Term
| what is the triple response of lewis? |
|
Definition
| 3 things that classically happen in allergic reaction: vasodilation, increased vascular permeability, and binding to afferent nerve endings resulting in reactive flare |
|
|
Term
| what are 4 things the mast cell releases upon degranulation in hypersensitivity? |
|
Definition
| histamine (triple response of lewis), platelet activating factor (pulls in neutrophils and eosinophils), TNF-alpha (proinflammatory cytokine, increases adhesion molecules and stimulates monocytes), IL3 IL5 and CSF (maintenance cytokines, go to bone marrow and stimulate release of more eosinophils) |
|
|
Term
| if there is enough of a strong signal (in hypersensitivity reaction) what happens via phospholipase A2? |
|
Definition
| phospholipase A2 cleaves arachadonic acid (inner cell membrane) and either goes thru the cyclooxygenase pathway (forms prostaglandins, which are proinflammatory) or the lipoxygenase pathway (form leukotrines C4, D4 and E4, which are slow reactive substances of anaphylaxis. 1000x more potent than histamine causing bronchoconstriction, increased vascular permeability and vasodilation) |
|
|
Term
| give 3 examples of hypersensitivity type II reaction? |
|
Definition
| heparin-induced thrombocytopenia, RH+/- reaction with mother/fetus, induced hemolytic anemia (pcn) |
|
|
Term
| describe hypersensitivity type III reactions? |
|
Definition
| soluble protein ag binds with their IgG Ab --> in mid to late response the IC circulate to various places in the body (joints, kidney, skin, brain) --> complement activated and C5a is formed (neutrophil chemoattractant) --> neutrophil mediated tissue and organ damage can result (neutrophils eat and release granules --> localized damage) |
|
|
Term
| what are 2 examples of type III hypersensitivity reactions? |
|
Definition
| systemic lupus erythematosus and serum sickness from prolonged use of high-dose pcn |
|
|
Term
| what is an arthus reaction? |
|
Definition
| Ag is re-introduced into the skin (tb test, etc) --> IgG specific for that Ag binds to it and in situ IC formed with resultant inflammatory reponses (d/t complement activation and C5a pulling neutrophils into the area causing localized inflammation) |
|
|
Term
| Describe the Th1 mediated hypersensitivity reaction aka macrophage-meditated (subclass of type IV DTH)? |
|
Definition
| ag presented to sensitized CD4 T cells that produce Th1 cytokines (INFgamma and TNFalpha) --> produce macrophages --> swelling (ex: TB skin test) OR ag --> development of cell granulomas form in an attempt to wall off the unknown ag --> irreversible tissue damage and organ dysfunction (ex: sarcoidosis - these pts often have clinical anergy bc the CD4 cells are preoccupied with the site of active disease and cannot mount an effective cell mediated memory response to the skin test) |
|
|
Term
|
Definition
| when we don't respond properly to recall antigens (candida and trichophyton, both skin fungi) to which the population at large is exposed. results from immunosuppression either as a result of drugs being given or immunodeficiency |
|
|
Term
| what 3 types of substances are produced by Th1 cells in Th1 mediated hypersensitivity? |
|
Definition
| chemokines (macrophage recruitment to ag site); cytokines (IFNgamma activates macrophages and increases release of inflammatory mediators, IL3 and GM-CSF monocyte production by bone marrow stem cells); cytotoxins (TNFalpha and beta --> local tissue destruction, increased expression of adhesion molecules on local blood vessels) |
|
|
Term
| describe Th2 mediated hypersensitivity aka mast-cell mediated hypersensitivity? |
|
Definition
| mast cell signals --> late-phase response involving influx of eosinophils and Th2 lymphocytes (i.e. airway changes in chronic allergic asthma and allergic rhinitis) |
|
|
Term
| describe the CD8-mediated type IV hypersensitivity reaction. |
|
Definition
| when ag is cell-associated --> immunologic memory response results in CD8 destruction of cells to which ag is associated (i.e. contact dermatitis with poison ivy. exposed once --> pentadecacatechol associates with and modifies proteins in our skin cells --> modified proteins processed by dendritic cells, presented with MHC I to T-cells in local lymph node --> re-exposure to poison ivy --> memory response --> cytotoxicity to any skin cell exposed --> typical papular-vesicular skin lesion pruritic! |
|
|
Term
| what are 4 things that make cell injury irreversible? |
|
Definition
| any profound disturbance of the membrane function, release of lysosomes, nuclear injury that causes pyknosis, karyorrhexis, or karyolysis; lastly, increased swelling of mitochondrial membrane with vacuolization of mitochondria, cristae, and inner mitochondrial membrane and increased calcification |
|
|
Term
| describe coagulation necrosis |
|
Definition
| cell swelling or rupture. loss ofnucleus but preservation of cell "ghost" most commonlyhappens after hypoxic, ischemic, or chemical cell injury. grey firm mass like cooked meat. |
|
|
Term
| describe liquefactive necrosis |
|
Definition
| ischemia --> proteolytic digestion of lipid --> loss of original architecture. results in cystic cavities. characteristic of brain lesions and abscesses |
|
|
Term
|
Definition
| occurs anywhere fatty (i.e. breast, pancreas, fatty tissue). enzymatic lipolytic activity --> cleaves triglycerides into glycerol and free fatty acids --> forms calcium soaps, chalky white deposits in areas of fat necrosis |
|
|
Term
| describe caseous necrosis |
|
Definition
| seen in well circumscribed granulomas (become filled with cheesy, amorphous, protinaceous, caseous material). typically found in the center of TB lesions. no original architecture seen |
|
|
Term
| describe fibrinoid necrosis |
|
Definition
| accumulation of plasma proteins --> alteration of injured blood vessels |
|
|
Term
| what type of necrosis is gangrene and what are the 3 different types? |
|
Definition
| coagulative necrosis, usually affects a leg that has lost its blood supply. (1)dry - ischemic necrosis of a limb, dry, dark brown to black (2)wet - saprophytic bacteria superimposed on dry gangrene causes putrefactive changes (3)gas - wet gangrene in which saprophytic bacteria are gas formers |
|
|
Term
| what is the function of BCL-2? |
|
Definition
| it is anti-apoptotic. prevents the release of cytochrome C from the mitochondria and prevents capase (apoptotic cascade enzyme) activation |
|
|
Term
| what three things induce apoptosis? |
|
Definition
| growth factor deprivation, DNA damage, and cytotoxic T cells |
|
|
Term
|
Definition
| apoptosis induced by loss of cell adhesion on the extracellular matrix (ECM provides physical scaffold on which cells adhere and the orientation context for the cells in a multicellular organism) |
|
|
Term
|
Definition
| they trigger a cell to undergo apoptosis (whereas BCL-2 and NF-kB favor cell survival) |
|
|
Term
| what are the enzymes used in necrosis? apoptosis? |
|
Definition
| necrosis - lysosomal hydrolases; apoptosis - capases |
|
|
Term
| what do proteosomes do in response to cell injury? if they are not successful, what happens? |
|
Definition
| unfold and refold denatured polypeptides to restore their function and reverse partial denaturation. if they cannot restore function, ubiquitin binds to the denatured protein for disposal |
|
|
Term
| describe dystrophic calcification |
|
Definition
| abnormal deposition of calcium salts in injured or dead tissues. the serum calcium is NOT increased. extracellular deposition with lipid accumulation. happens in vasculature and heart valves --> compromises function by narrowing arteries and limiting blood flow, valves become stiffened and may limit movement |
|
|
Term
| describe metastatic calcification |
|
Definition
| deposition of calcium salts in undamaged (normal) tissues when serum calcium abnormally increased. (could be d/t: hyperparathyroidism, sarcoidosis, cancer with bony metastases, hypervitaminosis D, immobilization, milk-alkali syndrome) |
|
|
Term
| what is the pathophysiology of fatty change? |
|
Definition
| excessive mobilization and delivery of free fatty acids to cells. inability to convert fatty acids to phospholipids. increased esterification of fatty acids to triglycerides. impaired synthesisofproteins needed for transport of secreted lipoproteins. (occurs with ischemia, hypoxia, and alcohol abuse) |
|
|
Term
| glycogen accumulation in cells is most often a result of? |
|
Definition
|
|
Term
| what are the 2 main areas of excess protein production, and what does intracellular protein accumulation cause? |
|
Definition
| antibody-forming plasma cells (B-cells) and renal tubules when protein is excreted. causes compression and disruption of organelles |
|
|
Term
|
Definition
| accumulation of carbon (coal dust) in alveolar macrophages of the lungs (d/t burning of fossil fuels) harmless condition |
|
|
Term
|
Definition
| accumulation of silica, asbestosis, silver, lead, or iron. can lead to mesothelioma (cancer) |
|
|
Term
| what is the effect of too much tetracycline? |
|
Definition
| chronic maternal use stains teeth and soft fetal tissue |
|
|
Term
|
Definition
| intracellular accumulation of lipids and protein d/t wear and tear. yellow-brown. not digestible. increases with age. seen in heart, nerve, liver. not injurious to cell structure or function |
|
|
Term
| what is melanin accumulation? |
|
Definition
| intracellular accumulation of melanin --> brown-black, formed i n melanocytes by oxidation of tyrosine. normally in skin, retina, leptomeninges, substantia nigra. melanomas usually produce melanin. albinos have a hereditary lack of tyrosinase. |
|
|
Term
| describe intracellular increase in hemosiderin and its local and systemic causes. |
|
Definition
| accumulation in macrophages usually from hemoglobin, contains iron. golden-yellow. ferritin aggregates forming apoferritin-iron complex. local cause is bruising/hemmorrhage. systemic cause is iron-overload disorders (hemochromatosis, hemolysis, excessive blood transfusions) deposition in liver, pancreas, spleen, lymph node, bone marrow. can cause fibrosis if severe. |
|
|
Term
| describe intracellular accumulation of hemozoin |
|
Definition
| golden-brown, comes from hemoglobin accumulating in kupffer cells in malaria |
|
|
Term
| describe intracelllular accumulation of bilirubin |
|
Definition
| yellow-orange to green-brown. from hemoglobin, NO iron, normal bile pigment. increase --> jaundice. retention is either d/t overproduction or inability to excrete it. product of abnormal synthesis or metabolism |
|
|
Term
| what are 4 examples of how free radicals can cause cell injury? |
|
Definition
| (1)metabolism of drugs, i.e. acetaminophen overdose. produces free radicals that cannot be cleared quickly enough by glutathione --> liver necrosis (2)chemicals, ie CCl4, when transformed into CCl3, becomes free radical that impairs hepatic protein synthesis --> inability to transport lipids out of cell --> rapid buildup in hepatic triglycerides --> diffuse fatty change --> necrosis in centrilobular liver where CCl4 is stored (3) lipid peroxidation, double bonds of lipids in membranes attacked by free radicals --> produce peroxides (unstable) --> autocatalytic chain reaction to membranes, organelles, and cells (4)oxidation of amino acids and ssDNA breaks |
|
|
Term
| describe how reperfusion injury happens and how we treat it |
|
Definition
| ischemia --> no oxygen --> no reactive oxygen species being created. during ischemia, xanthine dehydrogenase converted to xanthine oxidase, which accumulates in the cell. when oxygen is restored --> xanthine is oxidized producing ROS (does not affect cells that are irreversibly damaged, but in viable cells that have damaged mitochondria and a compromised antioxidant system are vulnerable to damage) tx: give supplemental free radical scavengers to help neutralize the ROS created after reperfusion, or give allopurinal, which inhibits xanthine oxidase altogether |
|
|
Term
|
Definition
| abnormally folded proteins that get deposited as FIBRILS extracellularly (particularly in blood vessels and basement membranes)amorphous, eosinophilic, hyaline. they form as a result of a failure to break down abnormally folded proteins. |
|
|
Term
| amyloid has morphological similarity to which other 2 substances? how do we determine its amyloid? |
|
Definition
| collagen and fibrin. histologically distinctive under light microscopy with affinity for special dyes ie. congo red, turns green under polarized light. also, they have beaded nonbranching fibrils and beta-pleated sheet under xray crystallography |
|
|
Term
| describe immunocyte dyscrasia with amyloidosis (primary amyloidosis) |
|
Definition
| most common form of amyloidosis. occurs in patients who synthesize abnormal amounts of a specific immunoglobulin (monoclonal gammopathy), such as multiple myeloma (occurs 5-15%) and other monoclonal B cell plasma dyscrasias. **the fibroid that gets deposited is amyloid light chain (AL) with lambda>kappa |
|
|
Term
| describe reactive systemic amyloidosis (secondary amyloidosis) |
|
Definition
| **protein causing fibril: AA (amyloid associated protein)non-immunoglobulin, synthesized in liver** (precursors of AA are SAA and alpha-1 globulin)occur in cases of drawn-out cell injury ie chronic injury and chronic inflammation. frequent in rheumatoid arthritis, inflammatory bowel disease, heroin use, renal cell carcinoma, hodgkins, tb, osteomyelitis |
|
|
Term
| describe hemodialysis-associated amyloidosis |
|
Definition
| **protein fibril: B2-microglobulin** deposits in synovium, joints, and tendon sheaths of long-term dialysis patients |
|
|
Term
| what fibril involved in hederofamilial amyloidosis? |
|
Definition
| AA or transthyretin. recurring episodes of inflammation, rare, characteristically in black males in conjunction with cardiac failure |
|
|
Term
| what fibril associated with localized amyloidosis? |
|
Definition
| AL. localized form of immunocyte-derived amyloid |
|
|
Term
| fibril involved in amyloid of aging? |
|
Definition
|
|
Term
| fibril associated with alzheimers disease? |
|
Definition
| beta-amyloid (in blood vessels in the brain) |
|
|
Term
| describe the causes of nutritional edema |
|
Definition
| (due to decrease in intravascular osmotic pressure as a result of a profound decrease in albumin) (1)liver failure --> decreased albumin synthesis by liver (2)nephrotic syndrome (glomerular capillary damage) --> loss of albumin through kidney (3)starvation --> profound decrease in protein intake |
|
|
Term
| describe the differences b/w transudate and exudate |
|
Definition
| transudate= passive, hydrostatic, sterile, clear, low protein content, few cells, usually indicates heart failure. exudate=active, secondary to inflammation, infection, tumor etc. not sterile (has microorganisms), cloudy, high protein content, numerous cells, usually indicative of infection or tumor |
|
|
Term
| briefly describe the process of hemostasis |
|
Definition
| (clotting after vessel is severed) vessel severed --> transient, insignificant arteriole constriction --> interruption of laminar blood flow --> platelets leave vessel and adhere to extracellular matrix/collagen via binding to von willebrand factor --> platelet release reaction (platelets secrete ADP, thromboxane A2, which mediate platelet to platelet adhesion and aggregation) --> form primary hemostatic plug (reversible) --> platelets fuse --> activation of coagulation cascade --> generation of thrombin --> fibrinogen --> fibrin, which stabilizes the clot and makes the secondary hemostatic plug --> endothelium regenerates, clot undergoes fibrinolysis via plasmin,e tc |
|
|
Term
|
Definition
| 3 major risk factors that can predispose someone to thrombus formation: (1)endothelial injury (2)disturbances of blood flow (stasis in veins, turbulence in arteries) (3)disturbances in the composition of blood (hypercoagulable states, increased viscosity of the blood, sickle cell) |
|
|
Term
| how is the morphology of arterial thrombi different from venus thrombi? |
|
Definition
| arterial thrombi resembles a platelet-fibrin plug (usually d/t endothelial injury, if it occurs in the left heart, will have systemic effect); venous thrombi develops laminations (lines of ZAHN, composed of fibrin and platelet deposits alternating with layers of erythrocytes) d/t stasis, will end up in lung usually |
|
|
Term
| what are the 3 most common sites of pulmonary thromboemboli? |
|
Definition
| deep veins of the leg, pelvic plexuses (periprostatic, utero-ovarian), brachial veins or right atrium (rare) |
|
|
Term
| what part of the immune system responds to typical acute extracellular bacterial infection? |
|
Definition
| humoral immunity (antibody-mediated) ie. opsonization, complement fixation, bacterial immobilization, adhesion blockage, toxin neutralization |
|
|
Term
| phagocytes have 2 important receptors on their surface. what are they? |
|
Definition
| Fc receptor (for opsonization of encapsualted bacteria especially) and C3b receptor (for complement fixation) |
|
|
Term
| people with defects in the lytic pathway of complement have markedly increased susceptibility to what bacterial species? |
|
Definition
| neisseria (ie repeated instances of meningitis or sepsis caused by N. meningitidis) |
|
|
Term
| what 2 processes are considered bacterial neutralization? |
|
Definition
| anti-flagellar antibodies (flagella can be antigen) immobilize bacteria; antibodies against bacterial surface adhesins can block their adhesion to host tissue surfaces |
|
|
Term
| how does toxin neutralization work against bacterial infection and why is it important |
|
Definition
| specific antibody for a toxin can neutralize it by sterically blocking their active sites or by allosteric interaction - is an immediate effect. important bc killing toxigenic bacteria has no effect on the toxin they already made/released. |
|
|
Term
| what defenses are best used against an intracellular bacterial infection? |
|
Definition
| CD8 cytotoxic T lymphocytes and macrophage activation by CD4 helper T cells (TH1) |
|
|
Term
| how does the body defend itself against infection caused by opportunistic environmental molds? |
|
Definition
| IR is largely irrelevant. they primarily infect patients who have defective neutrophil numbers or activity (leukemia, diabetes). |
|
|
Term
| what role does cell-mediated immunity have against molds? |
|
Definition
| CMI necessary to control infections and may itself contribute to most of the sx. in its absence the sx are different and disease takes more progressive course. these molds are similar to mycobacteria |
|
|
Term
| whats our defense against helminths? |
|
Definition
| TH2 response - release of toxic granule contents from eosinophils and mast cells, targeted at helminths by immune IgE molecules. may eliminate worms or decrease the ultimate worm burden as infection is established. (more effective in smaller larvae. no real defense against established helminths) |
|
|
Term
| major cytokines of inflammatory rxn? |
|
Definition
|
|
Term
| describe INF (alpha and beta) |
|
Definition
| products of any cell infected by a virus; transmissable from cell to cell; shuts down cell translation (viral and host proteins not being made); nonspecific; pro-TH1 |
|
|
Term
|
Definition
| they kill virally infected cells. they have activating and inhibiting receptors on cells. healthy cells make inhibitors (ie MHC I, virally infected cells lose their MHC I) |
|
|
Term
| explain original antigenic sin |
|
Definition
| for some pathogens (ie influenza) epitopes are changing all the time (phase variation) so our IR to it via memory cells gets weaker and weaker. suppression of IgM in secondary response bc circulating IgGs from 1st exposure coat the ag and prevent a robust response by naive B cells (therefore we dont create NEW memory cells for the NEW epitopes that are mixed in). the ag does trigger a robust memory B cell response to the 'old' epitopes. naive B cells shut down bc new epitopes are physically linked to the 'old' epitopes that have already been recognized by the b cell. |
|
|
Term
| describe the herd immunity formula for how many people must be vaccinated? |
|
Definition
| (1-1/R)/(vaccine efficiency) ie we need to decrease the # of susceptible individuals to less than the reciprocal of R. |
|
|
Term
| briefly describe the lac operon |
|
Definition
| absence of lactose --> lac repressor diffuses thru cytosol and binds to lac operator, prevents initiation of RNA polymerase at lac promoter. lactose present --> conformational change lactose to allolactose --> allolactose binds to repressor, changes conformation of the repressor --> repressor falls off of the DNA --> RNA polymerase free to move along lac operon and mRNA can be transcribed to yield genes that allow lactose to be digested |
|
|
Term
| briefly describe catabolite repression |
|
Definition
| glucose high --> cAMP low. glucose low --> cAMP high --> cAMP binds to CAP protein (catabolite activator protein) --> CAP protein binds to CAP binding site near promoter --> activates transcription perhaps by increasing the affinity of the promoter for RNA polymerase. (lac operon requires both de-repression via lactose and activation via CAP for transcription to occur) |
|
|
Term
| what does the DtxR regulate? and how is the DtxR toxin and operon system an example of end-product inhibition? |
|
Definition
| DtxR regulates all operons dealing with Fe levels (>18 different operator sequences controlled by this toxin) controls synthesis of iron binding proteins (siderophores), iron transport, etc. it is an ex of end product inhibition bc the presence of iron shuts off transcription frmo operons and genes required for iron acquisition and utilization |
|
|
Term
| how does the presence of iron activate the operon repressor? |
|
Definition
| if iron is present --> will bind to the repressor and keep the repressor in its proper conformation necessary for it to keep repressing. iron absent? --> iron falls off receptor --> repressor assumes an improper/irregular shape --> repressor falls off the DNA |
|
|
Term
| describe the two-component regulation system via the example of bordetella pertussis |
|
Definition
| two proteins involved - BvgS (sensor protein, detects environmental changes in temp) and BvgA (DNA binding protein, functions as activator of the transcription of virulence genes). at 37 degrees --> BvgS autophosphorylates --> activates BvgA --> activates transcription of virulence genes |
|
|
Term
| what is an insertion sequence and what does it do? |
|
Definition
| small sequence containing a gene coding for a single enzyme (recombinase or transposase), which cuts DNA and allows it to come off and be moved somewhere else. bounded by inverted repeats. may result in extreme polar effects, constitutive gene expression, or inactivation and/or rearrangement of nearby genes (contributes to genetic plasticity) |
|
|
Term
| describe phase variation controlled by DNA inversion (salmonella flagella!) |
|
Definition
| flagellins H1 and H2 mutually exclusive. phase 2: H1 gene silenced by repressor protein (rh1) formed along with H2 flagellin. phase 1: inversion of DNA segment catalyzed by a recombinase (hin) encoded by it --> loss of promoter for H2 and the repressor for H1 --> H1 now expressed. (further inversions switch system back and forth between those two phases) |
|
|
Term
| describe class I (composite) transposons |
|
Definition
| genes flanked by 2 IS elements (genes can encode for drug resistance, etc.) ends of transposon can transpose separately. can be nonreplicative or replicative |
|
|
Term
| describe class II (complex) transposons |
|
Definition
| contain 1 or more genes within a single IS element. must transpose as a unit. (necessarily replicative) |
|
|
Term
| how does phase variation work? |
|
Definition
| an IS element in bacterial genome can flip its orientation by the recombinase (random) and can turn on or turn off a series of genes. (if protein subject is on the surface of the cell --> subject to antigenic selection ie. influenza with new epitopes all the time) |
|
|
Term
| for bacterial conjugation, what direction is the dna transferred to the recipient cell? and which secretion system is employed? |
|
Definition
| 5-->3 direction. type IV secretion system |
|
|
Term
| describe generalized transduction |
|
Definition
| occurs during the lytic phase of bacteriophage transduction. observed with bacterial viruses that dont completely degrade host DNA --> packaging of host DNA into viral capsids |
|
|
Term
| what's abortive transduction and what's the consequence/result? |
|
Definition
| when host DNA that was not efficiently broken down gets packaged into viral capsids --> infects another bacterial cell --> host DNA gets transferred but not integrated into new cell's DNA --> persists unreplicated for a few generations --> genetic info gets expressed in recipient cell --> formation of minute colonies under selective conditions |
|
|
Term
| describe specialized (restricted) transduction |
|
Definition
| occurs during the lysogenic phase of bacteriophage infection. (when conditions favor lysogenic state, phage DNA integrates into specific site in bac chromosome --> environmental conditions cause phage to excise its dna from host and enter lytic cycle) --> if excision not precise, bacterial DNA can be excised with the phage DNA --> if packaged into a capsid, that transducing particle may or may not be defective depending upon whether essential or non-essential phage genes were left behind |
|
|
Term
| type III secretion systems are widespread among gram____ bacteria? what processes do they facilitate? |
|
Definition
| gram NEG. allow bacteria to inject virulence proteins into cytosol of eukaryotic host cells. allow bacteria to invade non-phagocytic cells, inhibit phagocytosis, down/up regulate inflammatory response, induce apoptosis, modulate intracellular trafficking |
|
|
Term
| how do bacteria force non-phagocyte cells to phagocytose them? |
|
Definition
| gram NEG bacteria secrete invasin into eukaryotic host cell --> invasin makes change in cell surface (introduced by type III secretion system) --> invasins send in other materials to rearrange cellular actin --> cause changes to host cell cytoskeleton --> engulfment by host cell |
|
|
Term
| how does bacteria inhibit phagocytosis? |
|
Definition
| bacteria adheres to phagocyte by bundle forming pili --> secretes virulence factors into host cell (ie Tir) --> signal transduction --> actin recruitment --> rearranges cell surface into pedestals and actin brings Tir up to surface of pedstals so e coli can be more tightly bound --> pedestal formation inhibits phagocytosis |
|
|
Term
| explain the mechanics of flagella movement |
|
Definition
| related to type III secretion systems. drives its force by proton flow through proteins in the envelope --> counter clockwise rotation --> energy runs low --> motion stops and reverses (cell tumbles)--> new surge of energy? --> reversal to counterclockwise |
|
|
Term
| what are 3 ways bacteria can get iron from the host celL? |
|
Definition
| 1. release siderophores which bind to receptors on bacterial surface --> iron taken up by cell from lactoferrin/transferrin/ferritin/hemin 2. bacteria binds directly to cellular iron chelator proteins 3. bacteria excretes proteases that kill host cells --> iron released and available for uptake |
|
|
Term
| what are 2 ways LPS can be modified by pathogens to affect its interaction with complement? |
|
Definition
| 1. attachment of sialic acid residues to the LPS O antigen --> prevents formation of C3 convertase 2. LPS with long, intact O antigen side chains can prevent effective MAC killing |
|
|
Term
| how do bacteria "neutralize" antibodies? |
|
Definition
| some bacteria release soluble antigenic surface components (ie protein A) into surrounding fluids by gram NEG bacteria --> protein A in soluble form binds to Fc region of IgG --> agglutinate --> partially inactivates IgG. surface-bound protein A --> binds IgG in wrong orientation to exert its antibacterial activity (Fc region, not Fab) |
|
|
Term
| describe type I secretion system |
|
Definition
| 3 proteins form transmembrane channel, driven by ATP-binding cassette. proteins lack a signal peptide. |
|
|
Term
| describe type II secretion system |
|
Definition
| (2-step secretion) uses "general secretion pathway" to move proteins into periplasm --> protease cleaves N-terminus signal peptide upon transfer --> N-terminal signal sequence seen in periplasm --> step 2: 14 accessory proteins move secreted protein across the outer membrane. require ATP. |
|
|
Term
| describe type III secretion system |
|
Definition
| (for contact-dependent secretion) involves 20 proteins, including an ATP-binding protein and chaperone protein specific for each different protein to be secreted. --> direct injection of secreted protein into cytoplasm of mammalian host cell |
|
|
Term
| describe type IV secretion system |
|
Definition
| used to transfer DNA from donor cell to recipient cell during conjugation. plays crucial role in spread of antibiotic resistance genes |
|
|
Term
|
Definition
| auto-transporter - no helper protein required for translocation through outer membrane (secreted protein itself serves this function). is a 2-step system which requires the general secretion system |
|
|
Term
| endotoxin vs exotoxin - which is denatured by boiling? |
|
Definition
|
|
Term
| endotoxin vs exotoxin - which can be treated to form a toxoid? |
|
Definition
|
|
Term
| endotoxin vs exotoxin - which has a higher degree of specificity? |
|
Definition
|
|
Term
| endotoxin vs exotoxin - which one is more pyrogenic? |
|
Definition
|
|
Term
| where are the genes for exotoxins usually found? |
|
Definition
| plasmids or temperate phages (can be mobilized to nontoxigenic bacteria) |
|
|
Term
| give a few examples of exotoxins that work outside the cell (not intrinsically toxic). |
|
Definition
| hyaluronidase, collagenase, DNAase, streptokinase, fibrinolysin, coagulase |
|
|
Term
| give 2 examples of exotoxins that work on the cell surface. |
|
Definition
| lipases, pore-forming toxins |
|
|
Term
| describe the mechanism of lipase exotoxins (via example of lecithinase or alpha toxin) |
|
Definition
| intended to lyse phagocytic cells and increase the availability of nutrients to bacteria. cleaves the hydrophilic head of lipid membrane components --> destabilizes the membrane --> membrane rupture. at high concentrations, alpha toxin --> massive degradation of phosphatidylcholine --> membrane disruption. small amounts of toxin --> limited hydrolysis of phosphatidylcholine (generate diacylglycerol) --> signals transduction pathways leading to uncontrolled production of cellular mediators (adhesion molecues, IL8, TNFa, platelet-activating factor..all of which contribute to increased vascular permeability and edema) |
|
|
Term
| describe mechanism of pore-forming toxin action |
|
Definition
| toxins bind to cell surface --> oligomerize to form a pore (homogeneous vs heterogenous) --> pore partially inserts into cytoplasmic membrane --> depletion of ions and metabolites --> allow H20 to enter cell --> cell bursts |
|
|
Term
| describe the mechanism of toxins that act inside the cell |
|
Definition
| A-B toxins. (can be on same polypeptide or on 2 different ones bridged by disulfide bonds). B moiety gets the toxin bound to and taken up by the cell --> A moiety activated by proteolytic cleavage or reduction of disulfide bridges --> act as ADP phosphoribosyltransferases, transfer ADP from NAD to a particular target protein in cell --> kill target cell or elevate/depress normal cell function w/o killing the target cell --> can move onto another host cell |
|
|
Term
| describe how the diptheria toxin gets into a cell and what it does inside the cell |
|
Definition
| (max levels of toxin when iron levels low) B component binds to specific receptors and cleaved into A and B portions, which remain associated via disulfide linkages --> endocytosis --> A component released by reduction of disulfide linkage by the acidification of the cell interior --> toxin acts upon EF-2 via ADP ribosylation of a modified histine residue (EF-2 is a GTP hydrolase required for ribosomal translocation)--> EF-2 modification inhibits protein synthesis --> local tissue necrosis |
|
|
Term
| describe the pathophysiology of diptheria exotoxin action (ie what happens after cell protein synthesis is inhibited and tissue becomes necrotic) |
|
Definition
| affects superficial layers of skin lesions or usually respiratory mucosa. dense necrotic coagulum forms gray-brown adherent pseudomembrane (removal difficult and reveals bleeding submucosa)-->paralysis of palate and hypopharynx. toxin absorption can lead to kidney tubule necrosis, thrombocytopenia, cardiomyopathy and demyelination of nerves. |
|
|
Term
| describe the cellular mechanism of cholera toxin |
|
Definition
| drink contaminated water --> vibrio comes into contact with gut --> B unit binds with high affinity to GMI ganglioside (contact type III secretion) --> toxin-GMI complex forms --> conformational alteration of holotixn allows presentation of A subunit to cell surface --> A component taken up via endocytic vesicles--> A component finds G protein on cAMP kinase system and ribosylates it(inactivates it, locking adenylate cyclase in "on" mode) --> uncontrolled release of cAMP --> epithelial cells move large amt of fluid across intestinal membrane into gut lumen |
|
|
Term
| describe the cellular mechanism of tetanus toxin action |
|
Definition
| wound contamination by bacterial spores --> spread through lymphatics and vascular system --> enter myoneuronal junctions by binding to ganglioside receptors and getting internalized --> migrates thru CNS by retrograde axonal transport --> B chains bind specific receptors on neuron membranes and A chain is the zinc endopepsidase --> cleaves synaptobrevin (on the vesicle, forms assoc w/SNAP & syntaxin on membrane surface and cause vesicle to come down to membrane and fuse and release) --> no assoc of vesicle with membrane --> no release of inhibitory neurotransmitters (GABA and Gly) --> generalized contraction/rigid paralysis |
|
|
Term
| describe the cellular mechanism of botulinum toxin |
|
Definition
| disease results from ingestion of the toxin (true intoxication) --> once across the gut toxin carried in the blood to neuromuscular junctions --> binds to ganglioside receptors and is taken up --> toxin causes presynaptic block by cleaving synaptobrevin and/or syntaxin or snap --> blocks release of acetylcholine --> irreversible flaccid paralysis (death thru respiratory arrest) |
|
|
Term
| what is the basic structure of the anthrax toxin? |
|
Definition
| AB toxin. single B subunit (protective antigen) and 2 alternative A subunits (edema factor and lethal factor) |
|
|
Term
| 4 structural domains of anthrax toxin B subunit (PA or protective antigen) |
|
Definition
| domain 1 - proteolytic activation site; domain 2 - B-barrel core containing large flexible loop for pore formation; domain 3 - involved in heptamer formation; domain 4 - binds to anthrax toxin receptor |
|
|
Term
| 4 domains of anthrax toxin's lethal factor LF (one of the A subunits) |
|
Definition
| domain 1 - PA binding domain; domain 2 - forms binding pocket for substrate peptide; domain 3 - restricts access to binding pocket; domain 4 - catalytic center |
|
|
Term
| what does EF (edema factor) of the anthrax toxin do? |
|
Definition
| calcium-calmodulin dependent adenylate cyclcase that causes dramatic increases in intracellular concentrations of cAMP |
|
|
Term
| what does LF (lethal factor) of the anthrax toxin do? |
|
Definition
| zinc-dependent protease, cleaves mitogen-activated protein kinase kinases in amino-terminal regions. early in infection suppresses immune cell and cytokine responses --> promoting bacterial outgrowth. later in disease induces cytokine independent shock-like death associated with anthrax. |
|
|
Term
| how is anthrax toxin introduced into the cell? |
|
Definition
| PA (B component) binds to cell surface anthrax toxin receptor --> PA cleaved by furin or furin-like protease into PA20 (amino terminal) and PA63 (receptor-bound carboxy terminal) --> PA63 internalized and directed to endosomes --> low pH in endosome induces conformational change in PA63 heptamer --> formation of cation-selective channel --> translocation of EF and/or LF across endosomal membrane |
|
|
Term
| describe the cellular mechanism of the shigella toxin |
|
Definition
| A subunit and 5 molecules of B subunit. B subunits bind to G3b (component of cell membrane) --> enters cell --> A subunit modifies 28s ribosomal RNA and inactivates protein synthesis --> cell death (toxin acts on vascular endothelium --> breakdown of lining --> hemorrhage) first response = bloody diarrhea. effective in GI tract, kidney and lungs |
|
|
Term
| how does LPS alert the body to the presence of gram-negative organisms? |
|
Definition
| sets off series of alarm reactions. fever (via release of IL-1 and TNF by mononuclear phagocytes), activation of complement (via alternate pathway, and anaphylatoxins result in vasodilation and inflammation), activation of macrophages, stimulation of B-lymphocytes (at high concentrations can induce shock and disseminated vascular coagulation) |
|
|
Term
| what are the 2 stages of pertussus infection? |
|
Definition
| catarrhal stage (nonspecific cold-like symptos, very contagious, organism present in high concentrations in URT secretions, easily identifiable via culture) and paroxysmal stage (more severe and frequent bouts of coughing, organism concentration dramatically decreased, coughing interferes w/normal breathing can cause hypoxia, seizures, coma, vomiting, weight loss) |
|
|
Term
| how do we test for bordetella pertussis? |
|
Definition
| need to plate on growth medium specifically formulated for b. pertussis (fastidious) during catarrhal stage. no test or culture is sensitive during paroxysmal stage therefore must suspect it clinically and order specific tests early on. serology useful in hindsight. |
|
|
Term
| what treatment do we administer for pertussis? |
|
Definition
| tx helps shorten period of transmission. erythromycin, macrolides, doxycycline, sulfonamides. problem with tx is that damage to respiratory epithelium is irreversible until epithelium regenerates so clearing of the infection doesnt do much about the damage or the sx. |
|
|
Term
| how does b. pertussis cause a cough? |
|
Definition
| b. pertussis has tropism for ciliated respiratory epithelium --> binds to and disables ciliary motion --> failure to properly clear respiratory secretions and also kills epithelial cells |
|
|
Term
| how do the bacterial toxins pertussigen and invasive adenylate cyclase work in pertussis? |
|
Definition
| pertussigen is AB toxin. on cell surface of bacterial cells serves as adhesion to tracheal epithelium. can induce lymphocytosis and interferes w/normal functions of phagocytes, lymphocytes, and tracheal epithelial cells --> epithelial damage, mucous accumulation, blunting of immune response. toxin is an ADP ribosylase, ribosylates inhibitory G-protein which normally deactivates adenylate cyclase --> cAMP accumulates --> different effects in different cell types |
|
|
Term
| what does tracheal cytotoxin do in pertussis? |
|
Definition
| decreases ciliary function and in high enough doses induces epithelial cell production of proinflammatory mediators (IL-1 and NO) that contribute to killing epithelial cells |
|
|
Term
| what does dermonecrotic toxin do in pertussis? |
|
Definition
| vasoconstrictive effects. inactivates rho-GTPase, resulting in constitutive signaling by rho GTP-binding protein. helps kill epithelial cells |
|
|
Term
| what does filamentous hemagglutinin do in pertussis? |
|
Definition
| lipo-oligosac. func as adhesins together with surface-bound pertussis toxin. bacteria binds to cells with both adhesins --> adhesins x-link cilia --> mechanically disable cilia and disable effective mucous clearance |
|
|
Term
| what is the main branch of immune sys responsible for recovery from infection of pertussis? |
|
Definition
| humoral immunity. ab titer rises with decline of recoverable bacteria on mucosal surface. |
|
|
Term
| what are the 3 mycoplasmal species that are unambiguously associated with human disease? |
|
Definition
| mycoplasma pneumoniae (primary atypical pneumonia); mycoplasma hominis (PID, pyelonephritis); ureaplasma urealyticum (NGU) |
|
|
Term
| compare primary atypical (mycoplasma) pneumonia to classical lobar (strep) pneumonia |
|
Definition
| classical - looks like alveolar infection with whole lobe consolidation (on xrays), respiratory complaint = chief compaint. atypical - inflammatory infiltrate of parenchyma has patchy appearance on xrays, much less of a severe infection, more likely see general systemic illness complaints |
|
|
Term
| what causes the cough in primary atypical pneumonia? |
|
Definition
| inhibition of ciliary function--> poor mucous clearance --> cough. no specific inhibitory toxins have been identified, but evidence for ciliary toxicity of bacterial metabolic products such as hydrogen peroxide. little structural damage to epithelium. |
|
|
Term
| how helpful is tx with antibiotics for atypical pneumonia? |
|
Definition
| without tx, infection is self-limited, resolves gradually over several weeks. with tx (macrolides, tetracyclines) can shorten sx, but does not result in faster clearance of organism from body bc they multiply intracellularly. |
|
|
Term
| what are cold agglutins and how do we test for them? |
|
Definition
| common autoimmune mechanism symptomatic of atypical pneumonia. formulation of auto-ab against patient's RBC. draw blood and anticoagulate and refridgerate --> agglutination (reversible, if we warm blood back up, will go back into suspension) can cause hemolytic anemia |
|
|
Term
| give some examples of how sx in mycoplasma pneumonia moreso come from host immune system than bac toxins. |
|
Definition
| no toxins identified. rash and polyurithritis (d/t circulating IC and type 3 hypersensitivity rxn); auto-immune like phenomena aka cold agglutins, hemolytic anemia (bacteria mimic host proteins aka they share epitopes, so we accidentally mount our IR against self-proteins thinking theyre bacterial) |
|
|
Term
|
Definition
|
|
Term
| staphylococci metabolism? |
|
Definition
|
|
Term
|
Definition
| anaerobic spore-forming bacilli |
|
|
Term
| 3 ways to distinguish strep species from one another? |
|
Definition
| 1. lancefield groups (group carbohydrate antigens - primarily for subtyping of beta-hemolytic streptococci) 2. hemolysins (B, A) 3. antigenic specificity of M protein for subtyping of group A streptococci (virulence factor involved in resistance to opsonization) |
|
|
Term
| where do the endospores for clostridium form? |
|
Definition
| fecally-contaminated soil - major constituent of flora of some farm animals (only minor constituent of normal human flora) |
|
|
Term
| are streptococci hardy or fastidious? what do they require to grow? |
|
Definition
| fastidious. require blood agar and elevated atmospheric CO2 |
|
|
Term
| how do we differentiate between enterococci and streptococci in lab? |
|
Definition
| enterococci are hardier organisms and can tolerate high salt. bile salt can be used to differentiate them in lab. |
|
|
Term
| how is pneumococci classified from other streptococci? |
|
Definition
| presence of capsular polysac antigens --> pneumococci |
|
|
Term
| what are some common infections of skin and throat caused by strep pyogenes? |
|
Definition
| impetigo, pyoderma, pharyngitis (strep throat) |
|
|
Term
| what are systemic toxinoses caused by strep pyogenes? |
|
Definition
| scarlet fever, streptococcal toxic shock-like syndrome |
|
|
Term
| what are some autoimmune sequelae caused by strep pyogenes? |
|
Definition
| acute rheumatic fever, post-streptococcal glomerulonephritis |
|
|
Term
| what are 3 ways streptococcus can infect deep tissue? |
|
Definition
| 1. cellulitis of deeper tissue can result from extension of superficial skin infections (impetigo) --> erysipelas, myosistis 2. cellulitis of deeper tissue by inoculation by puncture wound 3. hematogenous spread (presumably from throat) after blunt trauma to affected area that injures muscle w/o penetrating skin (changes in circulation and/or vascular permeability favor colonization by circulating bacteria) |
|
|
Term
| what are the main IR players in resolution of streptococcal infections? |
|
Definition
| phagocytosis - ability to make opsonizing antibody and to activate complement (thick cell wall of gram + organisms makes strep naturally resistant to complement MAC) and field phagocytes. specific humoral immunity (esp to M protein) promotes opsonization and provides relative protection. |
|
|
Term
| what are the 3 most important virulence mechanisms for strep? |
|
Definition
| 1. adherence to epithelia 2. elaboration of locally acting exotoxins 3. toxin-mediated and non-toxin mediated evasion of phagocytes |
|
|
Term
| what are strep's major adherence proteins? |
|
Definition
| protein F (key adhesin) binds to fibronectin (ubiquitous extracellular matrix protein). antibodies against protein M block mucosa adherence, but only bc these ab sterically block the protein F pilus while bound to the M protein pilus. lipoteichoic acid cooperates in adherence also. |
|
|
Term
| what do streptolysin O and S do to increase strep virulence? |
|
Definition
| cytolytic toxins. (streptolysin O = oxygen labile, diffusible porin; streptolysin S = oxygen stable, bound to bacterial cell surface) general cytotoxins, lyse tissue cells and immunocytes (leukocidins) these are the hemolysins that make strep B-hemolytic |
|
|
Term
| what does streptokinase do to promote strep virulence? |
|
Definition
| cleaves plasminogen to plasmin (plasmin is fibrinolytic) --> counteracts IR deposition of fibrin which otherwise would lead to walled-off abscesses --> makes strep a spreading infection |
|
|
Term
| what does hyaluronidase do to promote the bacterial virulence of strep? |
|
Definition
| classic "spreading factor" digests extracellular matrix of connective tissue and contributes to spread of infection along tissue planes |
|
|
Term
| how does DNAase promote bacterial virulence in strep? |
|
Definition
| pus is viscous bc released genomic DNA of lysed neutrophils and immunocytes has high molecular weight --> DNAase attacks/nicks DNA --> decreases viscosity --> bacteria can move more easily through pus (otherwise trapped for WBC attack) |
|
|
Term
| when is retrospective seradiagnosis useful? |
|
Definition
| when you're worried about sequelae after infection is over (i.e. in strep we worry about glomerulonephritis and rheumatic fever) |
|
|
Term
| why is phagocytosis the main defense against strep? |
|
Definition
| thick gram+ cell wall makes it resistant to complement MAC. phagocytosis is dependent on alternate pathway of complement or classical pathway + specific abs. strep has not evolved mechanisms for intracellular survival and is rapidly killed after phagocytosis by neutrophils or macrophages. |
|
|
Term
| what are strep's means of avoiding phagocytosis? |
|
Definition
| 1. avoid trapping in an abscess 2. capsules (dubious importance) 3. M protein 4. c5a peptidase 5. protein G 6. superantigen exotoxins |
|
|
Term
| how does c5a peptidase help strep avoid phagocytes? |
|
Definition
| it inactivates phagocyte binding of c5a, which would otherwise strongly activate the phagocytes for binding and phagocytosis of c3b coated bacteria |
|
|
Term
| how does M protein help strep avoid phagocytosis? |
|
Definition
| M protein binds and locally concentrates factor H, soluble negative regulator of the alternate pathway C3 convertase --> inhibits deposition of major opsonin C3b on cell surface. (mimics natural binding of factor H to host cells to protect them from alternate complement lysis) destruction of bacteria by classical pathway and specific abs still works though! |
|
|
Term
| how does protein G help strep avoid phagocytosis? |
|
Definition
| protein G is a surface Fc receptor. thought to cloak the bacterial surface in self-antigens and sterically block immunogenic or effector functions of immune recognition |
|
|
Term
| what are the systemic toxins of strep pyogenes and what do they do? |
|
Definition
| streptococcal pyrogenic exotoxin A-E (erythrogenic toxin)--> induce lymphocytes to release inflammatory lymphokines (TNFa, IL1, IL6) --> fever, vasodilation via NO, vascular permeabilization, coagulation |
|
|
Term
| how do the streptococcal pyrogenic exotoxins (spes) induce lymphokine production? |
|
Definition
| they function as superantigens --> immediate strong general stimulation of immune system --> depletes components necessary for optimal specific IR, leads to a lot of pointless systemic inflammation --> immune paralysis. superantigens also synergize with polyclonal activators acting through other receptors like LPS from intestinal flora (LPS directly stimulate monocytes and macs to release inflammatory mediators) |
|
|
Term
|
Definition
| confluent red macular rash of trunk that may spread to extremities, with fever, occuring in the course of strep throat |
|
|
Term
| sx of streptococcal toxic shock like syndrome? |
|
Definition
| sudden onset in the course of an invasive infection with bacteremia --> fever, profound hypovolemic shock secondary to vasodilation and capillary leakage --> multisystem failure |
|
|
Term
| what does the frequency, manifestation, and severity of systemic strep pyogenes toxinosis depend on? |
|
Definition
| what spes and M proteins are present together in the strains infecting a given population and the degree of immunity to those proteins that are present in the population |
|
|
Term
| discuss how someone comes to have acute rheumatic fever after having a resolved strep infection and what the sx are. |
|
Definition
| occurs several weeks after acute group A strep inf (usually strep throat) --> multisystemic inflammatory disorder affecting joints, skin, blood vessels, NS, heart - myocardial damage, permanent valvular defects. only appears after infections with a subset of M protein subtypes, some of which have been shown to cross-react with cardiac epitopes (type II hypersensitivity) --> x-reactive immune response to self |
|
|
Term
| discuss post-strep glomerulonephritis |
|
Definition
| occurs really quickly after group A strep inf (usually after skin inf) --> manifests as acute renal insufficiency --> resolves completely (may progress to chronic renal disease in adult pts). limited to certain M protein subtypes (nephritogenic strains). probably d/t immune complex disease (type III hypersensitivity) |
|
|
Term
| what is the significance of strep bovis (group d)? |
|
Definition
| found in blood cultures taken from febrile patients, statistically assoc with concurrent colon carcinoma (should prompt a search for it) |
|
|
Term
| what do enterococci most commonly cause? |
|
Definition
| autoinfectious UTI, and in compromised patients, major threat for generalized sepsis (major normal flora of bowel) |
|
|
Term
| subclassification of staph aureus strains is done by? |
|
Definition
| phage typing - members of diff phage groups are susceptible to inf by diff spectra of bacteriophages |
|
|
Term
| what are the systemic toxinoses of staph aureus? |
|
Definition
| toxic shock syndrome, scalded skin syndrome, and staph food poisoning |
|
|
Term
| what do alpha, beta, gamma, and delta hemolysins do to promote staph aureus virulence |
|
Definition
| lyse RBC, are cytotoxins, allow spread through tissue and kill immunocytes (alpha hemolysin is staph aureus's most important virulence factor) |
|
|
Term
| how does coagulase toxin contribute to staph aureus virulence |
|
Definition
| promotes deposition of fibrin to form abscess wall (denies access to IR) |
|
|
Term
| how does staph aureus survive IR? |
|
Definition
| can survive in and possibly kill phagocytes, surface protein A binds Fc portion of host ab molecules --> coats surface of bcteria with self-antigens --> cloaks bacteria against immune recognition; teichoic acid = soluble decomplementation antigen, results in local depletion of early complement components |
|
|
Term
| describe the systemic exotoxin exfoliatin |
|
Definition
| promotes exfoliation in scalded skin syndrome by weakening the cell-cell adhesions between epidermal cells (also pyrogenic, might be superantigens) |
|
|
Term
| describe the systemic toxin enterotoxin (for staph aureus) |
|
Definition
| dual mode of action: increase fluid secretion in small int --> diarrhea. act on vomiting center in brain via small bowel neural receptors, have superantigen activity |
|
|
Term
| describe pyrogenic exotoxins (systemic toxin of staph aureus) |
|
Definition
| act by superantigen mechanism, includes toxic shock syndrom toxin 1 (causes fever, vasodilation, shock in extreme cases) |
|
|
Term
| what is clostridia's characteristic pattern of metabolic rxn? |
|
Definition
| hemolytic, produces frothy, foul-smelling cultures in liquid media --> copious production of gases as fermentation product = virulence factor bc gas released physicall disrupts tissue |
|
|
Term
| what is clostridia's major locally acting toxin? |
|
Definition
| alpha-hemolysin (lecithinase, phospholipase C) --> splits phosphatidylcholine in cell membranes --> disrupts the membrane |
|
|
Term
| describe how we can become infected by clostridium difficile |
|
Definition
| causes pseudomembranous colitis, frequently serious and sometimes fatal complication of antibiotic therapy. (normal intestinal flora, can overgrow and cause disease when high percentage of competing flora are killed by antibiotic to which cl. difficle is resistant) |
|
|
Term
| briefly describe some characteristics of rickettsiae. (staining? method of reproduction? means of obtaining atp? how spread? what 3 diseases do they cause?) |
|
Definition
| do not stain positive or negative by grams stain; reproduce by binary fission; can generate ATP from their own metabolism but also have systems for import of host cytosolic ATP; are zoonotic and spread by vectors; cause epidemic typhus, rocky mountain spotted fever, ehrlichiosis; mostly responsible for chronic, indolent infections (not acute) |
|
|
Term
| how is the typical rickettsiae infection initiated and carried out on the cellular level? (typical as in not ehrlichosis) |
|
Definition
| inf initiated at site of vector bite --> rickettsiae invade endothelial cells by induced phagocytosis --> replicate locally for extended incubation period --> once inside cell, induce lysis of phagosome and replicate in the cytoplasmic compartment --> escape from phagosome by gross or localized cell membrane lysis --> eventual seeding of endothelium at distant sites with sx production |
|
|
Term
| explain why we might see an eschar at the site of local replication |
|
Definition
| intracytoplasmic multiplication --> presentation of rickettsial antigens on class I MHC --> acute necrotic response mediated by cytotoxic T lymphocytes --> formation of black necrotic scab |
|
|
Term
| what ticks transmit rocky mountain spotted fever? |
|
Definition
| hard ticks - wood tick in the west and the dog tick dermacentor in the east |
|
|
Term
| describe how rocky mountain spotted fever progresses from local infection to whole body |
|
Definition
| tick bite --> local multiplication with eschar formation --> cell to cell spread via filopodia (local cell membrane lysis) --> hematogenous spread to whole body. |
|
|
Term
| what are the sx of rocky mountain spoted fever? |
|
Definition
| sx referable to vascular damage: rash (distal to axial, extends to palms and soles; macular at first from vasodilation then petechial from capillary leak), fever, altered mental status, cardiac arrhythmias, ..... |
|
|
Term
| what is mortality rate and cause in rocky mountain spotted fever? what is the going tx?? |
|
Definition
| 25% untx'd, from organ failure and shock. doxycycline |
|
|
Term
| how is epidemic typhus spread? |
|
Definition
| (all rickettsiae inf are dead-end in humans, except this one) rickettsia prowazeckii, spread human to human thru feces of the body louse which gets scratched into skin. |
|
|
Term
| describe the sx of epidemic typhus |
|
Definition
| no eschar, rash (macular or papular, sometimes petechial; rash axial to distal and palms and soles spared); vasculitic nodules can occlude small vessels resulting in distal gangrene of digits, nose or ears; fever; severe headache; CNS sx (lethargy, coma) |
|
|
Term
|
Definition
| occasionally, after typhus inf, clinical latency and disease may return years to decades later |
|
|
Term
| what 2 species are responsible for ehrlichosis |
|
Definition
| ehrlichia chaffeensis (mainly infects monocytes and macrophages) and anaplasma phagocytophilia (mainly infects neutrophils) |
|
|
Term
| what are the ticks that transmit e. chaffeensis and a. phagocytophilia? |
|
Definition
| e.chaffeensis = lone star tick; a.phagocytophilia = ixodes tick |
|
|
Term
| what makes ehrlichosis inf different from RMSF or typhus? |
|
Definition
| infections take place in the endosomal compartment of the infected WBC (vs in the cytosol) |
|
|
Term
|
Definition
| similar to other rickettsiae, but no rash. multi-system sx |
|
|
Term
| describe the cell wall of chlamydiae |
|
Definition
| modified gram-negative cell envelope. inner and outer cytoplasmic membrane, outer membrane with LPS, but with peptidoglycan replaced by a proteinaceous matrix |
|
|
Term
| describe chlamydiae's 2 stage developmental cycle |
|
Definition
| 1. elementary body - non-growing, metabolically inert, relatively hardy extracellular stage. binds to variety of normal cell surface proteins that act as receptors for receptor-mediated endocytosis. after endocytosis --> EB prevents acidification of endocytic vesicle and fusion with lysosomes --> EB undergoes transition into reticulate body! 2. reticulate body - grows and divides like any other bacterial cell. form proteinaceous tubular structures that cross vesicle membrane and connect chlamydial and host cytoplasms, permitting direct import of host cell ATP and metabolites. hundreds of RBs accumulate, host cell deteriorates from depletion of nutritional supply, RBs develop into EBs that escape from the cell |
|
|
Term
| what are the 3 major chlamydial pathogens |
|
Definition
| chlamydia trachomatis, chlamydophilia pneumoniae, and chlamydophilia psittaci |
|
|
Term
| what are 3 conditions associated with chlamydia trachomatis |
|
Definition
| 1. NGU (chlamydia) an exudative instead of ulcerative std 2. lymphogranuloma venereum - an ulcerative std assoc with massive lymphadenopathy 3. trachoma - chronic conjunctivitis, frequently leads to blindness |
|
|
Term
| what is the result of perinatal transmission of chlamydia? |
|
Definition
| baby gets pneumonia or conjunctivitis |
|
|
Term
| chlamydial NGU is the most frequent trigger for what? |
|
Definition
| reactive arthritis, an autoimmune sequelae |
|
|
Term
| what are the sx of chlamydophilia pneumoniae? |
|
Definition
| frequent cause of atypical pneumonia and URT inf. long incubation, dry cough, variably fever, confined to airways, no peripheral leukocytosis, infiltrates (minor, lower lobe, no lobar consolidation) |
|
|
Term
| what is the usual clinical presentation of chlamydophilia psittaci? |
|
Definition
| atypical pneumonia, from birds remember. |
|
|
Term
| what are 2 examples of diseases caused by legionella pneumophilia? |
|
Definition
| legionnaires disease and pontiac fever |
|
|
Term
| how are legionella diseases spread? |
|
Definition
| fastidious gamma proteobacterium, parasitizes several common aquatic amoebae and is acquired by inhalation or aspiration of water droplets containing them. outbreaks assoc with heating and cooling systems, more common in hot than cold water supplies, shower heads, supermarket produce misters(no person to person spread, just common source spread) common nosocomial infection |
|
|
Term
| how do legionellae get into cells and how do they multiply? |
|
Definition
| phagocytosed by macrophages using either C3 or Fc receptors --> products of their dot genes prevent phagosome-lysosome fusion --> multiply to high # within endosome --> escape as cell disintegrates |
|
|
Term
| where does the pathology in legionallae diseases come from? |
|
Definition
| results from inflammatory and immune responses to the infection - macrophages activated to kill or inhibit them via TH1 lymphocytes in immune individuals or to a lesser extent by TNF alpha produced in the inflammatory response in pre-immune individuals |
|
|
Term
| what are some clinical sx of legionellae diseases? |
|
Definition
| sx mimick pneumococcal pneumonia to some extent: lobar consolidation, alveolitis. nonspecific febrile influenza-like illness. point of distinction: frequent extrapulm sx affecting CNS (delirium, coma) or GI system (diarrhea). |
|
|
Term
| how do we diagnose legionallae disease? |
|
Definition
| best way: urine antigen detection. can plate on culture but must plate with charcoal to absorb growth inhibitors; can be visualized in sputum samples as faintly staining gram-negative coccobacilli |
|
|
Term
| what kind of drugs are used to tx legionallae? |
|
Definition
| drugs with good cell penetration i.e. macrolides, fluoroquinolones, tetracyclnes, sulfonamides, rifampin. not clinically responsive to beta-lactams bc poor cell penetration |
|
|
Term
| listeria monocytogenes, how do we get it? who is this most hazardous to? |
|
Definition
| acquired by eating uncooked food, esp refridgerated food like pate, milk, soft cheeses, deli meats, coleslaw. unusual capacity for growing at cold temps and resists moderate heating (ie pasteurization). most hazardous to immunocompromised adults and pregnant women |
|
|
Term
| how are listeria taken up by cells and how do they multiply/replicate? |
|
Definition
| complement-opsonized listeriae phagocytized in GI tract by macrophages via c3 receptors --> TH1 activated macrophages kill the bacteria, but in other cells bacteria lyse the primary phagosome using listeriolysin and phospholipase and escape into the cytoplasm --> multiply in cytoplasm, secrete ActA protein at one bacterial pole --> organize cellular actin into polar "tails" that provide them with intracellular motility and ability to push out filopoida in cytoplasmic membrane and break through into neighboring cells (rocket motility) --> initiate new round of intracellular multiplication |
|
|
Term
| what are the local and distant sx of listeriosis? |
|
Definition
| influenza-like sx (fever, myalgia), diarrhea. spread to CNS (meningitis, encephalitis, brain abscess) or joints and bones, lungs. |
|
|
Term
| what happens to pregnant women and their babies who are infected with listeria? |
|
Definition
| infection of placenta --> miscarriage or premature delivery or systemic inf of fetus w/disseminated abscesses or granulomas. perinatal inf --> neonatal meningitis. 3rd trimester is greatest risk bc increasing immunosuppression. |
|
|
Term
| how do we diagnose listeria monocytogenes? |
|
Definition
| readily gram stained and grows on routine media. |
|
|
Term
| how do we treat listeriosis? |
|
Definition
| gram +, so susceptible to beta-lactam antibiotics (pcn, etc) |
|
|
Term
| what is the organism that causes Q fever and what is the mechanism it uses to get into cells and how does it replicate once there? |
|
Definition
| Coxiella Burnetti. infects macrophages by phagocytosis, permits phagosome-lysosome fusion, persists in the acidified phagolysosome. |
|
|
Term
| how is coxiella burnetti spread? |
|
Definition
| zoonotic infection, primarily of livestock (sheep). high concentration in infected animal tissues, body fluids. is hardier and can be spread by inhalation or tick bites. largely an occupational disease, affecting farmers, vets, and lab workers. |
|
|
Term
| describe the 2 cell variants in coxiella burnetti development |
|
Definition
| large cell variant (actively dividing) and small cell variant (resting, hardy, accounts for its environmental persistance) |
|
|
Term
| describe the sx of q fever (c. burnetti) |
|
Definition
| multiple organ systems affected. elicits granulomatous host response. pathophysiology mostly immune-mediated. asymptomatic to influenza-like, self limiting. development of chronic infection (can manifest as endocarditis) is serious and results from granuloma formation and immune complex deposition |
|
|
Term
| how do we come into contact with brucellosis? |
|
Definition
|
|
Term
| what is the intracellular mechanism of replication for brucellosis? |
|
Definition
| get phagocytized by macrophages, prevent phagosome-lysosome fusion, grow in phagosome, produce granulomatous reactions --> infected macrophages carry the pathogen to 2ndary lymphoid tissue and thence to all organ systems |
|
|
Term
| what are the 4 cardinal signs of acute inflammation? |
|
Definition
| redness (d/t congestion/vasodilation); warmth (d/t congestion/vasodilation); swelling (d/t edema/increased vascular permeability); pain (d/t chemicals? stretched nn?) |
|
|
Term
| what happens in the general response to injury? (when sublethal injury is serious enough) |
|
Definition
| mediators that are produced and act locally are in such great quantity (IL1, IL6, TNF alpha) --> into blood stream --> go to 1. liver --> induce liver to produce acute phase proteins (fibrinogen, c reactive protein, and serum amyloid protein); 2. go to the hypothalamus to thermal regulatory center to induce production of prostaglandin E2 --> sets thermic center temperature higher --> fever and 3. go to bone marrow to chase out sequestered neutrophils --> leukocytosis. also activate colony stimulating factors so leukocytes can be sustained |
|
|
Term
| what causes early permeability in inflammation? |
|
Definition
| histamine release (venules first to be affected. cause exudation as they dilate) |
|
|
Term
| what causes late permeability in inflammation? |
|
Definition
| clotting factor XII is activated --> activates PKA --> activates kalligreinogen --> cleaved into kallikrein --> made into kininogen --> made into kinins (bradykinin) --> late permeability (capillary damage, mediated by prostaglandin E) |
|
|
Term
| during inflammation, describe the process of neutrophils leaving the blood stream to travel to site of injury. |
|
Definition
| after stasis of laminar blood flow (caused by edema) --> neutrophils marginalize, adhere to selectins which are expressed both on the leukocyte and on the endothelium (only on endothelium when there's injury - IL1, IL6 and TNFa activate endothelium so these selectins are exposed) --> roll along selectins --> bind to integrins and become stuck --> migrate toward endothelial gaps --> neutrophils are then under the influence of chemoattractants |
|
|
Term
| how is necrosis brought about in foreign body caseating granulomas? |
|
Definition
| toxic irritant phagocytized --> toxic to macrophages, so rip up phagocytic membrane --> release enzymes into cytoplasm --> kill cell --> cell releases powerful enzymes into the environment --> necrosis |
|
|
Term
| how do phagocytes kill pathogens that are adapted to survive in the phagosome or lysosome? |
|
Definition
| 1. everytime macrophage phagocytizes, undergoes respiratory burst --> rapid uptake of O2 and in presence of oxidase --> forms superoxide anion and H202 --> radical acts on organism, kills it. 2. myeloperoxidase - enzyme that, when in contact with H202 and a halide --> form H202-myeloperoxidase-halide-system --> hyperchloride/chloox = powerful antibac |
|
|
Term
|
Definition
| large # of dead and dying neutrophils, copious amounts of fibrin, necrotic debris, in an area of liquefactive necrosis (neutrophils get there, die, release enzymes, liquefy area) |
|
|
Term
| what happens when tissue cannot regenerate after acute inflammation (aka how do scars form)? |
|
Definition
| ingrowth of granulation tissue from the viable margins to replace the destroyed non-regenerating parenchyma. (starts in periphery and works its way into the abscess) mediated by vascular endothelial growth factors. when the vessels form, no tight junctions, so edema is common. granulation tissue = proliferating new capillaries and fibroblasts --> fibroblasts secrete collagen --> collagen shrinks and squeezes out capillaries and fibroblast nuclei --> left with avascular, acellular fibrosis/scar |
|
|
Term
| what are the causes of chronic inflammation? |
|
Definition
| when abscess does not heal properly, nondigestible persistant irritant (i.e. silica, TB), autoimmune rxn (where ag exits forever), persistent or repetitive injury, infection by resistant microbes |
|
|
Term
| macrophages are the distinguishing cells in chronic inflammation. what are their 2 main roles? |
|
Definition
| 1. activated macrophages act as key scavenger cells, remove necrotic tissue 2. contribute to tissue destruction at sites of inflammation and stimulate repair and fibrosis through their release of growth factors and cytokines |
|
|
Term
|
Definition
| focal, localized, circumscribed aggregate of macrophages or their transformed derivatives, the epithelioid cells, in solid tissue or highly confined space |
|
|
Term
| what is an immune granuloma and how do we get necrosis? |
|
Definition
| the antigenic components of the irritant (intracellular pathogen) evoke a vigorous cell-mediated IR. the immune (hypersensitivity) response --> local production of cytokines --> attract large numbers of macrophages and activates them --> upon dying these macrophages spill their cytokine-activated powerful lysosomal enzymes into surrounding tissues --> conspicuous necrosis |
|
|
Term
| what are non-caseating granulomas? |
|
Definition
| foreign substance inside that are not toxic nor antigenic. necrosis not seen. no collections of lymphocytes or plasma cells. granulomas are pure macrophagic granulomas. |
|
|
Term
| leukocyte rolling, what proteins/molecules are involved? |
|
Definition
| P and E selectins on endothelium, sialylated lewis X (oligosac) on neutrophil |
|
|
Term
| stable leukocyte adhesion, what proteins are involved? |
|
Definition
| ICAM-1 on endothelium, B2-integrin on neutrophil |
|
|
Term
| what 3 things mediate pain in inflammation? |
|
Definition
| bradykinin, PGE2, damaged nerves |
|
|
Term
| what 3 factors are important in scar formation? |
|
Definition
| TGF-B (most important), fibroblast growth factor, platelet derived growth factor |
|
|
Term
| what factors are involved in inflammatory vasodilation? |
|
Definition
| NO, PGI2, PGE2, platelet activating factor |
|
|
Term
| which genera of spirochetes has hooked tail? |
|
Definition
|
|
Term
| which genera of spirochetes are anaerobic/facultatively anerobic/microerophilic? |
|
Definition
|
|
Term
| which genera of spirochetes are aerobic? |
|
Definition
|
|
Term
| how do all treponemas spread? |
|
Definition
| direct contact - are pathogenic only to humans, so cannot be cultured in vitro |
|
|
Term
| how are borrelias spread? |
|
Definition
| arthropod vectors (large, only ones that can be seen with LM) |
|
|
Term
| do syphilis infected individuals develop resistance to reinfection? |
|
Definition
| yes, but become susceptible again after treatment. |
|
|
Term
| what IR are active during syphilis? |
|
Definition
| TH1 response during primary and secondary syphilis, TH2 response predominates during resolution of lesions; both humoral and CMI necessary for protection |
|
|
Term
| describe the non-treponemal screening test in syphilis testing? |
|
Definition
| RPR - use phospholipid antigen, cardiolipin, which naturally occurs in genus treponema and mitochondiral membranes. are of prognostic value bc their titers decrease within weeks or revert to non-reactive in a few months of successful therapy |
|
|
Term
| what is the confirmatory treponemal test? |
|
Definition
| Fluorescent Treponemal Antibody - ABSorption (FTA-ABS). treat serum with treponema sp. extracts to remove nonspecific cross-reacting abs --> serum reacts with treponema pallidum on a microscope slide --> wash --> application of fluoresceien-labeled anti-human globulin |
|
|
Term
| what is the strain of spirochete that causes lyme disease? and what are the species of ticks that transmit it? |
|
Definition
| caused by borrelia burgdorfen; ixodes scapularis in eastern, I. pacificus in western. (reservoir: white footed mouse and white tailed deer) |
|
|
Term
| what organism causes relapsing fever? and what causes the fever to relapse? |
|
Definition
| borrelia hermsii, borrelia recurrentis; organisms undergo remarkable antigenic variation, relapses due to selection of variants with the major surface protein different from that which produced the previous relapse |
|
|
Term
| How do we contract Leptospirosis? |
|
Definition
| water contaminated with animal urine (worldwide disease of various mammals) |
|
|
Term
| what are the characteristic signs of the jarisch-herxheimer (J-H) reaction? |
|
Definition
| increase in temp and pulse, decrease in systolic and diastolic BP, increase in TNF-a IL-1 IL-6 and IL-8 |
|
|
Term
| for weak acid: if pH of the medium is less than the pKa of the drug... |
|
Definition
| more unionized form will be present than ionized |
|
|
Term
| for a weak base: if pH of the medium is less than the pKa of the drug... |
|
Definition
| there will be more of the ionized form than the unionized |
|
|
Term
| what is bioavailability and what does it depend on? |
|
Definition
| fraction of administered drug reaching the systemic circulation. depends on fraction absorbed and first pass elimination. (measured as AUCoral/AUCiv |
|
|
Term
| what is bioequivalence and how do we measure it? |
|
Definition
| compares equivalence of two supposedly identical drugs. measure 1. area under curve (make sure both drugs are absorbed to the same extent) and 2. peak effect (make sure they have the same maximum concentration in the blood) |
|
|
Term
| how do you calculate apparent volume of distribution |
|
Definition
| Vd=apparent vol of distribution = dose/[drug] in plasma. [drug] extrapolated back to t=o on a [drug] vs. time plot and that concentration is plasma concentration |
|
|
Term
| how does infantile bilirubin poisoning happen? |
|
Definition
| infants have a high level of bilirubin (bc theyre hemolyzing RBC), which binds tightly to plasma albumin. infants have poor liver funcion and not a well formed BBB. Medications can displace bilirubin from albumin --> bilirubin diffuses into CNS --> toxic |
|
|
Term
| what protein binds to acidic drugs? basic drugs? |
|
Definition
| albumin binds to acidic drugs; alpha1 acid glycoprotein binds to basic drugs |
|
|
Term
| for urine, if you want to increase acidic drug excretion, what do you do to the urine pH and vv? |
|
Definition
| for increased acidic drug excretion, make pH more alkaline. for increased basic drug ecretion, make pH more acidic. |
|
|
Term
| how do resins and charcoals help us excrete drugs? |
|
Definition
| they absorb/bind to substances (drugs) by binding to them in the GI tract and preventing their absorption --> used to decrease their therapeutic effect |
|
|
Term
| drug metabolism: describe non-synthetic or phase I reaction |
|
Definition
| drug or metabolite undergoes hydrolysis, oxidation, or reduction |
|
|
Term
| drug metabolism: describe synthetic (conjugation) aka phase II reactions |
|
Definition
| drug or metabolite coupled to an endogenous substrate (carb, AA, glutathione, sulfate, etc) usually occurs after drug has gone thru a phase I reaction and requires energy |
|
|
Term
| the P450 enzymes associated with drug metabolism are associated mainly with what cellular organelle? |
|
Definition
|
|
Term
| in what organs are the P450s moreso associated with the mitochondria? what do they do there? |
|
Definition
| adrenal cortex, testes, ovaries (form pregnenolone from cholesterol) and in the adrenal cortex form cortisol from 11-deoxycortisol |
|
|
Term
| what is the general reaction of how drugs are metabolized by P450? |
|
Definition
| drug binds to oxidized P450(Fe3+) --> NADPH provides e- to reduce oxidized P450-drug complex (to Fe2+) --> molecular O2 associates with the complex, iron oxidized, oxycytochrome P450 complex formed --> NADPH provides another e- (sometimes NADH) and reduces oxycytochrome P450 complex forming active peroide anion species --> one atom of activated oxygen reduced to water --> second oxygen atom incorporated into substrate (drug) molecule --> oxidized P450 released |
|
|
Term
| what are 3 ways that P450 can be inhibited |
|
Definition
| 1. competition of an endogenous compound or a drug for a particular species of P450 which metabolizes another drug. (thus, magnitude of inhibition tends to be dose related over the dosage range of the inhibitor) 2. inhibition as a result of destruction of the heme group of P450 as a result of the formation of a reactive metabolite of a drug during metabolism (ethinyl estradiol suicide substrate) 3. CO inhibits P450 activity by binding with the reduced drug-P450 complex |
|
|
Term
| what is therapeutic index? how does this affect the way we monitor P450 inhibition? |
|
Definition
| measure of the impunity with which you can give an overdose (if desired and lethal effects are far apart, wont have a problem, if they are close together, we must be very careful about P450 inhibition from other compounds/drugs) |
|
|
Term
| how does acetaminophen overdose work? |
|
Definition
| acitaminophen gets metabolized by P450 --> Nacetyl-p-benzoquinone imine --> binds to glutathione and eliminated as mercapturic acids (but if theres too much drug, GSH depletes --> covalent binding to nucleophilic centers in protein, dna, rna --> liver and kidney necrosis --> death) |
|
|
Term
| what does food deprivation do to the inducing effects of drugs on P450s? |
|
Definition
|
|
Term
| what effect does feeding have on the inducing effects of drugs on the P450? |
|
Definition
|
|
Term
| describe how the process of glucuronidation leads to the excretion of endogenous compounds |
|
Definition
| UDP-glucuronyl transferase catalyzes the conjugation of UDP-glucuronic acid to seeral endogenous compounds --> glucuronides of most drugs (MW <300) are excreted in urine. higher compounds form glucuronides --> secreted into bile --> enter intestine --> compounds hydrolyzed by beta-glucuronidase --> reabsorbed --> again conjugated in liver --> excreted into bile |
|
|
Term
| what happens in glutathione conjugations? |
|
Definition
| glutathione S-transferases replace halo- nitro- sulfonate- or sulfonamide groups with GSH --> several additional rxns --> mercapturic acids (for excretion) |
|
|
Term
| in first order rxns: clearance is? and absolute rate of elimination is? |
|
Definition
| clearance is constant; absolute rate of elimination is not constant. V varies linearly with Cp (when Cp |
|
|
Term
| zero order rxn: clearance is? absolute rate of elimination is? |
|
Definition
| clearance is not constant; ARE is constant (bc removing the same AMOUNT of drug per unit time) V approaches Vmax (when Cp>Km) "saturation kinetics" bc our ability to eliminate is saturated |
|
|
Term
| describe time-dependent kinetics |
|
Definition
| when a drug is given --> you get an increase or decrease in regulation of metabolic enzymes in the liver --> then you get a change in the ability to eliminate drugs (bc of the very fact that the drug has been given) |
|
|
Term
| histamine functions as a neurotransmitter in the CNS to mediate what 3 things? |
|
Definition
| emesis center (triggers emesis), homeostasis (thirst, hungger), neuroendocrine function (ADH release) |
|
|
Term
| what are the 2 main pathways that histamine is metabolized through |
|
Definition
| imidazole-N-methyltransferase; diaminoxidase |
|
|
Term
| how do histamine liberators work? |
|
Definition
| directly stimulate histamine release from mast cells w/o prior sensitization (w/o IgE). raises intracellular calcium --> stimulates histamine release, causes mast cell lysis, or directly displaces histamine from inside mast cell |
|
|
Term
| which histamine receptors are responsible for vasodilation |
|
Definition
| H1 (faster onset, shorter duration); H2 (slower onset but longer duration) |
|
|
Term
| which histamine receptors are responsible for increased vascular permeability? |
|
Definition
| H1 (only receptor on endothelial cells) some of the plasma proteins that leak out are inflammatory themselves (c-reactive protein) and histamine is chemotatic for other inflammatory mediators |
|
|
Term
| what is the "triple response" observed after intradermal application of histamine |
|
Definition
| localized red spot (vasodilation of small vessels); flare (bright red flush 1cm beyond red spot; d/t axon mediated vasodilation via H1 receptors on peripheral nerve endings); wheal (local edema d/t increased vascular permeability H1) |
|
|
Term
| how does H1 mediate vasodilation? |
|
Definition
| located on vascular endothelial cells, leads to release of NO --> smooth muscle relaxation |
|
|
Term
| how do H2 receptors mediate vasodilation? |
|
Definition
| located on vascular smooth muscle. rise in cAMP and decrease in intracellular Ca --> Ca is a stimulator of mm. contraction, so decrease in Ca --> relaxation of vessel |
|
|
Term
| how does increase in histamine cause bronchoconstriction? |
|
Definition
| H1 receptors on bronchial smooth muscle, constrictor effect mediated by increased IP3 --> rise in IC Ca --> bronchoconstriction |
|
|
Term
| which histamine receptors are important in mediating emesis, especially motion sickness? |
|
Definition
|
|
Term
| which histamine receptors mediate homeostasis? |
|
Definition
|
|
Term
| where are histamine receptors located in the stomach and what do they do? |
|
Definition
| on parietal (HCl-secreting cells)cells. mediate release of gastric acid and pepsin |
|
|
Term
| are 1st generation or 2nd generation agents more useful in combating bronchospasm? |
|
Definition
| 2nd generation bc they may additionally inhibit mediator release from mast cells and basophils (whereas 1st generation does not usually block completely bc other mediators are usually involved) |
|
|
Term
| how do H1-antagonists exert local anesthetic actions? |
|
Definition
| via blockade of sodium channels on nerve cells |
|
|
Term
| why shouldnt patients with glaucoma take 1st generation H1 blockers? |
|
Definition
| 1st gen drugs have a cros-over specificity with other receptor types (cholinergic) --> drugs can have anti-cholinergic function that manifests as anti-muscarinic effects (drying of nose and mouth, blurred vision) |
|
|
Term
| explain the significance of COXI and COXII |
|
Definition
| arachidonic acid found in biological membranes, esterified into phospholipids. phospholipase A2 de-esterifies arachidonic acid and bc it is unstable, arachidonic acid will be rapidly metabolized into eicosinoids via cyclooxygenase, lipoxygenase, and cytochrome P450. COX I and COX II are the 2 forms of cyclooxygenase - COX I constitutively present, involved in maintaining gastric cytoprotection. COX II is an immediate early response gene product that is induced 10fold by cytokines, GF, and tumor promoters (form prostaglandins) |
|
|
Term
| the lipoxygenase pathway of arachidonic acid metabolism yields what? |
|
Definition
| most commonly: 5-lipoxygenase (in white cells), 12-lipoxygenase (in platelets), and 15-lipoxygenase (in macrophages and epithelial cells). 5-lipoxygenase --> leukotrienes |
|
|
Term
| what does 5-lipoxygenase produce? |
|
Definition
| hydroperoxide (5-HPETE) --> LTA4 --> LTB4 (leukocyte chemoattractant) or LTC4/LTD4/LTE4 (peptidoleukotrienes that form the slow-reacting substance of anaphylaxis, likely the physiological factors that cause bronchospasm) |
|
|
Term
| what is the receptor for LTB4 and where is it located? |
|
Definition
| BLT - neutrophils, lung, spleen |
|
|
Term
| where is the receptor for LTD4 and LTE4 located and what is it? |
|
Definition
| cysLT1 - smooth muscle, especially in lung |
|
|
Term
| what is the receptor for LTC4 and where is it located? |
|
Definition
| cysLT2 - endothelium and smooth muscle |
|
|
Term
| what determines which prostaglandins are formed in cells? |
|
Definition
| from arachidonic acid, COX II makes PGG2 --> gets converted by many diff enzymes into various other prostaglandins depending on what enzyme is present in which cell (lung and spleen produce most products; platelets only have thromboxane synthase; endothelial cells only have prostacyclin synthase) |
|
|
Term
| the adenylate cyclase pathway (AC) vs calcium calmodulin pathway (PLC) - how do we know which causes constriction and which causes dilation? |
|
Definition
| Myosin light chain gets phosphorylated by ATP. as rxn moves in direction of MLC phosphorylation (PLC pathway) we get constriction; as rxn moves in direction of dephosphorylation (AC pathway) we get relaxation/dilation |
|
|
Term
| which prostaglandins generally go thru the AC route (relaxation)? |
|
Definition
| PGI (prostacyclin) PGA and sometimes PGE |
|
|
Term
| which prostaglandins go thru the PLC (contraction) route? |
|
Definition
| PGF, TXA2, PGH2, leukotrienes |
|
|
Term
|
Definition
| CBG is a high affinity low capacity binder of glucocorticoids. albumin is a low affinity high capacity binder |
|
|
Term
| why is 11-betahydroxysteroid important? |
|
Definition
| inactive cortisone cannot bind to mineralcorticoid OR glucocorticoid receptors (must be converted to active cortisol by 11-beta-hydroxysteroid 1 in order to bind to glucocorticoid and mineralcorticoid receptors) cortisol binds the mineralcorticoid receptor for aldosterone with high affinity, so in order to keep the MR from being swamped by cortisol, 11-beta-hydroxysteroid 2 converts it to inactive cortisone. |
|
|
Term
| how do glucocorticoids affect carbohydrate and protein metabolism? |
|
Definition
| decrease glucose uptake and utilization; also mobilize AA which serve as substrates for hepatic glycogen and glucose production (activities of several heptaic enzymes involved in gluconeogenesis enhanced). results in tendency twds hyperglycemia |
|
|
Term
| what do high doses of glucocorticoids do to muscle? |
|
Definition
| causes muscle wasting. steroid-induced myopathy can result from prolonged glucocorticoid therapy |
|
|
Term
| what is the effect of glucocorticoids on cell growth and division? |
|
Definition
| can inhibit cell division or DNA synthesis (reduce growth in children, premature closure of epiphyseal plates, delay wound healing, skin thinning, GI ulcerations) |
|
|
Term
| what effect do glucocorticoids have on prostaglandin synthesis? |
|
Definition
| inhibit COXII and induce lipocortin (phospholipid binding protein) which reduces the availability of the phospholipid substrates of phospholipases (inhibits release of arachidonic acid), inhibits phospholipase A2 |
|
|
Term
| what is NF-kB and how does glucocorticoid interfere with it? |
|
Definition
| NF-kB is an essential transcription factor for a variety of pro-inflammatory cytokines, inflammatory enzymes, adhesion molecules, chemokynes, receptors. NF-kB sequestered in cytoplasm by I-kB proteins. upon activation by inflammatory stimuli, I-kB degraded and NF-kB enters nucleus and transcribes products for inflammation. glucocorticoids induce synthesis of I-kBa which binds to and inhibits action of NF-kB |
|
|
Term
| what are the 3 major ways that glucocorticoids influence immune system? |
|
Definition
| 1. redistribute circulating leukocytes (causing neutrophilia, lymphocytopenia, monocytopenia, basopenia, eosinopenia) 2. inhibits T-cell activation and proliferation 3. inhibits cytokine synthesis by interfering with transcription |
|
|
