DD Unit 2

Question 1

major causes/etiologies of cell injury

Answer 1

a.Physical agents: trauma/heat
b.Chemical and drugs: drug toxicity, poisoning
c.Infection: pathogenic bacteria, virus, fungi, protozoa
d.Immunologic insults: anaphylaxis, autoimmunity
e.Genetic derangement: phenylketonuria, cystic fibrosis
f.Nutritional imbalance: atherosclerosis, protein and vitamin deficient
g.HYPOXIA: cells receive too little O2, causes: lung disease, heart failure, shock, arterial or venous thrombosis.
h.Injury from temperature extremes
heat stroke
hyperthermia
Hypothermia
Electrical injury

Question 2

how cell injury leads to pathogenesis of disease

Answer 2

injury: non-lethal, physical damage or alteration of normal
perturbed cell can’t perform: metabolize nutrients, synthesize needed produce -> illness

most injury leading to disease = epithelial injury- 1st tissue to encounter environment

injury to one tissue typically affects other adjacent ones

Question 3

morphologic changes from cell injury that cause signs and symptoms of disease

Answer 3

symptoms: complaints voiced by patient
signs: abnormal findings observed by MD

injury commonly changes:
cell membranes- lipid in membrane is easily oxidized and supports oxidative chain rxn; membrane damage harms ion pups; leads to cell swelling from inc Na+ and H2O

mitochondria- inc in H2O and dec in O2-dependent synthesis of ATP required to fuel ion pumps

endoplasmic reticulum- cistern are distended and polyribosomes detach; dec in protein synthesis

nucleus- altered appearance; probably affects rRNA synthesis, causing dec in protein synthesis

Question 4

free radicals, how they arise, how they produce injury, how they’re eliminated

Answer 4

chem species w/ unpaired e-

chemically damage proteins, DNA, RNA, trigger lipid peroxidation in membranes

generated by intrinsic oxidases (in ER of all cells and in PMNs) and radiation, esp in high pO2

superoxide O2- can be removed via superoxide dismutase

remove free radicals:

• antioxidants: uric acid, Vit E, etc
• catalase
• glutathione peroxidase

Question 5

how hypoxia/ischemia makes free radical damage an important cause of cell injury

Answer 5

hypoxia: cell receives too little O2
ischemia: lack of O2 from poor blood perfusion (worse than HPX- cells aren’t getting O2 or nutrients)
HPX leads to ischemia

HPX:
insufficient ATP production; ROS following O2 therapy
acute inflammation- PMNs have ROS-producing enzymes
reperfusion of HPX tissue- produces ROS after HPX is corrected

Question 6

necrosis vs apoptosis

Answer 6

necrosis: mostly commonly seen with ischemia; problem with blood flow; many cells die at once
signs- elevation of intracellular Ca2+, no ATP synthesis, release lysosomal hydrolyses, swollen cytoplasm; DNA fragmentation

apoptosis: programmed cell death of individual cells; highly regulated w/ surface binding receptors Fas/CD95; mito switch caspases and endonuclease; cells shrink; large membrane blebs; uniformly compact and dense DNA; patterned DNA breakage

Question 7

adaptations associated with chronic injury

Answer 7

chronic hypertension- cells may hypertrophy (L ventricle working harder; needs more mito)

cells may atrophy when func is less needed- (gross muscle atrophy in a cast)

metaplasia- chronic mechanical stress (cigarette smoke replacing one cell type for another)

hyperplasia- inc in # of cells; when adrenal cortical cells increase in number after tumors produce ACTH-like polypeptides

Question 8

4 major types of necrosis

Answer 8

coagulative- dead cells are ghost-like remnants of former selves; common in MI; chromatin clumps and causes pyknosis; removal of chromatin is then called karyolysis

liquefactive- dead cell dissolves away as lysosomal hydrolyses digest cell components; most common in brain and spleen

caseous- THINK TB; central portion of infected lymph node is necrotic and has chalky white appearance

fat- necrotic adipose tissue that develops after acute pancreatitis or trauma; fats are hydrolyzed into free fatty acids which precipitate Ca2+ producing “peculiar” chalky grey material

Question 9

reversible and irreversible alterations during hypoxic injury

Answer 9

reversible:
dec ATP
dec Na+ pump (swelling)
dec protein synthesis
inc glycolysis, dec pH

irreversible:
inc Ca2+ influx
DNA and protein degradation
activation of lysosomal enzymes

Question 10

acute vs chronic inflammation

onset
cellular infiltrate
tissue injury, fibrosis
local and systemic signs

Answer 10

acute:
fast; min/hrs
mainly NEUTROPHILS/PMNs
usually mild and self-limited
prominent
--innate immunity; exudation of fluid and plasma proteins (edema); emigration of leukocytes

chronic:
slow; days
MACROPHAGES, monocytes and lymphocytes 
often severe and progressive
less
--adaptive immunity; more tissue destruction; proliferation of RBCs, deposition of CT

Question 11

classic clinical signs of inflammation

local and systemic

Answer 11

local:
redness- rubor
heat- color
swelling- tumor
pain- dolor
loss of function
vasodilation
vascular permeability
swelling from mediators/pressure on nerves

systemic:
sleepiness/grogginess
anorexia
fever
high WBC count
blood pressure alterations

Question 12

transudate and exudate

Answer 12

transudate:
inc hydrostatic pressure/ reduced oncotic pressure
low specific gravity
low total protein

exudate:
inflammation
inc specific gravity
inc total protein

Question 13

TLRs and inflammation

Answer 13

microbes breach barrier; TLRs recognize and initiate response

Question 14

potential outcomes of inflammation

Answer 14

best to worst:

complete resolution
(macrophage cleans up necrotic debris; tissue regeneration; lymphatic drainage decreases edema)
scarring ("patch" not 100% functional)
abscess formation (wall off infection)
progression to chronic inflammation

Question 15

collateral tissue damage associated with inflammation

Answer 15

Nofsinger’s bomb analogy

inflammation- tissues get damaged
cells responsible for damage:
leukocytes (once they’re activated they don’t differentiate between offender and host)
neutrophils and macrophages (produce ROS, NO, and lysosomal enzymes) within phagolysosome- released into ECF and causes damage
cytokines- recruiting leukocytes

Question 16

granulomatous inflammation

Answer 16

specific type of chronic inflammatory rxn characterized by accumulation of modified macrophages, giant cells, lymphocytes, and occasional plasma cells
initiated by variety of infectious/noninfectious agents
occurs in presence of poorly digestible irritants

ex:
bac (TB, leprosy, syphilis)
parasitic (schiostomiasis)
fungal 
inorganic metal/dust (silicosis, berylliosis)
foreign body (suture)
sarcoidosis (unknown etiology; non-necrotizing)
Crohn's disease (non-caseation)

typically don’t see neutrophils

Question 17

cytokines and systemic responses

Answer 17

cytokine rxns responsive of systemic manifestations of acute inflammation

bacterial products (LPS) and inflammatory stimuli lead to cytokine production; then systemic effects

key mediators:
cytokines TNF, IL-1, IL-6

findings:
fever
acute-phase proteins
leukocytosis

Question 18

role of Hageman factor in systems (Factor XII)

Answer 18

activation of Hageman factor by exposure to collagen/basement membrane in setting of inc vascular permeability, leading to 3 pathways below:

coagulation pathway (activate thrombin)
Factor XII via intrinsic pathway- activates clotting cascade; activates thrombin to convert fibrinogen to fibrin; clot formation
thrombin also binds PARs protease activated receptors
thrombin promotes formation of prostaglandins, cytokines, nitric oxide, PAF

fibrinolysis pathway (activate plasmin)
goal is to degrade fibrin
plasminogen is activated to form plasmin, which cleaves fibrin to form fibrin degradation products;
increases vascular permeability and activates C3 to C3a

activation of kallikrein/Kinin system-
pre-kallikrein converted to kallikrein protease; activates kininogen to bradykinin
this process activates C3 to C3a
leads to vasodilation, inc vascular permeability, bronchial smooth muscle contraction, and PAIN
kinin system quickly inactivated by kinases

Question 19

features of repair processes

Answer 19

macrophages play central role in repair
-clear offending agents, provide growth factors, secrete cytokines

repair begins w/in 24 hrs; emigration of fibroblasts for proliferation phase; proliferation of fibroblasts (produce collagen and EC matrix) and endothelial proliferation (neovascularization)
3-5 days later specialized granulation tissue formation; scar (via epithelial cells- epidermis, mucosa) (liver regenerates)

Question 20

granulation tissue and its components

Answer 20

new CT and blood vessels that form on surface of wound during healing; forms EC matrix
a response to injury
part of scar formation

fibroblasts come in and form collagen
endothelial cells neovascularize
macrophages remove waste
typically don’t see neutrophils

Question 21

repair of epithelium

Answer 21

re-epithelialization via:
adjacent cells, bulge stem cells (deep) and epidermal stem cells
stem cells line along follicle; start to regenerate deep;
epidermal stem cells in skin regenerate epithelium

Question 22

liver regneration

Answer 22

remarkable regernation capacity
2 mechs:
-proliferation of remaining hepatocytes
-repopulation from progenitor cells

proliferation- triggered by cytokines and protein GFs

• priming phase: IL-6 produced by Kupffer cells make parenchymal cells able to receive/respond to growth factor signals
• Growth Factor phase: HGF and TGF-alpha stimulate cell metabolism and cell cycle; almost all hepatocytes replicate; followed by nonparenchymal cells
• hepatocyte replication phase: same as GF phase
• termination phase: hepatocytes return to quiescence

if proliferative capacity is impaired: liver regenerates from progenitor cells

Question 23

scar formations

normal
hypertrophic
keloid
contracture

Answer 23

fibrous tissue (fibrosis) that replaces normal skin after injury

hypertrophic- raised scar; growing beyond boundaries of injury, but REGRESSES

keloid- raised scar, growing beyond boundaries of injury; NO REGRESS/REMODEL/CONTRACT

contracture- result of a contractile wound-healing process occurring in a scar that has already been re-epithelialized and adequately healed

Question 24

local and systemic factors influencing repair/regeneration process

Answer 24

local:
infection
persistence of insult (Hep C and alcohol)
trauma- early movement prior to complete repair
trauma- foreign material
size/location

systemic:
nutritional (impairs collagen synthesis)
-protein deficiency
-Vit C deficiency
metabolic- delay repair
-diabetes
glucocorticoids: inhibit collagen synthesis
vascular: ischemia, venous drainage
arteriosclerosis and atherosclerosis
venous drainage impairment: varicose veins

Question 25

5-lipoxygenase and COX-1 and COX-2

Answer 25

5-lipoxygenase: critical enzyme in pathway for production of leukotrienes from arachidonic acid COX-1 and COX-2 are critical for prostaglandin formation critical for acute inflammation response

Question 26

COX-1 vs COX-2 ``` expression tissue locale physiologic role inducers inhibitors ```

Answer 26

COX-1 constitutively GI, platelets, kidney, vascular smooth muscle, bone inc aggregation, inc renal blood flow, vasodilation/cons, bone form/resorb baseline levels of activity at all times actions diminished by NSAID use COX-2 as needed, in inflamed tissue areas of pain, hypothalamus, fever, kidney, endothelia, uterine SM, ductus arterioles enhance edema, heat, stress, vasodilator, anti-aggregators to platelets, inc contractions IL-1, IL-2, INFgamma, lipopolysaccharides, shear stress, growth factors diminished by NSAID use

Question 27

effects of prostaglandins on:

Answer 27

vascular smooth muscle: PGE2/I2 causes vasodilation TXA2 causes vasoconstriction platelets: TXA2 has pro-aggregators effect GI tract smooth muscle/secretory cells: PGE2/PGI2 inhibit HCl secretion, increase mucous secretion, inc smooth muscle contractions kidney: PGE2/PGI2 increases renal blood flow, promotes diuresis uterus: PGF2a/E2 induces contractions inflammatory cells: PGE2/PGI2 potentiate pain, edema, fever NSAIDs that inhibit COX-w would possess therapeutic actions (pain, fever, inflammation relief) -potential side effects: acute renal failure, thrombototic events, prolonged gestation inhibiting COX-1 produces potential side effects of GI ulceration and prolonged bleeding time, and acute renal failure

Question 28

effects of leukotrienes on inflammatory cell func and pulm/vascular smooth muscle

Answer 28

LTB4: neutrophil chemotaxis, aggregation, and transmigration through endothelium LTC4/LTD4/LTE4: inc vascular permeability, bronchoconstriction, vasoconstriction -important in pathophys of asthma, psoriasis, arthritic/allergic/hypersensitive processes

Question 29

interaction of prostacyclin and thromboxane A2 related to vascular smooth muscle and platelets

Answer 29

thromboxane effects: vascular smooth muscle- constriction (mainly in platelets) platelets- aggregation ``` prostacyclin effects (opposite): vascular smooth muscle- dilation (mainly in endothelium) platelets- disaggregation ```

Question 30

effect on COX 1 and 2 aspirin acetaminophen NSAIDs COX-2 selective inhibitors effect on COX therapeutic use adverse rxns

Answer 30

Aspirin: 1 and 2 irreversible analgesic, antipyretic, anti-inflammatory, antithrombotic GI irritation, inc bleeding, allergy, avoid if flu, pregnant, renal insufficiency acetaminophen: neither analgesic and antipyretic properties; not a true NSAID less GI symptoms, CNS COX2 NSAIDs 1 and 2 reversible analgesic, antipyretic, anti-inflammatory, antithrombogenesis GI, bleeding, renal failure/nephritis, low uterine contractions, inc MI, inc stroke COX-2 selective inhibitors 2 reversible analgesic, antipyretic, anti-inflammatory less GI, inc MI, inc stroke (due to platelet comparaggregation)

Question 31

aspirin at low doses is able to exert anti-thrombotic/cardioprotective effect vs COX2 selective agents:

Answer 31

aspirin is irreversible COX-1 and 2 inhibitor @ low doses: active aspirin concentrates in hepatic portal vein; selective inhibitory effect on platelet COX1 and endothelial COX2; preferentially inhibitory effect on COX1; blocks pro-clotting COX1 = antithrombotic effect COX1 selective bc as soon as COX2 is knocked out, body starts making more faster; gives you temporal advantage @ high dose: no conc gradient is generated between platelet and endothelial; balance each other out; no effect COX-2 selective agents: COX2 is expressed to prevent clotting inhibiting COX2 allows COX1's pro-aggregation to increase thrombus formation no COX2 = clotting

Question 32

``` therapeutic uses metabolism/excrete common side effects overdose toxicity contraindications D-D interactions ``` aspirin acetaminophen ibuprofen celicoxib

Answer 32

aspirin: analgesic, antipyretic, anti-inflame, antithrombotic Phase 2, renal GI irr, bleeds, allergies severe acidosis avoid when flu, pregnant, renal insufficiency phenytoin, Warfarin, alcohol, Lithium ``` Acetaminophen: analgesic, antipyretic Phase 2 inc hepatic enzymes, CNS madness liver damage can take when pregnant alcohol induces formation of hepatotoxic metabolite ``` ibuprofen: analgesic, antipyretic, anti-inflammmatory hepatic, renal GI (less than aspirin), reversible platelet effects -- pregnant -- Celicoxib: analgesic, antipyretic, anti-inflame, reversible inhibit of COX2 hepatic, renal renal, CV events, better for GI and platelets -- pregnant Warfarin-inc bleed chances

Question 33

regulation of glucocorticoid secretion by hypothalamic-pituitary-adrenal gland axis

Answer 33

3 modes of regulation: diurnal rhythm -sleep/wake cycles; hypothalamus release CRH; anterior pituitary releases ACTH; cortisol release negative feedback - circulating corticosteroids; regulates (neg feedback) on hypothalamus and pituitary; dec ACTH release + steroidogenesis - chronic pharmacologic doses of glucocorticoids can suppress HPA axis; adrenal atrophy and insufficient adrenal response (neg feedback) stress- hemorrhage, severe infection, surgery, hypoglycemia, cold, pain, fear; overrides negative feedback; anterior pituitary releases ACTH; cortisol releases

Question 34

effects associated with glucocorticoids and adverse effects when use as pharmacotherapeutic agents

Answer 34

glucocorticoids are used in inflammatory-type disorders incl: allergic rxns, collagen-vascular probs, eye disease, GI disease, hematologic disorders, neurologic disorders, pulm disease, skin disease, hypercalcemia, mtn sickness adrenal crisis, hyperglycemia-diabetes like states, tissue breakdown and muscle wasting, atrophy of skin and CT, centripetal obesity mineralocorticoid effects: inc absorption of Na, more secretion of H+ and K+, hypertension, edema, hypokalemia, metabolic acidosis

Question 35

describe how glucocorticoid agents are used as anti-inflammatory and immunosuppressive drugs

Answer 35

Glucocorticoids act by suppressing T-cell activation, suppressing cytokine production, and preventing mast cells and eosinophils from releasing various chemical mediators of inflammation [histamine, prostaglandins, leukotrienes and other substances] that cause tissue damage, vasodilation and edema.

Question 36

hydrocortisone

Answer 36

glucocorticoid- mineralocorticoid actions physiologic doses as replacement therapy- emergencies

Question 37

prednisone turning into prednisolone

Answer 37

glucocorticoid- mineralocorticoid actions activated in liver- first pass hepatic metabolism most commonly used oral agent for steroid burst therapy

Question 38

methylprednisolone

Answer 38

minimal mineralocorticoid action steroid burst

Question 39

dexamethasone

Answer 39

most potent anti-inflammatory agent no mineracorticoid action treat cerebral edema, chemotherapy-induced vomiting greatest suppression of ACTH secretion at pituitary

Question 40

triamcinolone

Answer 40

no mineralocorticoid action potent systemic agent

Question 41

mineralocorticoid and glucocorticoid effects

Answer 41

mineralocorticoid: salt and water retention; edema; hypertension; hypokalemia glucocorticoid: glucose intolerance in diabetics, mood changes, insomnia, GI upset

Question 42

glucocorticoid relative salt retaining activity vs anti-inflammatory activities ``` glucocorticoid activity (anti-inflammatory/dec ACTH) mineralocorticoid activity (salt retention) route of admin ``` ``` hydrocortisone prednisone methylprednisolone dexamethasone triamcinolone fludrocortisone ```

Answer 42

hydrocortisone moderate moderate oral; parenteral prednisone moderate-high moderate oral IV methylprednisolone high minimal oral IV dexamethasone high minimal oral parenteral triamcinolone moderate none oral depot fludrocortisone moderate high -?

Question 43

rationale for alternate day therapy and tapered withdrawal following chronic glucocorticoid therapy

Answer 43

alternate day schedule: can minimize adverse side effects of using corticosteroids give drugs on non-consecutive days anti-inflammatory actions last longer than suppressive effect on HPA axis use after disease control is achieved make gradual transition from daily to alternate tapered withdrawal following chronic therapy: pt's body gets hooked if taken > 7 days cause severe rebound of disease or adrenal crisis

Question 44

transudate vs exudate ``` definition etiology protein:serum ratio specific gravity fluid glucose ratio leukocyte number ```

Answer 44

``` transudate: plasma leaking from capillaries inc hydrostatic pressure or dec osmotic pressure dec dec inc (think nutrition) not many ``` ``` exudate: protein rich fluid leaking from vessels due to inflammation inflammation inc inc dec many, due to infection ```

Question 45

Virchow's Triad involvement in thrombosis

Answer 45

3 factors that promote thrombosis (blood clot) abnormal blood flow -turbulent; causing whirls in blood; slower flow means clotting factors can build up, esp in deep leg veins endothelial injury -can cause hyperactive clotting cascade hypercoagulability - factor V Leiden: makes clotting harder to turn off - disseminated cancer: makes you more likely to clot

Question 46

formation and consequences of embolus formation in right and left side circulation

Answer 46

most common type of embolus: thromboembolus formation: via Virchows Triald left (arterial)- can affect any organ (common in legs or brain) right (venous)- commonly lodges in lungs, slow blood flow in legs; DVT; thrombus gets bigger/less stable; can break off and flow freely through vessels; get stuck in small (lung) vessels; prevent blood flow; pulmonary embolism

Question 47

cariogenic, hypovolemic, septic shock

Answer 47

shock: can't perfuse tissue with enough blood cardiogenic- heart not pumping well enough hypovolemic- not enough blood volume septic- from infection (bac, fungal)

Question 48

infarction, features, arterial vs venous, total vs partial obstruction, reversibility, healing, modifying factors

Answer 48

infarct- area of necrosis caused by ischemia classified as red (hemorrhagic) or white (anemic) irreversible necrosis arterial: white total and partial obstruction can lead to: -total obstruction of target tissue -no infarction (tissue supplied by collateral arteries) heart, kidney, spleen venous: red loose tissue; permits movement of blood into necrotic area; harder to infarct due to dual blood supply lung, liver, intestine

Question 49

disseminated intravascular coagulation

Answer 49

DIC: thrombosis and hemorrhage occurs simultaneously endothelial cell injury; release procoagulants; activate clotting; widespread thrombosis; consumption of platelets and clotting factors; continued bleeding

Question 50

edema

Answer 50

fluid movement out of capillaries into adj tissue due to inc hydrostatic P and dec plasma oncotic P heart failure fluid overload (infusion, renal failure) venous obstruction/compression arteriolar dilation dec oncotic P- protein loss (kidney, GI) low protein production (liver, malnutrition)

Question 51

effusion

Answer 51

fluid movement out of capillaries and into body cavity similar to edema- due to inc in hydrostatic P and dec in plasma oncotic P

Question 52

hyperemia

Answer 52

active inc in blood flow due to arteriolar dilation

Question 53

congestion

Answer 53

pathologic accumulation of blood due to impaired outflow of venous blood accumulation of deoxygenation

Question 54

hemorrhage

Answer 54

blood outside vasculature due to vessel damage

Question 55

ischemia

Answer 55

dec blood supply to tissue due to vessel problems

Question 56

hypoxia

Answer 56

dec oxygen supply to tissue can be caused by ischemia

Question 57

thrombus

Answer 57

blod clot due to Virchow triad

Question 58

embolus

Answer 58

detached, traveling intravascular mass many causes

Question 59

vegetation

Answer 59

infected mass due to growth of bac

Question 60

pericardial, pleural effusions and ascites

Answer 60

pericardial- fluid build up in pericardial cavity (between heart and surrounding sac) pleural- in pleural cavity ascites- in peritoneal cavity

Question 61

key concepts of normal cell growth and differentiation control

Answer 61

morphogenesis (normal func) starts w/ single cell and ends w/ complex multicellular organism w/ specialized tissues cells can: proliferate, migrate, differentiate, change relationship to neighbors, apoptose

Question 62

``` hypertrophy hyperplasia metaplasia dysplasia neoplasia tumor ```

Answer 62

hypertrophy- inc in cell size physiologic (pregnant uterus) or pathologic (cardiac hypertrophy) hyperplasia- inc in cell number breasts during puberty/pregnancy pathologic (endometrium); may predispose to neoplasia metaplasia- change from one cell type to another; usually response to injury (inflammation); may predispose to neoplasia dysplasia- "disordered growth" in epithelia; hallmark of premalignant neoplasia; loss of cytologic uniformity; loss of normal histologic maturation; loss of architectural orientation neoplasia- autonomous, progressive cell growth, involving clonal cell pop tumor- "swelling" originally; but generally synonymous with neoplasm

Question 63

gross and microscopic benign and malignant neoplasms

Answer 63

benign may remain non-invasive or progress to malignant malignant synonymous with cancer; hallmark is "tumor progression"- invade surrounding tissue and vasculature, seed distant organs (metastasis)

Question 64

malignant neoplasms

Answer 64

etiology: age, lifestyle/environment, occupational hazards, radiation, infectious agents, chronic inflammation, genetics epidemiology: 1 in 5 Americans will die of cancer biology: activate growth-promoting oncogenes and inactivate growth-inhibitory tumor suppressor genes -genetic mutation, gene copy amplification/deletion, promoter methylation, chromosomal translocations limitless replicative potential and angiogenesis

Question 65

TNM classification

Answer 65

TNM is used for "staging" T= size of tumor and whether it's invaded nearby tissue N= any lymph nodes involved M= distant metastasis looked at collectively to stage a cancer different scales used for different cancers; used to determine prognosis no TNM classification for brain tumors

Question 66

Sate of Colorado Certificate of Death Forms

Answer 66

immediate cause of death: disease, injury, or complication (resulting from underlying cause) underlying cause of death: disease or injury that initiated the chain of events leading to death avoid using "mechanisms of death" (like arrhythmia, cardiac arrest, which are result of anatomic abnormality) which don't belong on death certificate "manner of death" is based on clinical scenario- natural, accidental, suicide, homicide, undetermined

Question 67

pulmonary embolism effects

Answer 67

sudden death find a clot in pulmonary artery usually coming from deep veins in legs

Question 68

right congestive heart failure clinical features

Answer 68

heart failure cells (macrophages filled with hemosiderin) could be found any place nutmeg liver hepatosplenomegaly congestion

Question 69

hypertension in vessels and myocardium

Answer 69

could have brain hemorrhage, specifically in basal ganglia or intraventricular spaces that start as Charot Bouchard aneurisms, as well as glomerulosclerosis leading to infarcts and fibrosis in kidney

Question 70

define metastasis

Answer 70

transfer of malignant cells from primary site to secondary site -tumors discontinus with primary tumor invasion of basement membrane

Question 71

mechanisms of metastasis

Answer 71

pre-invasive stage "carcinoma in situ" -epithelial cells appear malignant, but haven't invaded basement membrane yet 3 pathways cancer can spread "dissemination": direct seeding of body cavities or surfaces "hopping along tissue" - cancer breaks off and seeds somewhere else - ovarian cancer lymphatic spread - intra and extravasation occurs in lymph - most common route of metastasis for carcinomas (not sarcomas) hematogenous spread - intra and extravasation occurs in blood - most common route of metastasis for sarcomas

Question 72

theories metastasis motive

Answer 72

may be adventitious for primary tumor to metastasize - strong direct relationship between primary tumor size and risk of metastasis - selection pressure- crowded/harsh conditions in primary tumor; move out! - reach oxygen and nutrient diffusion limits - growing faster than it can vascularize cancer can: - modify cell metabolism to effectively support neoplastic proliferation (allows cancer to evade immunological destruction) - genetic instability drives tumor progression - inflammatory responses feed tumor growth

Question 73

theories metastasis occurs

Answer 73

carcinoma cells must invade ECM by: breeching underlying basement membrane traverse interstitial CT gain access to circulation by penetrating vascular basement membrane (called intravasation) ``` via: changes "loosening up" of tumor cell-cell interactions -dissociation of cells from e/o -loss of E-cadherin degradation of ECM attachment to ECM components migration of tumor cells ```

Question 74

4 major theories to explain bias of metastasis toward certain organs

Answer 74

- caused by rare variant clones that develop in primary tumor - caused by gene expression pattern of most cells of primary tumor, referred to as metastatic signature - combo of A and B - greatly influenced by the tumor microenvironment, which affects angiogenesis, local invasiveness, and resistance to immune elimination

Question 75

metastatic cascade

Answer 75

invasion through basement membrane and ECM -causes loss of E-cadherin, so cells can't adhere to e/o intravasation- getting into blood/lymph extravasation- getting out of vessel at new site colonization- ability to grow at new site

Question 76

ultimate effects of metastases

Answer 76

direct: invasive masses directly interfere with normal func indirect: "paraneoplastic syndrome" (paracrine/endocrine effects) think hormones or cytokines disease or symptom that is a consequence of cancer ``` mortality: 42% infection 19% organ failure 12% thromboembolism 9% hemorrhage 8% emaciation ```

Question 77

epidemiology implicating environmental factors causing most cases of cancer

Answer 77

80% of all malignant neoplasms caused by environmental factors this concl is largely based on variations in incidence of specific types of cancer seen among different regions of a country and countries around world; and from different rates between immigrants and the population that the immigrants left many types, therefore, should be preventable if the significant risk factors in environment could be identified (or anti-risk factors)

Question 78

3 most common types of cancer in men and women other than skin cancer leading types for mortality

Answer 78

``` males: prostate, lung, colon/rectum deaths: 34% lung 12% prostate 11% colon/rectum ``` ``` females: breast, lung, colon/rectum deaths: 21% lung 18% breast 13% colon/rectum ```

Question 79

how environmental chemicals can cause cancer and "activation" by microsomal enzymes

Answer 79

4 main compd groups studied as carcinogens: polycyclic aromatic hydrocarbons (burning fossil fuels) aromatic amines (aniline dyes) nitrosamines (processed meat) aflatoxins (mold) each must be activated to a carcinogenic form by microsomal enzymes (cytochrome P450) the active metabolite is a strong electrophile electrophilic species can modify protein, RNA, and DNA

Question 80

Ames test

Answer 80

an elegant test which measures the ability of a given chemical to "mutagenize" a set of specific strains of the bacterium Salmonella typhimurium. These tester strains are His- (they require histidine for growth because one of the genes for the biosynthesis of histidine is mutated) suspected mutagen is applied to a central disc on bac agar plate containing media w/o histamine, 108 His- bad, and crude fraction of liver microsomal enzymes if a chem is mutagenic, then large numbers of His+ revertants arise around central disc

Question 81

principles of carcinogenesis learned from animal testing

Answer 81

about 90% of carcinogens tested are mutagens in the Ames test potency parallels carcinogenicity carcinogenesis requires time- several years carcinogenesis requires cell proliferation cell changes triggering carcinogenesis are transmitted to daughter cells (cancer cells resemble e/o moreso than the tissue they came from) stem cell is most at-risk for becoming malignant (fully differentiated cell can't) a malignant cell is a stem cell that fails to differentiate normally; differentiation is aberrant and incomplete

Question 82

adjuvant neoadjuvant primary chemotherapy options

Answer 82

adjuvant- after local treatment, trying to kill micro metastases neoadjuvant- before localized treatment such as surgery, trying to make that treatment more effective and less damaging primary- on its own with no other therapy in a few cases curative, more often for palliation of symptoms in patients with advanced disease

Question 83

targeted therapies vs conventional cytotoxics

Answer 83

conventional agents damage normal cells as well as tumor cells- therapeutic window is largely based on tumor cells being closer to their apoptotic threshold, MTD relevant for conventional agents less so for targeted agents, which are usually less toxic, resistance mechanisms different remember: conventional cytoxics hit specific targets just like targeted agents do, but the difference is that with the newer targeted agents we aim to hit a target that is different/faulty in tumor cells but not normal cells

Question 84

basis for combining anti-tumor agents

Answer 84

combine agents that work to some extent on their own (but avoid overlapping toxicities), using drugs at optimal doses, and keep treatment-free schedules as short as possible works: heterogeneity in tumor cell population needs different drugs to attack it

Question 85

anti-tumor agent info

Answer 85

mech of action: DNA damaging agents, toposiomerase interacting agents, microtubule interacting agents, hormonal agents, antibodies, kinase inhibitors resistance mechs generally applicable: drug efflux through transporters resistance to apoptosis resistance mechs specific to agent: mutations in drug target, activation of repair mechs, other ways to activate steroid receptors many drugs have similar toxicities- usually associated with damage to fast growing cells (GI toxicity, myelosuppression) specific toxicities depend upon mech of action -neurotoxicity associated with microtubule-interacting agents