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L Wartofsky

Publications and source records attributed to L Wartofsky.

At least 73 records · Page 4Linked to original sources
PubMed1991

Thyrotropin modulates receptor-mediated processing of the atrial natriuretic peptide receptor in cultured thyroid cells.

In a prior study of atrial natriuretic peptide (ANP) binding to cultured thyroid cells, we reported that at 4 C, more than 95% of bound ANP is recovered on cell membranes, with negligible ANP internalization observed. Since ANP binding was inhibited by TSH, we have further studied TSH effects on postbinding ANP processing to determine whether this phenomenon reflects enhanced endocytosis of the ANP-receptor complex. An ANP chase study was initiated by binding [125I] ANP to thyroid cells at 4 C for 2 h, followed by incubation at 37 C. ANP processing was then traced by following 125I activity at various time intervals in three fractions: cell surface membranes, incubation medium, and inside the cells. Radioactivity released into medium represented processed ANP rather than ANP dissociated from surface membranes, since prebound [125I]ANP could not be competitively dissociated by a high concentration of ANP (1 mumol/L) at 37 C. Chase study results showed that prebound ANP quickly disappeared from cell membranes down to 34% by 30 min. Internalized ANP peaked at 10 min, with 21% of initial prebound ANP found inside the cells. At the same time, radioactivity recovered in incubation medium sharply increased between 10-30 min from 8% to 52%. Preincubation of cells with chloroquine (which blocks degradation of the ANP-receptor complex by inhibiting lysosomal hydrolase) caused a 146% increase in internalized [125I]ANP by 30 min (39% compared to 15% control), while medium radioactivity decreased from 52% to 16%, suggesting that processing of the receptor complex is mediated via lysosomal enzymes. In chase studies employing cells pretreated with chloroquine, TSH stimulated the internalization rate of ANP-receptor complex. By 30 min, TSH significantly reduced the membrane-bound ANP, and the decrease was inversely correlated to the increase in internalized radioactivity. In the absence of ANP ligand, TSH also modulated receptor translocation, resulting in decreased receptor number on surface membrane. However, TSH did not affect ANP degradation on the basis of analysis by immunoprecipitation and high performance liquid chromatography. Taken together, these data suggest that TSH downregulates ANP receptor on thyroid cell surface membranes, and that an ANP degradative pathway exists which is not mediated through receptor binding.

Cells, Cultured↗
PubMed1990

Characterization by affinity cross-linking of a receptor for atrial natriuretic peptide in cultured human thyroid cells associated with reductions in both adenosine 3',5'-monophosphate production and thyroglobulin secretion.

We have previously identified specific atriopeptin (ANP) receptors in cultured human thyroid cells and demonstrated that ANP reduced thyroglobulin (Tg) secretion. In this report the relationship of Tg inhibition to cyclic nucleotide intermediate pathways was explored, and the thyroidal ANP receptor was characterized by affinity cross-linking. Concentrations of Tg, cGMP, and cAMP were measured in medium from thyroid cells cocultured with ANP. ANP significantly inhibited cAMP production at the lower concentration of 0.1 nmol/L and stimulated cGMP levels at a higher concentration of 10 nmol/L. The percentage of inhibition of Tg release over the ANP range of 0.01-10 nmol/L appeared to parallel cAMP, but not cGMP, levels, suggesting that ANP acts via a cAMP pathway in the thyroid. Affinity cross-linking studies characterizing the ANP receptor in thyrocytes and a bovine endothelial cell line known to be cGMP responsive to ANP indicated a single unit ANP receptor of 140 kD coupled to guanylate cyclase in endothelial cells, while a 70-kD receptor was found in thyroid cells which specifically binds to ANP, atriopeptin-I, and atriopeptin-III. These studies in thyrocytes suggest that reduced Tg release may be mediated by a specific single 70-kD ANP receptor associated with an inhibitor cAMP pathway and provide additional insight into the nature of a newly described thyroid-ANP interaction.

Atrial Natriuretic Factor↗
PubMed1990

Current trends in the management of Graves' disease.

Members of the American Thyroid Association were invited to participate in a survey of the management of Graves' disease. One primary case and several variations were provided, which differed in respect to age, sex, goiter size, severity, etc. The questionnaire was based on the format used in a similar survey of members of the European Thyroid Association. The aim of the survey was to determine 1) how expert thyroidologist employ diagnostic procedures for this disorder, and 2) the choice of therapy of the three treatment options and its manner of implementation. Questionnaires were sent only to clinically active members. The overall response rate was 62%. Data analysis was possible on 52% of members surveyed and was performed using SPSS and a specific Fortran program. In the laboratory evaluation of the primary case a radioiodine uptake, scan, serum total T4, and basal TSH were requested by 92%, 47%, 83%, and 66%, respectively, with 84% of respondents using an ultrasensitive TSH assay. For management of the primary case, radioiodine treatment was the first choice of 69% of the respondents. Antithyroid drugs were used briefly (3-7 days) before 131I by 28%, whereas 41% said they would employ thioureas after 131I. Of those using 131I, 66% tailored the dose to achieve euthyroidism as the goal of therapy, while 34% aimed for hypothyroidism requiring T4 replacement. Only 30% of respondents chose thioureas as a first line of treatment (72% propylthiouracil; 28% tapazole). The duration of drug therapy was a predetermined fixed interval for 80% of the respondents, with 90% treating for 1-2 yr. Other specific trends in diagnostic approach and therapeutic preferences were identified for the eight variations on the primary case problem.

Adrenergic beta-Antagonists↗
PubMed1990

Malabsorption of thyroxine, calcium, and vitamin D in a thyroparathyroidectomized woman: efficacy of therapy with medium-chain triglyceride oil.

A 28-year-old woman with surgically induced hypothyroidism and hypoparathyroidism required large doses of replacement medications due to malabsorption from short bowel syndrome. Malabsorption of thyroxine was documented using the technique of double isotope radioiodothyronine turnover studies. Therapy with medium-chain triglyceride oil improved her malabsorption and favorably influenced the absorption of her medications.

Adult↗
PubMed1990

Management of patients with thyroid carcinoma: application of thallium-201 scintigraphy and magnetic resonance imaging.

Thyroid carcinoma has the ability to concentrate radioiodine, an attribute that can be used both for detection of thyroid cells and for treatment. Unfortunately, however, radioiodine uptake is not observed in all patients and a radioiodine scan requires that the patient be rendered hypothyroid for 4-6 wk. In the present study, we analyzed the utility of thallium-201 scanning and the usefulness of magnetic resonance imaging (MRI) in the detection of thyroid cancer. Nineteen patients with thyroid cancer had a total of 24 radioiodine scans, 33 thallium scans, and 10 MRI examinations. Of the 19 patients in the study, 17 had differentiated thyroid carcinoma. In these 17 cases, all paired studies were concordant for the presence (n = 7) or absence (n = 10) of disease. However, in one case (Patient 10), the 201Tl studies showed far more extensive disease than was observed on the 131I scan. Thyroid cancer was also detected on seven MRI studies. In summary, thallium and MRI scans are adjunctive techniques to radioiodine scanning that can either confirm the presence of neck bed activity, residual disease or metastatic cancer and may delineate tumor deposits not detected by radioiodine scanning. Thallium may be capable of detecting tumor deposits even while a patient remains euthyroid.

Adenocarcinoma↗
PubMed1989

Binding of thyrotropin to selected Mycoplasma species: detection of serum antibodies against a specific Mycoplasma membrane antigen in patients with autoimmune thyroid disease.

Radiolabeled human (hTSH) and bovine (bTSH) thyroid stimulating hormone was shown to bind to five species of Mycoplasma, the wall-less prokaryotes. The maximum binding capacity of 125I-bTSH to these five species was about 7.9 x 10(-13) moles-1.4 x 10(-12) moles for 50-100 micrograms protein with dissociation constants of approximately 1.7 to 2.2 x 10(-7)M. Approximately 50% of the 125I-bTSH binding was displaced by excess, unlabeled bTSH or hTSH, but labeled bTSH was not effectively displaced by growth hormone, LH, FSH, prolactin, or the beta subunit of hTSH, FSH and LH. Antisera prepared against Mycoplasma gallisepticum and Mycoplasma pneumoniae bound to human thyroid membranes and guinea pig fat cells, suggesting that receptors on human thyroid tissues and on Mycoplasma cells may have similarities in antigenicity. These findings were substantiated by the occurrence of TSH binding to Mycoplasma antisera. Further, sera from three of six patients with Graves' disease containing antibodies to thyroid tissues also reacted to a 108 Kd polypeptide of Mycoplasma gallisepticum.

Animals↗
PubMed1989

Receptors for atrial natriuretic peptide (ANP) and regulation of thyroglobulin secretion by ANP in human thyroid cells.

Specific binding sites for atrial natriuretic peptide (ANP) were identified and characterized in primary cultures of human thyroid cells. Saturation analysis using [125I] alpha rat ANP as the ligand showed a single class of high affinity binding (Kd = 0.2 nM) which was inhibited by atriopeptin I and the alpha -human form of ANP, but not by a C-terminal fragment of the peptide. The number of ANP binding sites in these cultures was not altered by the thyroid hormone concentration of the medium. In a dose-response experiment, thyro-globulin secretion was significantly reduced in the presence of 0.01 nM ANP and was maximally reduced (to 25% of control value) with 10 nM ANP. Cyclic GMP production was increased threefold in the presence of 100 nM ANP, but was unchanged with lower doses (0.01 and 0.1 nM) of the peptide. The finding of receptors in thyroid follicular cells suggests a hitherto unrecognized role of ANP in the thyroid gland.

Atrial Natriuretic Factor↗
PubMed1989

Thyrotropin modulates receptors for atrial natriuretic peptide on intact human thyroid cells.

Interest in the mechanism of impaired salt and water metabolism in hypothyroidism has led to growing evidence of an interaction between atrial natriuretic peptide (ANP) and the thyroid, which includes reports of direct effects of thyroid hormone on ANP synthesis and circulating ANP levels, and of the presence of specific ANP receptors in human thyroid tissue, which may act to inhibit thyroglobulin (Tg) secretion. The authors questioned whether or not thyrotropin (TSH) has a role in this interaction. They used 125I-ANP to study the effect of TSH on ANP binding to human thyroid cells in primary culture. Binding competition by increasing concentrations of unlabeled ANP in the presence or absence of TSH was assessed by Scatchard analysis. At lower temperatures of 4 degrees C or 23 degrees C, TSH had no effect either on the ANP receptor equilibrium dissociation constant (Kd) or number of binding sites. However, at 37 degrees C, bovine TSH at 1 mU/ml reduced measurable binding sites by about 50% without affecting receptor affinity (Kd = 0.2 nM). Prolonged (6 days) coincubation of TSH with thyroid cells decreased the assayable ANP receptor. The effects of TSH appear to be specific because human luteinizing hormone, follicle-stimulatory hormone, growth hormone, human chorionic gonadotropin and iodide had no effect on ANP binding. Thus, human thyroid cells possess a single class of high-affinity, specific receptors for ANP with binding activity that is temperature dependent and modulated by TSH at physiologic temperature. TSH-mediated reduction of binding at 37 degrees C but not at 4 degrees C suggests an energy-dependent process that acts possibly by activating an ANP degradative enzyme or by changing the rate of receptor internalization and subsequent degradation.

Atrial Natriuretic Factor↗
PubMed1989

Effects of epidermal growth factor on thyroglobulin and adenosine 3',5'-monophosphate production by cultured human thyrocytes.

While several workers have identified epidermal growth factor (EGF) receptors on human thyroid membranes, very few reports have described EGF effects on intact human thyroid cells in primary culture, and these were short term studies indicating that EGF effects were primarily inhibitory [reduced iodide uptake and thyroglobulin (Tg), T4, and T3 release]. Paradoxically, in vivo EGF stimulates thyroid growth and increases colloid stores. In this study we examined the effects of EGF on cultured thyroid cells in regard to thymidine incorporation, Tg secretion, and cAMP production during a 12-day period. Addition of EGF (0-30 ng/mL) to medium for 6 or 12 days stimulated thymidine incorporation and enhanced Tg synthesis by thyroid cells. However, the profile of Tg release into medium was biphasic. Tg release was inhibited by EGF (0.1-10 ng/mL) during the first 3 days of culture, but the inhibitory effect disappeared by the sixth day, and EGF stimulated Tg release by day 12 and thereafter. EGF enhanced endogenous cAMP levels in thyroid cells, but did not augment TSH-stimulated increases in cAMP production. Our observations of EGF-stimulated growth and inhibited Tg secretion during short term culture are consistent with the findings of earlier studies with nonhuman thyrocytes. However, the later phase of enhanced cAMP levels with stimulation of Tg secretion indicates that EGF may have trophic effects on thyrocytes previously unrecognized because of the short term nature of the studies. These observations suggest an important role for EGF in maintenance of normal thyroid physiology.

Cells, Cultured↗
PubMed1988

Alterations in magnesium and zinc metabolism in thyroid disease.

Magnesium (Mg) and zinc (Zn) status was assessed in subjects to evaluate the effects of thyroid diseases on Mg and Zn metabolism. Plasma and red blood cell (RBC) concentration and peripheral blood mononuclear cell (MNC) content of Mg and Zn, and 24-hour urinary excretion of Mg, Zn, creatinine (Cr), calcium (Ca), sodium (Na), and potassium (K) were measured in 11 thyrotoxic, 29 hypothyroid, and 25 euthyroid control subjects. Serum albumin, alpha 2-macroglobulin, and the binding of Zn to albumin were also determined. Plasma and RBC Mg concentrations were low in half of the hyperthyroid subjects, but mean values were not significantly different from controls. Urinary excretion and clearance of Mg were lower in hypothyroid subjects, but differences were removed when expressed relative to Cr excretion and clearance. Similar patterns were noted for urinary Ca, Na, and K, suggesting that their reduced excretion reflects alterations in renal hemodynamics. Plasma Zn was lower in hypothyroid subjects and correlated with serum albumin; MNC Zn and urinary Zn were also low. Plasma Zn concentration was normal and serum albumin significantly lower in the hyperthyroid group than in the control group. Further, RBC Zn content was significantly lower in hyperthyroid subjects, and inversely related to plasma thyroxine concentration. The hyperthyroid group also excreted significantly greater amounts of Zn than controls, indicative of a catabolic process. This increased urinary loss may reflect a shift in the distribution of plasma Zn between ultrafilterable and Zn-albumin complexes. In summary, this study provides evidence for marked alterations in Zn homeostasis in persons with thyroid disease. Whether the observations indicate deficiency states and have clinical implications will require further investigation.

Adolescent↗
PubMed1988

Natural killer cell activity and serum autoantibodies in women with postpartum thyroiditis.

Postpartum thyroiditis (PPT) is a form of painless lymphocytic thyroiditis which is thought to be caused by an exacerbation of underlying subclinical autoimmune thyroid disease during a postpartum period of immune rebound. The purposes of this study were to analyze natural killer cell (NK) functional activity and antibody-dependent cell-mediated cytotoxicity (ADCC) of peripheral blood mononuclear cells in patients with PPT compared to those in normal nonpostpartum and postpartum women. NK activity and ADCC were determined by specific lysis of 51Cr-labeled K562 human erythroleukemia tumor cells at varying effector (mononuclear cell) to target cell ratios. Nineteen PPT patients between 4-9 months [mean, 6.5 +/- 0.4 (+/- SE)] postpartum were compared to 20 nonpostpartum women, 31 healthy women between 4-9 months (6.7 +/- 0.3) postpartum, and 14 women 2 days after delivery. There were significant differences in the NK functional activities of the 4 groups (F = 7.95; P = 0.0002). The mean NK activities, as measured by percent specific lysis at an effector to target cell ratio of 10:1, were 31.1 +/- 3.3%, 20.9 +/- 2.3%, 22.5 +/- 2.8%, and 11.5 +/- 2.0% in the nonpostpartum, PPT, postpartum, and 2-day postpartum groups, respectively. Specific lysis by ADCC was not significantly different from lysis by NK activity in any group. The PPT, postpartum, and 2-day postpartum groups had significantly lower NK activity compared to that in nonpostpartum women (P less than 0.05). Both the PPT and postpartum women had higher NK activities than the 2-day postpartum women (P less than 0.05). However, there were no significant differences in the NK activities of the PPT patients compared to those of the healthy postpartum women. Patients with PPT were also found to have associated autoimmune dysfunction. The PPT group had significantly higher serum antinuclear antibody titers; 8 of 24 patients (33%) had titers of 1:160 or greater compared to only 2 of 29 healthy postpartum women (7.4%; P less than 0.05). Seven of the PPT patients had serum immune complexes, and 3 had TSH receptor antibodies. We conclude that functional NK activity and ADCC in peripheral lymphocytes of PPT patients are not different from those in healthy postpartum women; however, the postpartum women had significantly decreased activity compared to that in nonpostpartum women. These data emphasize the importance of studying healthy postpartum women in investigations of PPT, since the immunological changes in pregnancy and the postpartum period remain largely undefined.

Adult↗
PubMed1988

Autoantibodies to insulin are present in sera of patients with autoimmune thyroid disease.

It has been clinically suspected that patients with autoimmune thyroid disease are at an increased risk of developing other autoimmune diseases later in life. To determine the presence and potential importance of a more generalized deregulation of immune response in patients with Grave's disease and Hashimoto's disease, sera from 33 patients with Graves' disease and 16 patients with Hashimoto's disease were screened for the presence of anti-insulin antibodies and anti-insulin-receptor antibodies. An enzyme-linked immunosorbent assay was used to identify the presence of IgG against human insulin. The optical density indicating the presence of IgG against insulin in sera from patients with Graves' disease averaged .172 +/- .024 (mean +/- SE; range .010-.802), compared to the mean normal value of .098 +/- .0009 (range .012-.238) in 33 control subjects. Ten of 33 patients with Graves' disease had values greater than .200, whereas control sera values were less than .200 in all but one case (P less than .005, Graves' sera vs. controls). The sera from patients with Hashimoto's disease had a mean optical density of .110 +/- .016, with 15 of 16 values between .010 and .200. These values were not significantly different from controls with an insulin-binding inhibition assay. Anti-insulin-receptor antibodies were not detected in any of 33 patients with Graves' disease, and cytoplasmic islet cell antibodies were not detected in sera from seven patients with Graves' disease who had insulin-binding antibodies. These data support the hypothesis that the immunologic response in autoimmune thyroid disease may be more heterogeneous and polyclonal than previously believed.

Autoantibodies↗
PubMed1988

Seronegative Hashimoto thyroiditis with thyroid autoantibody production localized to the thyroid.

A patient without serologic evidence of an autoimmune disorder had a thyroidectomy for neck compression caused by her goiter. Histologic examination of the gland revealed pathologic changes compatible with Hashimoto disease, and lymphocytes isolated from her thyroid gland were transformed into lymphoblastoid cells in vitro by Epstein-Barr virus in the presence of cyclosporine. These cells produced antibodies against thyroglobulin, thyroid microsome, thyrocyte membrane, and thyrotropin, whereas lymphoblastoid cells produced from the patient's peripheral blood lymphocytes showed no antithyroid activity. Several human monoclonal antibodies were produced from the intrathyroidal lymphocytes by fusion with the SHM-D33 heteromyeloma, and the resulting cell lines produced antibodies with high-affinity binding specific for thyroid antigens. These studies show that lymphocytes capable of producing antithyroid antibodies can be present in the thyroid glands of patients with Hashimoto disease without evidence of a peripheral immune response, thus indicating that Hashimoto disease can exist as an organ-restricted autoimmune disorder.

Adipose Tissue↗
PubMed1988

Eponyms.

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Eponyms↗
PubMed1987

Thyrocyte specific killer cell activity is decreased in patients with thyroid carcinoma.

Natural killer cells (NK) are important in immune surveillance, and they have found to be decreased in the serum of patients with various types of malignancies. In patients with thyroid carcinoma, we investigated NK activity of peripheral lymphocytes directed against either a standard tumor cell target, K562, or against the clinically relevant target cell, the thyrocyte. Although NK-cell activity was normal when directed against K562 cell targets, NK-cell activity was reduced when labeled thyrocytes were used as target cells. At effector to target cell ratios of 100:1 and 20:1, there was 43 +/- 3% (n = 7) and 29 +/- 3% (n = 7) lyses of thyrocytes using normal lymphocytes, and 17 +/- 4% (n = 5) and 13 +/- 2% (n = 3) using lymphocytes from patients with thyroid carcinoma. These findings suggest that NK-cells have distinct subpopulations and that immune surveillance against specific thyrocyte target cells may be important in thyroid cancer.

Adult↗
PubMed1987

Intrinsic abnormality of thyroid cells from a patient with a Brobdingnagian goiter.

Thyrocytes from normal and goitrous portions of the thyroid gland from a patient with an enormous (635 gm) goiter were cultured in media, and their relative abilities to uptake thymidine, synthesize DNA, and secrete Tg and T4 were assessed. Tg, T4 and the ratio Tg/T4 in media at 72 h were 120 micrograms/dl, 1.6 micrograms/dl and 75 for normal cells, and 410 micrograms/dl and 273 for goitrous cells. DNA synthesis was 30-100% greater in goitrous than normal cells over a period of 72 h indicating abnormally high rates of cell division and growth, but their thymidine uptake was only 20% of that in normal cells. TSH elicited stimulation of thymidine uptake and DNA synthesis both in goitrous and in normal cells, but to a lesser extent in goitrous cells. No evidence of growth stimulating autoantibody activity was detected in the patient's serum. These data indicate that although the ability of goitrous cells to uptake thymidine was impaired, their DNA synthesis was more active than normal thyroid, which may have led to disordered cell growth as evidenced by the enormous goiter size in this patient. Although goitrous cells secreted more than three times as much Tg into media compared to normal, media T4 levels were similar, indicating an increased synthesis yet low iodination of Tg in goitrous cells. There does not appear to be any support for TGSI mediation of the goiter in this patient, but rather, the goiter may have been due to an intrinsic alteration in DNA synthesis resulting in vigorous cell growth.

Cells, Cultured↗