A full subtraction approach for finite element method based source analysis using constrained Delaunay tetrahedralisation

A mathematical dipole is widely used as a model for the primary current source in electroencephalography (EEG) source analysis. In the governing Poisson-type differential equation, the dipole leads to a singularity on the right-hand side, which has to be treated specifically. In this paper, we will present a full subtraction approach where the total potential is divided into a singularity and a correction potential. The singularity potential is due to a dipole in an infinite region of homogeneous conductivity. The correction potential is computed using the finite element (FE) method. Special care is taken in order to evaluate the right-hand side integral appropriately with the objective of achieving highest possible convergence order for linear basis functions. Our new approach allows the construction of transfer matrices for fast computation of the inverse problem for anisotropic volume conductors. A constrained Delaunay tetrahedralisation (CDT) approach is used for the generation of high-quality FE meshes. We validate the new approach in a four-layer sphere model with a highly conductive cerebrospinal fluid (CSF) and an anisotropic skull compartment. For radial and tangential sources with eccentricities up to 1 mm below the CSF compartment, we achieve a maximal relative error of 0.71% in a CDT-FE model with 360 k nodes which is not locally refined around the source singularity and therefore useful for arbitrary dipole locations. The combination of the full subtraction approach with the high quality CDT meshes leads to accuracies that, to the best of the author's knowledge, have not yet been presented before.     

Interdisziplinäre Psoriasisschulung in Blockform für erwachsene Patienten

BACKGROUND: The aim of our pilot study was to evaluate effects of an interdisciplinary training program for adult psoriasis patients after six months follow-up.SUBJECTS AND METHODS: Eleven patients with psoriasis participated in an interdisciplinary training program over a weekend taught by dermatologists, psychologists/psychiatrists, and dieticians. Six months follow-up was performed with a questionnaire.RESULTS: The knowledge acquired improved the cooperation with the treating dermatologist (7 of 11), the patients' ability to cope with their disease (11 of 11), and their ability to improving their health status (8 of 11). Their general well-being was increased (9 of 11) and they could better care for their skin disease because they better understood the need for care (9 of 11), and could better judge the best approach for various levels of disease activity (8 of 11).CONCLUSION: These data show early benefits and suggest such a longer lasting effect of this type of psoriasis training and prevention program. Further studies with larger samples and control parameters will have to examine if these results can be confirmed.     

Interfering with VE-PTP stabilizes endothelial junctions in vivo via Tie-2 in the absence of VE-cadherin

Vascular endothelial (VE)–protein tyrosine phosphatase (PTP) associates with VE-cadherin, thereby supporting its adhesive activity and endothelial junction integrity. VE-PTP also associates with Tie-2, dampening the tyrosine kinase activity of this receptor that can support stabilization of endothelial junctions. Here, we have analyzed how interference with VE-PTP affects the stability of endothelial junctions in vivo. Blocking VE-PTP by antibodies, a specific pharmacological inhibitor (AKB-9778), and gene ablation counteracted vascular leak induction by inflammatory mediators. In addition, leukocyte transmigration through the endothelial barrier was attenuated. Interference with Tie-2 expression in vivo reversed junction-stabilizing effects of AKB-9778 into junction-destabilizing effects. Furthermore, lack of Tie-2 was sufficient to weaken the vessel barrier. Mechanistically, inhibition of VE-PTP stabilized endothelial junctions via Tie-2, which triggered activation of Rap1, which then caused the dissolution of radial stress fibers via Rac1 and suppression of nonmuscle myosin II. Remarkably, VE-cadherin gene ablation did not abolish the junction-stabilizing effect of the VE-PTP inhibitor. Collectively, we conclude that inhibition of VE-PTP stabilizes challenged endothelial junctions in vivo via Tie-2 by a VE-cadherin–independent mechanism. In the absence of Tie-2, however, VE-PTP inhibition destabilizes endothelial barrier integrity in agreement with the VE-cadherin–supportive effect of VE-PTP.The endothelium of the blood vessel wall forms a barrier for blood solutes and for leukocytes. The entry of molecules and cells of the immune system into inflamed tissue is mainly regulated via endothelial junctions. Vascular endothelial (VE)–cadherin is a central component of these junctions, and it is generally considered one of the major adhesive mechanisms that controls the stability and barrier function of the endothelium (Dejana and Vestweber, 2013). Antibodies against VE-cadherin can destabilize endothelial junctions in vitro and in vivo (Breviario et al., 1995; Gotsch et al., 1997; Corada et al., 1999). In agreement with this, enhancing the adhesive function of VE-cadherin by directly fusing it to α-catenin blocks the induction of vascular permeability in the skin of the respective knock-in mice and strongly reduces leukocyte extravasation in various tissues (Schulte et al., 2011).The VE–protein tyrosine phosphatase (PTP) was shown to associate with VE-cadherin and thereby enhance the adhesive function of VE-cadherin (Nawroth et al., 2002; Nottebaum et al., 2008). Permeability-inducing mediators such as VE growth factor (VEGF) and the attachment of leukocytes to endothelial cells (ECs) both stimulate a signaling pathway that triggers the dissociation of VE-PTP from VE-cadherin (Nottebaum et al., 2008; Vockel and Vestweber, 2013). This dissociation is necessary for the induction of vascular permeability and for leukocyte extravasation in vivo. Evidence for this has been based on the analysis of knock-in mice where modified forms of VE-cadherin and VE-PTP, each containing a different binding site for a small molecular weight compound, had been knocked into the VE-cadherin locus (Broermann et al., 2011). In these mice, administration of the appropriate compound inhibited the dissociation of VE-PTP from VE-cadherin and thereby attenuated the induction of vascular permeability and leukocyte extravasation, demonstrating the importance of VE-cadherin–associated VE-PTP for the control of endothelial junction stability in vivo. Moreover, HIF2α was recently reported to enhance endothelial barrier integrity, in part through induced VE-PTP expression (Gong et al., 2015). In line with these findings, tyrosine phosphorylation of VE-cadherin has been demonstrated to be involved in the regulation of EC contacts in vitro (Allingham et al., 2007; Turowski et al., 2008; Monaghan-Benson and Burridge, 2009) and in vivo (Orsenigo et al., 2012; Wessel et al., 2014).VE-PTP also associates with Tie-2 (Fachinger et al., 1999), an endothelial tyrosine kinase receptor that regulates angiogenesis and can support the integrity of endothelial junctions. VE-PTP gene ablation causes embryonic lethality at embryonic day (E) 9.5 (Bäumer et al., 2006; Dominguez et al., 2007). This is caused by a defect in blood vessel remodeling leading to enlarged and fused vessel structures. Antibodies against VE-PTP caused similar defects when incubated with explant cultures of allantois from WT mice, but not if the tissue originated from Tie-2 gene–deficient mice (Winderlich et al., 2009). In addition, these antibodies against the extracellular part of VE-PTP dissociated the phosphatase from Tie-2 and caused phosphorylation of this receptor and signaling (Winderlich et al., 2009).We have recently shown that a specific pharmacological inhibitor of VE-PTP catalytic activity, AKB-9778, activated Tie-2 in the mouse, and this correlated with suppression of ocular neovascularization and blocking of VEGF-induced vascular leak (Shen et al., 2014). Although direct evidence for the relevance of Tie-2 is still missing, these results are in line with studies reporting that the Tie-2 ligand Angiopoietin-1 (Ang1) protects the vasculature against plasma leakage (Gamble et al., 2000; Thurston et al., 2000; Mammoto et al., 2007; Gavard et al., 2008). In a mouse breast cancer model, AKB-9778 normalized tumor vessels and delayed tumor growth (Goel et al., 2013). VE-PTP was also found to associate with VEGF receptor-2 (VEGFR-2; Mellberg et al., 2009), and this interaction was suggested to affect VEGFR-2 activity in endothelial sprouts of mouse embryoid bodies (Hayashi et al., 2013).Here we have analyzed how interference with VE-PTP activity influences endothelial junctions in adult mice and how this relates to the functions of Tie-2 and VE-cadherin. We found that conditional gene ablation of VE-PTP, as well as interference with antibodies or administering the inhibitor AKB-9778 each stabilized challenged endothelial junctions, thereby preventing enhanced permeability and leukocyte extravasation induced by inflammatory mediators. These effects required the expression of Tie-2 because blocking its expression in vivo reversed the effect of the VE-PTP inhibitor on endothelial junction integrity. Thus, VE-PTP inhibition stabilizes challenged endothelial junctions via Tie-2 and destabilizes them in the absence of Tie-2. Remarkably, the junction-stabilizing effect was even observed in mice conditionally gene deficient for VE-cadherin. Inhibition of leak formation was accompanied by activation of Rap1 and cytoskeletal remodeling and reduced radial stress fiber formation. Our results reveal that inhibition of VE-PTP in vivo has opposing effects on endothelial junctions as the result of its different effects on VE-cadherin and on Tie-2. Activation of Tie-2 via inhibition of VE-PTP protects endothelial junctions against inflammation-induced destabilization and overrides the negative effect of VE-PTP inhibition on the adhesive function of VE-cadherin.     

DACH-LIGA homocystein (german, austrian and swiss homocysteine society): consensus paper on the rational clinical use of homocysteine, folic acid and B-vitamins in cardiovascular and thrombotic diseases: guidelines and recommendations.

About half of all deaths are due to cardiovascular disease and its complications. The economic burden on society and the healthcare system from cardiovascular disability, complications, and treatments is huge and getting larger in the rapidly aging populations of developed countries. As conventional risk factors fail to account for part of the cases, homocysteine, a "new" risk factor, is being viewed with mounting interest. Homocysteine is a sulfur-containing intermediate product in the normal metabolism of methionine, an essential amino acid. Folic acid, vitamin B12, and vitamin B6 deficiencies and reduced enzyme activities inhibit the breakdown of homocysteine, thus increasing the intracellular homocysteine concentration. Numerous retrospective and prospective studies have consistently found an independent relationship between mild hyperhomocysteinemia and cardiovascular disease or all-cause mortality. Starting at a plasma homocysteine concentration of approximately 10 micromol/l, the risk increase follows a linear dose-response relationship with no specific threshold level. Hyperhomocysteinemia as an independent risk factor for cardiovascular disease is thought to be responsible for about 10% of total risk. Elevated plasma homocysteine levels (>12 micromol/l; moderate hyperhomocysteinemia) are considered cytotoxic and are found in 5 to 10% of the general population and in up to 40% of patients with vascular disease. Additional risk factors (smoking, arterial hypertension, diabetes, and hyperlipidemia) may additively or, by interacting with homocysteine, synergistically (and hence over-proportionally) increase overall risk. Hyperhomocysteinemia is associated with alterations in vascular morphology, loss of endothelial anti-thrombotic function, and induction of a procoagulant environment. Most known forms of damage or injury are due to homocysteine-mediated oxidative stress. Especially when acting as direct or indirect antagonists of cofactors and enzyme activities, numerous agents, drugs, diseases, and lifestyle factors have an impact on homocysteine metabolism. Folic acid deficiency is considered the most common cause of hyperhomocysteinemia. An adequate intake of at least 400 microg of folate per day is difficult to maintain even with a balanced diet, and high-risk groups often find it impossible to meet these folate requirements. Based on the available evidence, there is an increasing call for the diagnosis and treatment of elevated homocysteine levels in high-risk individuals in general and patients with manifest vascular disease in particular. Subjects of both populations should first have a baseline homocysteine assay. Except where manifestations are already present, intervention, if any, should be guided by the severity of hyperhomocysteinemia. Consistent with other working parties and consensus groups, we recommend a target plasma homocysteine level of <10 micromol/l. Based on various calculation models, reduction of elevated plasma homocysteine concentrations may theoretically prevent up to 25% of cardiovascular events. Supplementation is inexpensive, potentially effective, and devoid of adverse effects and, therefore, has an exceptionally favorable benefit/risk ratio. The results of ongoing randomized controlled intervention trials must be available before screening for, and treatment of, hyperhomocysteinemia can be recommended for the apparently healthy general population.