Diagnosis of the partial androgen insensitivity syndrome during infancy.
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Disorders of Sex Development↗
Biomedical subjects
T R Brown
Publications and source records attributed to T R Brown.
Studies of anaerobic and aerobic glycolysis in Saccharomyces cerevisiae.
Glucose metabolism was followed in suspensions of Saccharomyces cerevisiae by using 13C NMR and 14C radioactive labeling techniques and by Warburg manometer experiments. These experiments were performed for cells grown with various carbon sources in the growth medium, so as to evaluate the effect of catabolite repression. The rate of glucose utilization was most conveniently determined by the 13C NMR experiments, which measured the concentration of [1-13C]glucose, whereas the distribution of end products was determined from the 13C and the 14C experiments. By combining these measurements the flows into the various pathways that contribute to glucose catabolism were estimated, and the effect of oxygen upon glucose catabolism was evaluated. From these measurements, the Pasteur quotient (PQ) for glucose catabolism was calculated to be 2.95 for acetate-grown cells and 1.89 for cells grown on glucose into saturation. The Warburg experiments provided an independent estimate of glucose catabolism. The PQ estimated from Warburg experiments was 2.9 for acetate-grown cells in excellent agreement with the labeled carbon experiments and 4.6 for cells grown into saturation, which did not agree. Possible explanations of these differences are discussed. From these data an estimate is obtained of the net flow through the Embden-Meyerhof-Parnas pathway. The backward flow through fructose-1,6-bisphosphatase (Fru-1,6-P2-ase) was calculated from the "scrambling" of the 13C label of [1-13C]glucose into the C1 and C6 positions of trehalose. Combining these data allowed us to calculate the net flux through phosphofructokinase (PFK). For acetate-grown cells we found that the relative flow through PFK is a factor of 1.7 faster anaerobically than aerobically.(ABSTRACT TRUNCATED AT 250 WORDS)
Aerobiosis↗
Androgen receptors in normal and abnormal male sexual differentiation.
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3-Oxo-5-alpha-Steroid 4-Dehydrogenase↗
Liquid chromatographic separation of enantiomers of adrenergic agonists.
Many established and experimental adrenergic agonists are derivatives of 2-aminoethanol with a phenol or catechol moiety in the 1-position. There is considerable interest in the stereochemical aspects of the actions of such chiral drugs. Surprisingly, however, little has been published on the chromatographic separation of the enantiomers of these compounds, and what has been published involved nearly exclusively capillary gas-liquid chromatography. In this report, the resolution of the racemates of ten adrenergic agents using reversed-phase liquid chromatography is described. The procedure is based on derivatizing the racemic mixture of each agent with the chiral reagent 2,3,4,6-tetra-O-acetyl-beta-D-glucopyranosyl isothiocyanate, followed by separation of the resulting diastereomers on octadecylsilane columns using methanol-aqueous ammonium acetate mixtures as mobile phase. Detection was at 254 nm. The separation of the enantiomers of norphenylephrine and of octopamine was less than complete; the resolution of the other agents, i.e., synephrine, N-ethylnorphenylephrine, p-hydroxyephedrine, p-hydroxynorephedrine, metanephrine, normetanephrine, isoproterenol, and nordefrin, was complete. The derivative of (-)-isoproterenol eluted before that of its antipode. The procedure may be applicable to other similar agents.
Adrenergic Agonists↗
Adaptation of male and female rats to iodine deficiency.
The response of the hypothalamic pituitary axis to chronic iodine deficiency was compared in male and female Sprague-Dawley rats. The animals were kept on a low iodine diet for 12 weeks. Blood samples as well as thyroid and pituitary weights were obtained every two weeks. Baseline values of thyroid weight and serum thyroxine (T4) were similar in both sexes. However, females had lower serum TSH and higher serum triiodothyronine (T3), pituitary weight and pituitary TSH content. After initiation of the low iodine diet, both sexes showed similar decreases in serum T4 and similar increases of serum TSH and thyroid weight. Serum T3, pituitary weight and TSH content remained higher in females throughout the study. Pituitary TSH was directly correlated with serum TSH in both sexes. When adjusted for pituitary TSH and analyzed by a stepwise regression analysis, serum TSH was lower in females suggesting a difference in TSH secretion between males and females. Our studies demonstrate significant sex differences in the regulation of TSH secretion and maintenance of serum T3 level in response to a chronic stimulus.
Adaptation, Physiological↗
Phosphagen and intracellular pH changes during contraction of creatine-depleted rat muscle.
To evaluate the functional role of phosphocreatine (PCr) and creatine in muscle metabolism, these compounds were depleted by feeding rats the creatine analogue, beta-guanidinopropionate (beta-GPA, 2% of diet). Changes in phosphate metabolites and intracellular pH were monitored in gastrocnemius muscle in situ by phosphorus nuclear magnetic resonance (31P-NMR) at 162 MHz using the surface coil technique. After 3 mo of feeding, 25 mumol/g of phosphorylated beta-GPA (beta-GPAP) had accumulated, and PCr, creatine, and ATP levels were reduced to 6, 17, and 56%, respectively, compared with muscles of control animals. In resting muscle, there was no measurable exchange of phosphate between beta-GPAP and ATP by the NMR saturation transfer method. During muscle stimulation at 1 and 5 Hz, the maximum net rate of beta-GPAP hydrolysis was 10% that of PCr in control muscles, so that after 150 s inorganic phosphate had increased to less than 50% of the level attained in control muscles. At both rates, peak twitch force declined toward a steady state more rapidly in beta-GPA-loaded muscles, but after 100 s force was either not different (1 Hz) or significantly greater (5 Hz) in the beta-GPA-fed animals. Intracellular pH initially decreased more rapidly during stimulation and recovered more rapidly afterward in the beta-GPA-loaded muscles compared with controls. This difference could be explained by the difference in expected proton consumption due to net PCr hydrolysis. However, despite buffering by PCr hydrolysis, pH ultimately decreased more in control muscle (6.1 vs. 6.3 for 5 Hz), indicating greater acid accumulation compared with beta-GPA-loaded muscles. In the superficial, predominantly fast-twitch glycolytic section of muscles clamp-frozen after 5-Hz stimulation for 150 s, lactate accumulation was twofold greater in controls. The results indicate that PCr is not essential for steady-state energy production but that the phosphate from PCr hydrolysis may be important for maximum activation of glycogenolysis and/or glycolysis.
Adenosine Triphosphate↗
Androgen binding in nuclear matrix of human genital skin fibroblasts from patients with androgen insensitivity syndrome.
Specific sex steroid-binding sites are associated with the salt-insoluble nuclear matrix from which lipids, histones, and chromatin have been extracted. In intact cultured normal human genital skin fibroblasts incubated for 1 h at 37 C with a saturating concentration (2 nM) of [3H]dihydrotestosterone [( 3H]DHT), approximately 50% of the total intracellular androgen receptor-steroid complexes were found in the nucleus. Within isolated nuclei from such cells, 28-49% of the specific androgen receptor binding was associated with the nuclear matrix. The antiandrogen cyproterone acetate inhibited DHT binding within the nuclear matrix. Cultured genital skin fibroblasts from two unrelated patients with receptor-positive complete androgen insensitivity (CAIS, AR+), had normal (approximately 50%) nuclear binding of DHT, and 35% and 45% of it was localized to the nuclear matrix. Genital skin fibroblasts from a patient with receptor-negative complete androgen insensitivity (CAIS, AR-) had no specific DHT binding in isolated nuclei or nuclear matrix. Scatchard analysis of specific DHT binding in the nuclear matrix isolated from cells of normal subjects after an in vitro exchange assay (0 C; 24 h) revealed the presence of saturable (maximum binding, approximately equal to 200 fmol/mg nuclear DNA), high affinity (Kd approximately equal to 1.0 nM) binding sites. By contrast, in the nuclear matrix isolated from cells of a patient with CAIS, AR+, the binding affinity for DHT was 3-fold lower (Kd approximately equal to 3.0 nM). When cytosolic androgen receptor-DHT complexes prepared from cells preincubated at 37 C for 1 h with [3H]DHT were incubated at 0 C for 1 h with isolated nuclei and nuclear matrix in the presence of 0.15 M KCl, 40-60% of specific nuclear binding was associated with the nuclear matrix. In these cell-free in vitro experiments, radiolabeled DHT-receptor complexes prepared from normal or mutant cells were mixed with isolated nuclei and nuclear matrix prepared from cells of normal subjects or patients with CAIS, AR+ or CAIS, AR-. Under these conditions, specific DHT binding in nuclei and nuclear matrix was quantitatively similar in the presence of a mutant (CAIS, AR+) receptor-steroid complex or in the presence of nuclei or nuclear matrix from the mutant cells (CAIS, AR- or AR+) when compared simultaneously with the same subcellular fractions prepared from the cells of normal subjects.(ABSTRACT TRUNCATED AT 400 WORDS)
Adult↗
Time-dependent biphasic response of aromatase to dexamethasone in cultured human skin fibroblasts.
Human genital skin fibroblasts grown in cell culture possess aromatase activity and, therefore, provide a model to investigate the molecular mechanisms that control aromatase in extraglandular tissues. Following the observation by other investigators that glucocorticoids stimulated aromatase activity in cultured stromal-vascular cells from adipose tissue, we examined the influence of dexamethasone (DEX) on aromatase in cultured skin fibroblasts. Preincubation of skin fibroblasts with DEX stimulated aromatase expression in all cell strains. In time-course studies, aromatase activity showed a biphasic curve, with peak levels at 12 h and a return to baseline levels by 72 h. When DEX was removed after 12 h, aromatase activity could be completely restimulated by DEX only after a period of 60-72 h. The DEX stimulation appeared to involve glucocorticoid receptor function, since the concentration of DEX required for half-maximal stimulation of aromatase activity (4.2 nM) was similar to the dissociation constant (Kd, 4.3 nM) of the receptor (for DEX). Actinomycin D and cycloheximide (CHX) inhibited DEX stimulation of aromatase when they were present in the preincubation and assay media. When cells were preincubated with DEX and CHX and then washed free of CHX and DEX before the assay, superinduction of aromatase activity occurred. Our data concerning the time course and superinduction of aromatase activity by DEX are in contrast to the findings reported by others for adipose tissue stromal-vascular cells and suggest that the mechanisms for the control of aromatase in extraglandular tissue may vary significantly in different tissues.
Adult↗
A review of the role of job dissatisfaction in the employee turnover process.
Pharmacist dissatisfaction has manifested itself in absenteeism, poor performance, and turnover. Much has been written on the subject of employee turnover by researchers in the fields of psychology and management. However, there is very little in the literature on pharmacy management concerning the relationship between job satisfaction and turnover among hospital pharmacists. The purpose of this article is to review the major theories and models of employee turnover in an effort to better understand the role of job satisfaction/dissatisfaction in the turnover process of the hospital pharmacist.
Job Satisfaction↗
Induction of autoimmune thyroiditis in chickens by dietary iodine.
Clinical studies have suggested that excess dietary iodine promotes autoimmune thyroiditis; however, the lack of a suitable animal model has hampered investigation of the phenomenon. In this study, different amounts of potassium iodide were added to the diets of chicken strains known to be genetically susceptible to autoimmune thyroiditis. Administration of iodine during the first 10 weeks of life increased the incidence of the disease, as determined by histology and the measurement of autoantibodies to triiodothyronine, thyroxine, and thyroglobulin. Further support for the relation between iodine and autoimmune thyroiditis was provided by an experiment in which iodine-deficient regimens decreased the incidence of thyroid autoantibodies in a highly susceptible strain. These results suggest that excessive consumption of iodine in the United States may be responsible for the increased incidence of autoimmune thyroiditis.
Animals↗
Phosphorus nuclear magnetic resonance of fast- and slow-twitch muscle.
Phosphorus nuclear magnetic resonance (NMR) spectra were obtained at 109.3 MHz from isolated, arterially perfused cat biceps brachi (greater than 75% fast-twitch, glycolytic fibers) and soleus (greater than 92% slow-twitch, oxidative) muscles at 30 degrees C. The perfused muscles were stable with respect to O2 consumption, twitch characteristics, and ATP and phosphocreatine (PC) levels for up to 10 h. NMR spectra showed a higher PC/Pi ratio in the biceps (11) than in the soleus (1.7). Relatively higher Pi levels were observed in extracts of clamp-frozen muscles than in the intact muscles. This difference could be accounted for by artifactual hydrolysis of PC during muscle freezing. Based on the NMR and chemical data, the free cytosolic ADP level, calculated from the creatine kinase equilibrium, was 14 microM in the soleus and less than 1 microM in the biceps. Intracellular Pi concentration was 10 mM in the soleus and 3 mM in the biceps. Intracellular pH, estimated from the chemical shift of phosphate or 2-deoxyglucose 6-phosphate, was 7.0 in both muscles (perfusate pH 7.2). Both extracellular space and pH measurements were obtained from NMR spectra of muscles perfused with 10 mM sodium phenylphosphonate added to the perfusate. These results document larger differences in the phosphate metabolites in the two types of mammalian muscles than previously reported.
Adenosine Diphosphate↗
Familial gynecomastia with increased extraglandular aromatization of plasma carbon19-steroids.
We evaluated a family in which gynecomastia occurred in five males in two generations. In each affected subject, gynecomastia and male sexual maturation began at an early age. The ratio of the concentration of plasma estradiol-17 beta to that of plasma testosterone was elevated in each affected subject. In the three siblings with gynecomastia, the transfer constant of conversion of androstenedione to estrone (i.e., the fraction of plasma androstenedione that was converted to estrone as measured in the urine) was 10 times that of normal persons. The transfer constant of conversion of testosterone to estradiol-17 beta in the one subject studied also was 8-10 times that of normal men, whereas the transfer constants of conversion of estrone to estradiol-17 beta and of estradiol-17 beta to estrone were normal. Despite the elevation in extraglandular aromatase activity, there was a normal response of the hypothalamic-pituitary axis to provocative stimuli. This is the second documentation of gynecomastia that is associated with increased extraglandular aromatase activity, and the first time that the defect was found to be familial with a probable X-linked (or autosomal dominant, sex limited) mode of inheritance.
Adolescent↗
Androgen receptor in cultured human testicular fibroblasts.
Androgen receptors and 5 alpha-reductase activity were studied previously in genital skin fibroblasts cultured from normal subjects and patients with abnormalities of sex differentiation. We have now identified and characterized the androgen receptor in cultured human testis fibroblasts (HTF). HTF possess specific receptor proteins for androgens and translocate the receptor-steroid complex to nuclei. Approximately 50% of total cell binding was within nuclei, and 60-70% of nuclear binding was extracted by 0.5 M KCl (1 h; 0 C). Specific binding of dihydrotestosterone (DHT) was absent in HTF cultured from three patients with receptor-negative complete androgen insensitivity. 5 alpha-Reductase activity was very low (less than 100 pg 5 alpha-reduced products/micrograms DNA X h) in HTF after incubation with 200 nM [3H] testosterone (T). Based on this finding, androgen receptor binding of T was studied and resulted in a maximum binding capacity similar to that for DHT, but with a slightly lesser binding affinity (Kd). Binding to the receptor in HTF was specific for androgens (DHT, T, and R1881). [3H]DHT (2 nM) binding in the presence of 100 nM radioinert steroid was decreased by DHT (87%), R1881 (82%), and T (72%), but less with estradiol (53%), progesterone (31%), androstanediol (23%), and dexamethasone (10%). The androgen receptor in HTF was characterized as a macromolecule which sedimented at 4-5S on 0.4 M KCl sucrose density gradients and eluted as three high mol wt peaks on Sephacryl S-300 chromatography. Low but detectable aromatase activity was present in HTF and had the characteristics of being induced by glucocorticoid and having a Km similar to that of aromatase activity for genital skin fibroblasts. In summary, specific androgen receptors are present in HTF, and their characteristics are similar to those previously described for genital skin fibroblasts.
3-Oxo-5-alpha-Steroid 4-Dehydrogenase↗
Studies on the mechanism of acute inhibition of thyroglobulin hydrolysis by iodine.
Iodine in excess is known to acutely inhibit thyroidal secretion. In the present study we have characterized the time course of the iodine effect in vitro and investigated the underlying mechanisms. Labelled thyroid glands were cultured in vitro in medium containing mononitrotyrosine, an inhibitor of iodotyrosine deiodinase. The rate of hydrolysis of labelled thyroglobulin was measured as the proportion of labelled iodotyrosines and iodothyronines recovered at the end of culture and was used as an index of thyroidal secretion. Thyrotrophin (TSH) administered in vivo acutely stimulated the rate of thyroglobulin hydrolysis. Addition of NaI to the culture medium acutely inhibited both basal and TSH-stimulated thyroglobulin hydrolysis. The effect of iodide was demonstrable after 2 h, maximal after 6 h and was not reversible upon removal of iodide. Iodide abolished the dibutyryl cAMP induced stimulation of thyroglobulin hydrolysis. Iodide required organic binding of iodine for its effect but new protein or RNA synthesis was not necessary. The inhibitory effects of iodide and lysosomotrophic agents such as NH4Cl and chloroquin on thyroglobulin hydrolysis were additive suggesting different sites of action. Iodide added in vitro altered the distribution of label in prelabelled thyroglobulin in a way that suggested increased coupling in the thyroglobulin molecule. These data indicate that 1) the iodide effect occurs progressively over a 6 h period, 2) continued presence of iodide is not necessary once the inhibition is established, 3) iodide exerts its action primarily at a post cAMP, prelysosomal site and 4) the effect requires organic binding of iodine, but not new RNA or protein synthesis.(ABSTRACT TRUNCATED AT 250 WORDS)
Ammonium Chloride↗
Repeated thyrotrophin stimulation of thyroid secretion: lack of refractoriness in vivo.
It has been reported that prior exposure of thyroid tissue to TSH in vitro induces a state of refractoriness to new challenges of the hormone. We have investigated the effect of repeated TSH treatment on thyroid secretion to determine whether such refractoriness exists in vivo. The rate of thyroid secretion was estimated by measuring the rate of hydrolysis of labelled thyroglobulin from mouse thyroid glands in vitro. The thyroid glands were labelled in vivo with 131I and then cultured for 20 h in the presence of mononitrotyrosine, an inhibitor of iodotyrosine deiodinase. The rate of hydrolysis of labelled thyroglobulin was measured as the percentage of radioactivity released as free iodotyrosines and iodothyronines into the gland and the medium at the end of incubation. Thyrotrophin was administered in vivo at hourly intervals for 2-4 injections. The corresponding control group received saline injections every hour except for the last injection when they received TSH. The peak rates of thyroglobulin hydrolysis, measured 2 h following the last injection, were similar in animals receiving two, three or four TSH injections and were not different from those in the control groups. Serum triiodothyronine and thyroxine concentrations 2 h after the last injection were higher in the groups receiving multiple TSH injections. Thyroidal cyclic AMP accumulation in response to TSH was markedly depressed in the group receiving multiple injections compared with the group receiving a single injection of TSH in vivo.(ABSTRACT TRUNCATED AT 250 WORDS)
Adenylyl Cyclases↗
Cardiac energy metabolism: contributions from nuclear magnetic resonance.
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Adenosine Diphosphate↗
Analysis of triiodothyronine and thyroxine-binding autoantibodies in chickens susceptible to autoimmune thyroiditis.
This report reveals a surprisingly high incidence of thyroid hormone (T3 and T4) autoantibodies (THA) and thyroglobulin autoantibodies in a closed flock of untreated Cornell strain (CS) White Leghorn chickens. This flock is closely related to the Obese strain chicken, which develops a severe spontaneous autoimmune thyroiditis. A sensitive electrophoretic autoradiographic assay for THA was developed. This assay was applied to the study of autoantibodies to T3 and T4 in the sera of adult female CS chickens. Of 109 females, 29.4% had antibodies to T3 and 18.4% had antibodies to T4. The incidence of thyroglobulin antibodies, determined by passive hemagglutination, was 15.6%. The presence of THA affected RIA measurements because serum T3 and T4 hormone concentrations appeared elevated in those birds with moderate to high antibody levels. There was major variance in the electrophoretic heterogeneity of the THA from individual chickens; i.e., some of the sera contained antibodies to T3 or T4 that appeared to be monoclonal, whereas other sera exhibited polyclonal multi-banded patterns. To determine if antibodies reactive with T3 and T4 (which are haptens) were generated by antibody responses to the T3/T4 sites on the thyroglobulin molecule, competitive binding assays were performed to determine the relative binding affinities of the antibodies for the haptens (T3/T4) and the "hapten-conjugate" (thyroglobulin). In these assays, thyroglobulin competed with the haptens, thus supporting the above hypothesis.
Animals↗
Etiologic evaluation of male pseudohermaphroditism in infancy and childhood.
We outlined a diagnostic scheme for use with prepubertal patients with male pseudohermaphroditism (MPH) that included karyotyping, a genitourethrogram, a human chorionic gonadotropin stimulation test with plasma hormone level determinations, and determination of 5 alpha-reductase activity and androgen receptor binding in genital skin fibroblasts. A thorough evaluation is warranted in all patients since the correct diagnosis may assist in determining gender assignment and providing appropriate genetic counseling. We studied 25 patients by the prescribed diagnostic scheme: seven of them had a partial gonadal dysgenesis, two were deficient in 5 alpha-reductase activity, two showed partial androgen insensitivity, four had multiple congenital malformations, one had a Wilms' tumor, and nine were considered as having an idiopathic form of MPH.
3-Oxo-5-alpha-Steroid 4-Dehydrogenase↗