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D F Dolan

Publications and source records attributed to D F Dolan.

At least 37 records · Page 2Linked to original sources
PubMed1996

[Application of laser scanning confocal microscopy in inner ear morphological studies].

Laser scanning confocal microscope (LSCM) enables one to observe both the surface structure and the inner configuration in the same specimen, by its possibility of direct, non-invasive serial optical sectioning of whole mounted specimens. The potential value of LSCM in the field of inner ear morphological study was evaluated. The configuration of upper parts of organ of Corti was observed with the LSCM combined with double-stained fluorescence immunohistochemistry technique. The actin filament of hair cells by phalloidin, and the cytokeratin of supporting cells by monoclonal pan-anticytokeratin antibody. The stereocilia, cuticular plate, and the cuticle-free area of hair cells were well demonstrated. In the same specimen, the head plate of outer pillar cell, the phalangeal apical plate and the phalangeal process of Deiter cells were clearly showed as well. LSCM provide a new tool to the morphological study of organ of Corti.

Animals↗
PubMed1995

Monoclonal antibody induced hearing loss.

Monoclonal antibodies KHRI-3 and KHRI-5 identify antigens expressed on inner ear supporting cells and auditory hair cells respectively. To determine if these antibodies affect inner ear function groups of syngeneic Balb/c mice were inoculated with hybridomas KHRI-3, KHRI-5 and other Ig-secreting hybridomas. Hybridomas UM-A9, UM-7F11, the non-secreting SP2/0 myeloma and mice with no hybridoma were used as controls. Animals were tested for auditory brainstem responses (ABR) for frequencies of 4, 8, 16 and 24 kHz, before the inoculation of the hybridomas and at intervals of 6 to 10 days thereafter or daily once tumors became palpable. In normal mice there were no changes in ABR thresholds over the course of the experiment. Other control animals showed little change in ABR even when the growth of the hybridoma or myeloma tumors were far advanced. Of the KHRI-5 hybridoma bearing animals only one of seven animals exhibited threshold shifts greater than 15 dB. In contrast, most mice bearing the KHRI-3 hybridoma exhibited high frequency threshold shifts of 40-50 dB that coincided temporally with the growth of the hybridoma, the presence of circulating KHRI-3 antibody, and greatly increased immunoglobulin titers. Ears from KHRI-3-bearing mice that developed high frequency hearing loss also had a novel type of lesion in the basal turn of the cochlea that was characterized by loss of outer hair cells and absence of typical supporting cell scars. Such changes were not found in control hybridoma-bearing mice. These findings suggest that KHRI-3 antibody has an effect on hearing that is secondary to damage to the organ of Corti and loss of outer hair cells. Our results have important implications for antibody-mediated mechanisms of hearing loss and provide an animal model in which to study this phenomenon.

Acoustic Stimulation↗
PubMed1994

Comment on "Modulation of the hair cell motor: a possible source of odd-order distortion" [J. Acoust. Soc. Am. 96, 2210-2215 (1994)].

This reply to the response by Brown [J. Acoust. Soc. Am. 96, 2210-2215 (1994) on the report "Intermodulation distortion (F2-F1) in inner hair cell and basilar membrane responses [J. Acoust. Soc. Am. 93. 2061-2068 (1993)]" by Nuttall and Dolan is for the purpose of adding additional data concerning the nature and origin of the round window (RW)-recorded quadratic distortion tone (QDT) signal. It is shown that a major portion of the RW electrical signal originates from the activity of auditory neurons since tetrodotoxin (TTX) applied to the cochlea diminished the distortion product by about 75%. The neural component is also responsible for the characteristic 900-Hz optimal frequency separation of the primaries in producing the response. These data support our earlier suggestion [Nuttall and Dolan, J. Acoust. Soc. Am 93, 2061-2068 (1993)] that the level of intracellular receptor potential at the QDT frequency would be a stimulus for afferent fibers at low sound levels. These new data do not force a reinterpretation of Brown's hypothesis on the relationship of quadratic and cubic intermodulation distortion.

Ear, Inner↗
PubMed1993

Two-tone suppression of inner hair cell and basilar membrane responses in the guinea pig.

Recordings of receptor potentials from inner hair cells (IHCs) and the basilar membrane (BM) motion were made in pigmented guinea pigs. The acoustic stimuli were single tones near best frequency (BF) and two-tone complexes. Single tone input/output (I/O) functions had a saturating growth for the magnitude and their phase shifts were strongly dependent on the tone frequency relative to BF. For IHCs, a BF tone stimulus produced no phase shift in the ac receptor potential response. Phase lag or lead occurred for tones below or above BF, respectively. BM velocity I/O functions were not as compressively saturating as IHC ac I/O curves. BM phase shifts (in relation to BF) were similar to those of the IHCs. Two-tone suppression was observed in both IHC and BM response measures. Suppressor tones on the low-frequency side of BF produced complex suppression results, which were inconsistent with a simple attenuation model for suppression. The growth of suppression was faster than the attenuation from equivalent level reductions of the probe tone, and phase shifts were phase lead. Depending upon experimental conditions, phase change with suppression may be in the opposite direction from phase change observed from pure attenuation of the probe tone. High-frequency suppressors (relative to BF) are consistent with an attenuation model of suppression for the IHCs of the current study. High side suppression of basilar membrane velocity, however, differed from the IHCs in a systematic way. The phase change caused by suppression of BM velocity was always smaller than that of an equivalent reduction in the probe tone level.

Acoustic Stimulation↗
PubMed1993

Intermodulation distortion (F2-F1) in inner hair cell and basilar membrane responses.

Round window (RW) recordings in guinea pigs show a large response at the frequency of the quadratic difference tone (QDT) at F2-F1 for high-frequency (> 8 kHz) tone pairs. The magnitude of the RW response is dependent on frequency and level of the primaries. The QDT cochlear microphonic produced is largest for primaries with a frequency separation of approximately 900 Hz. Its source is probably the local activity of hair cells in basal cochlear locations where the high-frequency tones interact. QDT measurements from locations inside the organ of Corti show that the magnitude of the QDT is largest in the inner hair cell (IHC) region and monotonically increases as the difference in the frequency of the primaries decreases. Measured as IHC intracellular ac receptor potential, the QDT appears to be the result of a mechanical stimulus to the cell rather than as an inherent property of the nonlinear transduction in the IHC. However, QDT of the same form is not evident in the velocity responses of the basilar membrane. These results suggest that the outer hair cells (OHC) produce a strong quadratic distortion product mechanical force to stimulate inner hair cells. This mechanical drive may not be present, or is a weak component, in basilar membrane motion.

Acoustic Stimulation↗
PubMed1991

Laser Doppler velocimetry of basilar membrane vibration.

A method is described for the measurement of basilar membrane (BM) vibration velocimeter (LDV). The instrumentation was coupled to a compound microscope which served to visualize reflective glass microbeads placed on the BM. The laser beam of the LDV was focused in the microscope object plane and positioned over the reflective bead. We show examples of frequency tuning curves and displacement input/output intensity functions obtained with the technique.

Acoustic Stimulation↗
PubMed1991

Cochlear microphonic enhancement in two tone interactions.

Two tone interaction functions of the cochlear microphonic (CM) were obtained from pigmented guinea pigs. First (basal) cochlear turn recording locations show optimally enhanced levels of CM when the interfering tone (F2) was positioned about 4 kHz above probe tones (F1) of 12 kHz and 20 kHz. Maximum enhancement occurred for equal level tones. No enhancement was seen for a probe tone of 4 kHz. When basal turn cochlear sensitivity was compromised, CM enhancement caused by the interfering tone was altered and only CM reduction was then seen. The CM reduction was the typical characteristic described by many earlier studies. Guinea pigs with various changes in cochlear sensitivity were studied, providing evidence in support of earlier reports that CM interference (both reductions and enhancements) depends on far field vector summation of the outputs of hair cells from a restricted area of the basilar membrane. No CM enhancement was seen in micropipette recordings from within the organ of Corti.

Acoustic Stimulation↗
PubMed1990

Transgenic mouse model of the mild dominant form of osteogenesis imperfecta.

Osteogenesis imperfecta type I is a mild, dominantly inherited, connective tissue disorder characterized by bone fragility. Mutations in type I collagen account for all known cases. In Mov-13 mice, integration of a murine retrovirus within the first intron of the alpha 1(I) collagen gene results in a null allele blocked at the level of transcription. This study demonstrates that mutant mice heterozygous for the null allele are a model of osteogenesis imperfecta type I. A defect in type I collagen production is associated with dominant-acting morphological and functional defects in mineralized and nonmineralized connective tissue and with progressive hearing loss. The model provides an opportunity to investigate the effect of a reduced amount of type I collagen on the structure and integrity of extracellular matrix. It also may represent a system in which therapeutic strategies to strengthen connective tissue can be developed.

Animals↗
PubMed1990

Inner hair cell responses to the 2f1-f2 intermodulation distortion product.

Recordings of dc and ac receptor potentials from pigmented guinea pig inner hair cells indicate strong responses to the 2f1-f2 intermodulation tone when f1 and f2 are greater than the hair cell characteristic frequency and do not cause a response when given individually. The effective magnitude of this cubic distortion product (CDP) was about 25-30 dB below equal sound level primaries over a 20-30-dB range of their sound levels. The relative strength of the CDP declined at a rate greater than 180-dB/oct separation of the primaries. When magnitude of f1 or f2 was held constant, the growth of CDP was nonmonotonic, exhibiting a distinct maximum. With a constant level of f1 or f2, optimal CDP was produced when the level of f2 was 10-15 dB greater than f1. Strong two-tone suppression from the primaries has a role in shaping the CDP growth. The ac receptor potentials of the CDP show a 150 degrees-200 degrees phase shift when the primaries are increased over a 50-dB range. These results support the hypothesis of a propagated CDP in the cochlea and are consistent with the major features of related studies of human psychoacoustic experiments, afferent nerve neural rate functions, and ear canal distortion products.

Acoustic Stimulation↗
PubMed1990

Asynchronous neural activity recorded from the round window.

Voltage recorded from an electrode on the round window (RW) of guinea pig has characteristics that reflect the activity of auditory-nerve fibers in the absence of acoustic stimulation. Fast Fourier transformation (FFT) of the noise recorded from the RW electrode shows a broad spectral peak from 0.8-1.0 kHz. The magnitude of the biological noise is increased by high-frequency, bandlimited acoustic noise stimulation. Pure tones can suppress or enhance the spectral components around 0.8-1.0 kHz depending on frequency and intensity. Kainic acid applied to the intact RW membrane eliminates the biological noise (and the evoked cochlear whole-nerve responses) without alteration of the cochlear microphonic or the summating potential. The spectral characteristics of the biological noise seem to be related to the elemental waveform contributed by the individual auditory-nerve fibers to the voltage recorded at the RW electrode [Kiang et al., Electrocochleography, edited by R. J. Ruben, C. Elbering, and G. Solomon (University Park, Baltimore, 1976)].

Animals↗
PubMed1990

Experimental model of immune-mediated hearing loss using cross-species immunization.

The presence of immune-mediated hearing loss was investigated in an animal model. Eight guinea pigs and four mice underwent immunizations with a preparation of chick or guinea pig cochlear tissue and Freund's adjuvant. Hearing thresholds were monitored by auditory brainstem response (ABR) testing over a 5-week period after immunization. The serum and temporal bones of test and control animals were then examined using an enzyme-linked immunosorbent assay (ELISA), immunocytochemical, and histological techniques. Hearing loss of 20 dB or greater occurred in eight animals. ELISA demonstrated antibodies to cochlear antigens in the sera of all test animals. Immunocytochemistry revealed immunostaining of hair cell stereocilia in the organ of Corti and saccule. Endolymphatic hydrops, and organ of Corti degeneration was observed in the temporal bones of three animals. This study provides evidence to suggest that cross-species immunization with cochlear antigens might produce a humoral response that can be associated with inner ear pathologic change and sensorineural hearing loss.

Animals↗
PubMed1989

Inner hair cell responses to tonal stimulation in the presence of broadband noise.

The effects of broadband noise (BBN) on the tone-evoked de receptor potential from inner hair cells of guinea pigs were measured. The effects of the noise were: suppression of the receptor potential, no net change, or greater depolarization relative to the tone alone, evoked receptor potential. The effects appear to be consistent with a two-tone suppression hypothesis. The time course of the suppression effect is immediate and constant in time. This observation suggests no obvious involvement of a local feedback loop in outer hair cells or one depending on the efferent nerves. Inner hair cell "sensitivity" is a variable in the magnitude of the suppression. Comparison of masked, tone-evoked de receptor potential intensity functions to responses from auditory-nerve fibers (taken from the literature for experiments using a similar paradigm) differentiates the phenomena of suppression and adaptation in the auditory periphery.

Acoustic Stimulation↗
PubMed1989

Characterization of an EPSP-like potential recorded remotely from the round window.

The whole-nerve cochlear action potential (CAP), to tone burst stimulation, was recorded before and after application of tetrodotoxin (TTX) to the intact round window (RW) membrane. TTX abolished the CAP leaving a residual negative potential without altering the summating potential (SP) or the cochlear microphonic (CM). The residual potential retained its polarity when recorded from scala vestibuli. The peak latency, amplitude, and tuning properties of the residual potential showed features similar to the CAP. Application of kainic acid to the RW membrane eliminated the residual potential, leaving the SP and CM unaltered. It is hypothesized that the sources of the residual potential are the excitatory post-synaptic potentials from the peripheral processes of afferent dendrites under the inner hair cells.

Acoustic Stimulation↗
PubMed1988

Masked cochlear whole-nerve response intensity functions altered by electrical stimulation of the crossed olivocochlear bundle.

Cochlear whole-nerve response (CAP) intensity functions were recorded from the guinea pig round window. The intensity functions were obtained in the presence of masking noise, with electrical stimulation of the crossed olivocochlear bundle (COCB), and the combination of masking noise and COCB stimulation. Electrical stimulation of the COCB produced the expected reduction of CAP magnitude for low- to moderate-intensity tone bursts. Masking noise produced reductions in CAP magnitude over the whole signal intensity range used in this study. The combination of electrical stimulation of the COCB with the masking noise produced CAP magnitude changes graded between reduction and enhancement dependent on signal and masker levels. In general, at low signal levels, the masked CAP magnitude is reduced compared to the masked alone condition. At high signal levels, the masked CAP is increased in magnitude. These results confirm and extend the earlier observations of Nieder and Nieder [Exp. Neurol. 28, 174-188 (1970); also, Nature 227, 184-185 (1970)].

Animals↗
PubMed1986

Ototoxicity of cisplatin vs. platinum analogs CBDCA (JM-8) and CHIP (JM-9).

Cis-diamminedichloroplatinum (cisplatin), a divalent platinum compound and cell-cycle nonspecific chemotherapeutic agent, produces a permanent high-frequency sensorineural hearing loss and a dose-related cumulative renal insufficiency with tubular necrosis and interstitial nephritis. Synthetic platinum analogs are presently being tested to identify an analog with greater antitumor activity, but less ototoxicity and nephrotoxicity than cisplatin. The objectives of this study were to analyze the potential cochlear and nephrotoxic effects of two synthetic platinum analogs presently in phases I and II of clinical trials, CBDCA [JM-8 or cis-diammine, 1,1-cyclobutane dicarboxylato (2)-0,0(1)-platinum (NSC-241240)] and CHIP [JM-9 or cis-dichloro-trans-dihydroxybisisopropylamine platinum IV (NSC-256927)]. Cytocochleography, auditory brain-stem evoked response (ABR), double-blind light microscopy of renal tissues, and gamma emission analysis of 195mpt localization in viscera and inner ear were employed in the evaluation of cisplatin and platinum analogs (JM-8 and JM-9) in adult guinea pigs. Final results indicate that the investigational chemotherapeutic analogs CBDCA (JM-8) and CHIP (JM-9) do not produce the ototoxicity and nephrotoxicity characteristic of cisplatin. Furthermore, these findings demonstrate 195mpt localization in the vestibular labyrinth and confirm previous platinum distribution studies in the organ of Corti and stria vascularis tissues.

Animals↗
PubMed1986

Vestibular morphological analysis of the effects of cisplatin vs. platinum analogs, CBDCA (JM-8) and CHIP (JM-9).

Synthetic second generation chemotherapeutic platinum analogs are presently being tested to identify an analog with greater antitumor activity, but less ototoxicity and nephrotoxicity than cisplatin. The objective of this study was to analyze potential vestibular effects of cisplatin and of the two platinum analogs, CBDCA (cis-diammine 1,1-cyclobutane dicarboxylato [2]-0,0(1) platinum or JM-8) and CHIP (cis-dichlorotrans-dihydroxy-bis(isopropylamine) platinum [IV] or JM-9) using scanning and transmission electron microscopy of vestibular neuroepithelium from the albino guinea pig. Vestibular neuroepithelial damage was not demonstrated in either cisplatin- or the analog-treated animals when administered at equitoxic doses.

Animals↗
PubMed1986

Amelioration of cisplatin-induced ototoxicity by fosfomycin.

The continued chemotherapeutic application of cisplatin (cis-diamminedichloroplatinum [II]) necessitates reduction of its dose-limiting toxicity without decreasing its tumoricidal effect. This research project evaluated the efficacy of fosfomycin, a phosphonic acid antibiotic, in decreasing or ameliorating the ototoxicity (high frequency sensorineural hearing loss) and nephrotoxicity (renal tubular necrosis and interstitial nephritis) of cisplatin. Experimentally, fosfomycin effectively inhibits aminoglycoside-induced ototoxicity and nephrotoxicity in animals and humans. The efficacy of fosfomycin in blocking platinum-induced toxicity in the guinea pig was evaluated histologically and functionally using cytocochleography and light microscopy of the organ of Corti and the auditory brain stem evoked response (ABR), and light microscopy of renal corticomedullary tissues, small bowel, liver, lung, and peripheral nerve. The results demonstrate that fosfomycin ameliorates the acute renal tubular necrosis and interstitial nephritis and markedly inhibits the elevation of ABR thresholds and simultaneous outer hair cell loss that can result from cisplatinum administration. Fosfomycin should be considered a potential antidote for the dose-limiting ototoxicity and nephrotoxicity of cisplatin chemotherapy.

Acute Kidney Injury↗