Term
| rational approach to drug therapy |
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Definition
| 1. prescription of drug dosage; 2. dose administration (not always the same as drug dosage); 3. routes of administration; 4. concentration at site of action; 5. pharmacological effects |
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Term
| factors determining amount of drug present at the active site |
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Definition
| route of drug, administration, absorption, distribution, metabolism and excretion |
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Term
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Definition
| how the body handles a drug and movement of the drug around the body (absorption, distribution, biotransformation, excretion) |
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Term
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Definition
| interactions between drug and biological system leading to pharmacological response (therapeutic, adverse reactions, toxicity, idosyncratic, hypersensitivty, lethal and placebo |
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Term
| adverse reactions and definitions |
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Definition
| 1. therapeutic-reason for taking the drug; 2. side effects-any other effect other than therapeutic effect; 3. toxic effect-occurs at higher dosage where some tissue pathology occurs; idosyncratic-unpredictable or unusual effect (tetracycline-acne photosensitivty); 5. hypersensitivity-immune effect |
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Term
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Definition
| want beneficial effect with minimal adverse reactions; standard dose for adult may not be the same for physiological and pathological changes |
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Term
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Definition
| most common pathway through oral route and is relatively safe; concerns include GI irritation, not good for emergency, and have first pass metabolism where some is metabolized in the liver |
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Term
| enteral related administration |
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Definition
| 1. sublingual-under the tongue and eliminates the first pass metabolism the drug must be made to dissolve in saliva includes nitroglycerine; 2. rectal-50% bypasses the liver used for infants and those who are noncompliant or with nausea and vomiting to be able to put down liquids |
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Term
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Definition
| those not using the GI tract- include: 1. respiratory-inhalation for local or systemic effects if lipophilic drug will dissolve in air and be taken directly to the brain; 2. subcutaneous-under the skin and then will be slowly absorbed; 3. intramuscular-can be used for a depot effect when want something to leech out of the muscle; 4. intravenous-directly into bloodstream, has rapid onset, excellent in emergency but can be dangerous; 6. skin-topical or transdermal-local effects on the skin; if lipid soluble can have systemic effect called inuction and transdermal is patch with drug reservoir goes through the skin into the blood |
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Term
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Definition
| 1. solids-tablets, capsules, caplets; 2. liquids-useful for pediatric formulation syrups (sugar) and elixirs (alcohol); 3. gaseous-NO |
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Term
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Definition
| absorption through biological membranes and this in which a drug moves across membranes based on lipid/water partition coefficeint |
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Term
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Definition
| other drugs may cross by carrier proteins which are saturable and utilize energy (ATP); facilitated diffusion (carrier mediated with concentration gradient) and filtration (passive through membrane pores) |
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Term
| factors influencing passive diffusion |
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Definition
| faster the rate of absorption when 1. higher the concentration of drug; 2. more lipid soluble; 3. the lower the molecular weight; 4. larger the surface area; 5. greater the regional blood flow (lidocaine with vasoconstrictor for dentist office) |
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Term
| absorption of weak acids and weak bases |
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Definition
| the non-ionized form of the drug is more lipid soluble and therefore it crosses membranes better; the degree of ionization is based on the pH of the physiological compartment and the pKa of the drug |
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Term
| general rules for oral absorption |
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Definition
| 1. weak acids-initial absorption occurs in the stomach and major absorption occurs in the upper part of small intestine; 2. weak bases-absorbed in the upper portion of the small intestiine; 3. charged molecule-poorly absorped; 4. neutral molecules-readily absorbed (like ethanol) |
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Term
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Definition
| amount of drug administered that enters the blood stream and factors that affect this include first pass metabolism, solubility of drug, chemical stability in the GI tract |
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Term
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Definition
| must demostrate for generic brands to have same peak height concentration, same time to peak heights, and same area under the blood concentration curve to advertise as same product |
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Term
| causes of cellular injury |
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Definition
| 1. hypoxia (reduced oxygenation) and ischemia (hypoxia due to impaired blood flow); 2. physical agents (tramua, temp, radiation, electric shock); 3. chemical agents; 4. infectious agents; 5. inflammation and immune reactions; 6. nutritional imbalances; 7. genetic abnormalities; 8. aging |
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Term
| factors affecting the response of a cell to injurious agent |
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Definition
| metabolic rate-more suceptible; specific viral agents; affinity for toxic agents; nutritional state; individual susceptibility |
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Term
| cellular systems involved in injury |
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Definition
| aerobic respiration; integrity of the membranes of the cell and subcelular organelles; protein synthesis; RNA and DNA synthesis |
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Term
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Definition
| caused by hypoxia and toxic inhibition of mitochondrial ATP production causing an increase in anaerobic glycoysis, with glycogen depletion, decreased pH and chromatin clumping, decreased sodium potassum dependent ATPase activity with accumulation of sodium ions and water producing cell swelling and decreased membrane phospholipid synthesis |
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Term
| increased cytosoic free Ca |
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Definition
| substantial amount is sequestered within mitochondria and ER and damgage to cell membrane can release intracellular stores to increase cytosolic concentration and activates enzymes of cell injury including endonucleases and exonucleases that degrade nucleic acids, phospholipases that hydrolyze membrane phospholipids and proteases that degrade membrane and cytoskeletal proteins |
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Term
| increased cytosoic free Ca |
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Definition
| substantial amount is sequestered within mitochondria and ER and damgage to cell membrane can release intracellular stores to increase cytosolic concentration and activates enzymes of cell injury including endonucleases and exonucleases that degrade nucleic acids, phospholipases that hydrolyze membrane phospholipids and proteases that degrade membrane and cytoskeletal proteins |
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Term
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Definition
| normal oxidative metabolism; H2O2; ionizing radiation, inflammatory cells, toxins can metabolize to free radicals, therapeutic oxygen and nitric oxide |
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Term
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Definition
| 1. peroxidation of membrane lipids-bending, breaking, cross linking; 2. post translational protein cross linking; 3. mutations base damages and breaks in nuclear and mitochondrial DNA |
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Term
| defenses against free radicals |
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Definition
| 1. superoxide dismutase 2H +o2 to H2O2 +O2; 2. catalase: 2H2O2 to O2 and 2H2O; 3. glutathione peroxidase-2GSH+2H2O2 to GSSG +2H2O; 4. antioxidant vitamins-C and E; 5. ceruloplasmin; 6. DNA repair pathways preventing mutagenesis |
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Term
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Definition
| caused by decreased phospholipid synthesis due to ATP depletion; degradation by Ca activated phospholipase A2 and proteases |
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Term
| effects of damage to cell membranes |
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Definition
| increase cytosol Ca, release of proteolytic enxymes from lysosomes, defects in membrane permeability, formation of irreversible high conductatance channel lethal via loss of membrane potential and cell constiuents leak into the circulation and can be measured in the blood |
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Term
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Definition
| some directly injure cells- like mercury binds sulhydryl groups in proteins and inhbiting transport ATPase and damaging cell membrane |
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Term
| activation of harmful chemicals |
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Definition
| occur by cytochrome p450 mixed function oxidases; hepatic toxicity by CCL4 turns into free radical of CCl3 and results in free radical mediated injuries; also metabolism of nitrosamines, aromatic amines and polycyclic aromatic hydrocarbons to carcinogens; meatbolism of drugs can augment toxicity (cocaine and acetaminophen |
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Term
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Definition
| hydropic degeneration, initial manifestation of most forms of injury to most cell types; inability to maintain ion and water balance; accumulation of fluids in vacoules; have plasma membrane changes, swelling and amorphous densities in mitochondria, endoplasmic reticulum dilatation, detachment of ribosomes |
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Term
| accumulation of triglycerides |
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Definition
| seen in hypoxic or chemical in cells active in lipid metabolism (hepatocytes, cardiac myocytes) |
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Term
| intracellular accumulations |
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Definition
| inability to metabolize certain endogenous substances or exogenous materials can lead to accumulation in cells; fatty change (steatosis) reversible accumulation of triglycerides within parenchymal cells due to increased free fatty acid production decreased free fatty acid oxidation and decreased lipoprotein synthesis ie liver following alcohol consumption; intially small intracytoplasmic vacuoles and later vacuoles coalesce and can become large enough to push the nucleus aside |
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Term
| cholesterol and cholesterol esters accumulation |
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Definition
| accumulate in macrophages and smooth muscle cells in atherosclerotic plaques |
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Term
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Definition
| polymer of hydroxyaromatic compounds skin protection from sunlight and free radical "sink" |
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Term
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Definition
| polymers of lipids and phospholipids with proteins, thought to be derived from peroxidation of membrane phopholipids which indicates free radical damage found in hepatocytes and cardiac myocytes in aged individuals without probable impairment of cell function "residual bodies" |
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Term
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Definition
| hemosiderin-lage aggregates of ferritin micells; red cell breakdown leads to hemosiderin accumulation in local macrophages; hemosiderosis-systemic iron overload with accumulation in macrophages in liver, spleen lymph nodes and bone marrow can also accumulate in parenchymal cells of various organs; hemochromatosis- hemosiderin accmulation in parenchymals cells producing organ dysfunction either primary-genetic disorder or secondary-acquired severe iron overload |
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Term
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Definition
| toxic breakdown product of open porphyrin ring without iron and can be seen in tissues of severely jaundiced patients |
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Term
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Definition
| ubiqutious air pollutant deposited in alveolar macrophages and lymph nodes and sometimes associated with severe pulmonary fibrosis in coal miners |
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Term
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Definition
| 1. dystrophic calcification-occurs in damaged or dead tissue in individuals with normal calcium homeostasis and found in necrotic tissues, atherosclerotic plaques, damaged heart valves; 2. metastatic calcification-occurs in normal tissues in individuals with hypercalcemia ex:primary hyperparathyroidism, malignancies involving bone |
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Term
| functions of immune system |
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Definition
| must be able to discriminate self from non-self and inappropriate response to self results in autoimmunity and failure to respond to antigens is called tolerance; self tolerance prevents autoimmunity |
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Term
| major types of immune responses |
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Definition
| adaptive and innate immune response with innate generally precede the adaptive response |
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Term
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Definition
| initial host responses includes the physical barriers to infection, also plasma proteins such as complement, lysozyme in tears can degrade bacterial cell wall and phagocytotic white blood cells can recognize and kill bacteria in absence of adaptive immunity |
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Term
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Definition
| are made by moncytes and macrophages when debris are introduced into mammalian host they are rapidly produced, play role in clearance of bacterail organisms and aid in development of adaptive immune responses; responsible for flu like responses and other signs of inflammation |
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Term
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Definition
| a foreign substance that binds to antibody or Tcell receptors and elicits an immune response |
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Term
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Definition
| exceptions to antigen definition and will not elicit an immune response unless bound to carrier molecule |
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Term
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Definition
| used to distinguish because of haptens and elicits the immune response |
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Term
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Definition
| defined as a portion of an antigen which consists of the antigenic determinant |
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Term
| characteristics needed to be imunogenic |
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Definition
| 1. must be recognized as non-self; 2. must have a correct chemical nature usually a protein, polysaccharide or glycoprotein, nucleic acids and sometiems lipids; must have correct size if too small will not elicit a response; molecules generally express multiple immunogenic determinants may be formed by primary amino acid sequence or by tertiary structure of the molecule |
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Term
| types of adaptive immunity |
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Definition
| 1. humoral immunity-is mediated principally by serum proteins called antibodies can be transferred to immnologically naive individuals by serum; 2. cellular immunity-mediated by lymphocytes can be transferred to naive individuals by cells; active immunity involves generation of an immune response to a specific antigen; passive immunity giving a naive recipient either antibody or immune cells from an immune individual |
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Term
| principal features of immune response |
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Definition
| 1. diversity-lymphocyte repertoire of an organism is extensive but finite; 2. specificty-foreign protein or other immunogenic substance stimulates a population of lymphocytes to react to it each lymphocyte only reacts one epitope on the antigen; 3. regulation-insufficient response may result in susceptibility to infection whereas uncontrolled immune response can lead to autoimmunity; 4. memory-exposure of the immune system to an antigen enhance ability to respond to that antigen a second time and this is more rapid and is of greater magnitude |
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Term
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Definition
| antibodies on the B cell surface are specific receptors for specific antigenic determinants and interaction induces proliferation of cells expressing the receptor some differentiate into memory cells also suggests that immunologic tolerance is due to clonal deletion of cells which recognize self antigens or other antigens at a critical period in development; B cells also need T cells in order to proliferate and make antibodies coming from cytokines |
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Term
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Definition
| lymphoid cells give rise to T and B lymphocytes and myeloid cells give rise to phagocytic cells such as macrophages and neutrophils |
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Term
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Definition
| primary lymphoid organs are the thymus and bone marrow in which lymphocytes mature and become antigentically committed immunocompetent cells; secondary lymphoid organs include spleen, lymph nodes, tonsils, etc and interconnected by lymphatic vessels and these interact for B cells, T cells and APCs required for development of an effective immune response |
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Term
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Definition
| chronic granulomatous disease-defective NADPH oxidase no respiratory burst following phagocytosis; also humoral deficiences, cell mediated deficiences, combines immunodeficiencies |
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Term
| characteristics of immunogens |
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Definition
| 1. foreigness-antibodies are not usually made to self molecules in native configuration those that recognize self molecules induced to undergo apoptosis; T cell epitopes are always linear and range from about 8-20 amino acids in length; susceptible to degradation-substances resistant to enzymatic degradation usually make poor immunogens and most are T cell dependent and must be degraded and presented to the T lymphocyte on surface of APC; T-independent antigens tend to be less complex in structure and apparently corsslink antigen receptors on the surface of B cells and most cases limited to IgM |
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Term
| characteristic of antibodies |
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Definition
| 1. chemical composition- belong to a class of molecules call immunoglobulins (glycoproteins); 2. location-found at highest concentration in serum also in lymph, saliva, CSF, mucous, tears, colostrium, seminal fluid and other sites; 4 polypeptide chains 2 heavy and 2 light linked by disulfide bonds and Ig consists of 1, 2 or 5 of these units |
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Term
| functional domains of antibodies |
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Definition
| 1. Fab-fragment antigen binding) portion binds to the antigenic determinant; 2. Fc fragment crystallized portion determines the class of immunoglobulin and characteristics unique to that class |
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Term
| structure of antigen binding site |
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Definition
| variable regions are located in the NH2 terminal portion of the heavy and ligh polypeptide chains and are linked by joining regions to constant regions of the chains; some sequences are conserved while others are hypervariable |
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Term
| classes of immunoglobulins |
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Definition
| IgA (2 subtypes), IgD, IgE, IgG(4 subtypes), and IgM and the class of immunoglobulin is determined by the heavy chain; A uses alpha chain, D delta, E epsilon, G gamma and M for mu; and two light chains designated kappa and lambda |
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Term
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Definition
| antigenic determinants present in all members of a species, constant region determinants which distingush each Ig class and subclass within a species |
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Term
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Definition
| antigenic determinants which vary between members of a species, consist of subtle amino acid differences coded for by different alleles |
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Term
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Definition
| antigenic determinants existing in the variable regions of the antibody molecule and an individual can make antibodies to idiotype determinants present on Ig molecules |
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Term
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Definition
| made by a single clone of antibody and all of the antibody molecules are the same and directed against the same epitope; used in diagnostic lab tests and to a lesser extent in diagnostic imaging and therapeutics; antibody can be labeled with radioactive isotopes for imaging purposes; humanized mouse monoclonal antibodies are generated by cloning mouse variable region genes and human constant region genes into cells which produce chimeric antibody molecules with reduced antigenicity and enhanced biologic function in the human system; transgenic mouse strains have been developed in which mouse Ig genes have been replaced with human Ig genes |
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Term
| basic functions and consequences of antibodies in the host |
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Definition
| 1. promote uptake of many types of organisms from tissue fluids or circulation by promoting their uptake by phagocytosis with PMNs and macrophages have receptors for the Fc portion of antibody; 2. neutralize microbial toxins; 3. promote bactericidal reactions by combination with complement; 4. block adherence of microbes to target tissues; 5. cause immunopathology due to unwanted antigen-antibody complexes |
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Term
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Definition
| presence of antibodies serves as a marker of prior microbial infection that triggered the immune system and we can raise antibodies to organisms to use as specific diagnostic reagents for microbial indentification |
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Term
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Definition
| antibody combining site can accommodate 5-6 sugar residues or 15-22 amino acids; only small portion of the molecule is recognized by a particular antibody |
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Term
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Definition
| strength of a single antigen combining site of an antibody and a single epitope; based on non covalent interactons: ionic, hydrogen and van der walls interactions and strength depends on fit |
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Term
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Definition
| the antigen-antibody reactions are reversisble and have association constant and higher the affinity the less tendency to dissociate and the higher the association constant |
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Term
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Definition
| less biochemically precise type of measurement is combing power of antiserum is measured, relative to another antiserum |
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Term
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Definition
| antibody raised to one epitope can combine with another epitope but usually to a lesser degree |
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Term
| pathological consequences of cross reactivity |
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Definition
| antibodies form against capsular M proteins of streptococci that cause pharyngitis and cross react with cardiac tissue resulting in rheumatic fever and cardiac valve defect |
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Term
| lattice formation in liquid |
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Definition
| antibody is raised against a soluble antigen which has multiple repeating determinants and if polysccharide solution and the antibody in solution are layered and interfacial ring containing a precipitate will form and will contain complex which has fallen out of solution, two identical combining sites of the antibody each bind to identical eptiope on a different molecule of the polysccharide forming a bridge and when mass becomes very large it becomes insoluble and precipitate results but haptens are monovalent and cannot form a lattice |
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Term
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Definition
| whether a precipitate appears depends on the size of the cross linked antigen antibody complexes and these depend on the ratio of antigen to antibody molecules; if antigen excess the complexes will be physically too small to precipitate |
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Term
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Definition
| concentration of antigen which precipitates all of the antibody in the serum and max occurs when molar ratios are close to one; IgG is most efficient isotype in precipitation reactions |
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Term
| surface plasmon resonance |
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Definition
| used to quantitate formation of antigen-antibody complexes in instrument that measures changes in the resonant angle of a beam of polarized light passing through the test solution and directly measures antigen antibody complexes without the need to chemically purify them and allows the use of protein antigens determines affinity and avidity and also antibody cross reactivity; if complexes form in vivo they can be deposited in capillary endothelium or in glomeruli and cause inflammatory response |
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Term
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Definition
| when antibody combines with antigenic determinants on particles that are insoluble but do not go back into solution in antigen excess a prozone can occur which is lack of agglutination due to unfavorable ratio of antibody to antigen particles; IgM is the best; a 4 fold rise in antibody to a pathogen between acute and concalescent serum is evidence of infection |
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Term
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Definition
| measure concentrations of hormones or antibiotic in the patients blood or hepB in blood and is inhibition test where unlabeled HBsAg competes with labels I-HBsAg for binding to anti HBsAg and the determinants from standard curve |
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Term
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Definition
| carried out to detect antibodies in serum; coat cells of plate with viral antigen, add serum to be tested, wash away unbound antibody, detect invisible bound antibody add anti-antibody tagged with an enzyme, add enzyme substrate plus chromophoore and read color development |
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Term
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Definition
| add an antibody specific for T cells to a sample of peripheral blood and the antibody will be covalently linked to a molecule with fluorescent properties when T cells are placed in a flow cytometer the cells tagged with antibody Fl are counted |
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Term
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Definition
| results from presence of different immunoglobulin gene segments that will recombine in the bone marrow during the course of differentiation of B lymphocytes; there are two genes for light chains located at 2 from kappa and 22 for lambda and the heavy chain on chromosome 14 and genes are encoded by multiple gene segments and much of DNA between gene segments is removed by recombination during B cell maturation |
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Term
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Definition
| increased cell size; ex enlargement of striated muscle cells cause from increased workload, increased protein synthesis, increased myofilaments, and change in protein isoforms increased function capacity; left ventricular hypertrophy (HTN, chronic ischemia, aortic stenosis) |
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Term
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Definition
| increased cell number-can increase size and functional capacity of affected tissue or organ accompanied by cellular hypertrophy; stimulation of target tissue by hormones or growth factors can be precursor of cancer; normal response to prolonged disturbances of homeostasis (parathyroid hyperplasia secondary to prolonged hypocalcemia); compensatory hyperplasia-liver regeneration |
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Term
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Definition
| decreased cell size can be combined with involution, have diminished capacity but not dead; can decrease size and functional capacity; decreased workload or denervation |
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Term
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Definition
| decreased cell number by apoptosis and decreases size and functional capacity of affected organ or tissue; ie hormonal withdrawl or development |
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Term
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Definition
| replacement of one normal differentiated cell type by another; involve change in pattern of gene expression by stem cells or undifferentiated mesenchymal in CT; ie squamous metaplasia of respiratory tract epithelium due to chronic irritation and better able to survive and loss of mucus secretion and ciliary removal of particulate matter |
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Term
| cellular proliferation capacity |
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Definition
| 1. labile cells-proliferate continuously (bone marrow, epithelium of skin); 2. stable cells-do not normally proliferate but can do so with proper stimulus (epithelium of endocrine and exocrine glands, cartilage, hepatocytes); 3. permanant cells-incapable of proliferation (neurons, cardiac muscle, skeletal muscle); labile or stable cells can adapt or repair themselves by hyperplasia and with permanant cells adapt by hypertrophy and repair injury by scarring |
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Term
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Definition
| 1. cell death-irreversible loss of cell function; necrosis-morphologic changes following cell death; oncotic necrosis-necrosis of cells en masse with cytoplasmic swelling; karyolysis-disappearance of chromatin substance, disappearance of nuclear membrane with retention of cellular shape; karyorrhexis-breakupof nucleus into small fragments; pyknosis-condensation of nuclear material into a small, deeply staining mass; apoptosis have all of that with cell shrinkage and affects individual cells |
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Term
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Definition
| nuclear changes-fading of chromatin and nuclear condensation or fragmentation; cytoplasmic changes-denaturation of proteins with maintainance of cell outlines (coagulation necrosis) and enzymic digestion of dead cells (liquefactive necrosis) |
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Term
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Definition
| coagulative necrosis-typical cell death due to ischemia/hypoxia; liquefactive necrosis-typical of bacterial infection, CNS infarction; caseous necrosis-most often due to infection with mycobacterium TB and have cheesy macroscopic appearance; fat necrosis-liquefactive necrosis of adipose tissue adjacent to injured exocrine glands releases of lipases; gangrene-infarction of extremeties; dry-sterile, coagulative and wet-secondarily infected with liquefactive necrosis |
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Term
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Definition
| necrosis-swelling of cells and cellular orgnanelles, leakage of cellular contents, inflammation of surrounding tissues; apoptosis-shrinkage of cells, breakdown of mitochondria and release of cytochrome C, blebs on surface, degradation of chromatin, cell breakage into small, membrane wrapped fragments, phagocytosis and no inflammation |
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Term
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Definition
| elimination of cells infected by viruses by cytotoxic T cells, removal of effector T cells to prevent attacks on body (elimination of forbidden clones); elimination of neutrophils of acute inflammation; elimination of cells with DNA damage (induction by p53); in development, and homeostatic mechanism to maintain cell population in tissues and defense mechanisms in immune reactions and cell damage by disease processes or noxious agents; and aging |
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Term
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Definition
| 1. commitment-multiple pathways; 2. control stage-positive and negative regulators; execution stage-caspases; phagocytosis |
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Term
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Definition
| 1. active signaling-death receptors, cellular monitors of DNA damage, cellular monitors of mitochondrial functions; 2. withdrawal of postive signals needed for survival-GFs for neurons, IL2 for lymphocyte mitosis, isolation of cells from normal environment; 3. receipt of negative signals-increased levels of intracellular oxidants, DNA damage, UV light, Xrays, chemicals, drugs, death activators that bnd to cell sruface receptors (TNF and Fas); molecular domains with apoptosis-caspase domains, death domains, death effector domains, CARDs, BIR domains, apoptosis suppressors and Bcl2 homology domains |
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Term
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Definition
| Bcl2 present on membrane surfaces, binds one molecule of Apaf-1 which is bound to procaspase to a trimer called apoptosome aggregated in cytoplasm; release of cytochrom C and ROS into cytoplasm and this activates caspase 9 causing cleavage of other caspases which causes digestion of proteins and DNA |
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Term
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Definition
| binding of factor by a death receptor transmits a signal to the cytoplasm and activates caspase 8 (through Fas and FADD) and cleavage and activation of other caspase by caspase 8 which also activates mitochondrial pathway and digestion of proteins and DNA |
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Term
| biochemistry of apoptosis |
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Definition
| protein hydrolysis-activation of caspases (cysteine proteases that cleave at aspartic acids); protein cross linking-activation of transglutaminase; DNA breakdown-into oligonucelosomes by Ca and Mg dependent endonucleases result in DNA ladders and results in double stranded DNA breaks; phagocytotic recognition signals-phosphotidylserine on outer layers of plasma membrane, thrombospondin on apoptotic bodies |
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Term
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Definition
| death receptors and ligands; survival stimuli-suppress apoptosis (hormones, cytokines, GFs); recetpor-ligand interactions-TNF binding to TNFR1 receptor; binding of Fas ligand to its receptor Fas in T cell development or clonal deletion; binding of TRAIL to its various receptors (DR3,4,5) involves activation of transcription factor NF-kB and several caspases |
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Term
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Definition
| hormones-glucocorticoid interactions with nuclear receptors; physicochemical agents-heat, radiation, chemicals, hypoxia; viral proteins; clustering of intracellular receptors (JNKK, IKKa, NIK) |
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Term
| transmission of signals of adapter proteins |
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Definition
| Fas-FasL mediated apoptosis-eliminates activated lymphocytes from immune rections; activation of TNFR1 association with adaptor protein TRADD results in caspase activation; cytotoxic T lymphocyte stimulated apoptosis-secretion of perforin results in cell membrane damage; integrins transmembrane receptors that promote survival-lack of signaling by ligands promotes apoptosis; apoptosis mediate by DNA damage by p53 |
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Term
| increased permeability of outer mitochondrial membranes |
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Definition
| release of cytochrome C into cytosol Bcl2 may promote cell death; other proteins may promote or inhibit apoptosis by protein protein interactions with Bcl2; role of Bcl2 family in channel formation |
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Term
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Definition
| Group1-ICE like, caspase 1,4 and 5 cleave adjacent bulky aromatic residues; Group2-capases 2,3,7 prefer Asp or Glu; Group3-CED3 like caspases 6,8,9,20 prefer adjacent aliphatic residues these are synthesized as proenzymes activated by proteolytic cleavage; caspase 8 and 9 activate caspase 3 which activates other caspases |
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Term
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Definition
| DNase, DFF45 normally complexed to CAD and cleavage of DFF45 by caspase 3 allows CAD to enter nucelus and degrade nuclear DNA and have cleavage of nuclear polyribose polymerase involved in DNA repair by caspase 3 |
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Term
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Definition
| three pathways and the cascade interaction depends on conversion of inactive enxyme precursors to active enzymes by proteolytic cleavage of small peptide fragments and can bind to biological membrane and catalyze next component in the pathway and there is amplification of the reaction can result in immunopathology due to generation of an unwanted inflammatory response |
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Term
| classic complement pathway |
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Definition
| are not antibodies and is found in normal and immune serum; is triggered after specific antibody combines with its antigen because C1q is exposed on the Fc portion of the antibody when it binds the antigen; IgM fixes best and IgG the next best and IgG4 does not fix C and IgE, IgD and IgA do not fix complement and activity is heat labile and antibody is not inactivated by heat |
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Term
| classic complement cascade |
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Definition
| C1q is fixed and C1r and C1s bind to C1q and acquire serine protease activity and C1s splits C4 and C2; C4b2a splits by C3 and C3b adheres to cell membranes via formation of covalent ester bond; C3a and C5a are small soluble split products of complement components are called anaphylatoxins and receptors for these on mast cells releasing histamine; C3b splits C5 and the C5b associates with 6,7,8 and poly C9 making up the MAC which forms a pore in membranes; 3 distinct sites |
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Term
| biological implications of complement fixation |
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Definition
| 1. increases phagocytosis of complement-Coated antigen have receptors for membrane bound C3b=CR1 acts as an opsonin; 2. increased inflammatory responses-C3a and C5a increase vasodilation by releasing histamine from mast cells and C5a is chemotactic for PMNs; 3. cytotoxicity to tagets-MAC bactericidal activity or bacteriolysis from Gram negative bacteria and cytotoxicity for mammalian cells; 4. viral neutralization via C3b and MAC-C3b promotes aggregation of viral particles in presence of bound antibody reducing the effective number of viral particles and promotes phagocytosis of coated viral particles and enveloped virused can be lysed by complement if C9 is fixed; 5. immunopathology-if antigen-antibody complexes persist in the circulation or are trapped in the kidney, and complement can be fixed |
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Term
| alternate complement pathway |
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Definition
| can be activated with depletion of C4 or C2 from the serum; usually triggered nonimmunologically and antibody is not required and large molecular weight polysaccharides such as zymosan and endotoxin can trigger it; there is slow tick over of C3 to C3b occuring all the due to an unstable thio ester bond binds facotr B forming complex and factor D splits B to Bb and properdin stabilizes the C3bBb complex into C3 convertase; results in all of important biological effects observed with the classical pathway part of innate immune system |
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Term
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Definition
| serum contains mannose binding lectin which has homology to C1q it can bind mannose residues on microbes and a MBLASP is added to the complex which is a serine protease with homology to C1es which splits C4 and C2 and independent of antigen-antibody complex but it consumes C4 and C2; C4b with C3b and 2a with Bb have structural homology |
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Term
| upregulation of complement activation |
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Definition
| triggering of classical pathway can result in alternative pathway involvement by generation of C3b; plasmin and kallikrein can trigger the complement cascade by activating C1 and plasmin can activate C3 |
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Term
| down regulation of complement |
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Definition
| 1. alternate pathway-factor H competes with factor B for a combing site on C3b and alters C3b so it is susceptible to degradation by factor I; 2. classical and lectin pathways-C1 inhibitoris serine protease inhibitor which blocks the activity of activated C1r and C1s, C4BP is involvedin degradation of C4b by factor I works homologous to factor H, MCP-membrane co-factor protein binds C4b and makes is susceptible to Factor I degradation |
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Term
| down regulation in all the pathways |
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Definition
| 1. factor S-binds free C5b67 and prevents its insertion in the membrane; 2. decay accelerating factor breaks down the C4b2a complex; 3. homologous restriction factor prevents polymerization of C9 and carboxypeptidases in serum degrade C3a and C5a by removal of C terminal arginine; many have short half lives |
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Term
| nonimmunologic innate host defenses |
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Definition
| 1. physical barriers-skin, epithelial cell; 2. mechanical clearance mechanisms-ciliary epithelium, tears, GI motility, urinary tract mucous; 3. chemical barriers-low pH of the stomach with acidity is toxic to many microbes; 4. normal flora-commensals and symbionts that reside in skin and GI tract protect against pathogens and lactic acid in vaginal tract protects vs potential pathogens; 5. chemical antibacterial substances-lysoxyme-in milk, tears, urine, saliva, respiratory mucus, neutrophil granules, lactoferrin-iron binding protein in granules of neutrophils and sequesters iron that microbes need to grow |
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Term
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Definition
| attempt to control growth of organism; neutrophils, monocytes, macrophages recognize bacteria, fungi and parasites and ingest and kill them; NK cells attack virally infected cells or tumor cells; dendritic cels and macrophages initiate adaptive immune response but also release cytokines |
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Term
| innate immune system cell types |
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Definition
| neutrophila-phagocytosis, ROS and nitrogen species, antimicrobial peptides; macrophages-phagocytosis, inflammatory mediators, antigen presentation, ROS and nitrogen species, cytokines, complement process; dendritic cells-antigen presentation, ROS, interferon, cytokines; NKCs-lysis of virally infected cells, macrophage activation |
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Term
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Definition
| large granular lymphocytes but do not have antigen specific receptors and can kill target cells by direct contact using molecules that released from preformed granules (virally infected or tumor cells); upregulated by IL12 produced by macrophages which induces them to secrete IFN gamma which activates macrophages to make NO which is microbicidal and tumoricidal |
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Term
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Definition
| neutrophils-first line of defense with preformed granules with antibacterial arsenal have primary granules have myeloperoxidase and secondary granules have lysozyme and lactoferrin have short half life of 1-2 days |
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Term
| mononuclear phagocyte system |
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Definition
| mature to macrophages in response to inflammation and are long lived-months to years; also Kupffer cells in the liver, spleen sinusoidal macrophages, alveolar macrophages, peitoneal macrophages, microglia in the brain, monocytes in the blood |
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Term
| actue vs chronic inflammation |
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Definition
| PMNs usually arrive at site of bacterial invasion or tissue damage then macrophages; acute infections are characterized by predominance of PMNs and chronic infections are characterized by macrophages |
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Term
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Definition
| 1. attachment-nonspecific interactions, receptors on PMNs and macrophages include CR3 and other receptors on macrophages include:scavenger receptors, mannose receptor, TLRs, and CD14, antibodies and complement components enhance phagocytosis called opsonins |
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Term
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Definition
| 1. PMNs-CR3 binds C3b and Fc recptor for bound IgG antibody; 2. monocyte/macrophage-CR3, Fc receptor for bound IgG, scavenger receptors, mannose receptors, CD14, TLRs |
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Term
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Definition
| phagosome formation-invaginated vescile that pinches off the cell membrane and encloses a microbe, lysosome-membranous vesicle that contains enzymes, phagolysosome-vesicle formed by the fusion of a phagosome constaining a microbe and a lysosom; digestion-lysosomal granules contain enzymes that degrade biological material including microbes |
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Term
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Definition
| 1. generation of reactive oxygen intermediates-include peroxide and superoxide and hypochlorite which are generated; chronic granulotamous deisease of childhood-caused by deficieny in generation of peroxide due to defects in NADPH oxidase enzyme complex; 2. reactive nitrogen intermediates-NO generated by macrophages when iNOS is induced by interferon gamma; combination of nitric oxide and superoxide can generate peroxynitrite which is microbicidal; cationic proteins-present in primary granules of PMNs that bind to outer membrane of gram-negative bacteria and form pores; defensins-found in PMNs and eptithelial cells that have microbicidal activity; lysozyme-enzyme in PMN granules that digests petidoglycan in cell walls of gram postive bacteria |
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Term
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Definition
| resident tissue macrophages sense microbial invaders elaborate cytokines and chemokines to activate other cells; cytokines low MW proteins that mediate communication between cells of the immune system; chemokines are subclass of cytokines that cause immune cells to undergo directed migration toward them; acute phase response proteins in blood-C reactive protein binds polysaccharides on pneumococci, mannose binding lectin-binds mannose motifs on bacteria and triggers complement activation, LpS binding protein, serum amyloid |
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Term
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Definition
| also called PRR or pattern recognition receptors and recognize pathogen associated molecular patterns or PAMPs; have leucine rich repeats in their extracellular domain; 2-products of gram positve; 3-double stranded RNA; 4-LPS; 5-flagellin; 6-mycobactrial lipopeptides and yeast cell walls; 7-single stranded RNA of viruses; triggering of TLR2 and 4 results in NF-kB mobilization and code for proinflammatory cytokines these include IL1, IL12, TNFa and IL6 |
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Term
|
Definition
| IL1-uprefulates adhesion molecules on endothelial cells induces fever; IL12-triggers NK cells to makeIFNy; TNFa-causes tissue damage and mediates the eptic syndrome; IL6 induces actue phase proteins in the liver; TLR4 can trigger sepsis or systemic inflammatory response syndrome |
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Term
| factors of initial distribution pattern |
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Definition
| 1. physiochemical properties of the drug-ability to pass biological membranes, lipid soluble, pKa, MW and presence of appropriate carrier; 2. cardiac output; 3. regional blood flow to various tissues; 4. degree of plasma protein binding-may facilitate absoprtion into blood but will reduce ability of the drug to enter other tissues and drugs may displace each other from binding sites; degree of binding to tissue proteins |
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Term
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Definition
| entrance to CNS is restricted but drugs with sufficient lipid solubility will distribute first to those areas with high regional blood flow and will accumulate less rapidly in skeletal muscle and adipose tissue; drugs may cross the placental barrier and affect fetus and cross into maternal milk and affect nursing infants |
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Term
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Definition
| changes in the volume of any given body water compartment (usual does*body weight)/70kg |
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Term
|
Definition
| movement of drug away from its active site to other tissues where it can be stored; factors include pysiocochemical properties and blood flow like a highly lipid soluble drug can redistribute away from its active site and stored in adipose tissue after going to sites that are highly perfused |
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Term
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Definition
| interaction of a drug with the biological system causing a chemical change in the drug and resultant compound is a metabolite or metabolic product some of these have pharmacological activity; also known as biotransformation; inactive to active (LDOPA) or active to more toxic (methanol) |
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Term
| purpose of drug metabolism |
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Definition
| most drugs are lipid soluble, remain mostly non-ionized at physiological pH and at least partially bound to plasma proteins so metabolism makes the drug less lipid soluble, more water soluble, and therefore more readily excreted in bodys aqueous excretions |
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Term
|
Definition
| non-synthetic-usually convert the parent drug to a more polar metabolite include oxidation, reduction, and hydrolysis |
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Term
|
Definition
| synthetic-adding a group to the structure aka conjugation reactions and involves high energy intermediates and transferases most yeild inactive products include glucuronidation, sulfate conjugation, acetylation, amino acid conjugation, methylation and glutathione conjugation |
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Term
| location of drug metabolism |
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Definition
| major site is the liver also may occur in plasma, kidney, lungs, GI tract and other tissues; may go through first pass effect where when absorbed in small intestine and transported via portal system to the liver undergoes extensive metabolism and may greatly limit the oral bioavailability of a drug and limiting effectiveness by the oral route |
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Term
| microsomal mixed function oxidase system |
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Definition
| located in lipophilic membranes of the SER and the enzymes require NADPH and molecular oxygen and one molecule of oxygen is consumed per substrate molecule and NADPH-cytochrome P450 reductace and cytochrome P450; substrate binds with the oxidized cytochrome and resulting complex is reduced by the reductase and the reduced complex combines with molecular oxygen and these catalyze a wide variety of chemical reactions and multiple forms of P450 exist with differing substrate specificity |
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Term
| non-cytochrome P450 mediated phase I reactions |
|
Definition
| include xanthine oxidase and alcohol dehydrogenase |
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Term
| factors influencing drug metabolism |
|
Definition
| rate of flow to liver; rate of entry into the liver; enzyme inhibition and induction, drug-drug interaction; indivual differences; genetic factors (polymorphisms); diet and environmental factors; age and gender; tissue pathology |
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Term
|
Definition
| several drugs, may induce P450 activity by increasing the rate of synthesis or reducing the rate of degradation of the enzymes and leads to an increase in the metabolism of some drugs (chronic ethanol, rifampin w/ warfarin; chronic ethanol; St Johns Wort) |
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Term
|
Definition
| some drugs may inhibit cytochrome P450 activity by competing with another drug for the same metabolic enzyme or by forming a complex with the enzyme which inactivates it (acute ethanol, cimetidine, disulfiram) |
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Term
|
Definition
| different populations may metabolize drugs differently; isonizid for TB in certain population 50% are fast and 50% are slow and more likely to have toxic effects |
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Term
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Definition
| removal of a drug or its metabolites from the body to external environment important in preventing or minimizing toxic effects; lungs for volitale drugs, or bodily secretions |
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Term
|
Definition
| any soluble substance with MW less than 5000 and free in plasma is filtered in glomerulus and drug is excreted into the urine |
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Term
|
Definition
| carrier mediated active transport process in the proximal tubule and distal tubule by which organic acids and bases may enter the nephron can compete with each otehr or endogenous compounds; active tubular reabsorption-active transport process in proximal tubule by which drugs may be reabsorbed back into the general circulation |
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Term
|
Definition
| process in the proximal and distal tubules in which a drug can reenter the circulation by passive diffusion; lipid soluble, non-ionized drugs will be reabsorbed instead of excreted; changing the pH in tubular filtrate can alter excretion of drug; excretion by filtration related to free concentration but active secretion depends on total plasma concentration because of the high affinity of drugs for the carrier of the transport system |
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Term
|
Definition
| drugs from general circulation may enter the liver and be excreted into the bile and there are at least three different carrier dependent systems; oraganic acids, for organic bases, and for some steroids; competition can occur within each group and those drugs have entered the gut via bile may be directly excreted in the feces or may undergo enterohepatic recirculation and thus re-entering the blood stream and prolong its half life in the body; active uptake into hepatocyte, storage or biotransformation in the hepatocyte, release into the bile |
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|
Term
| zero and first order kinetics |
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Definition
| 1st order elimination removal is proportional to their plasma concentration a plasma half life can be determined and for a few drugs the rate of elimination does not increase or decrease with changes in plasma concentration and eliminated by zero order kinetics |
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Term
| factors altering the rate of elimination |
|
Definition
| age, environmental factors, disease, gender, drug-drug interactions, individual variation |
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|
Term
| major function of T cells |
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Definition
| help B cells in antibody production; recognize and kill tumor and virus infected cells; activate macrophages; All T cells express TCR and common antigen CD3 and no T cells ahve surface immunoglobulins and no B cells have CD3 or TCR |
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Term
|
Definition
| cells should be stained with monoclonal antibodies followed by secondary antibodies labeled with covalently linked fluorescent groups and cells with surface marker become fluorescent |
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Term
|
Definition
| CD4 are T helper cells and activate macrophages and help in T cell development and help in antibody production (2); CD8-cytotoxic T cell and kill tumor and virus infected cells and reject histoincompatible grafts |
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Term
| structure of T cell receptor |
|
Definition
| different than Igs and are heterodimers composed of two different glycoprotein chains linked by disulfide bridge; C terminal sequence anchored in the cell membrane and rest is extracellular and the chain have variable and constant regions |
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Term
|
Definition
| most consist of these chains a small subset express gamma and delta and these are very similar to aB less than 10% though |
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Term
| organization of T cell receptor genes |
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Definition
| each chain is composed of segments encoded by a multi segment family and segments are rearranged during maturation generating an enormous diversity of T cell receptor chains and wide antigen binding specificity; but no somatic hypermutation and allelic exclusion for T cell receptors is not as strict; diversity of aB is higher than gamma delta and is rather limited and make it possible to consider them as part of innate immunity and these bind to antigens different from those recognized by aB T cell receptors |
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Term
|
Definition
| TCR chains have short cytoplasmic sequences CD3 have long cytoplasmic sequences mediates all cytoplasmic interactions involved in transmembrane signal transduction consists of six protein chains of four major types and do not contain variable regions |
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Term
| aB T cell antigen recognition |
|
Definition
| recognizes short peptides in complex with MHC molecules can only see processed antigens held on surface of APC by MHC molecules and peptides degenerated bind to class I or II MHCmolecules and transported to surface where they can be recognized; T helper cells recognize class II and cytotoxic T recognize class I; gamma delta can recognize non protein structures and also are not MHC dependent |
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Term
| CD4 and CD8 in antigen recognition |
|
Definition
| facilitate recognition of the MHC molecule CD4-class II and CD8-class I and are co-receptors and increase the avidity of the T cell receptor to the antigen presenting complex |
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Term
|
Definition
| recognition triggers a series of molecular events ultimately inducing a variety of T cell responses; 1. mediated by protein Ras and other pathway is mediated by the calcium dependent protein phosphatase calcineurin |
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Term
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Definition
| complex reaction to injurious agents in living vascularized tissue; destroys, dilute or sequester injurous agent and the damaged tissue to permit healing |
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Term
|
Definition
| intertwined with the inflammatory process allowing for the replacement of tissue with healthy tissue; begins during inflammation and completed after agent is removed; regeneration of parenchyma, formation of fibrous scar |
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Term
|
Definition
| rapid onset and short duration and exudation of fluid and plasma proteins resulting in edema and emigration of leukocytes mainly neutrophils |
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Term
|
Definition
| usually longer duration than acute presence of lymphocytes and macrophages, tissue destruction, formation of new vascularized tissue and fibrosis |
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Term
|
Definition
| invasion and multiplication of microorganisms in body tissues, only one of several causes of inflammation |
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Term
|
Definition
| microbial infection, decreased oxygen supply, immunologic reactions, metabolic injury, chemical injury, physical injury, trauma, irradiation |
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Term
| vascular changes in acute inflammation |
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Definition
| 1. altered vascular caliber to increase blood flow to the area; 2. structural changes in microvasculature to permit fluid, large molecules and cells to exit; 3. emigration of leukocytes to site of injury where they accumulate |
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Term
|
Definition
| escape of fluid, protein and blood cells into interstitium serous cavity; exudate-inflammatory extravascular fluid, rich in plasma fluid, protein and cellular debris |
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Term
|
Definition
| ultrafiltrate of plasma; fluid with low protein content results from increased intravascular pressure;edema is excess fluid in interstitial or serous cavity |
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Term
|
Definition
| purulent exudate-rich in leukocytes, debris from dead cells and microbes |
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Term
|
Definition
| 1. inconstant and transient vasoconstriction or arterioles is neural reflex; 2. vasodilation or arterioles resulting in increaed blood flow locally and intravascular hydrostatic pressure and the area becomes warm and red and vasodilation induced by chemical mediators; 3. increased vascular permeability-outpouring of protein rich fluid results in intravascular hemoconcentration, increased viscosity and slowing of blood flow (stasis) and leukocytes begin to marginate and roll along endothelium and finally firmly adhering to endothelium for transmigration |
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|
Term
| increased vascular permeability |
|
Definition
| results in escape of plasma proteins, causing a decrease in osmotic pressure and increase in extravscular osmotic pressure and marked outflow of fluid producing edema; 1. endothelial gaps in venules-caused by histamine, bradykinin, leukotrienes and is short lived and reversible caused by mediator causing endothelial contraction and cytokines cause endothelial retraction a reorganization of cytoskeleton at intercellular junctions; direct endothelial injury resulting in cell necrosis and detachment and leakage is immediate and sustained until vessels are thombose and are repaired; 3. pronlonged leakage delayed; 4. leukocyte mediated endothelial injury-caused by leukocytes adhering to enothelium at sites of inflammation and active while adherent and releasing toxic substances; leakage of regenerating capillaries |
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Term
|
Definition
| from vessel lumen to intersitial spaces is leuokocyte; leukocyte adhesion occur by binding of complementary adhesion molecules on leukocyte and endothelial surfaces; chemical mediators regulate this process by modulating/up regulating surface expression or affinity of the receptors |
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Term
|
Definition
| lectins involved in early transient adherence, rolling/tumbling; CD62-E on endothelium, CD62-P on platelets and CD-L on leukocytes and these bind oligosaccharides on mucin-like glycoproteins (CD34) expressed on opposite cells |
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Term
|
Definition
| ICAM1 and VCAM1 expressed on endothelium and are ligands for integrins on leukocytes; B2 to ICAM1 and B1 to VCAMs and caused firm attachment; expression of CD62-P is induced by histamine, PAF, thrombin; CD62-E is IL1, TNF, chemokines |
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Term
|
Definition
| occurs by receptor ligand interactions at intercellular junctions of endothelium; PECAM1 (CD31) present on leukocytes and endothelial cells and binds to itself occurs mainly in venules; neutrophils dominate the first 6-24 hours and monocytes in 24-48 hours because neutrophils more numerous in blood and respond more rapidly to chemokines and also short lived |
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Term
|
Definition
| unidirectional migration of cells up a chemical gradient; most common are bacterial products and endogenous agents include C5a, leukotriene B4 and cytokines like IL8 and these bind to GPCRs on surface of leukocytes and triggers assembly of polymerized actin at the leading edge of the cell, formation of pseudopods and cell mobility; binding also induced leukocyte activation in neutrophils, monocytes/macrophages increased synthetic activity, release of chemical mediators secretion of lysosomal enzymes and receptors include TLRs, GPCRs recognizing N-fmet; IFN-gamma receptors on phagocytes; receptors for opsonins to inititate phagocytosis |
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Term
|
Definition
| mechanism is oxygen dependent; due to burst in oxygen consumption due to activation of NADPH oxidase and formation of reactive oxygen intermediates within the lysosome; NADPH with O2 to superoxide and superoxide dismutases to H2O2 in lysosome and this is regulated by catalase, glutathione oxidase; and myeloperoxidase converts hydrogen peroxide to HOCl free radical which kills microbes by halogenation or lipid peroxidation and most effienct microbiocidal process in neutrophils cells deficient still kill microbes via superoxide and hydroxyl radical |
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|
Term
| oxygen independent mechanisms |
|
Definition
| include lysozyme, lactoferrin, cationic major basic protein and defensins and host of lysosomal enzymes |
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|
Term
| leukocyte induced tissue injury |
|
Definition
| result in release of sysosomal enzymes, ROmetabolites, prostaglandins, leukotrienes and if persistant and unchecked, leukocyte infiltration becomes the offender and underlies asthma, ARDS, vaculitis, septic shock, glomerulonephritis, chronic lung disease, arthritis and atherosclerosis; occurs by diverse mechanisms including regurgitation during feeding, frustrated phagocytosis, cytotoxic release of enzymes when phagocytes ingest membranolytic substances |
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|
Term
| defects in leukocyte function |
|
Definition
| include leukocyte adhesion defect and chediak higashi syndrome-neutopenia, defective degranulation and microbial killing with problem in membrane associated protein responsible for docking and fusion of intracellular vacuoles and leads to infection susceptibility; chronic granulomatous disease results from inherited defects in various components of NADPH oxidase and lack of superoxide and ROIs; |
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Term
| termination of acute inflammation |
|
Definition
| declines because mediators have short half lives and several stop signals also exist, synthesis of leukotrienes switches to antiinflammatory lipoxins, antiinflammatory TGFB and neural impulses to inhibit TNF production by macrophages |
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Term
|
Definition
| in granules in perivascular mast cells, platelets, basophils, released by degranulation of mast cells caused by physical injury immune reactions, binding of C3a and C5a, histamine releasing proteins, cytokines (IL1 and IL8) and neuropeptides (substance P); causes dilation of arterioles, increases permeability of venules, binds H receptors on the endothelial cells causing contraction, principal mediator of immediate transient phase inactivated by histaminase |
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Term
|
Definition
| present in platelets and enterochromaffin cells effects similar to histamine; platelet release reaction occurs when aggregate in response to contact with collagen, ADP, antigen-antibody complexes and also liberates histamine and PAF |
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|
Term
| complement in inflammation |
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Definition
| leukocyte adhesion , chemotaxis and activation, increased vascular permeability and vasodilation causing release of histamine, activation of lipoxygenase pathway of AA metabolism, opsonization and phagocytosis enhancement |
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Term
|
Definition
| hageman factor (XII) converst prekallikrein in plasma to kallikrein and releases bradykinin from kininogen precursor also activates XII, C5 to C5a and chemotactic; bradykinin causes vasodilation, increased vascular permeability, smooth muscle contraction and pain and quickly inactivated |
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|
Term
|
Definition
| main link between coagulation and inflammation bind to protease activated receptors expressed on platelets, endothelial cells, smooth muscle celss causes mobilization of Pselection production of chemokines expression of endothelial adhesion molecules for WBC integrins synthesis of prostaglandins and PAF and NO |
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Term
|
Definition
| lyses fibrin clots to produce fibrin split products which increase vascular permeability can activate factor XII and can split C3 to C3a and C3b |
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Term
|
Definition
| initiates 4 systems involved in inflammation: kinin system, clotting system, fibrinolytic system and complement system and kallikrein amplifies this by further activating XII |
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Term
|
Definition
| is released from phospholipids by cellular phospholipases and metabolites are produced by 2 pathways |
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Term
|
Definition
| synthesis of prostaglandins PGI2 is produced by endothelial cells and inhibitor of platelet aggregation, a vasodilaror and potentiates permeability increasing and chemotactic effects; TxA thromboxane-produced by platelets and is potent platelat aggregator, vasoconstrictor; PGD2, PGE2, PGF2 cause vasodilation and potentiate edema, fever and pain; COX1 is induced during inflammation and constitutive in most tissues and COX2 is inducidble; inhibited by NSAIDs and aspirin |
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Term
|
Definition
| synthesis of leukotrienes; 5HETE is chemotactic agent; LTB4 is potent chemotactic agent, enhances neutrophil adhesion and generation of free radicals and release of lysosomal enzymes; LTC4, LTD4, LTE4 cause intense vasoconstriction, bronchospasm, and increased vascular permeability of venules; lipoxins are derived from AA by trans cellular biosynthesis and inhibit leukocyte recruitment and cellular components of inflammation |
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|
Term
|
Definition
| are AA metabolites with inhibitory role |
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|
Term
| platelet activating factor |
|
Definition
| phospholipid with glycerol backbone; produced by platelets, basophils/mast cells, neutrophils, macrophages, and endothelial cells; platelet stimulation, bronchoconstiction, vasoconstriction; vasodilation and increased vascular permeability; stimulates leukocyte firm adhesion, activation chemotaxis and oxidative burst |
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|
Term
|
Definition
| play a role in inflammation; IL1 and TNF are produced mainly by activated macrophages secretion stimulated by bacterial products, endotoxin, immune complexes, physical injury and other inflammatory stimuli; activate endothelial cells by inducing synthesis of adhesion molecules and various chemical mediators; prime neutrophils; cause fibroblasts to proliferate and systemic acute phase responses associated with infection or injury |
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Term
|
Definition
| act mainly as chemoattractants; a chemokines-act on neutrophils IL8; Bchemokines-chemoattractants for moncytes, eosinophils, basophils and lymphocytes; y chemokines-lymphocytes |
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Term
|
Definition
| soluble gas produced by endothelial cells; three different NOS endothelial (eNOS) brain (nNOS) and iNOS is inducible in macrophages and other cells when activated with cytokines; NO is potent vasodilator by relaxing vascular smooth muscles and reduces platelet aggreation and adhesion andhihibts mast cell induced inflammation; it and its derivatives are microbicidal |
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Term
|
Definition
| tranmission of pain signals, regulation of blood pressure, stimulation of secretion by endothelial cells and increasing vascular permeability |
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|
Term
| outcomes of acute inflammation |
|
Definition
| 1. complete resolution-restoration of injured tissue to normal structure and function with mild injury and parenchymal cells that can regenerate; 2. healing by CT replacement fibrosis-occurs when there has been considerable tissue destruction or occurs in tissue that cannot be regenerated and can form into scar tissue; 3. progression to chronic inflammation-when acute inflammatory response cannot be resolved due to persistance of injurious agent |
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|
Term
| morphologic patterns of acute inflammation |
|
Definition
| 1. serous inflammation-characterized by outpouring of thin fluid derived from blood plasma or secretions; 2. fibrous inflammation-with more severity and greater vascular permeability may be removed by fibrinolysis and macrophages resulting in resolution but may stimulate ingrowth of fibroblasts and blood vessels forming granulation tissue with scarring; 3. purulent/suppurative inflammation-large amoutns of pus consisting of neutrophils, necrotic cells and edema fluid induced by certain bacteria; abscesses are localized collecetion of purulent inflammation buried in tissue; 3. ulcers-local defect of the surface of an organ or tissue produced by sloughing of inflamed necrotic tissue |
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Term
|
Definition
| expression of IL2 receptor a chain, IL2 and other cytokines and their receptors results in proliferation of T cells called clonal expansion |
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Term
|
Definition
| when T cells receive incomplete stimulation do not respond by clonal expansion but developing a state of non responsiveness results from lack of co stimulatory signal provided by the surface molecule CD28 of T cells interacting with the surface molecule B7 of APCs |
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Term
|
Definition
| induced death of T cell clones recognizing specific antigens is provided by T cell development in the thymus |
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Term
|
Definition
| T cells have to recognize antigens in the context of self MHC molecules and must not recognize self antigens otherwise they willa ttack the host organism tissues |
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|
Term
| T cell development pathways |
|
Definition
| progenitor cell from bone marrow migrate to the thymus; earliest detectable thymocytes lack CD4 and CD8 and referred to double negative cells and the rearrangement of T cell receptor genes has not yet taken place; those that undergo productive rearrangement of gamma delta chains develop into double negative CD3 accounting for 1% of thymocytes; majority of double negative cells rearrange the b chain and express it on the cell surface of pre T cell receptor paired with the prea chain stop further B chain rearrangement actively proliferate and begin a chain rearrangement and also begin expressing both CD4 and CD8 on surface these cells become CD3CD4CD8 aB thymocytes these cells undergo selection and lose either CD4 or CD8 and develop into single positive thymocytes |
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|
Term
| positive and negative selection |
|
Definition
| only those capable of bidning antigen in the context of self MHC molecules are permitted to mature (positive selection; thymocytes whose receptors demonstrate high affinity for self MHC molecule along are eliminated by negative selection; 99% die in thymus |
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Term
|
Definition
| double negative rearrange genes encoding B y and delta chains of TCR in absence of productive B chain rearrangements leads to double negative CD3 yd T cells and if B chain gene productively rearrange the yd doesnt stop and cells that fail to productively rearrange a chains become yd T cells but a chain rearrangement block the path of yd development |
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|
Term
| age related changes in the thymus |
|
Definition
| reaches maximal size at puberty and then atophies; thymic outpu gradually decreases with age but the repertoir of B chains in both naive and memory CD4 T cells was maintained until age of 65 only after 65 this repertoir collapses |
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Term
|
Definition
| naive T cells preferentially reside in secondary lymphoid organs; APCs reside in these organs trap, process and present antigens to T cells and B cell responses are intiated in the secondary lymphoid organs; when recognizes specific antigen MHC complex it becomes activated, initiating a primary response includes clonal expansion and differentiation; memory T cells preferentially home to the tissue in which they first encountered antigen; CD4CD25 cells negatively regulates immune responses is antigen specific and direct contact with their targets in needed |
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Term
|
Definition
| most drugs and endogenous compounds interact with specific receptors; most often on the cellular surface that may be transmembrane transport proteins and D and R interaction proceeds as a bimolecular reversible reaction governed by mass-action law and results in a D-R complex:DR; with forward reaction as the forward association and the k2 as the dissociation constant |
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|
Term
|
Definition
| at equilibrium this bound concentration Be depends on the drug concentration (C) the total receptor concentration (Rt) and constant K known as dissociation constant according to the equation: Be=(CRt)/(C+K); as C increases the C/(C+K) approaches unity and the bound concentration approaches Rt and K is numerically equivalent to concentration that yields a bound concentration=Rt/2 and K is the reciprocal of the affinity of D for R; K is specific for each D-R complex and thus characterizes the interaction |
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|
Term
|
Definition
| magnitude of the effect is expressed as the product of number of receptors bound (B) and the intrinsic activity, e, with e being a constant that relates the degree of stimulus to the receptor occupancy; determined by the drugs affinity |
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Term
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Definition
| a drug with intrinsic activity; if the intrinsic activity is high the effect can be large with minor receptor occupancy and there are spare receptors and termed a full/strong agonist; some drugs have low intrinsic activity that even full receptor occupancy does not produce a maximal effect; called a partial agonist |
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Term
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Definition
| for full agonist a common description is E=(Emax*D)/(D+G) and G is dose that gives 1/2 the maximal effect and termed D50 with D is the dose administered and Emax is the maximal effect |
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Term
| attributes from dose-response curve |
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Definition
| 1. efficacy-greatest effect of the drug; 2. potency is the left to right position evident from the D50 and a small D50 means high potency; partial agonists have lower efficacy than full agonists |
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Term
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Definition
| some drugs combine with the receptor but have zero intrinsic activity and lack efficacy and competes with drug A for the common receptor R; exs include: 1. norepi vs phentoalmine on vascular smooth muscle; 2. norepi vs prazosin on vascular smooth muscle; 3. acetylcholine vs d-tubocurarine on skeletal muscle; 4. ACh vs atropine on heart rate |
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Term
| antagonist change of dose-response curve |
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Definition
| in a fixed dose shifts the dose response curve to the right but sufficiently high doses of the agonist still produce its maximal effect and this is called competitive antagonism in presence of non-competitive antagonist the dose response curve is depressed |
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Term
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Definition
| depends on antagonist dose (B); when the graphs are constructed with log dose or conc they take on sigmoid shape and are parallel and the equation allows a determination of Kb and K b characterizes the receptor; A*/A=1+(B/Kb) |
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Term
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Definition
| A+R1=one effect and B+R2 produces another effect opposite of the other and includes norepinephrine and acetylcholine on the SA node of the heart |
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Term
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Definition
| Effect (A+B)> effectA+effectB ex is alcohol and barbiturates and equality in relation is additivity |
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Term
| all or none (quantal) dose response relations |
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Definition
| endpoint representing some effect is selected and the percentage of subjects who show this endpoint is plotted agaist the dose or log dose; the dose that gives the effect to 50% is the ED50 an effect can be death and the dose that is lethal in 50% is the LD50; therapeutic index is way of expressing the safety of a dose where TI=LD50/ED50 |
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Term
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Definition
| show increased production of both class II MHC molecules as well as co stimulatory B7 membrane molecules enabling macrophages to activate CD4 cells |
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Term
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Definition
| phagocytic cells contain a membrane associated oxidase which catalyzes the one electron reduction of O2 using NADPH and the superoxide generated as starting material for reactive oxidants |
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Term
| reactive oxidant intermediates |
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Definition
| not only bactericidal but serve as intermediate messengers which upregulate inflammation but inducing transcription of genes encoding inflammatory proteins and stimulate cellular hyperplasia; over production of ROI is believe to play an important role in the development of atherosclerosis and certain cancers |
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Term
| chronic granulomatous disease |
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Definition
| results from mutations in the genes encoding the NADPH oxidase and neutrophils and monocytes from affected individuals fail to produce O2 and H2O2 from the NADPH oxidase and have impaired intracellular killing ; granulomas are frequent because macrophages are unable to destroy ingested bacteria and macrophages can undergo persistent activation and accumulate |
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Term
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Definition
| a gene complex coding for cell surface glycoproteins; consists of tightly linked loci encoding for 3 classes of molecules and class 1 and class II are membrane bound glycoproteins that form complexes with antigenic peptides and present them to T cells for recognition; class III molecules are group of unrelated proteins that do not share structural or functional similarity with class I and II molecules; all alleles of MHC loci on a single chromosome are called a haplotype and all MHC genes are codominantly expressed; in man MHC is called HLA and is found on chromosome 6 |
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Term
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Definition
| single chain transmembrane glycoprotein molecules found in noncovalent association with B2microglobulin and expressed of most nucleated cells these bind peptide antigens and present them to CD8 cells |
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Term
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Definition
| two chain transmembrane, noncovalently associated glycoprotein molecules found on the membrane of APCs they present antigenic peptides to CD4 cells |
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Term
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Definition
| not cell membrane molecules and have a very different function encode various proteins involved in inflammation and including various complement proteins and TNFa |
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Term
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Definition
| peptide must fit into cleft of MHC molecule and are 8-15 aas in size and anchor residues to facilitate binding to the MHC molecule and without these the peptide cannot fit as well |
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Term
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Definition
| MHCI region codes for 20 gene with 3 (ABC) coding for MHC molecules and each molecule is distinct in structure and binding capacity encode proteins which bind and present antigenic peptide to CD8 cells and each individual inherits a variant of ABC from each parent for a total of 6 molecules |
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Term
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Definition
| this region contains genes which encode the a and b chains of MHC II molecule and there are three loci DP, DQ and DR each encoding for an a and b chain can have mixing and matching and each individual inherits a molecule from each parent for a total of 6 molecules and each individual can express 12 different molecules |
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Term
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Definition
| 1. dendritic cell-encytosis/phagocytosis have constiitutive class II MHC and B7 expression and activate naive T cells, effector T cells and memory T cells; 2. macrophages-phagocytosis class II are inducible as is B7 and activates effector T cells and memory T cells; B lymphocyte-receptor mediated endocytosis, constitutive class II MHC and inducible B7, activates effector T cells memory T cells, naive T cells, effector T cells and memory T cells |
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Term
| cell bio of antigen processing and presentation |
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Definition
| 1. antigen recognition by APC; 2. antigen internalization; 3. proteolytic degradation of antigen into small peptides, combination of antigen with MHC class II and expression of MHC class II Ag on cell surface; contact between APC and Ag specific T cell |
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Term
| recognition of antigen class I complexes |
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Definition
| all nucleated cells express MHC class I molecules; antigens that are being presented to T cells must be endogenously synthesized by the MHC I bearing cells; subset of T cells with CD8 on their surface recognize Ag-MHC class I by proteosomal degradation and small peptides fit into cleft with synthesis of MHC I in ER; in class II due to lysosomal degradation an invariant peptide sits in cleft until endosome combines with lysosome and is clipped |
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Term
| poly morphisms of MHC genes |
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Definition
| about 100 class I antigens and 40 class II antigens have been identified; occurs in hot spots or hyper variable regions |
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Term
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Definition
| ceratin antigens are associated with diseases and these diseases are often of unknown origin and may be associated with immunologic abnormalities; RR relative risk is the chance that an individual with a disease associated HLA antigen has of developing the disease compared to individual who lacks the antigen; ankylosing spondytisis B27 has RR of 90.1 |
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Term
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Definition
| is any biological macromolecule that binds to a drug and is the target of the drugs action many causes the target macromolecule is a physiological receptor but it can be an enzyme, structural protein, lipi membrane or nucleic acid |
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Term
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Definition
| cellular proteins whose normal function is to bind to endogenous regulatory ligands; endocrine, paracrine, autocrine, neurotransmission and binding of ligand elicits a series of reactions that result in a physiological response |
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Term
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Definition
| ATP for receptor P2X1-7 and allows Ca to enter the cell and role in activation |
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Term
| receptors coupled to phospholipase C |
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Definition
| similar to adenylyl cyclase receptor a1adrenergic, histamine, vasopression and transduced by Gq to phospholipase C cleaves to form DAG and IP3 from PIP2 |
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Term
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Definition
| undergoes a series of intramolecular transitions which activates the photoreceptor specific G protein, transducin and G protein stimulates the activity of cGMP phosphodiesterase causes a reduction in cytoplasmic concentration of cGMP and causes closure of cation selective cGMP gated channels located in the plasma membrane and reduces inward current normally carried by Na and Ca ions in the dark resulting in membrane hyperpolarization and decreased release of synaptic transmitter glutamate |
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Term
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Definition
| G protein regulated inward rectifier K channel in the absence of agonist the heterotrimeric G protein binds both the receptor and the GIRK channel and form a macromolecular complex and exchange of GTP for GDP at the Ga subunit catalyzed by the agonist bound receptor causes the G subunit to dissociate from the receptor and release the By dimer and this activates GIRK |
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Term
| receptors coupled to guanylyl cyclase |
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Definition
| two major kinds; 1. transmembrane receptor that binds atrial naturetic facotr on extracellular domain and contains intracellular guanylyl cyclase; form that is in the cytoplasm and activated by NO |
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Term
| receptors for insulin and growth factors |
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Definition
| three domains-1.extracellular domain, heavily glycosylated contains recognition or binding site for hormones; 2. transmembrane domain-a single a helix of 21 amino acids transduces signal into the cell; 3. intracellular domain-contains a protein kinase that phosphorylates tyrosine and this is essential for signal transduction |
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Term
| second messenger removal systems |
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Definition
| 1.cAMP and cGMP by phosphodiesterases; 2. IP3-phosphatases-convert IP3 to iositol; 3. DAG-enzymes return it to phospholipid pool; 4. Ca is resequestered into storage sites or pumped outside the cell |
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Term
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Definition
| 1.homologous-stimulation of a single receptor results in diminished response to further stimulation of that receptor; 2. heterologous-stimulation of single receptor results in a diminished response to further stimulation of both that receptor and other receptors; mechanisms-internalization, phosphorylation, down regulation reduced synthesis or increased breakdown |
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Term
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Definition
| four families include selectins; mucin like CAMs; integrins; Ig superfamily CAMs |
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Term
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Definition
| cell surface receptors that contain a carbohydrate binding domain L selectin, E selectin and P selectin; mucin like CAMs have a protein core with large mucins; L selectin binds mucins on endothelial cells and E selectin and P slectin on endothelial cells binds mucins on leukocytes they bind with low affinity |
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Term
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Definition
| made of non-covalently associated alpha and beta heterodimers; different alpha an beta subunits interact to generate different ligand specificity and they bind to Ig CAMs on endothelium; a4 and B2 integrin families are highly expressed on leukocytes |
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Term
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Definition
| ig CAM binds to itself and is expressed on both leukocyts and endothelial cells; on endothelial cells it is located at the inter cellular junctions important during diapedesis or trans endothelial migration |
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Term
| model of leukocyte recruitment |
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Definition
| 1. roll along the activated endothelium through low affinity interaction mediated by selectins and mucins reducing leukocyte velocity; 2. activated by chemokines present on the surface of endothelial cells to activate the integrins and change their conformation; 3. firm adhesion-activated integrins bind to the cell adhesion molecules on the endothelial cell surface to mediate firm adhesion; 4. leukocyte moves between the endothelial cells in a process called trans-endothelial cell migration or diapedesis mediated by PECAM |
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Term
| leukocyte adhesion deficiency |
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Definition
| abnormal recruitment of leukocytes to sites of inflammation LAD1 is due to a lack of B2 integrin so there is no firm adhesion and LADII is due to abnormalaties in carbohydrate side chains of mucin CAMs so there is improper rolling |
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