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Biomedical subjects

L A Fitzpatrick

Publications and source records attributed to L A Fitzpatrick.

At least 127 records · Page 7Linked to original sources
PubMed1988

Effect of prostaglandin F2 alpha on human parathyroid adenomas: evidence for uncoupling of parathyroid hormone secretion and cAMP accumulation.

Human parathyroid adenomas are aberrantly regulated by extracellular calcium. We tested pertussis toxin, which ADP-ribosylates and inactivates several guanine nucleotide regulatory proteins, to test the role of these proteins in the secretory control of adenomatous parathyroid tissue. Pertussis toxin did not affect basal cAMP accumulation in 12 adenomas and enhanced parathyroid hormone (PTH) release in 6 of 10 adenomas. Prostaglandin F2 alpha (PGF2 alpha) inhibited cAMP in three of six adenomas, and pertussis toxin pretreatment did not affect this result. PTH release in 7 of 10 adenomas was inhibited by PGF2 alpha, and pertussis toxin did not significantly alter PTH release. Pertussis toxin catalyzed ADP-ribosylation of a 40-kDa protein in all adenomas tested (n = 8). We conclude that cAMP accumulation was not affected by pertussis toxin but that in 6 of 10 adenomas, the toxin enhanced PTH release. We suggest that cAMP accumulation and PTH release may be uncoupled from negative control by inhibitory ligands in adenomatous tissue or that the G-proteins involved do not couple to regulatory receptors or to effector.

Adenoma↗
PubMed1988

Anti-endothelial cell antibodies: detection and characterization in sera from patients with autoimmune hypoparathyroidism.

In a previous report, we described antibodies in autoimmune hypoparathyroidism (AHP) that are cytotoxic for cultured bovine parathyroid cells. In the present study, we show that sera from six AHP patients, but not from 26 patients with other autoimmune diseases or from 7 healthy subjects, react with bovine endothelial cells in culture (by flow cytometry and fluorescence microscopy) and in tissue sections (by immunohistology). We found uniformly that the immunoglobulin class reacting is IgM. Adsorption experiments showed that the antigenic determinants reacting with AHP sera were similar on bovine cultured endothelial cell membranes and in tissue sections of bovine parathyroid glands. The AHP sera also reacted with endothelial cells cultured from bovine adrenal medulla and pulmonary artery. Immunoblot analysis showed antibody binding to two major bands of 200 and 130 kDa solubilized from the membrane fraction of bovine parathyroid endothelial cells. Only one AHP serum consistently recognized endothelium-related structures on frozen sections of three different human parathyroid adenomas; two other sera reacted with one adenoma each; and three did not react with human adenomas. This indicates that human material is less suitable than bovine in detecting endothelium-related immune phenomena in AHP sera. The anti-endothelium IgM antibodies appear to be disease-specific but are not organ- or species-specific. The identification of endothelial cells as the target for antibodies in AHP raises the possibility that the endothelium subserves an important local function for endocrine epithelium.

Animals↗
PubMed1988

Antibodies to an alpha subunit of skeletal muscle calcium channels regulate parathyroid cell secretion.

We have shown previously that Ca2+-channel agonists, which open Ca2+ channels, inhibit parathyroid hormone (PTH) secretion from dispersed bovine parathyroid cells, whereas Ca2+-channel antagonists, which close Ca2+ channels, stimulate PTH release. We now have tested the effects of mouse antibodies specific for purified alpha subunits of rat skeletal muscle Ca2+-channel proteins on PTH secretion by bovine parathyroid cells in vitro. Mouse antisera (MC-2, MC-3, MC-4) blocked the secretion of PTH from parathyroid cells incubated with 0.5 mM Ca2+ ions. Affinity-purified MC-4 antibodies inhibited PTH release in a concentration-dependent manner. Incubation of parathyroid cells with pertussis toxin markedly reduced MC-4-dependent inhibition of PTH secretion. Parathyroid cell membrane proteins were fractionated by NaDodSO4/polyacrylamide gel electrophoresis under either reducing or nonreducing conditions and immunoblotted with MC-4 antiserum. Antibodies bound to one major band of protein with Mr approximately equal to 150,000. These results suggest that the antibodies bind to Ca2+-channel alpha subunits and act as agonists that open the channels and inhibit PTH release.

Animals↗
PubMed1987

Acute primary hyperparathyroidism.

Acute primary hyperparathyroidism is an unusual form of primary hyperparathyroidism characterized by life-threatening hypercalcemia. Forty-three cases reported in the literature since 1974 are reviewed, along with five new cases. The average age of the patients was 55 (27 to 82), with an even distribution between men and women. Marked hypercalcemia (17.5 +/- 2.1 mg/dl) was accompanied by parathyroid hormone levels 20 times normal. Virtually all patients had symptoms. Hyperparathyroid bone disease occurred in 53 percent of patients; even more (69 percent) had nephrolithiasis or nephrocalcinosis. Combined renal and skeletal involvement was seen in 50 percent. Only three deaths were recorded. The pathophysiology of the acute hyperparathyroid state is unknown but appears to consist of uncontrolled parathyroid hormone secretion followed by cycles of hypercalcemia, polyuria, dehydration, reduced renal function, and worsening hypercalcemia. These features of acute primary hyperparathyroidism are compared with the features reported in the literature antedating multichannel screening, and with the features of the common form of primary hyperparathyroidism. Clinical guidelines by which the diagnosis may be suspected are also reviewed.

Acute Disease↗
PubMed1986

Control of PTH secretion is mediated through calcium channels and is blocked by pertussis toxin treatment of parathyroid cells.

Parathyroid hormone secretion is negatively regulated by calcium. We utilized calcium channel agents: +202-791, a calcium channel agonist and -202-791, a calcium channel antagonist, to evaluate the role of calcium channels in PTH secretion. +202-791 inhibited PTH release from bovine parathyroid cells and the antagonist stimulated release. Incubation with pertussis toxin which ADP-ribosylates and inactivates a guanine nucleotide regulatory protein (G-protein) releases the inhibition by the calcium channel agonist. These findings indicate that a G-protein is interposed between the calcium channel and a putative intracellular site controlling PTH secretion.

Animals↗
PubMed1986

Parathyroid mitogenic activity in plasma from patients with familial multiple endocrine neoplasia type 1.

Hyperplasia of the parathyroid glands is a central feature of familial multiple endocrine neoplasia type 1. We used cultured bovine parathyroid cells to test for mitogenic activity in plasma from patients with this disorder. Normal plasma stimulated [3H]thymidine incorporation, on the average, to the same extent as it was stimulated in a plasma-free control culture. This contrasted with the results of the tests with plasma from patients with familial multiple endocrine neoplasia type 1, in which parathyroid mitogenic activity increased 2400 percent over the control value (P less than 0.001). Plasma from these patients also stimulated the proliferation of bovine parathyroid cells in culture, whereas plasma from normal subjects inhibited it. Parathyroid mitogenic activity in plasma from the patients with familial multiple endocrine neoplasia type 1 was greater than that in plasma from patients with various other disorders, including sporadic primary hyperparathyroidism (with adenoma, hyperplasia, or cancer of the parathyroid), sporadic primary hypergastrinemia, sporadic pituitary tumor, familial hypocalciuric hypercalcemia, and multiple endocrine neoplasia type 2 (P less than 0.05). Parathyroid mitogenic activity in the plasma of patients with familial multiple endocrine neoplasia type 1 persisted for up to four years after total parathyroidectomy. The plasma also had far more mitogenic activity in cultures of parathyroid cells than did optimal concentrations of known growth factors or of any parathyroid secretagogue. This mitogenic activity had an apparent molecular weight of 50,000 to 55,000. We conclude that primary hyperparathyroidism in familial multiple endocrine neoplasia type 1 may have a humoral cause.

Adenoma↗
PubMed1986

Antibodies cytotoxic to bovine parathyroid cells in autoimmune hypoparathyroidism.

We utilized a recently developed long-term serum-free culture system for bovine parathyroid cells to detect antibodies in seven patients with autoimmune hypoparathyroidism (AHP). Antibodies were tested by indirect immunofluorescence methods and by cytotoxicity utilizing the chromium (51Cr) release technique. Seven AHP sera caused specific lysis [57 +/- 6% release of 51Cr vs. 5 +/- 1% for 56 controls (15 normal subjects and 41 patients with diverse other conditions associated with immune dysfunction)]. The least effect of any of the AHP sera on cell lysis exceeded the greatest effect of any of the control sera. Absorption of AHP sera (two cases) with bovine pituitary, thyroid, liver, or kidney cells did not affect lysis, but absorption with adrenal or parathyroid cells caused a marked decrease in specific lysis. Cytotoxicity determined by 51Cr release increased with antiserum concentration and time of incubation. Cytotoxicity was dependent on complement. Replicating parathyroid cells provide a uniform reproducible detection method for anti-parathyroid antibodies in AHP. The autoantibodies in AHP appear to be specific for tissue (parathyroid and adrenal cortex) but not for species.

Adrenal Cortex↗
PubMed1986

Bovine parathyroid cells: cultures maintained for more than 140 population doublings.

Primary cultures of bovine parathyroid cells were developed using Coon's modified Ham's F-12 medium containing low (0.3 mM) concentrations of calcium and supplements of bovine hypothalamic extract, bovine pituitary extract, epidermal growth factor, insulin, transferrin, selenous acid, hydrocortisone, triiodothyronine, retinoic acid, and galactose. These cells were cultured serially on serum-coated dishes for 140 population doublings before signs of senescence were detected. The cells were epithelioid and maintained a high degree of differentiation as evidenced by calcium regulation of both growth and secretion and by prostaglandin E1 stimulation of cAMP formation and hormone release.

Alprostadil↗
PubMed1986

Prostaglandin F2 alpha and alpha-adrenergic agonists regulate parathyroid cell function via the inhibitory guanine nucleotide regulatory protein.

Prostaglandin F2 alpha (PGF2 alpha) and alpha-adrenergic agonists inhibit cAMP production and PTH secretion in dispersed bovine parathyroid cells. We have tested the mechanism of these effects utilizing pertussis toxin which catalyzes ADP ribosylation and inactivation of the inhibitory adenylate cyclase coupling protein Ni. Dispersed bovine parathyroid cells treated with or without 0.5 micrograms/ml pertussis toxin were tested with stimulatory (epinephrine, isoproterenol) or inhibitory (PGF2 alpha) agonists for responses in cAMP accumulation (5-min incubation) or PTH (90-min incubation) release. Pertussis toxin produced an enhanced response to epinephrine (a mixed alpha-adrenergic and beta-adrenergic agonist) in cAMP production and in PTH secretion. PGF2 alpha inhibited intracellular cAMP by 40% and PTH secretion by 35%. Pertussis toxin treatment of bovine parathyroid cells reduced the PGF2 alpha inhibition. We conclude that: 1) inhibition of PTH release by PGF2 alpha and alpha-adrenergic agonists parallels inhibition of cAMP production; 2) pertussis toxin blocks the inhibitory actions of PGF2 alpha and alpha-adrenergic agents on cAMP accumulation and PTH secretion; 3) the inhibitory coupling protein Ni mediates the inhibitory effects of these agents.

Adenosine Diphosphate Ribose↗
PubMed1986

Calcium-controlled secretion is effected through a guanine nucleotide regulatory protein in parathyroid cells.

Calcium regulates parathyroid secretion through mechanisms yet to be elucidated. We have investigated this phenomenon through use of pertussis toxin which catalyzes ADP-ribosylation and inactivation of a guanine nucleotide regulatory protein, possibly Ni or No. Calcium inhibition of PTH release is blocked in cells treated with pertussis toxin, and there is concomitant ADP-ribosylation of a 40-kilodalton protein. The ionophore A23187 inhibits secretion in toxin-treated as well as in control cells. We conclude that a guanine nucleotide regulatory protein is involved in calcium regulation of PTH secretion at a locus proximal to the intracellular site effecting inhibition of secretion.

Adenosine Diphosphate Ribose↗
PubMed1986

Secretory dysfunction in parathyroid cells from a neonate with severe primary hyperparathyroidism.

We report a patient with neonatal severe primary hyperparathyroidism whose parathyroid cells were markedly refractory to regulation by calcium in vitro. He showed life-threatening hypercalcemia (4.8-5.2 mM vs. normal of 2.1-2.7 mM). A sibling had been treated previously for an identical disorder. At age 6.5 months, four hyperplastic parathyroid glands were removed, and portions of one were immediately grafted into the forearm. Serum calcium again became elevated post-operatively and then fall to the normal range after excision of grafted parathyroid tissue. Dispersed parathyroid cells from the first operation showed no suppression of PTH secretion by 2 mM calcium; however, there was normal maximal suppressibility at 4 mM calcium with half-maximal suppression at 2.53 mM (the calcium set point). This contrasts with much lower set points previously established for suppressible cells from normal (1.02 +/- 0.10 mM, mean +/- 1 SD), from primary hyperplastic (1.10 +/- 0.14 mM), or from adenomatous (1.26 +/- 0.14 mM) parathyroid glands. The strikingly high set point may not be unique because a small number of glands previously classified as nonsuppressible (by the criterion of failing to suppress below 50% maximum at calcium concentration up to 2-3 mM) might have shown similarly high set points if tested at higher calcium concentrations. We conclude that an unusual abnormality of PTH secretory control accounts, in large part, for both the marked hypercalcemia and for its refractoriness to surgical treatment in this patient.

Calcium↗
PubMed1985

Computerized technetium/thallium scans and parathyroid reoperation.

Twenty-three consecutive patients who underwent reoperation for persistent primary hyperparathyroidism were studied with computerized technetium/thallium scans to evaluate it as a localization test. Prospective and blinded retrospective readings of the scans were correlated with findings at surgery. Computerized technetium/thallium scanning detected 52% of the parathyroid adenomas found at surgery. Forty-two percent of adenomas were localized exactly. There were no false positive scans. No normal parathyroid glands were imaged. No mediastinal glands were imaged. The study was not observer dependent. We conclude that computerized technetium/thallium scanning is helpful in patients undergoing parathyroid reoperation. If positive, it can accurately localize adenomas. If negative, we recommend more invasive studies.

Adenoma↗
PubMed1984

A human myeloma immunoglobulin G binding four moles of calcium associated with asymptomatic hypercalcemia.

A calcium-binding immunoglobulin G (IgG1 lambda RUP) was identified in the serum of a patient with multiple myeloma, asymptomatic hypercalcemia, and a normal ionized serum calcium. Calcium binding by IgGRUP was confirmed by two-dimensional electrophoresis with calcium-45 and equilibrium dialysis. Amino acid analyses indicated an unusually high number of glutamic (or glutamine) residues in the L chain and Fab fragment but no detectable gamma-carboxyglutamic acid. As determined by equilibrium dialysis with 45Ca, the intact IgGRUP and its Fab fragments bound calcium at an optimum pH of 7.4. There was minimal binding of calcium to H chains and no binding by L chains or the Fc fragment. Recombination of H and L chains partially restored the binding activity. By Scatchard analysis, the binding affinity (Kd) of IgGRUP was 1.7 X 10(-3) M and the binding capacity was 4 mol of calcium/mol of IgG. The binding of 4 mol of calcium/mol of IgG is twice that reported previously for two other calcium-binding myeloma proteins and suggests unique properties of IgGRUP.

Aged↗
PubMed1981

Acute aflatoxicosis in calves fed peanut hay.

Acute aflatoxicosis was believed to be the cause of death of 12 to 90 drought-stricken Hereford calves fed peanut hay on the southern Darling Downs in Queensland. Jaundice, photosensitisation, diarrhoea, anorexia and depression were seen before death. Serum levels of enzymes of hepatic origin and bilirubin were elevated. After death haemorrhage, hepatocyte damage, bile ductule proliferation were found. Total aflatoxin levels up to 2230 microgram/kg were detected in the peanut hay with most toxin concentrated in nut-in-shell.

Aflatoxins↗
PubMedDate not supplied

Epidemiology and clinical features of osteoporosis in young individuals.

Due to the lack of epidemiologic data on osteoporosis in the young, we identified all 22 Olmsted County, MN, residents aged 20-44 years when first diagnosed with established osteoporosis in 1976-1990. The overall age- and sex-adjusted incidence rate was 4.1 per 100,000 person-years (95% CI 2.4-5.9) with a female to male ratio of age-adjusted rates of 1.2:1. The majority represented secondary osteoporosis (12 steroid-induced, 3 postmenopausal, 2 delayed puberty, 2 anticonvulsant-induced, 2 gastrointestinal disease, 2 alcoholism, 1 anorexia nervosa, and 7 other etiologies; some individuals had more than one factor present) but two had idiopathic osteoporosis (incidence 0.4 per 100,000 person-years, 95% CI 0-0.9). To further characterize the patients with idiopathic osteoporosis, we also reviewed the entire Mayo Clinic experience with such patients from 1976 to 1990, regardless of residency. A total of 56 patients (30 female/26 male) were identified with a median age at diagnosis of 34 years. Only 8% were hypercalciuric at presentation. There was a preponderance of cancellous bone fractures (vertebral 81%, rib 37%, wrist 13%), although 13% did have hip fractures. Transiliac bone biopsies were available in 18 patients. As compared to age- and sex-matched controls, the osteoporotic subjects had a significant reduction in trabecular bone volume, cortical thickness, and mean wall thickness, the latter suggesting an abnormality in osteoblast function in these individuals.(ABSTRACT TRUNCATED AT 250 WORDS)

Absorptiometry, Photon↗