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Biomedical subjects

L Wartofsky

Publications and source records attributed to L Wartofsky.

At least 19 recordsLinked to original sources
PubMed1992

Common thyroid disorders in the elderly.

Thyroid disease in the elderly is common but often has an insidious onset with symptoms that mimic those of normal aging. Understanding the significance of thyroid function test results requires an appreciation of the normal physiologic variations of aging and the complicating effects of diseases and medications; only then can one accurately discriminate between various disease processes, order additional appropriate tests, and deliver rational management. The increasing prevalence of thyroid disorders with age, coupled with the current and future dramatic growth of the elderly population, demands that primary care providers be vigilant to the likelihood of thyroid disease and informed as to its most proper, expedient, and cost-effective diagnosis and management.

Age Factors↗
PubMed1992

Generalized thyroid hormone resistance: identification of an arginine to cystine mutation in codon 315 of the c-erb A beta thyroid hormone receptor.

The present report studies a large kindred (WR) with generalized thyroid hormone resistance that has varying degrees of neuropsychological dysfunction, hyperactivity, poor attention span, decreased IQ and/or abnormalities in spatial perception. In this kindred, there has been found tight linkage of the syndrome with the c-erb A beta gene. The present study was performed to identify the presence of a possible gene mutation as a cause for this syndrome. DNA from peripheral leukocytes was isolated from 15 unaffected and 8 affected individuals from the kindred. Primers encompassing exons 9 (nucleotides 1171-1429) and 10 (nucleotides 1430-1698) were synthesized and used in PCR reactions to amplify these exons. Direct sequencing revealed a consistent substitution in each affected subject, but in none of the unaffected individuals, of a C to T change in one allele from nucleotide 1243, resulting in an arg to cys change in codon 315. The mutant and wild-type human beta 1 receptors were prepared and their translated proteins were analyzed for T3 binding. The WR T3 receptor from affected patients had reduced T3 binding affinity, with values approximately 2.5 x 10(10) M-1 compared to about 5 x 10(10) M-1 in normals. In summary, we have: i) identified a consistent and reproducible mutation of a C to T change in nucleotide 1243 in each of the affected but in none of the unaffected individuals of a large well characterized kindred with generalized thyroid hormone resistance; and ii) noted that the WR allele causes an approximate 50% decrease in the T3 binding affinity.(ABSTRACT TRUNCATED AT 250 WORDS)

Arginine↗
PubMed1992

Thyrotropin modulation of epidermal growth factor (EGF) binding to receptors on cultured thyroid cells.

Previous studies had shown that epidermal growth factor (EGF) will stimulate growth of cultured thyroid cells in vitro, and TSH will stimulate total assayable EGF receptor in cultured porcine thyroid cells. In this study, we report the effect of TSH on EGF binding to human thyroid cells. Addition of bTSH (1 mU/mL) in binding buffer during receptor assay stimulated specific EGF binding to cells, with an increase of 44% observed over the control after 1 h incubation at 37 degrees C. Affinity crosslinking of the [125I]EGF-receptor complex showed a single labeled band with molecular size of 170 kD. No additional band was detected in the presence of TSH. Preincubation of cells with chloroquine, which inhibits lysosomal degradative enzyme activity, caused a continuous accumulation of bound EGF over a 4 h study period at 37 degrees C, and TSH stimulated an increase in internalized EGF. In the presence of chloroquine, total specific bound EGF was linearly correlated to incubation time up to 4 h and can be expressed as Bound = slope*time+intercept (time0) Addition of TSH during the binding assay significantly increased the value of the slope when compared to control (p < 0.002). The rate at which prebound [125I]EGF was released into medium was not affected by the presence of TSH, indicating that TSH-enhanced binding may not be attributed to a reduction in EGF degradation. Coincubation of thyroid cells with EGF at 0 and 1 ng/mL and increasing concentrations of TSH (0-10 mU/mL) indicated that EGF stimulated thymidine incorporation, although TSH failed to synergistically enhance EGF-stimulated cell growth.(ABSTRACT TRUNCATED AT 250 WORDS)

Cell Membrane↗
PubMed1992

Receptors for endothelin in cultured human thyroid cells and inhibition by endothelin of thyroglobulin secretion.

Specific receptors for endothelin-1 (ET), a newly described vasoconstrictor peptide isolated from endothelium, have been identified in endocrine tissues such as hypothalamus, adrenal and pituitary. ET binding or action, not previously described in thyroid, were explored in this study. ET binding in cultured human thyrocytes was assayed at 4 C, 25 C, and 37 C, for 0.5-6 h with [125I]ET (0.1 nmol/L), and nonspecific binding estimated by coincubation with unlabeled ET (100 nmol/L). At 4 C, maximum specific binding was reached after 4 h; at 25 C and 37 C, specific binding increased in a time-dependent manner over 6 h with increased binding obtained at higher temperature. At 37 C after 2 h, 11% specific bound ET localized to surface membranes with 89% internalized. Scatchard analysis of surface membrane binding at 4 C for 4 h showed high affinity single class ET receptor (Kd = 0.20 nmol/L) and binding capacity of 4045 sites per cell. ET binding to thyroid cells had no effect on production of cAMP or cGMP. ET (0.1 nmol/L) significantly (P less than 0.001) inhibited thyroglobulin release from thyroid cells after 6 days with no effect on thymidine incorporation. Thus, we have identified specific receptors for endothelin in human thyrocytes, and an inhibitory action of the peptide on thyroglobulin release which is mediated by a noncyclic nucleotide mechanism.

Cells, Cultured↗
PubMed1992

Atrial natriuretic peptide receptors in human endometrial stromal cells.

Atrial natriuretic peptide (ANP) has been shown to affect water and ion transport and specific ANP binding has been identified in several secretory tissues. ANP commonly acts via stimulation of membrane-bound particulate guanylate cyclase with the production of cyclic guanosine monophosphate (cGMP). We questioned whether ANP played a role in the complex cyclic transformation of the endometrium into a secretory tissue, and whether its action was cGMP mediated. Endometrium was obtained by biopsy in regularly menstruating women and stromal cells were isolated and cultured for use in this study. ANP competitive binding assays were performed using 125I-labeled ANP (0.1 nmol/L) and increasing concentrations of unlabeled ANP (0-1000 nmol/L). Optimal binding was obtained after 3-h incubation at 4 C and binding characteristics, including dissociation constant and binding site quantity, were estimated by Scatchard analysis. Specific, high affinity (dissociation constant, 0.078 +/- 0.004 nmol/L) and low capacity (4,877 +/- 1,951 binding sites/cell) ANP binding was identified, with nonspecific binding representing less than or equal to 16% of total binding. Evaluation of ANP-stimulated cyclic nucleotide production revealed an increase in cGMP production, with a 7-fold increase at 1000 nmol/L ANP, and no effect on cAMP production. In conclusion, we have identified specific high affinity receptors for ANP in human endometrial cells, suggesting a role for ANP in endometrial cell function and/or development mediated via cGMP production. We propose that ANP may affect local salt and water metabolism, may be involved in the secretory evolution of glandular and stromal cells, and may further facilitate endometrial development via modulation of local vascular tone and endothelial permeability.

Atrial Natriuretic Factor↗
PubMed1992

Analysis of human TSH receptor gene and RNA transcripts in patients with thyroid disorders.

Human TSH receptor (hTSH-R) gene and RNA transcripts were analyzed by Southern and Northern blots in patients with various thyroid disorders, and in tissue cell lines. A 1.4 Kb cDNA encoding the extracellular human TSH-R domain was used as a probe. Southern analysis revealed two constant bands of 11.0 and 5.0 Kb (hTSH-R) in the thyroid and human white cell samples studied, regardless of the disease process. Northern analysis showed a predominant band at about 4.4 Kb in the thyroid tissues but not in non-thyroid tissue or cell lines tested. There were no gene rearrangements or abnormal transcripts in Graves' disease or multinodular goiter samples. In contrast, the labelled cDNA TSH-R probe did not bind to RNA isolated from 1 of 2 papillary cancer samples. A portion of the unique area of the h-TSH receptor (approximately nucleotides 1100-1230) was directly sequenced in thyroid glands from patients with Graves' disease, multinodular goiter, and differentiated thyroid cancer. No mutations or polymorphisms were identified in these samples, as compared to normal thyroid or control placenta, although further definition of sequence variation in other areas of the TSH receptor, as well as in more samples, needs to be performed. The present study indicates the normal patterns of DNA and RNA hybridization in a variety of thyroid tissues and disease states, and demonstrates that pathologic thyroid samples, with the possible exception of thyroid cancer, were not associated with specific nucleotide abnormalities in the unique area of the TSH receptor that was studied.

Adult↗
PubMed1991

Nucleotide and amino acid homology between the human thyrotropin receptor and the HIV-1 Nef protein: identification and functional analysis.

A comparison of the nucleotide sequence of the human thyrotropin receptor (hTSH-R) with that of HIV-1 revealed 61% homology between a 161 base pair region encoding a unique portion of the hTSH-R and an immunogenic HIV-1 regulatory protein, nef. Amino acid analysis of this region shows 27% homology, including a segment in which 7/10 consecutive amino acids are identical. Sera from rabbits successfully immunized with a 16 amino acid portion of the hTSH-R (352-367, p1) was assessed for reactivity against a partially homologous nef peptide (nef-1) by ELISA, with a finding five-fold higher post-immunization values compared to pre-immune sera. The specificity of this response was verified with Western blot, using recombinant nef protein. An ELISA using nef-1 gave 64% higher values with sera from Graves' disease patients than with normal controls. This homology and immunologic cross-reactivity suggests an avenue through which a shared immune response against an HIV-1 related retrovirus could play a role in the pathogenesis of Graves' disease.

Amino Acid Sequence↗
PubMed1991

Absence of retroviral sequences in Graves' disease.

An earlier report of HIV-1 gene sequences in thyroid cell genomic DNA from patients with Graves' disease prompted use of the polymerase chain reaction technique to identify such sequences in Graves' disease thyroid tissue and in white blood-cells from these patients. We were unable to confirm the existence of HIV-1-related DNA sequences in Graves' specimens.

DNA, Viral↗
PubMed1991

In vitro dissolution of calcium carbonate preparations.

Calcium supplements are widely used for the treatment of osteoporosis. The bioavailability of these preparations is unknown. Because poor tablet dissolution accounts for a majority of drug bioavailability problems, we determined the in vitro dissolution at 30, 60, and 90 minutes of 27 commercially available calcium carbonate supplements using the method of the U.S. Pharmacopoiea. At 30 minutes, five preparations (18%) were more than 75% dissolved, four (15%) between 33 and 74%, and the remaining 18 (67%) were less than 33% dissolved. After 90 minutes, 17 (63%) of the preparations were less than 50% dissolved. Dissolution correlated negatively with the weight of filler (noncalcium carbonate material in the tablet) (rs = -0.51, P less than 0.01) but not with tablet hardness or cost. Similar to previous studies, we also found no correlation of dissolution with the stated calcium content, chemical source of calcium carbonate (oyster shell or chemical precipitate), or retail source. We conclude that there is a wide range of in vitro dissolution among the calcium carbonate preparations tested, and that the filler is an important determinant of the dissolution of these tablets. These results raise concern about the bioavailability of the calcium in these preparations and may have important implications for the therapeutic use of the various calcium carbonate supplements.

Analysis of Variance↗
PubMed1991

Differences and similarities in the treatment of diffuse goiter in Europe and the United States.

In two separate studies, members of the American Thyroid Association (ATA), and the European Thyroid Association (ETA) were surveyed by questionnaire on their management of Graves' disease. The aim was to determine how expert clinical thyroidologists employ three different therapies which are available for this disorder. Herein we summarize, compare and contrast similarities and differences in the results of these surveys. For the index patient, radioiodine (RAI) was the therapy of choice for 69% of ATA respondents but only 22% of ETA respondents. In contrast, only 30.5% of ATA respondents chose antithyroid drugs as first line therapy compared to 77% of ETA respondents. There was consensus on the relative lack of a role for thyroidectomy. The implications of these differing approaches to the treatment of hyperthyroidism due to Graves' disease are discussed.

Adult↗
PubMed1991

Differences and similarities in the diagnosis and treatment of Graves' disease in Europe, Japan, and the United States.

In three separate studies, members of the American Thyroid Association (ATA), the European Thyroid Association (ETA), and the Japan Thyroid Association (JTA) were surveyed by questionnaire on their management of Graves' disease. The aim was to determine how expert clinical thyroidologists employ diagnostic procedures and the three different therapies that are available for this disorder. In this report, we identify, summarize, compare, and contrast similarities and differences in the results of these surveys in these three different regions of the world. In general, ATA members used fewer diagnostic tests than did their European or Japanese colleagues. For the index patient, radioiodine was the therapy of choice for 69% of ATA respondents but only 22% and 11% of ETA and JTA respondents, respectively. In contrast, only 30.5% of ATA respondents chose antithyroid drugs as first-line therapy compared to 77% of ETA and 88% of JTA respondents. There was consensus on the relative lack of a role for thyroidectomy except for narrow indications. The implications of these differing approaches for the diagnosis and treatment of hyperthyroidism due to Graves' disease are discussed.

Adolescent↗
PubMed1991

Lymphocytes express thyrotropin receptor-specific mRNA as detected by the PCR technique.

Human lymphocytes are known to play a critical role in autoimmune diseases both by producing antibodies and by participating in lymphokine-cellular interactions. TSH, a classic pituitary hormone, may be secreted by human lymphocytes, and controversy has existed whether a specific, authentic TSH receptor also was present on the surface of these cells. The objective of our study was to identify TSH receptor transcripts after designing specific oligonucleotides that would recognize a unique putative TSH binding area of the thyroidal TSH receptor. The existence of TSH receptor transcripts was probed by employing these primers in a PCR reaction with cDNA derived from normal peripheral human lymphocytes and human thyroid tissue, as well as with cDNA from a medullary cancer cell line and rat liver. Human lymphocytes and thyroid tissue, but not medullary cancer cells or rat liver, demonstrated specific TSH receptor amplification product both by ethidium bromide staining and by Southern blot hybridization with labeled TSH receptor cDNA. The lymphocyte cDNA was partially sequenced and found to be identical to the thyroid-derived cDNA. These findings indicate that normal, nonactivated, human lymphocytes produce transcript for a TSH receptor that appears identical to that in thyroid tissue. Future studies should focus on the regulation of this transcript, as well as on the role TSH and TSH receptor may play in modulating local lymphokine activation of T and B cells, both in normal conditions and in autoimmune thyroid disease.

Base Sequence↗
PubMed1991

Inhibition of TSH activation of human cultured thyroid cells by tumor necrosis factor: an explanation for decreased thyroid function in systemic illness?

Thyroidal economy in systemic nonthyroidal illness (the sick euthyroid syndrome) is marked by reductions in both thyroid function and peripheral T4 to T3 conversion, presumed to reflect a homeostatic mechanism to conserve energy. TSH levels tend to be normal in these patients, and the mechanism underlying reduced thyroidal secretion is unknown. Since increased blood levels of tumor necrosis factor (TNF) are found in many of the conditions associated with the sick euthyroid syndrome, we hypothesized that TNF might affect the function of the thyroid gland. We, therefore, explored the effects of TNF on TSH stimulation of the thyroid, employing a human thyrocyte cell culture model. Cells were incubated with various concentrations (0-1000 pg/mL) of recombinant human TNF-alpha and bTSH (1 mU/mL), with measurement of secreted thyroglobulin (Tg) and cyclic AMP (cAMP) as the end points of stimulation. TNF had no effect on either basal or TSH-stimulated cAMP generation, but significantly blunted TSH-stimulated Tg secretion. No loss of cell viability and growth was observed based on trypan blue exclusion and thymidine incorporation by cells. These studies demonstrated an inhibitory effect on TNF on human thyrocytes in concentrations comparable to blood levels seen in humans during systemic illness. We conclude that increases in serum TNF may be responsible for reduced thyroid function in patients with the sick euthyroid syndrome.

Cyclic AMP↗
PubMed1991

Use of sensitive TSH assay to determine optimal thyroid hormone therapy and avoid osteoporosis.

Reported deleterious effects of thyroid hormone on bone mineral density have alarmed clinicians and patients alike because of the potential risks of osteoporosis and fracture. The known adverse effects of excessive thyroid hormones on bone are briefly reviewed, with distinction made between the status and potential consequences of replacement versus suppressive therapy. Employing the newer ultrasensitive TSH assay, management guidelines are offered to the clinician that should minimize risks of osteopenia in patients taking thyroid hormone.

Female↗
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↗