Up-regulation of GAP-43 in the chinchilla ventral cochlear nucleus after carboplatin-induced hearing loss: correlations with inner hair cell loss and outer hair cell loss.

Inner ear damage leads to nerve fiber growth and synaptogenesis in the ventral cochlear nucleus (VCN). In this study, we documented the relationship between hair cell loss patterns and synaptic plasticity in the chinchilla VCN using immunolabeling of the growth associated protein-43 (GAP-43), a protein associated with axon outgrowth and modification of presynaptic endings. Unilateral round window application of carboplatin caused hair cell degeneration in which inner hair cells (IHC) were more vulnerable than outer hair cells (OHC). One month after carboplatin treatment (0.5-5 mg/ml), we observed varying patterns of cochlear hair cell loss and GAP-43 expression in VCN. Both IHC loss and OHC loss were strongly correlated with increased GAP-43 immunolabeling in the ipsilateral VCN. We speculate that two factors might promote the expression of GAP-43 in the VCN; one is the loss of afferent input through IHC or the associated type I auditory nerve fibers. The other occurs when the medial olivocochlear efferent neurons lose their cochlear targets, the OHC, and may as compensation increase their synapse numbers in the VCN.

Prevention and treatment of DNA vaccine encoding cockroach allergen Bla g 1 in a mouse model of allergic airway inflammation.

BACKGROUND: One-fourth of the US population is sensitized to the German cockroach. Primary German cockroach allergen Bla g 1 is detected in 63% of homes and 52% of childcare facilities in the United States. No effective treatment or vaccination strategies are yet available. OBJECTIVES: We evaluated the prophylactic and therapeutic efficacy of a plasmid DNA-mediated vaccination using the Bla g 1 gene in a mouse model of allergic inflammatory airway disease. METHODS: A plasmid DNA vector coding for the Bla g 1 allergen controlled by cytomegalovirus promoter was constructed. To estimate the protective efficacy, BALB/c mice were given three injections of plasmid DNA-Bla g 1 prior to sensitization with two priming doses of recombinant Bla g 1 (rBla g 1) antigens, followed by nebulized rBla g 1 challenge. In the therapeutic approach, sensitization was followed by administering Bla g 1 DNA vaccine. RESULTS: Bla g 1 vaccination significantly reduced allergen-induced airway inflammation, even after mice were presensitized and a Th2-dominant response was established. The Bla g 1 vaccination significantly reduced total inflammatory cell infiltrate, eosinophilia, secretion of Th2 cytokines IL-4 and IL-5 in bronchoalveolar lavage fluid, allergen-induced inflammatory infiltrates in the lungs, and Bla g 1-specific IgE in serum upon challenge with rBla g 1. Importantly, Bla g 1 DNA vaccination was able to induce IL-10-secreting regulatory T cells that could suppress the allergen-specific Th2 cells. CONCLUSION: DNA vaccination showed protective and therapeutic efficacy against a clinically relevant allergen Bla g 1.

Experimental autoimmune hearing loss is exacerbated in IL-10-deficient mice and reversed by IL-10 gene transfer.

Interleukin-10 (IL-10) has an important role in the homeostatic regulation of autoreactive T-cell repertoire. We hypothesized that endogenous IL-10 would regulate the severity of ß-tubulin-induced experimental autoimmune hearing loss (EAHL) and that exogenous IL-10 would abrogate it. BALB/c wild-type (WT) and homozygous IL-10-deficient mice (IL-10(-/-)) underwent ß-tubulin immunization to develop EAHL; some IL-10 mice with EAHL were administered IL-10 DNA at the peak of EAHL. Auditory brainstem responses were examined over time. EAHL developed progressively in both WT and IL-10(-/-) mice. However, the severity of hearing loss in the IL-10(-/-) mice was significantly greater than that in WT animals. Moreover, disease severity was associated with a significantly enhanced interferon-γ level and loss of hair cells in IL-10(-/-) mice. IL-10 administered to EAHL IL-10(-/-) mice promoted IL-10 expression. Consequently, hearing significantly improved by protecting hair cells in established EAHL. Importantly, IL-10 treatment suppressed proliferation of antigen-specific T-helper type 1 (Th1) cells, and the suppression can be attributed to inducing IL-10-secreting regulatory T cells that suppressed autoreactive T cells. We demonstrated that the lack of IL-10 exacerbated hearing loss, and the exogenous administration of IL-10 improved hearing. Mechanistically, our results indicate that IL-10 is capable of controlling autoimmune reaction severity by suppressing Th1-type proinflammatory responses and inducing IL-10-secreting regulatory T cells.

Time-intensity trade of bilaterally bone-conducted sounds in normal hearing subjects.

OBJECTIVE AND METHODS: In an effort to examine the rules by which information of bilaterally applied bone-conducted signals arising from interaural time differences (ITD) and interaural intensity differences (IID) is combined, data were measured for continuous 500 Hz narrow-band noise at 60 dBHL in 30 normal-hearing subjects using a centering method. Time-intensity trading functions were obtained by means of a sound image shifted towards one side by presenting an ITD, and shifted back to a centered sound image by varying the IID in the same ear. ITD values were varied from -600 to +600 microseconds at 200 microseconds steps, where negative values indicate delays to the right ear. RESULTS: Time-intensity trading functions in response to bone-conducted signals showed significantly lower discrimination thresholds across IIDs, when compared to a control group with applied air-conducted signals. These findings can be interpreted as a constructive interference effect related to the intimate mechanism of bilateral bone conduction, where interaural time differences play a major role. CONCLUSION: Time-intensity trade of bilaterally bone-conducted sounds in normal-hearing subjects is the highly sensitive. The high speed of sound through the skull may be the main reason for the high sensitivity of time-intensity trading.

Bone-conducted evoked myogenic potentials from the sternocleidomastoid muscle.

The aim of this study was to show that bone-conducted clicks and short tone bursts (STBs) can evoke myogenic potentials from the sternocleidomastoid muscle (SCM) and that these responses are of vestibular origin. Evoked potential responses to bone-conducted auditory stimuli were recorded from the SCMs of 20 normal volunteers and from 12 patients with well-defined lesions of the middle or inner ear or the VIIIth cranial nerve. The subjects, who had various labyrinthine and retro-labyrinthine pathologies, included five patients with bilateral profound conductive hearing loss, two with bilateral acoustic neuroma post-total neurectomy and five with bilateral sensorineural hearing loss. Air- and bone-conducted evoked myogenic potentials in response to clicks and STBs were recorded with surface electrodes over each SCM of each subject. In normal subjects, bone- and air-conducted clicks and STBs evoked biphasic responses from the SCM ipsilateral to the stimulated ear. The bone-conducted clicks evoked short-latency vestibular-evoked myogenic potential (VEMP) responses only in young subjects or in subjects with conductive hearing loss. STBs evoked VEMPs with higher amplitude and better waveform morphology than clicks with the same acoustic intensity. Patients with total VIIIth cranial nerve neurectomy showed no responses to air- or bone-conducted click or STB stimuli. Clear VEMP responses were evoked from patients with conductive or sensorineural hearing loss. It is concluded that loud auditory stimuli delivered by bone- as well as air conduction can evoke myogenic potentials from the SCM. These responses seem to be of vestibular origin.