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R L Smith

Publications and source records attributed to R L Smith.

At least 469 records · Page 26Linked to original sources
PubMed1982

Adaptation in auditory-nerve fibers: a revised model.

Adaptation of firing rates in auditory-nerve fibers appears to reflect two distinct processes. Rapid adaptation occupies the first few milliseconds of response and is superimposed upon short-term adaptation which has a time constant of about 40 ms. The properties of the two processes are reviewed and compared, and a phenomenological model is developed that successfully accounts for them. The model consists of several stages which have been tentatively associated with underlying physiological processes. In the first stage stimulus intensity is transformed by a static nonlinearity, followed by a low-pass filter. The filtered output may correspond to the hair-cell receptor potential. It modulates the release of a substance that possibly represents synaptic transmitter. Adaptation is produced by the depletion of transmitter which is located in three stores in cascade. A global store with fixed concentration controls the steady-state response and replenishes a local store which is responsible for short-term adaptation. The local store replenishes a rapidly depleted immediate store. Flow between stores is proportional to concentration gradients with the following exceptions. The immediate store is subdivided into independent volumes or sites and there is no flow among sites or back to the local store. A given site becomes activated only when the receptor potential exceeds its particular activation value and the number of activated sites is proportional to the receptor potential. The flow of transmitter from the immediate store is assumed to be proportional to neural firing rate, with some minor modifications described in the text. The properties of the model are determined from the underlying equations and from a computer simulation. The model produces realistic response properties including PST histograms, onset and steady-state rate-intensity functions, incremental and decremental responses, response modulation for amplitude modulated stimuli, and period histograms for low-frequency tones.

Acclimatization↗
PubMed1982

Metabolic oxidation of methaqualone in extensive and poor metabolisers of debrisoquine.

The metabolism of methaqualone to the glucuronides of 5 C-monohydroxy metabolites and to the N-oxide has been studied in 2 groups of healthy young adults phenotyped as extensive and poor metabolisers of debrisoquine. No significant interphenotype differences were observed with respect to the excretion of any of the 6 metabolites. It is probable that the genetic regulation of the pathways leading to these metabolites is at a locus other than that which is responsible for the regulation of the oxidation of debrisoquine, guanoxan, phenacetin, phenytoin and sparteine.

Adult↗
PubMed1982

Role of mitochondrial membrane potential in the regulation of murine erythroleukemia cell differentiation.

The level of cytoplasmic calcium ions appears to be important in the control of murine erythroleukemia (MEL) cell differentiation. Our interest in this study focuses on the relationship between the regulation of calcium concentration and differentiation. We used the fluorescent membrane probe DiOC6 to examine the relationship between MEL cell mitochondria and changes in cytoplasmic calcium levels occurring at the initiation of commitment. Fluorescence microscopy reveals the selective association of DiOC6 with MEL cell mitochondria, where an enhanced fluorescence is observed. Treatment of cells with dimethylsulfoxide (DMSO) or other inducers causes a decrease in mitochondria-associated fluorescence levels that occurs with the initiation of commitment. A decrease in DiOC6 fluorescence is caused by agents that reduce mitochondrial membrane potential, but is only slightly affected by agents that alter plasma membrane potential. Amiloride and EGTA, agents that prevent commitment and inhibit calcium uptake, also prevent the decrease in DiOC6 uptake caused by DMSO. The effect of DMSO on MEL cell mitochondria is mimicked by FCCP, a proton ionophore that dissipates mitochondrial membrane potential. FCCP also caused MEL cell mitochondria to release calcium into the cytoplasm. When MEL cells are treated with DMSO plus FCCP, commitment is initiated without the lag period observed when cells are treated with DMSO alone. These results are consistent with the hypothesis that mitochondrial transmembrane potential is important in the regulation of cytoplasmic calcium levels at the time of commitment of MEL cells to terminal differentiation.

Amiloride↗
PubMed1982

Intracellular and extracellular responses in the organ of Corti of the gerbil.

Techniques have been developed for recording from and staining cells in the organ of Corti of the Mongolian gerbil. Using physiological criteria as in the guinea pig, the cells were classified as either supporting cells or inner hair cells (IHCs). In addition, several IHCs were stained using HRP and identified in surface preparations. Extracellular responses in the vicinity of IHCs were tuned as sharply as auditory-nerve fibers. Intracellular tuning curves of IHCs were equally sharp near their tips. However, the tip-to-tail distances and sensitivities appeared to be somewhat reduced, presumably due to trauma caused by the recording electrode. Intensity functions, relating receptor depolarization to stimulus intensity level, were obtained for the IHCs. The functions have a consistent quantitative form for frequencies equal to or less than the characteristic frequency of a cell. At low stimulus levels the response increases in proportion to energy, i.e. the square of the sound pressure level. At high levels the response increases more slowly, but shows a greater operating range, and smaller effects of saturation, than do the steady-state responses of single auditory-nerve fibers.

Animals↗
PubMed1982

Anatomy and physiology of the gerbil cochlear nucleus: an improved surgical approach for microelectrode studies.

A new, improved surgical approach to the cochlear nucleus is developed in the gerbil. This new approach involves making a small hole in the lateral wall of the temporal bone located within the perimeter of the superior semicircular canal. Microelectrodes are passed through the intact parafloccular lobe of the cerebellum to the cochlear nucleus. One advantage of the new approach is that no removal of any CNS vasculature or neural tissue is necessary. Relations between the bulla, temporal bone and cochlear nucleus are presented in detail. The new approach is demonstrated by making single unit recordings from the cochlear nucleus and classifying response patterns as measured in PST histograms. All of the response types found in cat are found in the gerbil.

Animals↗
PubMed1982

2-(Aminomethyl)phenols, a new class of saluretic agents. 4. Effects of oxygen and/or nitrogen substitution.

A series of oxygen and/or nitrogen substituted 2-(aminomethyl)phenols was synthesized and tested orally in rats for saluretic and diuretic effects. Intravenous dog data are included as supplementary material to demonstrate diuretic responses, or lack thereof, in a second species. In general, substitution on nitrogen with groups other than lower alkyl or substitution on nitrogen and/or oxygen with groups resistant to hydrolysis substantially diminished or ablated saluretic effects.

Animals↗
PubMed1982

Genetic polymorphism of phenformin 4-hydroxylation.

The ability to oxidize a single 50-mg dose of phenformin to its 4-hydroxy metabolite was determined in 195 individuals. Variations in the urinary ratio of phenformin/4-hydroxyphenformin ranged from 1 to 184. Family studies were consistent with the hypothesis that this variability resulted from a single gene mode of inheritance in which impaired hydroxylation of phenformin appears as an autosomal recessive trait. Both genotype frequencies and the degree of dominance of the extensive metabolizer phenotype over the recessive showed a remarkable resemblance to those described for debrisoquine 4-hydroxylation, which was confirmed by the high degree of correlation (rs=0.785, P less than 0.0001) between the phenformin ratio and the debrisoquine metabolic ratio. Such close agreement between the metabolism of these drugs may indicate that the same genetic control is in operation. Such genetic polymorphism of phenformin hydroxylation may have important implications for therapeutic response and for the possibility of toxic effects in a few individuals.

Adolescent↗
PubMed1982

Neurological complications of arterial hypertension.

During a 10-year period 45 children were identified as having had neurological complications associated with severe arterial hypertension. Convulsions were the most common complication, occurring in 42 (82%) children. Two (4%) children each presented with a facial palsy and 2 (4%) with alterations in the level of consciousness. Nineteen (42%) presented with epileptic seizures as the first sign of arterial hypertension. The prognosis for children having had a single episode of hypertensive encephalopathy was good. Long-term follow-up showed no permanent neurological deficit on physical examination, and no focal abnormality on brain scan by computerised tomography. Psychometric analysis similarly failed to show any significant difference in cognitive assessment between children having had an episode of hypertensive encephalopathy and a control group with chronic renal disease, although reading skills were generally behind for chronological age and the average IQ was about 90 in both groups.

Adolescent↗
PubMed1982

Species differences in the metabolic C- and N-oxidation , and N-methylation of [14C]pyridine in vivo.

1. The metabolism of [2,6-14C]pyridine in vivo has been investigated in the rat, hamster, mouse, gerbil, rabbit, guinea-pig, cat and man, and the quantitative determination of the various urinary metabolites carried out by radiochromatographic analysis. 2. Unchanged pyridine and its N-methylated metabolite, N-methylpyridinium ion, were determined using a Partisil-10 SCX cation-exchange h.p.l.c. column, whereas the C- and N-oxidation products were assayed by reverse-phase chromatography, using a Partisil-10 ODS column. 3. Most of the species studied produce pyridine N-oxide, N-methylpyridinium ion, 2-pyridone, 3-hydroxypyridine and 4-pyridone as metabolites, but the proportion of the dose excreted as each of these metabolites is species-dependent.

Animals↗
PubMed1982

The metabolism of [carboxyl-14C]aspirin in man.

1. [carboxyl-14C]Aspirin has been orally administered to four male volunteers and the urinary metabolites examined by paper chromatography, t.l.c., h.p.l.c. and mass spectrometry. 2. 14C Radioactivity was eliminated rapidly in the urine, 94 to 98% of the dose in the first 24 h and approx. 1% in 24-48 h. 3. The major urinary metabolite was salicyluric acid (56-68% dose). In addition, free salicylic and gentisic acids were also detected as were both the acyl and phenolic glucuronides of salicylate. 4. A phenolic glucuronide of salicyluric acid has also been identified. The importance of this metabolite in relation to analytical methods for salicylphenolic glucuronide determination is discussed. 5. The presence of other di- and tri-hydroxybenzoic acids or gentisuric acid could not be demonstrated.

Adult↗
PubMed1982

The metabolism of [14C]cimetidine in man.

1. The excretion and metabolism of [2-(14)C]cimetidine (500 mg orally) was studied in five male volunteers. 2. Over 70% of the 14C was excreted in the urine after 24 h by all individuals with 5% in the faeces; 97% being recovered in total after three days. 3. Unchanged cimetidine was the largest urinary component (63%), followed by a polar conjugate tentatively identified as cimetidine N'-glucuronide (24%). Smaller amounts of the oxidized metabolites, cimetidine sulphoxide and 5-hydroxymethylcimetidine, together with the hydrolysis products, cimetidine guanylurea and cimetidine guanidine, were also observed. 4. Cimetidine and its sulphoxide were identified in faecal samples. Anaerobic incubations of cimetidine or cimetidine sulphoxide with faecal homogenates showed that reduction was the predominant reaction under these conditions. 5. Studies in one individual over a wide dose range (0.5 mg to 1.5 g orally) showed little variation in excretory profile or metabolic spectrum.

Administration, Oral↗
PubMed1981

First observation of amino acid side chain dynamics in membrane proteins using high field deuterium nuclear magnetic resonance spectroscopy.

We have obtained the first deuterium NMR spectra of an individual membrane protein, bacteriorhodopsin in the purple membrane of Halobacterium halobium R1. Biosynthetic isotopic enrichment with [gamma-2H6]valine and high field Fourier transform operation permitted rapid data acquisition on intact membranes, including measurement of relaxation times. At some temperatures high quality spectra could be obtained in less than 1 s. [U-14C]Valine tracer studies indicate that less than or equal to 2% of valine added to the growth medium is broken down and incorporated into other membrane constituents. The NMR results indicate that the valine side chain is a rather rigid structure. Motion about C alpha-C beta is slow (less than 10(5) s-1) at growth temperature, While motion about C beta-C gamma is as expected fast (much greater than 10(5) s-1) at all accessible temperatures. The activation energy for methyl group rotation from spin-lattice relaxation data between -75 and 53 degrees C is approximately 2.4 kcal/mol, in good agreement with previous 1H NMR studies on solid alkanes. Preliminary data on [gamma-2H6]valine-labeled Acholeplasma laidlawii B (PG9) cell membranes are also presented. Our results strongly suggest that it should now be possible to observe in great detail the motions of any type of amino acid side chain in membrane proteins, including the effects of lipid composition on protein dynamics.

Amino Acids↗