The Role of ACAID and CD4+CD25+FOXP3+ Regulatory T Cells on CTL Function Against MHC Alloantigens

Purpose: Anterior chamber associated immune deviation (ACAID) is an antigen-specific form of peripheral immune tolerance that is induced to exogenous antigens placed in the ocular anterior chamber, which leads to a suppression in delayed-type hypersensitivity (DTH). Considerable work has been done on ACAID induction to major histocompatibility (MHC) alloantigens. However, its role on cytotoxic T lymphocyte (CTL) activity is currently unknown. Methods: C57BL/6 (H-2b) mice received an intracameral (IC) inoculation with BALB/c (H-2d) splenocytes. Splenic CD4+ and CD8+ T cell populations were characterized by flow cytometry and proliferation assays during induction and expression phases of ACAID. Percentages of CD4+CD25+FoxP3+ T regulatory cells (Treg) were also followed. Lastly, CTL function was measured at various time points during ACAID expression, and Treg were added to identify potential alterations in CTL function. Results: CD4+ and CD8+ T cell percentages and proliferation increased in the spleen during ACAID induction but then sharply decreased in response to an allospecific immunization. Expression of ACAID also exhibited a significant drop in CTL function. However, while Treg expansion was observed, these cells did not directly mediate the CTL inhibition. Conclusions: ACAID mediates an inhibition of CTL function against MHC alloantigens. Furthermore, we found that ACAID induction leads to the expansion and proliferation of CD4+ and CD8+ T cells while ACAID expression is associated with a diminishment in T cell percentages due to proliferation impairment. Lastly, Treg also expand during ACAID induction. However, our data suggest that Treg do not directly inhibit CTL activity

Free and smooth boundaries in 2-D finite-difference schemes for transient elastic waves

A method is proposed for accurately describing arbitrary-shaped free boundaries in single-grid finite-difference schemes for elastodynamics, in a time-domain velocity-stress framework. The basic idea is as follows: fictitious values of the solution are built in vacuum, and injected into the numerical integration scheme near boundaries. The most original feature of this method is the way in which these fictitious values are calculated. They are based on boundary conditions and compatibility conditions satisfied by the successive spatial derivatives of the solution, up to a given order that depends on the spatial accuracy of the integration scheme adopted. Since the work is mostly done during the preprocessing step, the extra computational cost is negligible. Stress-free conditions can be designed at any arbitrary order without any numerical instability, as numerically checked. Using 10 grid nodes per minimal S-wavelength with a propagation distance of 50 wavelengths yields highly accurate results. With 5 grid nodes per minimal S-wavelength, the solution is less accurate but still acceptable. A subcell resolution of the boundary inside the Cartesian meshing is obtained, and the spurious diffractions induced by staircase descriptions of boundaries are avoided. Contrary to what occurs with the vacuum method, the quality of the numerical solution obtained with this method is almost independent of the angle between the free boundary and the Cartesian meshing.Comment: accepted and to be published in Geophys. J. In

Transdisciplinary unifying implications of circadian findings in the 1950s

A few puzzles relating to a small fraction of my endeavors in the 1950s are summarized herein, with answers to a few questions of the Editor-in-Chief, to suggest that the rules of variability in time complement the rules of genetics as a biological variability in space. I advocate to replace truisms such as a relative constancy or homeostasis, that have served bioscience very well for very long. They were never intended, however, to lower a curtain of ignorance over everyday physiology. In raising these curtains, we unveil a range of dynamics, resolvable in the data collection and as-one-goes analysis by computers built into smaller and smaller devices, for a continued self-surveillance of the normal and for an individualized detection of the abnormal. The current medical art based on spotchecks interpreted by reference to a time-unqualified normal range can become a science of time series with tests relating to the individual in inferential statistical terms. This is already doable for the case of blood pressure, but eventually should become possible for many other variables interpreted today only based on the quicksand of clinical trials on groups. These ignore individual differences and hence the individual's needs. Chronomics (mapping time structures) with the major aim of quantifying normalcy by dynamic reference values for detecting earliest risk elevation, also yields the dividend of allowing molecular biology to focus on the normal as well as on the grossly abnormal

Subendocardial contractile impairment in chronic ischemic myocardium: assessment by strain analysis of 3T tagged CMR

<p>Abstract</p> <p>Background</p> <p>The purpose of this study was to quantify myocardial strain on the subendocardial and epicardial layers of the left ventricle (LV) using tagged cardiovascular magnetic resonance (CMR) and to investigate the transmural degree of contractile impairment in the chronic ischemic myocardium.</p> <p>Methods</p> <p>3T tagged CMR was performed at rest in 12 patients with severe coronary artery disease who had been scheduled for coronary artery bypass grafting. Circumferential strain (C-strain) at end-systole on subendocardial and epicardial layers was measured using the short-axis tagged images of the LV and available software (Intag; Osirix). The myocardial segment was divided into stenotic and non-stenotic segments by invasive coronary angiography, and ischemic and non-ischemic segments by stress myocardial perfusion scintigraphy. The difference in C-strain between the two groups was analyzed using the Mann-Whitney U-test. The diagnostic capability of C-strain was analyzed using receiver operating characteristics analysis.</p> <p>Results</p> <p>The absolute subendocardial C-strain was significantly lower for stenotic (-7.5 ± 12.6%) than non-stenotic segment (-18.8 ± 10.2%, p < 0.0001). There was no difference in epicardial C-strain between the two groups. Use of cutoff thresholds for subendocardial C-strain differentiated stenotic segments from non-stenotic segments with a sensitivity of 77%, a specificity of 70%, and areas under the curve (AUC) of 0.76. The absolute subendocardial C-strain was significantly lower for ischemic (-6.7 ± 13.1%) than non-ischemic segments (-21.6 ± 7.0%, p < 0.0001). The absolute epicardial C-strain was also significantly lower for ischemic (-5.1 ± 7.8%) than non-ischemic segments (-9.6 ± 9.1%, p < 0.05). Use of cutoff thresholds for subendocardial C-strain differentiated ischemic segments from non-ischemic segments with sensitivities of 86%, specificities of 84%, and AUC of 0.86.</p> <p>Conclusions</p> <p>Analysis of tagged CMR can non-invasively demonstrate predominant impairment of subendocardial strain in the chronic ischemic myocardium at rest.</p

the WAF method for non-homogeneous SWE with pollutant

This paper deals with the extension of the WAF method to discretize Shallow Water Equations with pollutants. We consider two different versions of the WAF method, by approximating the intermediate waves using the flux of HLL or the direct approach of HLLC solver. It is seen that both versions can be written under the same form with different definitions for the approximation of the velocity waves. We also propose an extension of the method to non-homogeneous systems. In the case of homogeneous systems it is seen that we can rewrite the third component of the numerical flux in terms of an intermediate wave speed approximation. We conclude that – in order to have the same relation for non-homogeneous systems – the approximation of the intermediate wave speed must be modified. The proposed extension of the WAF method preserves all stationary solutions, up to second order accuracy, and water at rest in an exact way, even with arbitrary pollutant concentration. Finally, we perform several numerical tests, by comparing it with HLLC solver, reference solutions and analytical solutions

Rapid Accumulation of CD14+CD11c+ Dendritic Cells in Gut Mucosa of Celiac Disease after in vivo Gluten Challenge

Of antigen-presenting cells (APCs) expressing HLA-DQ molecules in the celiac disease (CD) lesion, CD11c(+) dendritic cells (DCs) co-expressing the monocyte marker CD14 are increased, whereas other DC subsets (CD1c(+) or CD103(+)) and CD163(+)CD11c(-) macrophages are all decreased. It is unclear whether these changes result from chronic inflammation or whether they represent early events in the gluten response. We have addressed this in a model of in vivo gluten challenge.Treated HLA-DQ2(+) CD patients (n = 12) and HLA-DQ2(+) gluten-sensitive control subjects (n = 12) on a gluten-free diet (GFD) were orally challenged with gluten for three days. Duodenal biopsies obtained before and after gluten challenge were subjected to immunohistochemistry. Single cell digests of duodenal biopsies from healthy controls (n = 4), treated CD (n = 3) and untreated CD (n = 3) patients were analyzed by flow cytometry.In treated CD patients, the gluten challenge increased the density of CD14(+)CD11c(+) DCs, whereas the density of CD103(+)CD11c(+) DCs and CD163(+)CD11c(-) macrophages decreased, and the density of CD1c(+)CD11c(+) DCs remained unchanged. Most CD14(+)CD11c(+) DCs co-expressed CCR2. The density of neutrophils also increased in the challenged mucosa, but in most patients no architectural changes or increase of CD3(+) intraepithelial lymphocytes (IELs) were found. In control tissue no significant changes were observed.Rapid accumulation of CD14(+)CD11c(+) DCs is specific to CD and precedes changes in mucosal architecture, indicating that this DC subset may be directly involved in the immunopathology of the disease. The expression of CCR2 and CD14 on the accumulating CD11c(+) DCs indicates that these cells are newly recruited monocytes

Inhibition of Progenitor Dendritic Cell Maturation by Plasma from Patients with Peripartum Cardiomyopathy: Role in Pregnancy-associated Heart Disease

Dendritic cells (DCs) play dual roles in innate and adaptive immunity based on their functional maturity, and both innate and adaptive immune responses have been implicated in myocardial tissue remodeling associated with cardiomyopathies. Peripartum cardiomyopathy (PPCM) is a rare disorder which affects women within one month antepartum to five months postpartum. A high occurrence of PPCM in central Haiti (1 in 300 live births) provided the unique opportunity to study the relationship of immune activation and DC maturation to the etiology of this disorder. Plasma samples from two groups (n = 12) of age- and parity-matched Haitian women with or without evidence of PPCM were tested for levels of biomarkers of cardiac tissue remodeling and immune activation. Significantly elevated levels of GM-CSF, endothelin-1, proBNP and CRP and decreased levels of TGF- were measured in PPCM subjects relative to controls. Yet despite these findings, in vitro maturation of normal human cord blood derived progenitor dendritic cells (CBDCs) was significantly reduced (p < 0.001) in the presence of plasma from PPCM patients relative to plasma from post-partum control subjects as determined by expression of CD80, CD86, CD83, CCR7, MHC class II and the ability of these matured CBDCs to induce allo-responses in PBMCs. These results represent the first findings linking inhibition of DC maturation to the dysregulation of normal physiologic cardiac tissue remodeling during pregnancy and the pathogenesis of PPCM