Search

We construct embedded functional connectivity networks (FCN) from benchmark resting-state functional magnetic resonance imaging (rsfMRI) data acquired from patients with schizophrenia and healthy controls based on linear and nonlinear manifold learning algorithms, namely, Multidimensional Scaling, Isometric Feature Mapping, Diffusion Maps, Locally Linear Embedding and kernel PCA. Furthermore, based on key global graph-theoretic properties of the embedded FCN, we compare their classification potential using machine learning. We also assess the performance of two metrics that are widely used for the construction of FCN from fMRI, namely the Euclidean distance and the cross correlation metric. We show that diffusion maps with the cross correlation metric outperform the other combinations.

Hereditary Hemorrhagic Telangiectasia type 1 (HHT1) is an autosomal dominant inherited disease characterized by arteriovenous malformations and hemorrhage. HHT1 is caused by mutations in ENDOGLIN, which encodes an ancillary receptor for Transforming Growth Factor-β/Bone Morphogenetic Protein-9 expressed in all vascular endothelial cells. Haploinsufficiency is widely accepted as the underlying mechanism for HHT1. However, it remains intriguing that only some, but not all, vascular beds are affected, as these causal gene mutations are present in vasculature throughout the body. Here, we have examined the endoglin expression levels in the blood vessels of multiple organs in mice and in humans. We found a positive correlation between low basal levels of endoglin and the general prevalence of clinical manifestations in selected organs. Endoglin was found to be particularly low in the skin, the earliest site of vascular lesions in HHT1, and even undetectable in the arteries and capillaries of heterozygous endoglin mice. Endoglin levels did not appear to be associated with organ-specific vascular functions. Instead, our data revealed a critical endoglin threshold compatible with the haploinsufficiency model, below which endothelial cells independent of their tissue of origin exhibited abnormal responses to Vascular Endothelial Growth Factor. Our results support the development of drugs promoting endoglin expression as potentially protective.

We localize the sources of brain activity of children with epilepsy based on electroencephalograph (EEG) recordings acquired during a visual discrimination working memory task. For the numerical solution of the inverse problem, with the aid of age-specific MRI scans processed from a publicly available database, we use and compare three regularization numerical methods, namely the standardized low resolution brain electromagnetic tomography (sLORETA), the weighted minimum norm estimation (wMNE) and the dynamic statistical parametric mapping (dSPM). We show that all three methods provide the same spatio-temporal patterns of differences between the groups of epileptic and control children. In particular, our analysis reveals statistically significant differences between the two groups in regions of the parietal cortex indicating that these may serve as "biomarkers" for diagnostic purposes and ultimately localized treatment.

Background: Hereditary Hemorrhagic Telangiectasia type 2 (HHT2) is an inherited genetic disorder characterized by vascular malformations and hemorrhage. HHT2 results from ACVRL1 haploinsufficiency, the remaining wild-type allele being unable to contribute sufficient protein to sustain endothelial cell function. Blood vessels function normally but are prone to respond to angiogenic stimuli, leading to the development of telangiectasic lesions that can bleed. How ACVRL1 haploinsufficiency leads to pathological angiogenesis is unknown. Methods: We took advantage of Acvrl1 +/− mutant mice that exhibit HHT2 vascular lesions and focused on the neonatal retina and the airway system after Mycoplasma pulmonis infection, as physiological and pathological models of angiogenesis, respectively. We elucidated underlying disease mechanisms in vitro by generating Acvrl1 +/− mouse embryonic stem cell lines that underwent sprouting angiogenesis and performed genetic complementation experiments. Finally, HHT2 plasma samples and skin biopsies were analyzed to determine whether the mechanisms evident in mice are conserved in humans. Results: Acvrl1 +/− retinas at postnatal day 7 showed excessive angiogenesis and numerous endothelial “tip cells” at the vascular front that displayed migratory defects. Vascular endothelial growth factor receptor 1 (VEGFR1; Flt-1) levels were reduced in Acvrl1 +/− mice and HHT2 patients, suggesting similar mechanisms in humans. In sprouting angiogenesis, VEGFR1 is expressed in stalk cells to inhibit VEGFR2 (Flk-1, KDR) signaling and thus limit tip cell formation. Soluble VEGFR1 (sVEGFR1) is also secreted, creating a VEGF gradient that promotes orientated sprout migration. Acvrl1 +/− embryonic stem cell lines recapitulated the vascular anomalies in Acvrl1 +/− (HHT2) mice. Genetic insertion of either the membrane or soluble form of VEGFR1 into the ROSA26 locus of Acvrl1 +/− embryonic stem cell lines prevented the vascular anomalies, suggesting that high VEGFR2 activity in Acvrl1 +/− endothelial cells induces HHT2 vascular anomalies. To confirm our hypothesis, Acvrl1 +/− mice were infected by Mycoplasma pulmonis to induce sustained airway inflammation. Infected Acvrl1 +/− tracheas showed excessive angiogenesis with the formation of multiple telangiectases, vascular defects that were prevented by VEGFR2 blocking antibodies. Conclusions: Our findings demonstrate a key role of VEGFR1 in HHT2 pathogenesis and provide mechanisms explaining why HHT2 blood vessels respond abnormally to angiogenic signals. This supports the case for using anti-VEGF therapy in HHT2.

Within the Interstitial Lung Diseases (ILD), patients with idiopathic pulmonary fibrosis (IPF) and a subset of those with non-IPF fibrotic ILD have a distinct clinical phenotype of progression despite management. This group of patients has been collectively termed the progressive fibrotic phenotype (PFP). Their early recognition may facilitate access to antifibrotic therapies to prevent or slow progression. Macrophages/monocytes within the lung orchestrate the progression and maintenance of fibrosis. A novel role for monocyte-derived macrophages during tissue damage and wound healing is the expression of collagens. We examined Collagen 1a1 expression in airway macrophages from ILD patients at diagnosis. COL1A1 mRNA levels from BAL cells were elevated in IPF and Non-IPF patients. The presence of a UIP pattern and a subsequent progressive phenotype were significantly associated with the higher BAL COL1A1 levels. In Non-IPF patients, higher COL1A1 levels were associated with a more than twofold increase in mortality. The intracellular localisation of COL1A1 in airway macrophages was demonstrated by confocal microscopy in CD45 and CD163 co-staining assays. Additionally, airway macrophages co-expressed COL1A1 with the profibrotic SPP1 gene product osteopontin. The levels of SPP1 mRNA and OPN in the BAL were significantly higher in IPF and Non-IPF patients relative to healthy. Our results suggest that profibrotic airway macrophages are increased in the BAL of patients with IPF and other ILDs and co-express COL1A1 and OPN. Importantly, COL1A1 expression by pro-fibrotic airway macrophages could be a marker of disease progression and poor survival in ILDs.

Hereditary hemorrhagic telangiectasia (HHT) is a genetic disorder characterized by multi-systemic vascular dysplasia affecting 1 in 5000 people worldwide. Individuals with HHT suffer from many complications including nose and gastrointestinal bleeding, anemia, iron deficiency, stroke, abscess, and high-output heart failure. Identification of the causative gene mutations and the generation of animal models have revealed that decreased transforming growth factor-β (TGF-β)/bone morphogenetic protein (BMP) signaling and increased vascular endothelial growth factor (VEGF) signaling activity in endothelial cells are responsible for the development of the vascular malformations in HHT. Perturbations in these key pathways are thought to lead to endothelial cell activation resulting in mural cell disengagement from the endothelium. This initial instability state causes the blood vessels to response inadequately when they are exposed to angiogenic triggers resulting in excessive blood vessel growth and the formation of vascular abnormalities that are prone to bleeding. Drugs promoting blood vessel stability have been reported as effective in preclinical models and in clinical trials indicating possible interventional targets based on a normalization approach for treating HHT. Here, we will review how disturbed TGF-β and VEGF signaling relates to blood vessel destabilization and HHT development and will discuss therapeutic opportunities based on the concept of vessel normalization to treat HHT.

Autotaxin (ATX) is a secreted glycoprotein, widely present in biological fluids including blood. ATX catalyzes the hydrolysis of lysophosphatidylcholine (LPC) to lysophosphatidic acid (LPA), a growth factor-like, signaling phospholipid. LPA exerts pleiotropic effects mediated by its G-protein-coupled receptors that are widely expressed and exhibit overlapping specificities. Although ATX also possesses matricellular properties, the majority of ATX reported functions in adulthood are thought to be mediated through the extracellular production of LPA. ATX-mediated LPA synthesis is likely localized at the cell surface through the possible interaction of ATX with integrins or other molecules, while LPA levels are further controlled by a group of membrane-associated lipid-phosphate phosphatases. ATX expression was shown to be necessary for embryonic development, and ATX deficient embryos exhibit defective vascular homeostasis and aberrant neuronal system development. In adult life, ATX is highly expressed in the adipose tissue and has been implicated in diet-induced obesity and glucose homeostasis with multiple implications in metabolic disorders. Additionally, LPA has been shown to affect multiple cell types, including stromal and immune cells in various ways. Therefore, LPA participates in many processes that are intricately involved in the pathogenesis of different chronic inflammatory diseases such as vascular homeostasis, skeletal and stromal remodeling, lymphocyte trafficking and immune regulation. Accordingly, increased ATX and LPA levels have been detected, locally and/or systemically, in patients with chronic inflammatory diseases, most notably idiopathic pulmonary fibrosis (IPF), chronic liver diseases, and rheumatoid arthritis. Genetic and pharmacological studies in mice have confirmed a pathogenetic role for ATX expression and LPA signaling in chronic inflammatory diseases, and provided the proof of principle for therapeutic interventions, as exemplified by the ongoing clinical trials for IPF.

The majority of end-stage renal patients undergoing maintenance hemodialysis (HD) develop anemia that adversely affects their quality of life and increases the risk for cardiovascular events and death. Thus, the development of safe and effective strategies aimed at correcting anemia in these patients is of utmost importance.1 Unfortunately, the response to erythropoietin (EPO) treatment is often suboptimal, due mainly to an imbalance between the surging iron requirements of the stimulated erythropoietic cells on the one hand and iron availability on the other. Thus, intravenous (i.v.) administration of iron-containing preparations is widely used in order to circumvent this imbalance. However, questions about the efficacy and the safety of this loading strategy still remain unanswered.1

Background High expression levels of Inhibitors of Apoptosis Proteins (IAPs) have been correlated with poor cancer prognosis and block the cell death pathway by interfering with caspase activation. SMAC-mimetics are small-molecule inhibitors of IAPs that mimic the endogenous SMAC and promote the induction of cell death by neutralizing IAPs. Methods In this study, anti-tumour activity of new SMAC-mimetics Birinapant and AT-406 is evaluated against colorectal adenocarcinoma cells and IAP cross-talk with either oncogenic BRAF or BCL-2, or with the TRAIL are further exploited towards rational combined protocols. Results It is shown that pre-treatment of SMAC-mimetics followed by their combined treatment with BRAF inhibitors can decrease cell viability, migration and can very efficiently sensitize colorectal tumour cells to apoptosis. Moreover, co-treatment of TRAIL with SMAC-mimetics can efficiently sensitize resistant tumour cells to apoptosis synergistically, as shown by median effect analysis. Finally, Birinapant and AT-406 can synergise with BCL-2 inhibitor ABT-199 to reduce viability of adenocarcinoma cells with high BCL-2 expression. Conclusions Proposed synergistic rational anticancer combined protocols of IAP antagonists Birinapant and AT-406 in 2D and 3D cultures can be later further exploited in vivo, from precision tumour biology to precision medical oncology. Electronic supplementary material The online version of this article (doi:10.1186/s12885-016-2606-5) contains supplementary material, which is available to authorized users.

Atrial fibrillation (AF) is the most common arrhythmia encountered in clinical practice representing a major health hazard. Owing to relative inefficacy and side effects of classic antiarrhythmic drugs, current interest has shifted to treatments that target AF substrate. Accumulating evidence suggests that there is a link between oxidative processes and AF. In atrial myocardium during AF, there is substantial oxidative damage that may contribute to atrial remodeling. Several pathophysiological changes that possibly associated with increased oxidative stress in AF have been proposed. These include changes in gene transcriptional profiles and mitochondrial DNA, increased activity of enzymes such as NAD(P)H oxidase and xanthine oxidase, inflammatory processes, activation of the renin-angiotensin system and others. Moreover, oxidative stress is involved in the pathophysiology of several predisposing factors and cardiovascular disorders that correspondingly associated with AF. Preliminary studies using dietary antioxidants such as vitamin C have shown promising results. More evidence has been obtained from studies examining agents with pleiotropic effects, including antioxidant, such as inhibitors of the renin-angiotensin system, statins, corticosteroids and carvedilol. Further investigations are needed in order to elucidate the impact of oxidative stress on atrial remodeling. The clarification of these processes in the setting of AF may lead to the development of novel therapeutic strategies.

The patient’s position during laparoscopic surgery can have a clinically relevant effect on lower limb and splanchnic circulation; this factor has not yet been investigated with respect to oxidative stress markers. In order to assess this effect, a prospective clinical trial was designed wherein 2 groups of patients were studied. In group A, 15 patients underwent upper abdominal nonhepatobiliary operations (13 modified Nissen fundoplications and 2 Taylor vagotomies) in the head-up position. In group B, 15 patients underwent lower abdominal operations (10 laparoscopic colectomies and 5 inguinal hernia repairs) in the head-down position. The pneumoperitoneum was maintained at 14 mm Hg in all cases. Plasma concentrations of thiobarbituric-acid reactive substances (TBARS), a marker of lipid peroxidation, plasma total antioxidant status (TAS), and serum uric acid concentrations were measured preoperatively, 5 minutes after deflation of the pneumoperitoneum, and 24 hours postoperatively. Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) serum activities were measured preoperatively and 24 hours postoperatively. In group A, there was a significant increase in TBARS levels (p

Background/Aims: Oxidative damage has been reported to be involved in the pathophysiology of chronic kidney disease (CKD) as well as in the pathogenesis of cardiovascular complications of CKD patients. The aim of the present investigation was to evaluate the levels of plasma carbonyl formation, a sensitive marker of enhanced oxidative stress in predialysis, hemodialysis (HD) and peritoneal dialysis (PD) patients. Methods: Plasma samples from 20 apparently healthy control individuals and 127 CKD (stages 2, 3, 4, HD and PD) patients were evaluated by Western blot analysis for the estimation of the levels of protein carbonyl formation. Results: Albumin represented the main plasma carbonylated protein. Increasing carbonylation of albumin was detected along with the severity of CKD, reaching significance at stages 3 and 4 (p < 0.01, compared to healthy controls). The carbonylation of albumin was even higher in the plasma of HD patients (p < 0.001), while in PD patients it was not statistically significant compared to controls (p = 0.224). Conclusions: The data presented in this work indicate that oxidative stress in CKD patients gradually increased during the development of the disease. This stress is probably intensified during HD, but not in PD subjects.

Apoptosis has been suggested to have an important role in the pathogenesis of restenosis in addition to cell migration and proliferation. The aim of the present study was to investigate in an experimental in vivo model the occurrence of apoptosis postangioplasty and its relation to bcl-2 and peroxynitrite detection. Eighteen hypercholesterolemic rabbits underwent transluminal angioplasty of the right iliac artery. The rabbits were sacrificed on the 1st, 2nd, 3rd, 7th, 15th, and 28th day postangioplasty (3 animals per time point) and both the angioplasted and non-injured arteries were studied. Apoptosis was assessed by the terminal uridine nick-end labeling method (TUNEL). Bcl-2 and peroxynitrite were detected by immunochemistry using anti-bcl-2 and anti-nitrotyrosine antibodies. In the angioplasted arteries the number of apoptotic cells was

Ischemia-reperfusion (IR) injury is a multifactorial process triggered when the liver or other organs are transiently subjected to reduced blood supply followed by reperfusion. It has been shown that "reactive oxygen species" (ROS) are generated during ischemia and reperfusion and may represent pivotal mediators of the ensuing pathological complications. In some cases, however, moderate production of ROS may exert protective effects, a phenomenon presumably related to "ischemic preconditioning". This review will focus mainly on: a) describing the sources and the biochemical mechanisms of ROS generation during ischemia and reperfusion, b) discussing current developments in understanding the biochemical pathways by which ROS may induce toxic or protective effects, c) critically evaluating the results of previous attempts to counteract the toxic effects of ROS by using a variety of antioxidant and transition metal-chelating agents, and d) if feasible, proposing potential new pharmaceutical agents aimed at ameliorating ROS-inducing deleterious effects during reperfusion. It is concluded that ROS are generated from different sources, at different periods during IR, and may act by a variety of not well understood biochemical mechanisms which ultimately lead to cell damage and tissue failure. Curr Pharm Des

Am J Kidney Dis

1. Apart from ‘no-reflow’ phenomenon/microvascular injury and myocardial injury/stunning, both of which undoubtedly constitute the MRI, one cannot ignore the reperfusion arrhythmias that considerably contribute to myocardial dysfunction observed in this setting [2]. 2. It is prudent to acknowledge that various problems in the experimental study of MRI still exist and sometimes provoke confusion [3,4]. The duration of ischemia, the timing of drug administration, the drug delivery method and the selection of end-points for cardioprotection, are some of them. For example, it is highly possible that intravenous (and not intracoronary) administration of drugs during ischemia may not reach the ischemic area in the absence of collaterals. 3. It is well established that repetitive short periods of ischemia may be cardioprotective due to induction of ischemic preconditioning [5]. On the other hand, repetitive stunning may lead to chronic stunning which is believed to be a form of myocardial hibernation [5,6]. Consequently, the concept of MRI has currently become more complex and subtle manipulations are needed in order to alleviate its detrimental effects and potentate its potential favorable effects.

● Background: A growing body of evidence suggesting that oxidative stress might be one of the most important complications occurring during hemodialysis (HD) has accumulated. However, although the role of reactive oxygen species has been investigated extensively, little is known about the involvement of reactive nitrogen species. In the present investigation, levels of protein modifications in the form of tyrosine nitration in patients undergoing long-term HD therapy were evaluated. Methods: Tyrosine nitration of plasma proteins was detected by means of Western blotting using a specific nitrotyrosine-recognizing monoclonal antibody, and band intensity was evaluated by using image analysis software. Immunoprecipitation of plasma proteins by antinitrotyrosine-agarose‐ conjugated antibodies, followed by Western blotting, was used in an attempt to identify the nitrated proteins. Results: Although several proteins with nitrated tyrosine residues were observed in plasma of healthy individuals, increased nitration levels were observed in some specific proteins in all patients tested (n 25) compared with controls (n 6). At least 6 apparent bands appeared to be more nitrated than their counterparts in plasma from controls. Ceruloplasmin was identified as 1 of the proteins with significantly increased nitration in patients. Conclusion: Results of the present investigation show that specific plasma proteins of HD patients are posttranslationally modified by nitration of their tyrosine residues. The nature of these proteins, as well as the exact molecular mechanisms and consequences of these modifications, warrant additional investigation. Am J Kidney Dis 44:286-292. © 2004 by the National Kidney Foundation, Inc.

Lancet

Ageing research in Greece is well established. Research groups located in universities, research institutes or public hospitals are studying various and complementary aspects of ageing. These research activities include (a) functional analysis of Clusterin/Apolipoprotein J, studies in healthy centenarians and work on protein degradation and the role of proteasome during senescence at the National Hellenic Research Foundation; (b) regulation of cell proliferation and tissue formation, a nationwide study of determinants and markers of successful ageing in Greek centenarians and studies of histone gene expression and acetylation at the National Center for Scientific Research, Demokritos; (c) work on amyloid precursor protein and Presenilin 1 at the University of Athens; (d) oxidative stress-induced DNA damage and the role of oncogenes in senescence at the University of Ioannina; (e) studies in the connective tissue at the University of Patras; (f) proteomic studies at the Biomedical Sciences Research Center Alexander Fleming; (g) work on Caenorhabditis elegans at the Foundation for Research and Technology; (h) the role of ultraviolet radiation in skin ageing at Andreas Sygros Hospital; (i) follow-up studies in healthy elderly at the Athens Home for the Aged; and (j) socio-cultural aspects of ageing at the National School of Public Health. These research activities are well recognized by the international scientific community as it is evident by the group's very good publication records as well as by their direct funding from both European Union and USA. This article summarizes these research activities and discuss future directions and efforts towards the further development of the ageing field in Greece. Exp Gerontol

Metals are necessary for the normal functioning of cells and the survival of organisms. However, exposure to higher than the physiological levels of several metals may lead to tumor development. Although the exact molecular mechanism(s) of metal-induced carcinogenesis is not clear, a vast body of evidence indicates that metal-induced generation of reactive oxygen species (ROS) may play a central role in this process. Two main pathways of ROS-induced effects are discussed in this chapter: (i) increased DNA damage induced either directly or indirectly by impeding DNA repair, and (ii) modulation of nuclear transcriptional factor activities, such as NF-kappaB and AP-1, through mitogen-activated protein kinases signal transduction mechanisms. Crit Rev Oncol Hematol

Intensive Care Med

Background: The induction of the pneumoperitoneum increases intraabdominal pressure (IAP), causing splanchnic ischemia, whereas its deflation normalizes IAP and splanchnic blood flow. This procedure appears to represent an ischemia-reperfusion model in humans. Methods: Thirty laparoscopic cholecystectomies (LC) were performed in 30 patients with a mean age of 54.6 ± 15.6 years. A group of 20 patients mean age, 57.3 ± 9.65 who underwent open cholecystectomy (OC) was also studied. Vein plasma levels of thiobarbituric acid-reactive substances (TBARS), a marker of free radical production; plasma total antioxidant status (TAS); and uric acid (UA) levels were measured preoperatively, 5 min after deflation of the pneumoperitoneum or at the end of operation, and 24 h postoperatively. Aspartate aminotransferase (AST), alanine aminotransferase (ALT), and total bilirubin (TBL) levels were measured preoperatively and 24 h after the operation. Results: In the LC group, significant elevations in the concentration of TBARS were observed in the early postoperative measurements in comparison with the preoperative measurements. TAS and UA levels were decreased significantly 24 h postoperatively compared to preoperative levels. The postoperative levels of AST, ALT, and TBL increased significantly in comparison with the preoperative levels. In the OC group, no alterations in the concentration of TBARS were observed in the postoperative period. The other parameters had changes similar to those recorded for the LC group. Conclusions: Free radical-induced lipid peroxidation associated with a decrease in plasma antioxidant capacity and UA levels as well as altered hepatic function is observed after deflation of the pneumoperitoneum. These results suggest that free radicals are generated at the end of a laparoscopic procedure, possibly as a result of an ischemia-reperfusion phenomenon induced by the inflation and deflation of the pneumoperitoneum.

OBJECTIVE: To evaluate the safety and efficacy of recombinant gamma interferon (rIFN gamma) in the treatment of patients with systemic sclerosis. METHODS: Sixteen patients with systemic sclerosis were treated with r-IFN gamma, 60 micrograms m-2 (low dose, n = 10) and 150 micrograms m-2 (high dose, n = 6), three times weekly in an open phase I/II trial of eight months duration. The patients were stratified in low and high dose according to the severity and the extent of scleroderma; the two groups were comparable. RESULTS: The treatment was well tolerated. The most common side effects, almost certainly related to r-IFN gamma, were fever, chills, dizziness, headache, and severe flu-like syndrome with decreasing intensity with the time of treatment. Severe aphthous stomatitis (n = 1), ventricular tachycardia (n = 1), severe oesophageal ulcers due to gastro-oesophageal reflux (n = 1), disease exacerbation alone with frank arthritis and slight pericardial effusion (n = 1), and inability to conform to the requirements of the study (n = 1) were the reasons for discontinuing treatment. Side effects and degree of response were evident during the first five months of treatment. A significant decrease in mean skin thickness score was observed and was higher in the high dose group. Reactive oxygen species of peripheral neutrophils and soluble interleukin-2 receptor serum concentrations were higher than those of normal individuals at study entry and decreased in parallel with clinical improvement. CONCLUSIONS: Treatment of systemic sclerosis patients with r-IFN gamma was relatively safe and well tolerated for doses as high as 150 micrograms m-2 three times weekly. Side effects and the degree of response can be seen during the first months of therapy and can be used as predictors of ultimate toxicity or response. The drug seems to be effective in treating cutaneous scleroderma. Ann Rheum Dis

Atrial fibrillation (AF) represents the most frequent The impact of these phenomena in AF remains to be sustained arrhythmia encountered in clinical practice elucidated [7]. [1]. Structural and electrophysiological remodeling is On the other hand, it has been proposed that being widely recognized as a critical process in the inflammatory processes may contribute to atrial repathophysiology of this disorder. Although the exact modeling and promote AF persistence. C-reactive underlying molecular mechanism(s) remain unknown, protein (CRP), a classic inflammatory marker, is calcium overload seems to contribute considerably to strongly associated with the risk for major carthese changes [1]. diovascular events, representing the total inflammaAccumulating evidence supports the role of oxidatory burden in atherosclerotic disease [8]. Currently, a tive stress in cardiac dysfunction under a wide variety novel fascinating association between AF and CRP of pathophysiological conditions [2,3]. Recently, was emerged. Two independent clinical trials that oxidative stress was found to be substantially inappeared simultaneously showed that CRP is sigvolved in the above-mentioned remodeling during AF nificantly elevated in AF patients [9,10]. The eleva[4,5]. In particular, ascorbate (vitamin C), an outtion was significantly greater in individuals suffering standing water-soluble antioxidant, was shown to from persistent AF than those from paroxysmal AF. ameliorate electrophysiological remodeling and reIn addition, CRP proposed to be a determinant of duce the occurrence of postoperative AF, possibly efficient cardioversion of paroxysmal AF in sinus through scavenging of peroxynitrite [5] and other rhythm [10]. Despite the uncertainty whether CRP reactive oxygen species [6]. These toxic molecules elevation is the cause or consequence of AF, the may promote oxidative modification of myofibrillar potential clinical applications of this inflammatory proteins as well as other essential cellular compomarker are promising. nents in atrial myocytes [4]. Furthermore, it is Compelling evidence is accumulating that inflamestablished that oxidative stress can promote calcium mation is associated with antioxidant status [11], overload in myocardial stunning [2] and reduce nitric giving rise to the assumption that CRP may correlate oxide bioavailability in endothelial dysfunction [3]. with oxidative stress observed in AF. It seems reasonable that antioxidant interventions may de*Corresponding author. Laboratory of Biological Chemistry, Universicrease CRP levels and exert favorable effects on ty of Ioannina, Medical School, 45110 Ioannina, Greece. Tel.: 130-6510atrial remodeling. Langlois et al. [12] demonstrated a 97562; fax: 130-6510-67868. E-mail address: pkor@oneway.gr (P. Korantzopoulos). negative association between ascorbate and CRP

Am Heart J