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Highlights: [•] Genome reduction may increase alternative splicing in the kiss system genes in fish. [•] In general, kissr mRNA levels are higher at the early stages of pubertal development. [•] There is a large interspecific variation in the expression of the paralog kiss genes. [•] We propose a criteria set to compare the expression of the kiss genes across species. [•] The upstream regulatory regions of both kiss and kissr need further characterization. [ABSTRACT FROM AUTHOR]

The hydroxy-methyl-glutaryl-CoA reductase inhibitors (statins) are used extensively in the treatment of dyslipidemia, and for the prevention and treatment of coronary artery disease and stroke. They have also demonstrated a benefit in a variety of other disease processes through their non-lipid lowering properties, known as pleiotropic effects. Our paper serves as a focused and updated discussion of the pleiotropic effects of statins in gastrointestinal disorders. [ABSTRACT FROM AUTHOR]

The mechanisms by which statins are beneficial are incompletely understood. While the lowering of low-density lipoprotein concentration is associated with regression of atherosclerosis, the observed benefit of statin therapy begins within months after its initiation, making regression an unlikely cause. Although LDL-C lowering is the main mechanism by which statin therapy reduces cardiovascular events, evidence suggests that at least some of the beneficial actions of statins may be mediated by their pleiotropic effects. Thus, statins may modulate the function of cardiovascular cells and key signalling proteins, including small G-proteins, to ultimately exert their pleiotropic effects. Sphingosine-1-phosphate (S1P) is a naturally occurring bioactive lysophospholipid that regulates diverse physiological functions in a variety of different organ systems. Within the cardiovascular system, S1P mediates cardioprotection following ischemia/reperfusion injury, anti-inflammatory response, improvement of endothelial function, increased mobilization and differentiation of endothelial progenitor cells, inhibition of oxidation, and anti-atherogenic and anti-thrombotic actions. Early evidence suggests that the pleiotropic effects of statins may be related to an increase in S1P signalling. This review focuses on S1P signalling as the potential mechanism underlying the pleiotropic effects of statins. An improved understanding of this mechanism may be vital for establishing the clinical relevance of statins and their importance in the treatment and prevention of coronary artery disease. [ABSTRACT FROM AUTHOR]

Abstract: Type 2 diabetes mellitus is a rising cause of cardiovascular morbidity and mortality. A number of studies have also identified diabetic patients as having increased risk for the development of cancer. Metformin is a widely prescribed antidiabetic drug with an established efficacy coupled with a favorable safety profile and low cost. An increasing number of studies have associated metformin treatment with a decrease of cancer risk. Moreover, metformin has also been associated with improved outcomes in cancer patients. These possible pleiotropic effects of metformin may establish metformin as a cancer prevention and treatment option. However, any favorable effects of metformin on cancer are not always corroborated by clinical trials. Larger studies are expected to better investigate the possible antineoplastic effects of metformin. [Copyright &y& Elsevier]

Aim: To investigate the effects of two different therapeutic regimes that may obtain equivalent LDL cholesterol (LDL-C) reduction (2400 mg of Xuezhikang [XZK] per day and coadministration of 600 mg of XZK plus 10 mg of ezetimibe [EZT] per day) on plasma levels of inflammatory markers in patients with dyslipidemia. Methods: A total of 46 patients with dyslipidemia were studied and were randomly divided into the two groups: group A (2400 mg XZK per day; n = 23) and group B (600 mg XZK/10 mg EZT per day; n = 23) for 6 weeks. The plasma levels of IL-6, IL-10 and CRP were analyzed at both baseline and 6 weeks. Results: Both therapy regimes resulted in similar reductions of LDL-C (p > 0.05). Compared with baseline, both treatments significantly increased plasma IL-10 and decreased IL-6, as well as CRP levels (p < 0.05 and p < 0.01, respectively), while no difference was found between the two groups (p > 0.05). Conclusion: When achieving a similar reduction in LDL-C, coadministration of low-dose XZK and EZT could also exert anti-inflammatory effects comparable with those obtained by single high-dose XZK. [ABSTRACT FROM AUTHOR]

Objectives. Statins decrease cardiovascular events mainly by lowering cholesterol but anti-inflammatory effects also play a role. The effects of the cholesterol absorption inhibitor ezetimibe on markers of inflammation remain unclear. We performed an exploratory post-hoc analysis whether these drugs influence the pro-inflammatory markers interleukin-6 and high-sensitivity C-reactive protein in subjects with very-low cardiovascular risk. Design. Single center, randomized, parallel 3-group study in 72 healthy men without apparent cardiovascular disease (age 32 ± 9 years, BMI 25.7 ± 3.2 kg/m²). Each group of 24 subjects received a 14-day treatment with either simvastatin 40 mg, ezetimibe 10 mg, or their combination. Results. Baseline IL-6 and hsCRP concentrations in the total cohort were 0.72 ±0.57 ng/1 and 0.40 ±0.65 mg/1, respectively, with no differences between the 3 groups. Median changes (interquartile range) in IL-6 and hsCRP concentrations were -22% (-43 to 0%) and -30% (-44 to +19%) after simvastatin, -5% (-36 to +30%) and +9% (-22 to +107%) after ezetimibe, and +15% (-15 to +86%) and +1 (-30 to +49%) after the combination. Using a generalized linear model, the multivariable adjusted overall P-values for these changes were 0.008 (IL-6) and 0.1 (hsCRP). Conclusions. Simvastatin decreases the pro-inflammatory markers IL-6 and almost significantly hsCRP while ezetimibe monotherapy or the combination with simvastatin has no effect. [ABSTRACT FROM AUTHOR]

Abstract: In most patients only a few sessions of apheresis treatment are necessary to see the benefit. This is the case of immunological diseases when the production of a pathologic component is limited in time or in microcirculation disturbances when changes of vascular function may occur. In the first instance the acute effect is likely due to the removal of the corresponding antibody, while in the second case the improvement of the endothelium-dependent vasodilation and the reduction of blood viscosity play a major role. In long-term treatment, as in the case of patients affected by familial hypercholesterolemia, the chronic effects of apheresis may lead to the repair of morphological alterations in the vascular wall. We report the recovery from ulcers in two hemodialysis patients suffering from peripheral arterial disease as the result of twenty-two sessions of rheopheresis. The reasons that justify these chronic actions may involve pleiotropic effects that are different according to the apheresis technique used. [Copyright &y& Elsevier]

Abstract: Lipoprotein apheresis is a well-established extracorporeal treatment in modality of severe hyperlipoproteinemia. Besides the reduction of LDL cholesterol and modifications to physiology of lipoprotein and lipid metabolism, Lipoprotein apheresis may have crucial effects on many other atherogenic factors as vascular inflammation, rheology and gene expressions in blood cells. These different effects of lipoprotein apheresis treatments are reviewed with respect to oxidative stress in plasma, red and white blood cells and in consequence to progression of atherosclerosis. However, in consideration of these reviewed aspects as a factor of biocompatibility lipoprotein apheresis remains safe. [Copyright &y& Elsevier]

Abstract: Objective: This study was designed to investigate whether metformin affects monocyte secretory function in patients with impaired fasting glucose receiving chronic statin therapy. Materials/Methods: The study included 48 patients with impaired fasting glucose treated for at least three months with simvastatin (40mg daily). These patients were randomized to either metformin (3g daily) or placebo, which was administered together with simvastatin for 90days. Plasma lipids, glucose homeostasis markers, monocyte cytokine release and plasma C-reactive protein levels were determined before randomization and at the end of the treatment. Results: Compared to placebo, metformin reduced monocyte release of tumor necrosis factor-α, interleukin-1β, interleukin-6, monocyte chemoattractant protein-1 and interleukin-8, as well as decreased plasma C-reactive protein levels, which were accompanied by an improvement in insulin sensitivity. Conclusions: The obtained results suggest that metformin may inhibit monocyte secretory function and reduce systemic inflammation in statin-treated patients with prediabetes. Impaired fasting glucose patients with high cardiovascular risk may receive the greatest benefits from concomitant treatment with a statin and metformin. [Copyright &y& Elsevier]

Abstract: Objective: No previous study has investigated whether metformin produces any effect on lymphocyte secretory function in patients with glucose metabolism abnormalities. Methods: Sixty-two subjects with impaired fasting glucose (IFG) treated for at least 3 months with simvastatin were allocated into one of two groups receiving, respectively, metformin (3 g daily) or placebo for the following 90 days. Plasma lipids, glucose homeostasis markers, plasma C-reactive protein and intercellular adhesion molecule-1 levels, as well as lymphocyte release of proinflammatory cytokines were determined before randomization and at the end of the treatment. Results: Fifty-eight patients completed the study. Metformin, but not placebo, administered to simvastatin-treated IFG subjects reduced plasma levels of C-reactive protein, soluble intercellular adhesion molecule-1, as well as lymphocyte release of interleukin-2, interferon-γ and tumor necrosis factor-α, which was accompanied by the improvement in insulin sensitivity and a reduction in free fatty acid levels. Conclusions: The obtained results indicate that metformin potentiates lymphocyte-suppressing and systemic anti-inflammatory effects of simvastatin in subjects with IFG. These effects of statin–metformin combination therapy may play a role in the prevention and treatment of atherosclerosis and its complications in patients with early glucose metabolism abnormalities. [Copyright &y& Elsevier]

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A large number of nutraceuticals with lipid-lowering activity are currently available on the market, however, for most of them, it is not known whether the lipid-lowering activity is associated with a concrete reduction in cardiovascular disease risk. The aim of this review is to evaluate whether the most commonly used lipid-lowering nutraceuticals (i.e., soluble fibers, phytosterols, garlic, soy proteins, monacolins, policosanols, berberine and n-3 fatty acids) also have some positive effects on other cardiovascular disease risk factors, on instrumental biomarkers of cardiovascular disease risk or the risk of cardiovascular events. Beyond red yeast rice and n-3 fatty acids, whose use was related to a significant and reliable decrease in cardiovascular disease morbidity and mortality, no evidence is available that demonstrates a preventive effect of lipid-lowering nutraceuticals on hard cardiovascular outcomes. However, for berberine and soluble fibers, the evidence of a positive multimetabolic effect is growing, contributing to a better control of both glucose and lipids values that consequently could be useful in the management of metabolic syndrome. [ABSTRACT FROM AUTHOR]

Background Hypovitaminosis D is common in chronic kidney disease (CKD). Effects of 25-hydroxyvitamin D replenishment in CKD are not well described. Methods An 8-week randomized, placebo-controlled, double-blind parallel intervention study was conducted in haemodialysis (HD) and non-HD CKD patients. Treatment consisted of 40 000 IU of cholecalciferol orally per week. Plasma 25-hydroxyvitamin D (25-OHD), plasma 1,25-dihydroxyvitamin D (1,25-diOHD), plasma parathyroid hormone (PTH), serum phosphate, ionized serum calcium and serum fibroblast growth factor 23 (FGF-23) were analysed. We also investigated biomarkers related to cardiovascular disease (plasma D-dimer, plasma fibrinogen, plasma von Willebrand factor antigen and activity, plasma interleukin 6, plasma C-reactive protein, blood pressure, aortic augmentation index, aortic pulse wave velocity and 24-h urinary protein loss). Objective and subjective health variables were assessed (muscle function tests, visual analogue scores and Health Assessment Questionnaire). Results Fifty-two CKD patients with 25-OHD <50 nmol/L at screening were included. Cholecalciferol supplementation led to a significant increase to a median of 155 nmol/L 25-OHD (interquartile range 137–173 nmol/L) in treated patients (n = 25, P < 0.001). In non-HD patients, we saw a significant increase in 1,25-diOHD (n = 13, P < 0.01) and a lowering of PTH (n = 13, P < 0.001). This was not observed in HD patients. Cholecalciferol supplementation caused a significant increase in serum calcium and FGF-23. Conclusions 25-OHD replenishment was effectively obtained with the employed cholecalciferol dosing. In non-HD patients, it had favourable effects on 1,25-diOHD and PTH. Vitamin D-supplemented patients must be monitored for hypercalcaemia. The present study could not identify significant pleiotropic effects of 25-OHD replenishment. [ABSTRACT FROM PUBLISHER]

Risk factors (RF) of cardiovascular diseases associated with modern lifestyle, such as stress, chronically increased blood pressure, hyperglycemia and dyslipidemia have a negative impact on the heart exposed to ischemia: their may facilitate its lethal injury (myocardial infarction) and occurrence of sudden death due to ventricular arrhythmias. On the other hand, some stressful stimuli related to RF including reactive oxygen species, transient episodes of ischemia (hypoxia), high glucose and other may play a dual role in the pathogenesis of ischemia/reperfusion (I/R) injury (IRI). Besides their deleterious effects, these factors may trigger adaptive processes in the heart resulting in greater resistance against IRI, which is also a characteristic feature of the female myocardium. However, sensitivity to ischemia is increasing with age in both genders. Current research indicates that comorbidity related to lifestyle may impair the cardiac response to acute ischemia not only by interference with pathophysiological mechanisms of IRI per se, but via suppression of intrinsic protective mechanisms in the heart and its ability to tolerate the ischemic challenges, although the role of RF has not been unequivocally proven. Moreover, even pathologically altered myocardium need not completely lose its adaptive potential. In addition, increased ischemic tolerance can be induced by the pleiotropic (independent of the primary) effects of some hypolipidemic and antidiabetic drugs, even in the diseased myocardium. This review addresses the issue of the impact of RF on cellular cardioprotective mechanisms and the possibilities to restore adaptive potential in subjects challenged with several RF. Reactivation of adaptive processes in the myocardium taking into consideration gender and age can contribute to optimalization of antiischemic therapy. [ABSTRACT FROM AUTHOR]

We analyzed two mutant mouse lines, ATE1 and ATE2, that carry point mutations in the enamelin gene which result in premature stop codons in exon 8 and exon 7, respectively. Both mutant lines show amelogenesis imperfecta. To establish the effect of mutations within the enamelin gene on different organs, we performed a systematic, standardized phenotypic analysis of both mutant lines in the German Mouse Clinic. In addition to the initially characterized tooth phenotype that is present in both mutant lines, we detected effects of enamelin mutations on bone and energy metabolism, as well as on clinical chemical and hematological parameters. These data raise the hypothesis that enamelin defects have pleiotropic effects on organs other than the teeth. [ABSTRACT FROM AUTHOR]

Clinical trials have reported reduced cardiovascular events with certain antihypertensive agents at a rate that could not be predicted by changes in brachial arterial pressure alone. These findings may be explained, in part, by pleiotropic effects of these agents and modulation of central blood pressures. This review focuses on the mechanisms by which calcium channel blockers exert pleiotropic effects, both alone and in combination with statins and inhibitors of the renin-angiotensin system. The essential role of nitric oxide (NO) in maintaining endothelial function and the relationship between NO and reactive oxygen species are discussed in the context of the etiology of hypertension. The importance of managing global cardiovascular risk is emphasized, as hypertension commonly clusters with dyslipidemia and loss of glucose control. From a mechanistic viewpoint, these risk factors contribute to endothelial dysfunction, oxidative stress, and inflammation in a synergistic fashion. A greater understanding of the mechanisms of actions of these cardiovascular agents may lead to more effective drug combinations, to the benefit of individual patients. Furthermore, by elucidating the biological mechanisms by which cardiovascular risk factors lead to vascular injury, we may highlight common pathways and identify novel therapeutic targets. [ABSTRACT FROM AUTHOR]

Abstract: The analysis of the causes of selection is in essence a problem in ecology Wade and Kalisz 1990 Past evolution determines the genetically determined available phenotypes in populations which affect ecological dynamics in communities, shaping in turn the selective pressures that further model phenotypes. Because an increase in temperature increases metabolic rates and encounter rates, climate change may have profound eco-evolutionary effects, possibly affecting the future persistence and functioning of food webs. We introduce a semi-spatially explicit individual-based model (IBM) framework to study functional eco-evolutionary dynamics in food webs. Each species embedded in the web includes 13 genetically determined and multidimensionally variable traits (the G matrix), 4 of which are flexible physiological and behavioural (personality) traits that respond to temperature. An increase in temperature and stronger correlation among traits leads to stronger trophic cascades but higher stochasticity, with higher probability of extinction for some trophic levels. A combination of the abiotic (temperature) and biotic (predators’ presence/absence) matrix of selective agents (the O matrix) generates differential selection for activation energies for metabolic rates and several instances of correlational selection (selection in one trait changes with the levels of another), suggesting how global warming might favour certain trait combinations. Our results and the future prospects of this IBM approach open new avenues for climate change research. [Copyright &y& Elsevier]

The hydroxy-methyl-glutaryl-CoA reductase inhibitors (statins) are used extensively in the treatment of hyperlipidemia. They have also demonstrated a benefit in a variety of other disease processes via actions known as pleiotropic effects. Our paper serves as a focused review of pre-clinical investigations and published clinical data regarding the pleiotropic effects of statins in malignancies and emphasizes the importance of randomized, placebo-controlled trials to further elucidate this interesting phenomenon. [ABSTRACT FROM AUTHOR]

The 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins) have potent anti-inflammatory, vasodilatory and anti-platelet effects that are independent of the lipid-lowering effects. These non-lipid-lowering or pleiotropic effects are dependent on HMG-CoA reductase inhibition in tissues other than the liver. In animal models, high-dose statins upregulate cytosolic phospholipase A and cyclooxygenase-2, leading to increased production of prostacyclin and 15-deoxy-PGJ. In addition, statins activate protein kinase A, which phosphorylates 5-lipoxygenase, resulting in decreased production of the pro-inflammatory leukotrienes and increased production of 15-epi-lipoxin A4, an eicosanoid with potent anti-inflammatory and inflammation-resolution properties. It is unclear, however, whether these effects occur in the clinical setting and whether these effects (partially) explain the anti-inflammatory effects of statins in patients. [ABSTRACT FROM AUTHOR]

Abstract: Rodents are mostly controlled by using anticoagulant rodenticides to minimise adverse effects along the food production chain. Genetic resistance to anticoagulant compounds occurs in populations of Norway rats (Rattus norvergicus) and other rodents throughout the world. This can be problematic for control operations and put predators and scavengers at risk because resistant prey individuals carry high anticoagulant loads. Single nucleotide polymorphisms (SNPs) in the vitamin K reductase complex subunit 1 (VKORC1) gene that are associated with rodenticide resistance are related to several pleiotropic effects including increased vitamin K requirement. The uptake of dietary vitamin K available from food sources present on farms including corn silage and garden herbs may mitigate such effects. We tested the preference for food rich in vitamin K1/3 in Norway rats susceptible or resistant to bromadiolone due to the homozygous amino acid variant Tyr139Cys. We also studied the effect of vitamin K consumption from several food sources on blood clotting in bromadiolone resistant and susceptible Norway rats. There was no general preference of rats for food sources rich in vitamin K. Surprisingly, there was no effect of vitamin K uptake on blood clotting times. However, the consumption of 4 of 5 corn silages prevented the rise in blood clotting times that otherwise occurred in vitamin K deficient bromadiolone resistant rats. This seemed to be due to substances with vitamin K activity present in silage and may contribute to the sustaining and spreading SNPs that are related to rodenticide resistance. As corn silage is becoming increasingly available to rats due to the expansion in generating bio-energy from corn silage, there may be a future increase in the occurrence of anticoagulant resistant Norway rats and associated problems in agro-ecosystems. [Copyright &y& Elsevier]

Although both lipophilic and more hydrophilic statins share the same pathway of the inhibition of HMG-CoA reductase, their pleiotropic cardioprotective effects associated with the ability to cross cellular membranes, including membranes of heart cells, may differ. To test this hypothesis, isolated rat hearts were Langendorff-perfused either with simvastatin (S, 10 µmol/l) or pravastatin (P, 30 µmol/l), 15 min prior to ischemia. Control untreated hearts (C) were perfused with perfusion medium only. Postischemic contractile dysfunction, reperfusion-induced ventricular arrhythmias and infarct size were investigated after exposure of the hearts to 30-min global ischemia and 2-h reperfusion. Both lipophilic S and hydrophilic P reduced the severity of ventricular arrhythmias (arrhythmia score) from 4.3±0.2 in C to 3.0±0 and 2.7±0.2 in S and P, respectively, (both P<0.05), decreased the duration of ventricular tachycardia and suppressed ventricular fibrillation. Likewise, the extent of lethal injury (infarct size) determined by tetrazolium staining and expressed in percentage of risk area, was significantly lower in both treated groups, moreover, the effect of P was more pronounced (27±2 % and 10±2 % in S and P groups, respectively, vs. 42±1 % in C; P<0.05). In contrast, only S, but not P, was able to improve postischemic recovery of left ventricular developed pressure (LVDP; 48±12 % of preischemic values vs. 25±4 % in C and 21±7 % in P groups; P<0.05). Our results suggest that differences in water solubility of statins indicating a different ability to cross cardiac membranes may underlie their distinct cardioprotective effects on myocardial stunning and lethal injury induced by ischemia/reperfusion. [ABSTRACT FROM AUTHOR]

Multiple previous reports confirm that several missense alleles of MSX1 exhibit Mendelian inheritance of an oligodontia phenotype (agenesis of more than six secondary teeth besides third molars). However, the extent to which missense MSX1 alleles contribute to common, multifactorial disorders is less certain. It is still not yet clear whether multiple non-synonomous MSX1-coding variants identified among patients with oral clefting are merely neutral polymorphisms or whether any of these might represent real mutations with mild effects. The present work steps toward resolving these issues for at least one MSX1 allele: R151S, previously identified in a single Japanese proband with unilateral cleft lip and palate. Candidate gene sequencing within a patient cohort demonstrating mild tooth agenesis (loss of six or less secondary teeth besides third molars, hypodontia), secondarily identified this same MSX1 variant, functioning as a mildly deleterious, moderately penetrant allele. Four of five heterozygous R151S individuals from one Japanese family exhibited the hypodontia phenotype. The in vitro functional assays of the variant protein display partial repression activity with normal nuclear localization. These data establish that the MSX1-R151S allele is a low-frequency, mildly deleterious allele for familial hypodontia that alone is insufficient to cause oral facial clefting. Yet, as this work also establishes its hypomorphic nature, it suggests that it may in fact contribute to the likelihood of common birth disorder phenotypes, such as partial tooth agenesis and oral facial clefting. Nevertheless, the exact mechanism in which differential pleiotropy is manifested will need further and deeper clinical and functional analyses. [ABSTRACT FROM AUTHOR]

Statins are potent lipid-lowering drugs but anti-inflammatory effects have also been suggested. Our aim was to investigate the effects of simvastatin on proinflammatory cytokines and matrix metalloproteinases (MMPs). Eighty hypercholesterolemic men were randomized to simvastatin 40 mg or placebo for 6 weeks. Simvastatin treatment significantly reduced C-reactive protein (CRP) levels while interleukin (IL)-6 levels remained unchanged. The ex vivo release of IL-1β and IL-6 was not altered by simvastatin, whereas the release of TNF-α and IL-8 increased after 6 weeks of simvastatin treatment. Similarly, the circulating levels of MMP-3 and TIMP-1 remained unaffected by simvastatin while MMP-9 increased. However, none of the effects except for the CRP reduction within the simvastatin group reached statistical significance when compared to the placebo group. Our findings are in contrast to previous in vitro and animal data and question the in vivo relevance of some of the pleiotropic effects of simvastatin. [ABSTRACT FROM AUTHOR]

Infectious diseases represent a continuously growing menace that has severe impact on health of the people worldwide, particularly in the developing countries. Therefore, novel prevention and treatment strategies are urgently needed to reduce the rate of these diseases in humans. For this reason, different options can be considered for the production of affordable vaccines. Plants have been proved as an alternative expression system for various compounds of biological importance. Particularly, plastid genetic engineering can be potentially used as a tool for cost-effective vaccine production. Antigenic proteins from different viruses and bacteria have been expressed in plastids. Initial immunological studies of chloroplast-derived vaccines have yielded promising results in animal models. However, because of certain limitations, these vaccines face many challenges on production and application level. Adaptations to the novel approaches are needed, which comprise codon usage and choice of proven expression cassettes for the optimal yield of expressed proteins, use of inducible systems, marker gene removal, selection of specific antigens with high immunogenicity and development of tissue culture systems for edible crops to prove the concept of low-cost edible vaccines. As various aspects of plant-based vaccines have been discussed in recent reviews, here we will focus on certain aspects of chloroplast transformation related to vaccine production against human diseases. [ABSTRACT FROM AUTHOR]

Abstract: Background: The full impact of statins on patients with chronic heart failure (CHF) is unknown. Therefore, we aimed to evaluate the pleiotropic effects of rosuvastatin on vascular and tissue regeneration, its impact on endothelial function and hemodynamics in CHF. Methods: Forty-two patients with CHF (LVEF 30±1%) were randomized to 12weeks of oral rosuvastatin (40mg/d) or placebo. At baseline and at 12weeks, VEGF and oxidized LDL (oxLDL) were assessed by ELISA. Circulating endothelial progenitor cells (CPCs) were quantified using FACS. CPC function was determined by matrigel assay. Number of CD34+ stem cells and capillary density were measured in skeletal muscle (SM). Flow-mediated dilatation (FMD) and left ventricular (LV) function were determined by ultrasound. Results: Rosuvastatin increased VEGF by +43% (p =0.004 vs. placebo) and decreased oxLDL by −27% (p =0.04 vs. placebo). This was associated with an elevation in CPC count by +224% (p =0.04 vs. placebo) and an augmentation of CPC integrative capacity by +91% (p =0.03 vs. placebo). Capillary density increased by +14% (p <0.001 vs. placebo), which was associated with an enhanced homing of CD34+ stem cells. Rosuvastatin improved FMD by +163% (p <0.001 vs. placebo) and enhanced ejection fraction by +27% (p <0.001 vs. placebo). Conclusion: In CHF, rosuvastatin activates CPCs that contribute to neovascularisation and to the enhancement of endothelial function. Correction of vascular abnormalities leads in part to an increase in LV function. Therefore, rosuvastatin''s non-lipid effects may have the potential to promote endogenous tissue regeneration and improve LV performance in CHF. [Copyright &y& Elsevier]

Protease inhibitors are a promising complement to Bt toxins for the development of insect-resistant transgenic crops, but their limited specificity against proteolytic enzymes and the ubiquity of protease-dependent processes in living organisms raise questions about their eventual non-target effects in agroecosystems. After a brief overview of the main factors driving the impacts of insect-resistant transgenic crops on non-target organisms, the possible effects of protease inhibitors are discussed from a multitrophic perspective, taking into account not only the target herbivore proteases but also the proteases of other organisms found along the trophic chain, including the plant itself. Major progress has been achieved in recent years towards the design of highly potent broad-spectrum inhibitors and the field deployment of protease inhibitor-expressing transgenic plants resistant to major herbivore pests. A thorough assessment of the current literature suggests that, whereas the non-specific inhibitory effects of recombinant protease inhibitors in plant food webs could often be negligible and their ‘unintended’ pleiotropic effects in planta of potential agronomic value, the innocuity of these proteins might always remain an issue to be assessed empirically, on a case-by-case basis. [ABSTRACT FROM PUBLISHER]

This paper compares the pleiotropic effects of statins and omega-3 fatty acids (n-3 PUFA) in treating and preventing cardiovascular disease (CVD) and deals with the possible interactions of those compounds. Statins represent one of the most important discoveries to have been made in the field of cardiovascular medicine in recent decades. Their beneficial cardiovascular effects, which have reduced the number of fatal events in patients with atherosclerosis, encompass more than their ability to lower cholesterol levels. The pleiotropic effects of statins involve their anti-inflammatory and antiplatelet properties and their ability to normalize endothelial function. In addition, these drugs may display antiarrhythmic activity, improve insulin sensitivity and counteract hypertension and obesity. The low rate of coronary disease documented in Eskimos corroborates the cardioprotective effects of the n-3 PUFA eicosapentaenoic (EPA) and docosahexaenoic acids beyond their hypolipemic effects. The reduction of CVD-related deaths attributable to the action of α-linolenic fatty acid appears to be related to its strong antiarrhythmic properties. In addition, as a precursor of EPA and this last fatty acid of thromboxane A3, prostacyclin I3, serie-3 prostaglandines and serie 5- leukotrines and inhibitor/modulator of thromboxane A2, prostacyclin I2, serie-2 prostaglandines and serie 4- leukotrienes formation, the α-linolenic acid may reduce inflammation and thrombogenesis. As results of some studies suggest that the combined use of statins and n-3 PUFA improves cardiovascular protection and reduces the CVD-related mortality rate; the paper also reviews the possible synergism between both groups of compounds on CVD treatment and concludes that clear benefits may be obtained. [ABSTRACT FROM AUTHOR]

Background and Aims It has been proposed that variation in pollinator preferences or a fluctuating environment can act to maintain flower colour polymorphism. These two hypotheses were tested in an aquatic monocot Butomus umbellatus (Butomaceae) with a pink or white gynoecium in the field population. Methods Pollinator visitation was compared in experimental arrays of equivalent flowering cymes from both colour morphs. Seed set was compared between inter- and intramorph pollination under different water levels to test the effect of fluctuating environment on seed fertility. Key Results Overall, the major pollinator groups did not discriminate between colour morphs. Compared with the white morph, seed production in the pink morph under intermorph, intramorph and open pollination treatments was significantly higher when the water level was low but not when it was high. Precipitation in July was correlated with yearly seed production in the pink morph but not in the white morph. Conclusions The results indicated that the two colour morphs differed in their tolerance to water level. Our study on this aquatic plant provides additional evidence to support the hypothesis that flower colour polymorphism can be preserved by environmental heterogeneity. [ABSTRACT FROM PUBLISHER]

The search for susceptibility loci in hereditary prostate cancer (HPC) is challenging because of locus and disease heterogeneity. One approach to reduce disease heterogeneity is to stratify families on the basis of the occurrence of multiple cancer types. This method may increase the power for detecting susceptibility loci, including those with pleiotropic effects. We have completed a genome-wide SNP linkage analysis of 96 HPC families, each of which has one or more first-degree relatives with colon cancer (CCa), and further analyzed the subset of families with two or more CCa cases (n=27). When only a prostate cancer (PCa) phenotype was considered to be affected, we observed suggestive evidence for linkage (LOD ≥1.86) at 15q14, 18q21 and 19q13 in all families, and at 1p32 and 15q11-q14 in families with two or more CCa cases. When both the PCa and CCa phenotypes were considered affected, suggestive evidence for linkage was observed at 11q25, 15q14 and 18q21 in all families, and at 1q31, 11q14 and 15q11-14 in families with two or more CCa cases. The strongest linkage signal was identified at 15q14 when both PCa and CCa phenotypes were considered to be affected in families with two or more CCa cases (recessive HLOD=3.88). These results provide further support for the presence of HPC susceptibility loci on chromosomes 11q14, 15q11-q14 and 19q13 and highlight loci at 1q31, 11q, 15q11-14 and 18q21 as having possible pleiotropic effects. This study shows the benefit of using a comprehensive family cancer history to create more genetically homogenous subsets of HPC families for linkage analyses. [ABSTRACT FROM AUTHOR]

The effective optimization of the modifiable risk factors for the development of atherosclerosis is the cornerstone preventive cardiology. Risk factor clustering has been demonstrated to occur in a higher prevalence than would be expected by chance alone. The common cardiovascular risk factors frequently share metabolic pathways. Inflammation and oxidative stress are demonstrable in the major cardiovascular risk factors. Hypertension and dyslipidemia frequently co-exist in an individual. The advent of statin therapy has allowed optimization of the lipid profile and achievement of therapeutic goals advocated by the Adult Treatment Panel of the National Cholesterol Education Program. Statin therapy has been demonstrated to exhibit a wide variety of nonlipid or pleiotropic effects. Observational studies have demonstrated that statin therapy may cause a small but statistically significant alteration of blood pressure. Prospective clinical trials have demonstrated that statin therapy reduces this cardiovascular risk in both hypertensive and normotensive individuals. The potential role of statin therapy in blood pressure reduction is compatible with several pleiotropic mechanisms of statin therapy. However, a significant body of data from prospective, well-designed, controlled clinical trials that have analyzed the effect of statin therapy on blood pressure as the primary end point is lacking. This review examines the observational relationship between hypertension and dyslipidemia, the potential mechanisms by which statin therapy may lower blood pressure, and selected clinical trial data. [ABSTRACT FROM AUTHOR]

Background. Cardiovascular morbidity and mortality are massively increased in patients with chronic kidney disease (CKD). Sevelamer hydrochloride has been shown to attenuate cardiovascular calcifications in CKD and end-stage renal disease (ESRD) patients. We assessed how sevelamer hydrochloride influences the evolution of serum fetuin-A and other serological factors predicting cardiovascular outcome and survival in haemodialysis patients. [ABSTRACT FROM PUBLISHER]

Statins are effective drugs for treatment and prevention of cardiovascular diseases. Besides their lipid-lowering properties, statins act through multiple pleiotropic effects including vasoprotective mechanisms, effects on coagulation, anti-inflammatory properties and stabilization of atherosclerotic plaques. In recent years many studies have investigated the effects of statins administered to patients in the perioperative period. Results indicate that the perioperative use of statins is beneficial, most of all for patients with a high cardiovascular risk profile. However, most study designs are retrospective and vulnerable to systematic bias. The number of randomized controlled trials is very limited and include only low numbers of patients. Currently it is not known when perioperative treatment with statin should be started and how long it should be continued postoperatively to reach optimal protective effects. A pre-existing statin therapy should be continued perioperatively because discontinuation leads to a higher rate of complications in the perioperative period. Larger randomized controlled trials are therefore necessary to evaluate the efficiency and the safety of perioperative statin use, especially for patients with a low or intermediate cardiovascular risk profile. [ABSTRACT FROM AUTHOR]

Abstract: Background: Pharmaceutical stabilisation of the abdominal aortic aneurysm (AAA) wall can delay surgery and improve outcome. Observational studies indicate statins can be used to reduce AAA growth but mechanistic data are scarce. In this study, our aim was to determine the pleiotropic effects of different statins on AAA wall composition. Methods: We included 216 patients undergoing open AAA repair, of which 60 used simvastatin, 52 atorvastatin and 23 pravastatin. The AAA wall histology and protein expression (IL 1β,2,4,5,6,8,10,12, interferon-gamma (IFNγ), tumour necrosis factor (TNF)α,β, matrix metalloproteinase (MMP)2 and 9 activities, total MMP8,9 and cathepsin A and B levels) between statin users and non-users were compared as also among the use of different statins. Results: As far as histological inflammation goes, the AAA walls of statin users did not differ from those not using them. After multivariate adjustment for risk factors, pravastatin use was associated with tendencies of increased MMP8 (p = 0.022), active MMP9 (p = 0.040) and higher cathepsin B (p = 0.056) levels. The AAA walls of simvastatin and atorvastatin users showed no differences in proteases or cytokines in multivariate analyses. Conclusions: The use of statins was not associated with a decrease in protease levels or inflammation. The trends of elevated protease levels associated with pravastatin use suggest pleiotropic differences among the various statins, supporting the need for further research to target pharmaceutical AAA treatment. [Copyright &y& Elsevier]

The objective of this study was to investigate the gene expression signature of monocyte/macrophages and the pleiotropic effects of atorvastatin on monocytes in atherosclerotic patients. Forty patients with coronary heart diseases were randomly assigned to double-blind therapy with either 20 or 80 mg per day of atorvastatin. Follow-up visits occurred at weeks 6 and 12, including complete chemistry and lipid analyses and quantification of 14 target genes in monocytes. After 12 weeks of therapy, both groups gained beneficial alterations in lipid profiles. Both groups experienced significant reductions in gene expression of lipoprotein-associated phospholipase A2, CD13, leptin receptor, matrix metalloproteases-1, legumain, and prolyl oligopeptidase after 12 weeks of therapy. Only tumor protein 53 was increased in the atorvastatin 80-mg group. Moreover, nonsignificant interactions between dosage and duration of therapy were found. The pleiotropic effects of statins in atherosclerotic patients include increased expression of genes involved in apoptosis of monocyte/ macrophage, inhibition of inflammatory responses, antioxi-dant properties, prevention of foam cell formation, and stabilization of atherosclerotic plaques. This property fuels potential clinical significance. [ABSTRACT FROM AUTHOR]

Statins possess several pleiotropic effects and have been shown in vitro and in vivo to inhibit the expression of inflammatory mediators and downregulate molecules involved in extracellular matrix (ECM) degradation. Recent observational studies in humans suggest that statins may have a role in abdominal aortic aneurysm (AAA) prevention or may even inhibit aneurysm expansion. In this review, we summarize the effects of statins on the vessel wall of aneurysmal aortas and currently available data concerning their inhibitory effects on aneurysm progression. [ABSTRACT FROM AUTHOR]

The 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) are the second most prescribed therapeutic drug class in the United States after analgesics. Although these agents are used predominantly to reduce cholesterol concentrations in patients with hyperlipidemia, numerous studies have investigated the pleiotropic effects of statins and their potential in the prevention and/or treatment of other disease states, including cancer. Many theories have been proposed as to how statins may affect the risk or development of malignancies, prompting a clinical review of the literature. Studies have revealed statins to be associated with both increased and decreased cancer risk. Most of the published studies have been observational and retrospective in nature, and most prospective trials evaluated cancer as a secondary end point or adverse event, making it difficult to determine causality. Although most of the available evidence suggests a possible beneficial effect of statins on cancer, further study is needed with better designed trials and/or increased efforts in evaluating cancer as secondary end points in all statin trials until definite conclusions regarding statin effects on cancer risk and occurrence can be made. [ABSTRACT FROM AUTHOR]

Objectives: This meta-analysis was performed to determine the effects of various cholesterol-lowering treatments on the risk of stroke and its relationship with the extent of cholesterol lowering. Background: Statins reduce the incidence of stroke, and it has been proposed that such effect is independent of cholesterol lowering and is explained by alternative mechanisms. Methods: We performed a meta-analysis of randomized trials of cholesterol-lowering treatments in cardiovascular disease reporting on stroke, involving 266,973 patients investigated and a cumulative 946,582 person-years of exposure, and a meta-regression analysis of the extent of stroke reduction as a function of changes in total cholesterol. Results: The odds ratio (OR) for the incidence of stroke in actively treated groups versus controls was 0.88 (95% confidence interval: 0.83 to 0.94, p < 0.001). No treatment affected fatal strokes. Whereas statins decreased the risk of total stroke significantly (OR: 0.85, 95% confidence interval: 0.78 to 0.92; p < 0.001), the benefit of nonstatin interventions was smaller and not statistically significant (diet OR: 0.92, fibrates OR: 0.98, other treatments OR: 0.81). We found a significant relationship between percent reduction of total (and low-density lipoprotein) cholesterol and percent reduction of total strokes (p = 0.0017), with each 1% reduction of total cholesterol predicting a 0.8% relative risk reduction of stroke. We found no significant association between stroke reduction and changes of high-density lipoprotein cholesterol levels, and inconsistent associations with reduction of triglycerides. Conclusions: Among cholesterol-lowering treatments, statins are the most effective at decreasing the risk of total stroke, but their benefit is proportional to the percent reduction of total cholesterol and low-density lipoprotein cholesterol. No lipid-lowering intervention was associated with a reduction of fatal stroke. [Copyright &y& Elsevier]

Objectives. To investigate the impact of lipid lowering therapy by different means on skin microvascular function in patients with dysglycaemia and coronary artery disease (CAD). Design and setting. Thirty-six patients were randomized to simvastatin 80 mg daily (S80, n = 19) or ezetimibe 10 mg and simvastatin 10 mg daily (E10/S10, n = 17) for 6 weeks. Skin microvascular function was assessed by laser Doppler fluxmetry (LDF) at rest, following arterial occlusion (peak postocclusive LDF) and following local heating on the forearm (heat arm LDF) and foot (heat foot LDF). LDF parameters and serum lipids were evaluated at baseline and follow-up. Results. At follow-up, LDL cholesterol had decreased from 3.1 (2.7–3.5) to 1.6 (1.5–1.8) (mmol L−1) and 3.0 (2.4–3.9) to 1.3 (1.1–1.8) (mmol L−1) in the E10/S10 and S80 groups respectively. In the entire study group ( n = 32), LDF parameters increased significantly; postocclusive LDF from 22 (17–27) to 26 (21–32) perfusion units (PU) ( P < 0.001), heat foot LDF from 61 (44–82) to 66 (45–83) PU ( P < 0.001) and heat arm LDF from 60 (48–121) to 75 (54–125) PU ( P < 0.01). The changes in LDF parameters did not differ between the E10/S10 and S80 groups. Conclusions. Lipid lowering improves microvascular function in patients with dysglycaemia and CAD. The data suggest that lipid lowering per se is more important than pleiotropic effects of statins for this effect. [ABSTRACT FROM AUTHOR]

Abstract: Endocrine systems have an important mechanistic role in structuring life-history trade-offs. During breeding, individual variation in prolactin (PRL) and corticosterone (CORT) levels affects behavioral and physiological processes that drive trade-offs between reproduction and self-maintenance. We examined patterns in baseline (BL) and stress induced (SI; level following a standard capture-restraint protocol) levels of PRL and CORT for breeding mourning doves (Zenaida macroura). We determined whether the relationship of adult condition and parental effort to hormone levels in wild birds was consistent with life-history predictions. Both BL PRL and BL CORT level in adults were positively related to nestling weight at early nestling ages, consistent with the prediction of a positive relationship of hormone levels to current parental effort of adults and associated increased energy demand. Results are consistent with the two hormones acting together at baseline levels to limit negative effects of CORT on reproduction while maintaining beneficial effects such as increased foraging for nestling feeding. Our data did not support predictions that SI responses would vary in response to nestling or adult condition. The magnitude of CORT response in the parents to our capture-restraint protocol was negatively correlated with subsequent parental effort. Average nestling weights for adults with the highest SI CORT response were on average 10–15% lighter than expected for their age in follow-up visits after the stress event. Our results demonstrated a relationship between individual hormone levels and within population variation in parental effort and suggested that hormonal control plays an important role in structuring reproductive decisions for mourning doves. [Copyright &y& Elsevier]

Abstract: The effects of statins in chronic kidney disease (CKD) are incompletely understood. To date, no clinical trial has provided definitive evidence that cholesterol lowering treatments reduce cardiovascular morbidity and mortality in CKD patients. Moreover, existing preclinical data suggest both a renoprotective effect of statins (highlighted by reduction in the rate of the decline of GFR and reduction of proteinuria) and a harmful effect (mainly by accelerating renal fibrosis) in the long-term management of patients with CKD. Although several post-hoc analyses and meta-analyses of large randomized clinical trials of statins in cardiovascular disease have provided important insights into their role in affecting the rate of renal function deterioration in CKD, no randomized clinical study has directly addressed this issue in CKD patients. In this review, we discuss the preclinical and clinical evidence supporting the beneficial or harmful effects of statins in CKD patients and propose specific recommendations regarding their use in this patient population. [Copyright &y& Elsevier]

Statins, the inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, are most frequently used drugs in the prevention of coronary artery disease due to their cholesterol-lowering activity. However, it is not exactly known whether these effects of statins or those independent of cholesterol decrease account for the protection against myocardial ischemia-reperfusion (I/R) injury. In this study, we investigated the effect of 5-day treatment with simvastatin (10 mg/kg) in Langendorff-perfused hearts of healthy control (C) and diabetic-hypercholesterolemic (D-H; streptozotocin + high fat-cholesterol diet, 5 days) rats subjected to 30-min global ischemia followed by 40-min reperfusion for the examination of postischemic contractile dysfunction and reperfusion-induced ventricular arrhythmias or to 30-min (left anterior descending) coronary artery occlusion and 2-h reperfusion for the infarct size determination (IS; tetrazolium staining). Postischemic recovery of left ventricular developed pressure (LVDP) in animals with D-H was improved by simvastatin therapy (62.7±18.2 % of preischemic values vs. 30.3±5.7 % in the untreated D-H; P<0.05), similar to the values in the simvastatin-treated C group, which were 2.5-fold higher than those in the untreated C group. No ventricular fibrillation occurred in the simvastatin-treated C and D-H animals during reperfusion. Likewise, simvastatin shortened the duration of ventricular tachycardia (10.2±8.1 s and 57.8±29.3 s in C and D-H vs. 143.6±28.6 s and 159.3±44.3 s in untreated C and D-H, respectively, both P<0.05). The decreased arrhythmogenesis in the simvastatin-treated groups correlated with the limitation of IS (in % of risk area) by 66 % and 62 % in C and D-H groups, respectively. However, simvastatin treatment decreased plasma cholesterol levels neither in the D-H animals nor in C. The results indicate that other effects of statins (independent of cholesterol lowering) are involved in the improvement of contractile recovery and attenuation of lethal I/R injury in both, healthy and diseased individuals. [ABSTRACT FROM AUTHOR]