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Biomedical subjects

J McGee

Publications and source records attributed to J McGee.

At least 37 records · Page 2Linked to original sources
PubMed1998

Pulmonary responses to oil fly ash particles in the rat differ by virtue of their specific soluble metals.

Occupational exposure to residual oil fly ash (ROFA) particulate has been associated with adverse respiratory health effects in humans. We hypothesized that ROFA collected at different sites within an oil burning power plant, by virtue of its differing metal and sulfate composition, will induce differential lung injury. Ten ROFA samples collected at various sites within a power plant were analyzed for water- and 1.0 M HCl-leachable arsenic (As), beryllium (Be), cadmium (Cd), cobalt (Co), chromium (Cr), copper (Cu), iron (Fe), manganese (Mn), nickel (Ni), lead (Pb), vanadium (V), zinc (Zn), and sulfur by inductively coupled plasma-atomic emission spectroscopy. All ROFA samples contained variable amounts of leachable (water-extractable) and 1.0 M HCl-extractable Fe, V, and/or Ni. All other metals, except Zn (ROFA No. 1 contained 3.43 and No. 3, 6.35 micrograms/mg Zn), were present in negligible quantities (< 1.0 microgram/mg) in the water extract. In vivo pulmonary injury from exposure to whole saline suspensions of these ROFA was evaluated. Male, SD rats (60 days old) were intratracheally instilled with either saline or saline suspension of whole ROFA (< 3.0 mass median aerodynamic diameter) at three concentrations (0.833, 3.33, or 8.33 mg/kg). After 24 h, lungs were lavaged and bronchoalveolar lavage fluid (BALF) was analyzed for cellular influx and protein content as well as lactate dehydrogenase (LDH) and N-acetyl glucosaminidase (NAG) activity and total hemoglobin as indicators of lung injury. ROFA-induced increases in BALF protein and LDH, but not neutrophilic inflammation, were associated with its water-leachable total metal, Ni, Fe, and sulfate content. However, the neutrophilic response following ROFA exposure was positively correlated with its water-leachable V content. Modest lung injury was observed with the ROFA samples which contained the smallest amounts of water-leachable metals. The ability of ROFA to induce oxidative burst in alveolar macrophage (AM) was determined in vitro using a chemiluminescence (CL) assay. AM CL signals in vitro were greatest with ROFA containing primarily soluble V and were less with ROFA containing Ni plus V. In summary, ROFA-induced in vivo acute pulmonary inflammation appears to be associated with its water-leachable V content; however, protein leakage appears to be associated with its water-leachable Ni content. ROFA-induced in vitro activation of AM was highest with ROFA containing leachable V but not with Ni plus V, suggesting that the potency and the mechanism of pulmonary injury will differ between emissions containing V and Ni.

Animals↗
PubMed1998

Ultrastructural, physiological, and molecular defects in the inner ear of a gene-knockout mouse model for autosomal Alport syndrome.

The cochleae from a COL4A3-deficient mouse line were examined for defects that might shed light on the molecular mechanism of otopathology observed in humans with Alport syndrome. At the light microscopic level no obvious defects were observed. Immunohistochemical analysis using antibodies specific for the basement membrane collagen chains revealed the absence of the COL4A3 and COL4A4 chains throughout the membranous labyrinth. The COL4A5 chain was absent from all cochlear basement membranes except those in the vessels of the stria vascularis. Expression of the COL4A1 and COL4A2 chains was unchanged in the mutant. Electron microscopic examination of the cochlear basement membranes revealed significant thinning of the basement membrane running from the spiral limbus, down the inner sulcus, across the basilar membrane and up to the spiral prominence. Basement membranes that normally ensheathe the root cells were not detectable. In contrast, the basement membranes surrounding the vessels of the stria vascularis were significantly thickened in the mutant. This was associated with endothelial cell swelling and a marked decrease in internal capillary diameter. In severe cases, pathology was observed in the marginal cells with a loss of basolateral infoldings. Immunohistochemical analysis of the strial vessels revealed an increase in entactin and collagen COL4A1 and COL4A2 chains. Auditory-evoked brainstem response measurements suggest a small increase in thresholds across all frequencies when successive measurements on individual mutant mice were examined between 6 and 8 postnatal weeks. Combined, these results illustrate changes in the basement membranes of the strial vessels that bear resemblance to Alport glomerular basement membrane pathology. A closer look at this compartment in human Alport biopsy specimen may be warranted.

Animals↗
PubMed1998

Metabotropic glutamate receptor activation modulates sound level processing in the cochlear nucleus.

The principal role of ionotropic glutamate receptors in the transmission and processing of information in the auditory pathway has been investigated extensively. In contrast, little is known about the functional contribution of the G-protein-coupled metabotropic glutamate receptors (mGluRs), although their anatomic location suggests that they exercise a significant influence on auditory processing. To investigate this issue, sound-evoked responses were obtained from single auditory neurons in the cochlear nuclear complex of anesthetized cats and gerbils, and metabotropic ligands were administered locally through microionophoretic pipettes. In general, microionophoresis of the mGluR agonists, (1S, 3R)-1-aminocyclopentane-1,3-dicarboxylic acid or (2S,1'S, 2'S)-2-(carboxycyclopropyl)glycine, initially produced a gradual increase in spontaneous and sound-evoked discharge rates. However, activation and recovery times were significantly longer than those observed for ionotropic agonists, such as N-methyl--aspartate or alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid, consistent with the recruitment of a second-messenger system. The efficacy of mGluR agonists was diminished after administration of the mGluR antagonist, (+)-alpha-methyl-4-carboxyphenylglycine, consistent with a selective action at metabotropic recognition sites. In contrast, two distinct changes were observed after the mGluR agonist had been discontinued for several minutes. Approximately 50% of neurons exhibited a chronic depression of sound-evoked discharge rate reminiscent of long-term depression, a cellular property observed in other systems. Approximately 30% of neurons exhibited a long-lasting enhancement of the sound-evoked response similar to the cellular phenomenon of long-term potentiation. These findings suggest that mGluR activation has a profound influence on the gain of primary afferent driven activity in the caudal cochlear nucleus.

Acoustic Stimulation↗
PubMed1997

A simple program for simulating the responses of neurons with arbitrarily structured and active dendritic trees.

We describe a simple program to simulate neural responses. This program is based on the compartmental approach, in which all compartments of a neuron (i.e. axon, soma or dendrite) are represented by the same basic electrical structure. A parameter file is used to store the model parameters, including the nonlinear channel characteristics of each compartment. The model is then automatically configured according to the values specified in the parameter file. The computation of the conductance of each active channel over time is handled by a unique subroutine optimized according to the kinetics of each channel. The equations for arbitrarily structured trees are solved implicitly using a simple algorithm similar to that of Hines (Hines, M. (1984) Int. J. Biomed. Comput., 15:69-76). The output of the model uses PostScript format. The advantage of this program is that it is small in size, simple to use, efficient, and is platform independent.

Algorithms↗
PubMed1997

Hearing loss in the RBF/DnJ mouse, a proposed animal model of Usher syndrome type IIa.

The Usher syndromes (US) are a group of inherited disorders that feature autosomal recessive neurosensory hearing loss or deafness with retinitis pigmentosa (RP). Moderate to severe non-progressive high frequency hearing loss with RP and normal vestibular function describes Usher syndrome type IIa, which has been localized to 1q41. Severe retinal degeneration in the inbred mouse strain RBF/DnJ is caused by rd3, a recessive gene located on mouse chromosome 1 distal to akp1 in a region which is orthologous to human 1q32-q42. We evaluated rd3 as a candidate for orthology with USH2A by first reducing and refining the relatively broad region in which rd3 is thought to reside. DNA of offspring from an RBF/DnJ x MOLF/Ei backcross was genotyped with PCR markers closely flanking the predicted location of rd3. Our haplotype analysis re-positioned rd3 to a 3.6 cM region between markers D1Mit273 (cen) and D1Mit209 (tel), consistent with the expected position of an USH2A murine orthologue. Consequently, rd3 is a positional candidate for Usher type IIa. Next we assessed the rd3/rd3 audiological phenotype to see how closely it paralleled that of Usher IIa. Audiological evaluation of mice at various ages revealed evidence of high frequency progressive hearing loss, previously unreported in the RBF/DnJ strain. However, this newly discovered hearing deficit was observed to be inherited independently of rd3, establishing that a completely different gene is responsible.

Animals↗
PubMed1997

Mechanisms of onset responses in octopus cells of the cochlear nucleus: implications of a model.

The octopus cells of the posteroventral cochlear nucleus receive inputs from auditory-nerve fibers and form one of the major ascending auditory pathways. They respond to acoustic and electrical stimulation transiently and are believed to carry temporal information in the precise timing of their action potentials. The mechanism whereby onset responses are generated is not clear. Proposals aimed at elucidating the mechanism range from neural circuitry and/or inhibition, "depolarization block" (or inactivation of Na+ channels), and the involvement of a 4-aminopyridine (4-AP)-sensitive, low-threshold channel (K(LT)). In the present study, we used a compartment model to investigate possible mechanisms. The model cell contains a soma, an axon, and four passive dendrites. Four kinds of ionic channels were included in the soma compartment: the Hodgkin-Huxley-like Na+ and K+ channels, a 4-AP-sensitive, low-threshold channel, K(LT), and a Cs+-sensitive, hyperpolarization-activated inward rectifier, Ih. DC currents and half-wave-rectified sine waves were used as stimuli. Our results showed that an onset response can be generated in the absence of neuronal circuitry of any form, thus suggesting that the onset response in octopus cells is regulated intrinsically. Among the many factors involved, low-input impedance, partly contributed by Ih, appears to be essential to the basic onset response pattern; also, the K(LT) conductance plays a major role, whereas the inactivation of Na+ channels probably plays only a secondary role. The dynamics of Ih also can modify the response pattern, but due to its slow kinetics, its role is probably limited to longer-term regulation under the conditions simulated in this study.

Acoustic Stimulation↗
PubMed1996

Onset and development of auditory brainstem responses in the Mongolian gerbil (Meriones unguiculatus).

The ontogeny of auditory function in the Mongolian gerbil (Meriones unguiculatus) was examined by measuring auditory brainstem response (ABR) thresholds for clicks and tone bursts at frequencies between 0.125 and 32 kHz. ABRs were elicited as early as 10 postnatal days (PND) in a small proportion of animals (28.6%). Three phases of development were identified based on the appearance of frequency-threshold curves: (a) an onset period (10-12 PND) during which ABRs could be elicited only by intense stimuli (95-110 dB SPL) within a restricted range of frequencies (0.25-8 kHz); (b) a transition period (13-14 PND) during which thresholds improved but frequency-threshold curves remained relatively flat; and (c) a refinement period (15-30 PND) during which frequency-threshold curves exhibited an adult-like ('V') shape and thresholds improved steadily to adult-like values. Opening of the external auditory meatus was associated with threshold improvements but not with changes in the frequency region of greatest sensitivity. Between the ages of 13 and 21 PND, low-frequency (0.125-1 kHz) and high-frequency (10-32 kHz) thresholds improved at statistically equivalent rates (4.9 and 5.6 dB/day, respectively), while thresholds for mid-frequency stimuli (2-8 kHz) improved at a significantly faster rate of 9.2 dB/day.

Acoustic Stimulation↗
PubMed1996

Distortion generated by the ear: its emergence and evolution during development.

Physiologically vulnerable active mechanics associated with the transduction of sounds in adults distort cochlear output. Specifically, frequencies not present in the incoming acoustic signal are represented in its output (ie., the spike trains of auditory nerve fibers). The purpose of this investigation was to study the appearance and evolution of intermodulation distortion during development. Established surgical and electrophysiologic techniques were used to record the extracellular electrical activity of individual auditory nerve fibers from developing kittens. Discharge-rate or synchrony-based responses to two tones (f1 and f2) presented simultaneously at various ratios of f2/f1 were recorded. The cubic distortion product (CDP; 2f1-f2, where f1<f2) and the difference tone (f2-f1) were the intermodulation distortion products (DPs) emphasized in the investigation. CDPs were first observed nearly 10 days after the earliest auditory nerve fiber responses to simple tone-burst stimuli could be elicited in neonatal cats. Furthermore, the spectrum of DPs generated in the cochlea changed dramatically during the second postnatal week and achieved adultlike characteristics after the first postnatal month. Findings reported here support the notion that cochlear transduction is initially linear in neonatal cats, possibly representing a critical period of auditory development, and that the content of distortion-related spectral information carried in auditory nerve fiber spike trains increases during development, in concert with other peripheral auditory attributes.

Animals↗
PubMed1996

Effects of stimulus rate on the feline brain-stem auditory evoked response during development. I. Peak latencies.

The effects of stimulation rate on the brain-stem auditory evoked response (BAER) of developing and adult cats were investigated. Age ranged from 10-post-natal days to young adults. Clicks were presented at levels of 90 dB pSPL and 20 dB above each animal's click threshold (20 dB SL). For all animals, a conventional BAER rate series was obtained at rates of 5, 10, 30, 60, and 90 Hz. BAERs were also obtained using pseudorandom pulse sequences called maximum length sequences (MLSs). The minimum time between pulses, the minimum pulse interval (MPI), included 0.5, 1, 2, 4, and 6 ms, which correspond to average rates of 1000, 500, 250, 125, and 83 Hz, respectively. Dependent variables included the latencies of the first four BAER peaks, labeled i through iv. MLS BAERs were indistinguishable from conventional BAERs at all ages studied. In general, for both conventional and MLS BAERs, peak latencies and the i-iv interval increased with increasing stimulus rate. Although absolute peak latencies and the i-iv interval decreased systematically with age, the relative shift in latency and i-iv interval induced by increasing stimulus rate decreased during development. The enhanced sensitivity to stimulus rate observed at younger ages was not the consequence of the threshold improvement that occurs during development since similar observations were made when stimuli were presented at a constant absolute level (90 dB pSPL) or at a constant level above threshold (20 dB SL). In addition, successive BAER peaks exhibited progressively larger latency shifts with increasing stimulus rate at all ages studied. These data suggest that higher stimulus rates produce greater neural adaptation resulting in prolonged BAER peak latencies. Furthermore, the effects of adaptation are cumulative across synapses, and the mechanisms responsible for the acquisition of adult-like adaptation properties develop during the early post-natal period in the cat.

Animals↗
PubMed1996

Effects of stimulus rate on the feline brain-stem auditory evoked response during development. II. Peak amplitudes.

The effects of click rate on brain-stem auditory evoked response (BAER) peak amplitudes were investigated in adult cats and kittens in four age groups: 10, 15, 20, and 30 post-natal days. Conventional BAERs were obtained at rates of 5, 10, 30, 60, and 90 Hz. Maximum length sequences (MLSs) were used to obtain responses at rates of 83, 125, 250, 500, and 1000 Hz. For both techniques, clicks were presented at 90 dB pSPL, and at 20 dB above threshold (20 dB SL). BAERs were observed for all age groups, at all click rates. However, not all peaks could be identified in all animals, with peak absence more common for the youngest kittens at the higher rates. BAER waves i through iv decreased in amplitude with increasing click rate for all age groups. In general, the smallest peak amplitudes were observed for the youngest animals (10- to 15-day-old) studied, while the largest amplitudes were found for the adult, 20- or 30-day-old animals, regardless of rate. When amplitudes were normalized to eliminate the influences of differences in absolute values due to developmental stage (i.e., made proportional to the amplitude observed at 5 Hz), the younger age groups exhibited enhanced sensitivity to the effects of stimulus rate. However, exceptions to this trend were observed. In general, amplitudes of BAER peaks obtained with the MLS procedure were smaller than those obtained using conventional averaging with a similar average click rate, regardless of age. Finally, the most efficient method for obtaining a response at a criterion signal-to-noise ratio was typically by the use of conventional averaging at a rate of 60 or 90 Hz, for all peaks and age groups, Overall, these data suggest that higher stimulus rates produce greater neural adaptation resulting in reduced BAER peak amplitudes. The mechanism responsible for the acquisition of adult-like adaptation properties appears to develop during the early post-natal period in the cat.

Animals↗
PubMed1996

Employer-specific versus community-wide report cards: is there a difference?

This article describes preliminary results from a natural experiment that tested the impact of report cards on employees. As part of the 1995 enrollment process, some members of the State of Minnesota Employee Group Insurance Program received report cards on the plans offered to them, and others did not. Both groups of employees had a chance to review a second community-wide report card covering all Minnesota plans that had been distributed by an independent organization through local newspapers. Both groups were surveyed before and after they made their health plan selections. We compare the likelihood of seeing, the intensity of reading, and the perceived helpfulness of the first, employer-specific report card with the second, community-wide report card for consumers who make plan selections.

Analysis of Variance↗
PubMed1995

Activity-dependent responses of developing cochlear nuclear neurons to microionophoretically-applied amino acids.

The experimental purpose of this investigation was to determine whether the efficacy of glutamate, N-methyl-D-aspartate (NMDA) and/or GABA is related to the activity state of neurons in the cochlear nuclear complex (CN). The hypothesis tested was that changes in discharge activity produced by glutamatergic and GABAergic ligands are, or may be, greater when neurons are stimulated at moderate to high acoustic levels compared to near threshold stimulation levels, when activity levels are high or low, respectively. All neurons from which discharge rate vs. sound pressure level curves were tested during simultaneous administration of amino acids exhibited characteristics commensurate with an activity-dependent system; at high sound levels, when discharge rates were elevated relative to rates produced by low level stimuli, both glutamate-induced increments and GABA-induced decrements in discharge rate were enhanced. The relationship between discharge rate and amino acid efficacy was a uniform property of neurons sampled throughout the first two postnatal weeks of development. In adults, preliminary indications are that activity-dependent neurotransmitter efficacy is characteristic of some cells, but not others. The activity-dependent nature of endogenous amino acid neurotransmission was demonstrated through the microionophoretic administration of NMDA and GABAA selective antagonists, D-alpha-aminoadipate (D alpha AA) and 2-amino-5-phosphonovalerate (APV), and bicuculline (BIC), respectively. These results suggest that postsynaptic actions elicited by membrane receptors subserving amino acid neurotransmission within the CN are activity-dependent.

2-Amino-5-phosphonovalerate↗
PubMed1995

The digital toolbox for teaching.

Continued improvements in computer technology have led to significant enhancement of clinical teaching. We describe a "digital toolbox" consisting of personally accessible hardware and software products to assist in clinical teaching. The areas covered are computer-assisted diagnosis, digitization and display of clinical materials, archiving of digitized clinical materials, and decision analysis. All products are commercially available, and none require special training or customization for medical teaching application.

Decision Support Techniques↗
PubMed1994

Responses of peripheral auditory neurons to two-tone stimuli during development: I. Correlation with frequency selectivity.

The responses of peripheral auditory neurons to two-tone stimuli were used to inferentially examine the nature of cochlear processing during development. Rate suppression was not seen in the youngest animals, and was first observed at 77 gestational days, in units exhibiting adultlike frequency selectivity. Suppression was highly correlated with the degree of tuning, and neurons were segregated into three classes based on these responses. Broadly tuned neurons (type IB) with low characteristic frequencies (CFs) did not exhibit suppression, and were observed early in postnatal life. Sharply tuned, but still immature neurons (type IS) exhibited suppression, but to a lesser degree than mature neurons (type M). One interpretation of these results is that basilar membrane mechanics are linear during the final stages of cochlear development, indicating that the immature signal transduction process is fundamentally different from that of adults.

Acoustic Stimulation↗
PubMed1994

Responses of peripheral auditory neurons to two-tone stimuli during development: II. Factors related to neural responsiveness.

In an accompanying paper (Fitzakerley et al., 1994), it was demonstrated that there is a significant developmental correlation between the appearance of tuning and two-tone suppression. However, it was also found that some sharply tuned neurons meeting minimal adult standards did not exhibit suppression. Therefore, in order to investigate other factors that may be related to the demonstration of suppression in peripheral auditory neurons, the relationship of two-tone suppression with various parameters related to neural responsiveness was studied in perinatal kittens. A positive correlation was made between the observance of suppression and driven discharge rate, characteristic frequency (CF), and threshold, all properties which change significantly during the final stages of cochlear differentiation. In older animals, suppression was also observed in higher percentages of neurons having low spontaneous rates (< 1 spk/s). Suppression was evoked less often by test tones placed below CF than above CF in neurons recorded from younger animals, and was generally produced by a narrower range of test tone intensities than those recorded from adults. As a result, the conventional description of suppression as observed in peripheral auditory neurons in mature animals must be extended to include these factors when responses of immature neurons are considered.

Acoustic Stimulation↗
PubMed1994

Health care report cards: what about consumers' perspectives?

Though the report card style is seen by many as a way to create better-informed consumers, very little is actually known about how consumers will respond to health care report cards. Report cards are only one of many factors that influence health care decision making. Much consumer-oriented effort and fine-tuning will be required to make report cards effective. Using the approach called "social marketing" as a framework, specific examples are used to outline some ideas for more intensive pursuit of consumers' perspectives in the design and distribution of report cards.

Consumer Behavior↗
PubMed1993

Development of glutamate and NMDA sensitivity of neurons within the cochlear nuclear complex of kittens.

1. The effects of glutamate, N-methyl-D-aspartate (NMDA), and NMDA receptor antagonists, D-alpha-aminoadipate (D alpha AA) and 2-amino-5-phosphonovalerate (APV), microionophoretically applied onto neurons in the caudal divisions (posteroventral and dorsal subnuclei) of the cochlear nuclear complex (CN), were investigated during postnatal development in kittens with the use of extracellular techniques. From birth through postnatal day 7, microionophoretically applied glutamate elevated the acoustically evoked discharge rates of nearly 80% of neurons studied. Although fewer neurons were studied with the use of NMDA, approximately 65% of these responded to this glutamatergic agonist, and no developmental changes in the percentage of responsive neurons were observed. The actions of NMDA antagonists were studied in a relatively small number of neurons, and results support the supposition that glutamate, or a glutamate-like substance, acts as a CN neurotransmitter throughout postnatal life. 2. Approximately 64% of CN neurons encountered among neonatal animals were unresponsive to acoustic stimulation, even at the highest output levels available (> 120 dB SPL). That percentage declined monotonically during the next three postnatal days, such that approximately 23% of neurons encountered were unresponsive to acoustic stimulation on the third day. Essentially all encountered neurons were responsive to acoustic stimulation by the middle of the second postnatal week. Under conditions of simultaneous glutamate and acoustic stimulation, neurons in this general class of "acoustically unresponsive" neurons segregated into two groups. Glutamate increased spontaneous discharge rate in 45% of the neurons studied, however, these units remained acoustically unresponsive during combined sound and excitatory amino acid stimulation (group A1). In the second group (A2), 55% of the neurons that were acoustically unresponsive under control (sound alone) conditions responded to the acoustic component of the combined acoustic and glutamate stimulation (the experimental condition) in a frequency-dependent manner. A2 neurons exhibited temporal firing patterns characteristic of acoustically responsive neurons of corresponding age, suggesting that these neurons are functionally connected to the auditory periphery, whereas A1 neurons are not. 3. Dose-response curves were either sigmoidal or linear over the range that measurements were made, and maximum discharge rates evoked by high doses of glutamate in the youngest animals studied tended to be lower than those produced by acoustic stimulation alone in older animals. These results suggest that intrinsic properties contribute to the mechanism(s) that limits neuronal responsiveness. Average dose-response curve slopes were higher for neurons recorded from older animals, also indicating that intrinsic properties regulating dynamic response range are acquired postnatally in the kitten CN.(ABSTRACT TRUNCATED AT 400 WORDS)

2-Amino-5-phosphonovalerate↗