Biological characteristics of adenomatous nodules, adenomas, and hyperfunctioning nodules as defined by adenylate cyclase activity and TSH receptors.
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Adenoma↗
Biomedical subjects
C G Thomas
Publications and source records attributed to C G Thomas.
Divergent effects of forskolin on 3',5' cyclic adenosine monophosphate production and parathyroid hormone secretion.
Forskolin, a diterpene which directly stimulates adenylate cyclase, markedly stimulated cAMP production in intact rat parathyroid glands and dispersed cells from hyperplastic and adenomatous human parathyroid tissues. Stimulation of cAMP production in human parathyroid adenomas occurred as early as 2 min and continued for at least 2 h; furthermore, a dose-response relationship was observed, with a maximal 80-fold cAMP response occurring at 100 microM forskolin. When PTH secretion by rat or human parathyroid tissues was studied at low (0.5 mM) and high (2.5 mM) extracellular Ca2+ in either the presence or absence of forskolin, no significant stimulation by forskolin was observed at 15 min, 1 h, and 2 h. When 10 human parathyroid specimens were studied with varying concentrations of forskolin at 1 mM Ca2+, 6 failed to show stimulation of PTH secretion and 4 showed modest but detectable increases in PTH that did not appear dose-related. We conclude that (1) at low and high Ca2+ levels, marked stimulation of cAMP production by forskolin can occur without a corresponding increase in PTH secretion; (2) inhibition of PTH secretion by high extracellular Ca2+ levels continues unchanged despite stimulation of cAMP production by forskolin; and (3) at intermediate Ca2+ levels (1.0 mM), PTH secretion is affected either minimally or not at all by forskolin in human hyperparathyroid tissue preparations. The marked stimulation of parathyroid adenylate cyclase by forskolin without concomitant increases in PTH secretion in the majority of tissues suggests that the level of cAMP production is not a primary or sufficient determinant of hormone secretion.
Adenoma↗
Fatal overwhelming postsplenectomy sepsis following autologous splenic transplantation in severe congenital osteopetrosis.
We report a boy with severe congenital osteopetrosis who underwent splenectomy at age 4, with simultaneous transplantation of portions of the spleen into the anterior rectus compartments. Despite demonstrated survival and partial functioning of the splenic implants, the patient died 9 years later from an overwhelming postsplenectomy infection (OPSI). This report suggests that the presence of the amount of retained splenic tissue transplanted in this case after splenectomy ultimately provides relatively ineffective protection against OPSI in congenital osteopetrosis.
Adolescent↗
Hyperadrenalism in childhood and adolescence.
Hyperadrenalism in childhood and adolescence has unique features that influence diagnosis and management. We reviewed our experience with 18 patients, ranging in age from 18 months to 18 years. Nine had bilateral adrenal hyperplasia, eight had adrenal neoplasms, and one had micronodular hyperplasia. Patients with congenital adrenal hyperplasia and hyperaldosteronism were excluded. Six patients with Cushing's disease diagnosed in earlier years were treated by total adrenalectomy and recently two patients underwent transsphenoidal removal of pituitary tumors. Bilateral adrenalectomy was carried out in one patient with micronodular hyperplasia and in a second because of elevated adrenocorticotrophic hormone (ACTH) levels from an undefined source. Eight patients had adrenal neoplasms, including five adenomas and three carcinomas. We found no reliable criteria to differentiate before surgery between adrenal adenomas and adrenal carcinomas. The most recognizable characteristic of malignancy was tumor size, specifically weight greater than 75 gms. Of the three patients with adrenal carcinoma, one expired 20 months after adrenalectomy and 8 months after receiving palliative partial hepatectomy for liver metastasis. Two patients are well with normal growth and development at 11 and 20 years following adrenalectomy. With the exception of one patient who died 6 years after surgery from a glioblastoma multiforme, all patients with adrenal adenomas are well. Eight patients underwent bilateral adrenalectomy for hypercortisolism. Five of the six who have reached their adult stature are significantly stunted. Four of six patients with Cushing's disease, treated by total adrenalectomy, have developed Nelson's syndrome at 2, 6, 10, and 12 years after surgery. Of the two patients undergoing transsphenoidal surgery, one had recurrent disease at 2 years and was treated by pituitary irradiation with recovery. The patients undergoing adrenalectomy for micronodular hyperplasia and ectopic ACTH are well at 2 and 4 years, respectively. Cushing's disease in children and adolescents is best treated by transsphenoidal removal of the pituitary adenoma. Adrenalectomy, once the most accepted approach, plays a secondary role and is indicated primarily in micronodular adrenal hyperplasia, in patients with ectopic ACTH production of an undefined source, and in recurrent Cushing's disease following prior pituitary irradiation. The high incidence of Nelson's syndrome in children treated by adrenalectomy mandates that patients at risk be monitored lifelong for the progression of a pituitary tumor.(ABSTRACT TRUNCATED AT 400 WORDS)
Adenoma↗
Nelson's syndrome after Cushing's disease in childhood: a continuing problem.
Nelson's syndrome--progressive cutaneous hyperpigmentation with x-ray film evidence of an expanding pituitary tumor--is now a well-recognized sequela of bilateral adrenalectomy for Cushing's disease. It is estimated to occur in 8% to 38% of adults. Because Cushing's disease is rare in children, a higher incidence of Nelson's syndrome has not been suggested until recently. Although transsphenoidal operation is now the treatment of choice for Cushing's disease, children who have undergone bilateral adrenalectomy remain at risk for the development of Nelson's syndrome. A review of our experience and the literature indicates that the incidence of Nelson's syndrome after the treatment of Cushing's disease is higher in children than in adults. In our six children who underwent adrenalectomy between 8 and 17 years of age, four developed Nelson's syndrome at 2, 6, 10, and 12 years after adrenalectomy. Two of these patients remain well at 6 and 9 years after treatment with external irradiation. One patient treated with external irradiation developed recurrence at 5 years and required total hypophysectomy. The fourth patient required total hypophysectomy followed by external irradiation. Of the 37 patients reviewed and analyzed, the mean age at diagnosis of Cushing's disease was 12 years, with a mean interval of 8.4 years between adrenalectomy and Nelson's syndrome. Information regarding treatment for Nelson's syndrome was known in 24 patients and included pituitary irradiation (four patients), pituitary operation (11 patients), pituitary irradiation followed by operation (six patients), and pituitary operation followed by irradiation (three patients).
Adolescent↗
Primary hyperparathyroidism during pregnancy.
Primary hyperparathyroidism during pregnancy is associated with significant risk of fetal loss and neonatal and maternal morbidity. Neonatal hypocalcemia probably results from transient hypoparathyroidism consequent to abnormal suppression by fetal hypercalcemia. Loss of the protective effect provided by the placental calcium transport mechanism produces significant maternal risk for development of acute hypercalcemia and possible crisis immediately postpartum. Management of maternal primary hyperparathyroidism diagnosed during pregnancy should be based on the patient's symptoms, severity of the disease, and gestational age of the fetus. Patients without symptoms and those with mild hypercalcemia may be managed effectively and safely for a short time with oral phosphate therapy, postponing operation until after delivery. More severe disease characterized by progressive symptoms and inadequately controlled hypercalcemia should be treated surgically after control of hypercalcemia has been achieved with diuretic and/or other medical therapy. Maternal operative morbidity is low and risk to the fetus is slight once organogenesis has been completed. Maternal parathyroidectomy should be performed preferably after the first trimester and should not be deferred unless delivery is imminent.
Adult↗
Transsacral approach to repair of rectal prolapse in children.
Rectal prolapse is not uncommon in the pediatric age group. Occurring more frequently in boys than girls and most often during the period of toilet training, the condition is usually self-limited. Treatment typically consists of nonoperative measures. There are patients, however, in whom operative intervention becomes necessary. Operative procedures described are based largely on adult experience and the most common repairs involve the use of a foreign body (Ripstein procedure) or colonic resection. These procedures are of considerable magnitude and may be attended by significant morbidity. As a result, there is reluctance to apply these techniques in children. There exists, then, a place for an efficacious method of repair for large prolapses that incurs minimal morbidity. This report recounts our experience with the treatment of four children with rectal prolapse using a transsacral rectopexy. The results indicate minimal perioperative morbidity, discharge within a few days, with the mechanisms of fecal continence being preserved. The longest follow-up is 17 years with a mean follow-up of 9 years. The overall treatment of rectal prolapse in children is reviewed with specific emphasis upon the indications for and technique of the transsacral approach.
Child↗
Partial splenectomy and overwhelming infection in rats.
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Animals↗
Regeneration of splenic remnants after partial splenectomy in rats.
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Animals↗
Separation of two thyrotropin binding components from porcine thyroid tissue by affinity chromatography: characterization of high and low affinity sites.
Two distinct thyrotropin (TSH) binding species have been separated from solubilized porcine thyroid membranes. Membranes was solubilized with 1% Triton X-100, and the supernatant was recovered by centrifugation at 105,000 X g. Scatchard analysis of thyrotropin binding to solubilized membranes (SM) yielded a nonlinear plot with Kd values for the high and low affinity components similar to those of intact membranes. Chromatography of the SM preparation on concanavalin A-Sepharose 4B resulted in the retention of 10-20% of the binding activity. Upon elution of the column, a peak of binding material (5-7% of total activity) was eluted at 0.3 M alpha-methyl-D-mannoside. This concanavalin A (Con A) bound fraction exhibited a linear Scatchard plot with a Kd value similar to that of the high affinity component of the SM. The protein fraction that did not bind to Con A (Con A unbound) also exhibited a linear Scatchard plot, but with affinity similar to that of the low affinity component of SM. Discontinuous sucrose density gradient ultracentrifugation revealed the presence of two major binding peaks in the solubilized membrane preparation. The slowly sedimenting peak corresponded to that seen in the Con A bound fraction, whereas the rapidly sedimenting peak corresponded to that of the Con A unbound fraction. Sepharose 6B chromatography indicated that in the case of the Con A unbound fraction, a single peak of specific binding activity was eluted in the void volume, and in the case of the Con A bound fraction, one major peak with an approximate Stokes radius of 67 A and several other minor peaks were eluted. These results demonstrate the physical separation of two distinct TSH binding species from thyroid membranes and provide further support for the model of multiple classes of binding sites.
Animals↗
Cancer of the thyroid in youth.
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Adenocarcinoma↗
Dissociation kinetics of the thyrotropin-receptor complex. Characterization of a slowly dissociable component.
The kinetics of the dissociation of thyrotropin (TSH) from human thyroid plasma membranes were studied in an attempt to further understand the molecular dynamics of the TSH--receptor interaction. Dissociation of bound [125I]TSH from thyroid plasma membranes was a biphasic process consisting of rapidly and slowly dissociable components, RDC and SDC, respectively. The dilution induced dissociation of bound [125I]TSH was enhanced by the addition of excess TSH (DEC). DEC was proportional to the dose of unlabeled TSH and its magnitude increased linearly with temperature. These results are in contrast to those reported for the kinetics of [125I]insulin dissociation. The functional significance of DEC remains largely unexplained. It was found that the fraction of SDC was dependent upon time of association in a temperature-dependent and apparently saturable process. It could not be attributed to alterations in the electrophoretic, immunologic or binding properties of [125I]TSH. Furthermore, no correlation was observed between generation of SDC and change in the Scatchard profile of TSH binding, in contrast to studies on growth hormone. These data suggest that, like some other polypeptide hormones, binding of TSH to its receptor does not proceed according to laws describing simple, rapidly reversible, bimolecular reactions. Furthermore, bound TSH undergoes a receptor-mediated conversion from a rapidly to a slowly dissociable state with time of incubation.
Animals↗
Surgical intervention in chronic (Hashimoto's) thyroiditis.
The incidence of chronic (Hashimoto's) thyroiditis in surgical specimens is relatively high, i.e., 13% in collected studies, for a disease with clinical and laboratory characteristics that are sufficiently specific, that thyroidectomy should rarely be required for diagnosis or treatment. This incidence is presumably related to the difficulty in distinguishing between thyroiditis and a thyroid neoplasm. Experience with 260 thyroidectomies at the North Carolina Memorial Hospital performed between 1875 and 1980 for a dominant thyroid mass was reviewed to determine the reliability of criteria for diagnosis and the indications for surgical treatment. Using the criteria of clinical findings, complemented by laboratory studies, e.g., free thyroxine index, thyroid autoantibodies, TSH level, thyroid scan, in addition to the judicious use of the cutting (core) needle biopsy procedure, the incidence of Hashimoto's thyroiditis in this series was 3% and cancer-27%. Four patients had Hashimoto's thyroiditis coincidental to another disease for which thyroidectomy was performed. In seven patients Hashimoto's thyroiditis alone constituted the indications for operation. The indications for operation in these patients were: autonomous function with mild hyperthyroidism (2 patients); associated cold nodule (2 patients); thyromegaly unresponsive to suppressive therapy (2 patients); and rapidly enlarging mass simulating a neoplasm (1 patient). Only one of 71 patients with well differentiated carcinoma had Hashimoto's thyroiditis. One patient with Hashimoto's thyroiditis had associated lymphoma. In most patients, Hashimoto's thyroiditis can be identified using appropriate clinical and laboratory criteria without resorting to thyroidectomy to differentiate between thyroiditis and a neoplasm. Operations are indicated in patients with suspected or established chronic thyroiditis for: 1) the presence of a dominant mass with incomplete regression on suppressive therapy. 2) Progression of thyromegaly despite suppressive therapy. 3) Historic or physical findings suggest a malignancy, e.g., irradiation, multiple endocrine adenomatosis (MEA) syndrome, nerve paralysis, pain, tracheal compression, stipple calcification and cervical lymph node enlargement. 4) Indeterminant findings on cutting needle biopsy, e.g., lymphoma versus thyroiditis. Rarely, an operation is required for an oppressive goiter or associated hyperthyroidism.
Adult↗
Regulation of thyroid adenylate cyclase: guanyl nucleotide modulation of thyrotropin receptor-adenylate cyclase function.
The role of guanyl nucleotides in regulating the hormonal responsiveness of adenylate cyclase was studied in thyroid plasma membranes. Guanyl-5'-yl-imidodiphosphate [Gpp(NH)p] alone stimulated the enzyme. At a low ATP concentration (0.2 mM), TSH alone had little or no effect, but when added with Gpp(NH)p, it resulted in a dose-dependent increase of enzyme activity. Kinetic studies revealed that Gpp(NH)p alone stimulated adenylate cyclase activity only after a 10-min lag. TSH abolished the lag, resulting in an apparent increase in activity and a lowering of the activation constant for Gpp(NH)p. GTP caused an initial increase in activity at 2 min, followed by a gradual decline below basal levels. This inhibition was not prevented by TSH. Further examination revealed that GDP caused inhibition of Gpp(NH)p-stimulated activity in a competitive manner, suggesting that conversion of GTP to GDP may be responsible for the time-dependent decay seen with GTP. To study the effects of guanyl nucleotides on coupling of the TSH receptor to adenylate cyclase, plasma membranes were preactivated with saturating amounts of Gpp(NH)p and washed extensively to remove unbound Gpp(NH)p. Incubation of preactivated membranes with either Gpp(NH)p or TSH gave no further stimulation of adenylate cyclase. However, Gpp(NH)p plus TSH produced 30% more stimulation. In contrast, the addition of TSH plus GDP to preactivated membranes led to a dose-dependent decrease in activity. Furthermore, promotion of further stimulation by TSH plus Gpp(NH)p was competitively inhibited by GDP, in the same manner as untreated membranes. This suggested that the dual action of TSH, i.e, stimulation and inhibition, is governed and mediated by specific guanyl nucleotides. Analysis of guanyl nucleotides effects on the binding of [125I[iodo-TSH to membranes revealed that although some inhibition of binding exists, this effect is 1) unrelated to the concentration effect of nucleotides on adenylate cyclase, and 2) not specific for guanosine phosphates. Scatchard analysis of TSH binding in the presence of guanyl nucleotides demonstrated that even at high concentrations, GTP had no effect on the high affinity, low capacity receptor for TSH. These results suggest that GDP or Gpp(NH)p plays no role in modulating TSH-receptor interaction. Thus, guanyl nucleotide regulation of TSH action appears to be limited to adenylate cyclase.
Adenylyl Cyclases↗
Thyrotropin receptor-adenylate cyclase function in human thyroid neoplasms.
The action of thyrotropin (TSH) on plasma membranes was studied to elucidate the mechanism of hormonal regulation of malignant versus normal human thyroid tissue. Thyroid plasma membranes of six specimens of papillary or follicular carcinoma and six of adenoma, as well as adjacent normal tissue obtained from these patients, were evaluated with respect to binding of 125I-labeled TSH and stimulation of adenylate cyclase. Scatchard analysis of TSH binding revealed the presence of two species of binding sites in normal thyroid of different affinities and capacities. In 11 of 12 tumors studied, the high-affinity binding site remained intact; however, the total number of low-affinity sites was markedly lower than normal tissue. Other parameters of binding were not altered in neoplastic thyroid. In each of these tissues, the hormone responsiveness and kinetics of adenylate cyclase activation were essentially identical to those observed in normal tissue, although basal activity was typically greater in the neoplasm. One carcinoma was totally deficient in both 125I-labeled TSH binding and TSH-stimulatable adenylate cyclase, although basal activity was detected. Furthermore, adenylate cyclase of this specimen was not activated by prostaglandin, in contrast to normal thyroid and other thyroid tumors. These results suggest that: (a) clinical behavior of thyroid carcinomas may not be reflected by TSH receptor-adenylate cyclase function; (b) lack of clinical response as manifest by tumor regression cannot be ascribed to the absence of functional TSH receptors or adenylate cyclase; and (c) decreased low-affinity binding present in tumors is not correlated with altered hormone responsiveness of adenylate cyclase but may reflect more general cancer-induced changes in membrane structure or composition.
Adenoma↗
Apparent "negative cooperativity" kinetics in the absence of a nonlinear Scatchard plot of thyrotropin-receptor interaction in a human thyroid adenoma.
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Adenoma↗
Thyrotropin receptors in normal human thyroid. Nonclassical binding kinetics not explained by the negative cooperativity model.
Saturation analysis of equilibrium binding of iodinated thyrotropin (125I-TSH) to normal human thyroid preparations yielded linear Scatchard plots under non-physiological conditions of pH 6.0 or 20 mM Tris/acetate buffer, pH 7.4. The apparent equilibrium dissociation constant of this binding was approximately 10(-8) M. By contrast, nonlinear plots were obtained under standard conditions of pH 7.4 and 40 mM Tris/acetate buffer. Resolution of the components of these curves by computer analysis revealed the presence of at least two classes of binding sites, one of which is of a low capacity and high affinity (approximately 10(-10) M) consistent with receptor binding. The other component is of a high capacity and lower affinity. Binding to non-target tissues of muscle, parathyroid, mammary carcinoma, and placenta was only demonstrable at pH 6.0 or in 20 mM Tris/acetate buffer, pH 7.4, yielding linear Scatchard plots with similar binding affinity (approximately 10(-8)M) to normal thyroid but much reduced capacity. Preincubation of thyroid tissue at 50 degrees C resulted in an apparent selective loss of the high affinity component of binding measured under standard conditions. Kinetic experiments on the dissociation of bound 125I-TSH were undertaken to determine whether the non-linearity of Scatchard plots was due to two or more classes of binding sites or negative cooperativity. It was found that the experimental determinant that is presently ascribed to a negative cooperativity phenomenon regulating receptor affinity (i.e. an enhanced dilution-induced dissociation rate in the presence of excess native hormone), although apparently hormone-specific, was demonstrated under nonphysiological binding conditions and in non-target tissue. Significantly, the phenomenon was found under conditions of pH 6.0 or 20 mM Tris where a linear Scatchard plot was obtained. The evidence thus suggests that 125I-TSH binds to heterogeneous binding sites (of which the high affinity is probably the receptor for TSH) and that the enhanced dilution-induced dissociation of bound hormone by native hormone for this system, is only a characteristic of the low affinity binding site (maybe gangliosides).
Breast Neoplasms↗