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Biomedical subjects

P Hellman

Publications and source records attributed to P Hellman.

At least 55 records · Page 3Linked to original sources
PubMed1994

Different secretory actions of pancreastatin in bovine and human parathyroid cells.

Chromogranin A is an acidic protein that is costored and cosecreted with parathyroid hormone (PTH) from parathyroid cells. Pancreastatin (PST), is derived from chromogranin A, and inhibits secretion from several endocrine/neuroendocrine tissues. Effects of different pancreastatin peptides were investigated on dispersed cells from bovine and human parathyroid glands. Bovine PST(1-47) and bovine PST(32-47) inhibited PTH release from bovine cells in a dose-dependent manner. The former peptide was more potent and suppressed the secretion at 1-100 nM. This inhibition was evident in 0.5 and 1.25 mM, but not in 3.0 mM external Ca2+. Both peptides failed to alter the concentration of cytoplasmic Ca2+ ([Ca2+]i) of bovine cells. Human PST(1-52) and PST(34-52) did not affect PTH release or [Ca2+]i of parathyroid cells from patients with hyperparathyroidism, nor [Ca2+]i of normal human parathyroid cells. Furthermore, bovine PST(1-47) and bovine PST(32-47) failed to alter the secretion of abnormal human parathyroid cells. The study indicates that PST exerts secretory inhibition on bovine but not human parathyroid cells, and that this action does not involve alterations of [Ca2+]i.

Animals↗
PubMed1994

Impaired parathyroid hormone release in human immunodeficiency virus infection.

Patients with human immunodeficiency virus type 1 (HIV-1) seropositivity exhibited significantly lower intact serum parathyroid hormone (PTH) values (mean, 13.6 ng/liter; n = 44) than healthy controls (mean, 38.1 ng/liter; p < 0.001; n = 50). The reduction was greater among patients with no or mild immunodeficiency (> 400 x 10(6) CD4+ lymphocytes/ml blood; n = 22) than in those with severe immunodeficiency (< 200 x 10(6) CD4+ lymphocytes/ml blood; n 22; p = 0.03), although total serum calcium was normal in all groups. Patients with severe immunodeficiency demonstrated an inverse correlation between total serum calcium and serum PTH (r2 = 0.367; p < 0.01), which was also present in healthy controls (r2 = 0.482; p < 0.001), but not among the seropositive patients with no or mild immunodeficiency (r2 = 0.017; p = 0.58). Parathyroid cells express a protein recognized by antibodies directed against CD4, the HIV-1 receptor. This implies that these cells may be directly infected with HIV-1 and also interact with circulating autoantibodies against CD4, thus resulting in impaired PTH release.

Autoantibodies↗
PubMed1994

Positron emission tomography with 11C-methionine in hyperparathyroidism.

BACKGROUND: Positron emission tomography (PET) has not been evaluated for preoperative localization and functional characterization of the parathyroid tissue in hyperparathyroidism. METHODS: Images of the neck and upper mediastinum of 23 patients with hyperparathyroidism were obtained by PET after intravenous administration of 400 to 800 MBq L-[methyl-11C]-methionine. The investigation was repeated in six patients after Na2-ethylenediamine tetraacetic acid infusion, whereby stable 65% to 157% rise in intact serum parathyroid hormone values was attained. RESULTS: Parathyroid surgical procedure revealed single (21 patients) or two enlarged parathyroid glands (two patients) that were characterized as chief cell adenoma (n = 13), hyperplasia (n = 10), or carcinoma (n = 2) and weighed 80 to 6000 mg. Twenty (80%) of these glands were localized by PET. The remaining examinations (20%) were false negative and mainly encompassed small parathyroids in juxtathyroid position. Among 15 patients undergoing parathyroid reoperation true-positive localizations were obtained for 87% of the glands. The images displayed lower tracer uptake in residual thyroid lobes (n = 40), esophagus, and cervical vertebrae. Na2-ethylenediamine tetraacetic acid infusion failed to enhance parathyroid uptake values. Ultrasonography, computed tomography, technetium-thallium scintigraphy, and venous sampling revealed 25% to 53% of the pathologic parathyroid tissues of the patients undergoing reoperation and was largely complementary to PET. CONCLUSIONS: The results suggest that PET may provide novel possibilities for the imaging of pathologic parathyroid glands in hyperparathyroidism.

Adult↗
PubMed1993

Regulation of proliferation in JEG-3 cells by a 500-kDa Ca2+ sensor and parathyroid hormone-related protein.

JEG-3 cells are derived from human trophoblasts and demonstrated to express a 500-kDa Ca2+ sensing protein, which elicits biphasic elevations of cytoplasmic Ca2+ concentrations ([Ca2+]i) and mediates Ca2+ regulation of parathyroid hormone-related protein (PTHrP) release from placental cytotrophoblasts. Cytocentrifuged JEG-3 cells were immunostained by monoclonal and polyclonal antiserum toward PTHrP (1-34) and (38-64). Elevation of external Ca2+ from 0.5 to 3.0 mM induced only a sluggish rise in [Ca2+]i and no stimulation of cAMP production despite a more than twofold elevation of PTHrP(1-34) release. Monoclonal antibodies recognizing functionally discrepant epitopes of the Ca2+ sensor protein substantiated uncoupling of this sensor in the Ca(2+)-regulated PTHrP release. Exogenous activation of protein kinase C by a phorbol ester strongly augmented the secretion of PTHrP(1-34), whereby uncoupling of the Ca2+ sensor was partially reversed. This functional differentiation was associated with reduced [3H]thymidine incorporation in JEG-3 cells. Proliferation of these cells was inhibited by 71% upon rise of extracellular Ca2+ from 0.5 to 3.0 mM, and this inhibition was abolished by antibody-mediated interference with the Ca2+ sensor function. PTHrP(1-86) and PTH(1-34) at concentrations up to 10(-7) M decreased proliferation and stimulated the cAMP content of JEG-3 cells. The findings support concomitant Ca2+ sensor and PTH/PTHrP receptor expression in JEG-3 cells, and that Ca2+ inhibits proliferation by actions on the Ca2+ sensor as well as by stimulation of PTHrP release possibly mediating autocrine growth inhibition.

Calcium↗
PubMed1993

Incidence, structure, and function of enlarged parathyroid glands discovered accidentally during thyroid surgery.

BACKGROUND: Operation on rare patients with mainly a severe renal stone disease and considerably elevated urinary calcium excretion has substantiated the association of parathyroid gland abnormalities with normocalcemia. This study examines incidence, structure, and functional characteristics of enlarged parathyroid glands of patients with normocalcemia scheduled for thyroid surgery. METHODS: Eleven enlarged parathyroid glands weighing 110 to 1000 mg were discovered in 9 (1.5%) of 594 patients with normocalcemia undergoing thyroid operation. The preoperative total serum calcium concentration was 2.30 to 2.52 mmol/L and less than 2.38 mmol/L in four of the nine patients. Intact serum parathyroid hormone and alkaline phosphatase levels were elevated in only one individual, and all patients showed normal serum creatinine values. RESULTS: All but three of the 11 enlarged parathyroid glands exhibited microscopic abnormality on routine histopathologic examination, including staining for cytoplasmic fat with oil red 0. Immunohistochemical staining with a monoclonal antibody recognizing the functionally important calcium receptor of the parathyroid cell surface and analysis of the calcium-regulated cytoplasmic Ca2+ concentration of dispersed parathyroid cells substantiated that only a single gland of 130 mg had no discernible functional abnormality. CONCLUSIONS: The findings underline the diagnostic difficulties of parathyroid histopathology and support the presence of disturbed parathyroid hormone secretion even in normocalcemic patients with enlarged parathyroid glands. The functional derangement of these glands substantiates the indication for their surgical excision even in patients exhibiting midnormal serum calcium concentrations, although their possible contribution to the development of a clinically overt hyperparathyroidism can only be speculated.

Adult↗
PubMed1992

Ga3+ inhibits parathyroid hormone release without interacting with the Ca2+ receptor of the parathyroid cell.

Gallium nitrate is an antihypercalcemic agent with established actions on bone. The effects of Ga(NO3)3 on parathyroid hormone (PTH) release, cytoplasmic Ca2+ concentration ([Ca2+]i) and cAMP production of enzymatically dispersed parathyroid cells from bovine as well as normal and pathological human parathyroid glands have now been studied. Ga3+ at 200 microM inhibited PTH release whereas 600 microM NO3- had no effect. The inhibition was additive to that obtained by elevating extracellular Ca2+. Unlike Ca2+, Ga3+ failed to increase [Ca2+]i or reduce cAMP formation. The results indicate that Ga3+ inhibits PTH release by a mechanism other than activation of the cation receptor of the parathyroid cells. This mechanism may contribute also to inhibition by other cations.

Animals↗
PubMed1992

Parathyroid-like regulation of parathyroid-hormone-related protein release and cytoplasmic calcium in cytotrophoblast cells of human placenta.

Immunohistochemical staining of human placenta revealed intense reactivity for amino terminal and midregional parathyroid-hormone-related protein (PTHrp) in the cytotrophoblast cells and weaker staining in the syncytiotrophoblasts. The cytotrophoblasts also displayed conspicuous surface staining with the monoclonal antibodies E11 and G11, which recognize a Ca2+ receptor mechanism regulating hormone release of parathyroid cells. Cytotrophoblasts enriched on Percoll gradients or by linking surface-bound E11 to magnetic beads revealed biphasic elevation of cytoplasmic Ca2+ ([Ca2+]i) upon a stepwise rise of external Ca2+ from 0.5 to 3.0 mM, with a half-maximal effect at 1.75 mM. Individual cytotrophoblasts identified by their E11 reactivity disclosed a temporary increase of [Ca2+]i upon elevation of external Mg2+, while Mn2+ triggered both a [Ca2+]i transient and an influx of itself. These effects were efficiently blocked by the G11 antibody. Depolarization with K+ or addition of the voltage-dependent Ca2+ channel blocker verapamil had only marginal effects on [Ca2+]i. Raised extracellular calcium inhibited release of PTHrp from the cells, and this inhibition was blocked by the G11 antibody. The virtually parathyroid-identical Ca2+ regulation of [Ca2+]i may mediate feedback control of PTHrp release from the cytotrophoblasts and thereby participate in the regulation of placental Ca2+ transport.

Calcitriol↗
PubMed1992

Neomycin interacts with Ca2+ sensing of normal and adenomatous parathyroid cells.

Effects of the polyvalent cationic antibiotic neomycin on regulation of the cytoplasmic Ca2+ concentration ([Ca2+]i) were studied in normal and adenomatous human, and bovine parathyroid cells. Parathyroid hormone (PTH) release was also measured in the bovine cells. Elevation of extracellular Ca2+ from 0.5 to 3 mM caused biphasic increase of [Ca2+]i and inhibition of PTH release. In low external Ca2+ neomycin inhibited PTH release and virtually only triggered the [Ca2+]i transient. In contrast [Ca2+]i was lowered and PTH release stimulated by neomycin in the presence of 3.0 mM Ca2+ or 7 mM Mg2+. These actions of Ca2+ and neomycin on [Ca2+]i were qualitatively similar but less pronounced in the adenomatous than normal human parathyroid cells. Some effects of neomycin were thus similar to those induced by other cationic agents interacting with the Ca2+ receptor mechanism on the parathyroid cell surface, whereas others may involve phospholipase C inhibition, protein kinase C activation or a direct reduction of the Ca2+ influx.

Adenoma↗
PubMed1992

Fluoride interactions with stimulus-secretion coupling of normal and pathological parathyroid cells.

Effects of the GTP binding protein (G-protein) activator NaF on parathyroid hormone (PTH) release, cytoplasmic Ca2+ concentration ([Ca2+]i) and cAMP content of bovine as well as normal and pathological human parathyroid cells were studied using precautions to avoid CaF2 precipitation. In 0.5 mM external Ca2+, NaF inhibited PTH release and lowered the cAMP content by 50-70% of the effects attained with 3.0 mM Ca2+. The NaF-induced increase of [Ca2+]i was considerably smaller than that obtained with rise of external Ca2+. It seems likely that NaF activates the inhibitory G1-protein involved in the regulation of cAMP generation. However, it is unclear whether the sluggish rise of [Ca2+]i induced by NaF is due to a direct effect of a G-protein on Ca2+ entry, or somehow related to the G-protein mediated formation of inositol 1,4,5-trisphosphate, which is part of the signal transduction pathway normally initiated by Ca2+ binding to its receptor on the parathyroid cell surface. Inhibition of PTH release by NaF probably results from the combined effects on [Ca2+]i and cAMP content. In hyperparathyroidism (HPT) the actions of NaF were not markedly affected despite severe impairments of Ca(2+)-inhibited PTH release and Ca2+ triggered increase of [Ca2+]i. Consistent with observations of down regulation of the parathyroid Ca2+ receptor in HPT, the present results indicate that the disease perturbs signal transduction at a level proximal to the site of action for NaF.

Animals↗
PubMed1992

Regulation of parathyroid hormone release in normal and pathological parathyroid cells exposed to modulators of protein kinase C.

Effects of the protein kinase C activating phorbol ester 12-O-tetradecanoyl phorbol 13-acetate and the inhibitor 1-(5-isoquinolinyl-sulfonyl)-2-methylpiperazine (H-7) on parathyroid hormone (PTH) release were studied in normal bovine and pathological human parathyroid cells. An increase of extracellular Ca2+ from 0.5 to 3.0 mmol/l inhibited PTH release by 60% in the bovine cells with half maximal effect (ED50) at 1.31 mmol/l. This inhibition reached less than 50% in the cells from patients with primary and uremic hyperparathyroidism, and the ED50 values were 1.49 and 1.42 mmol/l, respectively. The phorbol ester (0.1 mumol/l) made secretion insensitive to changes of extracellular Ca2+, an action counteracted by H-7 (50 mumol/l) in the bovine cells, whereas H-7 alone had no effects. The phorbol ester and H-7 had opposite actions on regulation of PTH release also from cells from patients with hyperparathyroidism. However, in pathological cells H-7 alone improved Ca2+ inhibition of secretion by stimulating release in low Ca2+ concentrations and decreasing the ED50 values. The magnitude of changes in ED50 values by H-7 increased with the severity of the secretory disturbance of the pathological cells. The results indicate that increased protein kinase C activity may be a factor of importance in the pathophysiology of hyperparathyroidism.

1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine↗
PubMed1991

Values of intact serum parathyroid hormone in different stages of renal insufficiency.

Intact serum parathyroid hormone (PTH) values were determined in 136 patients consulting the out-patient clinic for renal medicine and in 36 patients on maintenance hemodialysis in order to reveal the extent of parathyroid involvement in different stages of renal insufficiency. Elevated PTH values were found in 53 of the conservatively treated patients and in all but 4 of those on hemodialysis. Serum creatinine values and the duration of uremia correlated significantly to serum PTH, and multivariate analyses revealed that these variables were of dominating importance in determining the extent of PTH elevation. The negative relationship between PTH and plasma ionized calcium indicated maintained calcium regulation of hormone release from the parathyroid, although a relative secretory autonomy seemed to develop in parallel with the functional renal impairment. It is concluded that measurements of intact serum PTH values can demonstrate parathyroid hypersecretion in early renal insufficiency and constitutes a useful tool in the management of patients with renal disease.

Adolescent↗
PubMed1989

Influence of matrix on concentrations of somatotropin measured in serum with commercial immunoradiometric assays.

Using immunoradiometric assays (IRMAs) from Hybritech Inc. (H) and Nichols Institute Diagnostics (ND), we measured somatotropin (human growth hormone, hGH) in serum samples obtained every 20 min for 24 h from 10 prepubertal subjects with short stature. Results obtained with the ND reagents were 2.74 times greater than those obtained with the H reagents (P = 0.00001, r = 0.94, SEE = 3.9, n = 720). We therefore compared the IRMAs with the standard hGH RIA from the National Institutes of Health (NIH) National Hormone and Pituitary Program, using the genetically engineered hGH preparations (from Genentech Inc.) 22-kDa hGH and methionated 20-kDa hGH. We also assayed human pituitary hGH (NIH, lot no. AFP-4793B). Each hGH preparation was diluted in three diluent buffer systems: horse serum from H and from ND, and human serum. The RIA and H-IRMA gave superimposable standard curves for all hGH preparations in each diluent. The methionated 20-kDa hGH was not detected in the H-assay. Use of human serum matrix in the ND-IRMA shifted the standard curve as compared with the horse-serum matrix, giving equivalent binding at lower concentrations; i.e., serum hGH was overestimated in samples assayed against standards diluted in horse serum. Quality-control materials (Ciba-Corning) yielded disparate results in all three assays, yet human serum pools containing hGH gave similar results in the H and the NIH assays, and higher values in ND. When a human serum standard was used in the ND assay, both IRMAs gave similar results to the RIA assay for human serum samples. Reference intervals for hGH should be determined by each analytical laboratory, to prevent misdiagnosis of patients. Furthermore, quality-control material should be of human origin, because commercially supplied quality-control material does not react the same as human serum in some hGH assays.

Child↗
PubMed1983

Depolarization-independent net uptake of calcium into clonal insulin-releasing cells exposed to glucose.

Insulin release, net fluxes of Ca2+, and glucose metabolism were studied in a clonal cell line (RINm5F) established from a transplantable rat islet tumor. The insulin content amounted to only 0.03% of that of the total protein and decreased even further with subsequent passages. The insulin secretion was as high as 10 to 20% of the total hormone content per hour. Insulin release was stimulated by K+ depolarization but not by exposure to glucose. In contrast to this secretory pattern, glucose but not K+ stimulated the net uptake of Ca2+ at micromolar concentrations of the ion. The glucose effect was not mimicked by 20 mM 3-O-methylglucose. It was as pronounced at 1 mM as at 20 mM of the sugar and corresponded to an uptake of 119 fmol cm-2 s-1. Glucose metabolism was typical for tumor cells with a high glycolytic flux and an oxidation-to-utilization ratio as low as 0.05-0.15. Maximal oxidative degradation was attained already at 1 mM. This concentration was also equivalent to the Km for glucose utilization, indicating a substantial left-hand shift of the normal dose-response curve. It is suggested that glucose induces a depolarization-independent net uptake of Ca2+ by favouring intracellular buffering of the cation.

Adenoma, Islet Cell↗
PubMedDate not supplied

Primary hyperparathyroidism: epidemiology, diagnosis and clinical picture.

Primary hyperparathyroidism (HPT) is a common disorder that mainly afflicts elderly women. It can be diagnosed in at least 1% of all postmenopausal females and autopsy studies indicate an even higher frequency. Although the widespread use of automated serum calcium analyses has increased the awareness of HPT, only 10% of all cases seem to be identified. The diagnosis relies on the demonstration of an inappropriately elevated serum concentration of parathyroid hormone (PTH) relative to the serum calcium value, which need not be markedly raised. Measurements of intact PTH with immunometric methods have considerably improved the diagnostic precision but it is still difficult to evaluate patients with only marginal hypercalcemia. Few patients with diagnosed HPT are completely without symptoms. Symptoms commonly encountered are psychiatric and neuromuscular disturbances. Subclinical bone disease might be relevant but there is insufficient information about its importance in otherwise asymptomatic individuals. Various cardiovascular risk factors appear more commonly in patients with HPT and untreated disease is associated with an increased risk of premature death.

Female↗
PubMedDate not supplied

Findings and long-term results of parathyroid surgery in multiple endocrine neoplasia type 1.

Forty-two patients with primary hyperparathyroidism (HPT) of multiple endocrine neoplasia type 1 (MEN-1) were evaluated a mean of 8.9 years after subtotal parathyroid resection (SPX, n = 34) or total parathyroidectomy with autotransplantation to the forearm (TPX, n = 23). TPX as the primary operation revealed asymmetric and mainly nodular enlargement of the parathyroid glands with the presence of at least one normal-size gland in half of the individuals. TPX and SPX were accompanied by resolution of the hypercalcemia in 78% and 38% of the patients. Persistent and recurrent HPT occurred in 22% and 61% of the patients, while hypoparathyroidism requiring oral supplements occurred in 30% and 12% of the patients, respectively. Intact serum parathyroid hormone (PTH) in the arm of parathyroid autograft was high in the normocalcemic patients, somewhat lower in the patients with recurrent HPT, and normal to very low in the hypoparathyroid patients. Ratios of intact PTH between the grafted and non-grafted arms varied from 1 to 56.3, with average of 28.1 in the normocalcemic individuals, 8.2 in the patients with recurrent HPT, and 3.3 in those requiring supplements to maintain normocalcemia. These findings substantiate an 80% to 92% reversal of hypercalcemia during long-term follow-up of MEN-1 patients undergoing total parathyroidectomy or subtotal resection of 3-4 parathyroid glands as primary operative procedures and demonstrate the usefulness of intact serum PTH for functional evaluation of parathyroid autografts.

Adolescent↗