1,721,180 research outputs found
Revascularization for coronary artery disease in diabetes mellitus: Angioplasty, stents and coronary artery bypass grafting
Full text linkAuthor Manuscript: 2011 April 14Patients with diabetes mellitus (DM) are prone to a diffuse and rapidly progressive form of atherosclerosis, which increases their likelihood of requiring revascularization. However, the unique pathophysiology of atherosclerosis in patients with DM modifies the response to arterial injury, with profound clinical consequences for patients undergoing percutaneous coronary intervention (PCI). Multiple studies have shown that DM is a strong risk factor for restenosis following successful balloon angioplasty or coronary stenting, with greater need for repeat revascularization and inferior clinical outcomes. Early data suggest that drug eluting stents reduce restenosis rates and the need for repeat revascularization irrespective of the diabetic state and with no significant reduction in hard clinical endpoints such as myocardial infarction and mortality. For many patients with 1- or 2-vessel coronary artery disease, there is little prognostic benefit from any intervention over optimal medical therapy. PCI with drug-eluting or bare metal stents is appropriate for patients who remain symptomatic with medical therapy. However, selection of the optimal myocardial revascularization strategy for patients with DM and multivessel coronary artery disease is crucial. Randomized trials comparing multivessel PCI with balloon angioplasty or bare metal stents to coronary artery bypass grafting (CABG) consistently demonstrated the superiority of CABG in patients with treated DM. In the setting of diabetes CABG had greater survival, fewer recurrent infarctions or need for re-intervention. Limited data suggests that CABG is superior to multivessel PCI even when drug-eluting stents are used. Several ongoing randomized trials are evaluating the long-term comparative efficacy of PCI with drug-eluting stents and CABG in patients with DM. Only further study will continue to unravel the mechanisms at play and optimal therapy in the face of the profoundly virulent atherosclerotic potential that accompanies diabetes mellitus.National Institutes of Health (U.S.) (GM 49039
Target-responsive DNA/RNA nanomaterials for microRNA sensing and inhibition: The jack-of-all-trades in cancer nanotheranostics?
No full textmicroRNAs (miRNAs) show high potential for cancer treatment, however one of the most significant bottlenecks in enabling miRNA effect is the need for an efficient vehicle capable of selective targeting to tumor cells without disrupting normal cells. Even more challenging is the ability to detect and silence multiple targets simultaneously with high sensitivity while precluding resistance to the therapeutic agents. Focusing on the pervasive role of miRNAs, herein we review the multiple nanomaterial-based systems that encapsulate DNA/RNA for miRNA sensing and inhibition in cancer therapy. Understanding the potential of miRNA detection and silencing while overcoming existing limitations will be critical to the optimization and clinical utilization of this technology. Keywords: microRNA; RNAi; Nanomaterials; Surface modification; Biosensors; Cancer; Nanotheranostics; Translational medicin
Role of CABG in the management of obstructive coronary arterial disease in patients with diabetes mellitus
No full textMultiple studies have shown that diabetes mellitus (DM) can affect the efficacy of revascularization therapies and subsequent clinical outcomes. Selection of the appropriate myocardial revascularization strategy is critically important in the setting of multivessel coronary disease. Optimal medical therapy is an appropriate first-line strategy in patients with DM and mild symptoms. When medical therapy does not adequately control symptoms, revascularization with either PCI or CABG may be used. In patients with treated DM, moderate to severe symptoms and complex multivessel coronary disease, coronary artery bypass graft surgery provides better survival, fewer recurrent infarctions and greater freedom from re-intervention. Decisions regarding revascularization in patients with DM must take into account multiple factors and as such require a multidisciplinary team approach (‘heart team’).National Institutes of Health (U.S.) (R01 GM-49039
Monocyte-endothelial cell interactions in the regulation of vascular sprouting and liver regeneration in mouse
Full text linkBackground & Aims Regeneration of the hepatic mass is crucial to liver repair. Proliferation of hepatic parenchyma is intimately dependent on angiogenesis and resident macrophage-derived cytokines. However the role of circulating monocyte interactions in vascular and hepatic regeneration is not well-defined. We investigated the role of these interactions in regeneration in the presence and absence of intact monocyte adhesion. Methods Partial hepatectomy was performed in wild-type mice and those lacking the monocyte adhesion molecule CD11b. Vascular architecture, angiogenesis and macrophage location were analyzed in the whole livers using simultaneous angiography and macrophage staining with fluorescent multiphoton microscopy. Monocyte adhesion molecule expression and sprouting-related pathways were evaluated. Results Resident macrophages (Kupffer cells) did not migrate to interact with vessels whereas infiltrating monocytes were found adjacent to sprouting points. Infiltrated monocytes colocalized with Wnt5a, angiopoietin 1 and Notch-1 in contact points and commensurate with phosphorylation and disruption of VE-cadherin. Mice deficient in CD11b showed a severe reduction in angiogenesis, liver mass regeneration and survival following partial hepatectomy, and developed unstable and leaky vessels that eventually produced an aberrant hepatic vascular network and Kupffer cell distribution. Conclusions Direct vascular interactions of infiltrating monocytes are required for an ordered vascular growth and liver regeneration. These outcomes provide insight into hepatic repair and new strategies for hepatic regeneration.National Institutes of Health (U.S.) (Grant R01 GM 49039
J Waves of Osborn Revisited
Full text linkIn 1953, Joseph Osborn examined the physiologic effects of hypothermia and defined typical associated changes in the electrocardiogram (ECG), now known as J waves of Osborn. There is a subtlety, however: Osborn's J waves were absent in hypothermic animals whose pH was maintained via mechanical ventilation. Osborn wrote: “We regard this as evidence that the ECG changes … may not be associated with the low temperature directly, but rather may be more closely associated with faulty elimination of CO2under hypothermic conditions” (1).
This principle is illustrated in a 64-year-old man who presented hypothermic to 92°F and profoundly acidemic (pH 7.03) after cardiac arrest. Striking J waves are evident on initial ECG (A). Controlled cooling was initiated; hypothermia was maintained to preserve brain function. Intubation and resuscitation restored bicarbonate, carbon dioxide concentrations, and pH. At pH 7.33, although body temperature was identical at 92°F, the J waves had resolved (B)
Coronary Artery Disease and Diabetes Mellitus
No full textCoronary artery disease (CAD) is a major determinant of the long-term prognosis among patients with diabetes mellitus (DM). DM is associated with a 2 to 4-fold increased mortality risk from heart disease. Furthermore, in patients with DM there is an increased mortality after MI, and worse overall prognosis with CAD. Near-normal glycemic control for a median of 3.5 to 5 years does not reduce cardiovascular events. Thus, the general goal of HbA1c <7% appears reasonable for the majority of patients. Iatrogenic hypoglycemia is the limiting factor in the glycemic management of diabetes, and is an independent cause of excess morbidity and mortality. Statins are effective in reducing major coronary events, stroke, and the need for coronary revascularization
The effect of substrate modulus on the growth and function of matrix-embedded endothelial cells
No full textEndothelial cells (EC) are potent bioregulatory cells, modulating thrombosis, inflammation and control over mural smooth muscle cells and vascular health. The biochemical roles of EC are retained when cells are embedded within three-dimensional (3D) denatured collagen matrices. Though substrate mechanics have long been known to affect cellular morphology and function and 3D-EC systems are increasingly used as therapeutic modalities little is known about the effect of substrate mechanics on EC in these 3D systems. In this work, we examined the effect of isolated changes in modulus on EC growth and morphology, extracellular matrix gene expression, modulation of smooth muscle cell growth, and immunogenicity. EC growth, but not morphology was dependent on scaffold modulus. Increased scaffold modulus reduced secretion of smooth muscle cell growth inhibiting heparan sulfate proteoglycans (HSPGs), but had no effect on secreted growth factors, resulting in a loss of smooth muscle cell growth inhibition by EC on high modulus scaffolds. Expression of ICAM-1, VCAM-1 and induction of CD4[superscript +] T cell proliferation was reduced by increased scaffold modulus, and correlated with changes in integrin α5 expression. Expression of several common ECM proteins by EC on stiffer substrates dropped, including collagen IV(α1), collagen IV(α5), fibronectin, HSPGs (perlecan and biglycan). In contrast, expression of elastin and TIMPs were increased. This work shows even modest changes in substrate modulus can have a significant impact on EC function in three-dimensional systems. The mechanism of these changes is not clear, but the data presented here within suggests a model wherein EC attempt to neutralize changes in environmental force balance by altering ECM and integrin expression, leading to changes in effects on downstream signaling and function.National Institutes of Health (U.S.) (R01 GM49039)Else Kroner-Fresenius Stiftung (P36/07//A45/07
Pathology of Endovascular Stents
No full textContemporary endovascular stents are the product of an iterative design and development process that leverages evolving concepts in vascular biology and engineering. This article reviews how insights into vascular pathophysiology, materials science, and design mechanics drive stent design and explain modes of stent failure. Current knowledge of pathologic processes is providing a more complete picture of the factors mediating stent failure. Further evolution of endovascular stents includes bioresorbable platforms tailored to treat plaques acutely and to then disappear after lesion pacification. Ongoing refinement of stent technology will continue to require insights from pathology to understand adverse events, refine clinical protocols, and drive innovation. Keywords: Coronary artery disease; Pathology; Bare metal stent; Drug-eluting stent; In-stent restenosis; In-stent thrombosis; Atherosclerosis; NeoatherosclerosisNational Institutes of Health (U.S.) (Grant R01 GM-49039
Arterial Stiffening in Perspective: Advances in Physical and Physiological Science Over Centuries:
No full textArterial stiffening is not a new issue in medicine or research but was the prime concern of Richard Bright in the early 19th century and of the prominent London physicians and pathologists who tried to unscramble the relationship between kidney, heart, and cerebrovascular disease and hardness of the pulse in the late 19th century. It was of major concern to medical educators including Osler and Mackenzie who were still active in practice 100 years ago. It is all too easy (when dependent on the Internet) to consider arterial stiffness to be a new issue. The terms arterial stiffness, aortic stiffness, or wave reflection do not appear as categories for articles such as this in respectable journals, nor in categories for meetings of specialized physicians. Yet as described in this article, the subject was of interest to clinicians, to investigators such as Harvey in the 17th century, and to physicists who developed laws and principles of elasticity from the study of biological materials including ligaments and arteries. This paper provides a perspective on arterial stiffness from the time of William Harvey and Isaac Newton to the present, with a glance into the future.National Institutes of Health (U.S.) (Grant R01 GM 49039
Implantation of healthy matrix-embedded endothelial cells rescues dysfunctional endothelium and ischaemic tissue in liver engraftment
Full text linkObjective: Liver transplantation is limited by ischaemic injury which promotes endothelial cell and hepatocyte dysfunction and eventually organ failure. We sought to understand how endothelial state determines liver recovery after hepatectomy and engraftment. Design: Matrix-embedded endothelial cells (MEECs) with retained healthy phenotype or control acellular matrices were implanted in direct contact with the remaining median lobe of donor mice undergoing partial hepatectomy (70%), or in the interface between the remaining median lobe and an autograft or isograft from the left lobe in hepatectomised recipient mice. Hepatic vascular architecture, DNA fragmentation and apoptosis in the median lobe and grafts, serum markers of liver damage and phenotype of macrophage and lymphocyte subsets in the liver after engraftment were analysed 7 days post-op. Results: Healthy MEECs create a functional vascular splice in donor and recipient liver after 70% hepatectomy in mouse protecting these livers from ischaemic injury, hepatic congestion and inflammation. Macrophages recruited adjacent to the vascular nodes into the implants switched to an anti-inflammatory and regenerative profile M2. MEECs improved liver function and the rate of liver regeneration and prevented apoptosis in donor liver lobes, autologous grafts and syngeneic engraftment. Conclusions: Implants with healthy endothelial cells rescue liver donor and recipient endothelium and parenchyma from ischaemic injury after major hepatectomy and engraftment. This study highlights endothelial-hepatocyte crosstalk in hepatic repair and provides a promising new approach to improve regenerative medicine outcomes and liver transplantation
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