threshold induced by antigen exposure were inhibited by prior administration of pemirolast potassium (p < 0.05), an inhibitor of chemical mediator release from mast cells. A second challenge with antigen 7 days after the first also induced an increase in audiological threshold (p < 0.05) and nystagmus. These results suggest that studies of repeated antigen challenge in actively sensitized animal models may increase our understanding of the pathophysiology of Ménière's disease.