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56 Cards in this Set
- Front
- Back
How can damage occur in the cornea?
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-Scarring/vascularization
-Local effects can cause inflammation ( |
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How can damage occur in the iris?
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-Local effects include
inflammation ( |
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How can ocular damage occur in the eaqueous outflow system?
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-Nourishes cornea and lens
-Drains via canal of Schlemm -Blockage → increase i.o.p. → damage-may be associateed with damage to other parts of the eye |
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How can ocular damage occur in the lens?
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Damage (cataract → loss of transparency
-Local effects include UV radiation -Systemic effects include many drugs and chemicals |
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How can ocular damage occur in the ciliary body?
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-muscle damage for focusing of lens
secretory damage for formation of aqueous humor (diuretics?) |
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What ocular damage can occur in the retina/ choroid?
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-has Good blood supply
-Retinal damage can occur with visual disturbances or loss of vision - destruction of photoreceptors! -examples include: -chloroquinine retinopathy -cardiac glycosides -sildenafil (Viagra |
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What ocurlar damage can occur in the ganglion cells/optic nerve?
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-Damage is irreversible
-Classical agent = methanol! |
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How cna you assess ocular damage?
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-Examination includes
-slit-lamp microscope -tonogram -Draize test- irritation -Electrophysiology |
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How are aminoglycosides ototoxic?
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1. highly charged- eliminated renally
2. ototoxicity possible following systemic and topical administration 3. effect may be delayed and unilateral 4. damage hair cells 5. site of action- cochleotoxic vs. vestibulotoxic a. cochleotoxic dihydrostreptomycin, kanamycin, tobramycin b. vestibulotoxic streptomycin, gentamicin c. both- hydroxystreptomycin (potent) d. less toxic- netilmicin 6. mechanism of toxicity- free radicals involved? |
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How are loop diuretics ototoxic?
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1. ethacrynic acid, furosemide- cochleotoxic (usually reversible)
2. possible mechanism- alteration in ionic composition of endolymph? |
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What are ototoxic drugs/ chemicals?
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-aminoglycosides
-loop diuretics -NSAIDs -antineplastic agents |
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What are symptoms of ototoxicity?
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1. early vs. late
2. hearing loss may be subtle a. damage proceeds from base of cochlea to apex b. highest frequencies lost first |
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What are techniques in assessing ototoxicity?
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1. audiometry
2. animal behavioral studies |
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What are the general mechanisms of cardiotoxicity?
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-Altered coronary blood flow
-Vasoconstriction/blockages--> occlusion -Ischemia-reperfusion Injury (IRI) -Altered ion homeostasis -Channel/transport proteins--> channelopathies -Organelle dysfunction--> myopathy -Apoptosis/oncosis |
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How is vasoconstriction a mechanism of cardiotoxicity?
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Endothelial dysfunction:
-Clots at surface, -LDL accumulation, -Decreasse NO bioavailability SMC dysfunction: -Adrenergic responses -Lipid loading-->foam cells -Proliferation --> matrix -Ca mishandling--> spasticity |
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How are blockages a mechanism of cardiotoxicity?
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-Dec flow--> ischemia, hypoxia
-Inc turbulence--> inc cardiac work |
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What does altered (reduced) coronary flow ultimately cause?
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-ATHEROSCLEROSIS
-Occlusion (acute/chronic) -Myocardia Infarction |
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What is the mechanism of action of ischemia-reperfusion injury having to do with xanthine oxidase and the formulation of reactive oxygen species?
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Ischemia:
-Less O2 -more glycolysis -more lactic acid, less ATP -Transmembrane gradients dissipate -Cytosolic [Ca] increases -Proteases activated -XDH-> XO Reperfusion: +O2--> ROS --> +/- Fe--> CELL DEATH |
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What is the mechanism of action of ischemia-reperfusion injury by deregulation of pH control from cardiotoxins?
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-Ischemia --> dec Na/K-ATPase + inc NHE-->inc Na, inc Ca--> inc alkaline proteases; held at bay …
-w/reperfusion, massive H+ efflux, alkaline proteases destroy cell |
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What is the consequence of ischemia-reperfusion injury?
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-chronically, cardiomyopathy and/or congestive heart failure
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What is the impact of pre-conditioning on ishemia-reperfusion injury?
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Brief ( 2-5 min) ischemia bouts
Normal perfusion Prolonged ischemia-- initiated w/in 1 h ->2h, lose protection -2nd window 24-72h later Protection against IRI -Smaller infarcts, less enzyme release, fewer arrhythmias, maintained contractility -Modest inc in ROS, PKC, AMP-act PK, stabile MPTP |
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How are altered ion homeostasis or "channelopathies" a general mechanism of action of cardiotoxicity?
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-V.G. Na+ channels--> AP initiation
-V.G. K+ channels--> repolarization a. long ARP for cardiac myocytes b. No repolarization--> cardiac standstill -V.G. Ca++ channels--> both excitation AND contraction a. SA node/conduction: depolarization b. Contractile myocytes: prolonged depolar, contraction -Multi-subunit proteins, multi-gene determinants, onsite assembly, both extra-and intra-cellular modification = complex regulation |
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How is long QT syndrome or arrythmias a general mechanism of action of cardiotoxicity?
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-Inherited or drug-induced
-Long QT interval on ECG reflects malfunction of ion channels=> impaired ventricular repolarization - increased risk of torsade de pointes => ventricular arrhythmias, sudden cardiac death. a. (twisting of the points) = ventricular tachycardia, with QRS complexes of changing amplitude that appear to “twist” around isolectric line - INCIDENCE LQTS = LOW - CONSEQUENCES LQTS and TdP = HIGH a. Sudden cardiac death |
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What are general risk factors for acquired long QT syndrome?
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-Bradycardia (e.g., complete AV block, other bradyarrhythmias, even transient)
-Hypokalemia, hypomagnesemia -Structural/functional defects (myopathy, CHF, mitral valve prolapse -Diuretic use, high dose anti-arrhythmic drug use, AIDS -Female gender -Starvation (Anorexia, liquid protein diets, gastroplasty, celiac disease) - Nervous system injury (subarachnoid hemmorhage, pheochromocytoma) |
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What are specific drugs that are risks for acquired long QT syndrome?
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-Antiarrhythmics (class 1A (quinidine, disopyramide, procainamide); class III (sotalol, amiodarone, ibutilide)
-Antibiotics (erythromyocin, clindamyocin, …) -Histamine receptor antagonists (terfenadine, astemizole) -Antidepressants (tetra/tricyclic) -Antipsychotics (phenothiazines, haloperidol, sertindole) -Cholinergic antagonists (cisapride, organophosphates) |
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How is organelle dysfunction or myopathy a general mechanism of action of cardiotoxicity?
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-Ryanodine receptor irregularity
a. Calcium leak--> activation of Ca-dependent phospholipases, proteases-->degradation -Mitochondrial dysfunction a. Loss of ATP--> loss of membrane integrity -Endoplasmic reticulum dysfunction a. Protein misfolding, protein trafficking defects -Sarcolemmal injury a. Cytoplasmic calcium overload |
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What is the mechanism of action of myocardial apoptosis?
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- microRNAs (miRNAs)--> mask binding sites in mRNA or relief of translational repression
-immune-mediated cytokines and/or hypoxia-mediated cytokines -Adrenergic signalling |
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What are the various forms of angiotoxicity?
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-Atherosclerosis
a. Tissue hypoxia b. Hypertension c. Altered immune reactivity (C-reactive protein) -Vascular spasm a.Altered cytokine production b. Altered responsiveness to cytokines c. Excess adrenergic input/response -Altered hemodynamics a. Clot formation--> occlusion, emboli b. Turbulent, not laminar flow c. Plaque rupture, destabilization |
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How are angiotoxins selective?
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-Selected alterations in vascular reactivity (disruption of cellular membranes or contractile apparatus)
-Vessel-specific bioactivation of pro-toxicants -Erratic or aberrant detoxification of parent chemical or its metabolites -Preferential accumulation of active toxin in vascular cells |
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How is allylamine an angiotoxin?
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-Primary alkylamine that serves as an intermediate in the synthesis of a variety of pharmaceuticals and other commercial products)
-converted via amine oxidase to acrolein and hydrogen peroxide=>cell injury via lipid peroxidation, protein adduct formation, glutathione conjugation |
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How is benzo(a)pyrene an angiotoxin?
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• parent compound or metabolite-mediated “mutagenesis” --> genotoxicity via DNA adduct formation
• PKC inactivation --> altered smc proliferation ( deregulation of growth) • AH (aryl hydrocarbon) receptor activation--> enhanced transcription of growth-related genes |
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How is tobacco smoke an angiotoxin?
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-Endothelial injury
-Altered lipids -Proliferation of smooth muscle cells -Increased coagulation -Vascular spasm |
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How is homocysteine an angiotoxin?
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-HC = intermediate in methionine scavenger pathway
-HC emia/uria--> vascular toxicity, inc atherosclerosis -Endothelial injury -Altered lipid profiles -Proliferation of smooth muscle cells |
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What are the risk assessment tests of cardiovascular toxicity?
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-High throughput screening
a. Binding b. Rb flux, voltage sensitive fluorescent dyes -Patch clamp studies a. Xenopus oocytes, stably transfected cells, isolated myocardial cells -Small animal studies a. Telemetry b. Langendorff preps |
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What is hematotoxicity?
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-blood toxicity
- BONE MARROW--> cells of blood a. Stem cells--> blood cells (hematopoiesis) b. Pluripotent--> myeloid precursor - Cells, plasma (blood) a. Transport, hemostasis, defense b. Factors of import 1. High proliferation ( 1-3 X 106/sec) 2. High sensitivity (to intoxication) 3. Huge magnitude consequences |
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What is the primary hematotoxic response?
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-One or more blood components affected
e.g., xenobiotics, drugs -Alterations in rbc production, function, survival |
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What is the secondary hematotoxic response?
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-Consequences of other tissue/ systemic injury
-May be reactive or compensatory -Can be used to monitor toxic effects |
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What is bone marrow toxicity?
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-Aplastic anemia: stem cell destruction
-=>Pancytopenia, reticulocytopenia, bone marrow hypoplasia -High mortality -e.g., chloramphenicol, benzene, ionizing radiation -~50 % --> ~ 80% fat cells ( non-staining) |
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How do you monitor bone marrow toxicity?
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-Bone marrow biopsy/smear
-Clonogenic assays: a. Bone marrow or cord cells +/- specific growth factors +/- different doses of toxins b. What population(s) respond? |
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What are chemical-mediated blood toxicity?
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ANEMIAS:
-Hemolytic--> inc reticulocytes in blood ( rbcs destroyed) -Hypoproliferative a. Fe deficiency--> dec MCV, hypochromasia b. Sideroblastic (porphyrin synthesis def) --> inc Fe in erythroblast mito. c. Megaloblastic( folate, vit B12 deficiency) --> macrocytosis, inc MCV -Polycythemia (erythrocytosis): less common |
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What are non-oxidative mechanisms of damage or RBC?
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-Inhibition of erythropoiesis
a. Lead b. Other chemicals -Inhibition of rbc metabolism a. Copper |
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What are oxidative mechanisms of damage or RBC?
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-High O2 levels--> lipid peroxidation
-hereditary G-6PDH deficiency |
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What are immune-mediated mechanisms of damage to RBC?
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-Drug absorption (penicillins, cephalosporins)
-“innocent bystander” (quinidine, phenacetin) -Protein carrier (cephalosporins) a. Protein which binds to drug interacts with antibodies |
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What are the mechanisms of hemoglobin damage?
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-Altered hemoglobin synthesis
a. HU--> a and b chains b. Ethanol, zinc--> heme group c. NSAIDs--> iron deficiency -Methemoglobin (metHb) formation a. Amyl nitrate, gas additives, etc--> Ferrous to ferric oxidation b. Reversal mediated by NADH (cytochrome b5 reductase) or NADPH (methylene blue reductase) -Sulfhemoglobin (e.g., phenacetin, napthalene) a. irreversible sulfation--> denaturation -Heinz bodies (e.g. phenols, polyethylene glycol) a. inclusions ( aggregates?)--> hemolysis (species-dependent) - Carboxyhemoglobin (CO poisoning– cherry red pigment) a. Dec. O2 delivery, dec. O2 capacity-->hypoxia |
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How do you assess erythrocyte damage?
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-Complete blood count and hematocrit
a. RBC: 4-6 M/mm3 b. MCV: 86-98 mm3 (fL)/cell c. WBC: 4-10 K/mm3 -Hemoglobin levels: (12-18 g/dL) a. Hematocrit: adult male (41-50%), adult female (36-44%) -Cell morphology a. Nucleation b. Heinz bodies c. Volume and chromaticity |
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What are the mechanisms of damage to platelets and hemostasis?
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Pathologic conditions:
-Thrombocytopenia a.Megakaryocytes b. Platelets (<150,000/mm3) c. Bruising, petechiae -Thrombocytosis Interference with clot formation: -Alteration of platelet function (e.g. aspirin-->COX) -Decreased synthesis of clotting factors |
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How do you assess for platelet damage and hemostasis?
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-CBC/platelet count
a. RBC: 4-6 M/mm3 b. WBC: 4-10 K/mm3 1. Neutrophils (40-75%) 2. Lymphocytes (15-40%) 3. Monocytes (1-10%) 4. Eosinophils ( 1-6%), basophils (0-2%) b. MCV: 86-98 mm3 (fL)/cell c. Platelets: 150-450 K/mm3 -Cell morphology ( size, shape) -Bleeding time (PT= prothrombin time; PTT= partial thromboplastin time; INR= international normalized ratio for adjustments) |
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What cells are involved in innate immunotoxicity response? soluble mediators? specificity? Inc. response with challenge?
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-PMN, monocytes/Macrophages, Natural Killer cells
-Complement, lysosyme, acute phase proteins, TNF alpha/beta, other -none -no |
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What cells are involved in acquired immunotoxicity response? soluble mediators? specificity? Inc. response with challenge?
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-T cells, B cells, Macrophages, Natural Killer cells
-Antibody, cytokines -Yes (very) -Yes |
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What is the mechanism pathway of the humoral immunotoxicity response?
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-antigen + antigen presenting cell (APC) (B cells, Macrophages, dendritic cells)
-internalization, antigen processing, cell surface expression with MHC calls II peptides -interaction with lymphocytes -proliferation & differentiation -specific Antibody (Plaque)-forming cells--> Ag-specific ANTIBODIES (Abs) |
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What is the mechanism pathway of the cell-mediated immunotoxicity response?
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-Effector cell ( CTL, NK cells) recognition of target ( virally infected or tumor cell)
a. MHC-class I, Ab-specific -Reorientation of effector, degranulation into target -Disengagement of effector -Death (apoptosis) of target |
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What are the effects of immune suppression on phagocytes (neutrophils, macrophages)?
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-Neutropenia
a. Inhibition of granulopoiesis (antineoplastics, chloramphenicol, benzene) b. Premature destruction (aminopyrene) -Inhibition of chemotaxis ( e.g. colchicine) -Inhibition of phagocytosis ( e.g. colchicine) |
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What are the effects of immune suppression on lymphocytes?
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-B cells ( e.g. PCBs, dioxin)
-T cells (e.g., cyclosporin A, corticosteroids) -Tumor resistance ( Natural Killer cells) |
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What is autoimmunity as an immune enhancement?
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-Loss of tolerance for self antigens
-Chronic lymphocyte stiumation -Inhibition of T suppressor activity |
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What is hypersensitivity (allergy) as an immune enhancement? 4 types?
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-Type I ( e.g. penicillin): IgE-> mast cell degranulation--> swelling, redness, pain
Type II: IgG or IgM--> rbc destruction Type III: IgG or IgM-complexes--> tissue destruction Type IV (delayed): APC + T cells--> tissue damage |
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How do you assess immunotoxicity?
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General:
-CBC/WBC, lymphoid organ weights, bone marrow Contact hypersensitivity: -Animal allergic dermatitis, human allergen testing Popiteal lymph nodes: -Cell # or proliferation; Ab response Functional assays: -Phagocytosis by neutrophils or macrophages -Ab response to antigenic challenge -Target cell destruction by CTL -Host resistance to bacteria, viruses or tumor cells |