Faculty Bibliography

1. Coincidence-detection of excitatory synaptic potentials has long been considered to be the mechanism by which medial superior olivary (MSO) neurons compute interaural time differences. Here we demonstrate the contribution of synaptic inhibition in this circuit using a gerbil brain slice preparation. 2. Nearly all cells exhibited excitatory postsynaptic potentials (EPSPs) and action potentials (APs) after stimulation of either the ipsilateral or contralateral afferent pathway. In 44% of cells, the latency of APs depended on stimulus amplitude, exhibiting shifts of 0.25-2 ms. 3. Nearly all neurons (89%) exhibited stimulus-evoked synaptic inhibition. The inhibitory effects were enhanced at greater stimulus amplitudes and were usually able to block synaptically evoked APs. In addition, APs and EPSPs were reversibly blocked by delivering the inhibitory transmitter glycine in almost all tested cells (91%). 4. In the presence of the glycine antagonist strychnine, the effects of synaptic inhibition were suppressed. 5. The stimulus level-dependent inhibitory potentials influenced the probability that an MSO neuron would fire an AP, as well as the precise timing. Therefore, the present results have implications for the processing of interaural time differences by the MSO and at higher auditory centers

This study examines the histologic and biochemical features of wound healing in a cleft lip model in the mid-third-trimester fetal rabbit. At days 1, 2, and 4 after the procedure, control, unrepaired, and repaired fetal heads were obtained, sectioned, and stained for histologic examination. The localization of hyaluronic acid in the wound was documented using a cartilage-derived hyaluronic acid-binding protein. In both repaired and unrepaired wounds, the fetal cleft healed without inflammatory cell infiltration or scar formation. Six months after birth, the repaired cleft showed complete regeneration of muscle across the wound and the collagen fibers were of normal density and orientation. Decreased hyaluronic acid deposition was observed in unrepaired clefts as compared with adjacent tissue; no such difference was detected in repaired clefts. Our findings support the hypothesis that a cleft lip repaired in utero heals without the scarring that accompanies postnatal repair. This may explain the lack of maxillary growth restriction after in utero cleft lip repair.

Although composite data from separate subjects can be used to generate single-subject estimates, intersubject variation precludes rigorous ocular pharmacokinetic analysis. Therefore, a rabbit model in which sequential aqueous and vitreous humor samples were obtained following the administration of the quinolone fleroxacin was developed. Mean data from individual animals were used for pharmacokinetic analysis. Following direct intravitreal or systemic drug administration, sequential paracenteses did not alter pharmacokinetic constants or ocular penetration and were not associated with an increase in ocular protein; contamination of vitreous humor with blood was minimal (less than 0.1%). Following direct injection or intravenous administration, vitreous humor concentration-time data were best described by one- and two-compartment models, respectively. The maximum concentration and the penetration into the aqueous and vitreous humors were 1.54 and 0.5 micrograms/ml and 27 and 10%, respectively. Elimination rates from aqueous and vitreous humors and serum were similar following parenteral drug administration. Drug elimination following direct injection was rapid, and the elimination rate from the vitreous humor was not prolonged by the coadministration of probenecid. Our animal model provides a new approach to the rigorous examination of the ocular pharmacokinetics of quinolone antimicrobial agents in the eye.

Spasmodic dysphonia has been successfully treated by thyroarytenoid muscle injections of botulinum toxin (Botox) with dosages ranging from 0.625 to 25 U. In some patients, excessive paralysis with resulting breathiness and aspiration have been noted. In order to maximize the efficiency of Botox injections, the histologic effects of various Botox dosages were examined in the dog. Nine canine thyroarytenoid muscles were injected with 0.5 to 12.5 U of Botox. After 24 hours, the recurrent laryngeal nerve to the injected muscle was electrically stimulated in order to deplete the glycogen within the muscle fibers. Frozen sections of this muscle were then stained for glycogen. Those fibers that retained their glycogen were presumed paralyzed by the Botox injection. The extent of paralysis was found to be dose-related from 1.0 to 7.5 U. At 10 U and above the muscle was completely paralyzed. Spread of the toxin to the lateral cricoarytenoid muscle was seen at doses as low as 1.0 U. Clearly, doses less than 10 U appear sufficient for clinical paralysis.

Measurements of interfacial (double layer) capacitance, C(DL), and charge transfer resistance, R(CT), have been made as a function of temperature at fluid electrolyte interfaces with electrodes made from two different Tl-based high-temperature superconductor materials. Measurements spanning the 112-119 K superconducting transition temperatures, T(c), of the HTSC electrodes reveal a smooth decrease in C(DL) with decreasing temperatures, except that an abrupt, ca. 1 deg wide change in the shape of the C(DL) Vs temperature curve occurs at the T(c) of the electrode. These are the first data which show that the onset of superconductivity can be reflected in a chemical phenomenon at a molecular fluid/HTSC interface. Of the several contributors to interfacial capacitance, it is hypothesized that alteration in charge carrier distribution or polarizability over the outermost electrode lattice layer as electron pairs start to appear at T(c) is the most likely origin of the T(c)-correlated capacitance feature. Alterations in the charge transfer resistance for electrochemical solvent reduction appear over the same temperature interval as the capacitance feature, but not as consistently.

Studies of aural and other body tissues suggest that otosclerosis represents the local manifestation of a general disorder of connective tissue. In particular, collagen abnormalities have been described. We have undertaken a pilot study of the in vivo messenger RNA (mRNA) transcription for procollagenase (precursor of collagenase), as well as for stromelysin and tissue inhibitor of metalloprotease (TIMP), an activator and a specific inhibitor of tissue collagenase activity, respectively. Human skin from individuals with surgically confirmed otosclerosis was compared to skin from their family members (clinically positive and clinically negative) and from unrelated normal controls. Preliminary data indicate that on average there are significantly lower levels of mRNA production for stromelysin among individuals with otosclerosis as compared to all others tested. Similar trends were demonstrated for TIMP and procollagenase, although these did not achieve statistical significance. In addition to suggesting a pathogenetic mechanism for the development of the disease, these data could serve as the basis of possible confirmatory tests for early diagnosis of otosclerosis and as a method for evaluating the genotype of offspring of affected individuals prior to their age of clinical manifestation. This could translate into the application of prophylactic treatment regimens in the future. The proposed abnormalities also suggest candidate genes for otosclerosis.

Injury to either the peripheral or central nervous system results in the accumulation of growth factors at the wound site. Some of these growth factors have been shown to participate in the neural repair process. Adult auditory neurons grown in dissociated spiral ganglion cell cultures are injured (i.e. bilateral axotomy) as a result of the initial preparation of these cultures. Therefore, cell cultures of dissociated spiral ganglia provide a model for the study of repair processes of adult auditory neurons (e.g. effects of exogenous growth factors on the process of neuritogenesis by injured neurons). Auditory neurons do not survive in these dissociated ganglion cell cultures when only exogenous NGF is added to the defined culture medium. Previous work has identified substrate bound basic fibroblast growth factor (bFGF) as a survival factor for adult auditory neurons in vitro. Auditory neurons cultured on substrate bound bFGF also do not show increased survival in response to the addition of increasing concentrations of nerve growth factor (NGF) to the defined medium. This is in sharp contrast to the pronounced neurite outgrowth-promoting effects (concentration dependent) observed when exogenous NGF is added to adult auditory neurons cultured on substrate bound bFGF. We propose that several neuronotrophic factors (e.g. TGFB1, bFGF, NGF and other neurotrophins) are active in the spiral ganglions' response to injury. Several of these growth factors (i.e. bFGF, NGF) act in cooperation to promote the regeneration or repair of severed or traumatized neuritic processes.

The development of human hearing from the 26th week of fetal life to the third year post natal life is reviewed. The human fetus can perceive, react, and store auditory information from the 26th week of fetal life. This ability appears to play a role in the development of language. Infants by the 2nd to 3rd month of postpartum life have categorical perception for most phonemes whether or not these phonemes are native to their own language. The infant has a difference limen similar to that of the adult. The infant threshold is higher; the single-to-noise ratio is greater in infants than adults; and the infant's temporal processing is slower than that of the adult.