Abstract Mitochondrial dysfunction has been implicated in the pathogenesis of multiple sclerosis (MS) and systemic lupus erythematosus (SLE). This study re-investigates the roles of previously ...suggested candidate genes of energy metabolism (Complex I genes located in the nucleus and in the mitochondria) in patients with MS relative to ethnically matched SLE patients and healthy controls. After stringent correction for multiple testing, we reproduce the association of the mitochondrial (mt)DNA haplotype K⁎ with MS, but reject the importance of previously suggested borderline associations with nuclear genes of Complex I. In addition, we detect the association of common variants of the mitochondrial ND2 and ATP6 genes with both MS and SLE, which raises the possibility of a shared mitochondrial genetic background of these two autoimmune diseases.
Statin or 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR) inhibitor is widely used and plays a vital role in the management of cardiovascular and cerebrovascular diseases. Statin is generally ...safe and its side effects are mostly mild and self-limiting. Immune-mediated necrotizing myositis (IMNM) is a rare and serious side effect characterized by the presence of anti-HMGCR inhibitor and myositis. Long-term immunosuppressive therapy is often required to manage it, and in refractory cases, the treatment can be very challenging. We report the case of a 55-year-old female with underlying diabetes mellitus and hyperlipidemia who developed refractory statin-induced IMNM despite being administered prednisolone, methotrexate, azathioprine, and immunoglobulin. After the introduction of rituximab, steroids were able to be tapered down to the lowest maintenance dose. Unfortunately, the patient subsequently succumbed to severe coronary artery disease (CAD) likely caused by the long-term steroid therapy, highlighting the difficulty and complications associated with the treatment of IMNM, especially in patients with cardiovascular risk factors.
Abstract This follow up study aims to refine the roles of previously suggested candidate genes (CC chemokine ligands or CCLs) in multiple sclerosis (MS), and to test these markers in another ...autoimmune disorder, systemic lupus erythematosus (SLE). After stringent correction for multiple testing, we reject the importance of previously suggested borderline associations with CCLs in MS. A new finding is the differential distribution of CCL8 marker alleles and a haplotype in extreme severity subgroups of MS. In SLE, this study reveals strong associations with a marker and a haplotype encompassing the CCL14 gene, which suggests that a lupus relevant variant may lie within or in the proximity of this haplotype.
Abdominal aortic aneurysms (AAAs) involve chronic overexpression of proteases in the aortic wall that result in disruption of elastic fibers and consequent loss of vessel elasticity. Nearly 75% of ...AAAs contain flow-obstructing, fibrin-rich intraluminal thrombi (ILT), which act as a) a bioinert shield, protecting the underlying AAA wall from high hemodynamic stresses, and b) a reservoir of inflammatory cells and proteases that cause matrix breakdown. For these reasons, restoring flow through the aorta lumen and facilitating transmural diffusion of therapeutics from circulation to the AAA wall must be achieved by slow thrombolysis of the ILT to render it porous without rapid breakdown. Intravenously dosed tissue plasminogen activator (tPA) has been shown to rapidly lyse ILTs in acute stroke and myocardial infarctions. For future use in opening up AAA segments, in this study, we investigated the ability of tPA released from poly(lactic-co-glycolic acid) nanoparticles (PLGA NPs) to slowly lyse fibrin clots without inducing proteolytic injury and matrix synthesis-inhibitory effects on cultured rat aneurysmal smooth muscle cells (EaRASMCs). Fibrin clot lysis time was greatly extended over that in presence of exogenous tPA. Surface functionalization of NPs with a cationic amphiphile allowed them to bind to anionic fibrin clot, release tPA at a slower rate and to lyse the clot as a front proceeding outwards in unlike the more rapid and homogenous lysis that occurred due to anionic PLGA NPs. Elastic matrix content was decreased in EaRASMC cultures exposed to byproducts of clot lysis with exogenous tPA, but not tPA-NPs, and was likely due to increased proteolytic activity (MMPs, plasmin) in EaRASMC cultures exposed to exogenous tPA-lysed clots. Our results suggest that gradual ILT lysis via slow release of tPA from NPs will be likely beneficial over exogenous tPA delivery in preserving elastic matrix content and attenuating matrilysis in the adjoining AAA wall, in vivo, while rendering the ILT porous to facilitate transmural delivery of endoluminally delivered AAA therapeutics.
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•Formulated tPA-releasing PLGA NPs for slow lysis of fibrin-rich clots within small AAAs•NP-delivered tPA achieves much slower clot lysis versus equivalent dose of exogenous tPA.•NP-released tPA attenuates proteolysis and limits elastic matrix loss versus exogenous tPA.•NPs with cationic surfaces show improved clot binding and slowed clot lysis versus anionic NPs.
There are wide power variations across a chip leading to temperature variations. High power density components such as register files and arithmetic logic units will trend towards elevated ...temperatures while other lower power density units will be cooler. Higher temperatures in general decrease the lifetime reliability of digital systems through a number of mechanisms. Furthermore, continued scaling leads to an increase in soft error occurrences. To this end in addition to increasing the error resiliency of register files a proposal that would also lower energy per access is presented. The power modes available to save power also have the effect of lowering the rate of certain degradation. The effect of negative bias temperature instability (NBTI) on SRAM cells under power saving modes is investigated for leakage current, read and hold margins. This is done for both symmetric and asymmetric cells. Noting that temperature variations occurs across a chip, we present techniques to lower its effects on synchronous digital circuits propagation delay variation in general and clock skew in particular.
Thesis (M.A.)--University of Wisconsin--Madison, 1958.
Typescript. eContent provider-neutral record in process. Description based on print version record. Includes bibliographical references (leaves ...116-121)
Thesis (Ph. D.)--University of Wisconsin--Madison, 1967.
Typescript. Vita. Description based on print version record. Includes bibliographical references (leaves 167-178).
Every day in the UK, hundreds of children aged 11-15 years start smoking for the first time, 1 2 and there is compelling evidence that children's perceptions of cigarettes are influenced by branding. ...3 4 As health professionals working to prevent and treat lung disease caused by smoking, we welcome the government's decision to enable legislation for standardised packaging of cigarettes in an amendment to the Children and Families Bill. Industry documents make it clear that after the prohibition of tobacco advertising, promotion, and sponsorship cigarette packaging became the tobacco industry's key marketing tool to attract and retain customers.
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