bbm exam 2

pathology adaptations

hypertrophy- increase size of cells, increased protein production (causes- mechanical sensors detect increased load, signaling pathways)

• physio- increased stim by gf, functional demands (ex- uterine growth during pregnancy)

• pathologic- disease (heart in hypertension has to pump harder so cells enlarge)

hyperplasia- increase in number of cells (only if cells can divide, causes- gf driven proliferation can lead to cancer if not controlled)

• hypertrophy and hyperplasia can occur together reversibly in some tissues

• physio- hormones or gf when needed to increase functional capability or compensatory response after damage/resection (ex- kidney removed)

• patho- inappropriate/excessive hormonal (endometriosis)

atrophy- reduction in cell size and number due to decreased protein synthesis and increased protein degradation (ubiquitin proteasome path → autophagy)

• physiologic- normal in uterus postpartum

• pathologic- disuse, denervation, ischemia, atherosclerosis

metaplasia- cell type changes (reversible) ex: bladder stones change tissue from transitional to squamous

autophagy- cell eats itself in response to physio/patho stress (nucleation and isolation membrane → autophagosome forms from isolation membrane → sequestration of organelles → autophagosome fuses with lysosomes to deliver enzymes to degrade autophagosome)

cell injury

cell swelling (reversible up to 30 min)- earliest sign of injury → vacuoles (hydropic change or vacuole degeneration) caused by ischemia causing influx of Ca and h2o

nuclear changes

• pyknosis- nuclear shrinkage,

• karyorrhexis- pyknotic nucleus fragments

mechanisms of cell death

mitochondrial damage- ATP depleted → mitochondrial perm transition pore → loss of membrane potential → ox phos fails → Na/K pump → Na accumulates, water follows → inflammation and ER dilation → low cell pH from lactic acid (irreversible, necrosis) → Ca pump fails

membrane damage- ROS do lipid peroxidation to membrane → low phospholipid synthesis and increased phospholipid breakdown (esp if Ca present) → cytoskeletal abnormalities

Ca homeostasis disturbances- Ca ions are normally 2nd messengers but if released in excessive amounts cause injury → Ca pump fails → Ca accumulates in mito → mito transition pore and ATP generation fail → activate phospholipases, proteases, endonucleases, ATPases

necrosis- cell death (always pathologic)

caues- ischemia, toxins, burns, leakage of proteases

characterized by denaturation of cell proteins, leaking cell contents, local inflammation and enzymatic digestion of lethally injured cell

coagulative- architecture preserved, nucleus disappears (local area is infarct, heart, kidney, solid organs)

liquefactive necrosis- only in brain, abcess, digestion of dead cells → liquid mass

caseous- friable white appearance (granuloma = delimited aggregation of mononuclear inflammatory cells common in tb)

fatty- areas of fat destruction, release of lipases

fibrinoid- vascular damage from immune rxns → bright pink amorphous appearance

APOPTOSIS- regulated cell death caused by caspases degrading DNA and proteins

• can be pathologic or physiologic (cell and nucleus shrink, membrane blebbing)

• mito path- increased mito perm → pro-apoptotic proteins leak and activate caspase 9

• death receptor path- plasma membrane TNF and Fas

pharm terms

drug interacts with target→ change in biologic funtion → pharmacologic effect either activates changes or blocks receptor without producing a response

physicochemical characteristics- structural features determine ability to move through body and initiate effect (determine pharmacokinetic and pharmacodynamic properties)

pharmacokinetic properties- drug’s ability to be absorbed, distribute to site of action, metabolized, excreted

pharmacodynamic properties- receptor specificity, affinity, intrinsic activity

factors affecting duration of action- receptor affinity, irreversible binding, 2nd messenger activation, downregulation

receptor occupancy models

classical- increasing receptor occupancy → proportional increase in pharmocologic response (dose determines [drug] in bloodstream and [drug] at site of action)

• law of mass action: D + R → DR (in EQ), extent of receptor occupancy depends on [drug] and receptor affinity

• graded dose response curve- relationship between [drug] and magnitude of response by single subject (EC50- [drug] that produces 50% of max response)

relative efficacy- observed max responses of drug a and b binding same receptor is a function of relative intrinsic activity (drug with greater efficacy → greater effect when given in high enough dose to reach maximal effects)

relative potency- relative affinities of 2 drugs at same receptor when efficacy and receptor reserve are equal (lowest EC50)

competitive antagonist- druge binds reversibly to orthosteric site and compete with agonist for binding (inhibitory effects are surmountable with increasing agonist dose → agonist conc-effect curve shifts right but Emax not reduced)

irreversible antagonist- drug binds covalently or with very high affinity and prevent agonists from activating receptor (inhibitory effects are insurmountable even at high concentrations dose-response curve shifts rigt and down (suggests some degree of spare receptors))

2 state receptor occupancy theory

receptors in receptor pool exist in EQ in inactive and active state even in absense of drug (explains constitutive receptor activity, inverse agonism, why drugs with similar receptor occupancy can produce different effects)

partial agonist- greater affinity for active state and shift EQ toward active state only partially bc a substantial portion of rceptors remain in inactive state

neutral antagonists- equal affinity for both response forms and maintain same level of constitutive activity (appears without effect)

inverse agonists- preferentially bind inactive form and shift EQ to inactive state reducing activity

allosteric modulation model

receptors possess at least 2 binding sites and binding at allosteric site changes behavior or occupancy at orthosteric site

drug binding to allosteric site alters affinity of orthosteric ligand for receptor, efficacy of receptor activation, or both

positive allosteric modulator- shifts EC50 left (increases affinity/potency) or increases Emax for agonist

negative allosteric modulator- negative impact on EC50 and Emax (may reduce max effect or produce no measurable response depending on degree of modulation)

non receptor mechanisms of antagomism

physiologic/functional antagonism- produces physiologic effects opposing physiologic effects of another substance (opposite effects)

• ex insulin and glucagon; metacholine → bronchoconstriction, albuterol → bronchodilation

chemical antagonism- compound that directly interacts with agonist, modifying or sequestering it so drug is no longer capable of binding to receptor (product of combination is inactive and excreted)

• ex heparin is bound by protamine sulfate in bloodstream so heparin can’t bind to target so anticoagulant effect is neutralized

spare receptors

max response can be produced before all receptors are occupied (increases cell’s sensitivity to agonist)

EC50 <kd

• duration of effector activation may be greater than duration of drug-receptor interaction

• actual number of receptors may exceed number of effector molecules available

receptor dynamics

tachyphylaxis- observed phenomenon of rapid acute decrease in drug after continuous or repeat administration

receptor desensitization- decrease in coupling efficiency of receptors

receptor downregulation- decrease in # of receptors

receptor resensitization- after withdrawal of the agonist, cells recover full responsiveness to subsequent addition of the agonist

supersensitivity- exaggerated response when antagonist is removed

pharmacodynamic variability in a population

quantal dose response- all or none effect (generate info on margin of safety to be expected)

response elicited with each dose plotted vs. log dose of drug

determine- median effective dose (ED50), median toxic dose (TD50), estimation of safety (TD50/ED50 = TI)

• large TI = wide margin between effective and toxic dose

• therapeutic window- range of steady state concentrations at which likelihood of efficacy is high and probability of adverse effects is low

pharmacodynamic drug interactions

additive- combined effect of 2 rugs = sum of effect of each given alone

• ex- acetaminophen + ibuprofen → additive pain relief

synergistic- combined effect exceeds sum of effect of each drug given

• opoids + benzodiazepine → increase risk of CNS and respiratory depression

potentiation- accentuation of effect of 1 drug due to presence of another that alone has no effect

• amoxicillin + clavulanic acid → clavulanic acid inhibits bacterial enzymes that inactive amoxicillin → potentiate amoxicillin’s antibacterial effects

physiological antagonism- 2 xenobiotics produce opposite effects on same physiological function

• insulin + prednisone → even out blood sugar

chemical antagonism- rxn between 2 chemicals neutralizes their effects

• antacid chelates tetracycline in gut → reduced antibiotic efficacy

receptor antagonism- blockade of the effect of 1 drug by another that competes at common binding site or allosteric site

absorption

passive diffusion of lipid soluble drugs- driven by concentration gradient (magnitude to gradient, surface area, membrane permeability, lipid water partition coefficient, membrane thickness)

• weak acids and weak bases: uncharged form is more lipid soluble (greater fraction of weak acid will be in lipid soluble form in more acidic medium and vice versa)

  • ion trapping- ex- pyrimethamine (pka 7)- at blood pH only 0.4 of protonated will be present for each 1 unprotonated form (total [blood] = 1.4 umol/L); at urine pH 10 ionized form will be present for each 1 of the unprotonated (total [urine] = 11umol/L)

channels and carrier mediated transporters- potential for adverse effects and drug interactions

• SLC- carrier proteins and channels (facilitated diffusion down [] gradient), 2ndary active transporters (coupled uphill and downhill movement)

• ABC- primary active transport (active efflux of antibiotics) ex- P glycoprotein (atp dependent pump for active efflux of drugs from cell on apical side of membrane)

distribution

process by which drug reversibly leaves bloodstream and enters interstitial and intracellular fluids

first pass effect- fraction of an oral dose may be inactivated in GI and liver by metabolizing enzymes before reaching systemic circulation

bioavailability- fraction of dose of active drug that reaches systemic circulation

redistribution- change in plasma drug concentration significant enough to alter or terminate CNS effect of the drug (CNS effect happens rapidly); drug will then move back into blood and terminate the CNS effect

distribution across placenta- can cause anomalies (lipid solubility and extent of protein binding)

• P glycoprotein in blood-placenta barrier are there to limit the amount of drugs that can cross

drug reservoirs- reversible binding of drug to inert plasma proteins and tissue macromolecules tends to sequester the drug in those compartments (drugs are not free to travel or be metabolized when bound to intert molecules)

drug metabolism

enzyme catalyzed conversion of one chemical entity to another

liver is principal organ of drug metabolism- large blood flow, portal circulation, a lot of enzymes and transporters

• SLC in basolateral membrane of hepatocytes; ABC in bile canalicular membrane of hepatocytes

• hepatic drug transporters work with phase 1 and 2 drug metabolizing enzymes to mediate uptake and efflux

phase 1 rxns- redox, hydrolysis- unmask polar functional group that alters properties of drug (can be inactivated or activated or made toxic or pass through unchanged)

• CYPs enzymes have heme as a cofactor in liver for phase 1 rxns (relatively nonselective)

  • drug + reducing agent + o2 → drug product with oxygen +H2O +NADP+

phase 2 conjugation rxns- transfer hydrohilic molecule to substrate → hydrophilic metabolite (almost always inactive) → excretion through kidney

• transferases catalyze coupling of cofactor with drug (UGT, SULT, NAT, MT, GST, glycine)

enterohepatic circulation of glucuronide metabolites- excreted in bile are transported to duodenum with bile → B glucuronidase of intestinal flora cleave drug conjugates → drug liberated into intestinal lumen → passive diffusion through intestinal epithelium → drug reenters portal circulation back to liver

excretion

excretory organs eliminate polar compounds more efficiently than substances with high lipid solubility

renal drug handling- may be filtered from blood in glomerulus, secreted into PCT, reabsorbed from DCT and back into systemic circulation and excreted in urine

GFR is determinant of renal function = sum of functioning nephrons (serum creatinine and ceratinine clearance are GFR estimates)

variation in drug response- dose and frequency of admin vary in different patients

• older patient (concurrent diseases, organ function, structural and functional changes in brain)

• neonate (immature ADME processes - blood flow, GI function, low GFR and activity of drug metabolism enzymes, low muscle mass and body fat)

mechanism of induction of drug metabolizing enzymes

drug enters hepatocyte → interact w nuclear receptor → induce gene transcription → more mrna and protein synthesis → high metabolism → low plasma [substrate drug] → low pharmacological action of substrate drug and high [reactive metabolites] can exacerbate metabolite mediated toxicity

ex:

• CYP3A4 and P-gp inducers: phenytoin, carbamazepine, phenobarbital, rifampin, st. john’s wort

• CYP1A2 inducers: cigarette/marijuana (metabolize several medically important drugs and smoking increases exposure to PAHs which are metabolized by CYP1A2 to procarcinogens)

mechanisms of inhibition of drug metabolizing enzymes

drugs or their reactive intermediates that bind to the active/allosteric site of drug metabolizing enzymes → low catalytic activity of enzyme

mechanisms:

• competitive inhibition (ex- CYP heme iron)

• noncompetitive to allosteric site

• suicide inhibition (covalent binding to heme moiety, protein part of enzyme, or anything that causes heme fragmentation

CYP3A4 inhibitors- cimetidine (antacid), itraconazole (antifungal), erythromycin/clarithromycin, ritonavir (pharmacokinetic enhancer), grapefruit juice

parameters governing drug distribution

clearance, bioavailability, volume of distribution, elimination half life, steady state, area under [] vs. time curve

multicompartment model- central is highly perfused tissues, final is slowly perfused tissues

change in blood flow to various tissues can change rates of drug distribution to tissues (effect of drug at a site can vary depending on perfusion of these sites)

clearance

total systemic clearance = renal + hepatic + other (predicts rate of elimination in relation to [drug])

depends on: drug, blood flow, condition of elimination organs in patient

dosing rate = (clearance x [])/bioavailability

parameters

extraction ratio- organ’s intrinsic capacity for eliminating a drug in a single pass through the organ at steady state

• E = (in - out)/in; E = CL/blood flow

• effect of reduced hepatic blood flow on systemic drug levels-

  • for drugs with high Eh- shunting past the liver → substantial increases in drug in systemic circulation

  • for drugs with low Eh- shunting past the liver will cause little change in bioavailability

renal extraction- fraction of active drug excreted in uring

• renal blood flow, GFR, secretion from peritubular fluid into peritubular fluid, reabsorption of tubular fluid back into blood

bioavailability (F)- fraction of active drug that reaches systemic circulation (1- Eh)

• fraction of dose absorbed and escapes first pass elimination

• example- verapamil Eh = 0.67 so F= 1-0.67 = 33%

area under curve- extent of total body exposure to a dose of drug (can estimate clearance)- bioavailability determines [] in plasma which over time determines body exposure to the drug

• proportional to dose and extent of bioavailability for a drug if elimination is first order

equivalency between drug products

absolute bioavailibility- comparing a route to IV route of same drug

relative bioavailability- comparing bioavailability of different formulation of same drug or same formulation of same drug made by different companies

apparent volume of distribution- Vd=dose/[] (in plasma)

• high Vd- drug is in tissues, low Vd- drug in blood

effect of drug displacement from plasma proteins- changes in protein binding due to disease states and drug drug interactions are clinically relevant for a subset of drugs with narrow therapeutic window

half life = (0.693 x Vd)/Cl

• indicates time to reach steady state and be removed from body, and a way to estimate dosing interval

elimination

first order- rate of drug metabolism is directly proportional to [free drug] and fraction of drug removed is constant (on log graph will be linear)

zero order- clearance mechanisms become saturated so rate of metabolism is constant → constant amount of drug is metabolized per unit time (can be dangerous)

• if dosing rate exceeds elimination capacity, steady state cannot be achieves and [] will keep rising; changing dosing rate for drug with nonlinear kinetics is unpredictable; ethanol, aspirin and phenytoin exhibit zero order kinetics at therapeutic []

target concentration strategy- desired steady state [] selected and dose is calculated that is predicted to achieve this value (adjustments can be made)

maintenance dose = (C at steady state/F) x Cl (relates dosing rate to rate of elimination at steady state)

loading dose = (Vd x C at steady state)/F (relates amount of drug in body to [drug] in plasma but has a risk of toxicity)

acute inflammation

if hydrostatic pressure high → localized edema

if oncotic pressure low → generalized edema

vasodilation- inflammatory trigger → histamine → relax vascular smooth muscle → transudate → high blood flow → heat, edema, erythema

vascular permeability high- histamine retraction of endothelial cells → increased vascular permeability → fluid, proteins, cells leak out → exudate (high protein, cells, specific gravity)

vascular congestion/stasis- vasodilation increases diameter and transudation/permeability lose fluid → high blood viscosity and congestion → hemodynamic changes → neutrophils accumulate along epithelium (margination)

bradykinins- mediate vasodilation and help sensitize sensory nerves causing pain, redness, heat

cytokines- signaling proteins in response to injury (TNF and IL1)

cell response

• rolling (slow down leukocytes) → expression of selectins on endothelial cells

• adhesion (stop leukocytes)- activity of high affinity integrins on leukocytes and endothelial cells

• transmigration (migration of leukocytes through vessel wall)- endothelial cells retracted → leukocytes travel between them

• chemotaxis- WBCs follow chemical gradient to where stimuli for inflammation started

• complement- all pathways lead to C3 convertase enzyme which splits into C3A (vasodilation) and C3B (opsonozation and phagocytosis) and will ultimately lyse the cell

recognition of microbes and dead tissue

signaling paths in wbcs that result in increased cytosolic Ca → PKC and PLA2

after recognition comes removal (phagocytosis)

opsonization- opsonins coat microbes so wbcs can recognize them (C3b, IgG)

phagocytosis- ingestion (phagosomes + lysosomes → phagolysosome), killing (ROS activated by NADPH to reduce O2 to superoxide → superoxide dismutase reduces to H2O2 to combine with Cl- to kill)

acute inflammation types

serous- fluid build up (blisters, viral pleuritis)

fibrinous- high permeability → exudative fluid → high fibrin deposition (fibrinous pericarditis)

suppurative- exudative → pus (staph, abcess)

ulcer- excavation of inflamed necrotic tissue

chronic inflammation

causes- persistent infections, tissue destruction with attempts at healing, infiltration by mononuclear cells, immune mediated inflammatory diseases, prolonged exposure to toxins

monocytes go into connective tissue to become macrophages (dominate by 48 hours)

classically activated (M1 macrophages)- interferon gamma; kill ROS, lysosomal enzymes in acute; secrete IL-1, IL-12, IL-23 in chronic

alternatively activated (M2 macrophages)- IL-13, IL-4; promote gf for tissue repair and fibrosis; induce IL-10 for anti-inflammatory

T cells- progenitor T cells in bone marrow and further develop in thymus (become CD4 helper or CD8 cytotoxic)

B cells- produced in bone marrow and have Ig rearrangements → naive B cells (express IgM and IgD)

granulomatous inflammation- attempt to contain offending agent- Mac present ag to helper T → cytokines activate other T cells to perpetuate response by secreting IFN gamma → mac activation → mac become giant cells

tissue repair

restore tissue architecture and function using proliferation of injured tissue, vascular endothelial cells, fibroblasts

regeneration- replacing dead cells/tissue by cells of same type (proliferation of differentiated cells that survive injury and retain capacity to proliferate- must have intact basement membrane, immature cells, and connective tissue scaffold)

growth factors- PDGF (fibroblasts), VEGF (new vessel formation), FGF2 (reepithelization of skin), TGF-B (potent fibrogenic agent)

wound healing phases- inflammatory, proliferation (granulation, proliferation/migration of connective tissue cells, reepithelization of wound), maturation (scar tissue, ECM deposition, tissue remodeling, wound contraction)

granulation tissue- proliferation of fibroblasts and deposition of loose connective tissue along with new vessels and macrophages (angiogenesis from VEGF-A)

connective tissue deposition- migration of fibroblats to injury site (deposition of ECM proteins (collagen)) at 48 hr mark- fibrogenesis stim by TGF-B (type 3 collagen and fibronectin))

collagen types

1- high tensile strength (tendons, bone, mature scars)

2- cartilage, nucleus pulposus, vitreous humor

3- embryonic tissues, pliable organs, uterus, GI, vessels- 1st collagen deposited during wound healing

4- basement membranes, associated with laminin

cutaneous injury

inflammation (2-5 days)- bleeding stops, clot forms (clotting cascade from cell damage and bacteria) cells- neutrophils then macrophages

proliferation (2 days-3 weeks)- granulation tissue (fibroblasts lay down collagen, angiogenesis to supply the repair process)

maturation- type 3 collagen replaced by type 1 (final tensile strength), remodeling (scar tissue becomes avascular and acellular), wound contraction for secondary intention wounds (myofibroblasts)

complications- wound dehiscence (don’t have enough tissue), ulceration, excessive scar formation (keloid), contractures (palms, soles, anterior thorax after burns = exaggeration of contraction)

innate lines of defense (innate is 1st and 2nd)

1- physical, chemical, biological (ex- skin, ear wax, tears, bile, microcidal molecules, mucus)

2- inflammation (macrophages), fever, complement, IFN, NK cells, phagocytosis

• TNF-a: prothrombic, leukocyte adhesion and migration, macrophage activation, hematopoiesis; IgE makes mast cells and basophils; C3a and C5a cause mast cell degranulation; toll like receptors activate phagocytes to APCs

• complement- classical (adaptive), alternative and mannan binding lectin (innate)

• phagocytes- PMNS (neutrophils, eosinophils), MNs (monocytes, macrophages, osteoclasts, dendritic cells)

antibodies and antigens

antigens- each has multiple epitopes and antiobdies bind to the epitopes on the antigen to immobilize, neutralize and opsonize (IgM does not cross placenta; IgD is b cell receptor; IgG is 2nd ab; IgA is in mucosal protection; IgE activates mast cells and eosinophils)

agglutination- IgM IgA

neutralization IgG

Ab dependent cell mediated cytotoxicity (IgG)

complement fixation (IgM IgG)

adaptive immunity

specific, slow, memory (humoral and cell mediated)

MHC 1- every cell that has a nucleus, need to match during transplants (intracellular ags tagged with ubiquitin for UPP → ER → Golgi → display for CD8T cells)

MHC 2- on on APCs (mostly dendritic cells → actin dependent phagocytosis → display epitope on MHC 2 cell surface for CD4T cells)

MHC 3- complement

humoral response- antibodies for extracellular pathogens (Type 1, 2, 3 HSN)

CMI response- CD8T cells, intracellular (type 4 HSN)

CD4 helper t cell activation- contact with ag → prime T helper → Th1 (INF gamma or IL12), 2 (IL4 or 10), or 17 (IL6 or TGFB) or memory T cells (high CD28 expression)

CD8 killer t cell activation- recognize ag on MHC 1 → express IL2R → with help from helper T become cytotoxic → perforin and granzymes

B cells- recognize ag withor w/o MHC → ag binds to BCR → endocytosis and ag presentation to CD4 → TH2/th17 → plasma cells for memory

hypersensitivities

1- immediate/allergy- IgE → mast cells and basophils; asthma, allergies, anaphylaxis

2- ab mediated cytotoxicity- IgM/IgG interact w/ membrane or ECM; hemolytic anemia from mismatch, ab blocking function (myasthenia gravis), rheumatic fever

3- immune complex- circulating ab-ag complex (IgM/IgG → vasculitis; localized (abcess or necrotizing vasculitis), exogenous- ab/drug induced, endogenous- SLE, post strep glomerulonephritis

4- Th1/macrophage induced imflammation; topical (contact dermatitis), ag injected due to microbes, MS, rheumatoid arthritis

CD markers

CD56- marker for NK cells, CD3- marker for T cells, CD19- marker for B cells

T lymphocytes- 60-80% of lymphocytes

• T regulatory cells regulate immune response (CD4, CD25, FOXP3)

B lymphocytes- differentiate to ab-producing plasma cells (express BCR, MHCII, CD9, CD19, CD20)

NK cells- similar to cytotoxic T cells (part of innate immunity), express CD16a, CD56, CD94)

lymph vessels, tissues, nodes

lymph vessels- more permeable than capillaries, collect lymph and bring to lymph nodes through efferent lymp vessel → lymp trunk or thoracic duct → subclavian vein → SVC

Diffuse lymph tissue (MALT)- guard alimentary canal, genitourinary track, respiratory passages in lamina propria

• primary nodule (small lymphocytes), secondary nodule (germinal center for ag encounter), aggregates in tonsils, peyer’s patches of ileum, appendix

lymph nodes- encapsulated with trabeculae in cervical, axilla, groin, mesenteries

• stromal cells- reticular cells (type 3 collagen), dendritic cells, follicular dendritic cells (display ag-ab complexes for years, memory B cell affinity maturation, Fc receptors/no MHC class II)

• cortex- superficially mostly B cells, paracortex mostly T cells

• medulla- b cells organizes into cords separated by sinuses, macrophages monitor lymph and create barrier to trap cancer cells (can get overwhelmed)

thymus- fully formed and functional at birth by puberty → fat

• cortex- packed with T cells; epithelioreticular cells 1,2,3

• medulla- same as cortex but larger t cells, epithelio reticular cells 4,5,6

epithelioreticular cells

1- boundary of cortex, separate parenchyma from connective tissue

2- within cortex, express MHC 2

3- boundary of cortex/medulla, express MHC 2

4- close to type 3, barrier

5- within medulla, compartmentalize T cells and negative selection

6- hassall’s corpuscles, keratinized cells, t cell maturation and differentiation

blood thymus barrier- protect naive t cells from premature antigen exposure (continuous capillaries with zonula occludens, macrophages kill escaping age, type 1 epithelioreticular cells)

t cell differentiation/maturation

CD2/7 t cells migrate from bm to thymus → express CD1, TCR, CD3 and both CD4 and CD8 (double positive)

• positive selection- type 2 and 3 cells present self-ag to double positive cells on MHC class 1 (if they recognize → survive)

• negative selection- type 5 present self-ag on MHC class 2 (if they recognize → die)

epidemiology

rate- number of cases in a population over a period of time

incidence rate- # of new cases that occur during a period of time in a population at risk for developing the disease (measures risk)

prevalance rate- # of affected people in a population at a specific time over # of people in the population at that time (prevalence = incidence x duration of disease)

person years- number of years a person contributed to a study

case fatality rate- # of people who die from a disease over # of people who have that disease

crude rates- calculation performed with no consideration of additional factors

specific rates- particular subgroup of the population of interest

studies

cross sectional- 1 time sweep through a time point to assess prevalence of variables, diseases, risk factors (cannot conclude anything about risk or incidence)

case control- 2 groups (1 has disease and 1 doesn’t), identifies possible causes of disease by seeing how the 2 groups differ

• odds ratio = odds of exposure in diseased/odds of exposure in healthy OR odds of disease in exposed/odds of disease in unexposed

cohort- 2 or more groups of people that are free of disease and differ in extent of exposure are compared with respect to disease incidence

neoplasia

benign- encapsulated, well differentiated

malignant- metastasize, invade, irregular, high mitosis, anaplasia, pleomorphic, hyperchromasia, high nucleus/cytoplasm ratio

tumor differentiation- degree to which tumor cells resemble cells that they came from

grading- microscopy only; staging- size and degree of spread

naming tumors

• gland- adeno, smooth muscle- leiomyo, skeletal muscle- rhabdomyo, vessel- angio, blood vessel- hemangio, lymph vessel- lymphangio (benign ends in OMA, malignant from epithelial ends in carcinoma, malignant from mesenchyme ends in sarcoma)

warburg effect- tumor cells do glycolysis and have pyruvate converted to lactic acid (provides cancer cells with metabolic intermediates needed for making cell components)

apoptosis- both apoptotic paths evaded by cancer cells downregulating and phosphorylating caspases

telomerase- enzyme that extends telomeres → cancer cells immortal

Li fraumeni- inherit 1 hit of p53 (cancer develops young)

oncogenic microbes

EBV → hodgkin and burkitt lymphoma'

herpes 8→ b-cell lymphoma (primary effusion lymphoma)

hep c and b → hepatocellular carcinoma

HPV → squamous cell carcinoma of cervix and other squamous cells

human t cell leukemia virus → t cell leukemia/lymphoma

h pylori→ gastric adenocarcinoma or lymphoma

s. haematobium → bladder carcinoma

paraneoplastic syndromes- early manifestations of occult neoplasms

• endocrinopathies- ectopic hormone production, nypercalcemia (breast, lung, kidney, ovary, squamous cell carcinoma of lung)

• myasthenia gravis, vascular and hematological changes, dermatological disorders

antimicrobial agents

drug targets microbial molecules that are essential for biochemical rxns in microbes to interfere with pathways and kill it or slow growth and allow host immune mechanisms to eradicate them

• actively and rapidly growing organisms are more susceptible to drug action

selective toxicity- extent to which antimicrobial agent harms microbial cells but does not damage host cells

spectrum of activity- how many different organisms will be killed with given antibiotic (narrow spectrum- limited group, extended spectrum- large # of g- bacteria, broad spectrum- wide variety)

antimicrobial resistence- random events, natural selection when drug is present, selection pressure (increasing exposure to drug makes mutations more likely)

• intrinsic- inherently resistance; acquired- normally responsive but develop spontanous mutations or transfer resistance genes from other bacteria

• mechanisms- inactivation (enzymatic hydrolysis, chemical mod), drug does not reach target (efflux pumps, altered porins G-), target alteration, organism expresses alternate metabolic paths

• minimum inhibitory concentration- lowest concentration of antibacterial agent that inhibits visible growth (susceptibility testing- determine the possible antimicrobials that would be effective)

inhibitory effects of antimicrobial agents

microbicidal- kills infective organism (rapid killing, or impaired host defenses)

microbiostatic- inhibits microbial growth and replication allowing host immune system to eliminate the organisms to eradicate infection

IC50- half maximal inhibitory concentration (analagous to EC50)

• intermediate resistance- IC50 shifts right (need higher concentration to achieve effect

• decreasing Emax: increasing dose would not increase effect beyond a certain point

concentration dependent killing- dosing based on MIC and max concentration (high drug concentration increase rate and extent of killing)

exposure dependent killing- dosing based on AUC and MIC efficacy depends on maintaining adequate overall exposure over time (moderate postantibiotic effects)

time dependent killing- dosing based on percent of time that drug concentration remains above MIC (activity continues as long as drug concentrations are above MIC for 50% of the time, high peak levels are of no benefit for curing infection (mild postantibiotic effects)

antimicrobial pharmacokinetics

must penetrate into infected compartment in sufficient concentration to prevent/inhibit growth of organism (admin, distribution, elimination)

concentration of antibiotic must be adequate to kill/prevent growth of infective microorganism while being tolerable to host

treatment goals and duration of therapy clearly spelled out in beginning based on proper evidence

prophylactic- prevent infection in high risk

preemptive- prevent development of potentially dangerous disease in asymptomatic patient who has evidence of infection (ex CMV after stem cell transplant)

empiric- immediate broad spectrum when delay in initiating antibiotic could cause significant morbidity or fatality

definitive- specific narrow spectrum when organism and its susceptibility are identified

suppressive- for immunosuppressed individuals when og infection is not completely iradicated by initial therapy

combination- broaden antibiotic spectrum or synergistic/additive effect