Deans' stroke musings

Changing stroke rehab and research worldwide now.Time is Brain!Just think of all the trillions and trillions of neurons that DIE each day because there are NO effective hyperacute therapies besides tPA(only 12% effective). I have 493 posts on hyperacute therapy, enough for researchers to spend decades proving them out. These are my personal ideas and blog on stroke rehabilitation and stroke research. Do not attempt any of these without checking with your medical provider. Unless you join me in agitating, when you need these therapies they won't be there.

What this blog is for:

Shortly after getting out of the hospital and getting NO information on the process or protocols of stroke rehabilitation and recovery I started searching on the internet and found that no other survivor received useful information. This is an attempt to cover all stroke rehabilitation information that should be readily available to survivors so they can talk with informed knowledge to their medical staff. It's quite disgusting that this information is not available from every stroke association and doctors group.
My back ground story is here:

Friday, October 14, 2016

Proresolving Lipid Mediators Restore Balance to the Vulnerable Plaque

But is vulnerable plaque even fixable or findable?

Vulnerable Plaque: The Paradigm That Failed Feb. 2016
Edward B. Thorp

Atherosclerosis, the precursor to acute coronary syndromes, is a disease of chronic inflammation triggered initially by the focal subendothelial retention of apolipoprotein B100–containing lipoproteins and exacerbated by other risk factors, such as smoking, diabetes mellitus, and hypertension.1,2 The persistence of these stimuli promotes a cycle of nonresolving inflammation that promotes atherosclerotic lesion development and, most importantly, progression to the unique types of necrotic plaques that cause ACS. In order for inflammation to resolve, there must not only be an abatement of initiating risk factors but also an initiation of proresolving molecular and cellular pathways that act to restore tissue homeostasis and promote repair. On the basis of the observations of human and animal atherosclerotic plaque features, genetic and therapy-based causation studies in mice, and cell culture studies with macrophages, researchers over the past two decades have proposed that defective resolution drives atherosclerosis progression. For example, advanced atherosclerosis is characterized by failure to reduce plaque inflammatory cell number, inefficiency in removing dying cells, and suboptimal tissue repair. However, the molecular basis of defective inflammation in atherosclerosis remained to be precisely defined.
Article, see p 1030
The inflammation resolution program is carried out by several molecular and cellular effectors. Among these are a superfamily of unsaturated fatty acid–derived lipid mediators referred to as specialized proresolving mediators or SPMs. SPMs are biosynthesized by inflammatory cells during self-limited inflammation and, by interacting with specific cell-surface receptors on immune cells and other cell types, trigger processes that dampen inflammation and promote tissue repair. Moreover, exogenously administered SPMs and other proresolving mediators have shown efficacy in triggering resolution of several types of chronic diseases, including atherosclerosis. Although characterized within human arterial cells in the early 1990s by Brezinski et al,3 a comprehensive and direct cataloging of SPMs within atherosclerotic lesions is only now coming to light.

Implications for SPMs in Atherosclerosis

The major types of SPMs are the lipoxins (LX), resolvins (Rv), protectins (P), and maresins (MaR), each of which is endogenously biosynthesized in resolving exudates and activates specific G-protein–coupled receptors.4 The precursors of SPMs include diet-derived polyunsaturated fatty acids that are substrates for SPM biosynthetic enzymes, including lipoxygenases and cyclooxygenases. Lipoxins are derived from omega-6 arachidonic acid, whereas resolvins, protectins, and maresins are derived from omega-3 fatty acids, eicosapentaenoic acid, and docosahexaenoic acid. In human plasma, low levels of SPMs are correlated with peripheral and coronary artery disease.5 In mouse models of atherosclerosis, macrophage-specific overexpression of 12/15-lipoxygenase (LOX), which increased the local biosynthesis of LXA4, RvD1, and PD1, suppressed lesion development.6 In terms of human evidence, variants in the gene, ALOX5, which can synthesize proresolving SPMs in the presence of n-3 fatty acids but proinflammatory/proatherosclerotic leukotrienes in the presence of n-6 fatty acids, was associated with decreased or increased risk for subjects ingesting diets rich in n-3 versus n-6 fats, respectively.7 Interestingly, the benefit of fish oils when analyzed in the absence of genetic interactions has yielded conflicting results. In this setting of active investigation, what remained unclear were the levels and temporal patterns of lesional SPMs during atherosclerosis progression.

An Imbalance of Bioactive Lipids in Advanced Plaque

In a recent study in this issue of Circulation Research, Viola et al8 test the hypothesis that atherosclerosis progression is tied to a deficit of arterial SPMs. The investigators performed aortic lipid mediator profiling of advanced atherosclerotic lesions from fat-fed hyperlipidemic mice after carefully snap-freezing aortas and utilizing liquid chromatography in tandem with mass spectrometry. Their findings indicate that the levels of the inflammatory lipids leukotriene B4 and prostaglandin E2 increase as atherosclerotic plaques mature. Conversely, advanced plaques had significantly lower levels of 2 types of SPMs, RvD2, and Mar1. Importantly, these SPMs declined progressively with longer duration of fat feeding. Of note, RvD1, LXA4, and protectins were below detection limits. Thus, atheroprogression was associated with an increasing and unbalanced ratio of inflammatory versus resolving bioactive lipids in plaques.
In humans, lesions that are unstable and at risk for rupture are so-called vulnerable. Vulnerable plaques are marked, in part, by thin fibrous caps and increased cellular and macrophage death, the effects of which are compounded by defects in dead cell clearance, or efferocytosis. Taking into account these features of unstable plaques, Viola et al8 generated an index of plaque instability and found that increases in leukotriene B4 and prostaglandin E2 positively correlated with this index. In contrast, RvD2 and MaR1 levels correlated with opposing indices of plaque stability, including the aggregate of smooth muscle cell number, the surface area of collagen deposition, and fibrous cap thickness.

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