131I treatment of thyroid papillary carcinoma in a patient with renal failure.

Procedures for 131I ablation in renal failure are not known. In one patient receiving dialysis, detailed dosimetry and health safety aspects were obtained. The results showed insignificant contamination of equipment, but a surprisingly significant reduction in biologic half-life of 131I due to efficient dialysis extraction. The data indicate that 131I ablation can be done safely and easily during dialysis but that much higher 131I doses must be used to achieve equivalent results to those obtained in patients with normal renal function.

Androgen receptor defects in patients with minimal and partial androgen resistance classified according to a model of androgen-receptor complex energy states.

We have characterized intracellularly the androgen-receptor (A-R) complexes formed by genital skin fibroblasts from 2 unrelated males with qualitative defects of the androgen receptor: one has a small nonhypospadic penis as part of a syndrome of mild androgen resistance; the other was born with ambiguous external genitalia. The dissociation rate constants of testosterone, methyltrienolone (MT), dihydrotestosterone (DHT) and mibolerone (MB) from normal androgen receptors were determined at various temperatures: when plotted by the method of Arrhenius, they yielded a linear hierarchy of dissociation states with energies of state IV greater than III greater than II greater than I, respectively. Relative to this hierarchy, patient A-R complexes were displaced to higher, androgen-inappropriate energies in a mutant-distinctive pattern. MB- or MT-R complexes of both patients were thermolabile; however, both up-regulated normally in response to prolonged incubation with either hormone. Apparent equilibrium affinity constants (Kd) of the DHT- and MB-R complexes formed by both patients were normal; however, the binding capacity (Bmax) for MB in 1 case was subnormal. The distinctive biochemical phenotypes of A-R complexes in these 2 patients with androgen resistance will facilitate the definition of structure-function relations in the androgen receptor, a classical DNA-binding, transcription-regulating protein.

The effects of dithiothreitol on thyroid stimulation in vitro.

There is evidence that the porcine TSH receptor contains essential disulphide bridge(s) which can be disrupted by dithiothreitol (DTT). The aim of the present study was to determine whether exposure of intact thyroid cells to DTT leads to altered thyroid stimulation. TSH-stimulated iodine organification in cultured porcine thyroid cells was studied following short-term DTT exposure; a dose-dependent inhibition was observed with DTT but not oxidized DTT. Cell viability, follicle formation, and total protein synthesis were preserved. A minimum of 30 min incubation with DTT was required for inhibition. However, under identical conditions, DTT had no effect on TSH or forskolin-stimulated cyclic AMP (cAMP) production. These results suggest that DTT inhibition of organification is mediated by post-receptor mechanisms likely involving thyroid peroxidase. The effects of DTT on thyroid stimulation in vitro does not appear to involve disruption of the disulphide bridge(s) in the TSH receptor.

Cervical cord compression due to extension of a papillary thyroid carcinoma.

A 76-year-old man with a long-standing neck mass presented with the acute onset of paraplegia. Computed tomographic scanning of the neck revealed direct involvement of the mass with several cervical vertebral bodies and extension into the spinal canal. Biopsy of the mass demonstrated well-differentiated papillary thyroid carcinoma. He received external radiation to the lesion but died shortly thereafter. This is the first report of cervical cord compression due to extension of a papillary thyroid carcinoma.

Thyrotrophin blocking antibodies in the sera of mothers with congenitally hypothyroid infants.

We examined IgG from 15 mothers of infants with congenital hypothyroidism for their ability to block TSH-stimulated iodine organification in vitro. Only one out of 15 of these IgGs exhibited TSH-blocking activity. This IgG could inhibit TSH action by 30-50%. It could not block radiolabelled TSH from binding to its receptor but did inhibit dibutyryl cyclic AMP stimulation of iodine organification implying a unique effect on post-receptor processes via a membrane binding site distant from the TSH binding site. Interestingly there was no evidence of autoimmune thyroid disease in the mother. These results suggest that the transplacental passage of TSH-blocking antibodies plays little, if any, role in the development of congenital hypothyroidism.

Clinical applications of assays for thyrotropin-receptor antibodies in Graves' disease.

Graves' disease is characterized by hyperthyroidism, diffuse goitre, infiltrative ophthalmopathy and, rarely, pretibial myxedema. In 1956 a substance capable of prolonged thyroid stimulation was discovered in the serum of some patients with Graves' disease and termed long-acting thyroid stimulator (LATS). It was shown to be an antibody that could interact with the receptor for thyroid-stimulating hormone (TSH). The term LATS is usually reserved for the activity measured in a laborious in-vivo bioassay in mice. Today the activity of TSH-receptor antibodies (TSH-R Ab) can be measured by in-vitro bioassays or by radioreceptor assays. These assays are now becoming commercially available. TSH-R Ab assays may be useful in predicting the response to therapy for Graves' disease, investigating euthyroid ophthalmopathy and predicting the likelihood of neonatal hyperthyroidism.

Primary actinomycosis of the thyroid mimicking carcinoma.

Primary actinomycosis of the thyroid was diagnosed in a 59 year old farmer who presented with a hard, non-tender, thyroid nodule. The difficulties encountered in the diagnosis of actinomycetal infections, its pathogenesis, and treatment are discussed.

Thyrotrophin-binding-inhibition assay: comparison of crude and purified membrane preparations.

Two different thyroid membrane preparations (TMP), crude and pure, made from a homogenate of normal human thyroid tissue, were used to test purified serum IgG from 36 patients with Graves' disease, and 10 normal control subjects, in the thyrotrophin-binding-inhibition (TBI) assay. All reagents for the assay were identical, and aliquots of each IgG were tested in both TMP simultaneously, under exactly comparable conditions. Blood was drawn while the patients were hyperthyroid (19), euthyroid (13), or hypothyroid (4); 15 of the patients were untreated and 21 were being treated. The frequency of positive TBI was similar in both TMPs and highest among the 131I-treated patients. Comparison of TBI results in both TMP for each IgG sample revealed wide differences, and 47.1% of the Graves' IgGs were TBI positive in one membrane preparation, while negative in the other. There was no correlation of TBI values between the two TMP, or with clinical status, or the presence of standard thyroid antibodies. The findings indicate that the IgGs of Graves' disease, as now tested in the TBI assay, bind heterogeneous to different fractions of the thyroid membranes.

Characterization of a pituitary stone.

Calcification of the pituitary is unusual and functional studies of such cases have not been previously reported. We have been able to document persistent prolactin secretion both in vivo and in vitro in a patient with a severely calcified pituitary adenoma ("pituitary stone"), and have also documented prolactin granules within the calcified tissue mass. Normal menstrual function was restored after surgical removal of the "stone," and galactorrhea subsided although the prolactin response to thyrotropin-releasing hormone (TRH) remained abnormal. Two years after surgery the menstrual cycle has remained regular, but galactorrhea has recurred, emphasizing the need for prolonged follow-up in patients with prolactin-producing adenomas, despite apparent surgical cure. The in vitro studies showed that human pituitary tissue is secretory in culture and thus may serve as a useful tool for physiologic studies of the pituitary cell.

Comparison of thyroid antigens by the experimental production of precipitating antibodies to human thyroid fractions and the identification of an antibody which competes with long-acting thyroid stimulator (LATS) for thyroid binding.

Antibodies were raised to various sub-cellular fractions of human thyroids, (of Graves' disease, Hashimoto's thyroiditis, and non-toxic goitre). With one exception it was found that antibodies to the Graves' thyroid fractions crooss-reacted with both the non-toxic goitre and Hashimoto's thyroiditis fractions. This exception was in the antiserum to the Graves' 105 000 x g pellet (Gr4) which contained an anr the Hashimoto's (/) thyroid preparations. The antibody-antigen between A-1 and Gr4 could be blocked by the addition of LATS (or TSH) to the antigen, thus suggesting that A- 1 might be a LATS-like immunoglobulin. These results suggest that the TSH receptor can be produced in vivo. Production of such an antibody to the TSH receptor would permit the development for the first time fo a good animal model of Graves' disease.

Demonstration of the production of human thyroid-stimulating immunoglobulins (HTSI) by Graves' lymphocytes cultured in vitro with phytohaemagglutinin (PHA).

The lymphocytes from patients with Graves' disease or from healthy subjects have been cultured in vitro either alone or with phytohemagglutinin (PHA). After six days the culture supernatants have been assayed for their human thyroid-stimulating activity by measuring increases in adenosine 3',5' monophosphate (cyclic AMP) in human thyroid slices with which the supernatants have been incubated. Significant levels of human thyroid stimulator activity were found in the culture in which Graves' lymphocytes were cultured with PHA. This activity has been abolished by precipitation of the IgG from the culture supernatant with goat antihuman IgG serum. In contrast, when Graves' lymphocytes were cultured alone, or when control lymphocytes were cultured either alone or with PHA, there was no overall significant production of human thyroid-stimulating immunoglobulin (HTSI). It is concluded that Graves' lymphocytes can be stimulated by PHA to produce HTSI in vitro. Since PHA is known to stimulate only the T lymphocytes, which do not themselves elaborate immunoglobulins as the B lymphocytes do, the above observations indicate a cooperation between T and B lymphocytes in the production of HTSI, at least in this system.

Thyroid antigen stimulates lymphocytes from patients with Graves' disease to produce thyroid-stimulating immunoglobulin (TSI).

Circulating lymphocytes from patients with Graves' disease and from control subjects were cultured in vitro alone, with normal human thyroid tissue homogenates, and with other nonthyroid human tissue homogenates. The supernatants of these cultures were assayed for human thyroid-stimulating activity by incubation with human thyroid slices in which increases in cAMP levels were then measured. Human thyroid stimulator activity was demonstrated in 16 out of 20 experiments in which lymphocytes from patients with active untreated Graves' disease (with hyperthyroidism) were cultured with normal thyroid homogenate, in 4 out of 17 experiments when control lymphocytes were similarly cultured, and in one out of 12 experiments in which the lymphocytes from the patients with Graves' disease were cultured with liver or gastric mucosa homogenate. Thyroid-stimulating activity was abolished by precipitation of the globulin from the supernatant by goat anti-human globulin serum. These results demonstrate that normal human thyroid tissue homogenates can specifically stimulate most lymphocytes from patients with Graves' disease and lymphocytes from a few normal subjects to produce human thyroid-stimulating immunoglobulins in vitro. This suggests that the human thyroid-stimulating immunoglobulins are auto-antibodies to normal thyroid constituents, but the possiblity that an antigenic change in the thyroid initiates the disease cannot be entirely excluded. The findings suggest that the prime change in Graves' disease is immunologic, perhaps a failure of immunological suppression.

Follicular carcinoma of the thyroid with functioning metastases and clinical hyperthyroidism.

Hyperthyroidism associated with metastatic follicular carcinoma of the thyroid gland is rare. In one patient the mass of functioning follicular tissue in the primary and metastatic tumour was so great that excessive amounts of thyroxine and triiodothyronine were produced and, as a result, clinical hyperthyroidism developed. This was in spite of the fact that the activity per unit of tissue was not supranormal and may even have been slightly subnormal. The initial response of the metastases to 131I ablative therapy was excellent.