The pulmonary endothelium contributes to inflammation in chronic heart failure: the role of mechanical strain and bone morphogenetic protein-9

Chronic heart failure (CHF) is a debilitating condition with a poor prognosis. Remodelling of the alveolar capillary membrane (ACM) protects against pulmonary oedema, but also results in dyspnoea and a worsened prognosis. Systemic inflammation associated with CHF contributes to the pathophysiology and mortality of the syndrome. Monocyte chemoattractant protein (MCP)-1, a CC chemokine, is elevated in patients with CHF and associated with increased mortality. Also, deficiencies in the bone morphogentic protein receptor (BMPR) signalling contribute to the pathophysiology of vascular remodelling in pulmonary arterial hypertension (PAH), and similar changes are seen in CHF. The mechanisms underlying lung remodelling and inflammation in CHF are not known. This thesis investigated the contribution of the pulmonary endothelium to inflammation and ACM remodelling in CHF. We hypothesised that pulmonary venous hypertension (PVH) in CHF imparts mechanical strain at the ACM stimulating the release of mediators, contributing to lung remodelling. To model PVH cyclic mechanical strain (CMS) was applied to monolayers of human lung microvascular endothelial cells (HLMVEC) and to an endothelial cell line (EaHy 926). MCP-1 was identified as a stretch-induced inflammatory mediator whose induction was dependent on activation of the extracellular signal-related kinase (ERK 1/2) pathway. Supernatants from stretched compared to non-stretched cells increased fibroblast and pulmonary smooth muscle cell proliferation, and fibroblast differentiation. Bone morphogenetic protein (BMP)-9 stimulated pulmonary arterial endothelial cells to release endothelin-1 (ET-1) in a Smad-independent, p38MAPK-dependent, manner. In a rodent heart failure model, animals subjected to left coronary artery ligation had increased levels of MCP-1 in whole lung, serum and bronchoalveolar lavage. Animals treated with gene therapy (SERCA2a) demonstrated functional rescue with attenuated release of MCP-1 and ET-1. These data support a role for pulmonary ECs in inflammation and remodelling in CHF. Increased understanding of lung remodelling may lead to improved management of dyspnoea for CHF sufferers

Incoherent dynamics of vibrating single-molecule transistors

We study the tunneling conductance of nano-scale quantum ``shuttles'' in connection with a recent experiment (H. Park et al., Nature, 407, 57 (2000)) in which a vibrating C^60 molecule was apparently functioning as the island of a single electron transistor (SET). While our calculation starts from the same model of previous work (D. Boese and H. Schoeller, Europhys. Lett. 54, 66(2001)) we obtain quantitatively different dynamics. Calculated I-V curves exhibit most features present in experimental data with a physically reasonable parameter set, and point to a strong dependence of the oscillator's potential on the electrostatics of the island region. We propose that in a regime where the electric field due to the bias voltage itself affects island position, a "catastrophic" negative differential conductance (NDC) may be realized. This effect is directly attributable to the magnitude of overlap of final and initial quantum oscillator states, and as such represents experimental control over quantum transitions of the oscillator via the macroscopically controllable bias voltage.Comment: 6 pages, LaTex, 6 figure

Dyons in Nonabelian Born-Infeld Theory

We analyze a nonabelian extension of Born--Infeld action for the SU(2) group. In the class of spherically symmetric solutions we find that, besides the Gal'tsov--Kerner glueballs, only the analytic dyons have finite energy. The presented analytic and numerical investigation excludes the existence of pure magnetic monopoles of 't Hooft--Polyakov type.Comment: 12 pages, 3 figure

Male breast cancer: a disease distinct from female breast cancer

Purpose: Male breast cancer (BC) is rare, representing approximately 1% of cancers that occur in men and approximately 1% of all BCs worldwide. Because male BC is rare, not much is known about the disease, and treatment recommendations are typically extrapolated from data available from clinical trials enrolling female BC patients. Methods: We review the epidemiology, risk factors, prognosis, and the varied molecular and clinicopathologic features that characterize male BC. In addition, we summarize the available data for the use of systemic therapy in the treatment of male BC and explore the ongoing development of targeted therapeutic agents for the treatment of this subgroup of BCs. Results: There are important biological differences between male and female BC. Male BC is almost exclusively hormone receptor positive (+), including the androgen receptor (AR), and is associated with an increased prevalence of BRCA2 germline mutations, especially in men with increased risk for developing high-risk BC. Additional research is warranted to better characterize male BC. To accomplish this, a multi-national consortium approach, such as the International Male Breast Cancer Program, is needed in response to the scarcity of patients. This approach allows the pooling of information from a large number of men with BC and the creation of registries for future therapeutic-focused clinical trials. Conclusions: Given the unique biology of BC in men, promising new therapeutic targets are currently under investigation, including the use of poly-ADP-ribose polymerase inhibitors or AR-targeted agents either as monotherapy or in combination with other agents

The assessment of Shin's method for the prediction of creatinine kinase-MB elevation after percutaneous coronary intervention: an intravascular ultrasound study

Cardiac enzyme release is common after percutaneous coronary intervention (PCI). At present there is no established relationship between the quantity of necrotic core and dense calcium, as assessed by Shin's method using intravascular ultrasound virtual histology (VH-IVUS), and post-PCI creatinine kinase-MB (CK-MB) elevation. A total of 112 consecutive patients with unstable angina and a normal pre-PCI CK-MB level were imaged using VH-IVUS. Patients were divided into 2 groups according to the presence (CK-MB group, n = 22) or absence (non CK-MB group, n = 90) of a post-PCI CK-MB elevation >1.0 the upper limit of normal (3.6 ng/ml). Using Shin's method contours were drawn around the IVUS catheter (instead of the lumen), and the vessel. Mean area and volume of necrotic core and dense calcium were significantly greater in CK-MB group than in non CK-MB group (1.7 ± 0.9 mm2vs. 0.9 ± 0.6 mm2, P < 0.001; 17.2 ± 8.8 mm3vs. 8.8 ± 5.8 mm3, P < 0.001, and 0.9 ± 0.6 mm2vs. 0.4 ± 0.4 mm2, P = 0.001; 9.1 ± 5.8 mm3vs. 3.9 ± 3.7 mm3, P < 0.001, respectively). Percent necrotic core and dense calcium areas calculated by external elastic membrane (EEM) area were significantly greater in CK-MB group than in non CK-MB group (11.9 ± 5.1 vs. 6.6 ± 4.0%, P < 0.001 and 6.5 ± 4.0 vs. 3.0 ± 2.9%, P 

Neutron beam test of CsI crystal for dark matter search

We have studied the response of Tl-doped and Na-doped CsI crystals to nuclear recoils and $\gamma$'s below 10 keV. The response of CsI crystals to nuclear recoil was studied with mono-energetic neutrons produced by the $^3$H(p,n)$^3$He reaction. This was compared to the response to Compton electrons scattered by 662 keV $\gamma$-ray. Pulse shape discrimination between the response to these $\gamma$'s and nuclear recoils was studied, and quality factors were estimated. The quenching factors for nuclear recoils were derived for both CsI(Na) and CsI(Tl) crystals.Comment: 21pages, 14figures, submitted to NIM

On Low-Energy Effective Actions in N = 2, 4 Superconformal Theories in Four Dimensions

We study some aspects of low-energy effective actions in 4-d superconformal gauge theories on the Coulomb branch. We describe superconformal invariants constructed in terms of N=2 abelian vector multiplet which play the role of building blocks for the N=2,4 supersymmetric low-energy effective actions. We compute the one-loop effective actions in constant N=2 field strength background in N=4 SYM theory and in N=2 SU(2) SYM theory with four hypermultiplets in fundamental representation. Using the classification of superconformal invariants we then find the manifestly N=2 superconformal form of these effective actions. While our explicit computations are done in the one-loop approximation, our conclusions about the structure of the effective actions in N=2 superconformal theories are general. We comment on some applications to supergravity - gauge theory duality in the description of D-brane interactions.Comment: 18 pages, latex, comments/reference adde

Time resolution of Burle 85001 micro-channel plate photo-multipliers in comparison with Hamamatsu R2083

The CLAS detector will require improvements in its particle identification system to take advantage of the higher energies provided by the Jefferson Laboratory accelerator upgrade to 12 GeV. To this end, we have studied the timing characteristics of the micro-channel plate photo-multiplier 85001 from Burle, which can be operated in a high magnetic field environment. For reference and comparison, measurements were also made using the standard PMT R2083 from Hamamatsu using two timing methods. The cosmic ray method, which utilizes three identical scintillating counters 2cmx3cmx50cm with PMs at the ends, yields 59.1(0.7)ps. The location method of particles from radiative source with known coordiantes has been used to compare timing resolutions of R2083 and Burle-85001.This ``coordinate method'' requires only one counter instrumented with two PMs and it yields 59.5(0.7)ps. For the micro-channel plate photomultiplier from Burle with an external amplification of 10 to the signals, the coordinate method yields 130(4)ps. This method also makes it possible to estimate the number of primary photo-electrons.Comment: 23 pages, 13 figure

Directed geometrical worm algorithm applied to the quantum rotor model

We discuss the implementation of a directed geometrical worm algorithm for the study of quantum link-current models. In this algorithm Monte Carlo updates are made through the biased reptation of a worm through the lattice. A directed algorithm is an algorithm where, during the construction of the worm, the probability for erasing the immediately preceding part of the worm, when adding a new part,is minimal. We introduce a simple numerical procedure for minimizing this probability. The procedure only depends on appropriately defined local probabilities and should be generally applicable. Furthermore we show how correlation functions, C(r,tau) can be straightforwardly obtained from the probability of a worm to reach a site (r,tau) away from its starting point independent of whether or not a directed version of the algorithm is used. Detailed analytical proofs of the validity of the Monte Carlo algorithms are presented for both the directed and un-directed geometrical worm algorithms. Results for auto-correlation times and Green functions are presented for the quantum rotor model.Comment: 11 pages, 9 figures, v2 : Additional results and data calculated at an incorrect chemical potential replaced. Conclusions unchange