Thyroid-stimulating hormone a and (3 subunit genes are negatively regulated by thyroid hormone at the transcriptional level. Transient gene expression studies were used to demonstrate that the erbAfi form of the thyroid hormone receptor mediates negative regulation of the asubunit promoter in a hormone-dependent manner. In JEG-3 choriocarcinoma cells, which are deficient in thyroid hormone receptors, coexpression of erbAj3 with aCAT reporter genes markedly suppressed aCAT expression after treatment with thyroid hormone, whereas a reporter gene containing a known positive thyroid response element was induced. Thus, a single form of thyroid hormone receptor mediates both positive and negative responses to thyroid hormone in this system. Transient expression analyses of a gene 5' flanking sequence deletion mutants localized the negative thyroid response element to the proximal region of the promoter between -100 and +4 base pairs. The location of the negative thyroid response element in the a gene is therefore distinct from that of previously identified regulatory elements including the tissuespecific upstream regulatory elements, the cAMP response elements, and the glucocorticoid response elements. Overlapping segments of the a promoter were examined for potential thyroid hormone receptor binding sites by using gel shift assays and biotinylated DNA-binding studies. A specific thyroid hormone receptor binding site was identified between -22 and -7 base pairs, which is immediately downstream from the TATA box. This region of the a promoter interacts with erbAj3 receptor synthesized in vitro as well as with endogenous nuclear thyroid hormone receptors, and it competes for receptor binding to a known positive thyroid response element. These studies suggest a mechanism for negative regulation in which the thyroid hormone receptor interacts with the a gene promoter immediately downstream of the TATA box to inhibit transcription.Thyroid hormones exert a myriad of physiological effects, including modulation of growth and development, as well as regulation of a variety of pathways of intermediary metabolism (1). The DNA sequences that mediate transcriptional activation or repression in response to T3 are referred to as thyroid response elements (TREs). The TRE sequences bind T3 receptors with high affinity (4, 5) and have been studied extensively by using the rat growth hormone (rGH) promoter as a model of positive regulation (1). Negative regulation by T3 has also been demonstrated for a number of genes (6, 7), but the DNA response elements that confer negative regulation have not been fully defined.Thyroid-stimulating hormone (TSH) is a pituitary glycoprotein hormone that stimulates the thyroid gland to synthesize and secrete T3. TSH is a heterodimer composed of a and ,p subunits that are encoded by separate genes. In classic feedback fashion, T3 suppresses TSH secretion (8) and gene transcription (9). The kinetics of T3 action correlate with receptor occupancy and do not require new protein synthesis, suggesting...

Introduction Improvement in glycemic control is likely to reduce the risk of diabetic complication, while its effect on erectile dysfunction (ED) remains unclear. Aim The aim of this study was to evaluate the association of glycemic control with risk of ED in type 2 diabetics. Methods A self-administered questionnaire containing Sexual Health Inventory for Men was obtained from 792 subjects with type 2 diabetes at our institution. Clinical data were obtained through chart review. Main Outcome Measures The contribution of glycemic control assessed by glycated hemoglobin (HbA1c) level as well as age, duration of diabetes, hypertension (HT), dyslipidemia, and cigarette smoking to risk of ED was evaluated. Results Of 792 subjects, 83.6% reported having ED and 43.2% had severe ED. HbA1c level (%) adjusted for age and duration of diabetes was significantly associated with ED (OR 1.12, 95% CI: 1.01–1.25). None of HT, dyslipidemia, and cigarette smoking was a significant risk factor for ED after adjusted for age and duration of diabetes. HbA1c level, age, and duration of diabetes were significant independent risk factors for ED among the younger group (age ≤ 60 years), and only age and duration of diabetes were independent risk factors among the older group (age > 60 years). For the risk of severe ED, compared with no and mild to moderate ED, HbA1c level, duration of diabetes, and HT were independent risk factors among the younger group, and only age was an independent factor among the older group. Conclusions Better glycemic control probably would reduce the prevalence of ED and its severity among the younger men with type 2 diabetes. For the older group, aging was the major determinant for ED risk among this population with type 2 diabetes.

Current models for tumorigenesis propose that a series of genetic alterations occur during the progression from the normal cell to the malignant phenotype. Mutations in each of the three ras genes (K-ras, H-ras, and N-ras) have been identified in many human neoplasms, including thyroid cancer. In this study we examined genomic DNA from benign and malignant thyroid neoplasms for mutations that are known to activate the ras oncogenes (codons 12, 13, and 61). DNA from frozen surgically excised tissue (n = 8) and from formalin-fixed paraffin-embedded tissue (n = 30) was amplified by the polymerase chain reaction and screened for mutations using oligonucleotide-specific hybridization. No mutations were identified in follicular adenomas (n = 9). In follicular carcinomas, 2 of 14 tumors contained mutations (N-ras 61, Gln to Arg), and both of these patients had bone metastases. One of 15 papillary carcinomas had a ras mutation (H-ras 12, Gly to Ser). In contrast to other studies, we found that ras mutations are relatively uncommon in both benign and malignant thyroid neoplasms. Studies of larger numbers of tumors and comparisons of different patient populations will be required to assess a possible association of mutations in N-ras 61 with clinically aggressive follicular cancer.