Dialysis,cardiovascular disease,and the future

Atherosclerosis, particularly coronary atherosclerosis, is accelerated in renal failure, as originally postulated by Belding Scribner. But in contrast to previous opinion, myocardial infarction from coronary heart disease is not the single major cause of cardiac death in dialyzed patients, the most common causes being sudden death and cardiac failure. Apart from coronary heart disease, the following cardiomyopathic features are prevalent and explain a large part of the excess cardiac risk: cardiomyocyte dropout, left ventricular hypertrophy, cardiac interstitial fibrosis, microangiopathy with arteriolar thickening, and capillary deficit as well as reduced ischemia tolerance. Recently, cardiovascular risk factors related to abnormal mineral metabolism, particularly phosphate and vitamin D, have gained unanticipated importance. Controlled evidence has become available concerning intervention with ACE inhibitors, angiotensin receptor blockers, β‐blockers, and statins in dialyzed patients. It is imperative that apart from the “classical” cardiovascular risk factors that do not exhaustively explain the excessive cardiovascular risk in dialyzed patients, novel pathomechanisms are considered and investigated; potential examples include depression, sleep abnormalities, etc. The above arguments do not negate the fact that today's modalities of renal replacement therapy are poor substitutes for the normal kidney's function so that as a result alternative strategies, e.g., daily dialysis, may also dramatically improve cardiovascular risk.     

EPC 2000 – State of play nearly two years on

The European Patent Convention as revised in 2000 (EPC 2000) [1] entered into force on 13 December 2007. While the revision changed rather little in terms of substantive patent law, it did change procedural practice compared to the EPC in force before, drafted in 1973. This article looks at some key features of the European patent grant and post-grant procedures that either have changed fundamentally or have been newly introduced, and their effect on patent document collections.     

Role of VEGF-A and Its Receptors in Sporadic and MEN2-Associated Pheochromocytoma

Pheochromocytoma (PHEO), a rare catecholamine producing tumor arising from the chromaffin cells, may occurs sporadically (76%–80%) or as part of inherited syndromes (20%–24%). Angiogenesis is a fundamental step in tumor proliferation and vascular endothelial growth factor (VEGF-A) is the most well-characterized angiogenic factor. The role of angiogenic markers in PHEO is not fully understood; investigations were therefore made to evaluate the expression of VEGF-A and its receptors in PHEO and correlate to clinical parameters. Twenty-nine samples of PHEO were evaluated for VEGF-A, VEGF receptor-1 (VEGFR-1) VEGFR-2 expression and microvessel density (MVD) by immunohistochemistry. Clinical data were reviewed in medical records. The mean age of patients was 38 ± 14 years, and 69% were woman. VEGF-A, VEGFR-1 and VEGFR-2 staining were detected in nearly all PHEO samples. No significant correlation was observed between VEGF-A, VEGFR-1, VEGFR-2 expression or MVD and age at diagnosis, tumor size or sporadic and hereditary PHEO. However, the levels of expression of these molecules were significantly higher in malignant PHEO samples (p = 0.027, p = 0.003 and p = 0.026, respectively).VEGF-A and its receptors were shown to be up-regulated in malignant PHEO, suggesting that these molecules might be considered as therapeutic targets for unresectable or metastatic tumors.     

Binding to Large Enzyme Pockets: Small‐Molecule Inhibitors of Trypanothione Reductase

The causative agents of the parasitic disease human African trypanosomiasis belong to the family of trypanosomatids. These parasitic protozoa exhibit a unique thiol redox metabolism that is based on the flavoenzyme trypanothione reductase (TR). TR was identified as a potential drug target and features a large active site that allows a multitude of possible ligand orientations, which renders rational structure‐based inhibitor design highly challenging. Herein we describe the synthesis, binding properties, and kinetic analysis of a new series of small‐molecule inhibitors of TR. The conjunction of biological activities, mutation studies, and virtual ligand docking simulations led to the prediction of a binding mode that was confirmed by crystal structure analysis. The crystal structures revealed that the ligands bind to the hydrophobic wall of the so‐called “mepacrine binding site”. The binding conformation and potency of the inhibitors varied for TR from Trypanosoma brucei and T. cruzi.     

Integrated satellite-HAP systems

Thus far, high-altitude platform (HAP)-based systems have been mainly conceived as an alternative to satellites for complementing the terrestrial network. This article aims to show that HAP should no longer be seen as a competitor technology by investors of satellites, but as a key element for an efficient hybrid terrestrial-satellite communication system. Two integrated HAP-satellite scenarios are presented, in which the HAP is used to overcome some of the shortcomings of satellite-based communications. Moreover, it is shown that the integration of HAPs with satellite systems can be used to provide more efficient fleet-management and traffic-control services and more powerful data-relay systems.     

Melt Electrospinning Writing of Highly Ordered Large Volume Scaffold Architectures

The additive manufacturing of highly ordered, micrometer‐scale scaffolds is at the forefront of tissue engineering and regenerative medicine research. The fabrication of scaffolds for the regeneration of larger tissue volumes, in particular, remains a major challenge. A technology at the convergence of additive manufacturing and electrospinning–melt electrospinning writing (MEW)–is also limited in thickness/volume due to the accumulation of excess charge from the deposited material repelling and hence, distorting scaffold architectures. The underlying physical principles are studied that constrain MEW of thick, large volume scaffolds. Through computational modeling, numerical values variable working distances are established respectively, which maintain the electrostatic force at a constant level during the printing process. Based on the computational simulations, three voltage profiles are applied to determine the maximum height (exceeding 7 mm) of a highly ordered large volume scaffold. These thick MEW scaffolds have fully interconnected pores and allow cells to migrate and proliferate. To the best of the authors knowledge, this is the first study to report that z‐axis adjustment and increasing the voltage during the MEW process allows for the fabrication of high‐volume scaffolds with uniform morphologies and fiber diameters.     

Correlations and population dynamics in cortical networks

The function of cortical networks depends on the collective interplay between neurons and neuronal populations, which is reflected in the correlation of signals that can be recorded at different levels. To correctly interpret these observations it is important to understand the origin of neuronal correlations. Here we study how cells in large recurrent networks of excitatory and inhibitory neurons interact and how the associated correlations affect stationary states of idle network activity. We demonstrate that the structure of the connectivity matrix of such networks induces considerable correlations between synaptic currents as well as between subthreshold membrane potentials, provided Dale's principle is respected. If, in contrast, synaptic weights are randomly distributed, input correlations can vanish, even for densely connected networks. Although correlations are strongly attenuated when proceeding from membrane potentials to action potentials (spikes), the resulting weak correlations in the spike output can cause substantial fluctuations in the population activity, even in highly diluted networks. We show that simple mean-field models that take the structure of the coupling matrix into account can adequately describe the power spectra of the population activity. The consequences of Dale's principle on correlations and rate fluctuations are discussed in the light of recent experimental findings.     

ASSESSING THE CUMULATIVE IMPACTS OF HYDROPOWER REGULATION ON THE FLOW CHARACTERISTICS OF A LARGE ATLANTIC SALMON RIVER SYSTEM

We assessed the influence of hydropower on the flow characteristics of the river Tay, one of the UK's most heavily regulated catchments and important Atlantic salmon fisheries. Hydropower developments in the mid‐20th century preceded flow data collection, resulting in knowledge gaps over how far regulated flows deviate from natural and how ecosystem functioning might have been impacted. We used 29 unregulated catchments in and around the Tay to assess the relationships between hydroclimatic conditions, landscape structure and the overall flow regime, as well as the annual, monthly and daily flow metrics. This allowed the identification of flow characteristics by using an integrated suite of regression approaches (nonlinear, MLR and random forests) to assess likely impacts at 11 regulated sites. The results showed that the impacts of regulation are highly variable in both space and time. Headwater sub‐catchments are most heavily affected, and water imports or exports as part of hydropower schemes can increase or decrease annual runoff by up to 50%, respectively. On a monthly basis, regulation primarily increased summer low flows; winter high flows increased in catchments affected by water imports and reduced where there was a net water export. At larger catchment scales, impacts were relatively small, as unregulated tributaries re‐naturalize the flows and the effects of intra‐basin transfers balance. Non‐stationarity in climate and water use in the catchment dictates that adaptive management of flows may be necessary to protect ecosystems services. Copyright © 2013 John Wiley & Sons, Ltd.     

Modelling Sediment Input to Surface Waters for German States with MEPhos: Methodology, Sensitivity and Uncertainty

Soil erosion on arable land and on steep vineyards is a major problem in the state of Hesse (21,115 km2) in central Germany. The aim of a joint study between the Research Centre Jülich, the Hessian Agency for the Environment and Geology and the Hessian Ministry for the Environment, Energy, Agriculture and Consumer Protection was to delineate parcels which are severely affected by erosion and to identify sediment source areas. For this purpose, the ABAG, an adaptation of the USLE approach to German conditions, has been employed with the best available data sets on K-, C-, R- and LS-factor. Model results at the field scale show that soil losses in Hesse vary between <0.5 and >15 tonnes/hectare/year. The mean loss amounts to ca. 4.3 tonnes/hectare/year. The sediment delivery ratios for 450 sub-catchments range between 0.5 and 78% with a mean of 18%. Further analysis showed that LS- and C-factor are of highest sensitivity for the model output. Therefore, the effects of alternative algorithms or sources for LS- and C-factor on the results were assessed. An uncertainty analysis based on Gaussian error propagation and Monte Carlo simulation showed that the uncertainty of model results induced by input parameters is 1.7 tonnes/hectare/year or 34% of the mean annual soil loss. The model results are a good basis for further works concerning a soil erosion atlas and internet-based soil data viewer.