Detection of Soluble Angiotensin-Converting Enzyme 2 in Heart Failure Insights Into the Endogenous Counter-Regulatory Pathway of the Renin-Angiotensin-Aldosterone System

ObjectivesWe sought to determine whether circulating soluble angiotensin-converting enzyme 2 (sACE2) is increased in the plasma of patients with heart failure (HF).BackgroundAngiotensin-converting enzyme 2 (ACE2) is an integral membrane protein that antagonizes the actions of angiotensin II and prevents the development of HF in animal models. However, because of the need for invasive cardiac tissue sampling, little is known about whether ACE2 is involved in the pathophysiology of HF in humans.MethodsWe developed a sensitive and specific assay to measure sACE2 activity in human plasma and screened a heterogeneous group of patients suspected of having clinical HF.ResultsIncreasing sACE2 plasma activity strongly correlated with a clinical diagnosis of HF (p = 0.0002), worsening left ventricular ejection fraction (p < 0.0001), and increasing B-type natriuretic peptide levels (p < 0.0001). Similar to B-type natriuretic peptide, sACE2 activity reflected the severity of HF, with increasing levels associated with worsening New York Heart Association functional class (p < 0.0001). These associations were independent of other disease states and medication use. We found that sACE2 activity was increased in patients with both ischemic and nonischemic cardiomyopathies and also in patients with clinical HF but a preserved left ventricular ejection fraction.ConclusionsSoluble ACE2 activity is increased in patients with HF and correlates with disease severity, suggesting that a cardioprotective arm of the renin-angiotensin-aldosterone system is active in HF

Fully Electrified Neugebauer Spacetimes

Generalizing a method presented in an earlier paper, we express the complex potentials E and Phi of all stationary axisymmetric electrovac spacetimes that correspond to axis data of the form E(z,0) = (U-W)/(U+W) , Phi(z,0) = V/(U+W) , where U = z^{2} + U_{1} z + U_{2} , V = V_{1} z + V_{2} , W = W_{1} z + W_{2} , in terms of the complex parameters U_{1}, V_{1}, W_{1}, U_{2}, V_{2} and W_{2}, that are directly associated with the various multipole moments. (Revised to clarify certain subtle points.)Comment: 25 pages, REVTE

Microstructure and pinning properties of hexagonal-disc shaped single crystalline MgB2

We synthesized hexagonal-disc-shaped MgB2 single crystals under high-pressure conditions and analyzed the microstructure and pinning properties. The lattice constants and the Laue pattern of the crystals from X-ray micro-diffraction showed the crystal symmetry of MgB2. A thorough crystallographic mapping within a single crystal showed that the edge and c-axis of hexagonal-disc shape exactly matched the (10-10) and the (0001) directions of the MgB2 phase. Thus, these well-shaped single crystals may be the best candidates for studying the direction dependences of the physical properties. The magnetization curve and the magnetic hysteresis for these single crystals showed the existence of a wide reversible region and weak pinning properties, which supported our single crystals being very clean.Comment: 5 pages, 3 figures. submitted to Phys. Rev.

Comparison of cardiothoracic surgery training in usa and germany

<p>Abstract</p> <p>Background</p> <p>Training of cardiothoracic surgeons in Europe and the United States has expanded to incorporate new operative techniques and requirements. The purpose of this study was to compare the current structure of training programs in the United States and Germany.</p> <p>Methods</p> <p>We thoroughly reviewed the existing literature with particular focus on the curriculum, salary, board certification and quality of life for cardiothoracic trainees.</p> <p>Results</p> <p>The United States of America and the Federal Republic of Germany each have different cardiothoracic surgery training programs with specific strengths and weaknesses which are compared and presented in this publication.</p> <p>Conclusions</p> <p>The future of cardiothoracic surgery training will become affected by technological, demographic, economic and supply factors. Given current trends in training programs, creating an efficient training system would allow trainees to compete and grow in this constantly changing environment.</p

The diacylglycerol kinase α/Atypical PKC/β1 integrin pathway in SDF-1α mammary carcinoma invasiveness

Diacylglycerol kinase α (DGKα), by phosphorylating diacylglycerol into phosphatidic acid, provides a key signal driving cell migration and matrix invasion. We previously demonstrated that in epithelial cells activation of DGKα activity promotes cytoskeletal remodeling and matrix invasion by recruiting atypical PKC at ruffling sites and by promoting RCP-mediated recycling of α5β1 integrin to the tip of pseudopods. In here we investigate the signaling pathway by which DGKα mediates SDF-1α-induced matrix invasion of MDA-MB-231 invasive breast carcinoma cells. Indeed we showed that, following SDF-1α stimulation, DGKα is activated and localized at cell protrusion, thus promoting their elongation and mediating SDF-1α induced MMP-9 metalloproteinase secretion and matrix invasion. Phosphatidic acid generated by DGKα promotes localization at cell protrusions of atypical PKCs which play an essential role downstream of DGKα by promoting Rac-mediated protrusion elongation and localized recruitment of β1 integrin and MMP-9. We finally demonstrate that activation of DGKα, atypical PKCs signaling and β1 integrin are all essential for MDA-MB-231 invasiveness. These data indicates the existence of a SDF-1α induced DGKα - atypical PKC - β1 integrin signaling pathway, which is essential for matrix invasion of carcinoma cells

Detailed Mitochondrial Phenotyping by High Resolution Metabolomics

Mitochondrial phenotype is complex and difficult to define at the level of individual cell types. Newer metabolic profiling methods provide information on dozens of metabolic pathways from a relatively small sample. This pilot study used “top-down” metabolic profiling to determine the spectrum of metabolites present in liver mitochondria. High resolution mass spectral analyses and multivariate statistical tests provided global metabolic information about mitochondria and showed that liver mitochondria possess a significant phenotype based on gender and genotype. The data also show that mitochondria contain a large number of unidentified chemicals

?2-Microglobulin Amyloid Fibril-Induced Membrane Disruption Is Enhanced by Endosomal Lipids and Acidic pH

Although the molecular mechanisms underlying the pathology of amyloidoses are not well understood, the interaction between amyloid proteins and cell membranes is thought to play a role in several amyloid diseases. Amyloid fibrils of ?2-microglobulin (?2m), associated with dialysis-related amyloidosis (DRA), have been shown to cause disruption of anionic lipid bilayers in vitro. However, the effect of lipid composition and the chemical environment in which ?2m-lipid interactions occur have not been investigated previously. Here we examine membrane damage resulting from the interaction of ?2m monomers and fibrils with lipid bilayers. Using dye release, tryptophan fluorescence quenching and fluorescence confocal microscopy assays we investigate the effect of anionic lipid composition and pH on the susceptibility of liposomes to fibril-induced membrane damage. We show that ?2m fibril-induced membrane disruption is modulated by anionic lipid composition and is enhanced by acidic pH. Most strikingly, the greatest degree of membrane disruption is observed for liposomes containing bis(monoacylglycero)phosphate (BMP) at acidic pH, conditions likely to reflect those encountered in the endocytic pathway. The results suggest that the interaction between ?2m fibrils and membranes of endosomal origin may play a role in the molecular mechanism of ?2m amyloid-associated osteoarticular tissue destruction in DRA

Hematopoietic Cell Transplantation in Patients With Primary Immune Regulatory Disorders (PIRD): A Primary Immune Deficiency Treatment Consortium (PIDTC) Survey.

Primary Immune Regulatory Disorders (PIRD) are an expanding group of diseases caused by gene defects in several different immune pathways, such as regulatory T cell function. Patients with PIRD develop clinical manifestations associated with diminished and exaggerated immune responses. Management of these patients is complicated; oftentimes immunosuppressive therapies are insufficient, and patients may require hematopoietic cell transplant (HCT) for treatment. Analysis of HCT data in PIRD patients have previously focused on a single gene defect. This study surveyed transplanted patients with a phenotypic clinical picture consistent with PIRD treated in 33 Primary Immune Deficiency Treatment Consortium centers and European centers. Our data showed that PIRD patients often had immunodeficient and autoimmune features affecting multiple organ systems. Transplantation resulted in resolution of disease manifestations in more than half of the patients with an overall 5-years survival of 67%. This study, the first to encompass disorders across the PIRD spectrum, highlights the need for further research in PIRD management