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Biomedical subjects

J A Magner

Publications and source records attributed to J A Magner.

At least 19 recordsLinked to original sources
PubMed1997

Duodenal obstruction in thyroid storm.

A 35-year-old, previously healthy woman, known to be thyrotoxic, was transferred from a community hospital for "acute abdomen." Abdominal pain, distention, and hyperemesis resolved with placement of nasogastric tube (NGT) and return of 2,600 mL of bilious fluid. Continued high NGT output made oral or NGT administration of antithyroid drugs impossible. We gave propylthiouracil (PTU) by retention enemas with therapeutic serum levels and sublingual saturated solution of potassium iodide (SSKI) with 70% absorption based on 24-hour free iodine urinary excretion. The patient's thyroxine (T4) and triiodothyronine (T3) radioimmunoassays were normal on hospital days 10 and 12, respectively. However, free T4 and T3 resin uptake did not normalize until hospital day 31. On hospital day 32, she tolerated removal of NGT without nausea and 4 days later was taking a regular diet. We conclude that our patient's gastrointestinal symptoms were a prominent feature of her thyrotoxicosis and that rectal PTU and sublingual SSKI are effective in administration of antithyroid drugs.

Abdomen, Acute↗
PubMed1995

Prolonged effects of tumor necrosis factor-alpha on anterior pituitary hormone release.

We examined the chronic (72 h) effects of 30 ng/ml recombinant murine tumor necrosis factor (TNF)-alpha on release of immunoreactive growth hormone (GH), prolactin (PRL), thyrotropin (TSH), and TSH glycosylation, as assessed by lectin binding, in cultured rat anterior pituitary cells. In cultured cells from adult female rats, TNF-alpha significantly suppressed basal and GH-releasing hormone (GRH)-stimulated GH release. TNF-alpha also suppressed basal PRL release and completely abolished the PRL response to TRH (0.1-10 nM). Whereas TNF-alpha reduced basal TSH release, it significantly enhanced the maximal TSH response to TRH. TNF-alpha did not affect the concanavalin A and lentil lectin binding of TSH accumulated in the medium during the 4-day culture, but significantly decreased the lentil lectin binding of TSH released in response to acute TRH stimulation. TNF-alpha significantly enhanced the inhibitory effect of somatostatin on stimulated PRL release, but not on GH or TSH release. Compared to cell cultures from adult female rats, in anterior pituitary cell cultures from 12-day-old rats the effects of prolonged exposure to TNF-alpha on hormone release were diminished or absent. Pituitary hormone release was unaffected by acute (3 h) exposure to TNF-alpha. These results demonstrate a direct effect of TNF-alpha on anterior pituitary hormone release, which is cell-type specific and age dependent.

Animals↗
PubMed1995

beta-Galactoside alpha-2,3-sialyltransferase messenger RNA increases in thyrotrophs of hypothyroid mice.

Our goal was to learn about the cellular mechanism(s) responsible for the increased sialylation of thyroid-stimulating hormone (TSH) during hypothyroidism. We used in situ hybridization to examine the beta-galactoside alpha-2,3-sialyltransferase mRNA content in thyrotrophs and corticotrophs of euthyroid and hypothyroid [propylthiouracil (PTU)-treated] mice. The alpha-2,3-sialyltransferase mRNA level was 66, 70, 296, and 223% higher in hypothyroid thyrotrophs than in euthyroid thyrotrophs after mice received PTU for 1, 2, 3, and 6 weeks, respectively. Increased transcription of this gene, or mRNA stabilization, may partially explain the increased sialylation of TSH during hypothyroidism.

Animals↗
PubMed1995

Serum thyrotropin (TSH) heterogeneity in euthyroid subjects and patients with subclinical hypothyroidism: the core fucose content of TSH-releasing hormone-released TSH is altered, but not the net charge of TSH.

The aims of the present study were to determine the influence of brief subclinical hypothyroidism on the isoforms of serum thyrotropin (TSH) and to examine the net charge of TSH in different metabolic states. Sera were obtained from euthyroid subjects (n = 7) and from patients with subclinical hypothyroidism (n = 8) before and 30 min after the intravenous administration of 200 micrograms thyrotropin-releasing hormone (TRH). The TSH from human pituitary extracts (IRP 68/38), basal and TRH-stimulated serum TSH was immunoconcentrated and further analysed by isoelectric focusing (IEF) and lentil lectin affinity chromatography. TSH immunoreactivity was determined in each specimen or fraction with an automated highly sensitive chemiluminometric TSH assay. We found that basal TSH in subclinical hypothyroidism, and TRH-released TSH in euthyroidism and in subclinical hypothyroidism is distributed in a similar neutral to acidic pattern, which significantly differs from the more alkaline to neutral isoform pattern of intrapituitary TSH (P < 0.05). IEF analysis of pituitary standard TSH revealed 3 major peaks (pI values 7.5; 6.6; 5.8) whereas in most euthyroid or subclinically hypothyroid subjects 5 peaks were found. Lentil lectin affinity chromatography revealed that TRH-released TSH in euthyroid subjects has more core fucose residues than TSH from patients with subclinical hypothyroidism (64.6 +/- 6.7 vs 12.5 +/- 2.7%, P < 0.0001). Thus pituitary standard TSH seems to be less mature material than circulating TSH. Perhaps no alteration in the IEF pattern of TSH was detected during early hypothyroidism because sialylation of TSH was increasing as sulfatation was decreasing. Nevertheless, a change in the core fucose content of TSH was detectable by lentil analysis.

Adult↗
PubMed1994

Methimazole-induced agranulocytosis treated with recombinant human granulocyte colony-stimulating factor (G-CSF).

A 35-year-old female hematology technician with Graves' disease developed agranulocytosis a few days after starting therapy with Tapazole (methimazole). Because of a recent report of use of recombinant human granulocyte colony-stimulating factor (G-CSF) in patients with propylthiouracil-induced agranulocytosis, 5 micrograms/kg/day G-CSF was administered and her granulocyte count returned to normal after three doses, on the sixth day after the last dose of methimazole. We conclude that in patients with drug-induced agranulocytosis, the use of G-CSF, in addition to discontinuation of the offending drug, hastens recovery and reduces morbidity.

Adult↗
PubMed1994

Sialyltransferase messenger ribonucleic acid increases in thyrotrophs of hypothyroid mice: an in situ hybridization study.

Hypothyroid patients and mice have been shown to have circulating TSH that is more highly sialylated than their euthyroid counterparts. To learn about the underlying cellular mechanisms responsible for this increased sialylation of TSH, we used in situ hybridization to examine the beta-galactoside alpha-2,6-sialyltransferase (STase) mRNA content in thyrotrophs and corticotrophs of euthyroid and hypothyroid mice. Mice were treated with or without 0.05% propylthiouracil for 1, 2, 3, 4, or 6 weeks, then pituitaries were removed, and 5-microns slices were immunocytochemically stained for TSH and ACTH. Adjacent sections were used for in situ hybridization. A 48-mer deoxynucleotide probe to rat STase and two control probes were labeled with 35S, and autoradiography was performed. There was an approximately 140% increase in STase mRNA in hypothyroid thyrotrophs compared to euthyroid thyrotrophs by the first week, with a mean increase of 170% in weeks 1-6, whereas corticotrophs exhibited no change in STase mRNA. The increase in hybridization of the STase probe in hypothyroid thyrotrophs may be due to an increased transcription of the STase gene, stabilization of the STase mRNA, or both. Thus, modulation of the STase mRNA levels occurs in thyrotrophs and represents one important mechanism by which the oligosaccharides of TSH are altered under different physiological conditions.

Adrenocorticotropic Hormone↗
PubMed1994

Beta-1,4-galactosyltransferase and alpha-mannosidase-II messenger ribonucleic acid levels increase with different kinetics in thyrotrophs of hypothyroid mice.

Hypothyroid animals secrete not only more TSH, but also qualitatively different TSH, with altered oligosaccharides. To explore the cellular mechanism of oligosaccharide modulation by thyroid status, 40 mice were treated without or with propylthiouracil (PTU), and pituitaries were removed after 1, 2, 3, 4, and 6 weeks. Serum T4 levels confirmed that mice receiving PTU were hypothyroid even after only 1 week. Thyrotrophs and corticotrophs were identified in 5-microns thick pituitary slices using immunocytochemistry; in situ hybridization was performed using 35S-labeled 48-mer DNA probes to beta-1,4-galactosyltransferase and alpha-mannosidase-II messenger RNAs (mRNAs). A control probe also was used. Autoradiography was performed for 4 weeks. The cells and silver grains were scored, and the differences reported below were significant by analysis of variance. Compared to euthyroid thyrotrophs, the beta-1,4-galactosyltransferase mRNA level in thyrotrophs increased 440% after mice received PTU for 1 week; the mean increase within thyrotrophs over the 6-week period was 173%, whereas there was little change in corticotrophs. Compared to euthyroid thyrotrophs, the alpha-mannosidase-II mRNA level in thyrotrophs remained unchanged while mice received PTU for 4 weeks, but then increased 150% after week 6 of PTU treatment. Thus, thyroid status modulates mRNA levels of two glycosyltransferases in thyrotrophs, perhaps by affecting gene transcription or mRNA stability. Moreover, the kinetics of the modulation of the two glycosyltransferase mRNAs differ. This is the first report of the modulation of these glycosyltransferase mRNA levels in thyrotrophs and may explain in part the mechanism by which different isoforms of TSH are secreted in different physiological states.

Animals↗
PubMed1993

Octreotide changes serum thyrotropin (TSH) glycoisomer distribution as assessed by lectin chromatography in a TSH macroadenoma patient.

A 28-yr-old woman with hyperthyroidism due to a TSH/GH-secreting macroadenoma was treated preoperatively with octreotide to attain euthyroidal status. Lectin chromatography, performed on her immunopurified serum TSH obtained at baseline and 1 week after 50 micrograms three times daily octreotide therapy, revealed a significant increase in ricin binding after octreotide. This result is consistent with increased amounts of TSH isoforms with more exposed galactose residues. Further clinical studies to elucidate the effects of pharmacological agents on serum TSH isoforms and TSH bioactivity are needed.

Adenoma↗
PubMed1992

Binding of thyrotropin to lentil lectin is unchanged by thyrotropin-releasing hormone administration in three patients with thyrotropin-producing pituitary adenomas.

Glycoproteins have increased affinity for lentil lectin when fucose residues are bound to N-acetylglucosamine in the "core region" of their asparagine-linked oligosaccharides. In three patients with thyrotropin (TSH)-producing pituitary tumors, the proportion of serum TSH isoforms that bound to lentil (70.8% +/- 15%) was higher than that seen for TSH from normal persons (32.5 +/- 8%). Unlike normal subjects, the concentration of TSH circulating in the tumor patients after acute administration of TSH-releasing hormone (TRH) did not rise, and the TSH did not exhibit increased binding to lentil compared to basal TSH. The TSH binding to lentil in one tumor patient decreased after metoclopramide, but TSH binding to lentil generally remained unchanged after metoclopramide or L-dopa administration. We conclude that human thyrotropic tumor tissue, unlike normal thyrotrophs, generally fails to release more highly fucosylated isoforms of TSH after pharmacologic stimulation, perhaps because the tumor tissue is less readily modulated by endocrine stimuli, or because the TSH is already relatively highly fucosylated.

Adenoma↗
PubMed1992

Structures of high-mannose and complex oligosaccharides of mouse TSH and free alpha-subunits after in vitro incubation of thyrotropic tissue with TRH.

To determine whether incubation of mouse thyrotropic tissue with TRH in vitro influenced the oligosaccharide structure of TSH, thyrotropic tumor tissue or pituitary tissue was incubated in vitro with [3H]mannose or with [35S]sulfate and [3H]methionine, in the absence or presence of TRH for times up to 24 h. [3H]mannose-labeled oligosaccharides from intracellular TSH and free alpha-subunits were analyzed by paper chromatography, and were predominantly Man9GlcNAc and Man8GlcNAc units both in the absence and presence of TRH. The [35S]sulfate/[3H]methionine ratio in secreted molecules was greater for TSH than for free alpha-subunits; within TSH heterodimers the ratio was greater for beta-subunits than alpha-subunits. The [35S]/[3H] ratio was not altered in TSH or free alpha-subunits by TRH. Analyses of [3H]mannose-labeled charged oligosaccharides by HPLC anion-exchange chromatography revealed similar types of oligosaccharides present on TSH subunits and free alpha-subunits (having one or two sulfate residues, one or two sialic acid residues, or both a sulfate and a sialic acid residue). These charged oligosaccharides occurred in different proportions on TSH subunits compared to free alpha-subunits, and also differed depending on whether the tissue source was tumorous or nontumorous. The proportions of oligosaccharide unit types were not altered by TRH. Thus, while this study provided information concerning the high-mannose and complex oligosaccharides of mouse TSH, there was no evidence that short incubations of tissues with TRH in vitro caused modulation of TSH oligosaccharide structures.

Animals↗
PubMed1992

Intravenous thyrotropin (TSH)-releasing hormone releases human TSH that is structurally different from basal TSH.

To determine whether basal TSH differed structurally from TRH-released TSH, the TSH obtained from 11 normal subjects before and after the iv administration of TRH was characterized using lectin-affinity chromatography. TSH was applied to the following lectins: lentil, ricin (both before and after TSH treatment with neuraminidase), Concanavalin-A, wheat germ, Glycine max, Helix pomatia, Dolichos biflorus, Arachis hypogaea, and Vicia villosa (isolectin B4). After each column was washed to elute unbound TSH, the bound TSH was eluted using the appropriate specific sugar, and TSH in the column fractions was measured by immunoradiometric assay. Basal TSH was found to have a different oligosaccharide composition than TSH in serum 30 min after TRH administration. The basal TSH had fewer core fucose residues and more exposed galactose residues than the TSH released after TRH treatment. The amounts of oligosaccharide branching and the amounts of N-acetylglucosamine were similar, and the degrees of sialylation for both basal TSH and TRH-released TSH were highly variable. No exposed N-acetylgalactosamine residues were detected in either type of TSH; if present, these residues may have been uniformly sulfated. The biochemical differences detected in basal TSH vs. TRH-released TSH may reflect different post-translational processing and storage of these molecules in thyrotrophs. These data provide an example of the release of particular isoforms of human TSH depending on a hypothalamic factor, a general principle that may be important in the physiological control of thyroid function by the pituitary.

Acetylgalactosamine↗
PubMed1991

Processing to endoglycosidase H-resistant thyrotropin subunits occurs in the presence of brefeldin-A: evidence favoring the recycling of Golgi membranes to the rough endoplasmic reticulum in mouse thyrotrophs.

In order to assess the localization and physiologic redistribution of Golgi enzymes within mouse thyrotrophs, we studied the carbohydrate processing of TSH subunits in the presence of brefeldin A (BFA). Although this drug clearly causes endoglycosidase (endo) H-sensitive species to accumulate in most cell types, our purpose was to determine whether or not endoglycosidase H-resistant forms of free alpha-subunits and TSH subunits eventually accumulated in small but significant amounts within mouse thyrotrophic tumor cells or pituitary thyrotrophs incubated with BFA. This drug is known to block intracellular transport from the rough endoplasmic reticulum (RER) to the proximal Golgi. Stimulated thyrotrophs have been reported to have some Golgi enzymes active in their dilated RER. Accumulation of endo H-resistant forms in the presence of BFA might be explained by (1) drug-induced enhancement of Golgi to RER membrane recycling with further aberrant distribution of Golgi enzymes or (2) an uncharacteristic trapping of glycoproteins within Golgi elements that might be an unusual action of BFA peculiar to thyrotrophs. Free alpha-subunits and TSH were labeled in mouse thyrotrophic tumor tissue or pituitaries incubated in pulse-chase fashion with [35S]methionine in the absence or presence of BFA, carboxyl cyanide m-chlorophylhydrazone (CCCP), or swainsonine. The results in tumor and pituitary tissue were similar. In incubations without drugs, most TSH subunits (greater than 90%) became endo H-resistant after 5-h chase, and the majority (greater than 85%) were secreted. Doses of CCCP and BFA were selected that generally blocked the secretion of TSH subunits by greater than 85% (in some cases greater than 99%), presumably because of accumulation of secretory proteins in the RER. Yet, in the presence of CCCP, 35% and 42% of intracellular free alpha-subunits and TSH subunits, respectively, became endo H-resistant at 5 h chase. Compared to control incubations, intracellular subunits tended to remain endo H-sensitive in the presence of BFA, yet, compared to CCCP incubations, BFA slightly enhanced the attainment of endo H-resistance by free alpha-subunits and TSH subunits to 55% and 52%, respectively. Pretreatment of tumor tissue with BFA allowed more endo H-resistant species to appear, even during coincubation with CCCP. These data suggest that Golgi enzymes cycle back to the dilated RER of active thyrotrophs and that this phenomenon is enhanced by BFA.

Adenosine Triphosphate↗
PubMed1990

Susceptibility to endoglycosidase F and H at the individual glycosylation sites of mouse thyrotropin and free alpha-subunits.

We have studied the differential susceptibility to endoglycosidase F and H of oligosaccharides at the individual glycosylation sites of mouse TSH and free alpha-subunits. Mouse thyrotropic tumor tissue was incubated with D-[2-3H]mannose for 6 h. [3H]Man-labeled TSH and free alpha-subunits were obtained from homogenates using specific antisera and were digested with endoglycosidase F and H in their native states or after heat-denaturation and reduction in the presence of detergents. Tryptic fragments of the digestion products were then analyzed by reverse phase HPLC so that effects of endoglycosidase at the individual glycosylation sites could be determined. There was very little preferential cleavage by endoglycosidase H and F among the glycosylation sites of TSH subunits. Endoglycosidase F treatment of native free alpha-subunits showed slight preferential cleavage at Asn 82 of alpha-subunits after a 4 h incubation, whereas endoglycosidase H cleaved oligosaccharides equally well at Asn 56 and Asn 82. The Asn 82 oligosaccharide of native TSH heterodimers was also slightly preferentially cleaved by endoglycosidase F, but endoglycosidase H cleaved oligosaccharides equally well at all TSH glycosylation sites. Heat denaturation, reduction and the presence of detergent did not alter this slight preferential cleavage by endoglycosidase F at Asn 82 of alpha-subunits, suggesting that the primary structures of the TSH subunits in part influenced the efficiency of enzyme action at specific sites. Thus, the susceptibility to endoglycosidase F differs very slightly at the individual glycosylation sites of mouse TSH and free alpha-subunits, and these small differences could be due to properties of either the enzyme or substrates.

Acetylglucosaminidase↗