The interleukin 7 receptor alpha-chain (IL-7Ralpha) is essential for T cell development in both humans and mice and for B cell development in mice. Whereas the transcription factor PU.1 regulates IL-7Ralpha expression in mouse pro-B cells via a GGAA motif, we demonstrate here that GA binding protein (GABP) bound to this site and was essential in the regulation of IL-7Ralpha expression in T cells, where PU.1 is not expressed. Moreover, IL-7Ralpha expression was diminished substantially in thymocytes but was normal on B220(+) fetal liver cells from mouse embryos with diminished expression of GABPalpha. Thus, GABP is essential for the regulation of IL-7Ralpha expression in T cells, and the differential regulation of IL-7Ralpha in distinct lymphoid lineages is achieved at least in part by differential recruitment of factors to the same GGAA motif.

Complex structural and functional changes occur in the arterial system with advancing age. The aged artery is characterized by changes in microRNA expression patterns, autophagy, smooth muscle cell migration and proliferation, and arterial calcification with progressively increased mechanical vessel rigidity and stiffness. With age the vascular smooth muscle cells modify their phenotype from contractile to ‘synthetic’ determining the development of intimal thickening as early as the second decade of life as an adaptive response to forces acting on the arterial wall. The increased permeability observed in intimal thickening could represent the substrate on which low‐level atherosclerotic stimuli can promote the development of advanced atherosclerotic lesions. In elderly patients the atherosclerotic plaques tend to be larger with increased vascular stenosis. In these plaques there is a progressive accumulation of both lipids and collagen and a decrease of inflammation. Similarly the plaques from elderly patients show more calcification as compared with those from younger patients. The coronary artery calcium score is a well‐established marker of adverse cardiovascular outcomes. The presence of diffuse calcification in a severely stenotic segment probably induces changes in mechanical properties and shear stress of the arterial wall favouring the rupture of a vulnerable lesion in a less stenotic adjacent segment. Oxidative stress and inflammation appear to be the two primary pathological mechanisms of ageing‐related endothelial dysfunction even in the absence of clinical disease. Arterial ageing is no longer considered an inexorable process. Only a better understanding of the link between ageing and vascular dysfunction can lead to significant advances in both preventative and therapeutic treatments with the aim that in the future vascular ageing may be halted or even reversed.

The prevalence of the metabolic syndrome has increased worldwide over the past few years. Sympathetic nervous system overactivity is a key mechanism leading to hypertension in patients with the metabolic syndrome. Sympathetic activation can be triggered by reflex mechanisms as arterial baroreceptor impairment, by metabolic factors as insulin resistance, and by dysregulated adipokine production and secretion from visceral fat with a mainly permissive role of leptin and antagonist role of adiponectin. Chronic sympathetic nervous system overactivity contributes to a further decline of insulin sensitivity and creates a vicious circle that may contribute to the development of hypertension and of the metabolic syndrome and favor cardiovascular and kidney disease. Selective renal denervation is an emerging area of interest in the clinical management of obesity-related hypertension. This review focuses on current understanding of some mechanisms through which sympathetic overactivity may be interlaced to the metabolic syndrome, with particular regard to the role of insulin resistance and of some adipokines.

Abstract-Obesity is associated with endothelial dysfunction related to decreased NO bioavailability, increased endothelin 1 vasoconstrictor activity, and decreased circulating ghrelin. Therefore, we tested whether exogenous ghrelin may have benefits to improve the balance between endothelin 1 and NO in patients with obesity-related metabolic syndrome.Vasoactive actions of endothelin 1 and NO were assessed in 8 patients with metabolic syndrome and 8 matched controls by evaluating forearm blood flow responses (strain-gauge plethysmography) to intra-arterial infusion of BQ-123 (endothelin A receptor antagonist; 10 nmol/min), followed by N G -monomethyl-L-arginine (NO synthase inhibitor; 4 mol/min), before and after infusion of ghrelin (200 ng/min). In the absence of ghrelin, the vasodilator response to BQ-123 was greater in patients than in controls (PϽ0.001), whereas infusion of N G -monomethyl-L-arginine induced smaller vasoconstriction in patients than in controls (Pϭ0.006). Importantly, exogenous ghrelin decreased the vasodilator response to BQ-123 (Pϭ0.007 versus saline) and enhanced the magnitude of changes in forearm blood flow induced by N G -monomethyl-L-arginine (Pϭ0.003) in patients but not in controls (both PϾ0.05). The favorable effect of ghrelin on endothelin A-dependent vasoconstriction was likely related to the stimulation of NO production, because no change in the vascular effect of BQ-123 was observed after ghrelin (Pϭ0.44) in 5 patients with metabolic syndrome during continuous infusion of the NO donor sodium nitroprusside (0.2 g/min). In patients with metabolic syndrome, ghrelin has benefits to normalize the balance between vasoconstrictor (endothelin 1) and vasodilating (NO) mediators, thus suggesting that this peptide has important peripheral actions to preserve vascular homeostasis in humans. Key Words: abdominal obesity Ⅲ endothelin 1 Ⅲ ghrelin Ⅲ metabolic syndrome Ⅲ NO V ascular tone is regulated through the actions of locally produced agents and reflects the balance of opposing factors. Among the vasodilators, NO seems to be the most important contributor to the acute regulation of vascular tone, whereas endothelin (ET) 1 is the most potent vasoconstrictor exerting this action principally through type A ET (ET A ) receptors. 1 Endothelial dysfunction in obesity-related metabolic syndrome (MetS) is evident as a failure to vasodilate adequately after exposure to endothelium-dependent vasodilators, 2 but this phenomenon may reflect not only impaired NO bioavailability but also excess vasoconstrictor tone. Findings from both our laboratory 3 and others 4 suggest that endogenous ET-1-mediated vasoconstrictor tone is augmented in obesity and may, thus, contribute to vascular damage because of the multiple proatherogenic effects of It is interesting that both ET-1 and NO work as negative feedbacks for each other, 6 each one acting to limit the action of the other. It is, therefore, possible that ET-1 contributes to endothelial dysfunction both directly, through its vasoconstrictor effects, and i...

Obesity represents one of the most complex public health challenges and has recently reached epidemic proportions. Obesity is also considered to be primarily responsible for the rising prevalence of metabolic syndrome, defined as the coexistence in the same individual of several risk factors for atherosclerosis, including dyslipidemia, hypertension and hyperglycemia, as well as for cancer. Additionally, the presence of three of the five risk factors (abdominal obesity, low high-density lipoprotein cholesterol, high triglycerides, high fasting glucose and high blood pressure) characterizes metabolic syndrome, which has serious clinical consequences. The current study was conducted in order to identify metabolic differences in visceral adipose tissue (VAT) collected from obese (body mass index 43-48) human subjects who were diagnosed with metabolic syndrome, obese individuals who were metabolically healthy and nonobese healthy controls. Extensive gas chromatography/mass spectrometry (GC/MS) and liquid chromatography/mass spectrometry (LC/MS/MS) analyses were used to obtain the untargeted VAT metabolomic profiles of 481 metabolites belonging to all biochemical pathways. Our results indicated consistent increases in oxidative stress markers from the pathologically obese samples in addition to subtle markers of elevated glucose levels that may be consistent with metabolic syndrome. In the tissue derived from the pathologically obese subjects, there were significantly elevated levels of plasmalogens, which may be increased in response to oxidative changes in addition to changes in glycerolphosphorylcholine, glycerolphosphorylethanolamine glycerolphosphorylserine, ceramides and sphingolipids. These data could be potentially helpful for recognizing new pathways that underlie the metabolic-vascular complications of obesity and may lead to the development of innovative targeted therapies.

T lymphocytes play a central role in controlling adaptive immune responses. IL-2 critically regulates both T cell growth and death and is involved in maintaining peripheral tolerance, but the molecules involved in these and other IL-2 actions are only partially known. We now provide a comprehensive compendium of the genes expressed in T cells and of those regulated by IL-2 based on a combination of DNA microarrays and serial analysis of gene expression (SAGE). The newly identified IL-2 target genes include many genes previously linked to apoptosis in other cellular systems that may contribute to IL-2-dependent survival functions. We also studied the mRNA expression of known regulators of signaling pathways for their induction in response to IL-2 in order to identify potential novel positive and/or negative feedback regulators of IL-2 signaling. We show that IL-2 regulates only a limited number of these genes. These include suppressors of cytokine signaling (SOCS) 1, SOCS2, dual-specificity phosphatase (DUSP) 5, DUSP6 and non-receptor type phosphatase-7 (PTPN7). Additionally, we provide evidence that many genes expressed in T cells locate in chromosomal clusters, and that select IL-2-regulated genes are located in at least two clusters, one at 5q31, a known cytokine gene cluster, and the other at 6p21.3, a region that contains genes encoding the tumor necrosis factor (TNF) superfamily members TNF, LT-alpha and LT-beta.

These findings indicate that, under physiological conditions, leptin stimulates both ET-1 and NO activity in the human circulation. This effect is absent in hyperleptinemic patients with the MetS who are unresponsive to additional leptin. In these patients, therefore, hyperleptinemia may be a biomarker of vascular dysfunction, rather than a mediator of vascular damage.

Brown tumour represents a serious complication of hyperparathyroidism. Differential diagnosis, based on histological examination, is only presumptive and clinical, radiological and laboratory data are necessary for definitive diagnosis. Here we describe a case of a brown tumour localised in the maxilla due to secondary hyperparathyroidism in a young women with chronic renal failure. Hemodialysis and pharmacological treatment were unsuccessful in controlling secondary hyperparathyroidism making it necessary to proceed with a subtotal parathyroidectomy. The proper timing of the parathyroidectomy and its favourable effect on regression of the brown tumor made it possible to avoid a potentially disfiguring surgical removal of the brown tumor.