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Biomedical subjects

S Refetoff

Publications and source records attributed to S Refetoff.

At least 235 records · Page 13Linked to original sources
PubMed1976

Measurement of circulating thyroid microsomal antibodies by the tanned red cell haemagglutination technique: its usefulness in the diagnosis of autoimmune thyroid diseases.

Thyroid-microsomal antibodies were quantitated by a new technique utilizing tanned sheep red blood cells coated with human thyroid microsomal antigens. This haemagglutination assay (MCHA) correlated with the immunofluorescent antibody (FAB) but not with the thyroglobulin haemagglutination antibodies (TGHA) assay. Of forty-one patients with Hasmimoto's thyroiditis, thirty-nine (95%) were MCHA but only twenty-four (59%) TGHA positive. Titres were similar for the hypothyroid and euthyroid patients. Patients less than 20 years of age had either negative (50%) or low titre (less than 1:160) TGHA but 100% positive MCHA at titres greater than 1:1280. Of twenty-one patients with Graves' disease eighteen (86%) were MCHA and six (29%) TGHA positive. Of thirty-two patients without thyroid disease eleven (34%) were MCHA and/or TGHA positive. On the basis of family history and associated abnormalities, in eight of eleven, positive antibodies may have been due to subclinical Hashimoto's thyroiditis. Fourteen subjects of a control group (10%) were MCHA positive. Seven of ten examined had goitres. MCHA is a simple and quantitative test, useful in the diagnosis of autoimmune thyroid diseases.

Autoantibodies↗
PubMed1976

Metabolism of thyroxine-binding globulin in man. Abnormal rate of synthesis in inherited thyroxine-binding globulin deficiency and excess.

It has been previously suggested that inherited thyroxine-binding globulin (TBG) abnormalities in man may be due to mutations at a single X-chromosome-linked locus controlling TBG synthesis. However, abnormalities in TBG degradation have not been excluded. The availability of purified human TBG and its successful labeling with radioiodide allowed us to examine such possibility. Human TBG was purified by affinity chromatography, labeled under sterile conditions with 131I or 125I,, and mixed with [125I]thyroxine (T4) or [131I]T4, respectively, before their intravenous injection. Blood and urine samples were collected over a 10-day period, and the turnover parameters were calculated. In eight normal volunteers mean values +/-SD for TBG and T4 respectively, were as follows: Half time (t1/2) 5.3 +/- 0.4 and 7.0 +/- 0.6 days; distribution space (DS) 7.2 +/- 1.0 and 10.8 +/- 1.2 liters; and total daily degradation (D) 0.211 +/- 0.053 and 0.088 +/- 0.011 mumol/day. In all subjects, t1/2 of TBG was shorter than that of T4; and the DS was smaller. 2.4 mol of TBG was degraded for each mole of T4. In five of six subjects from four families, comprising hemizygous and heterozygous carriers of TBG absence, decrease, and excess, the t1/2 and DS for TBG were within the normal range. The D of TBG was proportional to the serum concentration of the protein. Changes in the T4 kinetics in these patients were compatible with euthyroidism and with the known alterations in the extrathyroidal T4 pool associated with the changes in serum TBG concentration. A striking decrease in the t1/2 of TBG was found only in a patient with acquired diminution in TBG concentration and in patients with thyrotoxicosis or other conditions apparently unrelated to thyroid dysfunction. TBG t1/2 was 2.5 days in a patient with multiple myeloma and 3.6 days in two patients with thyrotoxicosis. Decreased TBG t1/2 was also observed in three of six patients with nonthyroidal pathology and was associated with an increase in TBG D disproportionate to their level of serum TBG. These studies indicate that changes in TBG concentration in patients with X-chromosome-linked TBG abnormalities are due to alterations in its rate of synthesis. In other conditions, abnormalities of TBG degradation and/or rate of synthesis may be found.

Adult↗
PubMed1975

Differentiation of two abnormalities in thyroid peroxidase causing organification defect and goitrous hypothyroidism.

Clinical and laboratory evaluations are reported on two patients with congenital goiter and hypothyroidism due to iodide organification defect. In one patient, a 31-year-old white male with severe mental retardation, administration of perchlorate caused discharge of 69% of the radioiodine accumulated in the thyroid gland. Thyroid tissue had negligible peroxidase activity in the tyrosine-iodinase, triliodide, and guaiacol assays. Preincubation of subcellular fractions with hematin restored activity. The restored enzyme was labile to high concentrations of H2O2 (5.6times 10-4 h2o2 produced inhibition in the triiodide assay). Heating of the enzyme for 5 min at 46 degrees C produced 50% inactivation, while higher temperatures were required to half-inactivate normal peroxidases. This case represents a second example of the "peroxidase apoenzyme-prosthetic group defect" causing congenital goiter. The second patient, an example of the "deficient peroxidase defect," was a 10-yr-old girl with 35% discharge of thyroidal radioiodine by perchlorate. Peroxidase activity in the goiter tissue was quantitatively decreased (10%-20% of normal values) but kinetically normal with respect to apparent Km for H2O2. Hematin had little effect on the enzyme. Peroxidase activity had abnormal subcellular distribution, since pellets sedimenting between 39,000 and 105,000 g contained most of the activity. Normal thyroglobulin was observed in the thyroid gland of the patient. Two distinct defects of the peroxidase system can produce congenital goiter by limiting organification of iodide.

Adult↗
PubMed1975

Translation of thyroglobulin 33S messenger RNA as a means of determining thyroglobulin quaternary structure.

Thyroglobulin is a 19S protein of approximately 660,000 daltons and unknown quaternary structure. We have previously shown that a 33S mRNA purified from mammalian thyroids promoted synthesis in the Xenopus oocyte of a peptide immunologically related to thyroglobulin. Chemical identity to the native protein is now presented by means of a tryptic peptide analysis. Moreover, the 33S mRNA is shown to contain all the information required for the synthesis of a complete 19S thyroglobulin molecule. Gel filtration in Sepharose under denaturing conditions indicates that the reduced polypeptide encoded by the 33S mRNA is larger than 210,000 daltons. A model of a dimeric thyroglobulin with about 300,000 dalton subunits is presented.

Animals↗
PubMed1975

Studies on human thyroxine-binding globulin (TBG). IX. Some physical, chemical, and biological properties of radioiodinated TBG and partially desialylated TBG.

Thyroxine-binding globulin (TBG) and partially desialylated or slow TBG (STBG) were purified from human serum by affinity chromatography. Purified TBG was identical to TBG present in serum by the criteria of electrophoretic mobility, affinity for thyroxine (T4), and heat-inactivation response. Purified STBG had slower electrophoretic mobility and lower affinity for T4. Both bound T4 in an equimolar ratio, were immunoprecipitable, and had similar inactivation t1/2 at 61 degrees C. TBG and STBG were iodinated by the chloramine-T-catalyzed reaction. An average of from 0.02 to 6 atoms I could be incorporated per molecule of the protein by adjusting the conditions of the reaction (time, protein and iodide concentrations). 125-I, 131-I, and 127-I were used. Iodination increased the anodal mobility of TBG but did not affect the reversible T4-binding, precipitation by antiserum, or the heat-inactivation properties. "Heavily" and "lightly" iodinated TBG had identical disappearance half-times from serum in the rabbit. 15 min after the intravenous administration of [131-I]-STBG and [125-I]TBG mixture to rats, more than 90% of the injected 131-I dose was in the liver, and the liver 131-I/125-I ratio was 32-fold that of serum. Selective uptake of STBG by the liver was also observed in the rabbit and in man. The serum [125-I]STBG/[131-I]TBG ratio declined from 1 to 0.2 in 10 min in the intact rabbit but remained unchanged for 1 h in the acutely hepatectomized animal. In the rabbit, t 1/2 was approximately 3 min for STBG and 0.8-3.4 days for TBG. The radioiodine derived from the iodinated proteins is partly excreted in bile but the bulk was precipitable with specific antibodies. Some isotope in the form of iodide appeared in blood and was excreted in the urine. Since radioiodinated TBG and STBG preserve their biologic and immunologic properties they are useful as tracer materials for metabolic studies. In rat, rabbit, and man STBG is rapidly cleared from serum by the liver. Conversion of TBG to STBG may be the limiting step in the regulation of TBG metabolism.

Animals↗
PubMed1975

Carcinoembryonic antigen and humoral antibody response in patients with thyroid carcinoma.

Carcinoembryonic antigen and antibodies to thyroglobulin and to a microsomal fraction of thyroid were measured. Persons examined were normal volunteers, patients with thyroid cancer, and patients with a history of childhood irradiation to the thymus and/or tonsil who were otherwise normal. Elevated antigen and antibodies were most frequently found in the cancer thyroid group. Thyroid cancer patients with no previous history of childhood irradiation were more frequently positive for antigen and antibodies than all other categories studied. Thyroid cancer patients with a previous history of childhood irradiation showed normal frequencies of antigen and antibodies. The results suggest that the antigenic expression and host response to the tumor in patients with thyroid cancer depend on its pathogenesis. Mention is made of similar findings in animal model systems.

Antibodies↗
PubMed1974

Nuclear triiodothyronine-binding protein: partial characterization and binding to chromatin.

Nuclei were prepared by sucrose sedimentation of liver homogenates from rats given (125)I-labeled triiodothyronine in vivo. The nuclear extract obtained by treatment of the nuclear pellet with 0.4 M KCl contains the [(125)I]triiodothyronine that had been injected in vivo bound to protein(s). The triiodothyronine bound to nuclear protein(s) in vivo does not readily exchange with triiodothyronine added to the extract in vitro. This triiodothyronine.nuclear extract complex retains triiodothyronine during dialysis or exposure to anion exchange resin and migrates as a broad band on agarose-gel electrophoresis. It is rapidly destroyed by Pronase, by 8 M urea, and by p-chloromercuribenzoic acid, but not by RNase or by DNase. It is also susceptible to thermal inactivation at 37 degrees , possibly through changes in the affinity of triiodothyronine to the nuclear binding protein(s), since the bound triiodothyronine becomes more readily dialyzable, is absorbed by an anion exchange resin, but retains its characteristic mobility on electrophoresis. The triiodothyronine.nuclear extract complex formed in vivo binds to crude liver chromatin in vitro at low salt concentration, but can be completely extracted again at KCl concentrations greater than 0.2 M.

Animals↗