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P J Kim

Publications and source records attributed to P J Kim.

13 recordsLinked to original sources
PubMed1998

Single unit recordings in the auditory nerve of congenitally deaf white cats: morphological correlates in the cochlea and cochlear nucleus.

It is well known that experimentally induced cochlear damage produces structural, physiological, and biochemical alterations in neurons of the cochlear nucleus. In contrast, much less is known with respect to the naturally occurring cochlear pathology presented by congenital deafness. The present study attempts to relate organ of Corti structure and auditory nerve activity to the morphology of primary synaptic endings in the cochlear nucleus of congenitally deaf white cats. Our observations reveal that the amount of sound-evoked spike activity in auditory nerve fibers influences terminal morphology and synaptic structure in the anteroventral cochlear nucleus. Some white cats had no hearing. They exhibited severely reduced spontaneous activity and no sound-evoked activity in auditory nerve fibers. They had no recognizable organ of Corti, presented >90% loss of spiral ganglion cells, and displayed marked structural abnormalities of endbulbs of Held and their synapses. Other white cats had partial hearing and possessed auditory nerve fibers with a wide range of spontaneous activity but elevated sound-evoked thresholds (60-70 dB SPL). They also exhibited obvious abnormalities in the tectorial membrane, supporting cells, and Reissner's membrane throughout the cochlear duct and had complete inner and outer hair cell loss in the base. The spatial distribution of spiral ganglion cell loss correlated with the pattern of hair cell loss. Primary neurons of hearing-impaired cats displayed structural abnormalities of their endbulbs and synapses in the cochlear nucleus which were intermediate in form compared to normal and totally deaf cats. Changes in endbulb structure appear to correspond to relative levels of deafness. These data suggest that endbulb structure is significantly influenced by sound-evoked auditory nerve activity.

Animals↗
PubMed1998

Colocalization of heparin and receptor binding sites on keratinocyte growth factor.

Keratinocyte growth factor (KGF) is a member of the fibroblast growth factor (FGF) family. FGFs are also known as heparin-binding growth factors because they bind to heparin and their physical and biological properties are modulated by heparin. Consistent with a role as a paracrine effector, KGF is produced by cells of mesenchymal origin but is active primarily, if not exclusively, on epithelial cells. KGF is involved in a variety of physiological processes, including proliferation, differentiation, wound healing, and cytoprotection. To identify regions in KGF that contribute to heparin and tyrosine kinase receptor interactions, nine peptides spanning defined motifs in the predicted structure of KGF were synthesized, and their heparin and receptor binding properties were analyzed. Peptides at the amino and carboxyl termini bound heparin, and one peptide showed relative binding comparable to that of KGF. Competitive binding studies showed that this peptide along with two other overlapping peptides specifically displaced KGF bound to the KGF receptor. These three peptides were also selectively recognized by a neutralizing monoclonal antibody against KGF, though only in the presence of heparin. Together, these data suggest that the sites for heparin and receptor binding both reside in the amino and carboxyl termini of KGF, which are spatially juxtaposed in the predicted three-dimensional structure of this molecule.

Amino Acid Sequence↗
PubMed1998

Evaluation of RU28318 and RU40555 as selective mineralocorticoid receptor and glucocorticoid receptor antagonists, respectively: receptor measures and functional studies.

Corticosterone regulates a wide range of physiological parameters. Two receptors for corticosterone have been identified, the mineralocorticoid (type I) receptor (MR) and the glucocorticoid (type II) receptor (GR). To determine the relative role of these two receptors in mediating the effects of endogenous corticosterone, many studies have relied on the use of putative selective corticosteroid receptor antagonists. This study further examined the in vivo receptor selectivity of two compounds, RU28318 and RU40555 that are believed to be selective antagonists for MR and GR, respectively. Acute treatment of adrenalectomized rats with RU28318 (10-50 mg/kg) selectively decreased ex-vivo available MR binding in the hippocampus, whereas acute treatment with RU40555 (10-30 mg/kg) selectively decreased available GR binding in the hippocampus and pituitary. These receptor binding measures suggest that RU28318 in vivo selectively occupied MR, and that RU40555 in vivo selectively occupied GR. In functional studies, RU28318 (50 mg/kg) blocked the normalizing effect of aldosterone (120 microg/kg) on saline intake of adrenalectomized rats. RU40555 (30 mg/kg) blocked the suppressive effect of dexamethasone (50 microg/kg) on acute stress-induced corticosterone secretion. These studies further support the in vivo corticosteroid receptor selectivity of these two compounds and confirms their effective corticosteroid antagonistic properties.

Adrenalectomy↗
PubMed1998

Genetics of the deflagellation pathway in Chlamydomonas.

Signal-induced deflagellation in Chlamydomonas involves Ca2+-activated breakage of the nine outer-doublet axonemal microtubules at a specific site in the flagellar transition zone. In this study, we isolated 13 new deflagellation mutants that can be divided into two phenotypic classes, the Adf class and the Fa class. Cells with the Adf deflagellation phenotype are defective in acid-stimulated Ca2+ influx, but can be induced to deflagellate by treatment with nonionic detergent and Ca2+. Genetic analyses show that the five new Adf mutations, as well as the previously identified adf1 mutation, are alleles of the ADF1 gene. Mutants in the second phenotypic class, the Fa mutants, fail to deflagellate in response to any known chemical stimulus and are defective in Ca2+-activated microtubule severing. Genetic analysis of these eight new Fa strains demonstrated that they define two complementation groups, and one of these contains the previously identified fa1 mutation. Diploid analysis showed that five alleles map to the FA1 gene, whereas four alleles define a novel gene that we have named FA2. The isolation of multiple mutant alleles of each gene, generated by either ultraviolet irradiation or insertional mutagenesis, indicates that ADF1, FA1, and FA2 may be the only genes that can be identified in a loss-of-function screen. These alleles should provide a better understanding of the regulation of microtubule severing by Ca2+.

Animals↗
PubMed1998

Evidence for mineralocorticoid receptor facilitation of glucocorticoid receptor-dependent regulation of hypothalamic-pituitary-adrenal axis activity.

These studies further evaluated the relative role of mineralocorticoid (type I) and glucocorticoid (type II) receptors in mediating corticosteroid feedback regulation of the hypothalamic-pituitary-adrenal (HPA) axis. Acute treatment of rats with the selective mineralocorticoid receptor antagonist, RU28318 (50 mg/kg sc), produced elevated basal corticosterone levels in the morning, but had no effect on basal corticosterone levels in the evening or on restraint stress corticosterone levels at either time of day. Acute treatment with the selective glucocorticoid receptor antagonist, RU40555 (30 mg/kg sc) had no effect on basal or restraint stress corticosterone levels at either time of day. However, combined treatment with RU28318 and RU40555 produced an elevation of evening basal corticosterone levels (and morning basal on one occasion) and produced an increase in corticosterone levels during and after stress at both times of day. In a separate experiment conducted in the morning, the combined RU28318 and RU40555 treatment also produced elevated ACTH responses during restraint stress. Based on available corticosteroid receptor measures, the RU28318 treatment was estimated to selectively occupy approximately 85% of mineralocorticoid receptors in rat brain, whereas the RU40555 treatment was estimated to selectively occupy approximately 50% of glucocorticoid receptors in rat brain. We conclude that mineralocorticoid receptor activation is necessary and sufficient to maintain low basal corticosterone levels during the circadian trough, whereas glucocorticoid receptor activation is necessary to constrain corticosterone secretion during the circadian peak or during acute stress. However, even during the circadian peak or acute stress, mineralocorticoid receptor activation plays an important role in facilitating the glucocorticoid receptor dependent regulation of HPA axis activity by corticosterone.

Adrenocorticotropic Hormone↗
PubMed1997

Diazepam attenuation of restraint stress-induced corticosterone levels is enhanced by prior exposure to repeated restraint.

Prior research has demonstrated that diazepam decreases hypothalamic-pituitary-adrenal cortex (HPA) axis activity in stressful contexts but, paradoxically, acts as a stimulator of basal axis activity. Also, several investigators have reported that low doses of diazepam are not effective in reducing stress-induced corticosterone (CORT) levels, yet similar doses typically produce anxiolytic effects on behavioral measures of fear and anxiety. We have examined the effects of diazepam on plasma CORT levels in male Sprague-Dawley rats utilizing a repeated restraint paradigm. Consistent with most literature, diazepam administered IP (1.5, 3.0, or 6.0 mg/kg) 1 h prior to restraint increased non-stress, baseline plasma CORT levels in a dose-dependent fashion. During the first exposure to the 1 h restraint-stress procedure, CORT levels of diazepam-injected rats did not differ from the stress levels of controls except at the 60-min stress time point in those subjects receiving 6.0 mg/kg. However, diazepam at all three doses was able to attenuate the stress-induced increase in CORT following 5 days of diazepam+restraint treatment. Using the 3.0 mg/kg dose as a probe, it was found that this effect was not dependent on the repeated administration of diazepam, but rather on repeated exposure to restraint. These results suggest that repeated restraint produces a change in neural sensitivity to benzodiazepines.

Animals↗
PubMed1997

4-hydroxy-2-nonenal pyrrole adducts in human neurodegenerative disease.

Increasing age and inheritance of the epsilon 4 allele of apolipoprotein E (APOE4) are significant risk factors for sporadic and late onset familial Alzheimer disease (AD); however, the mechanisms by which either leads to AD are unknown. Numerous studies have associated advancing age with increased indices of oxidative challenge to brain, and with still further increased oxidative damage to relevant brain regions in AD patients. A major consequence of oxidative damage to brain is lipid peroxidation with production of the neurotoxic metabolite 4-hydroxy-2-nonenal (HNE). HNE reacts with protein to yield several adducts, including a pyrrole adduct that forms irreversibly in biological systems. Previously, we have shown in a small number of AD and control patients that HNE pyrrole adduct antiserum is immunoreactive with neurofibrillary tangles (NFT), and that this reactivity was significantly associated with inheritance of APOE4. Others have confirmed this pattern of immunoreactivity in AD brain but did not observe an association with APOE4. Herein, we have expanded the study group to 19 AD patients homozygous for APOE4 or APOE3, as well as 30 patients with other neurodegenerative diseases, including diffuse Lewy body disease, Pick's disease, progressive supranuclear palsy, Parkinson's disease, and human immunodeficiency virus-1 encephalitis. HNE pyrrole adduct immunoreactivity on NFT in AD patients was strongly associated with APOE4 homozygosity. With the exception of rare immunoreactive Pick bodies in one case of Pick's disease, no other structure was recognized by HNE pyrrole adduct antiserum in this series of patients. We propose that there is a significant difference between the interaction of apoE3 and apoE4 with lipid peroxidation in the brains of AD patients.

Adult↗
PubMed1997

Linear and nonlinear spectral integration in type IV neurons of the dorsal cochlear nucleus. II. Predicting responses with the use of nonlinear models.

Two nonlinear modeling methods were used to characterize the input/output relationships of type IV units, which are one principal cell type in the dorsal cochlear nucleus (DCN). In both cases, the goal was to derive predictive models, i.e., models that could predict the responses to other stimuli. In one method, frequency integration was estimated from response maps derived from single tones and simultaneous pairs of tones presented over a range of frequencies. This model combined linear integration of energy across frequency and nonlinear interactions of energy at different frequencies. The model was used to predict responses to noisebands with varying width and center frequency. In almost all cases, predictions using two-tone interactions were better than linear predictions based on single-tone responses only. In about half the cases, reasonable quantitative fits were achieved. The fits were best for noisebands with narrow bandwidth and low sound levels. In the second nonlinear method, the spectrotemporal receptive field (STRF) was derived from responses to broadband stimuli. The STRF could account for some qualitative features of the responses to broad noisebands and spectral notches embedded in broad noisebands. Quantitatively, however, the STRFs failed to predict the responses of type IV units even to simple broadband noise stimuli. For narrowband stimuli, the STRF failed to predict even qualitative features (such as excitatory and inhibitory frequency bands). The responses of DCN type IV units presumably result from interactions of two inhibitory sources, a strong one that is preferentially activated by narrowband stimuli and a weaker one that is preferentially activated by broadband stimuli. The results presented here suggest that the STRF measures effects related to the broadband inhibition, whereas two-tone interactions measure mostly effects related to narrowband inhibition. This explains why models based on two-tone interactions predict the responses to narrow noisebands much better then models based on STRFs. It is concluded that a minimal stimulus set for characterizing type IV units must contain both broadband and narrowband stimuli, because each stimulus class by itself activates only partially the integration mechanisms that shape the responses of type IV units. Similar conclusions are expected to hold in other parts of the auditory system: when characterizing a complex auditory unit, it is necessary to use a range of stimuli to ensure that all integration mechanisms are activated.

Acoustic Stimulation↗
PubMed1994

Comparative analysis of spectro-temporal receptive fields, reverse correlation functions, and frequency tuning curves of auditory-nerve fibers.

The tuning properties of single auditory-nerve fibers (ANFs) are characterized with spectro-temporal receptive fields (STRFs), reverse correlation functions (revcors), and frequency tuning curves (FTCs). Measures of tuning and latency from the STRFs and revcors are largely comparable to the traditional measures of tuning from FTCs and measures of latency from peristimulus time histograms (PSTHs), but several important differences are found. As is well known, revcors can only characterize low (< 6 kHz) best frequency (BF) units, whereas STRFs are able to characterize all units studied (BFs ranging from 0.26-23 kHz), except for a few very low-BF examples. Whereas tuning bandwidth derived from revcor exceeds that measured from FTCs at all BFs and increases with sound level. STRF bandwidth is comparable to FTC bandwidth, except at low BFs, and is stable with sound level. The STRF may reflect nonlinear properties of auditory-nerve fibers such as refractoriness and two-tone suppression that are absent in the FTC and revcor characterizations. The principal drawback of the STRF is its narrow dynamic range.

Animals↗
PubMed1975

Judgment error in category vs magnitude scales.

The effects of a variety of experimental conditions on the judgments (length of lines) of 16 normal and 16 mentally retarded observers were examined using category and magnitude scaling techniques. Using error and variability of judgment as criteria for measuring response bias, for normal subjects knowledge about the stimulus range, whether learned or provided, had as much to do with resulting judgments as the type of scale used. Judgment error of the retarded group was significantly greater than the normal group and appeared to be related to their limited ability to assign categories or proportions to the simuli used.

Adult↗