Biomedical subjects
Publications and source records attributed to R L Smith.
Actinomycotic infection should always be considered in any patient with persistent purulent conjunctivitis of chronic canaliculitis. The clinical features, investigation including macrodacryocystography, and treatment in four patients with actinomycotic canaliculitis are presented. The difficulty of microbiological diagnosis is stressed and the occurrence of associated lacrimal obstruction is reported.
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A population survey of 258 unrelated white British subjects showed a polymorphism for the 4-oxidation of debrisoquine. "Extensive metabolisers" (EM) and "poor metabolisers" (PM) are recognisable, 8.9% of the population being PM. Nine pedigrees ascertained through PM probands show that the PM phenotype is an autosomal Mendelian recessive character. The EM phenotype is dominant and the degree of dominance has been estimated at 30%. PM subjects are more prone to hypotension during debrisoquine therapy. The alleles controlling this polymorphism appear to control the oxidation of other drugs.
Glycylglycine stimulation of renal glutamine utilization was studied on the homogenate, subcellular and purified enzyme level. The results clearly establish the existence of two glutamine utilizing pathways, the mitochondrial dependent L-glutamine amidohydrolase (PDG) and a second, extramitochondrial pathway. In contrast to the mitochondrial pathway which produces stoichiometric amounts of ammonia and glutamate, this second pathway hydrolyzes glutamine to produce ammonia and transfers the gamma-glutamyl moiety, producing gamma-glutamyl peptides. In the crude systems, containing cyclotransferase, the gamma-glutamyl moiety appears mainly as 5-oxoproline; however, in the enzyme preparation, purified 112-fold, gamma-glutamyl peptides (transpeptidation) and a small amount of glutamate (hydrolysis) appear. D-Glutamine was also hydrolyzed, in contrast to the stereospecific PDG, but at less than one-half the rate of the L-isomer. The molecular weight of this extramitochondrial D- and L-glutamine utilizing enzyme was estimated by gel filtration on a Sephadex G-200 column and found to be approximately 70 000. Based on product formation, molecular weight estimation and copurification with the activity responsible for p-nitroanilide release from gamma-glutamyl-p-nitroanilide, we conclude that this reaction is catalyzed by gamma-glutamyltranspeptidase. Glycylglycine stimulated this enzyme to produce more ammonia while decreasing the appearance of glutamate; in contrast, the mitochondrial glutaminase was unaffected by glycylglycine. This extramitochondrial glutamine utilizing pathway can make a significant contribution to in vivo renal ammoniagenesis.
1. The quaternization of [14C]pyridine by metabolic N-methylation in vivo has been investigated in eight species by determination of the urinary excretion product, N-methylpyridinium. 2. All eight species N-methylated pyridine, but the extent to which this occurred was species-dependent; methylation was extensive (20-40% dose) in the cat, guinea-pig, gerbil, rabbit and hamster,but was low (5-12% dose) in rat, mouse and two human volunteers. The low N-methylation in the rat was not enhanced by DL-methionine supplementation. 3. In the rat and guinea-pig, the pattern of N-methylation was similar when the [14C]pyridine was given by the oral and intraperitoneal routes. In both species the reaction was dose-dependent. 4. N-Methylpyridinium excretion was found to be a valid parameter of the N-methylation of pyridine in vivo, since rats and guinea-pigs eliminated this compound in the urine unchanged following its intraperitoneal administration. 5. The pharmacological and toxicological implications of the biological quaternization of azaheterocycles are discussed.
1. The metabolic oxidation of debrisoquine has been studied in a group of 123 Nigerian volunteers. 2. All subjects excreted unchanged drug together with five oxidation products, namely, 4-, 5-, 6-, 7- and 8-hydroxy-debrisoquine. 3. The 4-hydroxylation reaction exhibits polymorphism; ten subjects were defective in their ability to effect this reaction. 4. The incidence (q) of the allele governing impaired 4-hydroxylation (DL) among Nigerians was calculated as being 0.28 (95% confidence limit of 0.20-0.37). 5. An association was demonstrated between the ability to effect 4-hydroxylation and 6- and 7-hydroxylation of debrisoquine, suggesting that the alleles controlling alicyclic oxidation also influence aromatic hydroxylation.
1. Debrisoquine 4-hydroxylation was polymorphic in 102 Saudi arab volunteers, the population comprising one phenotypically poor metabolizer and 101 phenotypically extensive metabolizers of debrisoquine. 2. Mean urinary recoveries of drug and metabolite were low in Saudis (15 +/- 10% dose, mean +/- S.D.), which compared well with previously studied populations of Egyptians (16%) and Ghanaians (18%), but which were lower than those seen in a UK white population (41%). 3. Saudis, like Egyptians, were more extensive metabolizers of debrisoquine than UK whites, as judged by the metabolic ratio (% dose as debrisoquine/% dose as 4-hydroxy-debrisoquine eliminated in the urine). 4. Neither sex, urine collection period nor urinary recovery of drug and metabolite had any statistically significant effect upon the distribution of metabolic ratios in Saudis. 5. The frequency of the DL allele controlling the recessive poor metabolizer trait was 0.099 +/- 0.049 (+/- S.E.M.) in Saudis, which compared well to Egyptians (0.118 +/- 0.059) but was significantly lower than that for UK whites (0.298 +/- 0.030). 6. These findings raise questions regarding the efficacy and safety in Saudis of drugs undergoing oxidative metabolism which have been evaluated for usage in European white subjects.
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Explore the source record for details and available documents.
Explore the source record for details and available documents.
Explore the source record for details and available documents.
In answer to a questionnaire administered in 1961, 90% of responding physicians indicated a preference for not telling a cancer patient his diagnosis. To assess attitudinal changes, the same questionnaire was submitted to 699 university-hospital medical staff. Of 264 respondents, 97% indicated a preference for telling a cancer patient his diagnosis--a complete reversal of attitude. As in 1961, clinical experience was the major policy determinant, but the 1977 population emphasized the influence of medical school and hospital training. Our respondents indicated less likelihood that they would change their present policy or be swayed by research. Clinical experience was the determining factor in shaping two opposite policies. Physicians are still basing their policies on emotion-laden personal conviction rather than the outcome of properly designed scientific studies.
The metabolism and kinetics of 14C-labeled theophylline have been studied after intravenous doses of 100 mg to healthy subjects, keeping to their usual diets after 7 days of abstention from methylxanthine-containing foods and beverages and again after such abstention while taking caffeine and theophylline in tablet form. The metabolism of oral 14C-theophylline has also been investigated. Metabolites were separated and quantitated by ion-exchange column chromatography, ion-exchange paper chromatography, and liquid scintillation counting. Three major metabolites were found in urine in addition to theophylline, namely 3-methylxanthine, 1,3-dimethyluric acid, and 1-methyluric acid, and 2 minor metabolites were detected but not identified. The elimination kinetics were studied after intravenous administration; theophylline, 1,3-dimethyluric acid, and 1-methyluric acid were eliminated by first-order processes, while elimination of 3-methylxanthine was described by Michaelis-Menten kinetics. Abstention from methylxanthine-containing foods and beverages led to a significant decrease in the urinary elimination half-life of 14C from 9.8 to 7.0 hr (p less than 0.02) due to increases in the elimination constants for theophylline, 3-methylxanthine, and 1,3-dimethyluric acid. When the methylxanthine content of the methylxanthine-containing foods and beverages was replaced by caffeine and theophylline in table form, kinetics and metabolism of theophylline were the same as in subjects on usual diets.
The alicyclic and aromatic hydroxylation of debrisoquin was studied in Ghanaians. As in a previously studied Caucasian population, the alicyclic 4-hydroxylation of debrisoquin in Ghanaians was polymorphic. Three phenotypes were observed: homozygous extensive metabolizers (58%), heterozygous extensive metabolizers (36%), and homozygous poor metabolizers (6%). In contrast, British Caucasians are primarily monomorphic extensive metabolizers (92%) and homozygous poor metabolizers comprise 8% of the population. Urinary recovery of the drug and its hydroxylated metabolites was significantly less in the Ghanaian subjects. In both Ghanaian and British populations, aromatic hydroxylation producing 5-, 6-, 7-, and 8-hydroxydebrisoquin was shown to parallel the alicyclic 4-hydroxylation of debrisoquin, and thus to be controlled by the same gene locus. Debrisoquin is advocated as a tool for uncovering polymorphism in drug oxidation and its interethnic variations.
Hypothyroidism was induced in neonatal Sprague-Dawley rats by adding propylthiouracil to the lactating female's food and water. Behavioral evaluation on a 6-item battery occurred from 70 to 114 days of age. Results indicated long-lasting behavioral changes in the neonatal hypothyroid animals characterized by increased activity and decreased performance on avoidance and escape learning. Serum thyroxine levels were reduced in the hypothyroid animals throughout the 120-day period. Experimental animals also had fewer synaptic contacts in the cerebellar cortex when analyzed at 90 days of age.
This article evaluates a preschool intervention program conducted as a part of the Wayne State University Preschool Project. The project's aim is (a) to provide early identification of preschool age children experiencing mental health problems, and (b) to reverse the diagnosed deficiencies, particularly among high risk children. The program was evaluated with children ranging in age from 3 to 4 years, within demographically comparable regions in the Detroit School System. Pretest and posttest measures were taken on the AML Scale and the Caldwell Preschool Inventory. Pretest scores were used to establish high risk children. A prescriptive intervention program was established within one region, aimed primarily at reducing adjustment problems among high risk children. The analysis of posttest data revealed more favorable scores among experimental children when compared to control children. In addition, evidence is provided of specific benefits for high risk children in the experimental program.
A school-based model of preventive intervention is described which identified and significantly overcame school maladaptation among preschool children enrolled in a Detroit Public School Title I Program. Children were screened by teachers for learning and behavioral difficulties using the AML Scale, the Classroom Adjustment Rating Scale, and the Caldwell Preschool Inventory. Sixty-four children were identified on the basis of these instruments as exhibiting some form of school maladaptation. These children were randomly assigned to an experimental condition (N = 32) or placebo control (N = 32). Individually designed prescriptive techniques were developed for high-risk children in the experimental group and were implemented by college student aides after training by the project staff. A multivariate analysis of variance and follow-up univariate analyses, testing differences between experimental and control groups on the posttests, were performed. The difference between the groups on all three criteria measures was significant and favored the experimental children.