Treatment With Methotrexate Inhibits Atherogenesis in Cholesterol-Fed Rabbits

A decrease in the number of cardiovascular events in patients with rheumatoid arthritis or psoriasis treated with methotrexate (MTX) has been observed in the literature. The aim of this study was to test whether MTX could promote anti-inflammatory effects and reduce the atherosclerotic lesions in rabbits with atherosclerosis induced by cholesterol feeding. Twenty male New Zealand rabbits were fed a 1% cholesterol diet for 60 days. Starting from day 30 of cholesterol feeding, 10 animals were treated with 4 weekly intravenous injections of MTX (4 mg/kg) and 10 with 4 weekly saline solution injections for 30 days. MTX reduced the size of the lesion areas of cholesterol-fed animals by 75% and intima-media ratio 2- fold. The drug inhibited macrophage migration into the intima by 50% and the presence of apoptotic cells by 84% but did not inhibit the intimal proliferation of smooth muscle cells. MTX treatment also diminished the positive staining area of metalloproteinase 9 in the intima, which is probably beneficial. In the tumor necrosis factor-alpha-treated human umbilical vein endothelial cell line, incubation with MTX led to downregulation of 5 pro-inflammatory genes, TNF-alpha, VAP-1, IL-1 beta, CXCL2, and TLR2, and upregulation of the antiinflammatory TGF-beta 1 gene, thus showing endothelium-protective properties. In conclusion, MTX showed direct in vivo anti-atherosclerotic action and may have potential in the treatment of this disorder.

Bioactive compounds with effects on inflammation markers in humans

Obesity and other chronic diseases are accompanied by adipose tissue, liver, pancreas, muscle and brain low-grade chronic inflammation. Indeed, the obese condition and metabolic syndrome are characterized by an increased expression of inflammatory cytokines and infiltration of immune cells in adipocytes. The inflammatory response promotes the activation of transcriptional factors and pro-inflammatory cytokines, which can lead to an unresolved inflammatory response associated with an inhibition of insulin signalling and high risk for cardiovascular events. Epidemiological and intervention studies have been carried out to find out dietary patterns, foods and bioactive compounds with protective anti-inflammatory actions. The most studied compounds are polyphenols, especially isoflavone and anthocyanin, but quercertin, catechin and resveratrol have also been investigated. Furthermore, some studies have reported the effects of milk peptides, plant sterol and stanol, L-carnitine and alpha-lipoic acid on inflammatory processes. This review aimed to collect and discuss those relevant studies reported in the scientific literature following a systematic scientific search about the effect of such bioactive compounds on inflammation in humans.

Eating behavior and nutritional status in patients who underwent coronary angioplasty

Introduction: The identification of stages of dietary change and the factors affecting food choices can direct more effective nutritional intervention against coronary heart disease progression. Objective: Identify the stages of change of eating behavior and its relation with nutritional status, food consumption and previous cardiovascular events in patients who underwent coronary angioplasty. Methods: A cross-sectional study with 200 hospitalized patients from a specialized cardiology hospital, after elective coronary angioplasty. They were applied an algorithm that identifies the provision of change of eating habits for a healthier pattern. Variables measured were stages of change of eating behavior, nutritional status, food consumption and cardiovascular events (previous myocardial infarction or angioplasty). It was realized comparison of averages by analysis of variance or Student's test and Chi-square test for qualitative variables. Value of significance was taken at 5%. Results: The patients were classified in the following stages: 36% maintenance, 26% preparation, 17% precontemplation, 12% action and 9% contemplation. It was observed higher cardiovascular events in maintenance/action group (p = 0.04), higher consumption of calories (p = 0.04), meat/eggs (p = 0.01) and sweets (p = 0.03) in preparation stage, comparing to maintenance group, and no association between nutritional status and stages of change (p = 0.13), although 62% of the individuals in maintenance stage were overweight. Conclusions: This work contributed to identifying the stages of change and conditions that favor changes in eating pattern. Even patients that classified themselves into the maintenance stage need to adjust their eating habits in order to reach a healthy weight.

Phosphorus Is Associated with Coronary Artery Disease in Patients with Preserved Renal Function

High serum phosphorus levels have been associated with mortality and cardiovascular events in patients with chronic kidney disease and in the general population. In addition, high phosphorus levels have been shown to induce vascular calcification and endothelial dysfunction in vitro. The aim of this study was to evaluate the relation of phosphorus and coronary calcification and atherosclerosis in the setting of normal renal function. This was a cross-sectional study involving 290 patients with suspected coronary artery disease and undergoing elective coronary angiography, with a creatinine clearance >60 ml/min/1.73 m(2). Coronary artery obstruction was assessed by the Friesinger score and coronary artery calcification by multislice computed tomography. Serum phosphorus was higher in patients with an Agatston score >10 than in those with an Agatston score <= 10 (3.63 +/- 0.55 versus 3.49 +/- 0.52 mg/dl; p = 0.02). In the patients with Friesinger scores >4, serum phosphorus was higher (3.6 +/- 0.5 versus 3.5 +/- 0.6 mg/dl, p = 0.04) and median intact fibroblast growth factor 23 was lower (40.3 pg/ml versus 45.7 pg/ml, p = 0.01). Each 0.1-mg/dl higher serum phosphate was associated with a 7.4% higher odds of having a Friesinger score >4 (p = 0.03) and a 6.1% greater risk of having an Agatston score >10 (p = 0.01). Fibroblast growth factor 23 was a negative predictor of Friesinger score ( p = 0.002). In conclusion, phosphorus is positively associated with coronary artery calcification and obstruction in patients with suspected coronary artery disease and preserved renal function.

Atorvastatin and hormone therapy effects on APOE mRNA expression in hypercholesterolemic postmenopausal women

Menopause is associated with changes in lipid levels resulting in increased risk of atherosclerosis and cardiovascular events. Hormone therapy (HT) and atorvastatin have been used to improve lipid profile in postmenopausal women. Effects of HT, atorvastatin and APOE polymorphisms on serum lipids and APOE and LXRA expression were evaluated in 87 hypercholesterolemic postmenopausal women, randomly selected for treatment with atorvastatin (AT, n=17), estrogen or estrogen plus progestagen (HT, n=34) and estrogen or estrogen plus progestagen associated with atorvastatin (HT+AT, n=36). RNA was extracted from peripheral blood mononuclear cells (PBMC) and mRNA expression was measured by TaqMan (R) PCR. APOE epsilon 2/epsilon 3/epsilon 4 genotyping was performed using PCR-RFLP. Total cholesterol (TC). LDL-c and apoB were reduced after each treatment (p<0.001). Triglycerides, VLDL-c and apoAl were reduced only after atorvastatin (p<0.05), whereas triglycerides and VLDL-c were increased after HT (p=0.01). HT women had lower reduction on TC, LDL-c and apoB than AT and HT+AT groups (p<0.05). APOE mRNA expression was reduced after atorvastatin treatment (p=0.03). Although LXRA gene expression was not modified by atorvastatin, it was correlated with APOE mRNA before and after treatments. Basal APOE mRNA expression was not influenced by gene polymorphisms, however the reduction on APOE expression was more pronounced in epsilon 3 epsilon 3 than in epsilon 3 epsilon 4 carriers. Atorvastatin down-regulates APOE mRNA expression and it is modified by APOE genotypes in PBMC from postmenopausal women. (C) 2011 Elsevier Ltd. All rights reserved.

Antioxidant and inflammatory aspects of lipoprotein-associated phospholipase A2 (Lp-PLA2 ): a review

The association of cardiovascular events with Lp-PLA2 has been studied continuously today. The enzyme has been strongly associated with several cardiovascular risk markers and events. Its discovery was directly related to the hydrolysis of the platelet-activating factor and oxidized phospholipids, which are considered protective functions. However, the hydrolysis of bioactive lipids generates lysophospholipids, compounds that have a pro-inflammatory function. Therefore, the evaluation of the distribution of Lp-PLA2 in the lipid fractions emphasized the dual role of the enzyme in the inflammatory process, since the HDL-Lp-PLA2 enzyme contributes to the reduction of atherosclerosis, while LDL-Lp-PLA2 stimulates this process. Recently, it has been verified that diet components and drugs can influence the enzyme activity and concentration. Thus, the effects of these treatments on Lp-PLA2 may represent a new kind of prevention of cardiovascular disease. Therefore, the association of the enzyme with the traditional assessment of cardiovascular risk may help to predict more accurately these diseases.

Influence of obesity and cardiometabolic makers on lipoprotein-associated phospholipase A2 (Lp-PLA2) activity in adolescents: the healthy young cross-sectional study

Abstract Background Lipoprotein-associated phospholipase A2 activity (Lp-PLA2) is a good marker of cardiovascular risk in adults. It is strongly associated with stroke and many others cardiovascular events. Despite this, the impact of obesity on this enzyme activity and its relation to biomarkers of cardiovascular disease in adolescents is not very well investigated. The purpose of this article is to evaluate the influence of obesity and cardiometabolic markers on Lp-PLA2 activity in adolescents. Results This cross-sectional study included 242 adolescents (10–19 years) of both gender. These subjects were classified in Healthy Weight (n = 77), Overweight (n = 82) and Obese (n = 83) groups. Lipid profile, glucose, insulin, HDL size, LDL(−) and anti-LDL(−) antibodies were analyzed. The Lp-PLA2 activity was determined by a colorimetric commercial kit. Body mass index (BMI), waist circumference and body composition were monitored. Food intake was evaluated using three 24-hour diet recalls. The Lp-PLA2 activity changed in function to high BMI, waist circumference and fat mass percentage. It was also positively associated with HOMA-IR, glucose, insulin and almost all variables of lipid profile. Furthermore, it was negatively related to Apo AI (β = −0.137; P = 0.038) and strongly positively associated with Apo B (β = 0.293; P < 0.001) and with Apo B/Apo AI ratio (β = 0.343; P < 0.001). The better predictor model for enzyme activity, on multivariate analysis, included Apo B/Apo AI (β = 0.327; P < 0.001), HDL size (β = −0.326; P < 0.001), WC (β = 0.171; P = 0.006) and glucose (β = 0.119; P = 0.038). Logistic regression analysis demonstrated that changes in Apo B/Apo AI ratio were associated with a 73.5 times higher risk to elevated Lp-PLA2 activity. Conclusions Lp-PLA2 changes in function of obesity, and that it shows important associations with markers of cardiovascular risk, in particular with waist circumference, glucose, HDL size and Apo B/Apo AI ratio. These results suggest that Lp-PLA2 activity can be a cardiovascular biomarker in adolescence.

Cardiac autonomic impairment and chronotropic incompetence in fibromyalgia

Abstract Introduction We aimed to gather knowledge on the cardiac autonomic modulation in patients with fibromyalgia (FM) in response to exercise and to investigate whether this population suffers from chronotropic incompetence (CI). Methods Fourteen women with FM (age: 46 ± 3 years; body mass index (BMI): 26.6 ± 1.4 kg/m2) and 14 gender-, BMI- (25.4 ± 1.3 kg/m2), and age-matched (age: 41 ± 4 years) healthy individuals (CTRL) took part in this cross-sectional study. A treadmill cardiorespiratory test was performed and heart-rate (HR) response during exercise was evaluated by the chronotropic reserve. HR recovery (deltaHRR) was defined as the difference between HR at peak exercise and at both first (deltaHRR1) and second (deltaHRR2) minutes after the exercise test. Results FM patients presented lower maximal oxygen consumption (VO2 max) when compared with healthy subjects (22 ± 1 versus CTRL: 32 ± 2 mL/kg/minute, respectively; P < 0.001). Additionally, FM patients presented lower chronotropic reserve (72.5 ± 5 versus CTRL: 106.1 ± 6, P < 0.001), deltaHRR1 (24.5 ± 3 versus CTRL: 32.6 ± 2, P = 0.059) and deltaHRR2 (34.3 ± 4 versus CTRL: 50.8 ± 3, P = 0.002) than their healthy peers. The prevalence of CI was 57.1% among patients with FM. Conclusions Patients with FM who undertook a graded exercise test may present CI and delayed HR recovery, both being indicative of cardiac autonomic impairment and higher risk of cardiovascular events and mortality.

Mechanisms of endothelial dysfunction in obesity-associated hypertension

Obesity is strongly associated with high blood pressure, dyslipidemia, and type 2 diabetes. These conditions synergistically increase the risk of cardiovascular events. A number of central and peripheral abnormalities can explain the development or maintenance of high blood pressure in obesity. Of great interest is endothelial dysfunction, considered to be a primary risk factor in the development of hypertension. Additional mechanisms also related to endothelial dysfunction have been proposed to mediate the development of hypertension in obese individuals. These include: increase in both peripheral vasoconstriction and renal tubular sodium reabsorption, increased sympathetic activity and overactivation of both the renin-angiotensin system and the endocannabinoid system and insulin resistance. The discovery of new mechanisms regulating metabolic and vascular function and a better understanding of how vascular function can be influenced by these systems would facilitate the development of new therapies for treatment of obesity-associated hypertension.

Identificazione di profili di rischio cardiovascolare nel trapianto di rene: polimorfismi di geni coinvolti nei processi di infiammazione e di apoptosi

Introduction. Cardiovascular disease (CVD) represents the main cause of morbidity and mortality in kidney recipients. This study was undertaken to assess the impact of functional polymorphisms located in cytokine and apoptosis genes on CVD after kidney transplantation. Cytokine polymorphisms, generally located in gene regulatory regions, are associated with high and low cytokine production and are likely to modulate the magnitude of inflammatory responses following transplantation, depending on the balance between the levels of pro-inflammatory and antiinflammatory cytokines. The role of apoptosis in atherosclerosis has not been completely elucidated, and here we explored the hypothesis that the heterogeneity in cardiovascular risk in kidney recipients may also be linked to functional polymorphisms involved in apoptosis induction. Purpose. In the search for relevant genetic markers of predisposition to CVD after renal transplant, the present investigation was undertaken to identify the clinical impact of polymorphisms of cytokines TNF-α, TGF-β, IL-10, IL-6, IFN-γ and IL-8 and of apoptosis genes Fas and Caspase 9 in a population of kidney transplant recipients. Materials and methods. The study involved 167 patients who received cadaveric kidney transplantation at our centre between 1997 and 2005 (minimum follow-up of 12 months); 35 of them had experienced cardiovascular events (CVD group) and 132 had no cardiovascular complications (non-CVD group). Genotyping was performed using RFLP (Restriction Fragment Length Polymorphism) for RFLP per IL-8/T-251A, Fas/G-670A e Casp9/R221Q polymorphism and SSP (Sequence Specific Primer) for TNF-α/G-308A, TGF-β/L10P, TGF-β/R25P, IL-10/G-1082A, IL- 10/C-819T, IL-10/C-592A, IL-6/G-174C, IFN-γ/T+874A polymorphisms.Results. We found a significant difference in TNF-α and IL-10 genotype frequencies between the patients who had suffered cardiovascular events and those with no CVD history. The high producer genotype for proflogistic cytokine TNF-α appeared to have a significantly superior prevalence in the CVD group compared to the non-CVD group (40.0% vs 21.2%) and it resulted in a 2.4-fold increased cardiovascular risk (OR=2.361; p=0.0289). On the other hand, the high producer genotype for the antiinflammatory cytokine IL-10 was found in 2.8% of the CVD group and in 16.7% of non-CVD group; logistic regression showed a 0.3-fold reduced risk of CVD associated with genetically determined high IL-10 production (OR=0.278; p<0.0001). The other polymorphisms did not prove to have any impact on CVD. Conclusions. TNF-α and IL-10 gene polymorphisms might represent cardiovascular risk markers in renal transplant recipients.

Pyrochlore der Pegmatit-Provinz Nazareno, Brasilien

Zusammenfassung:Mit Hilfe einer neuen Formel für die Minerale der Pyrochlor-Gruppe werden sämtliche Endglieder der Na-Ca-Mikrolithe und der Ba-haltigen Mikrolithe aus der Pegmatit-Provinz Nazareno beschrieben: Die Na-reichsten Proben haben nahezu die Idealzusammensetzung eines idealen Pyrochlors, d.h. . Die Ca-reichsten Varietäten weisen maximal auf, wobei der Besetzungsanteil des Ca am A2+ ca. 93% beträgt. Die Ba-haltigen Mikrolithe sind durch eine Defektstruktur gekennzeichnet, wobei für das mögliche Endglied kein Beispiel in den Daten vorliegt. Das Endglied mit dem geringsten Defektcharakter hat folgende Stöchiometrie:

La Restless Legs Syndrome aumenta il rischio cardiovascolare e la mortalità a breve termine nei pazienti emodializzati

Abstract Restless legs syndrome (RLS) is a sensori-motor neurological disorder characterzed by paraesthesia, dysaesthesia and irresistibile urge to move the legs especially at night. Its prevalence is much higher among dialysis patients at 12 to 62% compared to 3 to 9% in the general population. In our study we investigated the association between RLS and cardiovascular events risk and laboratory parameters in End-stage kidney disease (ESKD) patients on dialysis. We studied 100 ESKD patients undergoing hemodialysis that were enrolled in an 18-months prospective observational study. The main outcomes were the association of RLS with new cardiovascular events and cardiovascular mortality. RLS affected 31% of the study population. It was associated with female gender, gradual reduction in residual dieresis, lower albumin (P=0.039) and inflammation, but not the dialysis parameters spKt/V and URR. During observation, 47% of patients experienced new cardiovascular events (64.5% with and 39.1% without RLS; P=0.019). Mortality was 20.0% in all patients, 32.3% in those with and 14.5% in patients without RLS (P=0.04). This study confirmed the high prevalence of RLS among dialysis patients and the associations between the severity of RLS and the risk of new cardiovascular events and higher short-term mortality. Abstract Restless legs syndrome (RLS) is a sensori-motor neurological disorder characterzed by paraesthesia, dysaesthesia and irresistibile urge to move the legs especially at night. Its prevalence is much higher among dialysis patients at 12 to 62% compared to 3 to 9% in the general population. In our study we investigated the association between RLS and cardiovascular events risk and laboratory parameters in End-stage kidney disease (ESKD) patients on dialysis. We studied 100 ESKD patients undergoing hemodialysis that were enrolled in an 18-months prospective observational study. The main outcomes were the association of RLS with new cardiovascular events and cardiovascular mortality. RLS affected 31% of the study population. It was associated with female gender, gradual reduction in residual dieresis, lower albumin (P=0.039) and inflammation, but not the dialysis parameters spKt/V and URR. During observation, 47% of patients experienced new cardiovascular events (64.5% with and 39.1% without RLS; P=0.019). Mortality was 20.0% in all patients, 32.3% in those with and 14.5% in patients without RLS (P=0.04). This study confirmed the high prevalence of RLS among dialysis patients and the associations between the severity of RLS and the risk of new cardiovascular events and higher short-term mortality.

Attività autonomica cardiaca e funzioni neurocognitive nei pazienti affetti da sindrome delle gambe senza riposo (RLS): effetto dei farmaci dopamino agonisti in acuto e a lungo termine

Several studies showed that sleep loss/fragmentation may have a negative impact on cognitive performance, mood and autonomic activity. Specific neurocognitive domains, such as executive function (i.e.,prefrontal cortex), seems to be particularly vulnerable to sleep loss. Pearson et al.(2006) evaluated 16 RLS patients compared to controls by cognitive tests, including those particularly sensitive to prefrontal cortical (PFC) functioning and sleep loss. RLS patients showed significant deficits on two of the three PFC tests. It has been recently reported that RLS is associated with psychiatric manifestations. A high prevalence of depressive symptoms has been found in patients with RLS(Rothdach AJ et al., 2000). RLS could cause depression through its adverse influences on sleep and energy. On the other hand, symptoms of depression such as sleep deprivation, poor nutrition or lack of exercise may predispose an individual to the development of RLS. Moreover, depressed patients may amplify mild RLS, making occasional RLS symptoms appear to meet threshold criteria. The specific treatment of depression could be also implicated, since antidepressant compounds may worsen RLS and PLMD(Picchietti D et al., 2005; Damsa C et al., 2004). Interestingly, treatments used to relieve RLS symptoms (dopamine agonists) seem to have an antidepressant effects in RLS depressed patients(Saletu M et al., 2002&2003). During normal sleep there is a well-regulated pattern of the autonomic function, modulated by changes in sleep stages. It has been reported that chronic sleep deprivation is associated with cardiovascular events. In patients with sleep fragmentation increased number of arousals and increased cyclic alternating pattern rate is associated with an increase in sympathetic activity. It has been demonstrated that PLMS occurrence is associated with a shift to increased sympathetic activity without significant changes in cardiac parasympathetic activity (Sforza E et al., 2005). An increased association of RLS with hypertension and heart disease has been documented in several studies(Ulfberg J et al., 2001; Ohayon MM et al., 2002).

Flash floods and their effects on the development in El-Qaá plain area in South Sinai, Egypt

The arid regions are dominated to a much larger degree than humid regions by major catastrophic events. Although most of Egypt lies within the great hot desert belt; it experiences especially in the north some torrential rainfall, which causes flash floods all over Sinai Peninsula. Flash floods in hot deserts are characterized by high velocity and low duration with a sharp discharge peak. Large sediment loads may be carried by floods threatening fields and settlements in the wadis and even people who are living there. The extreme spottiness of rare heavy rainfall, well known to desert people everywhere, precludes any efficient forecasting. Thus, although the limitation of data still reflects pre-satellite methods, chances of developing a warning system for floods in the desert seem remote. The relatively short flood-to-peak interval, a characteristic of desert floods, presents an additional impediment to the efficient use of warning systems. The present thesis contains introduction and five chapters, chapter one points out the physical settings of the study area. There are the geological settings such as outcrop lithology of the study area and the deposits. The alluvial deposits of Wadi Moreikh had been analyzed using OSL dating to know deposits and palaeoclimatic conditions. The chapter points out as well the stratigraphy and the structure geology containing main faults and folds. In addition, it manifests the pesent climate conditions such as temperature, humidity, wind and evaporation. Besides, it presents type of soils and natural vegetation cover of the study area using unsupervised classification for ETM+ images. Chapter two points out the morphometric analysis of the main basins and their drainage network in the study area. It is divided into three parts: The first part manifests the morphometric analysis of the drainage networks which had been extracted from two main sources, topographic maps and DEM images. Basins and drainage networks are considered as major influencing factors on the flash floods; Most of elements were studied which affect the network such as stream order, bifurcation ratio, stream lengths, stream frequency, drainage density, and drainage patterns. The second part of this chapter shows the morphometric analysis of basins such as area, dimensions, shape and surface. Whereas, the third part points the morphometric analysis of alluvial fans which form most of El-Qaá plain. Chapter three manifests the surface runoff through rainfall and losses analysis. The main subject in this chapter is rainfall which has been studied in detail; it is the main reason for runoff. Therefore, all rainfall characteristics are regarded here such as rainfall types, distribution, rainfall intensity, duration, frequency, and the relationship between rainfall and runoff. While the second part of this chapter concerns with water losses estimation by evaporation and infiltration which are together the main losses with direct effect on the high of runoff. Finally, chapter three points out the factors influencing desert runoff and runoff generation mechanism. Chapter four is concerned with assessment of flood hazard, it is important to estimate runoff and tocreate a map of affected areas. Therefore, the chapter consists of four main parts; first part manifests the runoff estimation, the different methods to estimate runoff and its variables such as runoff coefficient lag time, time of concentration, runoff volume, and frequency analysis of flash flood. While the second part points out the extreme event analysis. The third part shows the map of affected areas for every basin and the flash floods degrees. In this point, it has been depending on the DEM to extract the drainage networks and to determine the main streams which are normally more dangerous than others. Finally, part four presets the risk zone map of total study area which is of high inerest for planning activities. Chapter five as the last chapter concerns with flash flood Hazard mitigation. It consists of three main parts. First flood prediction and the method which can be used to predict and forecast the flood. The second part aims to determine the best methods which can be helpful to mitigate flood hazard in the arid zone and especially the study area. Whereas, the third part points out the development perspective for the study area indicating the suitable places in El-Qaá plain for using in economic activities.

Inflammatory Biomarkers in Patients with Posttraumatic Stress Disorder Caused by Myocardial Infarction and the Role of Depressive Symptoms

Inflammation might link posttraumatic stress disorder (PTSD) with an increased risk of cardiovascular events. We explored the association between PTSD and inflammatory biomarkers related to cardiovascular morbidity and the role of co-morbid depressive symptoms in this relationship.