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Biomedical subjects

W E Nicholson

Publications and source records attributed to W E Nicholson.

At least 73 records · Page 4Linked to original sources
PubMed1978

Immunoreactive endorphins, lipotropins and corticotropins in a human nonpituitary tumor: evidence for a common precursor.

The immunoreactive (RIA), ACTH, LPH, alpha endorphin (alpha End) and beta End in an extract of a human pancreatic islet cell carcinoma causing the ectopic ACTH syndrome were assayed after gel exclusion chromatography. In addition to "big", "intermediate" and "little" ACTHs, beta lipotropin (beta LPH) and gamma LPH, the eluate fractions contained RIA-alpha End and -beta End. The major RIA-beta End component appeared to be h beta LPH, which has beta End as its carboxy-terminus, but significant concentrations of a component that coeluted with synthetic p beta End were also found. Small amounts of RIA-alpha End were found in two peaks, one that may have represented 1-76 h beta LPH, with alpha End as its carboxy-terminus, and one probably representing alpha End itself. RIA-ACTH, -LPH and -beta End were found in the void volume fractions. Thus, a human nonpituitary tumor that produced ACTH and LPHs also produced endorphins, all perhaps deriving from a common precursor.

Adenoma, Islet Cell↗
PubMed1978

Diurnal rhythm and disappearance half-time of endogenous plasma immunoreactive beta-MSH (LPH) and ACTH in man.

In order first to establish the disappearance t 1/2 of endogenous immunoreactive human beta-MSH (RIA-h beta MSH), which is now known to represent the lipotropins, human beta-LPH and human gamma-LPH, the plasma concentrations of RIA-h beta MSH, RIA-hACTH, and fluorogenic corticosteroids (cortisol) were measured before and during infusion of cortisol in three patients with primary adrenocortical insufficiency from whom steroid replacement had been withdrawn. The t 1/2 for RIA-h beta MSH ranged from 44-133 min (mean, 83), and for RIA-hACTH ranged from 20-51 min (mean, 40). On this basis, 30-min sampling intervals were chosen to measure plasma concentrations of RIA-h beta MSH, RIA-hACTH, and cortisol in three normal subjects for 24 h. Similar diurnal rhythms were observed for all three hormones. Highest values (58.0 +/- 5.8 pg/ml) for RIA-h beta MSH were observed at about the time of awaking and lowest values (15.0 +/- 2.1 pg/ml) shortly after retiring. The secretion of both RIA-h beta MSH and RIA-hACTH appeared to be episodic, with about 8-10 secretory episodes/24 h, and the timing of their secretory episodes appeared to be nearly identical. There was excellent correlation (P less than 0.001) between simultaneous concentrations of RIA-h beta MSH and RIA-hACTH in all three subjects. These results establish the presence of a diurnal rhythm in plasma lipotropins (RIA-h beta MSH) and suggest that roughly equimolar amounts of ACTH and LPH are secreted simultaneously by the pituitary under basal conditions in man.

Adrenocorticotropic Hormone↗
PubMed1978

Ectopic production of high molecular weight calcitonin and corticotropin by human small cell carcinoma cells in tissue culture: evidence for separate precursors.

The DMS-79 continuous line of human small cell lung carcinoma cells, which produces immunoreactive (IR)-corticotropin (ACTH), -lipotropin (LPH), and -beta-endorphin (beta END), was found to produce IR-calcitonin (CT). Two major high molecular weight (HMW) forms of IR-CT were observed after gel exclusion chromatography under denaturing conditions (mol wt. approximately 7,000 and approximately 14,000), as well as a minor HMW IR-CT component (mol. wt. approximately 70,000). None of these IR-CT materials was extracted from DMS-79 medium by affinity chromatography using an ACTH antibody covalently bound to agarose. These results demonstrate ectopic production of HMW forms of CT and ACTH/LPH/beta END by human lung tumor cells in tissue culture, but do not support the existence of a common CT/ACTH/LPH/beta END precursor molecule.

Adrenocorticotropic Hormone↗
PubMed1977

Ectopic production of antidiuretic hormone (adh), adrenocorticotrophic hormone (ACTH) and beta-melanocyte stimulating hormone (beta-MSH) by an oat cell carcinoma of the lung.

A 61 year old woman presented with profound hyponatremia and markedly low serum osmolality. Urine osmolality was greater than the serum osmolality, an abnormality that was corrected by water restriction, suggesting inappropriate ADH secretion. Although there were no physical signs of Cushing's syndrome, her serum potassium level was low and markedly elevated levels of plasma and urine corticosteroids were not altered by the administration of large amounts of dexamethasone, suggesting the ectopic ACTH-MSH syndrome. Plasma levels of immunoreactive ACTH and beta-MSH were elevated. At autopsy, a metastastic oat cell carcinoma of the lung, not detected antemortem by chest roentgenograms and bronchoscopy, was found. Immunoreactive ADH, ACTH and beta-MSH were detected in the primary tumor and in metastases to the liver. beta-MSH was also detected in the spleen, in which metastases were observed. This is the first documented case of the simultaneous production of ADH, ACTH and beta-MSH by neoplastic tissue associated with clinical manifestations of the syndrome of inappropriate ADH secretion and the ectopic ACTH-MSH syndrome.

Adrenocorticotropic Hormone↗
PubMed1977

Tissue-specific stimulation of ornithine decarboxylase activity by pituitary factors immunologically related to growth hormone.

Ornithine decarboxylase (L-ornithine carboxylase, EC 4.1.1.17) is an important enzyme in polyamine synthesis. Its activity is influenced by several peptides hormones, including growth hormones, which have physiological significance in various growth situations. A crude ovine pituitary growth hormone preparation (NIH-GH-S10) was subjected to gel exclusion chromatography (Sephadex G-100) and two major fractions were obtained. One of these corresponded to dimeric growth hormone (GH). The other fraction was excluded by the gel matrix, suggesting a material of higher molecular weight than GH. This was confirmed by polyacrylamide gel electrophoresis in the presence of sodium dodecyl sulfate. Analysis of a high molecular weight fraction by radioimmunoassay (antisera prepared against GH) and by bioassay (weight gain in hypophysectomized rats) gave apparent GH contents of 19% and 6%, respectively. On a weight basis, the high molecular weight fraction was more effective than GH in stimulating the activity of hepatic and adrenal ornithine decarboxylase, but GH was more effective in stimulating renal ornithine decarboxylase activity. Subfractionation of the high molecular weight fraction using a high porosity gel (Sephadex G-200) gave four fractions, which were shown by amino acid analysis and by polyacrylamide gel electrophoresis in the presence of sodium dodecyl sulfate to be distinct from GH and heterogenous. These subfractions had different potencies for stimulating renal and hepatic ornithine decarboxylase activity. The ability of crude growth hormone preparations to stimulate ornithine decarboxylase activity in some tissues may be a function of pituitary factors, in addition to GH, which have minimal growth promoting activity.

Adrenal Glands↗
PubMed1977

High molecular weight forms of human ACTH are glycoproteins.

The RIA-ACTH in a normal human pituitary, 2 ectopic ACTH-secreting tumors and plasma from a patient with Nelson's syndrome and one with ectopic ACTH syndrome was divided into 3 molecular weight classes after gel exclusion chromatography. The largest component appeared in or near the void volume and was designated "big" RIA-ACTH. The second, designated "intermediate" RIA-ACTH, eluted between the void volume and standard human 1-39 ACTH (mol. wt. 4,541). An immunoreactive material designated "little" ACTH-coeluted with standard human ACTH. A significant fraction (29-61%) of "big" RIA-ACTH from the tumors bound to concanavalin A-agarose and was eluted with 0.2 M alpha-methyl-D-mannopyranoside. An additional 16-22% of "big" RIA-ACTH was more tightly bound to the concanavalin A, but could be purged from the column with 0.1 M acetic acid. A smaller total percent of "big" RIA-ACTH from the pituitary (20%) and plasmas (5-10%) bound to the lectin and was similarly eluted and purged. Relatively little (less than 8%) of "intermediate" RIA-ACTH from all sources bound to concanavalin A, with the exception of that in the pitull sources was essentially excluded (greater than 93%) from the column. These data indicate that a significant fraction of human "big" RIA-ACTH is a glycoprotein and that human "intermediate" RIA-ACTH may be also.

Adenoma, Islet Cell↗
PubMed1976

Hormonal regulation of renal ornithine decarboxylase activity in the rat.

The regulation of the activity of the renal enzyme ornithine decarboxylase (L-ornithine carboxy-lyase, EC 4.1.1.17) was examined in the rat. In the intact animal adapted to a light/dark cycle of 14 hours and 10 hours, respectively, the level of renal ornithine decarboxylase activity was rhythmical and paralleled the diurnal rhythm in plasma corticosteroid concentration. Renal ornithine decarboxylase activity and plasma corticosterone were highest during the early hours of darkness and lowest during the hours of light. Following hypophysectomy, the level of renal ornithine decarboxylase activity declined rapidly and remained low and without a demonstrable diurnal rhythm. When pituitary hormone levels were temporarily restored in the hypophysectomized rat by the injection of pituitary extract, renal ornithine decarboxylase activity increased rapidly, reached a peak within 8 hours, and returned toward pre-injection levels by 12 hours. Exogenous growth hormone, ACTH and cortisol each increased renal ornithine decarboxylase activity in the hypophysectomized rat, with the highest levels of activity being achieved with growth hormone. Other pituitary hormones (FSH, LH, TSH and prolactin) were ineffective. After bilateral adrenalectomy, renal ornithine decarboxylase activity retained a rhythmical pattern similar to that observed in the intact rat, but the levels were increased. Growth hormone and cortisol increased renal ornitine decarboxylase activity in the adrenalectomized-hypophysectomized animal to the same extent as in the hypophysectomized animal, but ACTH was almost totally ineffective. These data suggest that the pituitary plays a major role in the regulation of renal ornithine decarboxylase activity in the rat, primarily through the rhythmical secretion of growth hormone and ACTH.

Adrenal Cortex Hormones↗
PubMed1976

Method for preparation of ampoules containing microgram quantities of polypeptide hormones for distribution and use as laboratory standards: synthetic human ACTH and beta-MSH.

There are a number of polypeptide hormones, their subunits, and other derivatives that are available in such short supply as to preclude distribution by conventional methods to the many qualified investigators who require them. This report describes a method for preparing sealed ampoules of two such hormones, the utilization of which can provide many qualified investigators with comparable, stable reference compounds for several years and eliminate unnecessary waste and error associated with the distribution and use of bulk quantitites of peptide hormone preparations. Sealed ampoules of synthetic human adrenocorticotrophic hormone (alpha(h)(1-39) ACTH) and beta melanocyte-stimulating hormone (beta(h)(1-22) MSH) were prepared. Each ampuole contains 50 mug of dried and recoverable peptide plus 1 mg of lactose, sealed under dry nitrogen at atmospheric pressure. The respective preparations are fully active, both biologically and radioimmunologically, and are suitable as reference compounds in all types of biologic and radioimmunologic assays of these hormones. In addition, radioactive iodine labeling of each peptide can be accomplished without prior removal of the lactose.

Adrenocorticotropic Hormone↗
PubMed1975

Evidence for structural dissociation of two biologic actions of growth hormone.

The effects of purified growth hormone and its CNBr fragments on somatomedin induction and on the stimulation of hepatic and renal ornithine decarboxylase (L-ornithine carboxylase, EC 4.1.1.17) activity in rats have been investigated. At the doses tested, none of the CNBr fragments induced somatomedin as evidenced by lack of an effect on sulfate, leucine, and thymidine incorporation into cartilage of hypophysectomized rats. However, the largest fragment, consisting of two peptides corresponding to Residues 6-124 and 150-179 linked by a disulfide bridge, stimulated both renal and hepatic ornithine decarboxylase activity in hypophysectomized rats and the activity of the hepatic enzyme in intact animals. A smaller CNBr fragment corresponding to Residues 125-149 slightly stimulated the activity of renal ornithine decarboxylase but failed to increase activity of the hepatic enzyme. A similar slight stimulation of the activity of the renal, but not the hepatic, enzyme was produced by a large carboxyl-terminal fragment (molecular weight 8000) prepared by proteolytic cleavage of partially purified ovine growth hormone. Circular dichroic spectra of the CNBr fragments demonstrated that the largest fragment retained much of the ordered secondary structure of intact growth hormone while two smaller CNBr fragments were devoid of ordered secondary structure. These observations indicate that different biological activities of growth hormone may be dissociated by fragmentation of the parent molecule.

Amino Acid Sequence↗
PubMed1975

Nature of the increase in renal ornithine decarboxylase activity after cycloheximide administration in the rat.

The present study was designed to determine whether the increase in rat renal ornithine decarboxylase (L-ornithine carboxy-lyase, EC 4.1.1.17) activity after cycloheximide administration was a primary effect on the kidney or was a secondary effect of adrenal or pituitary hormones released in response to the drug. Renal ornithine decarboxylase activity was reduced approximately 70% 1 hr after intraperitoneal administration of doses of cycloheximide that also inhibited renal protein synthesis by 68-95% within 1 hr. Protein synthesis began to recover by the second hour, accompanied by a rise in decarboxylase activity that reached a peak about six times greater than pretreatment values at 8 hr, then gradually declined to preinjection levels by 16 hr. Peak ornithine decarboxylase activity was directly proportional to cycloheximide doses up to 250 mug; larger doses, which almost abolished protein synthesis for 8 hr, where inhibitory. Plasma corticosterone rose rapidly after cycloheximide, reached a peak at 2 hr, then fell to baseline by 8 hr. Corticosterone response was also dose-dependent up to 250 mug, but larger doses were inhibitorymadrenalectomy did not reduce decarboxylase activity response to cycloheximide, nor did cortisol administration enhance it. Hypophysectomy greatly reduced baseline renal decarboxylase activity within 9 hr and all but abolished the increase in enzyme activity normally seen after cycloheximide administration to the intact rat. The hypophysectomized animal exhibited apparent increased sensitivity to cycloheximide, since a smaller dose of the drug caused a reduction in renal protein synthesis similar to that seen with a larger dose in the intact rat. As protein synthesis was recovering in the hypophysectomized animals, renal decarboxylase activity responded adequately to the injection of a crude pituitary extract. These data suggest that renal ornithine decarboxylase turnover is rapid, that baseline activity is.maintained by new protein synthesis, and that the increase in renal enzyme activity after cycloheximide is in larger part dependent upon pituitary hormone action.

Adrenal Glands↗
PubMed1975

The mechanism of ACTH stimulation of adrenal ornithine decarboxylase activity.

The mechanism of action of adrenocorticotrophin (ACTH) stimulation of rat adrenal orticotrophin (ACTH) stimulation of rat adrenal ornithine decarboxylase activity was investigated. ACTH induction or ornithine decarboxylase activity was not prevented by administration of drugs that inhibit adrenal steroid biosynthesis. A dose of ACTH that produced maximal levels of adrenal cyclic AMP did not induce ornthine decarboxylase activity. Ovine growth hormone, which caused no increase in adrenal cyclic AMP, stimulated adrenal ornithine decarboxyase activity. These observations suggest that the increase in adrenal ornithine decarboxylase activity stimulated by ACTH is not dependent upon steroidogenesis, nor is it dependent on the early peak of cyclic AMP, although it may be influenced by the sustained levels of tissue cyclic AMP that follow the administration of large doses of ACTH. Furthermore, it appears there may be a pathway of ornithine decarboxylase activation in the adrenal which is entirely independent of cyclic AMP mediation. The effects of hypophysectomy on adrenal ornithine decarboxylase response to ACTH were examined. In rats given ACTH 16 h after hypophysectomy, the increase in ornithine decarboxylase activity was delayed when compared with the response in animals given ACTH 1 h after hypophysectomy. Actinomycin D given during the first 3 h after ACTH in the 16 h hypophysectomized rat abolished the expected increase in ornithine decarboxylase activity. Thereafter, a progressive increase in ornithine decarboxylase activity was observed as the interval between ACTH and Actinomycin D administration was further increased. In contrast, Actinomycin D administered 15 min before ACTH in the 1 h hypophysectomized rat had no effect on the subsequent increase in ornithine decarboxylase activity, and actually progressively enhanced the response the longer its administration after ACTH was delayed. Cycloheximide abolished the response to ACTH in both the 1 h and the 16 h hypophysectomized rat. Thus, it appears that ACTH stimulates a post-transcriptional mechanism regulating ornithine decarboxylase activity in the acutely hypophysectomized animal, whereas, in the chronically hypophysectomized rat, ACTH must first stimulate transcription of new messenger RNA which is involved in regulation of adrenal ornithine decarboxylase synthesis.

Adrenal Glands↗
PubMed1973

Comparative effects of angiotensin and ACTH on cyclic AMP and steroidogenesis in isolated bovine adrenal cells.

The comparative effects of angiotensin II and adrenocorticotropic hormone (ACTH) on cyclic AMP and steroidogenesis were investigated employing isolated bovine adrenal cells from the zona fasciculata. Like ACTH, angiotensin produced a prompt increase in cyclic AMP which preceded the increase in corticosteroid production. Although this increase in cyclic AMP was small when compared to that induced by ACTH, it correlated with the amount of steroidogenesis. This observation is consistent with the view that cyclic AMP is the intracellular mediator of the steroidogenic action of angiotensin. Angiotensin acted synergistically with ACTH on cyclic AMP levels. This synergism was not explained by inhibition of phosphodiesterase activity. Unlike ACTH, angiotensin failed to stimulate adenylate cyclase in broken cell preparations. The observations suggest that more than one mechanism may be involved in effects of ACTH and angiotensin on cyclic AMP levels.

Adrenal Cortex Hormones↗
PubMed1973

Biologic and immunologic characterization and physical separation of ACTH and ACTH fragments in the ectopic ACTH syndrome.

Extracts of tumors from 32 patients with the ectopic ACTH syndrome were subjected to simultaneous bioassay and radioimmunoassays for ACTH. Radioimmunoassays were performed using three antisera, one of which reacts with the extreme N-terminal 1-13 amino acid sequence of ACTH, the second with the N-terminal 1-23 sequence of the ACTH molecule, and the third with the C-terminal 25-39 amino acid sequence of ACTH. There was, in general, good correlation between bioactivity and N-terminal ACTH immunoreactivity. However, there were large excesses of both extreme N-terminal and C-terminal immunoreactive materials in most tumor extracts, which were not found in extracts of three human pituitaries. Three tumor extracts were subjected to molecular sieve chromatography on Sephadex G-50 fine resin. The bioactive ACTH eluted in the same fractions as pituitary ACTH (mol wt approximately 4,500 daltons) and reacted equally in all three ACTH radioimmunoassay systems. The bioactive tumor ACTH was neutralized by incubation with the C-terminal antiserum, indicating it has an intact C-terminal sequence of amino acids. The next several fractions from the Sephadex column contained a material, mol wt approximately 3,100, which was biologically inactive and had C-terminal immunoreactivity but no N-terminal or extreme N-terminal immunoreactivity. Incubation with the N-terminal 1-23 ACTH antiserum did not adsorb these C-terminal fragments, indicating they lacked an intact sequence of amino acids in this region. A smaller ACTH fragment (mol wt approximately 1,800 daltons) eluted in still later fractions and reacted with the extreme N-terminal antiserum but not with the N-terminal or C-terminal antisera. It had no steroidogenic activity, but appeared to have significant melanocyte-stimulating activity. It is concluded that, in addition to an ACTH similar, if not identical, to pituitary ACTH, tumors of patients with the ectopic ACTH syndrome contain both N-terminal and C-terminal ACTH fragments.

Adrenocorticotropic Hormone↗