The pulse wave velocity (PWV) and the photoplethysmogram (PTG) are noninvasive methods for evaluating the pulse wave. The PWV has been associated with age and arterial hypertension, and an index of the second derivative of PTG (SDPTG) is correlated with age and other risk factors for atherosclerosis. The aim of this study was to compare SDPTG and PWV concerning the influencing factors of vascular compliance, including age and atherosclerosis, in a large hypertensive population. We studied consecutively 524 essential hypertensives, 140 with atherosclerotic alterations (AA), defined on the basis of clinical events including coronary heart disease, peripheral vascular disease, stroke, and abdominal aorta aneurysm. The PWV carotid-femoral was measured by a Complior device and the SDPTG was recorded by Fukuda FCP-3166. The augmentation index (AUI) of PTG was defined as the ratio of the late systolic peak to that of the early systolic peak in the pulse. The SDPTG consists of an a,b,c, and d wave in systole and an e wave in diastole; an SDPTG aging index (AI) was calculated as (b-c-d-e)/a. The patients with AA presented a higher PWV (14.9 +/- 4 m/sec v 12.4 +/- 2 m/sec, P < .001), PTG AUI (0.322 +/- 0.16 v 0.252 +/-0.09, P < .001), and SDPTG AI (-0.093 +/- 0.03 v -0.271 +/- 0.018, P < .001). However, in patients 60 years of age, only PWV remained higher in those with AA, whereas in patients >60 yr, both PWV and SDPTG AI remained higher in those with AA. The PWV was independently influenced by age, systolic blood pressure, glucose, AA, and plasma creatinine, whereas the PTG AUI was influenced by age and systolic pressure and the SDPTG AI by age and AA. In a logistic regression model for the presence of AA, including age, plasma creatinine, smoking, and diastolic BP, PWV was a significant independent determinant of AA, whereas SDPTG-AI weakly entered into the model. This study provides evidence that the aortic PWV reflects better than the SDPTG the modifications of the arterial compliance related to age, blood pressure, and atherosclerosis. However, the SDPTG AI may be useful for evaluation of vascular aging in hypertensives.

Epigenetic modifications at the histone level affect gene regulation in response to extracellular signals. However, regulated epigenetic modifications at the DNA level, especially active DNA demethylation, in gene activation are not well understood. Here we report that DNA methylation/demethylation is hormonally switched to control transcription of the cytochrome p450 27B1 (CYP27B1) gene. Reflecting vitamin-D-mediated transrepression of the CYP27B1 gene by the negative vitamin D response element (nVDRE), methylation of CpG sites ((5m)CpG) is induced by vitamin D in this gene promoter. Conversely, treatment with parathyroid hormone, a hormone known to activate the CYP27B1 gene, induces active demethylation of the (5m)CpG sites in this promoter. Biochemical purification of a complex associated with the nVDRE-binding protein (VDIR, also known as TCF3) identified two DNA methyltransferases, DNMT1 and DNMT3B, for methylation of CpG sites, as well as a DNA glycosylase, MBD4 (ref. 10). Protein-kinase-C-phosphorylated MBD4 by parathyroid hormone stimulation promotes incision of methylated DNA through glycosylase activity, and a base-excision repair process seems to complete DNA demethylation in the MBD4-bound promoter. Such parathyroid-hormone-induced DNA demethylation and subsequent transcriptional derepression are impaired in Mbd4(-/-) mice. Thus, the present findings suggest that methylation switching at the DNA level contributes to the hormonal control of transcription.

Interferon regulatory factor-1 (IRF-1) acts as a transcriptional activator in the interferon system and as a tumor suppressor. The loss of functional IRF-1 has been observed in a signi®cant number of patients with myelodysplastic syndrome (MDS) and leukemia, suggesting a potentially critical role of IRF-1 in human oncostasis. Here we report an alternative mechanism by which IRF-1 may be inactivated. We puri®ed an IRF-1 association molecule which was revealed to be identical to a nuclear factor nucleophosmin (NPM)/B23/numatrin. Functional analysis showed that NPM inhibited the DNA-binding and transcriptional activity of IRF-1. Moreover, NPM was overexpressed in several clinical leukemia samples and human-derived leukemia cell lines. Finally, overexpression of NPM in NIH3T3 cells resulted in malignant transformation. These results suggest the possible involvement of NPM in inactivating IRF-1-dependent anti-oncogenic surveillance in human cancer development.

Receptor activator of NF-kappaB ligand (RANKL) has been identified as requisite for osteoclastogenesis. To elucidate the molecular mechanism that conducts its catabolic action on bone, the effect of 1alpha,25 dihydroxyvitamin D(3) (1alpha,25(OH)(2)D(3)) on osteoclastogenesis and RANKL mRNA expression was examined by coculture, RT-PCR and nuclear run-on studies. By accelerating the transcription rate of the RANKL gene in SaOS2 osteoblastic cells, 1alpha,25(OH)(2)D(3) enhanced in vitro osteoclast formation from peripheral monocytes. Cloning and characterization of the 5'-flanking region of the human RANKL gene revealed that the basic promoter comprises inverted TATA- and CAAT-boxes flanked by RUNX2 binding sites. Both electrophoresis mobility shift assay (EMSA) and transfection studies demonstrated that 1alpha,25(OH)(2)D(3) activated human RANKL promoter through vitamin D responsive elements (VDRE) located at -1584/-1570 by binding VDR and RXRalpha heterodimers in a ligand-dependent manner. The results provide direct evidence that 1alpha,25(OH)(2)D(3) augments osteoclastogenesis by transactivating the human RANKL gene in osteoblastic cells through VDRE.