Evidence for the stress-linked immunocompetence handicap hypothesis in humans

Secondary sexual traits that develop under the action of testosterone, such as masculine human male facial characteristics, have been proposed to signal the strength of the immune system due to the sex hormone's immunosuppressive action. Recent work has suggested that glucocorticoid stress hormones may also influence expression of such sexual signals due to their effects on immune function. Precise roles, however, remain unclear. Here we show positive relationships between testosterone, facial attractiveness and immune function (antibody response to a hepatitis B vaccine) in human males, and present some preliminary evidence that these relationships are moderated by naturally co-occurring cortisol (a glucocorticoid stress hormone involved in the fight-or-flight response). We conclude that our results provide support for a role of glucocorticoids in hormonally mediated sexual selection

Magnetic anisotropy of vicinal (001) fcc Co films: role of crystal splitting and structure relaxation in step-decoration effect

The uniaxial in-plane magnetic anisotropy (UIP-MA) constant is calculated for a single step on the (001) surface of fcc Co($N$) films. The calculations are done for both an undecorated step and the step decorated with one or more, up to 7, Cu wires. Our objective is to explain the mechanisms by which the decoration decreases the UIP-MA constant, which is the effect observed experimentally for ultrathin Co films deposited on vicinal (001) Cu surfaces and can lead to reorientation of magnetization within the film plane. Theoretical calculations performed with a realistic tight-binding model show that the step decoration changes the UIP-MA constant significantly only if the splitting between the on-site energies of various $d$-orbitals is included for atoms located near the step edge. The local relaxation of atomic structure around the step is also shown to have a significant effect on the shift of the UIP-MA constant. The influence of these two relevant factors is analyzed further by examining individual contributions to the UIP-MA constant from atoms around the step. The magnitude of the obtained UIP-MA shift agrees well with experimental data. It is also found that an additional shift due to possible charge transfer between Cu and Co atoms is very small.Comment: 12 pages,9 figures, RevTeX, submitted to Physical Review B version 3: additions to content version 2: minor correction

Heterogeneity of autoreactive T cell clones specific for the E2 component of the pyruvate dehydrogenase complex in primary biliary cirrhosis.

The extraordinary specificity of bile duct destruction in primary biliary cirrhosis (PBC) and the presence of T cell infiltrates in the portal tracts have suggested that biliary epithelial cells are the targets of an autoimmune response. The immunodominant antimitochondrial response in patients with PBC is directed against the E2 component of pyruvate dehydrogenase (PDC-E2). Hitherto, there have only been limited reports on the characterization and V beta usage of PDC-E2-specific cloned T cell lines. In this study, we examined peripheral blood mononuclear cells (PBMC) for their reactivity to the entire PDC complex as well as to the E1- and E2-specific components. We also examined the phenotype, lymphokine profile, and V beta usage of PDC-specific T cell clones isolated from cellular infiltrates from the livers of PBC patients. We report that PBMC from 16/19 patients with PBC, but not 12 control patients, respond to the PDC-E2 subunit. Interestingly, this response was directed to the inner and/or the outer lipoyl domains, despite the serologic observation that the autoantibody response is directed predominantly to the inner lipoyl domain. Additionally, lymphokine analysis of interleukin (IL) 2/IL-4/interferon gamma production from individual liver-derived autoantigen-specific T cell clones suggests that both T helper cell Th1- and Th2-like clones are present in the liver. Moreover, there was considerable heterogeneity in the T cell receptor for antigen (TCR) V beta usage of these antigen-specific autoreactive T cell clones. This is in contrast to murine studies in which animals are induced to develop autoimmunity by specific immunization and have an extremely limited T cell V beta repertoire. Thus, our data suggest that in human organ-specific autoimmune diseases, such as PBC, the TCR V beta repertoire is heterogenous

Efficiency of energy transfer, but not external work, is maximized in stunned myocardium

There is no evidence regarding the effect of stunning on maximization of regional myocardial external work (EW) or efficiency of energy transfer (EET) in relation to regional afterload (end-systolic stress, sigma(es)). To that end, we studied these relationships in both the left anterior descending coronary artery (LADCA) and left circumflex coronary artery regions in anesthetized, open-chest pigs before and after LADCA stunning. In normal myocardium, EET vs. sigma(es) was maximal at 75.4 (69.7-81.0)%, whereas EW vs. sigma(es) was submaximal at 12.0 (6.61-17.3) x 10(2) J/m(3). Increasing sigma(es) increased EW by 18 (10-27)%. Regional myocardial stunning decreased EET (27%) and EW (36%) and caused the myocardium to operate both at maximal EW (EW(max)) and at maximal EET (EET(max)). EET and EW became also more sensitive to changes in sigma(es). In the nonstunned region the situation remained unchanged. Combining the data from before and after stunning, both EW(max) and EET(max) displayed a positive relationship with contractility. In conclusion, the normal regional myocardium operated at maximal EET rather than at maximal EW. Therefore, additional EW could be recruited by increasing regional afterload. After myocardial stunning, the myocardium operated at both maximal EW and maximal EET, at the cost of increased afterload sensitivity. Contractility was a major determinant of this shift

Contrast enhancement by differently sized paramagnetic MRI contrast agents in mice with two phenotypes of atherosclerotic plaque

Interest in the use of contrast-enhanced MRI to enable in vivo specific characterization of atherosclerotic plaques is increasing. In this study the intrinsic ability of three differently sized gadolinium-based contrast agents to permeate different mouse plaque phenotypes was evaluated with MRI. A tapered cast was implanted around the right carotid artery of apoE-/- mice to induce two different plaque phenotypes: a thin cap fibroatheroma (TCFA) and a non-TCFA lesion. Both plaques were allowed to develop over 6 and 9 weeks, leading to an intermediate and advanced lesion, respectively. Signal enhancement in the carotid artery wall, following intravenous injection of Gd-HP-DO3A as well as paramagnetic micelles and liposomes was evaluated. In vivo T1-weighted MRI plaque enhancement characteristics were complemented by fluorescence microscopy and correlated to lesion phenotype. The two smallest contrast agents, i.e. Gd-HP-DO3A and micelles, were found to enhance contrast in T1-weighted MR images of all investigated plaque phenotypes. Maximum contrast enhancement ranged between 53 and 70% at 6¿min after injection of Gd-HP-DO3A with highest enhancement and longest retention in the non-TCFA lesion. Twenty-four hours after injection of micelles maximum contrast enhancement ranged between 24 and 35% in all plaque phenotypes. Administration of the larger liposomes did not cause significant contrast enhancement in the atherosclerotic plaques. Confocal fluorescence microscopy confirmed the MRI-based differences in plaque permeation between micelles and liposomes. Plaque permeation of contrast agents was strongly dependent on size. Our results implicate that, when equipped with targeting ligands, liposomes are most suitable for the imaging of plaque-associated endothelial markers due to low background enhancement, whereas micelles, which accumulate extravascularly on a long timescale, are suited for imaging of less abundant markers inside plaques. Low molecular weight compounds may be employed for target-specific imaging of highly abundant extravascular plaque-associated target

Mechanical efficiency of stunned myocardium is modulated by increased afterload dependency

Oxygen consumption (MVO2) of stunned myocardium is relatively high compared to, and poorly correlated with, systolic contractile function. The aim of this study was to investigate whether an increased afterload dependency, induced by the decreased contractility of the stunned myocardium, contributes to the large variability in the mechanical efficiency data. Methods: In 13 anaesthetised open thorax pigs undergoing two cycles of 10 min occlusion of left anterior descending coronary artery and 30 min reperfusion, segment shortening, the slope of end systolic pressure segment length relationship (Ees), external work (EW, derived from the area inside the left ventricular pressure segment length loop), the efficiency of energy conversion (EET, = Embedded Image × 100%, where PLA = total pressure-segment length area), mechanical efficiency (Embedded Image), and their dependency on left ventricular end systolic pressure (Pes) were determined before and after induction of stunning, and during subsequent inotropic stimulation with dobutamine (1 and 3 μg·kg−1·min−1 over 15 min). Results: The stunning protocol not only caused significant decreases in segment shortening, external work, energy conversion efficiency, and Embedded Image but also increased the afterload dependency of these variab Before stunning an increase in Pes from 100 to 160 mm Hg decreased segment shortening from 18(SEM 1)% to 14(2)% (P > 0.05) and increased external work from 206(18) to 254(32) mm Hg·mm (P < 0.05). After induction of stunning the same increase in Pes caused a decrease in segment shortening from 9.5(1.8)% to −4.6(2.1)% (P < 0.05) and in external work from 149(21) to −11(10) mm Hg·mm (P < 0.05). The afterload dependency of the PLA was not altered by stunning, but the afterload dependency of energy conversion efficiency increased, since efficiency decreased from 67(3)% to 59(5)% as Pes was increased from 100 to 160 mm Hg before stunning, but from 57(5) to −7(5)% after induction of stunning (P < 0.05). Furthermore, the same increase in Pes resulted in an 8% decrease of Embedded Image before stunning and 107% after inducti stunning. Infusion of dobutamine not only restored segment shortening, external work, energy conversion efficiency, and Embedded Image of the stunned myocardium, but also attenuated their afterload dependency to levels. Conclusions: Myocardial stunning increases the afterload dependency of segment shortening, external work, energy conversion efficiency, and mechanical efficiency, which can be attenuated by inotropic stimulation with dobutamine. However, the decrease in left ventricular end systolic pressure, which accompanies the induction of stunning, counteracts the decrease in these variables. These two mechanisms can explain most of the reported scatter in mechanical efficiency

Assessment of the nano-mechanical properties of healthy and atherosclerotic coronary arteries by atomic force microscopy.

Nano-indentation techniques might be better equipped to assess the heterogeneous material properties of plaques than macroscopic methods but there are no bespoke protocols for this kind of material testing for coronary arteries. Therefore, we developed a measurement protocol to extract mechanical properties from healthy and atherosclerotic coronary artery tissue sections. Young's modulus was derived from force-indentation data. Metrics of collagen fibre density were extracted from the same tissue, and the local material properties were co-registered to the local collagen microstructure with a robust framework. The locations of the indentation were retrospectively classified by histological category (healthy, plaque, lipid-rich, fibrous cap) according to Picrosirius Red stain and adjacent Hematoxylin & Eosin and Oil-Red-O stains. Plaque tissue was softer (p < 0.001) than the healthy coronary wall. Areas rich in collagen within the plaque (fibrous cap) were significantly (p < 0.001) stiffer than areas poor in collagen/lipid-rich, but less than half as stiff as the healthy coronary media. Young's moduli correlated (Pearson's ρ = 0.53, p < 0.05) with collagen content. Atomic force microscopy (AFM) is capable of detecting tissue stiffness changes related to collagen density in healthy and diseased cardiovascular tissue. Mechanical characterization of atherosclerotic plaques with nano-indentation techniques could refine constitutive models for computational modelling

Atherosclerotic Plaque Stability Is Affected by the Chemokine CXCL10 in Both Mice and Humans.

Background. The chemokine CXCL10 is specifically upregulated during experimental development of plaque with an unstable phenotype. In this study we evaluated the functional consequences of these findings in mice and humans. Methods and Results. In ApoE(-/-) mice, we induced unstable plaque with using a flow-altering device around the carotid artery. From week 1 to 4, mice were injected with a neutralizing CXCL10 antibody. After 9 weeks, CXCL10 inhibition resulted in a more stable plaque phenotype: collagen increased by 58% (P = 0.002), smooth muscle cell content increased 2-fold (P = 0.03), while macrophage MHC class II expression decreased by 50% (P = 0.005). Also, the size of necrotic cores decreased by 41% (P = 0.01). In 106 human carotid endarterectomy specimens we found that increasing concentrations of CXCL10 strongly associate with an increase in atheromatous plaque phenotype (ANOVA, P = 0.003), with high macrophage, low smooth muscle cell, and low collagen content. Conclusions. In the present study we showed that CXCL10 is associated with the development of vulnerable plaque in human and mice. We conclude that CXCL10 might provide a new lead towards plaque-stabilizing therapy