Thyroid-stimulating activity in sera of normal pregnant women

To evaluate the effect of a thyroid stimulator on thyroid function in the sera of normal pregnant women, we measured thyroid-stimulating activity (TSA) using a highly sensitive bioassay based on cAMP accumulation in cultured rat FRTL-5 thyroid cells. Serum was pretreated with 10% polyethylene glycol (PEG), and the supernatant (PEG-pretreated serum) was then used in the following studies. FRTL-5 cells were preincubated in 5H medium and incubated for 2 h with PEG pretreated serum, and cAMP was measured. All 11 patients with untreated hyperthyroid Graves' disease with strongly positive thyroid-stimulating antibody activity had normal TSA, because only 5.6% of their immunoglobulin G was recovered in the PEG-pretreated serum. In 32 normal pregnant women, 29 (91%) had positive TSA. Their TSA showed statistically significant positive correlations with serum hCG and free T4 levels, and a negative correlation with serum TSH levels. Moreover, when hCG was absorbed from sera by incubation with the solid phase anti-HCG monoclonal antibody, a significant positive correlation was observed between the rate of decrease in hCG and that in TSA. In conclusion, 1) TSA exists in the sera of normal pregnant women, which reflects hCG itself; and 2) thyroid glands of normal pregnant women may be stimulated by TSA to induce a slight suppression of TSH but not sufficient to induce overt hyperthyroidism.     

21-hydroxylase deficiency associated with adrenal tumor: case report of two brothers

Described herein are two brothers with 21-hydroxylase deficiency (21-OHD) associated with adrenal tumors, and these possible mechanisms are discussed. A 34-year-old male was admitted on Jan. 9, 1984 because of an enlarged and tender left breast. Physical examination revealed short stature (152 cm, 76.5 kg), gynecomastia and shortening of metacarpal bone. His testes were small (2.6 X 1.6 X 1.9 cm). Urinary excretion of 17-OHCS was within normal range (5.9 mg/day), but those of 17-KS, 17-KGS and pregnanetriol were markedly increased (44.4, 110 and 22.6 mg/day, respectively). Plasma concentrations of progesterone and ACTH and urinary excretions of estrone, estradiol and estriol were also increased. Urinary excretions of 17-KS were decreased to 11.7 mg/day and 17-KGS to 22.3 mg/day after the ingestion of 2 mg/day dexamethasone for two days. The computed tomography and a scintigraphy with 131I-Adosterol revealed a tumor in the left adrenal gland, and the adrenal arteriography revealed a neovascularity and a tumor stain in the tumor. These data indicated that the patient was suffering from both 21-OHD and the left adrenal tumor. At this point, adenoma or adenocarcinoma of the adrenal gland was suspected. The left adrenal tumor (85 g) was resected on April 10, 1984, and the pathological diagnosis was adrenal adenoma. The patient's endocrinological abnormalities, however, did not improve after the operation. Urinary excretions of 17-KS and KGS were increased to 57.9 and 108.5 mg/day, respectively, in the patient's elder brother, and 63.3 and 127.9 mg/day, respectively, in his younger brother, indicating that they also had 21-OHD. Interestingly, an adrenal tumor was diagnosed by abdominal computed tomography in the elder brother who had the same HLA typing as the present case. The three brothers had 21-OHD, and two of them had both 21-OHD and adrenal tumor. To our knowledge, this is the first report documenting the co-existence of adrenal tumors in brothers with 21-OHD. This suggests that adenoma can be one of the complications of 21-OHD, probably due to the chronic stimulation by ACTH, and that a possible linkage to HLA may exist in such cases.     

Triiodothyronine generation from thyroxine in human thyroid: enhanced conversion in Graves' thyroid tissue

Conversion of T4 to T3 was studied in normal, Graves', and neoplastic thyroid tissues obtained at surgery. Homogenates of human thyroid follicular adenoma and carcinomas were incubated with [125I]T4 and dithiothreitol (DTT) at 37 C for 60 min under N2 gas. T3 formation was assessed by measuring [125I]T3 formed, using paper chromatography. In the second series of experiments, the suspensions of the 100,000 X g pellet of normal thyroid tissues adjacent to the tumor and Graves' thyroid tissues were incubated with unlabeled T4 and DTT at 37 C for 60 min under N2 gas. T3 generated was measured by RIA. T3 generation in the thyroid tissue was dependent on incubation time, amount of the tissue used, concentration of DTT, temperature, and pH. Propylthioracil inhibited T3 formation, while methimazole had no effect. A kinetic study with the homogenate of a thyroid adenoma and 100,000 X g pellet suspensions of two normal and three Graves' thyroids gave apparent Km values of 2.7, 4.9, and 4.1 microM for T4, respectively, and Vmax values of 0.8, 3.0, and 10.9 pmol T3/mg protein.min, respectively. Conversion of T4 to T3 was observed in two of three tumor tissues studied and was markedly enhanced in Graves' thyroid tissues (mean +/- SE, 11.9 +/- 2.0 pmol/mg protein.min) compared to that of normal thyroid tissues (3.2 +/- 0.6 pmol/mg protein.min; P less than 0.01). It is concluded that T4 is enzymatically converted to T3 in normal and Graves' thyroids and differentiated thyroid neoplasms. Moreover, enhanced conversion of T4 to T3 was found in Graves' thyroid tissue.     

Segmental pulmonary vein antrum isolation using the "large-size" lasso catheter in patients with atrial fibrillation.

BACKGROUND: The limited efficacy and complications of segmental ostial pulmonary vein isolation (PVI) for treating atrial fibrillation (AF) have been discussed so, in the present study the feasibility and efficiency of performing segmental pulmonary vein (PV) antrum isolation to treat AF were assessed. METHODS AND RESULTS: A total of 187 patients with drug-refractory AF (paroxysmal 120, persistent 67) underwent segmental PVI guided by circumferential 20-electrode catheters (Lasso). Radiofrequency (RF) current was delivered either at the ostium using a regular Lasso (15-20 mm in diameter, 70 patients: Group 1) or at the antrum using a larger Lasso (25-30 mm in diameter, 117 patients: Group 2). A significantly wider region had to be ablated, with a longer RF application time, to isolate all 4 PVs in Group 2 patients than in Group 1 patients. Although the rate of recurrence of AF after the initial session was equal in both groups, a significantly greater number of patients were free from AF after a mean of 1.4 procedures in Group 2 than in Group 1 (93% vs 76% for paroxysmal AF, 78% vs 48% for persistent AF). CONCLUSIONS: Segmental antral PVI using large-sized Lasso catheters was found to be more effective and safer than ostial PVI for the treatment of AF.     

Clinical implication of multiple risk factor control in the management of diabetic macrovasucular complications

Using cross-sectional and prospective analyses, the risk factors for macroangiopathy (MA) in nonobese Type 2 diabetic patients were evaluated. In the cross-sectional study, we determined a cutoff point for each variable at which changes in the prevalence of total MA reached statistically significant levels. In the prospective study, those who met more than four out of seven control criteria as set forth in the Multiclinical Study for Diabetic Macroangiopathy (MSDM) had less risk of MA in Type 2 diabetes initially diagnosed without MA compared with those who fulfilled less than three factors. These results suggest that multiple risk factor control is the most effective and reasonable way to lower the incidence of MA in Type 2 diabetes.     

Pharmacologic properties of candesartan cilexetil--possible mechanisms of long-acting antihypertensive action

Candesartan cilexetil has shown potent and long-lasting antihypertensive effects in clinical trials and in several animal models of hypertension. In spontaneously hypertensive rats, the duration of the antihypertensive effect of candesartan cilexetil was compared to those of losartan, valsartan, eprosartan, and irbesartan at the same degree of maximal blood pressure reduction. A single oral dose of candesartan cilexetil at 0.3 mg/kg reduced maximal blood pressure by about 25 mm Hg, and the antihypertensive effect of candesartan cilexetil lasted the longest, continuing for more than 1 week, without an effect on circadian rhythm. In a rabbit aortic preparation, candesartan, active form of candesartan cilexetil, decreased the maximal contractile response of angiotensin II. This inhibitory mode was different from that of other angiotensin II-receptor antagonists, and showed a shift to the right in the angiotensin II-induced contraction curve and/or a small depression of the maximal response. In kinetic studies using bovine adrenal cortical membrane and tritiated candesartan, both receptor association and dissociation were found to be slow. The dissociation rate of tritiated candesartan binding (t1/2 = 66 min) was five times slower than that of radiolabelled angiotensin II binding (t1/2 = 12 min). The insurmountable inhibition of candesartan in vascular contraction is the result of its tight binding and slow dissociation from angiotensin II AT1 receptors. These characteristics are related to the potency and long duration of action in candesartan cilexetil.     

Mechanism of thyroid stimulation by human chorionic gonadotropin in sera of normal pregnant women.

To elucidate the mechanism of thyrotropic activity of human chorionic gonadotropin in sera of normal pregnant women, we examined the effect of blockade of the TSH receptor on the serum-induced cAMP accumulation and the effect of hCG on the TSH binding to FRTL-5 cells. In the presence of crude immunoglobulin fractions in sera from patients with primary hypothyroidism, cAMP accumulation induced by both crude and purified hCG, and normal pregnant women serum were significantly inhibited compared with that in the presence of normal IgGs. The mode of inhibition of these IgGs on the cAMP accumulation was similar for TSH and hCG when analysed by Lineweaver-Burk plots. Moreover, binding of [125I]bTSH to the TSH receptor in porcine thyroid cell membrane was apparently inhibited by adding 4 x 10(6) IU/l of purified hCG. Binding studies of TSH in FRTL-5 cells also indicated the dose-dependent displacements of [125I]TSH by hCG. Although half-maximal inhibitory concentration of hCG was about 20 times as high as that of TSH on a molar basis, displacement of [125I]TSH was observed at a concentration of hCG of 10(5)IU/l or more, which could be a physiological concentration of hCG in sera of normal pregnant women. These results suggest that thyrotropic activity of hCG in sera of normal pregnant women is, at least in a part, mediated by TSH receptors.