N-Octanoyl-Dopamine inhibits cytokine production in activated T-cells and diminishes MHC-class-II expression as well as adhesion molecules in IFN gamma-stimulated endothelial cells

IFN gamma enhances allograft immunogenicity and facilitates T-cell mediated rejection. This may cause interstitial fibrosis and tubular atrophy (IFTA), contributing to chronic allograft loss. We assessed if inhibition of T-cell activation by N-octanoyl dopamine (NOD) impairs adherence of activated T-cells to endothelial cells and the ability of activated T-cells to produce IFN gamma. We also assessed if NOD affects IFN gamma mediated gene expression in endothelial cells. The presence of NOD during T-cell activation significantly blunted their adhesion to unstimulated and cytokine stimulated HUVEC. Supernatants of these T-cells displayed significantly lower concentrations of TNF alpha and IFN gamma and were less capable to facilitate T-cell adhesion. In the presence of NOD VLA-4 (CD49d/CD29) and LFA-1 (CD11a/CD18) expression on T-cells was reduced. NOD treatment of IFN gamma stimulated HUVEC reduced the expression of MHC class II transactivator (CIITA), of MHC class II and its associated invariant chain CD74. Since IFTA is associated with T-cell mediated rejection and IFN gamma to a large extent regulates immunogenicity of allografts, our current data suggest a potential clinical use of NOD in the treatment of transplant recipients. Further in vivo studies are warranted to confirm these in vitro findings and to assess the benefit of NOD on IFTA in clinically relevant models

A GIS-Cellular Automata-Based Model for Coupling Urban Sprawl and Flood Susceptibility Assessment

In Urban Planning (UP), it is necessary to take under serious consideration the inhibitors of the spread of a settlement in a specific direction. This means that all those parameters for which serious problems may arise in the future should be considered. Among these parameters are geo-hazards, such as floods, landslides, mud movement, etc. This study deals with UP taking into account the possibility of widespread flooding in settlement expansion areas. There is a large flooding history in Greece, which is accompanied by a significant number of disasters in different types of land use/land cover, with a large financial cost of compensation and/or rehabilitation. The study area is the drainage basin of Erasinos River in the Attica Region, where many and frequent flood events have been recorded. The main goal of this study is to determine the flood susceptibility of the study area, taking into account possible factors that are decisive in flood occurrence. Furthermore, the flood susceptibility is also determined, taking into account the scenarios of precipitation and the urban sprawl scenario in the area of reference. The study of flood events uses the Analytic Hierarchy Process (AHP) model and the urban sprawl model SLEUTH, which calibrates historical urban growth, using open and cost-free data and software. Eventually, flood susceptibility maps were overlaid with future urban areas to find the vulnerable areas. Following, three scenarios of flood susceptibility with the corresponding susceptibility maps and vulnerability maps, which measure the flood susceptibility of the current and future urban space of the study area, are presented. The results have shown significant peaks in the moderate class of flood susceptibility, while, in the third scenario, high values of flood susceptibility seem to appear. The proposed methodology and specifically the output maps can serve as a decision support tool to assist urban planners and hazard managers in making informed decisions towards sustainable urban planning

A GIS-Cellular Automata-Based Model for Coupling Urban Sprawl and Flood Susceptibility Assessment

In Urban Planning (UP), it is necessary to take under serious consideration the inhibitors of the spread of a settlement in a specific direction. This means that all those parameters for which serious problems may arise in the future should be considered. Among these parameters are geo-hazards, such as floods, landslides, mud movement, etc. This study deals with UP taking into account the possibility of widespread flooding in settlement expansion areas. There is a large flooding history in Greece, which is accompanied by a significant number of disasters in different types of land use/land cover, with a large financial cost of compensation and/or rehabilitation. The study area is the drainage basin of Erasinos River in the Attica Region, where many and frequent flood events have been recorded. The main goal of this study is to determine the flood susceptibility of the study area, taking into account possible factors that are decisive in flood occurrence. Furthermore, the flood susceptibility is also determined, taking into account the scenarios of precipitation and the urban sprawl scenario in the area of reference. The study of flood events uses the Analytic Hierarchy Process (AHP) model and the urban sprawl model SLEUTH, which calibrates historical urban growth, using open and cost-free data and software. Eventually, flood susceptibility maps were overlaid with future urban areas to find the vulnerable areas. Following, three scenarios of flood susceptibility with the corresponding susceptibility maps and vulnerability maps, which measure the flood susceptibility of the current and future urban space of the study area, are presented. The results have shown significant peaks in the moderate class of flood susceptibility, while, in the third scenario, high values of flood susceptibility seem to appear. The proposed methodology and specifically the output maps can serve as a decision support tool to assist urban planners and hazard managers in making informed decisions towards sustainable urban planning

Identifying individuals at risk of needing CKD associated medications in a European kidney disease cohort

Background The consequences of chronic kidney disease (CKD) can be addressed with a range of pharmacotherapies primarily prescribed by nephrologists. More accurate information regarding future CKD-related pharmacotherapy requirements could guide clinical decisions including follow-up frequency. Methods Following assignment to derivation and validation groups (2,1), variables predicting individually future use of vitamin D receptor agonists (VDRA), phosphate binders, erythropoiesis stimulating agents (ESAs) and iron were identified using logistic regression in a prospective cohort study containing demography, comorbidity, hospitalization, laboratory, and mortality data in patients with CKD stage G4/G5 across six European countries. Discriminative ability was measured using C-statistics, and predicted probability of medication use used to inform follow-up frequency. Results A total of 2196 patients were included in the analysis. During a median follow-up of 735 days 648 initiated hemodialysis and 1548 did not. Combinations of age, diabetes status and iPTH, calcium, hemoglobin and serum albumin levels predicted the use of ESA, iron, phosphate binder or VDRA, with C-statistics of 0.70, 0.64, 0.73 and 0.63 in derivation cohorts respectively. Model performance in validation cohorts were similar. Sixteen percent of patients were predicted to have a likelihood of receiving any of these medications of less than 20%. Conclusions In a multi-country CKD cohort, prediction of ESA and phosphate binder use over a two-year period can be made based on patient characteristics with the potential to reduce frequency of follow-up in individuals with low risk for requiring these medications

Atrial fibrillation in chronic hemodialysis patients: Prevalence, types, predictors, and treatment practices in Greece

Atrial fibrillation (AF), the most common sustained arrhythmia in clinical practice, is associated with increased mortality and cardiovascular morbidity both in nonuremic and (recently) in dialysis patients. The aims of this study are: (i) to assess the prevalence of AF, the risk factors, and predictors of its presence in a cohort of incident hemodialysis (HD) patients in Greece and (ii) to report on current practices in the management of these patients. This is a prospective, cross-sectional, multicenter study of 574 patients on a regular HD program for >6 months. Demographic characteristics, cause of renal disease, cardiovascular risk factors, medication use, dialysis data (Kt/V, dialysis method, type of dialysate), 12-lead electrocardiogram (ECG) (interdialytic day), and cardiac echo data were collected. Pertinent demographic, ECG, and echocardiographic data were entered into univariate and multivariate analyses to evaluate associations with AF. The CHADS2 score (congestive heart failure [HF], hypertension, age ≥75, diabetes, previous stroke/transient ischemic attack [TIA]) was estimated and clinical practices in high-risk (CHADS2 score ≥2) patients were evaluated. The cohort included 368 men (64.1%) and 206 (35.8%) women (mean age 65.1±14.4 years) with a mean duration on dialysis of 72.1±60.4 months. Hypertension (75.6%) and coronary artery disease (47.2%) were the commonest cardiovascular risk factors for AF. The prevalence of AF was 23.2% and showed an age-dependent increase; in patients <50 years, AF was present in 9.3%, while in patients ≥80 years, its prevalence increased to 36.4%. Furthermore, 8.3% of patients had permanent, 1.8% persistent, 12.7% paroxysmal AF, while the prevalence of paroxysmal atrial flutter and sick sinus syndrome were 1.2 and 2%, respectively. Logistic regression analysis showed that age, smoking, left atrial and aortic root diameter, β-blocker and α-calcidol use, HF, and the presence of valvular calcifications (VC) on cardiac echo were independently associated to the presence of AF. VC on cardiac echo had an almost sevenfold increased association with AF (odds ratio 6.72, 95% confidence interval 3.23-13.98, P<0.0001). Only 25.5% of high-risk (CHADS2 score ≥2) patients were receiving anticoagulants. AF is a frequent arrhythmia in HD patients. Apart from well-known risk factors, VC merits special attention in this patient population. Less than one-third of high-risk AF patients receive anticoagulants, possibly reflecting the absence of definite guidelines for the management of AF in HD patients. © 2011, the Authors. Artificial Organs © 2011, International Center for Artificial Organs and Transplantation and Wiley Periodicals, Inc

Enzyme-triggered CO-releasing molecules (ET-CORMs): Evaluation of biological activity in relation to their structure

Acyloxydiene-Fe(CO)(3) complexes act as enzyme-triggered CO-releasing molecules (ET-CORMs) and can deliver CO intracellularly via esterase-mediated hydrolysis. The protective properties of structurally different ET-CORMs on hypothermic preservation damage and their ability to inhibit VCAM-1 expression were tested on cultured human umbilical vein endothelial cells (HUVEC) and renal proximal tubular epithelial cells (PTEC) using a structure-activity approach. Cytotoxicity of ET-CORMs, protection against hypothermic preservation damage, and inhibition of VCAM-1 expression were assessed. Cytotoxicity of 2-cyclohexenone and 1,3-cyclohexanedione-derived ET-CORMs was more pronounced in HUVEC compared to PTEC and was dependent on the position and type of the ester (acyloxy) substituent(s) (acetate > pivalate > palmitate). Protection against hypothermic preservation injury was only observed for 2-cyclohexenone-derived ET-CORMs and was not mediated by the ET-CORM decomposition product 2-cyclohexenone itself. Structural requirements for protection by these ET-CORMs were different for HUVEC and PTEC. Protection was affected by the nature of the ester functionality in both cell lines. VCAM-1 expression was inhibited by both 2-cyclohexenone- and 1,3-cyclohexanedione-derived ET-CORMs. 2-Cyclohexenone, but not 1,3-cyclohexanedione, also inhibited VCAM-1 expression. We demonstrate that structural alterations of ET-CORMs significantly affect their biological activity. Our data also indicate that different ET-CORMs behave differently in various cell types (epithelial vs endothelial). These findings warrant further studies not only to elucidate the structure-activity relation of ET-CORMs in mechanistic terms but also to assess if structural optimization will yield ET-CORMs with restricted cell specificity. (C) 2013 Elsevier Inc. All rights reserved

Different design of enzyme-triggered CO-releasing molecules (ET-CORMs) reveals quantitative differences in biological activities in terms of toxicity and inflammation

Acyloxydiene–Fe(CO)3 complexes can act as enzyme-triggered CO-releasing molecules (ET-CORMs). Their biological activity strongly depends on the mother compound from which they are derived, i.e. cyclohexenone or cyclohexanedione, and on the position of the ester functionality they harbour. The present study addresses if the latter characteristic affects CO release, if cytotoxicity of ET-CORMs is mediated through iron release or inhibition of cell respiration and to what extent cyclohexenone and cyclohexanedione derived ET-CORMs differ in their ability to counteract TNF-α mediated inflammation. Irrespective of the formulation (DMSO or cyclodextrin), toxicity in HUVEC was significantly higher for ET-CORMs bearing the ester functionality at the outer (rac-4), as compared to the inner (rac-1) position of the cyclohexenone moiety. This was paralleled by an increased CO release from the former ET-CORM. Toxicity was not mediated via iron as EC50 values for rac-4 were significantly lower than for FeCl2 or FeCl3 and were not influenced by iron chelation. ATP depletion preceded toxicity suggesting impaired cell respiration as putative cause for cell death. In long-term HUVEC cultures inhibition of VCAM-1 expression by rac-1 waned in time, while for the cyclohexanedione derived rac-8 inhibition seems to increase. NFκB was inhibited by both rac-1 and rac-8 independent of IκBα degradation. Both ET-CORMs activated Nrf-2 and consequently induced the expression of HO-1. This study further provides a rational framework for designing acyloxydiene–Fe(CO)3 complexes as ET-CORMs with differential CO release and biological activities. We also provide a better understanding of how these complexes affect cell-biology in mechanistic terms