Predictive value of codon 215 reverse transcriptase mutation on the efficacy of didanosine in HIV-infected, zidovudine-experienced patients.

We investigated whether or not mutations at codon 215 in the HIV reverse-transcriptase-encoding gene predicted a lower efficacy of didanosine therapy, as defined by survival of patients and change in CD4 cell counts in 121 HIV-infected, zidovudine-experienced patients. A trend for shorter survival, although not reaching significance, was observed for patients with HIV strains with the reverse transcriptase codon 215 mutation (P = 0.07), but this trend disappeared after adjustment for initial CD4 cell counts. During the first 3 months on didanosine therapy, the increase in CD4 cell counts was greater in patients who were wild type at codon 215 than in those with the mutation at codon 215 (P = 0.03). These data suggest that there was a better initial CD4 response to didanosine therapy in patients with HIV without the mutation at codon 215, but that this response did not translate into increased survival.

Severe but not mild alterations of thyroid function modulate the density of thyroid-stimulating hormone receptors in the rat thyroid gland.

TSH initiates its action by binding to specific membrane receptors' thyroid cells and induces activation of the adenylate cyclase-cAMP cascade. The factors involved in the regulation of TSH receptors are poorly known, except for the TSH dose-dependent regulatory effect. The fact that the thyroid gland of Graves' patients has a normal density of TSH receptors with suppressed TSH and high T4 and T3 levels suggests a modulatory role of thyroid hormones on TSH receptors. To evaluate this hypothesis, the density of TSH receptors and the activity of adenylate cyclase were determined in the thyroid membranes from hyperthyroid and hypothyroid adult male rats; they were rendered hyperthyroid either with bovine TSH, TRH, or T3 for 7 days and hypothyroid by propylthiouracil treatment or by hypophysectomy. NaCl was given to the control group. Plasma T4, T3, and TSH were also quantified. Bovine TSH and TRH treatments induced mild hyperthyroidism with a small goiter and a 50% reduction in the density of TSH receptors due to hyperstimulation of the gland by either exogenous or endogenous high TSH levels. Severe hyperthyroidism caused by T3 treatment resulted in low T4, high T3, and suppressed TSH thyrocyte stimulation; it was associated with a significant increase in the number of TSH receptors (29.6 +/- 2.3 vs. control 17.9 +/- 1.7 mU TSH/mg protein). These last results suggest a putative positive effect of T3 on TSH receptors. To confirm this effect, hypothyroid rats were investigated. Severe primary hypothyroidism due to propylthiouracil treatment was associated with a large goiter, high plasma TSH levels (11.8 +/- 1.2 vs. control 1.5 +/- 0.1 mU TSH/ml), low plasma T4 and T3, and a 70% reduction in TSH receptors, confirming the down-regulatory effect of high TSH on the thyroid cell. However, in hypophysectomized rats, a 45% reduction in the density of TSH receptors was also observed in the absence of TSH. Injections of either TSH or T3 to these hypophysectomized rats restored a normal number of TSH-binding sites, and simultaneous TSH and T3 treatments resulted in a mildly additive effect in the number of TSH receptors, which was slightly greater than that of the controls. No important changes were found in the adenylate cyclase activity in the thyroid membrane preparations from hyperthyroid and hypothyroid rats despite variations in the density of TSH receptors.(ABSTRACT TRUNCATED AT 400 WORDS)

Simultaneous assay for three types of thyrotropin receptor antibody activities using FRTL-5 cells in patients with autoimmune thyroid diseases.

The relationships between the different circulating thyrotropin receptor antibodies (TSH-R-abs) in autoimmune thyroid disease (AITD) are complex. In order to investigate them, we have developed an assay for the simultaneous measurement of three types of TSH-R-abs: TSH-binding inhibiting immunoglobulin (TBII): thyroid-stimulating antibody (TS-ab) and TSH-stimulation blocking antibody (TSB-ab). A large number of patients with Graves' disease (GD)--untreated and treated--Hashimoto's thyroiditis (HT), primary myxedema (PM) and non-immune goiter (NIG) were investigated. In untreated Graves' patients the frequency of positive TS-ab and TBII sera was found to be 90 and 69%, respectively, the presence of TS-ab and/or TBII being detected in 98%. After long-term antithyroid treatment administered to GD patients, the frequency of positivity of both TBII and TS-ab was decreased, whether hyperthyroidism was cured or not. The TSB-ab was detected in the serum of 8% of patients with GD, and the frequency of TSB-ab did not increase following treatment and alteration in thyroid function. No significant correlation was found between TSB-ab and thyroid function in Graves' patients. Besides, we found that all the GD patients presenting positive TSB-ab were also TBII positive. A follow-up study of the three TSH-R-abs was performed in 35 patients with GD during a mean of 14.3 +/- 8.5 months (4-34 months) of antithyroid drug treatment. Ten out of 24 patients (42%) with positive TBII and 16 out of 32 (50%) with positive TS-ab turned from positive to negative during the time of follow-up. Regarding relapse in hyperthyroid GD, we found that TS-ab was positive in 80% and TBII was positive in 40% of the patients with Graves' relapse, indicating that the presence of TS-ab is a better index for relapse prediction in Graves' hyperthyroidism than TBII. The TSB-ab was found with higher frequency in HT and PM than in GD, i.e. 21%, 18% and 8%, respectively., The TSB-ab positivity was correlated significantly with TBII in our patients with AITD when TSB-ab was positive. This new simultaneous assay of the three TSH-R-abs should be very helpful for further investigation of the autoimmune aspects of AITD and it should help us to progress in a better understanding of the pathogeny of the different AITDs.

Thyrotropin action is impaired in the thyroid gland of old rats.

Aging in rats is characterized by low plasma concentrations of thyroid hormones with unchanged levels of TSH, suggesting an altered TSH action in addition to the impaired regulation of TSH secretion. To evaluate TSH action we determined TSH binding to thyroid membranes of young and old male rats (3-4 and 24-26 months of age), as well as the activity of adenylate cyclase in basal and stimulated conditions. Saturation analyses of [125I]-bTSH to thyroid membranes in the presence of increasing quantities of unlabelled bTSH (0.03-100 mU) show two types of binding sites, one of high affinity (Ka 1.5 10(9) mol l-1) the other of lower affinity (Ka 1.2 10(8) mol l-1), which are similar in both age groups. The number of TSH binding sites of high affinity is less in old rats than in young rats (7.6 +/- 0.9 vs 14.8 +/- 1.1 TSH mU/mg protein, N = 11 and 10 respectively, p less than 0.001), whereas the number of binding sites of low affinity is not significantly different (76.0 +/- 8.2 vs 99.1 +/- 9.0 TSH mU/mg protein). The activity of adenylate cyclase determined in basal conditions is similar in both old and young rats (1.11 +/- 0.12 vs 1.04 +/- 0.9 nmol cAMP/2 h x mg/protein). TSH (10 mU) induced a significant increase in cAMP formation with the thyroid membranes from young rats but not with those from old rats. In contrast, the stimulation of cAMP formation by GTP (2 mmol/l) or forskolin (10 mmol/l), two direct stimulators of adenylate cyclase, is similar in both groups of rats (200% and 250%, respectively).(ABSTRACT TRUNCATED AT 250 WORDS)