Biomedical subjects

J C Saunders

Publications and source records attributed to J C Saunders.

At least 19 recordsLinked to original sources

PubMed2004

Spatial tuning curves along the chick basilar papilla in normal and sound-exposed ears.

Intense sound exposure destroys chick short hair cells and damages the tectorial membrane. Within a few days postexposure, signs of repair appear resulting in nearly complete structural recovery of the inner ear. Tectorial membrane repair, however, is incomplete, leaving a permanent defect on the sensory surface. The consequences of this defect on cochlear function, and particularly frequency analysis, are unclear. The present study organizes the sound-induced discharge activity of cochlear nerve units to describe the distribution of neural activity along the tonotopic axis of the basilar papilla. The distribution of this activity is compared in 12-day postexposed and age-matched control groups. Spontaneous activity, tuning curves, and rate-intensity functions were measured in each unit. Discharge activity at 60 frequency and intensity combinations was identified in the tuning curves of hundreds of units. Activity at each of these criterion frequency/intensity combinations was plotted against the unit's characteristic frequency to construct spatial tuning curves (STCs). The STCs depict tone-driven cochlear nerve activity along the length of the papilla. Tuning sharpness, low- and high- frequency slopes, and the maximum response were quantified for each STC. The sharpness of tuning increased with increasing criterion frequency. However, within a frequency, increasing sound intensity yielded more broadly tuned STCs. Also, the high-frequency slope was consistently steeper than the low-frequency slope. The STCs of exposed ears exhibited slightly less frequency selectivity than control ears across all frequencies and larger maximum responses for STCs with criterion frequencies spanning the tectorial membrane defect. When rate-intensity types were segregated, differences were observed in the STCs between saturating and sloping-up units. We propose that STC shape may be determined by global mechanical events, as well as localized tuning and nonlinear processes associated with individual hair cells. The results indicated that 12 days after intense sound exposure, global and local contributions to spatially distributed neural activity are restored.

Animals↗

PubMed2001

Chick cochlear hair cell exocytosis mediated by dihydropyridine-sensitive calcium channels.

1. A semi-intact preparation of the chick basilar papilla was developed to study calcium-dependent neurotransmitter release by tall hair cells (avian equivalent of cochlear inner hair cells). 2. Tall hair cell depolarization resulted in changes in cell membrane capacitance (DeltaC(m)) that reflected cell surface area increases following synaptic vesicle exocytosis and provided a surrogate measure of neurotransmitter release. Both calcium current (I(Ca)) and DeltaC(m) were reversibly blocked by cobalt, and exhibited a similar bell-shaped dependency on voltage with a peak response around -10 mV. 3. Pharmacological agents selective for L-type calcium channels were employed to assess the role of this channel type in neurotransmitter exocytosis. Nimodipine, a dihydropyridine (DHP) antagonist, suppressed I(Ca) and blocked DeltaC(m). Conversely, the DHP agonist Bay K 8644 increased both I(Ca) and DeltaC(m) amplitude nearly 3-fold. These findings suggest that chick tall hair cell neurotransmitter release is mediated by calcium influx through L-type calcium channels.

Animals↗

PubMed2001

Effects of surgery and other experimental factors on the evaluation of middle ear function in gekkonoid lizards.

This study examines three artificial factors likely to cause variation between results from different investigations of auditory function, at least in lizards. Controlled tests were performed on gecko lizards, by external laser interferometry of the middle ear transfer function at the tympanic membrane (TM). In conclusion, studies of middle ear function should examine motion both at the insertion of the columella-extracolumella shaft onto the TM, and at the tip of the extracolumellar pars inferior, because the internal proportions and function of the extracolumellar lever vary among species. At least in scansorial geckos, auditory experiments may be conducted with the animal on its back, as this posture introduces no acoustic artifacts. Positioning the subject on its belly, with the throat resting on the substrate, imposes small but significant artifacts on middle ear function. Similar artifacts occur with the belly up but the throat loaded with a modeling clay plate. The surgical fenestration of the ventral throat wall, common in auditory studies on lizards, causes (at least in Eublepharis) artificial enhancement of sensitivity at low frequencies and erratic responses at high frequencies.

Animals↗

PubMed2001

Hair bundle profiles along the chick basilar papilla.

Cochlear hair cells play a central role in the transduction of sound into neural output. Anatomical descriptions of these cells, and their protruding hair bundles, are of fundamental interest since hair cell transduction is dependent on hair bundle micromechanics and hair bundle micromechanics depends on hair bundle morphology. In this paper, we describe quantitatively changes in the staircase profile of the hair bundle along the apical portion of the chick's basilar papilla. Images of hair cells from 8 discretely dissected segments of the apical 3rd of the basilar papilla were archived, and the profile contour outlined by the tips of the stereocilia was digitised and curves were fitted by linear and power equations. The hair bundles of tall hair cells exhibited both linear and curvilinear profiles, which were equally distributed along the papilla. All short hair cells in our sample had straight contours. The differences in hair bundle shape among the tall hair cells may lead to differential susceptibility to injury and some variance in the current-displacement transduction curves due to differences in the translation of forces throughout the hair bundle.

Animals↗

PubMed2001

A comparison of monopolar electrosurgery to a new multipolar electrosurgical system in a rat model.

OBJECTIVES/HYPOTHESIS: The purpose of this study is to compare collateral tissue damage and wound healing in incisions created by electro-dissociation and conventional electrosurgery. Conventional electrosurgery has been used as an alternative to the scalpel to improve hemostasis. However, the heat generated by this instrument can cause tissue damage surrounding the incision, limiting its use around nerves and large blood vessels. A new technology, Coblation (Arthrocare Corp., Sunnyvale, CA), uses "electro-dissociation" to achieve similar results by creating charged particles from a conductive medium to make an incision while simultaneously achieving hemostasis. This new approach to electrosurgery may reduce soft tissue damage. STUDY DESIGN METHODS: Two prospective, matched design experiments were performed. In experiment I, both devices were set at the same electrical power in watts and then used to create an incision on the tongue of rats. In experiment II, the electrical power settings of both devices were adjusted until they created incisions of the same size. Epithelial destruction and collateral tissue damage were measured in histologically prepared tissue in both experiments, and the wound healing process was observed in experiment II at 0, 3, 7, and 14 days after surgery. RESULTS: The results showed that the electro-dissociation method created significantly less epithelial destruction and collateral tissue damage in both experiments. Granulation tissue formation was also significantly less extensive in the electrodissociation-induced incision after 7 and 14 days of recovery. CONCLUSIONS: Wound healing may be faster than with conventional electrosurgery if the Coblation device is used.

Animals↗

PubMed2001

Double-blind, placebo-controlled comparison of intramuscular olanzapine and intramuscular haloperidol in the treatment of acute agitation in schizophrenia.

OBJECTIVE: The authors evaluated the comparative efficacy and safety of intramuscular olanzapine, intramuscular haloperidol, and intramuscular placebo for the treatment of acute agitation in schizophrenia. METHOD: Hospitalized patients with schizophrenia received one to three injections of intramuscular olanzapine, 10 mg, intramuscular haloperidol, 7.5 mg, or intramuscular placebo over a 24-hour period. Agitation was measured with the excited component of the Positive and Negative Syndrome Scale and two additional scales. RESULTS: According to scores on the excited component of the Positive and Negative Syndrome Scale, both intramuscular olanzapine and intramuscular haloperidol reduced agitation significantly more than intramuscular placebo 2 and 24 hours following the first injection. Intramuscular olanzapine reduced agitation significantly more than intramuscular haloperidol 15, 30, and 45 minutes following the first injection. No patients treated with intramuscular olanzapine experienced acute dystonia, compared with 7% of those who were treated with intramuscular haloperidol. No significant QT(c) interval changes were observed in any patients. CONCLUSIONS: Intramuscular olanzapine represents a rapid, effective, and safe treatment for acute agitation in schizophrenia.

Acute Disease↗

PubMed2000

The sex-linked fidget mutation abolishes Brn4/Pou3f4 gene expression in the embryonic inner ear.

We have demonstrated that the phenotype of the mouse mutant sex-linked fidget ( slf ) is caused by developmental malformations of the inner ear that result in hearing loss and vestibular dysfunction. Recently, pilot mapping experiments suggested that the mouse Brn4 / Pou3f4 gene co-segregated with the slf locus on the mouse X chromosome. These mapping data, in conjunction with the observation that the vertical head-shaking phenotype of slf mutants is identical to that observed in mice with a targeted deletion of the Brn4 gene, suggested that slf is a mutant allele of the Brn4 gene. In this paper, we have identified the nature of the slf mutation, and demonstrated that it is an X chromosomal inversion with one breakpoint close to Brn4. This inversion selectively eliminates the expression of the Brn4 gene in the developing inner ear, but not the neural tube. Finally, these results demonstrate that the slf mutation is a good mouse model for the most prevalent form of X-linked congenital deafness in man, which is associated with mutations in the human Brn4 ortholog, POU3F4.

Animals↗

PubMed2000

Stereocilium injury mediates hair bundle stiffness loss and recovery following intense water-jet stimulation.

Inner ear hair cells exhibit many pathologies following exposure to intense sound, and the hair bundle is a major site of damage. This paper measures in vitro hair bundle motion on chick cochlear hair cells after intense in vitro and in vivo stimulation to explore the nature of hair bundle injury. Hair bundle stiffness, as well as relative and asymmetric motion of individual stereocilia, is controlled largely by the extracellular tip links, and a change in hair bundle motion was used to assess tip-link destruction following overstimulation. Intense in vitro stimulation caused a loss in stiffness that fully recovered within 10 min post-exposure. Relative and asymmetric stereocilia motion, however, were unchanged following the exposure, implying that tip links remained intact while the core or rootlet of the stereocilia were damaged and subsequently repaired. Intense and prolonged in vivo sound exposures produced stereocilia movements, measured in vitro, that were indicative of damage to stereocilia and tip links. Finally, the relative susceptibility of hair bundles to overstimulation was addressed by comparing stiffness loss with morphological features in the hair bundles. The loss of stiffness significantly increased as the amount of curvature in the hair bundle contour increased.

Acoustic Stimulation↗

PubMed2000

Control of ovine hepatic growth hormone receptor and insulin-like growth factor I by thyroid hormones in utero.

By use of RNase protection assays, hepatic growth hormone receptor (GHR) and insulin-like growth factor I (IGF-I) mRNA abundances were measured in sheep fetuses after experimental manipulation of fetal plasma thyroid hormone concentrations by fetal thyroidectomy (TX) and exogenous infusion of triiodothyronine (T(3)) and cortisol. TX abolished the normal prepartum rise in hepatic GHR abundance but had little effect on hepatic GHR gene expression at 127-130 days (term 145 +/- 2 days). By contrast, it upregulated basal IGF-I expression in immature fetal liver by increasing both Class 1 and Class 2 transcript abundance but had no further effects on IGF-I gene mRNA levels at 142-145 days. Raising plasma T(3) to prepartum values by exogenous infusion of either T(3) or cortisol into immature intact fetuses prematurely raised hepatic GHR and IGF-I mRNA abundances to values similar to those seen in intact fetuses at 142-145 days. In TX fetuses, cortisol infusion increased hepatic GHR mRNA but not total IGF-I mRNA abundance at 127-130 days. These findings show that thyroid hormones have an important role in the regulation of hepatic GHR and IGF-I gene expression in fetal sheep during late gestation and suggest that T(3) mediates the maturational effects of cortisol on the hepatic somatotropic axis close to term.

Animals↗

PubMed1999

Distribution of rate-intensity function types in chick cochlear nerve after exposure to intense sound.

Intense sound exposure to the chick ear produces cochlear damage and losses in auditory function. At twelve days post exposure there is considerable structural repair, although a defect on the sensory epithelium remains in the form of an incompletely healed 'patch' lesion. Auditory function significantly recovers 12 days after the exposure, but it, too, is incomplete. In this paper we describe the relationship between stimulus intensity and cochlear nerve discharge rate (the rate-intensity function) in two groups of chicks. One is exposed to damaging sound levels but allowed 12 days to recover, while the other is a group of non-exposed and age-matched control animals. Three different types of rate-intensity functions were identified; saturating, sloping, and straight. The percentage of saturating and sloping functions was compared across all characteristic frequencies in both groups of animals. A significant change was observed in the distribution of these types for recovered units with characteristic frequencies within the region of the patch lesion. In addition, the rate-intensity functions of these units exhibited a steeper slope and a higher maximum response. The distribution of rate-intensity function types and their slope and maximum responses, for units with characteristic frequencies outside of the patch lesion, was similar to those found in control ears. The changes in the cochlear nerve response in exposed chicks may be due to alterations in cochlear mechanics, hair cell or synaptic membrane properties, hair cell innervation, or the loss of a tonic suppression of afferent activity exerted by the damaged short hair cells.

Acoustic Stimulation↗

PubMed1999

Targeted mutagenesis of the POU-domain gene Brn4/Pou3f4 causes developmental defects in the inner ear.

Targeted mutagenesis in mice demonstrates that the POU-domain gene Brn4/Pou3f4 plays a crucial role in the patterning of the mesenchymal compartment of the inner ear. Brn4 is expressed extensively throughout the condensing mesenchyme of the developing inner ear. Mutant animals displayed behavioral anomalies that resulted from functional deficits in both the auditory and vestibular systems, including vertical head bobbing, changes in gait, and hearing loss. Anatomical analyses of the temporal bone, which is derived in part from the otic mesenchyme, demonstrated several dysplastic features in the mutant animals, including enlargement of the internal auditory meatus. Many phenotypic features of the mutant animals resulted from the reduction or thinning of the bony compartment of the inner ear. Histological analyses demonstrated a hypoplasia of those regions of the cochlea derived from otic mesenchyme, including the spiral limbus, the scala tympani, and strial fibrocytes. Interestingly, we observed a reduction in the coiling of the cochlea, which suggests that Brn-4 plays a role in the epithelial-mesenchymal communication necessary for the cochlear anlage to develop correctly. Finally, the stapes demonstrated several malformations, including changes in the size and morphology of its footplate. Because the stapes anlage does not express the Brn4 gene, stapes malformations suggest that the Brn4 gene also plays a role in mesenchymal-mesenchymal signaling. On the basis of these data, we suggest that Brn-4 enhances the survival of mesodermal cells during the mesenchymal remodeling that forms the mature bony labyrinth and regulates inductive signaling mechanisms in the otic mesenchyme.

Acoustic Stimulation↗

PubMed1999

The tip link's role in asymmetric stereocilia motion of chick cochlear hair cells.

The symmetry of chick cochlear hair bundle motion was examined in this study. Isolated segments from the basilar papilla were incubated in vitro in either normal or low calcium medium, which is known to disrupt tip links. Stereociliary bundles, stimulated with an oscillating water microjet, were oriented in profile and viewed in slow motion at high magnification with stroboscopic illumination. The displacement of the tallest hair in the bundle was fixed to 20 degrees peak-to-peak (P-P) motion. The angular deflections of the shortest and tallest hairs were then measured in both the positive (towards the tallest hair) and negative (towards the shortest) directions with respect to the non-stimulated position of the hair. The tallest hairs exhibited nearly symmetric motion in medium containing normal and low calcium. The shortest hairs, in normal calcium, displayed considerable asymmetry with angular deflections in the positive direction significantly larger than in the negative direction. This asymmetric motion disappeared after incubation in low calcium. The shortest hair angular displacement in the negative direction, however, was the same in both normal and low calcium conditions. These results indicated that the tallest and shortest hairs moved with equal angular deflection in the negative direction, while in the positive direction the shortest hair moved through a significantly greater angular deflection than the tallest hair. The implication of this finding is that the tip links contributed significantly to hair bundle motion in the positive direction only.

Animals↗

PubMed1999

Distal separation of chick cochlear hair cell stereocilia: analysis of contact-constraint models.

One model often used in the study of hair bundle micromechanics assumes simple geometric relationships between hair displacements, constrained by contact between neighboring hairs at their distal tips. Recent observations of hair bundle motion provided the opportunity to evaluate the contact-constraint model against measured displacements for the tallest and shortest sensory hairs. A contact-constraint model was developed based on the geometry of a single column of stereocilia. The model used morphological data from chick hair bundles for which displacement data in the excitatory and inhibitory directions were also available. For each hair bundle, a unique sensory hair radius was determined so that the calculated resting bundle morphology matched the measured values. The model was then evaluated against the displacement data for each hair bundle. In each case, the model underestimated the excitatory displacement of the shortest hairs. Failure of the model to accurately predict bundle motion raises the possibility of a distal separation between the hairs at rest. It is suggested that tip links pull the hairs through this separation during excitatory deflections. Perhaps at damaging levels of displacement, the hairs suddenly come into contact, tip-link tension dramatically increases, and the tip-links are fractured.

Animals↗

PubMed1999

Tip-link integrity on chick tall hair cell stereocilia following intense sound exposure.

Hair bundle tip links have been implicated in the process of hair cell transduction, and previous studies have shown that acoustic overstimulation or exposure to low calcium can disrupt them. Severed tip links would thus be expected to cause a loss in hair cell function. This study investigates the presence of tip links on chick tall hair cells at three exposure durations and three recovery durations. After 4, 24, or 48 h of exposure, and 24, 96, and 288 h of recovery, the basilar papilla was harvested and prepared for scanning electron microscopy. Photomicrographs of hair bundles from sound-exposed and age-matched control ears were obtained in regions of the papilla adjacent to the 'patch' lesion. The percentage of tip links present on these hair bundles was determined from the photomicrographs. After 4, 24, or 48 h of exposure, an average of 49%, 41.1% and 52% of the observed sensory hairs exhibited links. This was significantly lower than that seen in the control ears (71.2%). There also was a reliable recovery of tip links between 24 and 48 h of exposure. The recovery continued and by 24 h post exposure, tip links were present on 61.3% of the sensory hairs. At subsequent recovery intervals, the mean number of tip links on sound-exposed tall hair cells was statistically the same as seen on control cells. The results indicated a predictable loss in the number of tip links during the exposure and their restoration within a relatively short time after the exposure. This structural damage to the tall hair cell, and its recovery, could account for some of the loss and recovery of function in the auditory periphery of these sound-damaged chicks.

Animals↗

PubMed1999

Activation of the adult mode of ovine growth hormone receptor gene expression by cortisol during late fetal development.

The developmental and tissue-specific regulation of growth hormone receptor (GHR) mRNA expression is complex and involves alternate leader exon usage. The transcript composition of hepatic GHR mRNA has therefore been determined in fetal sheep during late gestation and after experimental manipulation of fetal plasma cortisol levels by fetal adrenalectomy and exogenous cortisol infusion, using RNase protection assays and a riboprobe containing exons 1A, 2, and 3 of the ovine GHR gene. Expression of the adult liver-specific GHR mRNA transcript containing exon 1A was not detected earlier than 138 days of gestation (term 145 +/-2 days). Thereafter, expression of this leader exon increased and accounted for 25-30% of the total GHR mRNA in the fetal liver at term. Hepatic GHR mRNA derived from leader exons other than 1A was detectable at 97 days and increased in abundance toward term in parallel with the normal prepartum rise in fetal plasma cortisol. Abolition of this cortisol surge by fetal adrenalectomy prevented both the activation of exon 1A expression and the prepartum rise in GHR mRNA derived from the other leader exons in fetal ovine liver. Conversely, raising cortisol levels by exogenous infusion earlier in gestation prematurely activated exon 1A expression and enhanced the abundance of GHR mRNA transcripts derived from the other leader exons. Cortisol therefore appears to activate the adult mode of GHR gene expression in fetal ovine liver during late gestation. These observations have important implications for the maturation of the somatotrophic axis and for the onset of GH-dependent growth after birth.

Adrenalectomy↗

PubMed1999

Sensitivity to simulated directional sound motion in the rat primary auditory cortex.

Sensitivity to simulated directional sound motion in the rat primary auditory cortex. This paper examines neuron responses in rat primary auditory cortex (AI) during sound stimulation of the two ears designed to simulate sound motion in the horizontal plane. The simulated sound motion was synthesized from mathematical equations that generated dynamic changes in interaural phase, intensity, and Doppler shifts at the two ears. The simulated sounds were based on moving sources in the right frontal horizontal quadrant. Stimuli consisted of three circumferential segments between 0 and 30 degrees, 30 and 60 degrees, and 60 and 90 degrees and four radial segments at 0, 30, 60, and 90 degrees. The constant velocity portion of each segment was 0.84 m long. The circumferential segments and center of the radial segments were calculated to simulate a distance of 2 m from the head. Each segment had two trajectories that simulated motion in both directions, and each trajectory was presented at two velocities. Young adult rats were anesthetized, the left primary auditory cortex was exposed, and microelectrode recordings were obtained from sound responsive cells in AI. All testing took place at a tonal frequency that most closely approximated the best frequency of the unit at a level 20 dB above the tuning curve threshold. The results were presented on polar plots that emphasized the two directions of simulated motion for each segment rather than the location of sound in space. The trajectory exhibiting a "maximum motion response" could be identified from these plots. "Neuron discharge profiles" within these trajectories were used to demonstrate neuron activity for the two motion directions. Cells were identified that clearly responded to simulated uni- or multidirectional sound motion (39%), that were sensitive to sound location only (19%), or that were sound driven but insensitive to our location or sound motion stimuli (42%). The results demonstrated the capacity of neurons in rat auditory cortex to selectively process dynamic stimulus conditions representing simulated motion on the horizontal plane. Our data further show that some cells were responsive to location along the horizontal plane but not sensitive to motion. Cells sensitive to motion, however, also responded best to the moving sound at a particular location within the trajectory. It would seem that the mechanisms underlying sensitivity to sound location as well as direction of motion converge on the same cell.

Acoustic Stimulation↗

PubMed1998

Transcriptional regulation of insulin-like growth factor-II gene expression by cortisol in fetal sheep during late gestation.

The objective of this study was to determine the mechanisms by which cortisol down-regulates hepatic insulin-like growth factor-II (IGF-II) gene expression in late gestation. Leader exons 6 and 7 of the ovine IGF-II gene, with their 5'-flanking regions, were first isolated. Characterization of transcription start sites revealed a unique site for exon 6 and three dispersed sites for exon 7. Nuclear run-on assays showed a 5-fold higher transcription rate of the IGF-II gene in liver of adrenalectomized fetuses compared with control animals, suggesting that regulation of IGF-II gene expression by cortisol is at the transcriptional level. RNase protection assays demonstrated hepatic leader exon 7 expression in adrenalectomized fetuses to be more than 2-fold higher than in controls, whereas it was reduced by 50% in cortisol-infused fetuses compared with controls. There was no effect on the expression of other leader exons. Functions of the upstream regulatory region of leader exon 7 (i.e. promoter P4) were investigated by luciferase transient expression. A region of -172 bases downstream relative to the first transcription site of leader exon 7 was shown to retain basal promoter activity and respond to cortisol. These results suggest that cortisol may induce the prenatal decline in ovine hepatic IGF-II expression by suppressing promoter P4 of the IGF-II gene.

Animals↗

PubMed1998

Morphometric changes in the chick nucleus magnocellularis following acoustic overstimulation.

The present investigation considered the effects of cochlear damage caused by exposure to intense sound on the nucleus magnocellularis of the chick. Neonatal chicks exposed to intense sound were separated into four groups with post-exposure recovery durations of 0, 15, 27, and 43 days. Four age-matched, non-exposed control groups were also formed. At each recovery interval, the control and exposed birds were sacrificed and their brains prepared for paraffin embedding. The brain stem region containing the nucleus magnocellularis (NM) was serially sectioned in the coronal plane. All sections containing NM cells were identified and then coded in terms of their percentile distance from the most caudolateral section. Sections along the nucleus at the 15th, 30th, 50th, 65th, 80th, and 95th percentile positions were selected for evaluation, and the cross-sectional areas of individual NM cells in these sections were then measured. Cell areas were corrected for the bias introduced by eccentricity of the nucleus. The number of NM cells per 1,000 microm2 was also calculated at the 50th and 65th percentile positions. These procedures were repeated for the age-matched, non-exposed control animals. The cross-sectional cell area in exposed animals, immediately after the exposure, was reduced significantly at all positions, but returned to near normal by 43 days of recovery. However, the coronal area of NM in the sections at the 50th and 65th percentile position, as well as NM cell density, were unaffected by the exposure at all recovery intervals. The observation of structural recovery in NM cells at 43 days post-exposure was remarkable because it occurred at least 4 weeks after complete functional restoration of single-cell activity in the NM. The shrinkage in NM cell size throughout the nucleus may be due to a general reduction in spontaneous activity in the cochlear nerve fibers caused by the acoustic injury to the chick basilar papilla.

Acoustic Stimulation↗