Aliskiren, a renin inhibitor, downregulates TNF-α-induced tissue factor expression in HUVECS

Angiotensin (Ang)II, the effector arm of the locally active renin—angiotensin system (RAS), modulates Tissue Factor (TF), the principal initiator of blood coagulation and a key promoter of atherothrombotic events. Consistent with that knowledge, previous data showed inhibitory properties of angiotensin-converting enzyme inhibitor (ACEI)s and angiotensin II type-1 receptor blocker (ARB)s, but no data are available about the effect of renin inhibition. We aimed to evaluate whether aliskiren, a direct renin inhibitor (DRI), modulates TNF-α-stimulated TF expression in cultured human umbilical vein endothelial cells (HUVECs). Zofenopril, an ACEI, and olmesartan, an ARB, were the controls. HUVECs were incubated with experimental drugs (1 nM) 30 min prior to TNF-α stimulation (0.1 ng/ml × 4 h). Main evaluation variables were procoagulant activity (single-stage clotting assay), TF antigen (ELISA) and mRNA expression (real-time polymerase chain reaction) in cell lysates. TNF-α stimulated procoagulant activity and increased TF antigen and mRNA expression. Aliskiren inhibited TNF-α-mediated TF stimulation; zofenopril and olmesartan exerted a comparable effect. We conclude that aliskiren, a DRI, downregulates TNF-α-stimulated TF expression in HUVECs, possibly as a reflection of endothelial renin activation by the cytokine

The effect of angiotensin receptor blockers on C-reactive protein and other circulating inflammatory indices in man

Anti-inflammatory properties may contribute to the pharmacological effects of angiotensin II receptor blockers (ARBs), a leading therapeutic class in the management of hypertension and related cardiovascular and renal diseases. That possibility, supported by consistent evidence from in-vitro and animal studies showing pro-inflammatory properties of angiotensin II, has been evaluated clinically by measuring the effect of ARBs on C-reactive protein and other circulating indices of inflammation (e-selectin, adhesion molecules, interleukin-6, tissue necrosis factor-alpha, monocyte chemoattractant protein-1) of potential clinical relevance, a body of evidence that this paper aims to review

Lack of a relationship between circulating gamma-glutamyltransferase levels and carotid intima media thickness in hypertensive and diabetic patients

Marco Nuti, Paolo Spontoni, Chrysanthos Grigoratos, Giulia Dell'Omo, Alberto Balbarini, Roberto PedrinelliDipartimento Cardio Toracico e Vascolare, Università di Pisa, Pisa, ItalyBackground: By increasing the intracellular prooxidant burden, gamma-glutamyltransferase (GGT) may accelerate atherosclerotic vascular disease. That noxious influence may be reflected by circulating enzyme levels, a correlate of cardiovascular risk factors, and a predictor of incident events. To evaluate this hypothesis, we tested the association between circulating GGT and common carotid intima-media thickness (CIMT), a surrogate index of systemic atherosclerotic involvement, in a large and well-characterized group of patients at risk of cardiovascular disease (CVD).Patients: This study analyzed 548 patients with hypertension and/or diabetes and a widely prevalent history of CVD. Subjects with known hepatic disease and abnormal GGT values were excluded.Methods: CIMT (B-mode ultrasonography) values were the mean of four far-wall measurements at both common carotids. Metabolic syndrome (MetS) was diagnosed according to National Cholesterol Education Program-Adult Treatment Panel III criteria. Due to inherent sex-related differences in GGT levels, the data were analyzed separately in males and females in samples dichotomized by the median.Results: The age-adjusted CIMT values did not differ by GGT levels in males or females. In contrast, the carotid wall was consistently thicker in patients with a history of CVD and MetS independent of age and concurrent GGT values. In both sexes, GGT was associated with key components of the MetS such as triglycerides, fasting plasma glucose, and body mass index.Conclusion: The data collected in this mixed group of hypertensive and/or diabetic patients with widely prevalent history of CVD do not support the concept of a direct pathophysiological link between GGT levels within reference limits and atherosclerotic involvement.Keywords: gamma-glutamyltransferase, carotid intima-media thickness, atherosclerosis, metabolic syndrom

The use of bone bridges in transtibial amputations

OBJETIVO: Descrever a técnica da osteoperiosteoplastia em adultos e apresentar a variação para a utilização em crianças, procurando demonstrar sua aplicabilidade como opção nas amputações transtibiais eletivas. CASUÍSTICA E MÉTODOS: O artigo apresenta um estudo prospectivo de 15 amputações transtibiais realizadas entre 1992 e 1995 em que se utilizou a técnica da osteoperiosteoplastia. A idade dos pacientes variou de 8 a 48 anos, com média de 22,53 anos. A técnica consistiu na confecção de um cilindro de periósteo retirado da tíbia, contendo fragmentos de osso cortical presos ao mesmo, para promover uma sinostose tibiofibular na extremidade distal do coto de amputação. Observou-se que os fragmentos de osso cortical eram dispensáveis quando a técnica foi empregada em crianças, pela maior capacidade osteogênica do periósteo. Isto levou a uma variação da técnica original, que consiste numa periosteoplastia sem a utilização de fragmentos de osso cortical. RESULTADOS: O tempo médio despendido com a técnica, sem variação significativa entre adultos e crianças, foi de 171 minutos. A adaptação da prótese definitiva dos pacientes foi obtida entre 20 e 576 dias, com média de 180 dias. Revisões da técnica empregada foram necessárias em três amputações (20%). CONCLUSÃO: A técnica encontra aplicação nas amputações transtibiais em que o comprimento final do coto seja próximo da transição musculotendínea do gastrocnêmio e nas revisões de cotos de amputação de crianças onde a técnica mostrou ser efetiva na prevenção das lesões decorrentes do excessivo crescimento ósseo.We sought to describe the bone bridge technique in adults, and present a variation for use in children, as well as to present its applicability as an option in elective transtibial amputations. This paper presents a prospective study of 15 transtibial amputations performed between 1992 and 1995 in which the bone bridge technique was employed. The patients' ages ranged from 8 to 48 years, with an average of 22.5 years. This technique consisted of the preparation of a cylinder of periosteum extracted from the tibia and with cortical bone fragments attached to it to promote a tibiofibular synostosis on the distal extremity of the amputation stump. We noted that the cortical bone fragments were dispensable when the technique was employed in children, due to the increased osteogenic capacity of the periosteum. This led to a variation of the original technique, a bone bridge without the use of the cortical bone fragments. RESULTS: The average time spent with this procedure, without any significant variation between adults and children, was 171 minutes. The adaptation to the definitive prosthesis was accomplished between 20 and 576 days, with an average of 180 days. Revision of the procedure was necessary in 3 amputations. CONCLUSIONS: This technique may be employed in transtibial amputations in which the final length of the stump lies next to the musculotendinous transition of the gastrocnemius muscle, as well as in the revision of amputation stumps in children, where the procedure has been shown to be effective in the prevention of lesions due to excessive bone growth

miR-19a and miR-20a and tissue factor expression in activated human peripheral blood mononuclear cells

Background and Aims. To investigate the behaviour of miR-19a and miR-20a, two microRNAs involved in posttranscriptional modulation of TF expression in peripheral blood mononuclear cells (PBMCs) exposed to high glucose (HG) and lipopolysaccharide (LPS), and to evaluate the involvement of angiotensin II in that process. Methods. TF Procoagulant Activity (PCA, one-stage clotting assay), antigen (Ag, ELISA), and miR-19a and miR-20a levels (specific TaqMan® MicroRNA Assays) were evaluated in PBMCs exposed to high glucose (HG, 50 mM), LPS (100 ng/mL), and Olmesartan (OLM, 10−6 M), an angiotensin II type 1 receptor antagonist. Results. HG increased TF expression and decreased both miRs as compared to control glucose conditions (11.1 mM). In HG-activated PBMCs, LPS stimulated TF expression and downregulated miR-20a, an effect reverted by OLM (10−6 M); miR-19a expression was unchanged by LPS in both CG and HG conditions. Conclusions. miR-19a and miR-20a are inhibited by inflammatory stimuli active on TF expression and their response differs by the stimulus under investigation; angiotensin II may participate in that mechanism

Rapid shedding of proinflammatory microparticles by human mononuclear cells exposed to cigarette smoke is dependent on Ca(2+) mobilization.

Microparticles are membrane vesicles shed by cells upon activation and apoptosis. Agonists capable of inducing microparticle generation include cytokines, bacterial products, P-selectin, histamine. Cigarette smoke extract has also been recognized as an agonist involved in microparticle generation with an apoptosis-dependent mechanism. We investigated the possibility that cigarette smoke extract induces the rapid generation of proinflammatory microparticles by human mononuclear cells with a calcium-dependent mechanism.Human mononuclear cells were exposed to cigarette smoke extract. [Ca(2+)]i mobilization was assessed with the fluorescent probe Fluo-4 NW. Microparticles were quantified with a prothrombinase assay and by flow cytometry. Normal human bronchial epithelial cells and A549 alveolar cells were incubated with cigarette smoke extract-induced microparticles and the generation of ICAM-1, IL-8, and MCP-1 was assessed by ELISA.Exposure to cigarette smoke extract induced a rapid increase in [Ca(2+)]i mobilization. Microparticle generation was also increased. EGTA, verapamil and the calmodulin inhibitor, W-7, inhibited microparticle generation. Incubation of lung epithelial cells with cigarette smoke extract-induced microparticles increased the expression of proinflammatory mediators.Exposure of mononuclear cells to cigarette smoke extract causes a rapid shedding of microparticles with a proinflammatory potential that might add to the mechanisms of disease from tobacco use

Peptide glutamine supplementation for tolerance of intermittent exercise in soccer players

OBJECTIVE: To investigate whether supplementation of carbohydrate together with peptide glutamine would increase exercise tolerance in soccer players. METHODS: Nine male soccer players (mean age: 18.4 ± 1.1 years; body mass: 69.2 ± 4.6 kg; height: 175.5 ± 7.3 cm; and maximum oxygen consumption of 57.7 ± 4.8 ml.kg-1.min-1) were evaluated. All of them underwent a cardiopulmonary exercise test and followed a protocol that simulated the movements of a soccer game in order to evaluate their tolerance to intermittent exercise. By means of a draw, either carbohydrate with peptide glutamine (CARBOGLUT: 50g of maltodextrin + 3.5g of peptide glutamine in 250 ml of water) or carbohydrate alone (CARBO: 50g of maltodextrin in 250 ml of water) was administered in order to investigate the enhancement of the soccer players' performances. The solution was given thirty minutes before beginning the test, which was performed twice with a one-week interval between tests. RESULTS: A great improvement in the time and distance covered was observed when the athletes consumed the CARBOGLUT mixture. Total distance covered was 12750 ± 4037m when using CARBO, and 15571 ± 4184m when using CARBOGLUT (p<0.01); total duration of tolerance was 73 ± 23 min when using CARBO and 88 ± 24 min when using CARBOGLUT (p<0.01). CONCLUSION: The CARBOGLUT mixture was more efficient in increasing the distance covered and the length of time for which intermittent exercise was tolerated. CARBOGLUT also reduced feelings of fatigue in the players compared with the use of the CARBO mixture alone

Primary Prevention Of Cardiovascular Risk In Octogenarians By Risk Factors Control

Primary prevention of cardiovascular events in older adults is a relevant problem, because of lack of evidence for safe and efficacious therapy, its costs and elderly quality of life, Italy's aging population is constantly increasing, so cardiovascular disease (CVD) primary prevention in the elderly is a prime objective. Life expectancy has dramatically increased over the last 2 decades,the proportion of individuals aged 80 years and older has grown rapidly in Europe and United States,but cost / effective ratio of CVD prevention through risk factors control is debated. It is therefore important to implement cardiovascular risk factors estimation in the elderly to maximize quality of life of patients and to lengthen their healthy life expectancy, choosing the better treatment for each patient sharing the choice with himself when it is possible, always remembering that elderly patients often have multiple co-morbidities that require a high number of concurrent medications; this may increase the risk for drug-drug interactions, thereby reducing the potential benefits of CVD prevention therapy. Anyway CVD are not an inevitable concomitant of aging. Sometimes autopsy in the elderly reveals atheroma-free coronary arteries,a normal-sized heart and unscarred valves. All primary prevention strategy decisions should consider estimated life expectancy and overall function not only cardiovascular event risks, magnitude and time to benefit or harm, potentially altered adverse effect profiles, and informed patient preferences.CVD primary prevention need to be more implemented in the elderly, this might contribute to improve health status and quality of life in this growing population if correctly performed