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Biomedical subjects

K D Burman

Publications and source records attributed to K D Burman.

At least 37 records · Page 2Linked to original sources
PubMed1997

Hodgkin's disease treated with neck radiation is associated with increased antibody-dependent cellular cytotoxicity against human extraocular muscle cells.

Patients with Hodgkin's disease have higher a prevalence of thyroid function abnormalities and, perhaps, orbitopathy than the general population, but the pathophysiology of this association and its relationship to Hodgkin's disease treatment remain unclear. We analyzed the frequency of thyroid function abnormalities, autoantibodies against thyroid antigens, and autoimmunity against extraocular muscle cell antigens by Western blot analyses and antibody-dependent cellular cytotoxicity (ADCC) assays in patients with Hodgkin's disease (n = 20) and controls (n = 10). Hodgkin's disease patients were subdivided into those treated with thyroidal external beam radiation therapy (XRT, n = 15) or chemotherapy (MOPP/ABVD, n = 5). The ADCC assay against extraocular muscle cells was increased in patients with Hodgkin's disease (5.5% vs. <1.0%, p = .026) when compared with controls. In addition, Hodgkin's disease patients treated with XRT (with or without chemotherapy) had significantly higher ADCC tests than controls (9.7% vs. <1.0%, p = .010), In contrast, ADCC assays were not different between Hodgkin's disease patients treated with chemotherapy alone and controls (<1.0% vs. <1.0%, p = .53). Hodgkin's patients treated with XRT had higher ADCC assays than those treated with chemotherapy alone (p = .087), although this difference did not achieve statistical significance. Serum measurements of antithyroid peroxidase (TPO) antibodies, antithyroglobulin (Tg) antibodies, thyroid binding inhibitory immunoglobulins (TBII), and thyroid stimulating immunoglobulin (TSI) were similar in all groups. Antibodies against the 64 kDa orbital antigen were detected in 1 patient and 1 control subject. Excluding patients already treated with L-thyroxine for hypothyroidism (n = 5), free T3, but not free T4, was lower in the Hodgkin's disease group than in controls (2.2 pg/mL vs. 2.7 pg/mL, p = .008). Thyrotropin (TSH) concentrations were not statistically different between these groups. In summary, these data show: (1) ADCC against human orbital muscle cells is increased in patients with Hodgkin's disease compared with controls: (2) these differences were noted among Hodgkin's disease patients treated with thyroidal XRT, with or without chemotherapy, and not among those patients treated with chemotherapy alone; and (3) no statistically significant differences in the frequency of thyroid autoantibodies were found. These data suggest that patients with Hodgkin's disease display altered antibody-dependent immune function toward extraocular muscle cells that may possibly be related to by XRT. Larger, prospective studies assessing thyroid and orbital-related immunologic abnormalities in Hodgkin's disease are warranted.

Adult↗
PubMed1997

Soluble interleukin-2 receptor is a thyroid hormone-dependent early-response marker in the treatment of thyrotoxicosis.

Thyrotoxic patients exhibit increased levels of immune activation molecules (soluble interleukin-2 receptor [sIL-2R], intercellular adhesion molecule-1 [ICAM-1], and endothelial-leukocyte adhesion molecule-1 [ELAM-1]) in serum, although the clinical significance of these measurements remains unclear. In a randomized 4-week study, we have recently shown that in the treatment of hyperthyroidism, the combination of cholestyramine and methimazole (MMI) resulted in faster lowering of serum thyroid-hormone levels than did MMI alone. Stored serial serum samples from patients participating in this randomized treatment trial were analyzed for sIL-2R, soluble ICAM-1 (sICAM-1), and soluble ELAM-1 (sELAM-1). The levels of all three molecules were elevated in patients with hyperthyroidism. Although the levels of sICAM-1 and sELAM-1 remained elevated through the 4-week follow-up period in both groups of patients, the sIL-2R levels (normal levels, 1.0 to 4.2 ng/ml) decreased significantly in the 10 patients who received cholestyramine in addition to MMI (week 0, 14.2 +/- 1.5 ng/ml; week 2, 10.8 +/- 1.2 ng/ml; week 4, 8.9 +/- 1.5 ng/ml). In eight patients who received MMI alone, sIL-2R decreased less rapidly (week 0, 12.3 +/- 1.4 ng/ml; week 2, 12.3 +/- 1.3 ng/ml; week 4, 10.9 +/- 1.3 ng/ml). sICAM-1 and sELAM-1 were elevated at baseline but did not decrease during therapy. In the former group, free thyroxine and free triiodothyronine decreased faster. These data show that levels of sIL-2R in serum, but not those of sICAM-1 and sELAM-1, may be of clinical use in the early follow-up evaluation of medically treated patients.

Antithyroid Agents↗
PubMed1996

Unusual types of thyroid neoplasms.

This article discusses several unusual forms of primary thyroid neoplasms. The TCV of PTC and insular thyroid carcinoma appears to have a more aggressive clinical behavior than DTC in most patient groups and may respond to thyroid hormone suppression and radioiodine. Anaplastic thyroid carcinoma, which may develop from differentiated thyroid tumors, has a poor prognosis which may be altered by surgery and radiation therapy but not typically by radioiodine and thyroid hormone suppression. Primary squamous cell carcinoma of the thyroid is an unusual entity that may be associated with a clinical syndrome that includes leukocytosis, fever, and hypercalcemia. Primary thyroid lymphoma is frequently associated with Hashimoto's thyroiditis and should be considered especially in older patients with rapidly enlarging thyroid masses. Although there are no studies assessing this issue, it seems reasonable that patients who have undergone thyroidectomy for neoplasms of thyroid cells that are poorly differentiated and do not concentrate radioiodine (e.g., squamous cell, anaplastic) should receive sufficient thyroid hormone suppression, if tolerated, to reduce TSH (third-generation assay) to approximately 0.1 to 0.3 mu U/mL, because TSH may be a growth factor. If, however, the tumor concentrates or responds to radioiodine, suggesting more differentiated cells (e.g., TCV, insular carcinoma), the target TSH level (third-generation assay) should range from 0.01 to 0.1 mu U/mL, as tolerated. Patients with primary thyroid neoplasms arising from cells other than thyrocytes (e.g., lymphoma) can be maintained at a TSH level of 0.5 to 1.5 mu U/mL. Our conclusions and analyses are often based upon small, retrospective, poorly controlled reports, and further studies are required to allow a better understanding of the evaluation and treatment of these neoplasms.

Adenomatous Polyposis Coli↗
PubMed1996

Current trends in the management of well differentiated papillary thyroid carcinoma.

Clinical members of the American Thyroid Association were surveyed in regard to their diagnostic assessment, treatment, and long term assessment of differentiated papillary thyroid carcinoma. For a 39-yr-old female with a 2-cm solitary nodule and no history of radiation (index patient), respondents were asked to provide their preferences for diagnostic evaluation, treatment assuming a papillary carcinoma was focal, and follow-up. Of 408 surveys mailed, 233 (57.1%) were analyzed. Diagnostic studies included thyroid scan (56%), fine needle aspiration (96%), total serum T4 (49%), and third generation TSH (56%). Treatment included surgery (99%), with 86% preferring near-total/total thyroidectomy. After surgery, 61% recommended 131I ablation; long term therapy using L-T4 alone was recommended by 97%, with most preferring suppression to a target TSH level of less than 0.01 microIU/mL (22%), 0.01-0.05 (38%), or 0.06-0.50 (32%). For variations from the index patient, respondents' treatment were not different for a history of radiation, age of either 16 or 60 yr, nodule size of 1.5 cm, male sex, the presence of less than 1-cm multiple foci in the contralateral lobe, or capsular invasion of the nodule. Treatment and follow-up did change if there was blood vessel invasion or distant metastasis. In summary, our survey indicated consensus on diagnostic assessment of the index patient by fine needle aspiration and management by surgery and 131I therapy. However, management varied widely for the ablative dose of 131I, the target TSH level after ablation, and the frequency and type of follow up.

Adolescent↗
PubMed1996

Immunoglobulins from Graves' disease patients stimulate phospholipase A2 and C systems in FRTL-5 and human thyroid cells.

We have studied the effects of immunoglobulin G from Graves' disease patients on phospholipase A2 (PLA2) and C(PLC) systems in FRTL-5 and human thyroid cells. Immunoglobulin G (IgG) from Graves' disease patients stimulated arachidonic acid (AA) release in a time- and dose-dependent manner. In FRTL-5 thyroid cells, removal of external calcium had no significant effect on the IgG (20 micrograms/ml)-induced AA release in FRTL-5 thyroid cells. U-73122 (3 mumol/l), a PLC inhibitor, and quinacrine (100 mumol/l) but not U-26384 (5 mumol/l), PLA2 inhibitors, blocked the IgG-induced (20 micrograms/ml) AA release in FRTL-5 thyroid cells. Immunoglobulin G (100 micrograms/ml) also stimulated accumulation of inositol-1,4,5-triphosphate (IP3) in a time- and dose-dependent (20-300 micrograms/ml) manner in FRTL-5 cells. Immunoglobulin G from Graves' disease patients induced a significant increase of IP3 production (p = 0.01) compared to IgG from normal subjects. Removal of external calcium had no significant effect on the IgG-induced IP3 production. The PLC inhibitor U-73122 completely blocked IgG-induced IP3 production from FRTL-5 thyroid cells. Also, in human thyroid cells, IgG from Graves' disease patients induced a significant increase of AA release (p = 0.001) and IP3 production (p = 0.004) compared to the IgG from normal subjects. These data indicate that IgG from Graves' disease patients induced PLA2 activity that was PLC dependent, a pattern referred to as sequential activation. Our studies suggest that IgG from Graves' disease patients activates PLA2 and PLC systems in FRTL-5 and human thyroid cells. These signal transduction pathways could be involved in the pathogenesis of Graves' disease and future studies are warranted to investigate this area.

Adult↗
PubMed1995

Thyrotropin receptor T cell epitopes in autoimmune thyroid disease.

The human TSH receptor represents the primary target of thyroid-stimulating immunoglobulins responsible for the hyperthyroidism of Graves' disease. In the present series of investigations, the distribution of T cell epitopes has been mapped using synthetic peptides spanning the entire extracellular region of the human TSH receptor. In vitro proliferative responses of the mononuclear cells were measured using flow cytometric analysis of bromodeoxyuridine incorporation into nuclei. In 8 of 11 samples from patients with Graves' disease, at least one (and up to 9) regions of the human TSH receptor induced proliferation, with the mean stimulation index being 39.8 +/- 47.3. No single universal stimulatory peptide was identified. In contrast, stimulation was not observed in three control subjects, while one control subject showed minimal stimulation (index of 5.7) to peptides encompassing a limited area (amino acids 31-65). The immunodominant epitope of patients with recent-onset Graves' disease was localized between amino acids 271 and 365, whereas the immunodominant epitope of patients with disease duration greater than 1 year localized between amino acids 91 and 215. We conclude that the bromodeoxyuridine incorporation method is a useful and important tool for detecting antigen-induced lymphocyte proliferation. The TSH receptor-specific T cells from different Graves' disease patients recognize variable distinct sites within the extracellular region of the TSH receptor, and the immunodominant epitope apparently shifts toward the N-terminus of the receptor protein during the course of treated Graves' disease.

Bromodeoxyuridine↗
PubMed1995

The influence of triiodothyronine, thyroxine, thyrotropin, and methimazole on thyroid cell MHC class II antigen expression.

We have studied the influence of triiodothyronine (T3), thyroxine (T4), thyrotropin (TSH), and methimazole (MMI) on the expression of major histocompatibility (MHC) Class II antigen expression in human thyroid cells. T3, T4, TSH, and MMI in various combinations were added together with interferon-gamma (IFN-gamma) to human thyrocytes or to cultured FRTL-5 cells. Neither T3 nor T4, alone, caused inhibition of the IFN-gamma stimulation of thyrocyte HLA-DR expression. Moreover, the combination of both drugs at various concentrations did not inhibit this expression except only in low ranges (T3 at 0.3 nmol/liter and T4 at 12.9 nmol/liter). MMI only at a concentration of 3.0 mmol/liter caused significant inhibition of IFN-gamma-induced HLA-DR expression. However, the addition of T3 (range, 0.3-9.2 nmol/liter) or T4 (12.9-129.0 nmol/liter) prevented the MMI-induced inhibition. This phenomenon may be explained by the action of MMI on inhibiting the synthesis of T3 and T4. At a concentration of 100 microU/ml, TSH enhanced IFN-gamma-induced HLA-DR expression. It is possible that TSH induced the expression of large numbers of IFN-gamma receptors, thereby enhancing the production of HLA-DR in response to IFN-gamma. Our studies suggest that MMI does not alter thyrocyte HLA-DR expression in vitro, especially when combined with T3 or T4; however, MMI may still induce or perpetuate immune effects in vivo secondary to its influence on thyroid hormone production or thyroid antigen presentation.

Animals↗
PubMed1994

Discontinuing antithyroid drug therapy before ablation with radioiodine in Graves disease.

OBJECTIVE: To determine the relative effects on thyroid hormone levels of discontinuing antithyroid drug therapy and subsequent ablation with radioiodine in patients with hyperthyroid Graves disease. DESIGN: A clinical trial with a prospective analysis of the relative change in thyroid hormone levels over time in response to therapy in two study groups. SETTING: An outpatient endocrine clinic at a tertiary care hospital. PATIENTS: 21 patients with a clinical diagnosis of hyperthyroid Graves disease scheduled to receive ablation therapy with radioiodine (131I): 17 patients were pretreated with antithyroid drugs, and 4 were not. METHODS: Antithyroid drugs were stopped 6 days before radioiodine therapy. Patients were monitored clinically and biochemically with measurement of free and total levels of thyroxine (T4) and triiodothyronine (T3) on days -6, -3, -1; the day of radioiodine therapy; and days 1, 2, 3, 4, 5, 7, and 14. RESULTS: Before radioiodine treatment and compared with baseline measurement, the mean increase in free T4 levels after discontinuation of antithyroid therapy was 86% (95% CI, 16.1% to 156%), with a concurrent mean increase in free T3 levels of 71.6% (CI, 31% to 112%). Radioiodine therapy resulted in a mean decrease in free T3 levels of 28.7% (CI, -44.1% to -13.2%), a mean decrease in total T3 levels of 22.9% (CI, -39.4% to -6.4%), and stability in free and total T4 levels rather than aggravation of thyrotoxicosis. A smaller group of patients not receiving antithyroid drugs experienced a course qualitatively similar to that of pretreated patients after 131I treatment, with a mean reduction in free T4 levels of 39.8% (CI, -69.9% to -9.7%) and a mean decrease in free T3 levels of 49.4% (CI, -93.7% to -5.1%). CONCLUSION: Short-term increases in thyroid hormone levels in patients with Graves disease receiving radioiodine ablation occur primarily as a result of discontinuing antithyroid therapy rather than as a result of treatment with 131I. Stability or decrease in thyroid hormone levels, rather than further elevation, occurs during the 2-week interval after ablation therapy with 131I. Antithyroid drug therapy before radioiodine ablation may have little effect on the short-term biochemical course after 131I therapy for Graves disease. The homogeneity of our sample regarding age, diagnosis, and general health may prevent application of these findings to other populations without further study.

Adult↗
PubMed1994

TSH receptor gene expression in retroocular fibroblasts.

RNA was isolated from fibroblasts from the retroocular area, from endomysial fibroblasts obtained from orbital lateral rectus muscle, and from abdominal skin fibroblasts. The RNA was reverse transcribed into cDNA which was then used as a template for PCR with primers encompassing a portion (nucleotides 989-1235) of the extra-cellular domain of the human TSH receptor (hTSH-R). A definite 247 BP product was detected from fibroblast RNA by ethidium bromide staining, and was confirmed by hybridization with labelled hTSH-R cDNA. The product had homology with the known TSH-R cDNA. These studies indicate that human fibroblasts can express hTSH-R, and they suggest that a cross reactive immunologic response between anti-hTSH-R and these fibroblast TSH receptors may play a role in the genesis of Graves' ophthalmopathy.

Base Sequence↗
PubMed1994

Thyrotropin receptor antisera for the detection of immunoreactive protein species in retroocular fibroblasts obtained from patients with Graves' ophthalmopathy.

Autoimmunity against the TSH receptor (hTSH-R) is known to be the proximate cause of thyroidal activation in Graves' disease, but has not been definitively linked to extrathyroidal manifestations of this disorder, such as ophthalmopathy and pretibial myxedema. In an effort to increase our knowledge concerning mechanisms responsible for Graves' ophthalmopathy, we used antiserum directed against a highly immunogenic portion of the hTSH-R (amino acids 352-367; P1) to assess the presence of this receptor or immunologically related protein in cultured human retroocular fibroblasts obtained from patients with Graves' ophthalmopathy. Immunoenzymatic and immunofluorescent studies revealed specific staining of both cytoplasmic and cell membrane-associated protein in discrete vesicles. To further evaluate the immunoreactive species present in these cells, immunoblotting experiments were performed using hTSH-R-specific antisera (anti-P1) and sera obtained from patients with Graves' disease. Several protein bands were identified using both anti-P1 and Graves' disease patient sera, including species at mol wt of 95, 71, and 18 kilodaltons, the possible significance of which is discussed. The results support the hypothesis that immunity against the hTSH-R or related proteins contributes to the ophthalmopathy of Graves' disease.

Amino Acid Sequence↗
PubMed1993

Expression polymerase chain reaction for the in vitro synthesis and epitope mapping of autoantigen. Application to the human thyrotropin receptor.

The clinical applicability of a newly described polymerase chain reaction directed protein expression system was assessed for the in vitro synthesis and partial epitope mapping of large radiolabeled human thyrotropin receptor (hTSH-R) protein segments. PCR amplification of targeted regions within the hTSH-R cDNA followed by in vitro transcription and translation permitted rapid synthesis of protein segments ranging in size from 18 to 62 kDa. Initial epitope mapping was directed at a 52 amino acid segment unique to the hTSH-R compared to otherwise homologous glycoprotein hormone receptors. Sera from Graves' disease patients known to have autoantibodies against the hTSH-R were used to immunoprecipitate two protein fragments differing only by the presence of the unique region in the larger fragment (E5) but not in the smaller fragment (E4). Dense precipitation bands were obtained using Graves' sera to immunoprecipitate E5 whereas little or no specific immunoprecipitation of E4 occurred. Normal sera gave only weak immunoprecipitation bands of E5. The technique provides significant advantages over conventional cloning methods and should have general applicability in the study of other protein targets of autoimmune disease.

Amino Acid Sequence↗
PubMed1993

Prevalence of fractures in postmenopausal women with thyroid disease.

We interviewed 300 white postmenopausal women (160 with thyroid disease, 140 without thyroid disease) to investigate whether having thyroid disease or taking thyroid hormone increased the prevalence of having a hip, vertebral, or forearm fracture. Thirty-seven (23%) women with thyroid disease and 45 (32%) women without thyroid disease had had a fracture, and there were no significant differences between these groups in the number or type of fractures. Dose of thyroid hormone and duration of therapy or disease did not affect fracture occurrence in women with thyroid disease. Women with a history of hyperthyroidism (9 of 32) or thyroid cancer (2 of 11) appeared to have their first fracture earlier (p < 0.01) than women without thyroid disease. In summary, women taking thyroid hormone for a variety of thyroid disorders do not appear to have an enhanced prevalence of a hip, vertebral, or forearm fractures, but women with a history of hyperthyroidism may have a propensity for their fractures to occur earlier in life.

Aged↗
PubMed1993

TSH beta subunit gene expression in human lymphocytes.

Production of neuroendocrine peptides by human lymphocytes is thought to facilitate control of the immune response. The presence of neuroendocrine peptide gene expression, specifically the TSH beta subunit gene, was studied in human lymphocytes using Northern blot analysis and polymerase chain reaction (PCR) techniques. Northern blot analysis of human lymphocyte RNA probed with a TSH beta cDNA probe failed to demonstrate TSH beta subunit steady state message levels. PCR amplification of lymphocyte-derived cDNA using TSH beta subunit complementary primers resulted in amplification of a .38 Kb DNA fragment, confirming expression and initial exonic splicing of TSH beta subunit gene exons 2 and 3 in human lymphocytes. Sequence analysis of this .38 Kb DNA fragment demonstrated conservation of exon borders after splicing (exons 2 and 3) and predicted an amino acid translation product similar, if not identical, to human TSH beta peptide sequence. Hybridization with a TSH beta subunit cDNA probe of PCR-amplified reverse-transcribed lymphocyte RNA suggested that: (1) the abundance of TSH beta subunit gene transcripts in human lymphocytes is less than the relative abundance in T3-treated pituitary; and (2) this messenger RNA may be modulated by the presence of certain thyromimetic compounds (T2, T3, TRIAC).

Amino Acid Sequence↗