Ultrasound findings of noninvasive follicular thyroid neoplasm with papillary-like nuclear features compared with those of follicular variant of papillary carcinoma and encapsulated papillary carcinoma: a single-institution study in Japan.

Noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP) is a new entity adopted by the newest World Health Organization classification. It is differentiated from follicular variant papillary thyroid carcinoma (FVPTC) and regarded as non-malignant disease. Here, we compared the ultrasound findings of NIFTP (n = 40) with those of FVPTC (n = 94) and encapsulated PTC (encap-PTC) (n = 157). The NIFTP group showed benign findings on ultrasound significantly more frequently than the FVPTC group based on the Japan Society of Ultrasonics in Medicine criteria: a regular shape (p < 0.001), well edge definition (p = 0.007), smooth character (p < 0.001), isoechoic and homogeneous internal echoes (p < 0.001), lack of punctate microcalcification (p = 0.027), and a regular marginal hypoechoic zone (p < 0.001). Compared to encap-PTC, NIFTP has a significantly higher incidence of benign findings: isoechoic and homogeneous internal echoes (p < 0.001), lack of punctate microcalcification (p < 0.001), and a regular marginal hypoechoic zone (p = 0.004). Based on the ultrasound classification (USC) system at Kuma Hospital, no cases were classified as malignant (USC ≥3.5), but 55.4% of the FVPTCs and 53.5% of the encap-PTCs were diagnosed as malignancy. However, on cytology, the incidence of NIFTP classified as Bethesda-V or -VI (PTC) was very high at 86.9%. All patients underwent surgical treatment, but none of the NIFTP patients showed postoperative recurrence. Although avoiding surgery might be difficult because of the high incidence of malignant cytology, overtreatment (including extensive surgery) for NIFTP can be avoided by paying close attention to the lack of malignant findings on ultrasound.

Regulation of the KCNJ5 gene by SF-1 in the adrenal cortex: Complete genomic organization and promoter function.

Activating mutations in the KCNJ5 gene are responsible for the significant number of aldosterone-producing adenomas. To elucidate the molecular mechanisms underlying KCNJ5 expression, we characterized the entire human KCNJ5 gene. The gene spanned approximately 29.8 kb and contained three exons and two introns. The strongest expression of KCNJ5 mRNA was observed in the adrenal gland. The promoter region contained a putative binding site for SF-1 at -1782 bp. A construct containing -2444 bp of the promoter region exhibited the strongest promoter activity in adrenal H295R cells, and the introduction of a mutation in the SF-1 binding site almost completely abolished promoter activity. Furthermore, deletion mutation, EMSA, and knockdown analyses revealed that SF-1 bound to this element and was functional. Immunochemistry showed that KCNJ5 was predominantly expressed in the zona glomerulosa, while SF-1 was ubiquitously expressed in the adrenal cortex. These results demonstrated that SF-1 mediates the expression of human KCNJ5 in the adrenal cortex.

Age-Dependent Progression of Renal Dysfunction After Adrenalectomy for Aldosterone-Producing Adenomas in Japan.

CONTEXT: In patients with aldosterone-producing adenomas (APAs), adrenalectomy causes a rapid decrease in blood pressure and increase in blood potassium levels; however, the effects of these intensive metabolic changes on kidney function with age have not yet been examined in Japan. OBJECTIVE: To investigate factors related to the progression of kidney dysfunction after adrenalectomy in different age groups. PARTICIPANTS: Fifty Japanese patients with APAs and 27,572 health checkup patients as controls were examined. MAIN OUTCOME MEASURES: We investigated changes in estimated glomerular filtration rate (eGFR) after adrenalectomy and characterized patients who progressed to chronic kidney disease (CKD). RESULTS: The postoperative cutoff age of CKD is 50 years and age is a unique factor for the progression of CKD after adrenalectomy. Among preoperative patients, CKD was 6% for those <50 years old and 40% for those ≥50 years old, indicating a higher prevalence of CKD with APAs than in control subjects. Median eGFR <50 mL/min/1.73 m2 did not significantly change after adrenalectomy but decreased from 67 to 42 mL/min/1.73 m2 in those with APAs ≥50 years old. Patients with APAs ≥50 years old who progressed to CKD showed higher preoperative aldosterone/renin ratios, lower potassium and chloride levels, lower body mass index, and a higher incidence of a history of cardiovascular events and KCNJ5 mutation rates. CONCLUSION: Age is the most important predictor of the progression of kidney dysfunction after adrenalectomy in Japanese patients with APAs, particularly those with a history of cardiovascular events and positivity for KCNJ5 mutations.

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.

GNAS mutations in adrenal aldosterone-producing adenomas.

Mutations in GNAS, which encodes Gsα, have been documented in detail, particularly in human pituitary GH-secreting adenomas. Mutations have also recently been reported in adrenal cortisol-producing adenomas (CPAs), in addition to those in the PRKACA gene. However, mutations have not yet been examined in aldosterone-producing adenomas (APAs). Therefore, we herein investigated mutations in the GNAS gene in APAs. Two of the 15 (13%) CPAs with overt Cushing's syndrome and one of the 9 (11%) CPAs with subclinical Cushing's syndrome examined had the somatic mutations, p.R201S and p.R201C in the GNAS gene. We identified mutations in the GNAS gene (p.R201C) in 2 out of the 33 (6%) APAs tested, both of which showed autonomous cortisol secretion, while 24 APAs had mutations in the KCNJ5 gene (18 with p.G151R and 6 with p.L168R). These GNAS and KCNJ5 mutations were mutually exclusive in these adenomas. We herein demonstrated for the first time the presence of GNAS mutations in APAs, as well as in some cortisol-secreting adenomas. Our results suggest that these mutations, in addition to mutations in the KCNJ5 gene and other genes such as ATP1A1, ATP2B3 and CACNA1D, may be responsible for the tumorigenesis of APAs and CPAs with subclinical Cushing's syndrome.

A leech capable of surviving exposure to extremely low temperatures.

It is widely considered that most organisms cannot survive prolonged exposure to temperatures below 0°C, primarily because of the damage caused by the water in cells as it freezes. However, some organisms are capable of surviving extreme variations in environmental conditions. In the case of temperature, the ability to survive subzero temperatures is referred to as cryobiosis. We show that the ozobranchid leech, Ozobranchus jantseanus, a parasite of freshwater turtles, has a surprisingly high tolerance to freezing and thawing. This finding is particularly interesting because the leach can survive these temperatures without any acclimation period or pretreatment. Specifically, the leech survived exposure to super-low temperatures by storage in liquid nitrogen (-196°C) for 24 hours, as well as long-term storage at temperatures as low as -90°C for up to 32 months. The leech was also capable of enduring repeated freeze-thaw cycles in the temperature range 20°C to -100°C and then back to 20°C. The results demonstrated that the novel cryotolerance mechanisms employed by O. jantseanus enable the leech to withstand a wider range of temperatures than those reported previously for cryobiotic organisms. We anticipate that the mechanism for the observed tolerance to freezing and thawing in O. jantseanus will prove useful for future studies of cryopreservation.