Predominant role of 25OHD in the negative regulation of PTH expression: clinical relevance for hypovitaminosis D.

Although severe deficiency of bioactive vitamin D (1,25OH2D) causes rickets, mild insufficiency of the hormone, known as hypovitaminosis D, is responsible for the occurrence of secondary hyperparathyroidism and osteoporosis. To clarify the pathophysiology of the disease, we studied the negative feedback effect of 1,25OH2D and its precursor 25OHD on the transcriptional activity of parathyroid hormone (PTH) gene using the PT-r parathyroid cell line. We found that PT-r cells express endogenous 1alpha-hydroxylase as well as PTH mRNAs. We also found the potent suppressive effect of physiological concentration of 25OHD on the transcriptional activity of PTH gene. A similar effect was obtained with 1,25OH2D but only with pharmacological concentration. Interestingly, the effect of 25OHD was completely abolished when the cells were treated with 1alpha-hydroxylase inhibitor ketoconazole. These results suggest that the negative feedback regulation of vitamin D on PTH gene transcription occurs not by the end-product 1,25OH2D but by its prohormone 25OHD via intracellular activation by 1alpha-hydroxylase within the parathyroid cells.

A male case of nonclassical 21-hydroxylase deficiency first manifested in his sixties with adrenocortical incidentaloma.

Nonclassical form of 21-hydroxylase deficiency (NC 21OHD) as a frequent variant on the milder end of the disease spectrum has been widely acknowledged, but its potential contribution to adrenocortical tumorigenesis has not been fully elucidated. We report a 66-year old male case of bilateral adrenocortical incidentaloma, associated with partial 21OHD without any episodes of hypoadrenocorticism in his past history. He was demonstrated to be a compound heterozygous mutant of CYP21A2 gene (IVS2-13A/C>G/I172N). The two tumors in the left adrenal, which were interpreted as myelolipoma by imaging studies, were followed by sequential observation, whereas the contralateral large solid tumor associated with inhomogeneous radiological appearance was subsequently removed. The resected tumor was diagnosed an adrenocortical adenoma, which was devoid of P450c21 immunoreactivity. 21OHD is often associated with benign adrenocortical tumors, but bilateral adrenal tumors with heterogeneous components in both adrenals have not been reported to the best of our knowledge.

Evaluation and treatment of patients with lower extremity peripheral artery disease: consensus definitions from Peripheral Academic Research Consortium (PARC).

The lack of consistent definitions and nomenclature across clinical trials of novel devices, drugs, or biologics poses a significant barrier to accrual of knowledge in and across peripheral artery disease therapies and technologies. Recognizing this problem, the Peripheral Academic Research Consortium, together with the U.S. Food and Drug Administration and the Japanese Pharmaceuticals and Medical Devices Agency, has developed a series of pragmatic consensus definitions for patients being treated for peripheral artery disease affecting the lower extremities. These consensus definitions include the clinical presentation, anatomic depiction, interventional outcomes, surrogate imaging and physiological follow-up, and clinical outcomes of patients with lower-extremity peripheral artery disease. Consistent application of these definitions in clinical trials evaluating novel revascularization technologies should result in more efficient regulatory evaluation and best practice guidelines to inform clinical decisions in patients with lower extremity peripheral artery disease.

Involvement of GCMB in the transcriptional regulation of the human parathyroid hormone gene in a parathyroid-derived cell line PT-r: effects of calcium and 1,25(OH)2D3.

Expression of the PTH gene is known to be under strict tissue-specific control and is also regulated by extracellular calcium and 1,25(OH)(2)D. However, the precise mode of transcriptional regulation remains to be elucidated, because of the unavailability of appropriate cell lines derived from the parathyroid gland. We tried to identify the transcription factor(s) regulating the human PTH gene transcription using the PT-r cell line. We found that PT-r cells endogenously express PTH and several parathyroid-related genes. Using the cells, we investigated the transcriptional regulation of human PTH gene. We found that GCMB binds to the PTH gene 5'-promoter (-390/-383 bp) and positively regulates its transcription. On the other hand, 1,25(OH)(2)D(3), and, in the presence of the calcium sensing receptor, high extracellular calcium, exerted inhibitory effects on PTH gene expression. These results indicate that GCMB and vitamin D receptor are involved in the positive and negative regulation of PTH gene expression, respectively. Our data also suggest that PT-r cells retain some of the characteristics of parathyroid cells.