[Show abstract][Hide abstract] ABSTRACT: Background Renin Angiotensin System plays a complex role in regulating physiopathologic functional and morphological modifications at vascular level. While large information exist about Angiotensin (AT) II roles, namely in the development of vascular damage under early inflammatory conditions, little is known about AT 1-7 functions, supposed to play counteracting actions vs AT II
Objectives To evaluate if, in the early phases of an experimental inflammatory systemic condition namely the one induced by streptozotocin (SZ), the treatment with AT 1-7 could prevent inflammatory, pro-oxidative and structural vascular modifications, and further prevent the in vivo leukocyte trafficking activation, induced by local stimulation of well known arthritis-related proinflammatory mediators, such as thrombin (THR) or activated terminal complement complex (aTCC).
Methods In compliance with European (86/609/EEC) and the Italian (D.L.116/92) rules for animal experiments, 4 groups each of 10-12 male Wistar rats were randomly grouped and treated respectively with sterile saline, or AT 1-7 (576 μg/kg/day), either in the presence or absence (healthy control group) of a preliminary standardized bolus intra vein infusion of 50mg/kg SZ. Saline and AT 1-7 were daily infused by osmotic sc minipump. After 3 weeks, in 4 anesthesized rats from each group, the occurrence of either basal, or THR or aTCC-induced local inflammatory inflammatory stimulation, stable adherence to the endothelial layer and extravasation of circulating fluorescently-labelled leukocytes were assessed at microvascular level by using an in vivo videomicroscopy technique. In the other rats, the immunohistochemical staining (IHS) and gene expression ex vivo analysis of mesentery vascular content of IL-6, MCP-1, Nitrotyrosine, connective tissue growth factor (CTGF), proliferative cell nuclear antigen (PCNA), together with structural changes, assessed by median wall:total vessel area ratio (W/TV) and extracellular matrix content, were also assessed.
Results AT 1-7 did not induce any significant modification in control, healthy animals, differently AT 1-7 partly reduced the overall increase of leukocyte trafficking and extravasation in a time ranging from 15 to 60 minutes after topical exposure to THR and aTCC, while significantly inhibiting these effects (p<0.01) in rats previously treated with SZ. AT 1-7 also reduced the SZ induced percent increase of W/TV ratio (61±5 vs 87±6 of saline treated, p<0.001), local vascular content (ng/μg prot.) of IL-6 (7±1,2 vs 3±0.8, p<0.01) and MCP-1 (12±4 vs 7±2.5, p<0.05), and the percent IHS of Nitrotyrosine (25.5±6.7 vs 9.5±4, p<001), CTGF (21±4 vs 14.5±2.5, p<0.01) and PCNA (medial layer=8±3.2 vs 2.5±0.15, p<0.01). Gene expression assessments are still under evaluation
Conclusions These data suggest that AT 1-7 could play an immune modulating role even in the earlier phases of inflammatory conditions, with prevention of secondary structural tissue alterations. This could be of relevance in the development of arthritis disease, therefore our group has recently been starting new experiments with the aim of demonstrating any AT 1-7 protective effects also in experimental arthritis
Disclosure of Interest None declared
Annals of the Rheumatic Diseases 06/2015; 74(Suppl 2):911.2-911. DOI:10.1136/annrheumdis-2015-eular.5572 · 10.38 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: . Radiofrequency ablation (RFA) has been recently advocated as an effective technique for the treatment of symptomatic benign thyroid nodules. It is not known to what extent it may affect any subsequent thyroid surgery and/or histological diagnosis.
Materials and Methods
. RFA was performed on 64 symptomatic Thy2 nodules (benign nodules) and 6 symptomatic Thy3 nodules (follicular lesions/follicular neoplasms). Two Thy3 nodules regrew after the procedure, and these patients accepted to undergo a total thyroidectomy. Here we present how RFA has affected the operation and the final pathological features of the surgically removed nodules.
Results and Conclusions
. RFA is effective for the treatment of Thy2 nodules, but it should not be recommended as first-line therapy for the treatment of Thy3 nodules (irrespective of their mutational status), as it delays surgery in case of malignancy. Moreover, it is unknown whether RFA might promote residual tumor progression or neoplastic progression of Thy3 lesions. Nevertheless, here we show for the first time that one session of RFA does not affect subsequent thyroid surgery and/or histological diagnosis.
[Show abstract][Hide abstract] ABSTRACT: At this time, good quality randomized clinical trials assessing the effects of vitamin D supplementation on cardiometabolic outcomes are lacking in the international literature.
To fill this gap, the Working Group on Vitamin D and Cardiorenal Disorders established jointly by the Italian Society of Hypertension (SIIA) and the Forum in Bone and Mineral Research conceived the HYPODD study (HYPOvitaminosis D and organ Damage).
HYPODD is a no-profit multicenter 12-month parallel-group double-blind placebo controlled randomized trial aiming to assess the effects of cholecalciferol supplementation on blood pressure control, antihypertensive drugs consumption and progression of target organ damage in patients with essential hypertension and 25-hydroxyvitamin D serum level lower than 20 ng/ml (vitamin D deficiency). HYPODD is coordinated by the European Society Excellence Center of Hypertension of Federico II University, Naples, and involves 12 academic institutions in Italy (Ancona, Milan, Padua, Perugia, Rome, Siena, Trieste, Turin, Udine, Varese, and Verona).
The HYPODD study has been registered at the Agenzia Italiana del Farmaco-Osservatorio sulla Sperimentazione Clinica del Farmaco (AIFA-OsSC) and EUDRACT sites (n° 2012-003514-14) and has been approved by the Ethical Committees of all the Centers involved in the study. The patients' recruitment is currently underway.
High Blood Pressure & Cardiovascular Prevention 03/2015; 22(2). DOI:10.1007/s40292-015-0080-9
[Show abstract][Hide abstract] ABSTRACT: TRAIL or tumor necrosis factor (TNF) related apoptosis-inducing ligand is a member of the TNF superfamily of proteins, whose best characterized function is the induction of apoptosis in tumor, infected, or transformed cells through activation of specific receptors. In nontransformed cells, however, the actions of TRAIL are less well characterized. Recent studies suggest that TRAIL may be implicated in the development and progression of diabetes. Here we review TRAIL biological actions, its effects on the immune system, and how and to what extent it has been shown to protect against diabetes.
Journal of Immunology Research 02/2015; 2015:680749. DOI:10.1155/2015/680749 · 2.93 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Gender identity is the sense one has of being male or female. Gender dysphoria (GD) refers to the distress caused by the incongruence between gender identity and biological sex in gender-nonconforming individuals. Cross-sex hormone therapy (CHT) aims at easing GD, improving well-being, and quality of life of gender-nonconforming individuals. This can be achieved by inducing and maintaining the desired-sex characteristics in accordance with the specific aspirations and expectations of each individual. Nevertheless, CHT can be associated with potentially serious long-term complications.
Here, we review when, how, and how long to prescribe CHT to adult transsexuals as well as what to expect and monitor once it has been initiated.
In recent years, transsexualism has become more and more recognized and depathologized. To manage GD, National and International Standards of Care have been established. Nevertheless, the needs of transgender patients can still be ignored or dismissed. Moreover, some questions remain unanswered because of the lack of specific retrospective or prospective studies on CHT.
Education and culturally sensitive training must be supplied to healthcare professionals to overcome the existing issues on GD management and change the perspectives of transsexual people.
[Show abstract][Hide abstract] ABSTRACT: Background
Inflammation is believed to link obesity to insulin resistance, as in the setting of metabolic syndrome (MetS). Osteoprotegerin (OPG) is a soluble protein that seems to exert proatherogenic and prodiabetogenic effects. This study aims at determining OPG levels in MetS and whether OPG might contribute to MetS development and progression.
Circulating OPG was measured in 46 patients with MetS and 63 controls, and was found significantly elevated in those with MetS. In addition, circulating and tissue OPG was significantly increased in high-fat diet (HFD) fed C57BL6 mice, which is one of the animal models for the study of MetS. To evaluate the consequences of OPG elevation, we delivered this protein to C57BL6 mice, finding that it promoted systemic and adipose tissue proinflammatory changes in association with metabolic abnormalities.
These data suggest that OPG may trigger adipose tissue proinflammatory changes in MetS/HFD-induced obesity.
[Show abstract][Hide abstract] ABSTRACT: Objective. Benign thyroid nodules are a common occurrence whose only remedy, in case of symptoms, has always been surgery until the advent of new techniques, such as radiofrequency ablation (RFA). This study aimed at evaluating RFA efficacy, tolerability, and costs and comparing them to hemithyroidectomy for the treatment of benign thyroid nodules. Design and Methods. 37 patients who underwent RFA were retrospectively compared to 74 patients surgically treated, either in a standard inpatient or in a short-stay surgical regimen. Efficacy, tolerability, and costs were compared. The contribution of final pathology was also taken into account. Results. RFA reduced nodular volume by 70% after 12 months and it was an effective method for treating nodule-related clinical problems, but it was not as effective as surgery for the treatment of hot nodules. RFA and surgery were both safe, although RFA had less complications and pain was rare. RFA costed €1,661.50, surgery costed €4,556.30, and short-stay surgery costed €4,139.40 per patient. RFA, however, did not allow for any pathologic analysis of the nodules, which, in 6 patients who had undergone surgery (8%), revealed that the nodules harboured malignant cells. Conclusions. RFA might transform our approach to benign thyroid nodules.
International Journal of Endocrinology 06/2014; 2014:934595. DOI:10.1155/2014/934595 · 1.95 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Background Chronic immune-mediated arthritis development is based upon the occurrence of both leukocyte tissue infiltration and neoangiogenesis. Proper evaluation of the pattern of development of leukocyte influx and newly expressed microvessels during the early phases of autoimmune synovitis might be of primary relevance.
Objectives We aimed to set up technical procedures for visualizing in vivo the occurrence of microvascular modifications, as well as for analyzing the parallel degree of leukocyte trafficking, further evaluating the relationships existing between these parameters and the extent of tissue damage scores and cytokine synovial fluid levels in the course of the early phases of an immune complex-mediated model of experimental arthritis, namely the antigen-induced arthritis (AIA).
Methods Following legal animal care policies, AIA was induced in the right knee joint of 20 Wistar male rats. At different time points, up to 10 days after arthritis induction, anesthetized rats underwent surgical preparation for the in vivo visualization of sub-patellar tendon synovial joint tissue, by using a videomicroscopy device suitable for analogic-digital conversion of videoimages. Microvessels shapes and diameters, and the interplay between leukocytes and endothelial cells, were analyzed respectively by intravenously injecting FITC-labelled bovine serum albumin or acridine orange, at pre-established concentrations. Microvessel and adhering/extravasated leukocyte numbers were compared with the degree of tissue damage score, of infiltrating neutrophils and of synovial fluid concentrations of TNF-α, IL-6, and MCP-1 as assessed from a parallel set of comparable AIA experimental settings (n=12 animals).
Results In the arthritic joints a significantly increased total number of microvessels (p<0,001) was observed already after the third day of disease and this feature showed to be persistently evident along the entire period of clinical follow-up. A higher degree of vessels with diameter lower than 20μm (marker for capillary vessels) was also evidently detectable, reaching a peak number at he 5th day after arthritis induction. Morphologically deranged vessels, with branched and irregular patterns, were observed in the arthritic joints. Stable adhesion of fluoresceinated leukocytes to the endothelial layer of synovial microvessels was significantly increased (29±4 vs 8±6 cells/200μm; p<0,01) soon after the 1st day of induced arthritis, and this difference further increased with a peak level at the 5th day after arthritis induction. Microvessels increase and leukocyte infiltration were significantly (p<0.01) related with the degree of damage score, of infiltrating neutrophils and of synovial fluid concentrations of TNF-alpha and MCP-1.
Conclusions The in vivo pattern of development of newly expressed microvessels and of leukocytes trafficking in the early evolving phases of an experimental model of arthritis was here described and related with some more commonly described ex vivo parameters of inflammation. This experimental approach could be helpful for analyzing more detailed arthritis-related molecular pathogenic mechanisms and vascular-targeted therapeutic interventions.
Disclosure of Interest None Declared
[Show abstract][Hide abstract] ABSTRACT: Cushing's syndrome is associated with high cardiovascular morbility and mortality. Blood pressure (BP) variability within a 24-h period is increasingly recognized as an independent predictor of cardiovascular risk. The aim of our study was to investigate the short-term BP variability indices in Cushing's syndrome. Twenty-five patients with Cushing's syndrome (mean age 49 ± 13 years, 4 males; 21 Cushing's disease and 4 adrenal adenoma patients) underwent 24-h ambulatory BP monitoring (ABPM) and evaluation of cardiovascular risk factors. Cushing patients were divided into 8 normotensive (NOR-CUSH) and 17 hypertensive (HYP-CUSH) patients and were compared with 20 normotensive (NOR-CTR) and 20 hypertensive (HYP-CTR) age-, sex-, and BMI-matched control subjects. Short-term BP variability was derived from ABPM and calculated as the following: (1) standard deviation (SD) of 24-h, daytime, and nighttime BP; (2) 24-h weighted SD of BP; and (3) average real variability (ARV), i.e., the average of the absolute differences between consecutive BP measurements over 24 h. In comparison with controls, patients with Cushing's syndrome, either normotensive or hypertensive, had higher 24-h and daytime SD of BP, as well as higher 24-h weighted SD and ARV of BP (P = 0.03 to P < 0.0001). No difference in metabolic parameters was observed between NOR-CTR and NOR-CUSH or between HYP-CTR and HYP-CUSH subgroups. ABPM-derived short-term BP variability is increased in Cushing's syndrome, independent of BP elevation. It may represent an additional cardiovascular risk factor in this disease. The role of excess cortisol in BP variability has to be further clarified.
[Show abstract][Hide abstract] ABSTRACT: Menopause is associated with increased arterial stiffness, an independent marker of cardiovascular risk. Omega-3 polyunsaturated fatty acids (N3-PUFAs) are thought to have multiple cardiovascular benefits, including prevention of arterial stiffness. We investigated whether treatment with N3-PUFA prevents increase in arterial stiffness in ovariectomized rats, an animal model of experimental menopause.
A total of 43 Wistar rats, 2 months old, were divided into 3 groups, control, sham surgery, normal diet (CTRL, n = 15); ovariectomy, normal diet (OVX, n = 14); and ovariectomy with N3-PUFA supplementation (0.8 g/kg/d in daily gavages administration; OVX + O3, n = 14). Two months after surgery, carotid-femoral pulse wave velocity (PWV) and arterial blood pressure (BP) were measured by carotid and femoral cannulation. Aortic morphometric measurements were performed after dissection.
Ovariectomy caused a significant increase in BP (P < .05), PWV (P < .0001), and elastic modulus (P = .001) compared to CTRL. After ovariectomy, N3-PUFA supplementation completely prevented increase in arterial stiffness (P < .0001 vs OVX) and BP (P < .05 vs OVX) and resulted in a significant increase in body weight and aortic thickness.
In an experimental model of menopause, N3-PUFA supplementation prevents arterial stiffening and other vascular changes induced by ovariectomy. These results represent a therapeutic benefit of N3-PUFAs in prevention of postmenopausal cardiovascular disease.
Journal of Cardiovascular Pharmacology and Therapeutics 09/2013; 19(1). DOI:10.1177/1074248413500716 · 2.09 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Menopause is associated with endothelial dysfunction and oxidative stress. In this condition, reduced n-3 polyunsaturated fatty acids (n-3 PUFAs) contribute to cardiovascular disease. We investigated whether treatment with n-3 PUFA reverses endothelial dysfunction and oxidative stress in experimental menopause. Thirty female rats underwent either sham-surgery or bilateral ovariectomy or bilateral ovariectomy+oral n-3 PUFA (0.8 g kg(-1) day(-1) for 2 months). Ovariectomy caused endothelial dysfunction to acetylcholine, which was reversed by superoxide scavenger Tiron. Erythrocyte membrane lipid composition was characterized by reduced n-3 PUFA total content and omega-3 index, and by concomitant increase in n-6:n-3 PUFA ratio. Ovariectomy-related oxidative stress, demonstrated by both enhanced superoxide production and 3-nitrotyrosine expression in aorta, was associated with increased nicotinamide adenine dinucleotide phosphate (NADPH) oxidase subunit NOX-4 protein expression. Endothelial nitric oxide synthase (eNOS) functional inhibition by l-NG-nitroarginine methyl ester, protein expression and activity did not change. In ovariectomized rats, treatment with n-3 PUFA increased n-3 PUFA total content and omega-3 index and decreased n-6:n-3 PUFA ratio in erythrocyte membrane, reversed vascular oxidative stress, endothelial dysfunction, aortic 3-nitrotyrosine and markedly lowered NOX-4 protein expression; eNOS protein expression also increased, paralleled by reversal of inhibitory binding to Caveolin-1, while ex-vivo functional inhibition and NOS synthesis were unchanged. These findings demonstrate in vivo a therapeutic benefit of n-3 PUFA on menopause-associated endothelial dysfunction by reversal of alterations in membrane lipid composition induced by ovariectomy and by reduction of vascular oxidative stress. In this setting they also identify NOX-4 as a potential target to reduce oxidative stress-mediated vascular complications.
The Journal of nutritional biochemistry 11/2012; 24(1). DOI:10.1016/j.jnutbio.2012.07.012 · 3.79 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Background and aim:
Non-alcoholic fatty liver disease (NAFLD) has been found to be strongly related to an increased arterial stiffness in patients with essential hypertension, suggesting a pathophysiologic link between major cardiovascular and metabolic abnormalities associated with liver steatosis and the functional and structural alterations of the arterial wall. The aim of our study was to investigate, in a group of essential hypertensive patients without additional cardiovascular risk factors, the relationship between NAFLD and arterial stiffness.
Methods and results:
Sixty-eight consecutive patients with essential hypertension underwent 24-h ambulatory blood pressure monitoring (ABPM) and were separated according to the presence (n = 40) or absence (n = 28) of NAFLD at liver ultrasonography. The Ambulatory Arterial Stiffness Index (AASI) and Symmetric AASI (Sym-AASI) were derived from ABPM tracings. Patients with diabetes, obesity, hyperlipidaemia or other risk factors for cardiovascular or liver disease were excluded. Hypertensive patients were compared with a normotensive control group.The two hypertensive groups had comparable age, sex distribution and clinic/ABPM blood pressure levels. In hypertensive patients with NAFLD, body mass index, fasting glucose, insulin, homeostasis model of assessment of insulin resistance index and triglyceride levels were higher, whereas plasma adiponectin was lower than in patients without NAFLD. In hypertensive patients, AASI and Sym-AASI were higher (P < 0.001) than in normotensive subjects, but both indices of vascular stiffness were comparable in patients with and without NAFLD.
In essential hypertensive patients without additional cardiovascular risk factors, NAFLD is associated with insulin resistance but not with increased arterial stiffness.
[Show abstract][Hide abstract] ABSTRACT: This review focuses on TNF-related apoptosis-inducing ligand (TRAIL), also called Apo2 ligand, a protein belonging to the TNF superfamily. TRAIL can be found either in its transmembrane or circulating form, and its mostly studied peripheral effect is the induction of cellular apoptosis. Here, we discuss the evidences supporting the use of TRAIL as biomarker of cardiovascular diseases as well as the evidences showing the potential beneficial therapeutic effects of TRAIL on cardiovascular diseases and diabetes.
Current drug targets 06/2012; 13(9):1215-21. DOI:10.2174/138945012802002357 · 3.02 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: TRAIL [TNF (tumour necrosis factor)-related apoptosis-inducing ligand] has recently been shown to ameliorate the natural history of DM (diabetes mellitus). It has not been determined yet whether systemic TRAIL delivery would prevent the metabolic abnormalities due to an HFD [HF (high-fat) diet]. For this purpose, 27 male C57bl6 mice aged 8 weeks were randomly fed on a standard diet, HFD or HFD+TRAIL for 12 weeks. TRAIL was delivered weekly by intraperitoneal injection. Body composition was evaluated; indirect calorimetry studies, GTT (glucose tolerance test) and ITT (insulin tolerance test) were performed. Pro-inflammatory cytokines, together with adipose tissue gene expression and apoptosis, were measured. TRAIL treatment reduced significantly the increased adiposity associated with an HFD. Moreover, it reduced significantly hyperglycaemia and hyperinsulinaemia during a GTT and it improved significantly the peripheral response to insulin. TRAIL reversed the changes in substrate utilization induced by the HFD and ameliorated skeletal muscle non-esterified fatty acids oxidation rate. This was associated with a significant reduction of pro-inflammatory cytokines together with a modulation of adipose tissue gene expression and apoptosis. These findings shed light on the possible anti-adipogenic and anti-inflammatory effects of TRAIL and open new therapeutic possibilities against obesity, systemic inflammation and T2DM (Type 2 DM).
[Show abstract][Hide abstract] ABSTRACT: Deficiency of ACE2 (angiotensin-converting enzyme 2), which degrades Ang (angiotensin) II, promotes the development of glomerular lesions. However, the mechanisms explaining why the reduction in ACE2 is associated with the development of glomerular lesions have still to be fully clarified. We hypothesized that ACE2 may regulate the renoprotective actions of ANP (atrial natriuretic peptide). The aim of the present study was to investigate the effect of ACE2 deficiency on the renal production of ANP. We evaluated molecular and structural abnormalities, as well as the expression of ANP in the kidneys of ACE2-deficient mice and C57BL/6 mice. We also exposed renal tubular cells to AngII and Ang-(1-7) in the presence and absence of inhibitors and agonists of RAS (renin-angiotensin system) signalling. ACE2 deficiency resulted in increased oxidative stress, as well as pro-inflammatory and profibrotic changes. This was associated with a down-regulation of the gene and protein expression on the renal production of ANP. Consistent with a role for the ACE2 pathway in modulating ANP, exposing cells to either Ang-(1-7) or ACE2 or the Mas receptor agonist up-regulated ANP gene expression. This work demonstrates that ACE2 regulates renal ANP via the generation of Ang-(1-7). This is a new mechanism whereby ACE2 counterbalances the renal effects of AngII and which explains why targeting ACE2 may be a promising strategy against kidney diseases, including diabetic nephropathy.