Term
| what part of vessels is key to maintaining in order to avoid atherosclerosis? |
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Definition
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Term
| how does vascular disease affect the lumen, endothelium and vessel walls? what can it contribute to? |
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Definition
| vascular disease narrows the lumen, injures the endothelium, and weakens vessel walls. vascular diseases also contribute to HTN and DM (and can be caused by them) |
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Term
| are vascular diseases a major cause of morbidity and mortality? |
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Definition
| yes, especially arterial disorders |
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Term
| what are the functions of the endothelium? |
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Definition
| maintainence of a permeable barrier, anti-coagulant (most of the time), pro-coagulant (after injury), modulate blood flow, regulation of inflammation and immunity, regulation of cell growth |
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Term
| what is arteriosclerosis? |
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Definition
| this is the broad term for "parting of arteries", a generic term of 3 types of vascular disease causing thickening and inelasticity of vessels: atherosclerosis, monckeberg's ateriosclerosis, and arteriolosclerosis |
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Term
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Definition
| the dominant pattern of arteriosclerosis, featuring intimal fibrofatty plaques - it is the cause of most morbidity and mortality |
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Term
| what is monckeberg's arteriosclerosis? when does it occur? |
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Definition
| medial (in the media) calcific sclerosis of muscular arteries, usually occuring after 50 - where a patent lumen is preserved and systolic BP may be falsely elevated. may be visible on x-ray, but not associated with morbidity or mortality |
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Term
| what is arteriolosclerosis? |
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Definition
| disease of small arteries/arterioles featuring sclerotic destruction of small blood vessels |
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Term
| does risk for athersclerosis increase with age? |
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Definition
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Term
| who is at greater risk for developing atherosclerosis, men or women? |
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Definition
| men, although postmenopause, women's risks increase |
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Term
| can risk for atherosclerosis be familially predisposed? |
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Definition
| yes, particularly familial hypercholesterolemia or hyperlipidemia |
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Term
| is HTN a treatable risk factor for atherosclerosis? |
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Definition
| yes, increased pressure in the endothelium can injure it |
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Term
| is smoking a treatable risk factor for atherosclerosis? |
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Definition
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Term
| how does diabetes contribute to atherosclerosis? |
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Definition
| high blood sugar can contribute to atherosclerosis |
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Term
| is homocystine a risk factor for athersclerosis? |
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Definition
| yes, it is also associated with strokes, CAD, and PVD |
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Term
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Definition
| an altered form of LDL associated with coronary artery and cerebrovascular risk independent of total cholesterol or LDL levels |
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Term
| how is C-reactive protein associated with atherosclerosis? |
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Definition
| C-reactive protein is a marker for inflammation as an acute phase reactant (synthesized mostly in the liver). it can activate endothelial cells and induce a prothrombotic state by increading the adhesiveness of endothelium for leukocytes. it can strongly predict the risk of MI, stroke, PVD, and sudden death |
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Term
| what causes most cases of HTN? are there different kinds of HTN? |
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Definition
| most cases of HTN are idiopathic. benign HTN increases gradually over time, malignant HTN is rapidly increasing HTN where pts can die within a year or two. the vessels of pt w/benign vs malignant HTN do look different |
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Term
| what factors influence HTN? |
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Definition
| CO, blood volume, HR, Na+, peripheral resistance (controlled by angiotension II, catecholamines), and multiple environmental/genetic factors |
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Term
| what two factors control BP? |
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Definition
| CO and peripheral resistance |
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Term
| what factors control cardiac output? |
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Definition
| blood volume (Na+, mineralocorticoids, atriopeptin) and cardiac factors (HR, contractility) |
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Term
| what factors control peripheral resistance? |
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Definition
| constrictors (angiotensin II, catecholamines, thromboxane, leukotrienes, endothelin) dilators (prostaglandins, kinins, NO/EDRF), neural factors (constrictors such as alpha adrenergics and dilators such as beta adrenergics), and local factors (autoregulation, pH, hypoxia) |
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Term
| what is hyaline arteriosclerosis? what kind of HTN is this seen in? |
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Definition
| pink, hyaline thickening of the walls of arterioles w/narrowing of the lumen. this is seen w/benign HTN |
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Term
| what is hyperplastic arteriolosclerosis? |
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Definition
| seen w/malignant HTN featuring onion skinning concentric narrowing |
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Term
| are hyperlipidemia, hypercholesterolemia (LDL, HDL), and hypertriglyceridemia (VLDL) all risk factors for atherosclerosis? |
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Definition
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Term
| what is the pathogenesis of atherosclerosis? |
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Definition
| 1) endothelial injury and dysfunction 2) smooth muscle emigration to the media 3) smooth muscle and macrophages engulf lipid 4) smooth muscle proliferation 5) collagen deposition = all this leads to plaque formation |
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Term
| what does endothelial dysfunction lead to? |
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Definition
| increased permeability, enhanced leukocyte adhesion, alteration in expression of endothelial gene products |
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Term
| what can cause endothelial dysfunction? |
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Definition
| smoking, homocysteine, inflammation, and hypercholesterolemia |
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Term
| what are hemodynamic forces associated with endothelial injury? |
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Definition
| turbulent flow and shear stress - often seen at vessel bifurcations |
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Term
| what role does V-CAM play in inflammation and ultimately endothelial damage? |
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Definition
| V-CAM binds leukocytes, including monocytes and T cells |
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Term
| what do monocytes do in terms of endothelial damage once bound by V-CAM? |
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Definition
| monocytes transform into macrophages which engulf lipid and secrete cytokines such as IL-1 and TNF. macrophages also produce toxic O2 species that can oxidize LDL |
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Term
| what part do T cells play in endothelial inflammation and injury associated with atherosclerosis? |
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Definition
| *T cells adhere to VCAM-1 on activated endothelial cells and migrate into the vessel wall, secreting proinflammatory molecules. they are also recruited into the intima and cross-link with macrophages - causing cellular and humoral immune activation. |
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Term
| how does T cell activation of SMCs, macrophages and endothelial cells cause significant narrowing of vasculature? can decreased T cells reduce atherosclerosis? |
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Definition
| activated lymphocytes release fibrogenic growth factors that increase SMCs and contribute to elaboration of dense ECM found in advanced atherosclerotic lesions. reduced T cells can decrease atherosclerosis. |
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Term
| what are the major lipids in atheromatous plaques? |
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Definition
| cholesterol and cholesterol esters (where foamy appearance comes from) |
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Term
| how can antioxidants aid slowing of atherosclerotic plaques? |
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Definition
| LDL becomes oxidized by macrophages, and antioxidants can halt or slow this process |
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Term
| what genetically is associated with accelerated atherosclerosis? |
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Definition
| genetic defects in lipoprotein metabolism |
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Term
| what in terms of lifestyle choices can slow the progression of atherosclerotic plaques? |
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Definition
| lowering serum cholesterol by diet, drugs, and exercise |
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Term
| how can chronic lipidemia impair endothelial cell function? |
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Definition
| by increased production of O2 free radicals that deactivate NO - a major endothelial relaxing factor |
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Term
| where do lipoproteins accumulate? |
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Definition
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Term
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Definition
| oxidized LDL is ingested by macrophages |
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Term
| what part do smooth muscle cells play in atherosclerosis? |
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Definition
| smooth muscle cells migrate to the intima and proliferate, depositing ECM components (*collagen and proteoglycans*) that stablize and contribute to the growth of plaques. this connective tissue formation in the intima causes a fibrous cap, the disruption of which can lead to fatal complications such as an MI (*collagen free in the CV is very pro-thrombotic) |
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Term
| what do atherosclerotic plaques begin as? |
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Definition
| fatty streaks, often see on the aortic valve, thoraic aorta - at this stage, they can and may regress |
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Term
| how do atheromatous plaques appear? where are they found? |
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Definition
| as bright yellow, w/irregular cores of yellow lipid material - often eccentric. they are found in the 1)abdominal aorta (high flow state, near area of bifurcation at common illiacs: can lead to turbulence/shearing forces), 2) coronary arteries, 3) thoracic aorta, 4) carotid arteries and 5) circle of willis |
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Term
| what are atherosclerotic plaques composed of? complicated plaques? |
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Definition
| smooth muscle cells, macrophages, lymphocytes, connective tissue fibers, matrix and lipids. complicated plaques contain calcification, ulceration, thrombosis and often hemorrhage |
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Term
| what can be found in the center of fibrous caps? |
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Definition
| a necrotic center w/cell debris, cholesterol crystals, foam cells and calcium |
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Term
| what characterizes the start of endothelial dysfunction? |
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Definition
| increased permeability, leukocyte adhesion, monocyte adhesion, and emigration. platelets also may begin to aggregate |
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Term
| after increased permeability in the endothelial cells, and associated emigration/adhesions, what is the next step? |
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Definition
| smooth muscle emigrates from the media to the intima (inward) and macrophages are activated - oxidizing LDLs and forming foam cells |
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Term
| as smooth muscel cells and macrophages engulf lipids, what start to form? |
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Definition
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Term
| what can fatty streaks form due to smooth muscle proliferation, collagen/other ECM deposition, and extracellular lipid deposition? |
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Definition
| fibrofatty atheromas - composed of lymphocytes, collagen and lipid debris w/a fibrous cap |
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Term
| can HDL help with atherosclerosis? |
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Definition
| yes, HDLs can assist in cholesterol efflux away from plaques |
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Term
| what are 3 pathological events which can happen with advanced vulnerable atherosclerotic plaques? |
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Definition
| aneurysm and rupture, occlusion by thrombosis, critical stenosis - leading to MIs, cerebral infarcts, gangrene of extremities, and abdominal aortic aneurysms |
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Term
| what is the link between diabetes and macrovascular and microvascular disease? what are some factors responsible for this? |
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Definition
| macrovascularly: large and medium sized arteries in diabetic pts are at increased risk for atherosclerosis, increased MIs, strokes and gangrene (particularly in the feet). microvascularly: the retina, kidney and peripheral nerves. three metabolic pathways specifically in diabetic contribute to this state: formation of advanced glycation end products, activation of protein kinase C, and disturbance in polyol pathways |
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Term
| how can diabetic pts' increased risk for atherosclerosis be controlled? |
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Definition
| through strict control of blood glucose |
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Term
| what are AGE's and how are they formed? can they interact with ECM components? |
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Definition
| advanced glycation end products are formed in the reaction between intracellular glucose derived *dicarbonyl precursors w/amino groups on intracellular and extracellular proteins. AGEs can cause crosslinking between peptides on ECM components |
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Term
| what happens when advanced glycation end products crosslink among peptides in the ECM? |
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Definition
| these abnormal matrix-matrix and matrix-cell interactions involving cross-linking of collagen I decrease elasticity and contribute to endothelial injury |
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Term
| what happens when AGEs enable cross-linking between collagen IV? how does this change the properties of proteins involved? |
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Definition
| AGE-enabled collagen IV crosslinking in the basement membrane increases fluid filtration. AGE-crosslinked proteins are resistant to proteolytic degradation - decreasing protein removal and increasing protein deposition |
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Term
| what can be trapped by AGE crosslinked matrix components contributing to atherosclerosis? |
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Definition
| AGE modified matrix components trap nonglycated or interstial material, such as LDLs which contribute to atherosclerosis. albumin may bind to glycated basement membrane - which causes thickening of the basement membrane seen in microangiopathy |
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Term
| how do AGEs affect circulating plasma proteins? |
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Definition
| circulating plasma proteins are modified by addition of AGE residues. these modified proteins then may bind to the AGE receptor of macrophages/endothelial cells/mesangial cells. this results in the generation of cytokines, growth factors and pro inflammatory molecules (leading to increased ECM synthesis, increased endothelial permeability, and increased procoagulant activity on endothelial cells/macrophages) |
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Term
| what is the effect of protein kinase C being activated by intracelluar hyperglycemia? |
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Definition
| intracellular hyperglycemia causes synthesis of diacylglycerol and activation of PKC -> which leads to increased production of *VEGF (leads to neovascularization in diabetic retinopathy) and increases activity of *vasoconstrictor endothelin 1* and decreases activity of *vasodilator endothelin NO synthase |
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Term
| along with neovascularization and vasoconstriction, how else does hyperglycemic activation of PKC contribute to decreased blood flow through the vasculature in diabetics? |
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Definition
| PKC increases production of profibrogenic molecules, such as transforming growth factor beta (TGF-b) which *increases ECM deposition, thickening the basement membrane. PKC also produces procoagulant molecule *plasminogen activator inhibitor-1 (causing decreased fibrinolysis and vascular occlusion) and other proinflammatory cytokines |
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Term
| how can intracellular hyperglycemia contribute to oxidative injury in the cell? |
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Definition
| intracellular hyperglycemia is associated with disturbances in polyol, it increases cell response to oxidative injury, and leads to increased intracellular glucose which is converted to fructose. this conversion require NADPH as a cofactor, which then cannot be used to synthesize glutathione - an antioxidant |
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Term
| is the pancreas changed dramatically in diabetes? what happens to the number and sizes of islets? |
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Definition
| there are no dramatic changes, but the number and size of islets/beta cells are decreased, esp in DM1 and there may be some T cell infiltration |
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Term
| what is the result of T cell infiltration in the pancreas? |
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Definition
| beta cell degranulation w/depletion of stored insulin |
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Term
| what happens to islets in DM2? |
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Definition
| amyloid replacements of islets occur around blood vessels and between cells |
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Term
| are non-diabetic newborns affected by diabetic mothers? |
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Definition
| they have hyperplasia of islets in response to maternal hyperglycemia |
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Term
| what is the most common cause of death in DM? |
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Definition
| MI from atherosclerosis (which are accelerated in DM pts) |
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Term
| can diabetic macrovascular disease cause gangrene of the lower extremities? |
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Definition
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Term
| is hyaline arteriosclerosis seen in diabetic pts? |
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Definition
| yes, this amorphous hyaline thickening of arteriole walls results in narrowing of the lumen |
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Term
| what is diabetic microangiopathy characterized by? |
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Definition
| diffuse thickening of the basement membrane featuring concentric layers of hyaline material (mostly type IV collagen), this causes plasma membrane leakage and underlies nephropathy, retinopathy, and neuropathy |
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