Regulatory effects of transforming growth factor-beta on IL-2- and IL-4-dependent T cell-cycle progression.

Previous studies suggested that the potent immunosuppressive activities of transforming growth factor-beta (TGF-beta) were mediated in part through the inhibition of IL-2-dependent S-phase progression and mitosis of activated T cells. To further investigate the mechanism of T cell growth inhibition by TGF-beta, two constitutively activated murine T cell clones were employed as defined model systems for the growth factor-dependent phase of T cell proliferation. The Th cell line, HT-2, proliferated in response to either IL-2 or IL-4, whereas the cytotoxic T cell line, CT6, exhibited strict dependence on IL-2 for growth stimulation. In both cell lines, picomolar concentrations of TGF-beta inhibited S-phase progression stimulated by IL-2 or IL-4. TGF-beta pretreatment decreased the expression of high affinity IL-2R on HT-2 cells, but not on CT6 cells. In contrast, IL-2-stimulated transferrin receptor expression was markedly inhibited by TGF-beta in both T cell lines. Analyses of growth factor-dependent specific mRNA accumulation revealed that TGF-beta exerted selective inhibitory effects on gene expression in HT-2 and CT6 cells. TGF-beta significantly reduced early (1 to 2 h) increases in c-myc mRNA levels stimulated by IL-2 or IL-4 in both cell lines. In HT-2 cells, TGF-beta pretreatment also inhibited the early increase in granulocyte-macrophage CSF mRNA stimulated by IL-2 or IL-4. The inhibition of c-myc and granulocyte-macrophage cyte-macrophage CSF gene expression by TGF-beta was explained, at least in part, by suppression of the growth factor-dependent transcriptional activation of these genes. These studies suggest that inhibition of c-myc gene transcription may play a fundamental role in the antiproliferative effect of TGF-beta on IL-2- or IL-4-stimulated T cells.

Differences between prebreakfast and late afternoon glycemic responses to exercise in IDDM patients.

Little information is available regarding the optimal timing of exercise in insulin-dependent diabetes mellitus (IDDM) patients. In this study, six IDDM patients receiving ultralente-based intensive insulin therapy were studied during 30 min of exercise (approximately 60% VO2max), before breakfast, and at 1600. On two other occasions, they were studied at rest. Plasma glucose increased from 6.7 +/- 0.4 to 9.1 +/- 0.4 mM during morning exercise (P less than 0.01). In contrast, mean plasma glucose did not change during afternoon exercise (delta = 0.3 +/- 0.5 mM, NS); however, there was a 0.3- to 1.0-mM decrease in three subjects. The observed difference in the glycemic response to exercise could not be explained on the basis of changes in plasma glucagon, growth hormone, norepinephrine, or epinephrine. Plasma cortisol was higher (P less than 0.02) in the morning than in the afternoon, and plasma free-insulin concentrations were lower (P less than 0.05). These data indicate that the risk of exercise-induced hypoglycemia is lowest before breakfast. The reason for the divergent glycemic responses to exercise is not entirely clear but may be related to the observed differences in free-insulin concentrations. Because of the lower risk of hypoglycemia, our results suggest prebreakfast exercise may be preferable for some IDDM patients receiving intensive insulin therapy. Whether these findings are relevant to patients receiving other types of insulin therapy will require further investigation.

Distant metastases in differentiated thyroid carcinoma: a multivariate analysis of prognostic variables.

From a cohort of 988 patients with differentiated thyroid carcinoma receiving primary surgical treatment between 1946 and 1970, we studied the 85 (9%) patients who had distant metastases diagnosed during life. Clinically detected metastases were found in 7% of the 859 patients with papillary cancers, 19% of the 100 patients with follicular cancers, and 34% of the 29 patients with Hürthle cell cancers. The total experience amounted to 607 patient-years of observation after the diagnosis of metastases, with a median follow-up in the 12 survivors of 23 yr (range, 13-32 yr). At the time of first diagnosis of metastases, the lungs only were involved in 53%, and bones only in 20%; 16% had multiple organ involvement. The overall mortality rates 5 and 10 yr after the diagnosis of metastases were 65% and 75%, respectively. Seventy-eight percent of all deaths were directly attributable to thyroid cancer; 82% of cancer deaths occurred within 5 yr. By univariate analysis, patient age, tumor extent, pattern of lung involvement, radioiodine uptake of the metastases, and radioiodine treatment were significant prognostic factors. By multivariate analysis, only age (as a continuous variable) at the time of first diagnosis of distant metastases (P less than 0.0001) and involvement of multiple organ sites (P = 0.0003) were independently associated with cancer mortality. The survival at 5 yr in 12 patients aged less than 40 yr with only a single organ involved was 92%. Older patients (aged greater than or equal to 40 yr) with a single metastasis (n = 59) had a lower survival (38% at 5 yr). The highest risk of cancer death (92% at 5 yr) was found in the 14 patients (any age) who at the time of first diagnosis of metastases had multiple organ involvement. The Cox regression model suggested that radioiodine therapy did not have a significant influence on survival, after adjusting for age and extent of metastatic involvement.