Paradoxical aortic stiffening and subsequent cardiac dysfunction in Hutchinson-Gilford progeria syndrome

[EN] Hutchinson-Gilford progeria syndrome (HGPS) is an ultra-rare disorder with devastating sequelae resulting in early death, presently thought to stem primarily from cardiovascular events. We analyse novel longitudinal cardiovascular data from a mouse model of HGPS (Lmna(G609G/G609G)) using allometric scaling, biomechanical phenotyping, and advanced computational modelling and show that late-stage diastolic dysfunction, with preserved systolic function, emerges with an increase in the pulse wave velocity and an associated loss of aortic function, independent of sex. Specifically, there is a dramatic late-stage loss of smooth muscle function and cells and an excessive accumulation of proteoglycans along the aorta, which result in a loss of biomechanical function (contractility and elastic energy storage) and a marked structural stiffening despite a distinctly low intrinsic material stiffness that is consistent with the lack of functional lamin A. Importantly, the vascular function appears to arise normally from the low-stress environment of development, only to succumb progressively to pressure-related effects of the lamin A mutation and become extreme in the peri-morbid period. Because the dramatic life-threatening aortic phenotype manifests during the last third of life there may be a therapeutic window in maturity that could alleviate concerns with therapies administered during early periods of arterial development.This work was supported, in part, by grants from the US National Institutes of Health: R01 HL105297 (J.D.H.) and P01 HL134605 (Dan Rifkin) and R01 AG047632 and R33 ES025636 (G.S.S.)Murtada, SI.; Kawamura, Y.; Caulk, AW.; Ahmadzadeh, H.; Mikush, N.; Zimmerman, K.; Kavanagh, D.... (2020). Paradoxical aortic stiffening and subsequent cardiac dysfunction in Hutchinson-Gilford progeria syndrome. Journal of The Royal Society Interface. 17(166):1-12. https://doi.org/10.1098/rsif.2020.00661121716

Is the Public willing to help the Nigerian Police during the Boko Haram crisis? A look at moderating factors.

This paper sought the opinion of 200 Nigerians on their willingness to cooperate with the Police during the Boko Haram crisis. Public perceptions of Police effectiveness during the crisis, residence location, gender and religious affiliation were used as moderators. Data was analysed using an explanatory factor analysis and structural equation modelling. Results indicated a strong association between perceived effectiveness and willingness to report to the Police with respondents who question the effectiveness of the Police being less likely to be willing to report criminal activity about Boko Haram. Further to this, the impact of religion on willingness to report was at least partially mediated by perceived effectiveness of the Police with the results showing that Christian respondents perceived the Police as less effective. Females and those living in the North were significantly less willing to report criminal activity to the Police The findings are then discussed in relation to the BH crises and directions for future research are given

Reduced Biaxial Contractility in the Descending Thoracic Aorta of Fibulin-5 Deficient Mice

The precise role of smooth muscle cell contractility in elastic arteries remains unclear, but accumulating evidence suggests that smooth muscle dysfunction plays an important role in the development of thoracic aortic aneurysms and dissections (TAADs). Given the increasing availability of mouse models of these conditions, there is a special opportunity to study roles of contractility ex vivo in intact vessels subjected to different mechanical loads. In parallel, of course, there is a similar need to study smooth muscle contractility in models that do not predispose to TAADs, particularly in cases where disease might be expected. Multiple mouse models having compromised glycoproteins that normally associate with elastin to form medial elastic fibers present with TAADs, yet those with fibulin-5 deficiency do not. In this paper, we show that deletion of the fibulin-5 gene results in a significantly diminished contractility of the thoracic aorta in response to potassium loading despite otherwise preserved characteristic active behaviors, including axial force generation and rates of contraction and relaxation. Interestingly, this diminished response manifests around an altered passive state that is defined primarily by a reduced in vivo axial stretch. Given this significant coupling between passive and active properties, a lack of significant changes in passive material stiffness may help to offset the diminished contractility and thereby protect the wall from detrimental mechanosensing and its sequelae

Reduced Biaxial Contractility in the Descending Thoracic Aorta of Fibulin-5 Deficient Mice

The precise role of smooth muscle cell contractility in elastic arteries remains unclear, but accumulating evidence suggests that smooth muscle dysfunction plays an important role in the development of thoracic aortic aneurysms and dissections (TAADs). Given the increasing availability of mouse models of these conditions, there is a special opportunity to study roles of contractility ex vivo in intact vessels subjected to different mechanical loads. In parallel, of course, there is a similar need to study smooth muscle contractility in models that do not predispose to TAADs, particularly in cases where disease might be expected. Multiple mouse models having compromised glycoproteins that normally associate with elastin to form medial elastic fibers present with TAADs, yet those with fibulin-5 deficiency do not. In this paper, we show that deletion of the fibulin-5 gene results in a significantly diminished contractility of the thoracic aorta in response to potassium loading despite otherwise preserved characteristic active behaviors, including axial force generation and rates of contraction and relaxation. Interestingly, this diminished response manifests around an altered passive state that is defined primarily by a reduced in vivo axial stretch. Given this significant coupling between passive and active properties, a lack of significant changes in passive material stiffness may help to offset the diminished contractility and thereby protect the wall from detrimental mechanosensing and its sequelae