cytokines – Chemistry – Flashcards
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| what is a cytokine? lymphokine? why are some cytokines called interleukins? |
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| a polypeptide produced in response to microbes or other antigens that mediate and regulate immune and inflammatory reactions. lymphkines are cytokines secreted by lymphocytes. interleukins are cytokines that are made by lymphocytes to act on other lymphocytes |
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| how long is the action of cytokines? can one cytokine have more than one effect/can multiple cytokines have the same function? can cytokines affect the function and activity of other cytokines? |
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| cytokine secretion is brief and self-limited. cytokines are pleiotropic and redundant, (each cytokine mediates diverse effects/mult. cytokines have the same function. cytokines can influence the secretion/activity of other cytokines with effects that can be additive, synergistic, or antagonistic |
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| do cytokines have local or systemic effects? do cytokines on specific cell surface receptors, what is this regulated by? what does the cellular response to cytokines involve? |
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| cytokine action may be autocrine, paracrine, or endocrine. cytokines act on specific cell surface receptors, regulated by external signals. the cellular reponse to cytokines involves gene expression, resulting in the aquisition of new function or proliferation, (more often than not). |
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| what are the main cytokines produced in innate immunity and their producers/targets? |
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| IFN-gamma, (NK->macrophage), IL-12, (macrophage->NK), TNF, IL-1, (macrophage->vascular epithelial cells |
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| what are the main cytokines produced in adaptive immunity and their producers/targets? |
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| IL-2, (APC->CD4+), IFN-gamma, (CD4+->macrophages), IL-2, IL-4, IFN-gamma, (CD4+->B cells), IL-2, (CD4+->CD8+) |
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| what are important cytokines that mediate and regulate innate immunity? |
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| TNF-alpha is the prototype, others are type I IFNs, pro-inflammatory cytokines such as TNF,IL-1, and IL-6. also, chemokines, IL-12, IL-10, IL-15, IL-18 |
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| how many genes are there for IFN alpha? beta? where do each come from? |
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| IFN alpha comes from about ~20 genes, though IFN beta comes from only gene. IFN alpha comes from predominately mononuclear phagocytes, and IFN beta is probably from multiple cells |
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| how many genes are there for IFN alpha? beta? where do each come from? do they have redundant activity? |
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| IFN alpha comes from about ~20 genes, (18kDa polypeptide), though IFN beta comes from only gene,(20kDa polypeptide). IFN alpha comes from predominately mononuclear phagocytes, and IFN beta is probably from multiple cells. they have very redundant activity. |
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| what are the targets for type 1 IFNs? what receptor do they interact with? what are they important for? |
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| type 1 IFNs target virtually all cells and interact with the same receptor. they are very important in limiting the spread of certain viral infections. viruses the most potent stimulator of IFN production, (esp those w/ds RNA), and activated T cells can also stimulate IFN production in mononuclear phagocytes |
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| what is the method of signal transduction for type 1 IFNs? |
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| type 1 IFNs use the receptor associated JAK/STAT protein kinase pathway, (janus associated kinase activates a family of transcriptional factors:STAT). these kinases phosphorylate a specific transcriptional factor which moves from the cytoplasm to the nucleus, these transcriptional factors then bind to the interferon sequence response elements, (ISRE), in promoter regions of interferon inducible genes. |
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| what is are some enzymes that are upregulated in response to type 1 interferons? |
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| oligoadenylate synthetase. dsRNA-activated serine/threonine kinase, (PKR16), which functions to block viral transcription and translation. several RNAases. |
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| other than inhibition of viral replication, what are some other effects of type 1 IFNs in regards to MHC, Th1+2 levels, lymphocyte migration, NK cells and cell proliferation? |
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| increased class I MHC espression, (enhances viral expression to CD8+), enhanced production of Th1 in humans, (via increased IL-12R expression), promotion of lymphocyte sequestration in lymph nodes to enhance their activation by antigens, (esp viral). also enhanced NK cell cytotoxicity and inhibition of proliferation of many cell types in vitro |
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| what kinds of cancer can be treated by IFNs? what viral infections? any other conditions? |
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| malignant melanoma, renal cells carcinomas, and chromic myelogenous leukemia have all been treated by IFNs. hepatitis C, (along with antiviral rx ribavirin), and relapsing-remitting mult. sclerosis |
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| what are some toxic effects of IFNs when used systemically/exogenously? |
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| fever, chills, malaise, myalgias, myelosuppression, headaches and depression = why you feel bad w/viral infections |
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| what are the proinflammatory cytokines? |
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| TNF, IL-1, Il-6, chemokines |
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| what is the principal mediator of acute inflammatory response to gram negative bacteria? |
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| TNF is the principal mediator of acute inflammatory response to gram negative bacteria, (along with other infectious microbes) |
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| what is TNF associated with systemically? what is it also called? |
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| TNF is responsible for systemic complications of a severe infection, (sepsis). TNF is also called TNF alpha |
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| what is the major source of TNF alpha? what is the major inducer for TNF? |
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| TNFs major source is activated mononuclear phagocytes, (as well as activated T cells, NK cells + mast cells). the major inducer for TNF is LPS. |
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| what is IFN-gamma's effect on TNF production? |
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| TNFs production is augmented by interferon gamma. |
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| what is the only cytokine that can be produced from a cell w/out denovo transcription? how? |
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| TNF is stored in mast cell granules which is released in a bollus during an allergic event. |
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| what are the biologic effects of TNF on endothelial cells? |
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| TNF activates endothelial cells, upregulating expression of adhesion molecules such as selectins and VCAM-1, ICAM-1, (bind neutrophils, then monocytes and lymphocytes) |
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| what are the biologic effects of TNF on macrophage chemokine secretion? |
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| this enhances the affinity of leukocyte integrins for their integrins and induces leukocyte chemotaxis/recruitment |
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| is TNF secretion associated with clot formation? |
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| TNF produces factors that promote clot formation, (one of the hallmarks of sepsis) |
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| how does TNF affect IL-1 production? does it stimulate anything in neutrophils or macrophages? |
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| TNF acts on mononuclear phagocytes to induce IL-1 production. it also stimulates microbicidal activity of neutrophils and macrophages, (though not as well as IFN-gamma). |
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| how does TNF act on the hypothalamus, how is this mediated? |
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| TNF acts on the hypthalamus to induce fever mediated by prostaglandins, (which is why ibuoprofen will take down a fever). |
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| how does TNF affect acute phase reactant levels? |
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| TNF acts on hepatocytes to induce acute phase reactant levels. |
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| what will prolonged TNF production lead to? |
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| prolonged TNF production will lead to cachexia, (fat/muscle wasting - seen in HIV), appetite suppression and reduced synthesis of lipoprotein lipase. |
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| beyond cachexia, what effects does TNF have on the heart, vasculature, and metabolism? |
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| in large amounts, TNF inhibits myocardial contractility and vascular smooth muscle tone, (marked blood pressure drop - septic shock), intravascular thrombosis, and severe metabolic disturbances such as a fall in blood glucose levels |
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| what do low levels of TNF promote? |
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| upregulation of adhesion molecules, IL-1/chemokine production, and leukocyte activation |
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| what do moderate levels of TNF promote? |
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| fever induced in the brain, acute phase protein induction in the liver, and leukocyte production in the bone marrow |
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| what do high levels of TNF promote? |
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| lowered cardiac output, lowered resistance in vasculature accompanied by thrombosis, and hypoglycemia in the liver |
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| is there therapeutic modulation of TNF-alpha? why would this be done? |
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| yes, there are a number of biologics that block TNF-alpha binding to TNF receptors. these would be used to treat inflammatory and/or auto immune disorders |
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| what are chemokines made up of? how are they classified? |
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| chemokines are composed of polypeptides with 2 internal disulfide loops. there are about 40-50, and they are classified on the basis of number/location of N-terminal cysteine residues |
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| what are CC cytokines? what do they act on? |
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| cysteines on the N-terminus are adjacent, these act on monocytes, lymphocytes, and eosinophils |
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| what are CXC cytokines? what do they act on? are there other versions. |
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| these have cystiene residues on the N-terminus separated by one amino acid, they act on neutrophils. CXCL8, (IL-*), recruits neutrophils from blood to infected area. other versions of chemokines include C or CXXXC. |
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| what are the biologic functions of chemokines in regard to immune cell function, epithelial cell function, and non-lymphoid organ function? |
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| chemokines recruit cells to sites of infection, they regulate the traffic of leukocytes and lymphocytes through peripheral lymphoid tissue, promote angiogenesis and wound healing, and are involved in development of diverse non-lymphoid organs |
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| what is the function of IL-12 in regard to the innate immune response? what makes it? |
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| IL-12 is an important mediator of the early innate immune response to intracellular microbes. it is made by mononuclear phagocytes and dendritic cells. |
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| what is IL-12 the key inducer/regulator of? how is it done? |
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| IL-12 is the key inducer/regulator of cell mediated immunity. it activates NK cells, stimulates IFN-gamma production, stimulates differentiation of Th1 cells, and enhances cytolytic function of NK and CD8+ T cells |
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| what 2 signals to a dendritic cell would lead to IL-12 production? once produced, what does it effect? |
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| macrophages interacting with it after picking up antigen via TLR or CD4+ cells that see antigen, activating macrophages via CD40. once produced, IL-12 stimulates IFN-gamma production in CD4+ TH1 cells, NK cells and CD8+. it also increases the cytotoxic effects of NK and CD8+ cells |
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| how do IL-12 and IL-10 interact? |
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| antagonistically, anything one does, the other does the opposite. IL-10 inhibits IL-12 production by activated macrophages/dendritic cells, downregulates IFN-gamma production, and inhibits expression of co-stimulators, class II MHC on macrophages/dendritic cells |
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| what does IL-10 do? who produces it? |
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| IL-10 is an inhibitor of activated macrophages and is produced mainly by activated macrophages, (unclear whether IL-12 and 10 share a stimulus). it is a clear example of a negative regulator. |
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| what happens if IL-10 is knocked out in mice? |
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| IBS develops, may lead to uncontrolled macrophage activation against enteric microbes |
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| what kind of immunity is IL-2 associated with? |
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| adaptive immunity |
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| what was IL-2 originally called? what does it do? |
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| T cell growth factor. IL-2 is the principal cytokine responsible for progression of activated T cells from G1 to S phase of the cell cycle - plays a major role regulating regulatory T cell responses |
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| what makes IL-2? cant it function in autocrine or paracrine manners? |
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| CD4+ and to a lesser degree, CD8. IL-2 can function in both autocrine and paracrine manners. |
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| what is IL-2 normally produced in response to? how often is it produced and why? |
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| IL-2 is normally produced in response to antigen and its production is transient to limit unchecked proliferation of T cells |
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| how does IL-2 affect T cells, NK cells and B cells? |
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| IL-2 is an autocrine growth factor for T cells via inducing expression of Bcl-2, (anti-apoptotic), IFN-gamma, and IL-4. it stimulates the growth of NK cells and enhances their cytolytic function. IL-2 is also a growth factor for B cells, and stimulus for antibody synthesis |
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| what is the primary non-redundant function of IL-2? what happens if this is not carried out? what does this suggest? |
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| IL-2 covers maintenance of regulatory CD4+ T cells, (T regs), response. if the IL-2 gene/receptor is knocked out, mice develop lymphadenopathy and T cell mediated autoimmunity. this suggests that simply the growth factor function of IL-2 is shared by other cytokines, (redundant). |
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| what functions of IL-2 is IL-15 redundant with? what is it made by, (the answer is NOT T cells)? what kind of immunity is it associated with? |
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| IL-15 is an important growth/survival factor for memory T cells and NK cells. it is made by mononuclear phagocytes in response to viral infection, LPS, and other triggers of innate immunity. it is structurally similar to IL-2, and their receptors are homologous, (share beta+gamma complex). |
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| what happens to T cells in terms of IL-2 and IL-2r when stimulated by antigen? |
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| a T cell is stimulated by antigen+costimulator, IL-2 is secreted, the IL-2r alpha chain is expressed and thus that cell and others are ready to respond to IL-2 |
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| what are clinical uses of IL-2? what are some associated toxicities? |
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| metastatic renal cell carcinoma, refractory malignany melanoma, (this disease responds well to immunotherapy). toxicities include vascular leakage, (pts swell up), and severe HTN, (due to edema). |
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| what does IFN-gamma do in terms of B cells? does it inhibit anything? |
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| IFN-gamma stimulates B cell differentiation, (esp class switching to IgG2 - particularly good opsonin) and inhibits Th2 cell growth. |
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| what does IFN-gamma do in terms of macrophages? is this the major function? |
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| IFN-gamma activates macrophages and increases both class I and II expression on both macrophages and other cells. this is the major function of IFN-gamma. |
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| does IFN-gamma activate NK cells? |
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| yes |
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| is IFN-gamma antiviral? |
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| yes |
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| what is filgrastim? what is it used in? |
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| recombinant G-CSF, (granulocyte colony stimulating factor) it is used in receving myelosuppressive anti-cancer regiment, (often have complications due to granulocytopenia and are highly susceptible to bacterial infections) |
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| what are the effects of G-CSF? are there side-effects? |
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| G-CSF increases neutrophil recovery and reduces infection. splenic rupture and allergic rxns are side effects |
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| flip to review image of cytokine effect on hematopoiesis |
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| [image] |
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| what is sargramostim? what is it used for? |
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| recombinant GM-CSF, (granulocyte/monocyte colony stimulating factor), which is used to achieve neutrophil recovery/reduce infection in bone marrow transplantations, (autologous/allogeneic), and AML |
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| what are side effects of CSFs and other stimulators of hematopoiesis? |
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| bone pain, fever, fluid retention |
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| when is erythropoeitin used? what are side effects? |
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| erythropoeitin is a cytokine used to combat anemia esp in chemo pts. side effects include HTN, headache, seizures, and thrombotic events |
