Background: There is a correlation between the sites of atheroma development and stress points in the arterial system. Generally, pulse pressure results in stresses acting on the vascular vessel, including longitudinal stress, radial or normal stress, tangential stress or hoop stress and shear stress. This paper explores the relationship between arterial wall shear stress and pulsatile blood pressure with the aim of furthering the understanding of atherogenesis and plaque progression. Methods:We computed the magnitude of the shear stresses within the carotid bifurcation geometry of a patient and calculated the increase in shear stress levels that would occur when the blood pressure and pulse pressures rise during exertion. We also determined in which layer of the artery wall the maximum shear stress is located, and computed the shear stress at different levels within the media. We used the theory of laminate analysis, (Classical Laminate Plate Theory), to analyse the stress distribution on the carotid artery wall. Computational Fluid Dynamics (CFD) analysis was used on anatomy based on a CT angiogram of the carotid bifurcation of a patient with a 90% stenosis on the right side and 10% on the left. The pulsatile non-Newtonian blood flow with a resting blood pressure of 120/80 mmHg and an exertion pressure of 200/100 mmHg was simulated and the resultant forces were transferred to an ANSYS Composite PrepPost (ACP) model for wall shear stress analysis. A multilayer elastic, anisotropic, and inhomogeneous arterial wall (intima, internal elastic lamina, media, external elastic lamina, and adventitial layers) was modelled and the shear stress magnitudes and change over time between the layers was calculated.Results: Shear stress in the individual composite layers is far greater than that acting on the endothelium (less than 5 Pa). At rest, the maximum variation of shear stress in the arterial wall occurs in the intima (138 Pa) and adventitia (135 Pa). The medial layer has the lowest variation of shear stress. Under severe exertion, the maximum shear stress magnitude in the intimal layer and the adjacent medial layer is near the ultimate stress level. The maximum/minimum shear stress ratios during the cardiac cycle vary most widely in the innermost part of the media, adjacent to the intima, with a four-fold ratio increase. This compares with a less than two-fold increase in all the other layers including the intima and adventitia, making the inner media the most vulnerable layer to mechanical injury.Conclusions: This study showed that the magnitude of exertion-induced shear stress approaches the ultimate stress limit in the intima and the immediate adjacent medial layer. The variation in stress is maximal in the inner layer of the media. These findings correlate the site of atheroma development with the most vulnerable site for injury in the media and emphasise the impact of pulse pressure. Further biological studies are required to ascertain whether this leads to injury that initiates atheroma that then precipitates an ...

Cross-presenting dendritic cells (DC) offer an attractive target for vaccination due to their unique ability to process exogenous antigens for presentation on MHC class I molecules. Recent reports have established that these DC express unique surface receptors and play a critical role in the initiation of anti-tumor immunity, opening the way for the development of vaccination strategies specifically targeting these cells. This study investigated whether targeting cross-presenting DC by two complementary mechanisms could improve vaccine effectiveness, in both a viral setting and in a murine melanoma model. Our novel vaccine construct contained the XCL1 ligand, to target uptake to XCR1+ cross-presenting DC, and a cell penetrating peptide (CPP) with endosomal escape properties, to enhance antigen delivery into the cross-presentation pathway. Using a prime-boost regimen, we demonstrated robust expansion of antigen-specific T cells following vaccination with our CPP-linked peptide vaccine and protective immunity against HSV-1 skin infection, where vaccine epitopes were natively expressed by the virus. Additionally, our novel vaccination strategy slowed tumor outgrowth in a B16 murine melanoma model, compared to adjuvant only controls, suggesting antigen-specific anti-tumor immunity was generated following vaccination. These findings suggest that novel strategies to target the antigen cross-presentation pathway in DC may be beneficial for the generation of anti-tumor immunity.

Atherosclerosis is the major pathology causing death in the developed world and, although risk factor modification has improved outcomes over the last decade, there is no cure. The role of the vasa vasora (VV) in the pathogenesis of atherosclerotic plaque is unclear but must relate to the predictability of diseased sites in the arterial tree. VV are small vessels found on major arteries and veins which supply nutrients and oxygen to the vessel wall itself while removing waste. Numerous studies have been carried out to investigate the anatomy and function of the VV as well as their significance in vascular disease. There is convincing evidence that VV are related to atherosclerotic plaque progression and vessel thrombosis, however, their link to the pathology of plaque initiation remains an interesting but neglected topic. We aim to present the evidence on the anatomy and functional behaviour of VV as well as their relationship to the initiation of atherosclerosis. At the same time, we wish to highlight inconsistencies in, and limitations of, the evidence available.