Transducin ß-like 1, X-linked and nuclear receptor co-repressor cooperatively augment the ligand-independent stimulation of TRH and TSHß gene promoters by thyroid hormone receptors.

Mutations in TBL1X, a component of the nuclear receptor co-repressor (N-CoR) and silencing mediator of retinoic acid and thyroid hormone receptor co-repressor complexes, have recently been implicated in isolated central hypothyroidism (CeH). However, the mechanisms by which TBL1X mutations affect negative feedback regulation in the hypothalamus-pituitary-thyroid axis remain unclear. N-CoR was previously reported to paradoxically enhance the ligand-independent stimulation of TRH and TSHß gene promoters by thyroid hormone receptors (TR) in cell culture systems. We herein investigated whether TBL1X affects the unliganded TR-mediated stimulation of the promoter activities of genes negatively regulated by T3 in cooperation with N-CoR. In a hypothalamic neuronal cell line, the unliganded TR-mediated stimulation of the TRH gene promoter was significantly enhanced by co-transfected TBL1X, and the co-transfection of TBL1X with N-CoR further enhanced promoter activity. In contrast, the knockdown of endogenous Tbl1x using short interfering RNA significantly attenuated the N-CoR-mediated enhancement of promoter activity in the presence of unliganded TR. The co-transfection of N365Y or Y458C, TBL1X mutants identified in CeH patients, showed impaired co-activation with N-CoR for the ligand-independent stimulation of the TRH promoter by TR. In the absence of T3, similar or impaired enhancement of the TSHß gene promoter by the wild type or TBL1X mutants, respectively, was observed in the presence of co-transfected TR and N-CoR in CV-1 cells. These results suggest that TBL1X is needed for the full activation of TRH and TSHß gene promoters by unliganded TR. Mutations in TBL1X may cause CeH due to the impaired up-regulation of TRH and/or TSHß gene transcription despite low T3 levels.

Diagnostic value of 18F-fluorodeoxyglucose uptake parameters to differentiate rheumatoid arthritis from other types of arthritis.

We aimed evaluate F-fluorodeoxyglucose uptake at major joints for differentiating patients with rheumatoid arthritis (RA) from those with non-RA arthritis using F-fluorodeoxyglucose (FDG)-positron emission tomography (PET).Eighteen patients with RA (13 women; age, 66.8 ±â€Š13.2 years) and 17 patients with non-RA (6 women; age, 50.8 ±â€Š12.5 years) were included. Twelve joints of each patient were examined: shoulder, elbow, wrist, hip, knee, and ankle on both sides. A visual scoring (VS) system was used; quantitative parameters such as maximum standardized uptake value (SUVmax), metabolic active volume (MAV), and total lesion glycolysis (TLG) were evaluated. Total score and value of each parameter were compared between the RA and non-RA groups.Total VS score (mean, 37.7 ±â€Š9.0 vs 21.9 ±â€Š7.2; P < .0001) and SUVmax (mean, 28.1 ±â€Š8.5 vs 17.9 ±â€Š5.8; P < .001) were significantly higher in the RA group than in the non-RA group. A significant between-group difference was also observed with respect to total MAV (608.3 ±â€Š370.7 vs 176.5 ±â€Š217.8; P < .001) and total TLG (1139.3 ±â€Š759.1 vs 289.5 ±â€Š395.4; P < .001). Receiver operating characteristic curve analysis revealed that total VS had the highest area under curve (.92), with sensitivity and specificity of 88.9% and 76.4%, respectively.Quantitative PET parameters could differentiate RA from non-RA. Total VS score, however, appears to be the best convenient qualitative tool for diagnosing RA.

Whole-Exome Sequencing Study of Thyrotropin-Secreting Pituitary Adenomas.

Context: Thyrotropin (TSH)-secreting pituitary adenomas (TSHomas) are a rare cause of hyperthyroidism, and the genetic aberrations responsible remain unknown. Objective: To identify somatic genetic abnormalities in TSHomas. Design and Setting: A single-nucleotide polymorphism (SNP) array analysis was performed on 8 TSHomas. Four tumors with no allelic losses or limited loss of heterozygosity were selected, and whole-exome sequencing was performed, including their corresponding blood samples. Somatic variants were confirmed by Sanger sequencing. A set of 8 tumors was also assessed to validate candidate genes. Patients: Twelve patients with sporadic TSHomas were examined. Results: The overall performance of whole-exome sequencing was good, with an average coverage of each base in the targeted region of 97.6%. Six DNA variants were confirmed as candidate driver mutations, with an average of 1.5 somatic mutations per tumor. No mutations were recurrent. Two of these mutations were found in genes with an established role in malignant tumorigenesis (SMOX and SYTL3), and 4 had unknown roles (ZSCAN23, ASTN2, R3HDM2, and CWH43). Similarly, an SNP array analysis revealed frequent chromosomal regions of copy number gains, including recurrent gains at loci harboring 4 of these 6 genes. Conclusions: Several candidate somatic mutations and changes in copy numbers for TSHomas were identified. The results showed no recurrence of mutations in the tumors studied but a low number of mutations, thereby highlighting their benign nature. Further studies on a larger cohort of TSHomas, along with the use of epigenetic and transcriptomic approaches, may reveal the underlying genetic lesions.

Changes in visceral and subcutaneous fat mass in patients with pheochromocytoma.

CONTEXT: Overproduction of catecholamine induces not only hypertension but also glucose intolerance and hyperlipidemia. However, little is known about its effect on visceral and subcutaneous fat. OBJECTIVE: Our objective was to investigate changes of metabolic factors including visceral and subcutaneous fat areas in patients with pheochromocytoma (Pheo). DESIGN AND PATIENTS: This was a cross-sectional and longitudinal follow-up study of cases collected from Gunma University Hospital between 2002 and 2013. Forty-two patients with Pheo and 23 with non-functioning adrenal adenoma (NFA) were analyzed before and after adrenalectomy. RESULTS: Multivariate logistic-regression analysis adjusted by age and gender revealed that glucose intolerance was more common in patients with Pheo than in patients with NFA (21/42, 51% vs. 4/23, 17%, p<0.05). Abdominal visceral fat area (VFA) and subcutaneous fat area (SFA) were significantly lower in patients with Pheo than in those with NFA (80.2±38.7 vs. 124.3±61.8cm(2), p<0.05; 114.6±58.9 vs. 164.3±40.3cm(2), p<0.05, respectively). Significant correlations were observed between fractionated urine noradrenaline level and serum HDL-cholesterol level (r = 0.36, p<0.05), urine normetanephrine level and tumor size (r=0.57, p<0.01), and urine adrenaline level and systolic blood pressure (r=0.35, p<0.05) in Pheo. However, there were no significant correlations between adrenaline and noradrenaline levels and other parameters, including serum LDL-cholesterol and triglyceride levels, and HbA1c. Furthermore, both VFA and SFA, body weight, and BMI were significantly increased, and serum HbA1c as well as HDL-cholesterol levels were decreased after adrenalectomy in Pheo. CONCLUSION: These findings suggest for the first time that catecholamines might regulate the serum HDL-cholesterol level and both abdominal visceral and subcutaneous fat mass in men.