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hypoxia and the patient has exertional dyspnea with anemia, exercise intolerance.
a. Carbon monoxide (CO): classic heater in winter; in a closed space with a heater (heater have many combustable materials;
automobile exhaust and house fire. In the house fire scenario, two things cause tissue hypoxia:
1) CO poisoning and 2) Cyanide poisoning b/c upholstery is made of polyurethrane products. When theres heat, cyanide gas is
given off; therefore pts from house fires commonly have CO and cyanide poisoning.
CO is very diffusible and has a high affinity for Hb, therefore the O2 saturation, will be decreased b/c its sitting on the heme
group, instead of O2 (remember that CO has a 200X affinity for Hb).
(Hb is normal its NOT anemia, pO2 (O2 dissolved in plasma) is normal, too); when O2 diffuses into the RBC, CO already sitting there,
and CO has a higher affinity for heme. To treat, give 100% O2. Decrease of O2 satn = clinical evidence is cyanosis
Not seen in CO poisoning b/c cherry red pigment MASKS it, therefore makes the diagnosis hard to make. MC symptom of CO
poisoning = headache
b. Methemoglobin:
Methemoglobin is Fe3+ on heme group, therefore O2 CANNOT bind. Therefore, in methemoglobin poisoning, the only thing screwed
up is O2 saturation (b/c the iron is +3, instead of +2). Example: pt that has drawn blood, which is chocolate colored b/c there is no O 2
on heme groups (normal pO2, Hb concentration is normal, but the O 2 saturation is not normal); seat is empty, but cannot sit in it, b/c
its +3. RBCs have a methemoglobin reductase system in glycolytic cycle (reduction can reduce +3 to +2).
Example: Pt from rocky mountains was cyanotic; they gave him 100% O 2, and he was still cyanotic (was drinking water in mountains
water has nitrites and nitrates, which are oxidizing agents that oxidize Hb so the iron become +3 instead of +2). Clue was that O 2 did
not correct the cyanosis. Rx: IV methylene blue (DOC); ancillary Rx = vitamin C (a reducing agent).
Most recent drug, Dapsone (used to Rx leprosy) is a sulfa and nitryl drug. Therefore does two things:
1) produce methemoglobin and 2) have potential in producing hemolytic anemia in glucose 6 phosphate dehydrogenase deficiencies.
Therefore, hemolysis in G6PD def is referring to oxidizing agents, causing an increase in peroxide, which destroys the RBC; the same
drugs that produce hemolysis in G6PD def are sulfa and nitryl drugs. These drugs also produce methemoglobin. Therefore, exposure
to dapsone, primaquine, and TMP-SMX, or nitryl drugs (nitroglycerin/nitroprusside), there can be a combo of hemolytic anemia,
G6PD def, and methemoglobinemia b/c they are oxidizing agents. Common to see methemoglobinemia in HIV b/c pt is on TMP-SMX
for Rx of PCP. Therefore, potential complication of that therapy is methemoglobinemia.
c. Curves: left and right shifts
Want a right shifted curve want Hb with a decreased affinity for O 2, so it can release O2 to tissues. Causes: 2,3 bisphosphoglycerate
(BPG), fever, low pH (acidosis), high altitude (have a resp alkalosis, therefore have to hyperventilate b/c you will decrease the CO 2,
leading to an increase in pO2, leading to a right shift b/c there is an increase in synthesis of 2,3 BPG).
Left shift CO, methemoglobin, HbF (fetal Hb), decrease in 2,3-BPG, alkalosis Therefore, with CO, there is a decrease in O 2 satn
(hypoxia) and left shift.
4. Problems related to problems related to oxidative pathway
a. Most imp: cytochrome oxidase (last enzyme before it transfers the electrons to O 2. Remember the 3 Cs cytochrome oxidase,
cyanide, CO all inhibit cytochrome oxidase.
Therefore 3 things for CO (1) decrease in O 2 sat (hypoxia), (2) left shifts (so, what little you carry, you cant release), and (3) if you
were able to release it, it blocks cytochrome oxidase, so the entire system shuts down
b. Uncoupling ability for inner mito membrane to synthesize ATP. Inner mito membrane is permeable to protons. You only want
protons to go through a certain pore, where ATP synthase is the base, leading to production of ATP; you dont want random influx of
protons and that is what uncoupling agents do.
Examples: dinitrylphenol (chemical for preserving wood), alcohol, salicylates. Uncoupling agents causes protons to go right through
the membrane; therefore you are draining all the protons, and very little ATP being made. B/c our body is in total equilibrium with
each other, rxns that produce protons increase (rxns that make NADH and FADH, these were the protons that were delivered to the
electron transport system). Therefore any rxn that makes NADH and FADH that leads to proton production will rev up rxns making
NADH and FADH to make more protons. With increased rate of rxns, leads to an increase in temperature; therefore, will also see
HYPERTHERMIA. Complication of salicylate toxic = hyperthermia (b/c it is an uncoupling agent).
Another example: alcoholic on hot day will lead to heat stroke b/c already have uncoupling of oxidative phosphorylation
(b/c mito are already messed up). These are all the causes of tissue hypoxia (ischemia, Hb related, cyto oxidase block, uncoupling
agents). Absolute key things!
5. What happens when there is:
a. resp acidosis Hb stays same, O2 satn decreased, partial pressure of O2 decreased (O2 sat decreased b/c pO2 is decreased)
b. anemia only Hb is affected (normal O2 satn and pO2)
c. CO/methemoglobin Hb normal, O2 satn decreased, pO2 normal
Rx CO 100% O2; methemo IV methyline blue (DOC) or vit C (ascorbic acid)
5. Aspirin + Tylenol = very bad for kidney (takes a long time for damage to be seen). Free radicals from acetaminophen
are destroying the renal medulla *only receives 10% of the blood supply-relatively hypoxic) and renal tubules. Aspirin is
knocking off the vasodilator PGE2, which is made in the afferent arteriole. Therefore AG II (a vasoconstrictor) is left in
charge of renal blood flow at the efferent arteriole. Either sloughing of medulla or destroyed ability to concentrate/dilute
your urine, which is called analgesic nephropathy (due mainly to acetaminophen).
III. Apoptosis
Programmed cell death. Apoptotic genes programmed to die (theory). Normal functions:
(1) embryo small bowel got lumens from apoptosis.
(2) King of the body Y chromosome (for men); MIF very imp b/c all mullarian structures (uterus, cervix, upper 1/3 of vagina) are
gone, therefore, no mullarian structures. MIF is a signal working with apoptosis, via caspasases. They destroy everything, then wrap
everything in apoptotic bodies to be destroyed, and lipofuscin is left over.
(3)For woman Xchromosome; only have one functioning one b/c the other is a barr body. Absence of y chromosome caused
germinal ridge to go the ovarian route, therefore apoptosis knocked off the wolfian structures (epidydymis, seminal vesicles, and vas
deferens).
(4)Thymus in anterior mediastinum large in kids; if absent, it is DiGeorge syndrome (absent thymic shadow), and would also
have tetany; cause of thymus to involute is apoptosis.
(5) Apoptosis is the major cancer killing mechanism.
(6) Process of atrophy and reduced cell or tissue mass is due to apoptosis. Ex. Hepatitis councilman body (looks like eosinophilic
cell without apoptosis) of apoptosis (individual cell death with inflammation around it). Just needs a signal (hormone or chemical)
which activate the caspases, and no inflammation is around it. Apoptosis of neurons loss brain mass and brain atrophy, and leads to
ischemia. Red cytoplasm, and pynotic nucleus. Atherosclerotic plaque. Therefore, apoptosis is involved in embryo, pathology,
and knocking off cancer cells.
IV. Types of necrosis manifestations of tissue damage.
A. Coagulation Necrosis: Results often from a sudden cutoff of blood supply to an organ i.e. Ischemia (definition of ischemia
= decrease in arterial blood flow). In ischemia, there is no oxygen therefore lactic acid builds up, and leads to coagulation necrosis.
Gross manifestation of coagulation necrosis is infarction. Under microscope, looks like cardiac muscle but there are no striations, no
nuclei, bright red, no inflammatory infiltrate, all due to lactic acid that has denatured and destroyed all the enzymes (cannot be broken
down neutrophils need to come in from the outside to breakdown). Therefore, vague outlines = coagulation necrosis (see color
change in heart).
1. Pale vs hemorrhagic infarctions: look at consistency of tissue.
(a) Good consistency = grossly look pale: infarct: heart, kidney, spleen, liver (rarest of the organ to infarct b/c dual blood
supply); ie coagulation necrosis. Example of a pale infarction of the spleen, most likely due to emboli from left side of
heart; causes of emboli: vegetations (rarely embolize in acute rheumatic fever); infective endocarditis; mitral
stenosis (heart is repeatedly attacked by group A beta hemolytic streptococcus); and clots/thrombi. The worst arrhythmia
associated with embolization in the systemic circulation is atrial fib b/c there is stasis in the atria, clot formation, then it
vibrates (little pieces of clot embolize).
Gangrenous Necrosis: dry and wet gangrene: Picture of a dry gangrene not wet gangrene b/c theres no pus. Occurs
in diabetics with atherosclerosis of popliteal artery and possible thrombosis; (dry gangrene related to coagulation necrosis
related with ischemia (definition of ischemia = decrease in arterial blood flow), which is due to atherosclerosis of the popliteal artery.
Pathogenesis of MI: coronary thrombosis overlying the atheromatous plaque, leading to ischemia, and lumen is blocked due to
thrombosis. MCC nontraumatic amputation = diabetes b/c enhanced atherosclerosis (popliteal artery = dangerous artery).
Coronary is also dangerous b/c small lumen. In wet gangrene, its complicated by infective heterolysis and consequent liquefactive
necrosis (b) Loose consistency of tissue= hemorrhagic infarct: bowel, testes (torsion of the testes), especially the lungs b/c is has a
loose consistency and when the blood vessels rupture, the RBCs will trickle out, leading to a hemorrhagic appearance.
Example: hemorrhagic infarction of small bowel due to indirect hernia. 2nd MCC of bowel infarction is getting a piece of small bowel
trapped in indirect hernial sac. MCC of bowel infarction is adhesions from previous surgery.
Example: In the Lung hemorrhagic infarction, wedge shaped, went to pleural surface, therefore have effusion and exudates;
neutrophils in it; have pleuritic chest pain (knife-like pain on inspiration). Pulmonary embolus leads to hemorrhagic infarction.
B. Liquefactive Necrosis:
Exception to rule of Coagulation necrosis seen with infarctions: brain.
MC site of infarction from carotid artery why we listen for a bruit (hearing for a noise that is going thru a vessel that has a
narrow lumen place with thrombus develops over atherosclerotic plaque and leads to stroke); leads to transient ischemic
attacks is little atherosclerotic plaques going to little vessels of the brain, producing motor and sensory abnormalities, that
go away in 24 hrs. Brain with meshwork in brain, astrocytes is analogous to the fibroblasts b/c of protoplasmic processes.
Therefore, acting like fibroblast (cant make collagen), but its protoplasmic processes gives some structure to the brain. Therefore,
infarction of the brain basically liquefies it (has no struct), and you see a cyst space liquefactive necrosis. Therefore, exception to the
rule of infarctions not being coagulative necrosis is the brain and it undergoes liquefactive necrosis (no struc, therefore leaves a hole).
Cerebral abscess and old atherosclerotic stroke -both are liquefactive necrosis. Liquefactive liquefies; think neutrophil, b/c their job
is to phagocytosis with their enzymes (to liquefy); liquefactive necrosis relates to an infection with neutrophils involved (usually
acute infection producing an abscess or an inflammatory condition, which liquefies tissue). Therefore, liquefactive necrosis usually
applies to acute inflammation, related to neutrophils damaging the tissue. Exception to the rule: liquefactive necrosis related to infarct
(not an inflammatory condition, it just liquefies) (slide shows liquefactive necrosis due to infection in the brain). So, if you infarct the
brain, or have an infection, or have an abscess it is the same process liquefactive necrosis.
Example: Abscess gram + cocci in clusters. Why are they in clusters? Coagulase, which leads to abscesses with staph aur.
Coagulase converts fibrinogen into fibrin, so it localizes the infection, fibrin strands get out, resulting in an abscess.
Strep: releases hyaluronidase, which breaks down GAGs in tissue, and infection spreads through the tissue (cellulitis).
From point of view of necrosis, neutrophils are involved, therefore it is liquefactive necrosis.
Example: ABSCESS: Lung yellowish areas, high fever and productive cough; gram stain showed gram + diplococcus,
which is strep pneumoniae. (MCC of bronchopneumonia.). Not hemorrhagic b/c its pale, and wedged shaped necrosis at the
periphery, which leads to pleuritic chest pain.
Example: pt with fever, night sweats, wt loss M tb, which has granulomatous (caseous) necrosis. Pathogenesis of granuloma
(involves IL-12 and subset of helper T cells and + PPD).
C. Caseous (cheesy consistency) Necrosis: either have mycobacterial infection (any infections, including atypicals, or systemic
fungal infection); these are the ONLY things that will produce caseation in a granuloma. It is the lipid in the cell wall of the organisms
leads to cheesy appearance. Sarcoidosis get granulomas, but they are not caseous b/c they are not mybacterium or systemic fungi
(hence noncaseating granulomas). Crohns dz get granulomas, but not caseous b/c not related to mycobacterium or systemic fungi.
D. Fat Necrosis:
1. Enzymatic Fat Necrosis: unique to pancreas
Example: pt with epigastric distress with pain radiating to the back pancreatitis (cannot be Peptic Ulcer Dz b/c pancreas is
retroperitoneal), therefore just have epigastric pain radiating to the back. A type of enzymatic FAT necrosis (therefore necrosis related
to enzymes). Enzymatic fat necrosis is unique to the pancreas b/c enzymes are breaking down fats into FAs, which combine with Ca
salts, forming chalky white areas of enzymatic fat necrosis (chalky white areas due to calcium bound to FAs saponification
(soap/like salt formation)); these can be seen on x-rays b/c have calcium in them.
Example: A pt with pain constently penetrating into the back, show x-ray of RUQ. Dx is pancreatitis and esp seen in alcoholics. Histo
slide on enzymatic fat necrosis bluish discoloration, which is calcification (a type of dystrophic calcification-calcification of
damaged tissue). What enzyme would be elevated? Amylase and lipase (lipase is more specific b/c amylase is also in the parotid
gland, small bowel, and fallopian tubes). What type of necrosis? Another example: Enzymatic fat necrosis.
Underlying cause? Alcohol produces a thick secretion that will lead to activation of enzymes; which leads to pancreatitis.
Therefore, whenever you see blue discoloration and atherosclerotic plaque in a pancreas, it will be calcium.
2. Traumatic Fat Necrosis: Example: woman with damage to breasts is TRAUMATIC FAT necrosis (not enzymatic); it can
calcify, can look like cancer on mammogram. Diff btwn that and calcification in breast cancer is that it is painFUL. (cancer =
painless). Traumatic fat tissue usually occurs in breast tissue or other adipose tissue
E. Fibrinoid necrosis: (the -oid means: looks like, but isnt)
Therefore, looks like fibrin, but is not fibrin.it is the necrosis of immunologic dz:
Examples of immunologic dz:
Palpable purpura = small vessel vasculitis (immune complex type III)
Fibrinoid necrosis has immune complex deposition of small vessel.
Pathogenesis of immune complex: damage of type III HPY (an immune complex is an Ag-Ab circulating in the circulation; it
deposits wherever circulation takes it ie glomerulus, small vessel, wherever). It activates the complement system (the alt
system), which produces C5a, which is chemotactic to neutrophils. Therefore, damage done as a result of type III HPY is
done by neutrophils. And they are there b/c the immune complex activated the alternative complement system. The
complex has little to do with the damage, its the neutrophils do eventual damage)
Henoch-Scholein purpura feel persons legs, and see palpable purpura (due to type III HPY).
Rhematic fever (vegetations off the mitral valve) have fibrin like (fibrinoid necrosis) materials (necrosis of immunologic dz).
Morning stiffness = rheumatoid arthritis, see fibrnoid necrosis b/c immunologic damage. Therefore, fibrinoid necrosis is necrosis of
immunologic damage (in vessel its a vasculitis, in kidney its a glomerulonephritis, and in lupus glomerulonephritis involving
immune complexes).
F. Liver: Triad area: portal vein, hepatic artery, bile duct. Liver is unique b/c it has dual blood supply and so hepatic artery and
and portal vein will dump blood into sinusoids. Other examples of sinusoid organs are BM and spleen. Characteristic of
sinusoids: gaps between endothelial cells, with nothing there so things can fit through (things like RBCs and inflammatory cells).
GBM is fenestrated, have little tiny pores within the cells, for filtration. Sinusoids have gaps so large cells can get through them
(not true with GBM b/c it is intact, and lil pores allow filtration). Portal vein blood and hepatic artery blood go through sinusoids,
and eventually taken up by central vein, which becomes the hepatic vein. The hepatic vein dumps into the inf vena cava, which
goes to the right side of the heart. Therefore, there is a communication between right heart and liver. Right HF (blood fills
behind failed heart), therefore the liver becomes congested with blood, leading to nutmeg liver (aka congestive hepatomegaly).
If you block the portal vein, nothing happens to the liver, b/c it is BEFORE the liver. Blockage of hepatic vein leads to budd chiari
and liver becomes congested. Which part of liver is most susceptible to injury normally? Around central vein, b/c it gets first
dibbies on O2 coming out of the sinusoids (zone 1). Zone 2 is where yellow fever will hit (midzone necrosis) due to ides egypti.
Zone 3, around portal vein, which will have least O2 (analogous to renal medulla, which only receives 10% of the blood supply,
and the cortex receives 90%). Fatty change is around zone 3 (part around central vein). Therefore, when asking about
acetaminophen toxicity, which part is most susceptible? Around the central vein b/c it gets the least amount O2, and therefore
cannot combat free radical injury.
(b) Metabolism of alcohol: NADH and acetyl CoA (acetate is a FA, and acetyl CoA can be converted to FAs in the cytosol). NADH is
part of the metabolism of alcohol, therefore, for biochemical rxns: What causes pyruvate to form lactate in anaerobic glycolysis?
NADH drove it in that direction, therefore always see lactic acidosis (a form of metabolic acidosis) in alcoholics b/c increased NADH
drives it in that direction. Also, in fasting state, alcoholic will have trouble making glucose by gluconeogenesis b/c need pyruvate to
start it off. However, you have lactate (and not pyruvate) therefore alcoholics will have fasting hypoglycemia.
Acetyl CoA can also make ketone bodies (acetoacetyl CoA, HMG CoA, and beta hydroxybutyric acid). See beta hydroxybutyric
ketone bodies in alcoholics b/c its a NADH driven reaction. Therefore, two types of metabolic acidosis seen in alcoholics are lactic
acidosis (b/c driving pyruvate into lactate) and increased synthesis of ketone bodies b/c excess acetyl CoA; main ketoacid = beta
hydroxybutyric acid.
Why does it produce fatty change? In glycolysis, around rxn 4, get intermediates dihydroxyacetone phoshphate (NADH
rxn) and is forced to become glycerol 3-phosphate. Big time board question! With glycerol 3 phosphate shuttle, get
ATP. Also imp to carbohydrate backbone for making tryglycerides (add 3 FAs to glycerol 3 phosphate, and you get
TGs). In liver, the lipid fraction if VLDL (endogenous TG is synthesized in the liver from glycerol 3 phosphate derived from
glycolysis). Restricting fat will NOT decrease the synthesis of VLDL. Restricting carbs WILL decrease the VLDL synthesis b/c it is
glucose intermediate it is made from. Glycerol 3 phosphate is a product of glycolysis which is why fatty liver is most commonly due
to alcoholism (this rxn)!
Audio file 3: Inflammation 1
2. Kwashiorkor kid with fatty change. The mechanism: when you make VLDL, and to be able to get it out of the liver, the VLDL
must be surrounded by apoproteins. In kwashiorkor, there is decreased protein intake; they have adequate number of calories, but its
all carbs. Therefore, they cannot get VLDL that they made in the liver out b/c there are no apolipoproteins to cover it and put it out in
the bloodstream and solubilize it in water. Lipid and water do not mix; therefore it is necessary to put proteins around the lipid to
dissolve it in water. Therefore, the protuberant abdomen in these pts is there for two reasons: 1) decreased protein intake which
decreases oncotic pressure, leading to ascites. 2) The biggest reason is that they have huge livers related to fatty change. The
mechanism for fatty change is different from alcohol b/c in alcohol; the mech is due to increased synthesis of VLDL. In this case,
there is a lack of protein to put around the VLDL and export it out of the liver.
3. Hemosiderin and Ferrtin: brief discussion: Ferritin = soluble form of circulating Fe, and is a good marker for Fe in BM. It is the test
of choice in diagnosing any Fe related problem Fe def anemia, or Anemia of Chronic Dz or Fe overload dzs such as
hemochromatosis and hemosiderosis (would be elevated). Ferritin is a soluble form of Fe, while hemosiderin is an insoluble form of
Fe storage, and is stored in macrophages and BM. Stain it with Prussian blue.
V. Types of calcification: dystrophic and metastatic
A. Dystrophic calcification: means abnormal calcification. The damaged tissue gets calcified.
1. Example: Seen in enzymatic fat necrosis (chalky white areas on x-ray are a result of dystrophic calcification).
2. Example: football player with hematoma in foot, that becomes calcified dsystrophically (Ca binds and co-produces dystrophic Ca
deposits). Serum Ca is normal, but damaged tissue becomes calcified. Occurs in atheromatous plaques (causes serious tissue damage),
therefore they are difficult to dissolve (need to be on the ornish diet a vegan diet).
3. MCC aortic stenosis (MCC: congenital bicuspid aortic valve) = dystrophic calcification (also leads to a hemolytic anemia).
Slide: the aorta has only 2 valves doing the job of three, and gets damaged, leading to dystrophic calcification which
narrows orifice of valve, leading to aortic stenosis.
B. Metastatic calcification: In cases of Hypercalcemia or hyperphosphatemia, Calcium is actually made to deposit in normal
tissues, non-damaged tissues.
MCC hypercalcemia (outside of hospital) = primary hyperparathyroidism
MCC hypercalcemia (inside the hospital) = malignancy induced hypercalcemia.
With hypercalcemia, can put Ca in NORMAL tissues; this is called metastatic calcification. In dystrophic calcification there is
Damaged tissue with normal serum Ca levels. Metastatic calcification is when there is high Ca or phosphorus serum levels (actually
when Ca is deposited into bone, it is the phosphorus part of solubility product that drives Ca into bone). High phosphate levels (very
dangerous) will take Ca and drive it into normal tissue. This is why have to put a pt with renal failure on dialysis (have high
phosphorus serum levels) therefore need to dialyze the phosphate b/c the phosphate will drive Ca into normal tissue ie heart,
conduction system, renal tubules, basement membrane (nephrocalcinosis) all lead to damage.
VI. Cell Membrane Defects
A. RBC membrane defect: Spherocytosis is a defect in spectrin within RBC cell membrane; if you cant see a central area of
pallor (if you dont see a donut) then its a spherocyte. Absence of spectrin with in the RBC does not allow the RBC to form a
biconcave disk; it is defective, and therefore forms a sphere.
B. Ubiquitin stress protein. High ubiquitin levels are associated with high levels of stress. Some of the intermediate filaments
(keratin, desmin, vimentin) are part of the superstructure of our cells (frame of the cell, upon which things are built).
When these intermediate filaments get damaged, the ubiquitin marks then for destruction. The intermediate filaments have been
tagged (ubiquinated) and marked for destruction. Some of these products have names, for example: there are open spaces within the
liver tisse, these spaces are fat and they are probably due to alcohol. The ubiquinited products of the liver are called Mallory bodies.
These are the result of ubiquinated filaments called keratin and these are seen in alcoholic hepatitis.
Another example: Silver stain of neurofibilary tangles Jacob crutzfelt and alzheimers dz. Tau protein is associated with
neurofib tangles; this is an example of a ubiquinated neurofilament. Example: Substantia nigra in Parkinsons Dz include
inclusions called Lewy bodies, neurotransmitter deficiency is dopamine. Lewy bodies are ubiquinated neurofilaments. Therefore,
Mallory bodies, Lewy bodies, and neurofib tangles are all examples of ubiquintation.
VII. Cell Cycle- very very important: big big big time
A. Different types of cells:
1. Labile cells cell where the division is via a stem cell. Three tissues that has stem cells: bone marrow, basement membrane of skin,
and the base of crypts in the intestine. These cells have the tendency of being in the cell cycle a lot. In pharm: there are cell cycle
specific and cell cycle nonspecific drugs. The cells that are most affected by these drugs are the labile cells b/c they are in the cell
cycle. Complications of these drugs are BM suppression, diarrhea, mucocidis, and rashes on the skin (there are stem cells in all these
tissues!).
2. Stable cells in resting phase, Go phase. Most of perenchymal organs (liver, spleen, and kidney) and smooth muscle are
stable cells. Stable cells can ungo division, but most of the time they are resting, and something must stimulate them to get into the
cell cycle and divide ie a hormone or a growth factor. For example: estrogen in woman will help in the proliferative phase of the
menstrual cycle. The endometrial cells are initially in the Go phase and then the estrogen stimulated the cells to go into the the cell
cycle. Therefore, they can divide, but they have to be invited by a hormone or a growth factor.
3. Permanent cells can no longer get into the cell cycle, and have been permanently differentiated. The other types of muscle cells:
striated, cardiac and neuronal cells. Only muscle that is NOT a permanent tissue = smooth muscle; hyperplasia = increase in #, while
hypertrophy = increase in size. Would a permanent cell be able to under hyperplasia? NO, b/c that means more copies of it. Can it go
under hypertrophy? Yes. A smooth muscle cell can undergo hyperplasia AND hypertrophy.
B. Different phases of cell cycle:
1. G1 phase: The most variable phase of cell cycle is the G1 phase. Compare with menstrual cycle: The most variable phase
is the proliferative phase (not the secretory phase). The prolifertive phase varies with stress; however, once ovulation has
occurred, it is 14 days. Therefore, proliferative phase is analogous to G1 phase of the cell cycle b/c it can be shorter or lengthened;
none of the other phases (S, G2, and M phase) changes, they stay the same. Therefore, in cancer cells, ones with a longer cell cycle
will have a longer G1 phase, and cancer cells with a shorter cell cycle will have a shorter G1 phase.
G1 phase is the mastermind of everything. Cyclin dependent kinase (kinase = phosphorylation = activation).
Phosphorylation usually involves sending a message to activate something. Glucagon is a phosphorylator, while insulin is a
dephosphorylator. Glucagon will phosphorylate protein kinase and activate it, while Insulin would dephosphorylate protein
kinase and inactivate it.
G1 to S phase: Inactive Cyclin d dependent kinase: Cyclin d activates it, and G1 phase makes cyclin D. Once cyclin D is
made in the G1 phase, it then activates the enzyme: cyclin dep. kinase (therefore it is now active). Key area to control in cell cycle:
transition from G1 to S phase. Because if you have a mutation and it goes into S phase, it then becomes
duplicated, then you have the potential for cancer. Two suppressor genes that control the transition: (1) Rb suppressor
gene: located on chromosome 13, which makes the Rb protein, which prevents the cell from going from the G1 to the S
phase. In general, to go from G1 to S, the active cyclin dep kinase phosphorylates the Rb protein; when it is
phosphorylated=activation, it can go from the G1 phase to the S phase. A problem occurs if there is a mutation. Therefore
the enzyme is checked by (2) p53 suppressor gene: located on chromosome 17, which makes a protein product that inhibits
the cyclin d dep kinase. Therefore, it cannot go into the S phase; p53 is the number 1, most imp gene that regulates
human cancer.
Example: HPV inactivates Rb suppressor gene and p53 suppressor gene. HPV makes two genes products E6 (which
knocks off the p53) and E7 (which knocks of the Rb suppressor gene).
If you have a point mutation the Rb suppressor gene, the Rb suppressor gene is knocked off, there will be no Rb protein, and the cell
will progress to the S phase b/c it is uncontrolled. This mutation in the Rb suppressor gene predisposing to many cancers, such as
retinoblastoma, osteogenic sarcoma (ie kid with pain around knees, Codmans triangle sunburst appearance on x-rays), and breast
cancer (Rb suppressor can be involved). Depending on the age bracket, it hits in different areas. If you knock of p53 suppressor gene:
the kinase will be always active, it will always phosphorylate the Rb protein, and that means that it will always go into the S phase,
and this is bad. If you knock off any of those genes, the cell will go into the S phase. The p53 suppressor gene is the guardian of the
genome, b/c it gives the cell time to detect if there are any defects/abnormalities in the DNA (splicing defects, codon thing, whatever,
etc). DNA repair enzymes can splice out the abnormality, correct it, and the cell is ready to go to the S phase. If the cell has too much
damaged DNA, then it is removed by apoptosis. Therefore this gene is imp b/c it gives the cell an opportunity to clean its DNA before
going into the S phase.
2. S phase = synthesis phase, where everything is doubled, includes DNA and chromosomes (from 2N to 4N). For example:
if its in muscle, it will have double the number of contractile elements.
3. G2 phase = where tubulin is made (imp to microtubule of the mitotic spindle); it is blocked by etoposide and bleomycin.
4. M phase = mitosis; where the cell divides into two 2N cells. The cell can either go into the Go resting phase, or can
continue dividing in the cycle, or can be permanently differentiated. p53 gene makes a protein to inhibit the kinase,
therefore prevents the Rb protein from being phosphorylated, therefore stays in the G1 phase. Therefore, when you knock it
off, no one is inactivating the kinase, and the cell is constantly phosphorylated and that keeps the cell dividing, and then has
the potential to lead to cancer.
C. Drugs that act on the cell cycle:
1. Drugs acting on S phase:
a) Ergot alkaloids work on the mitotic spindle in S phase
b) Methotrexate works in S phase: Example: pt with rheumatoid arthiritis has macrocytic anemia. Drug responsible for
this is in what phase of the cell cycle? S phase b/c it is methotrexate blocking dihydrofolate reductase
skin, and raised red plaque, b/c excessive stratum corneum. This is why methotrexate works here, b/c its a cell cycle specific for the S
phase, and prevents the basal cells from proliferating.
5. Example: prostate gland and bladder hyperplasia of prostate glands, it a hormone related hyperplasia; all hormone
stimulated glands undergo hyperplasia, not hypertrophy. The wall of the bladder is too thick; b/c urine has to go out thru a
narrow opening in the urethra, therefore the muscle has to work harder which leads to hypertrophy of smooth muscle cells
of the bladder wall (more urine must go out against a greater force b/c of an increase in after load).
D. Metaplasia replacement of one adult cell type by another
1. Example: Slide of an esophagus, part of if is all ulcerated away. On a section surrounding the ulcer (right at the edge of
the muscosa) there are mucous secreting cells and goblet cells (these are grandular cells). These cells are not supposed to
be present in lower esophagus; squamous cells should be there (not glandular cells). Metastatic grandular: Barrets
esophagus is a precursor for adenocarcinoma. Adenocarcinoma has surpassed squamous cell carcinoma of mid-esophagus
as the MC cancer of the esophagus. Therefore, GERD is the number one precursor to esophageal cancer (adenocarcinoma).
Audio file 4: Inflammation 2
2. Example: Lining of mainstem bronchus ciliated columnar, pseudostatified columnar. In smokers, this would be an
example of metaplasia would be squamous
3. Example: There are increased goblet cells within mainstem bronchus of an old smoker, also see goblet cells in the terminal
bronchial. Normally there are goblet cells in the mainstem bronchus but there are no goblet cells in the terminal bronchus, therefore
this is an example of hyperplasia.
4. Example: Goblet cells in the stomach are abnormal (should be in the intestines, only). This is a glandular metaplasia, which is a
precursor for adenocarcinoma of the stomach. H. pylori are a precursor for adenocarcinoma in the stomach. B/c H. pylori causes
damage to pylorus and antral mucosa b/c it is a chronic gastritis which intestinal glandular metaplasia, which is a precursor for
adenocarcinoma. MCC adenocarcinoma of the stomach = H. pylori.
5. Example: Cases where metaplasia causes an increased risk to caner:
a) Remember that if hyperplasia is left unchecked, could potentially lead to cancer. For example: in endometrial hyperplasia the MC
precursor lesion to endometrial carcinoma due to unopposed estrogen. The exception is prostatic hyperplasia, which doesnt become
cancer.
b) Metaplasia can also go through a process leading to cancer:
(1) In lung, ciliated columnar epithelium BECOMES squamous, therefore, this is called SQUAMOUS metaplasia; this will lead to
squamous dysplasia, which then proceeds to cancer (squamous carcinoma);
(2) In distal esophagus, went from squamous to glandular epithelium b/c squamous epithelium cannot handle the acid, therefore it
needs mucous secreting epithelium as a defense against cellular injury. However, the glandular metaplasia can go on to an atypical
metaplasia, predisposing to adenocarcinoma of the distal esophagus.
(3) Parasites: 2 parasites produce cancer: chlonorchis sinesis leads to cholangiocarcinoma (Chinese liver fluke); and schistosoma
hematoabium. The schistosoma hematobium causes bladder cancer by causing the transitional epithelium to undergo squamous
metaplasia. This leads to squamous dysplasia, and then on to squamous cancer.
Transitional epithelium leads to squamous epithelium (called metaplasia), then dysplasia, then on to cancer.
E. Dysplasia is really an atypical hyperplasia.
1. Example: Slide of a squamous epithelium is disorganized, with nuclei that are larger near the surface and the basal cell layer is
responsible for the dividing; cells at top are bigger than the ones that are dividing, it has lack orientation.
If it was found during a cervical biopsy in pt with HPV infection, or if it was found in the mainstem bronchus biopsy, you should be
able to tell that it is dysplastic. Therefore dysplasia, whether glandular or squamous, is a precursor for cancer.
2. Example: There was a farmer with lesion on the back of his neck (can grow on any part of the body, due to sun exposure), which
could be scraped off and grew back actinic keratosis (aka solar keratosis) is a precursor for sq. cell carcinoma of the skin. UV-B
light damages the skin. Actinic keratosis does not predispose to basal cell carcinoma, even though basal cell carcinoma is the most
common skin cancer.
(6:38) Acute Inflammation
A. Cardinal signs of inflammation
In the scenario with a bee sting: you will see redness (rubor). The king of vasodilators is histamine and it vasodilates the
arterioles. Therefore, histamine is responsible for the redness of acute inflammation (ie bee sting), and is working on
arterioles. Now if we felt the area, it will be warm (Calor = heat), this is due to vasodilating the arterioles, which is caused
by histamine. For example in endotoxic and septic shock, the skin is warm b/c you are vasodilated. Tumor is a raised
structure caused by histamine. Histamine can lead to increased vessel permeability in the venules; is arterial thicker than
venules? Yes. The venules are very thin; they basically have an endothelial cell with a basement membrane, all you have to
is drill a hole through the BM and you are out. Therefore, increased vessel permeability occurs at the venule level, not the
arterial level. Histamine contracts the endothelial cells, and leaves the BM bare, leading to increased vessel permeability,
producing an exudate, and swelling of tissue, hence tumor of acute inflammation.
The area may hurt (Dolor = pain) but histamine does not have anything to do with this. Bradykinin is part of the kininogen system
between factor 11 and Hageman factor 12. So when you activate the intrinsic pathway, you automatically activate the kininogen
system. When you activate factor 12 (Hageman factor), it will activate 11 and the whole kininogen system. The end product is
bradykinin. ACE degrades bradykinin. Complication of ACE inhibitor is angioedema. Also inhibit metabolism of bradykinin, which
increases vessel permeability, producing the angioedema (swelling of the tissues). How bradykinin produces cough is not really
understood. Bradykinin and PGE2 cause pain (dolor) and is the only one out of the four Latin terms of acute inflammation that is not
due to histamine release.
B. Steps involved in Acute inflammation (this the normal sequence in acute inflammation):
1. Emigration: includes margination, paveenting, rolling, adhesion, and transmigration
Neutrophils in circulation start to become sticky b/c of adhesion molecule synthesis. Endothelial cells begin to synthesize adhesion
molecules. Eventatually, neutrophils will stick to endothelial cells, these steps are called pavmenting or margination. Then neutrophils
look for bare basement membrane on the venules and then they drill a hole through it via type 4 collagenase. Cancer cells also have
type 4 collagenase, thats how they metastasize. Cancer cells attach to endothelial via adhesion molecules, usually against laminin in
BM, and they have collagenase to get through the BM, therefore, cancer cells are pretty much like a neutrophil when invading tissue.
2. Chemotaxis: When they pass BM of small venules, they emigrate but they have to know what direction to go. They get directions
in a process called directed chemotaxis. C5a and LT-B4 (leukotriene B4) are the chemotactic agents. These chemotactic agents are also
involved in making adhesion molecules on neutrophils). Therefore, they make adhesion molecules AND give direction by acting like
chemotactic agents.
3. Phagocytosis via opsonization:
a) Example: in an acute inflammation with staph aureus, the bacteria are being processed by opsonins, which immobilize the particles
on the surface of the phagocyte. The two main opsonins are IgG and C3b. They help with phagocytosis.
b) Example of an opsonization defect: Brutons agammaglobinemia: an x-linked recessive dz, where all the immunoglobulins are
missing, including IgG. Therefore, MCC death in these pts is due to infection b/c cannot opsonize things. It produces hypogammaglobinemia, but the mechanism of infection is due to not having IgG to opsonize bacteria, therefore cannot phagocytose it.
Bacteria are opsonized by IgG and C3b, which means that neutrophils must have receptors for those. In acute inflammation the main
cell is neutrophil and in chronic inflammation the main cell is macrophage/monocyte (monocytes become macrophages). These cells
have to have receptors for these opsonins (IgG and C3b). Then they become phagocytosed or become phagolysomes. When they are
phagocytosed, the lysosomes go to microtubules and empty their enzyme into this.
c) Example: In I-cell disease: in this dz, mannose residues cannot be phosphorylate in golgi apparatus therefore the enzymes are not
marked with phosphorus, and the lysosome are empty.
4. Intracellular microbial killing:
a) Examples:
(1) Staph aureus in hot tub surrounded by enzymes
(2)Chlamydia can get out of phagolysosome, mechanism unknown, but sometimes they have mucous and all kinds of things around
them.
b) O2 dependent myeloperoxidase system is the boards!!
Molecular O2 is converted by NADPH oxidase, which is in the cell membrane of neutrophils and monocytes, but not macrophages.
The most important cofactor is NADPH, which is synthesized in the pentose phosphate shunt. The enzyme responsible is glucose 6
phosphate dehydrogenase, which converts G6P into 6-phosphogluconate, generating NADPH and a neutralizing factor for free
radicals (glutathione).
It is converting O2 into a free radical, superoxide. Superoxide has an unpaired electron giving off energy, which is called a resp burst,
which can be measured by radiation detectors; and by a negative NBT dye test. In the NBT test, you have a test tube, add the colorless
NBT dye; and if neutrophils and monocytes are working normally, they will phagocytose it, will have a respiratory burst, and the free
radical O2 will cause the color to change to blue, indicating that the resp burst is working. If there is no color change, there is not a resp
burst, therefore the pt has chronic granulomatous dz of childhood.
Free radical O2 is converted by SOD (its neutralizer) into peroxide. Peroxide itself could kill bugs, but it is used for another reason.
Within the neutrophils and monocytes are reddish granules which are lysosomes, and are seen in the peripheral blood.
Myeloperoxidase (one of the many enzymes in the granules) will catalyze the rxn. It will combine peroxide with chloride to from
bleach. This is the most potent bactericidal mechanism O2 dep myeloperoxidase system, which is in NEUTROPHILS and
MONOCYTES but NOT in macrophages, b/c macrophages lose the system when they convert from monocytes to macrophages and
they use lysosomes to kill.
Macrophages of the CNS are microglial cells, so the reservoir cell for CNS/ AIDS is the microbial cell. Outside the CNS, it is the
dendritic cell; it is a macrophage located in the lymph nodes.
c) In G6PD deficiency, infection is the MC precipitation of hemolysis b/c there is no NADPH, therefore there is no functioning O 2
dependent myeloperoxidase system, and therefore you are susceptible to infection, which will set of hemolysis of RBCS.
d) Chronic granulomatous dz of childhood = X linked recessive dz where the mom gives the dz to the boy, and is an asymptomatic
carrier, and they will transmit the dz to 50% of their sons. In this dz, there is a deficient activity of NADPH oxidase, and the NBT dye
test is negative (doesnt show color of die), therefore there's no respiratory burst. Do they have superoxide? No. Peroxide? No.
Myeloperoxidase? Yes. Chloride? Yes. Therefore, if they phagocytized a bacteria that could make peroxide, and add it inside the
phagolysosome, this is what the kid would need to kill the bacteria. These kids are missing PEROXIDE b/c there is no NADPH
oxidase. ALL living organisms make peroxide (including ALL bacteria). However, not all bacteria contain catalase, which is an
enzyme that breaks down peroxide. So, in chronic granulomatous dz, what can they and cant they kill? Cannot kill staph, but can kill
strep. Why? B/c staph is Coagulase and CATalase +; so, ie, if its staph. aureus and when it makes peroxide, it will also make
catalase and neutralize it, therefore the child cannot kill staph, and will kill the kid. If it was a streptococcus organism that makes
peroxide (does not have catalase therefore peroxide can be used by the child), it adds what kid really needed to make bleach, and the
bacteria is then wiped out. Therefore, can kill strep and not staph!
e) Myeloperoxidase deficiency: Do they have a resp burst? Yes b/c they have NADPH oxidase. Do they have peroxide? Yes. Do they
have superoxide free radicals? Yes. Do they have chloride? Yes. Do they have myeloperoxidase? No. They have a normal resp burst
and a normal NBT dye test, but they cant kill the bacteria b/c they cannot make bleach. This is called a myeloperoxidase defect. Other
types of defects:
(1) opsonization defects with brutons agammaglobulinemia(missing IgG), C3 defs;
(2) chemotactic defects where cells do not respond to chemotaxis;
(3) microbiocidal defects, the defect in the ablility to kill bacteria, example: chronic granulmatous dz of childhood and
myeloperoxidase deficiency are both microbiocidal dz, in that they cannot kill bacteria, but for different reasons.
In myeloperoxidase def the problem is that they cannot make bleach (b/c of the missing enzyme), but do have resp burst, and is
Autosomal recessive dz. In CGDz the problem is that they cannot make bleach either, but they have an ABSENT resp burst, and is a
X-LINKED recessive dz.
f) Child has an umbilical cord that doesnt fall off when it should. When it was removed and looked at histologically, they did not see
neutrophils in the tissue or neutrophils lining the small vessels. This is an adhesion molecule defect or beta 2 integrin defect.
Umblilcal cord needs to have an inflammatory rxn involving neutrophils; they have to stick in order to get out. Therefore, if the
neutrophils cant stick, they cant get out, and then they cant get rid of your umbilical cord this is a classic adhesion molecule
defect.
C. Chemical mediators:
1. Histamine: the king of chemical mediators of acute inflammation
a) What does it do to arterioles? Vasodilates
b) Venules? Increased vessel permeability
2. Serotonin:
a) What amino acid makes serotonin? Tryptophan
b) Is serotonin a neurotransmitter? Yes
c) In a deficiency, you get depression (also decreased NE)
d) a vasodilator and increases vascular permeability
3. Complement system: Anaphylatoxins C3a, C5a. Function: stimulate mast cells to release histamine, leading to
vasodilation and increased vessel permeablility. They also play a role in shock, b/c when there is inflammation the
compliment system is activated, therefore there will be mast cells and histamine, therefore C3a, and C5a will both be there.
4. Nitric oxide made mainly in endothelial cells, and is a potent vasodilator. It is used for treating pulmonary
hypertension. It has a big time role in septic shock.
5. IL-1 associated with a fever, it is a pyrogen, therefore stimulates the hypothalamus to make PGs, which stimulate thermoregulatory
system to produce fever. Aspirin works by inhibiting the synthesis of prostaglandins thereby reducing the fever.
6. Arachidonic acid metabolites:
a) Corticosteroids inhibits Phospholipase A2, therefore do not release arachidonic acid from phospholipids, therefore not
making PGs or leukotrienes. This is the supreme antiflammatory agent b/c BOTH PGs and leukotrienes are blocked by
blocking phospholipase A2. Arachidonic acids make linoleic acid (omega 3), which is found in fish oils and walnuts. It is
very good for you b/c it acts like aspirin, and blocks platelet aggregation, and thats how omega 3 protects your heart.
b) Lipoxygenase pathway: Zileuton blocks 5-lipoxgenase, other drugs act by blocking the receptors, example:
zafirlukast, etc. Leukotriene (LT) C4, D4, E4 (the slow reactor substances of anaphylaxis) seen in bronchial asthma.
They are potent bronchoconstrictors; therefore it can be seen why zileuton works well in asthma b/c it blocks the
leukotrienes, including these (LT-C4, D4, and E4). LT B4 is an adhesion molecule in chemotaxis.
c) Cyclooxygenase pathway: Aspirin blocks cycoloxygenase, irreversibly in platelets. PGH2: where everything seems to be derived
from. PGI2: derives from endothelial cells, its also called prostacyclin synthase; is a vasodilator and inhibits platelet aggregation
(exact the opposite of TxA2). Thrombaxane A2 (the enemy of PGI2) is made in the platelet; its a vasoconstrictor, a
bronchoconstrictor, and promotes platelet aggregation. What drug blocks thrombaxane synthase and is used to stress testing for CAD?
Dipyridamole blocks the enzyme, TxA2 synthase, therefore does not have to perform a treadmill stress test, all you have to do is use
the drug dipyridamole.
PGE2: vasodilator in kidney; keeps patent ductus patent in baby heart; makes the mucous barrier in GI (stomach) thereby preventing
ulcers; can cause dysmenorrhea woman and increased uterine contractility, and it an abortifactant, to get rid of fetal material.
d) COX 2-make sure you know how this works!
e) Corticosteroids blocks phospholipase A2, and it also decreases adhesion molecule synthesis, along with other steroids like
epinephrine and NE. Decreased adhesion molecule synthesis, will lead to increased neutrophils on CBC; in immuno, 50% neutrophils
are stuck to the endothelial vessels, and the other 50% are circulating, therefore, decreasing adhesion molecule synthesis will lead to
doubled WBC (b/c the 50% of neutrophils that were stuck are now circulating).
Corticosteroids destroy B-cells b/c they are lymphocytotoxic. Mechanism: decrease WBCs (B and T cells) via apoptosis; therefore,
corticosteroids are the signal to activate the caspasases.
Eosinophils, mainly seen in type one HPY rxn, corticosteroids decrease them. When on corticosteroids, the only thing that is increased
is neutrophils, via decreased adhesion molecule synthesis. Lymphocytes and eosinophils are decreased.
Example: If have Addisons, do not have cortisol, therefore the neutrophil count decreases and the eosinophil count will increase.
Example: a person with MI with an 18,000 CBC most of which are neutrophils. Mechanism: Epinephrine decreases adhesion molecule
sythesis and neutrophil count goes up.
D. Electron microscopy of inflammatory cells:
1. In lung, type II pneumocyte (black dots are lysosomes). Lamellar bodies structures where lecithin and phosphotidyl choline is
located; if ask where macrophage, is, will ask which makes surfactant.
2. Monocyte: single nucleus with a grayish cytoplasm has scavenged; can form foam cell in atherosclerotic plaque b/c it has
phagocytized oxidized LDLs (which is a free radical); Vit E neutralizes oxidized LDL.
3. Lymphocyte all nucleus and scant cyptoplasm, prob a T cell (60% of peripheral blood lymphocytes are T cells); ratio of helper to
suppressor: CD4:CD8 is (2:1), therefore, more likely to be a Helper T cell, then a suppressor T-cell, and B cells (20%) are least likely.
4. RER looks like a thumbprint, have ribosomes on it, and likes to make proteins, like Igs (therefore it is a plasma cell). Multiple
myeloma has eccentrically located nucleus, cytoplasm is always sky blue, making plasma cells are easy to recognize.
Plasma cells are derived from B cells, and located in the germinal follicle.
5. Granules eosinophil (have a red color similar to color of RBCs) have crystals in the granules. Eosinophils are the
only inflammatory cell that has crystals in the granules. They are called Charcot-Leiden crystals when its seen in the
sputum of asthmatic patient. They are degenerated eosinophils in sputum of asthmatic, and have formed crystals that look
like spear heads. Basophils have granules that are more purplish and darker, while basophils have darker colors.
6. Mech for killing invasive helminthesType II HPYmajor basic protein is involved. Remember that schistosome eggs are coated by
IgE Abs. Eosinophils have IgE receptors; therefore, eosinophils hook into the IgE receptor and release chemicals; the main one
released is major basic protein, which destroys the helminth, which is type II HPY, b/c it is a cell hooking into an Ab on the target cell.
The effector cell is Type II HPY rxn is the eosinophils; dont get confused with Type I HPY rxn where the effector cell is the MAST
CELL, and they release histamine (an eosinophil chemotactic factor), therefore they are invited to area of type I HPY b/c they have
histaminase and arylsulfatase, which neutralizes leukotrienes. The purpose of eosinophils in type I HPY is to knock off chemical
mediators produced in rxn; however, when an eosinophil kills an invasive helminth, it does so via type II HPY.
E. Cluster designations:
Helper t cell = CD4
Cytotoxic T cell = CD8
Marker for Ag recognition site for all T cells is CD3
Marker for histiocytes (including langerhans cells) is CD1
Marker for MC leukemia in children = CD10 (calla Ag); positive B-cell lymphoma
CD15 and 30 = RS cell
CD21, Only on B cells Epstein barr virus; hooks into CD21 on B cells, and actually the atypical lymphocytes are not B-cells
but T-cells reacting to the infected B-cells.
Burkitts is a B cell lymphoma
CD45 is found on all leukocytes, is a common antigen on everything
F. Fever IL-1 is responsible and PGE2 (this is what the hypothalamus is making) which stimulates the thermoregulatory center.
Fever is good! It right shifts the O2 dissoc curve. Why do we want more O2 in the tissues with an infection? B/c of O2 dependent
myeloperoxidase system. Therefore, with antipyretics its bad b/c thwarting the mechanism of getting O2 to neutrophils and monocytes
to do what they do best. Also, hot temps in the body are not good for reproduction of bacteria/viruses.
II. Types of inflammation (scenarios)
A. post partum woman, with pus coming out of lactiferous duct this is staph aureus suppurative inflammation
B. Bone of child with sepsis, on top of the bone, was a yellowish area, and it was an abscess osteomyelitis staph. aureus; if
the kid had sickle cell, it is salmonella; why at metaphysis of bone? B/c most of blood supply goes here, therefore, mechanism of
spread is hematogenous (therefore comes from another source, and then it gets to bone).
C. Hot, spread over face cellulitis due to strep (play odds!) group A pyogenes (called erysipilis, another name for cellulitis)
D. Diphtheria = pseudomembrane (corynebacterium diphtheria), a gram + rod, that makes an exotoxin, messing up ribosylation of
protiens via elongation factor 2, the toxin damages mucosa/submucosa, producing a pseudomembrane; when bacteria doesnt invade,
produces a toxin that damages the membrane; clostridium difficile also does this. It also produces a pseudomembrane and a toxin,
which we measure in stool to make the dx. Therefore, the answer is C. difficle.
E. Fibrinous pericarditis, usually with increased vessel permeability; seen in (1)lupus, leading to friction rub; also seen in (2) the
first week of MI, and then again 6 weeks later in dresslerss syndrome, (3) seen in Coxsackie
F. MC organism producing infection in third degree burns = pseudomonas aeruginosa. Color of pus: green due to pyocyanin.
G. Basal cell layer on both sides of clot, proliferate, and go underneath it to clot. In a primary wound its usually sealed off in
48 hrs (ie appendectomy). Key to wound healing is presence of granulation tissue.
Fibronectin is a very important proteoglycan and is involved in the healing of the wound. Fibronectin is an important adhesion agent
and chemotactic agent, inviting fibroblast in helping healing process. The granulation tissue starts at day 3 and is on its prime by day
5. If you ever picked at a scar and it bleed like mad and you try to stop it but it still bleed like mad, thats granulation tissue. No
granulation tissue means no healing of a wound. Type of collagen in initial stage of wound repair = type 3;
Type 4 collagen seen in BM;
Type 1 very strong tensile strength; seen in bone, skin, tendons, ligaments.
After a few months, after months, the collagen type 3 is broken down by collagenases, and a metalo- enzyme converts type 3
into type 1. Zinc is part of the metallic enzyme, this is why in a pt with zinc deficiency has poor wound healing b/c it screws up
the collagenase (must replace type 3 with type 1). Max tensile strength after 3 months = 80%. MCC poor wound healing =
infection
H. Ehlers Danlos defect in collagen due to syn/breaking down; have poor wound healing.
I. Marfan defect in fibrilin; also have poor wound healing
J. Pt with scurvy defect in hydroxylation of two aas (proline and lysine) via ascorbic acid. Remember its a triple helix; what
makes the triple helix stick together and increase tensile strength? Crossbridges. When you crossbridge things, they anchor into
areas where you have hydroxylated proline and lysine. Therefore have weak abnormal collagen in scurvy b/c there are no
crossbridges to attach, leading to not being able to heal wounds, hemorrhaging, hemarthroses.collagen has weak tensile strength b/c
cannot crossbridge.
shift.
C. Most potent system for killing bugs = O2 dependent myeloperoxidase system;
Myeloperoxidase is located in azurophilic granules, which are lysosomes.
Want a lot of lysosome in an acute inflammatory rxn, b/c therefore there is more myeloperoxidase around for killing bugs this
is what toxic granulation.
Therefore, toxic granulation ensures that there is enough myeloperoxidase to work that potent system to kill bugs (O 2 dep
myeloperoxidase system).
Cell Injury
Post 2: (Dated: Jan 12 - 2009)
Hypoxemia (decrease oxygen partial pressure) is a cause se of hypoxia
Hypoxemia is a cause of hypoxia.
Respiratory acidosis --> Up CO2 --> pO2 ALWAYS (and vice versa)
In case of ARDS and Hyline membrance disease... massive ventilation
defect... 100% cant cure
Hypoxemic patient .... po2 does't increase.... intrapulmanory shunt
increase.
Perfusion defect .... increase in dead space.... treatment ....100%
increases po2
Sarcoidosis or pulmonary edema .... Diffusion deffect.
J receptors acctivated by fluid in lund interstitium irritation ... J reflex
innervated by Tenth Nerve.
Anemia --- normal gas exchange --- Hb low --saturation normal --excertional dyspnea --- excercise intolerance.
CO poisoning --- House fire u get Cyanide poisoning + Co poisoning =
2 bonuses --- saturation dec, cure 100% O2) ---- cyanide n Co inhibits
Cytochrome oxidase.
Cyanosis in Co Poisoning --- decrease in O2 sat --- Red Pigment hides
cyanosis.
MtHb poisoning --- O2 Saturation dec --- chocolate colored blood --Fe3 present not Fe2 (cant carry O2) --- (Question = came from Rocky
Mountain - O2 could't cure ??? what is the reason) --- treatment: IV
methylene blue, Vitamin C.
---> brown pigment ---> atrophic organs in elderly ---> pigment cant
b digested.
Reperfusion injury is due to O2 Radicals
O2 Radical ---> destroys retina ---> blindness.
O2 Radicals ---> Bronchopulmonary dysplasia (fibrosis)
Iron loves making free radicals ----> cirrhosis, reactive
cardiomyopathy, pancreastic failure ---> Malabsorption n diabetes.
Tylenol (Acetaminophen) ---> produce free radicals ---> #1 cause of
Fulminant hepatitis (around central vein) ---> kidney damage ---->
Treatment : N-Acetyle Cystein (Increases Glutathione)
Superoxide dismutase neutralize superoxide ---> producing peroxide
Pentose phosphate shunt makes Glutathione and NADPH
CCl4 converted in to CCL3 ---> fulminant hepatitis
Acetaminophin (Tylenol) + Aspirin ---> damage kidney (renal medulla)
----> PG dec
Apoptosis ---> genes involved in prog cell death ---> (eg. embryo)
King of our body ---> Y chromosome ---> Mullerian inhibitory factors
---> erase mullerian str ---> caspases wipe them ---> Apoptosis --->
producing lipofusin
Cell Injury
Post 3: (Dated: Jan 13 - 2009)
In women ---> X chromosome ---> wolfian duct structures are
removed by apoptosis
Anterior mediastenum is smaller in adults as compare to children (Due
to thymus) ---> apoptosis in adults
Digeorge syndrome ---> Thymus absent ---> cause tetany
Apoptosis occurs in cancer cells
Apoptotis occurs in neuron cells ---> dec in brain mass ---> pyknotic
bodies.
Caspases involves in Apoptosis
Coagulation necrosis ---> Pale infarct - Heart, kidney, spleen, liver
Hemorrhagic infart: Bowel, testicle (torsion), lungs
Its depends on consistency of tissue whether it goes to coagulation or
hemorrhagic necrosis.
Left side of heart ---> most of the emboli arises
vegetation of acute rheumatic fever rarely embolize ---> Infective
endocarditis does
Clots of emboli or vegetation goes to spleen causing pale infarction
The arrhythmia mostly associated with systemic emboli is atrial
fibrillation ---> pieces of emboli travels out and stuck in vessels
Dry gangrene: no pus ---> Diabetics
Most common cause of non traumatic amputation is diabetes ("ATH of
popliteal artery)
Popliteal artery a most dangerous artery.
Most common cause of bowel infarction: #1: adhesions of previous
surgery, #2: piece of small bowel trapped in an Indirect inguinal hernia
in a sac.
Lung: Hemorhagic infarction ---> wedge shape ---> effusion present
--> neutrophils present ---> plueretic chest pain
Liquefactive necrosis (liquefy) is related to an infection - neutrophils
present - cyctic necrosis - acute inflamation related to neutrophils damaging the tissues.
Gram + = strep auerues ---> abcess ---> cellulitis ---> infetion
spreads thru tissues ---> liquefactive necrosis
Cell Injury
Post 4: (Dated: Jan 15 - 2009)
You need proteins around lipids to dissolve in water.
Ferritin: soluble form of iron ---> best marker for diagnosis of iron
dificiency anemia or hemosiderosis, hemochromatosis.
Hemosiderin (Insoluble iron storage), Stored in MP and BM, stained
with Prussian Blue Dystrophic calcification: Calcium loves to calcify
damaged tissue, normal serum calcium.... (Fat necrosis, ATH, aortic
stenosis, hemolytic anemia)
Aortic stenosis: two valves doing job of 3 ---> stenosis ---> Dystrophic
calcification
Primary Hyperparathyroidism most common cause of Hypercalcemia
Metastatic calcification: Hypercalcemia or hyperphosphatemia ---> Ca
deposits in normal tissue.
Cong bicuspid aortic valve most common cause of aortic stenosis in
USA ---> 2 valves instead of 3.
If u cant see a central area of Pallor ---> spherocyte
Spectrin: Needed to keep a bi-concave disc, if its defective --->
spherocytosis.
Ubiquitin: A stress protien
Intermediate filaments: framework of the house ---> when damaged
---> ubiquitin ubiquinate them
A liver with spaces in it ---> fatty liver
Ubiquination: Mallory bodies = alocoholics ---> fatty change
Silver stain Neurofibillary tangles = Alzheimer, Creutzfeld-Jakov
disease.
Tau protein associated with Neurofibillary tangles
Parkinsons: lewy bodies in substantia nigra - dompamine decreased
Cell cycle: Labile cell, division via stem cells (BM, Skin, Intestinal
crypts) are in cell cycle ---> most affected by drugs ---> specific or
non-specific drugs - BM supression, diarrhea, rash on skin (due to
presence of stem cells in these tissues).
Stable cells - G0 phase, stimulated to divide (Liver, spleen, Kidney,
Smooth muscle, endometium) - stimulated by hormone or growth
factor.
Permanent cell can not go in to cell cycle ---> can do hypertrophy
only.
prostate)
Unopposed estrogen (no progesterone) cause endometrial hyperplasia
---> atypical hyperplasia ---> endometrial cancer.
Prostate hyperplasia does not predispose to cancer.
Cell Injury
Post 5: (Dated: Jan 16 - 2009)
Gravid uterus (after delivery): 50% hypertrophy, 50% hyperplasia --->
of smooth muscles.
Normal 3 times many WBC than RBC
RBC hyperplasia in BoneMarrow may be caused by COPD --->
hypoxemia ---> raised Epo
Erythropoetin is made in the endothelial cells of the peri-tubular
capillaries
Psoriasis: Silvery Scales is an unregulated proliferation of squamous
cells in the skin (hyperplasia).
Treatment: MTX (works on the basal cells from proliferating).
All hormone stimulated glands go through hyperplasia, not
hypertrophy.
Urinary bladder goes through hypertrophy of smooth muscle cells
related to afterload caused by urethra narrowing due prostate
hyperplasia.
Barrets esophagus(Metaplasia) = glandular cells, mucus secreting,
goblets cells instead of squamous cells ---> precursor of adeno.ca
Mid esophageal Ca ---> most common Ca in USA
Lining of main stem bronchus ---> psuedost. columnar ---> smoker
---> undergo sq metaplasia
Inc Goblet cells in main stem bronchus ---> hyperplasia
Also smookers have goblet cells in terminal bronchioles --->
metaplasia (normally no goblet cells in this place)
If goblet cells in stomach = abnormal ---> should be present in
s.intestine ---> glandular metaplasia ---> precursor for
adenocarcinoma of stomach
H. Pylori is the most common cause of adenocarcinoma of the stomach
---> produce damage to the pylorus and antral mucosa ---> chronic
atrophic gastritis with intestinal glandular metaplasia ---> precursor
lession for adenocarcinoma
Lung: Cilliated columnar epithelium ---> sq metaplasia ---> sp
dysplasia ---> Cancer Sq Carcinoma
Distal Esophagus: Sq ---> glandular epithelium, mucus secreting --->
defense against acid injury ---> may go into atypical metaplasia --->
adenocarcinoma
Clonorchissinensis (Chinese liver fluke) is associated with cholangio
carcinoma Schistosome Haematubium causes squamus metaplasia
Microglial cells are the Macrophages of the CNS ---> reservoirs of CNS
Aids ???
Reservoir of Aids outside CNS are dendritic cells (Macrophages outside
CNS) are re located in lymph nodes.
G6Pd deficiency: Infection prrecipitates hemolysis ---> No NADPH --->
No Functioning O2- dependant Myeloperoxidase system --->
susceptible to infections ---> hemolysis
All females of male dominant disease ---> a-symptomatic carriers of
disease ---> transmit disease to 50% of sons.
CGD of childhood ---> X-linked recessive ---> boy gets from Mom
CGD: NADPH oxidase missing ---> no color in NBT dye test --->
lacking respiratory burst
Superoxide --> No
Peroxide ---> No
Myeloperoxidase ---> yes
Chloride ---> Yes
All living organisms make Peroxide including all bacterias
Not all bacterias contain catalase.
In CGD patients: They cannot kill staph; They can kill strep
Catalase + Coagulase positive (Staph. Aureus) breaks down peroxide
and prevent its utilization in CGD.
Strep doesnt have catalase, so it can be killed even in CGD patient.
In Myeloperoxide deficiency (AR),
Respiratory burst = Yes
Peroxide = Yes
Superoxide Free radicle = Yes
Chloride = Yes
Myeloperoxidase = No,
but no bleach ---> cant kill bacteria.
Opsonization defects (eg. Brutons agamaglobulinemia ---> missing
IgG; C3 deficiency).
LTC4, -D4, E4: the slow reacting substance of bronchial asthma --->
potent broncho-constrictors
Zileuton works great in asthma ---> blocks all Leukotrienes --->
including LTB4 (adhesion molecules and chemotaxis)
Aspirin blocks cycloxygenase irreversibly if we are talking about
platelet
TXA2 made in platelets ---> vasoconstrictor, brochconstrictor, platelet
aggregation.
PGI2 made in endothelial cells ---> vasodilator, inhibits platelet
aggregation.
PGE2 ---> vasodilator in kidney, keeps the fetus's patent ductus
patent, mucus barrier in stomach, primary dysmenorrhea, increase
uterine contractility (abortificant to express fetal material).
Dipyridamole inhibits TX synthase, used in stress test in coronary
artery disease.
Coticosteroids: Anti-inflamatory agent ---> block phospholipase A2;
decrease adhesion molecules synthesis along with other steroids like
Epi and N.Epi
White person: 50% of neutrophils already stuck to endothelium of
small vessels; 50%circulate.
Decrease in adhesion molecules synthesis ---> remaining 50% stuck
---> start to circulate ---> Neutrophils count increase in CBC.
Corticosteroids: Stimulate caspases of B-Cells ---> Apoptosis;
Eosinophils decreased; Only neutrophils increase ---> decrease
adhesion molecules.
Addison's disease: Decrease cortisol ---> Neutrophils count decrease;
Eosinophil count increase.
MI: Epinephrine ---> decreases adhesion molecules ---> Raised
adhesion molecules in CBC
Alveolar MP have a lot of lysosomes which are seen as black dots on
EM.
Lamellar bodies (where lechitin is located) are seen in pneumocyte
type 2.
Monocyte grayish cytoplasm, single nucleus, garbage in cytoplasm, on
Em.
Vitamin E neutralizes oxidized LDL
EM: All nucleus with very little cytoplasm = Lymphocyte
T-lymphocytes Vs B-lymphocytes: 60% T-lymphocytes in peripheral
blood
60% of lymphocytes are Th:Tc ratio is 2:1.
Slide: Thumb print ---> RER --> Ribosomes --> immonuglobullins --->
Plasma cells (M.Myeloma)
Plasma cell has a lot of ribosomes, because of Ig production. It is
located in germinal follicle.
Basophils: Granules ---> more purplish and darker
Eosinophils: Granules of color same as RBC
Eosinophils have crystals in their cytoplasm. In asthma: degenerating
eosinophils form Charcot-Leyden crystals seen in sputum.
Major basic proteins are released by eosinophils in type 2
HyperSensitivity to kill helminths.
Shisto ???: Eggs coated by IgE antibodies ---> Eosinophils have
receptors for IgE antibodies --->release chemicals ---> MBP Kill
helminths
T-2 Hypersensitivity: Cell hooking in to antibody on a target cell
(Eosinophils = effector cells).
T-1 Hypersensitivity: Mast cells = effector cells
Mast cells release histamine and eosinophil chemotactic factor in type
1 H-S.(from purple granules) ---> Eosinophils here release
hemoarthrosis.
Keloid: (hypertrophied scar) = excess of type 3 collagen deposition ;
genetic predisposition in blacks.
SCC is common in the setting of scars related to 3rd degree burns or
chronically draining sinus tract (in osteomyelitis).
IgM is the most potent activator of the complement system, because it
has 10 antigen recognition sites (pentamer). Main Ig of Acute
inflammation.
IgG complement activation doesnt go beyond C3 (no C5a and so on).
Main Ig of chronic inflammation. C5a is very important chemotactic
factor.
After 10 days to 2 weeks there is a isotype switching: Same plasma
cell making IgM ---> splice out the "Mu"-Heavy chain (Heavy chain
that defines specificities of an Ig) and it splices in a gamma heavy
chain.
Inflammation
Post 10: (Dated: Jan 21 - 2009)
Acute Allergic reactions: Key cell eosinophil, Mast cell is in tissues.
Viral infection: Key cell Lymphocytes
Chronic inflammation: Key cells Monocytes, macrophages, raised
plasma cells, raised lymphocytes.
Pus is not a characteristic of chronic (only of acute) inflammation:
Increased vessels permeability ---> neutrophils immigration in
interstitial tissue ---> protein rich fluid (exudate: 3gm protein/dl ), cell
rich fluid(exudate) called PUS ---> produces tumor in acute
inflammation.
Granuloma: roundish and pink, multinucleated giant cells. Type 4 H-S.
Sometimes gets calcified. Epitheloid cells are activated MP, when they
die they form multinucleated giant cells which are seen in granulomas.
Killing neoplastic cells or virally infected cells is also Type 4 H-S (no
antibodies)
Poison ivy: Type 4 H-s
MP and TH CD4 are the key cells of TB.
Key actors in delayed reaction H-S ---> Macrophage processes
antigens ---> presents antigen to Th cels ---> Th cells releases
cytokines ---> Gamma interferon and MP inhibitory factor (involved in
granuloma) ---> activates the MP to kill TB, cryptoccocus, Histoplasma
etc.
Subset1 Th cells ---> Type 4 H-S
MP release IL-12 ---> activates and presents antigens to subset1 Th
cells ---> turns into subset1 Cd4 Th cells (memmory T cells of the
event)
Marker of all histiocytes and MP have ---> cluster designation 1 ???
Langerhans cells (EM: birbeck granules looks likes tennis rackets) are
the MP of the skin, phagocytose PPD, proceses it and present it to Th
type 1 that has memory of previous exposure ---> release cytokines
that produce the inflammatory reaction which is part of the positive
PPD.
Old people usually don't have Type4 H-S. they have lesser than brisk
response to PPD. Some times they need double type of PPD, because
of decreased immune response.
HIV: less/no type 4 H-S (Th dec.), no granuloma formation in HIV ; No
Th cells.
PPD of 5 mm induration is enough to say positive in HIV ---> that
would be pretty good immune response.
Reaction to injury in permanent tissues ---> scar tissue (no
contraction)
Scar tissue: heart muscle, kidney (especially straight portion of PT,
TAL)
Damage to free wall of left ventricle ---> fibrous tissues does't contract
Inflammation
Post 11: (Dated: Jan 22 - 2009)
Urine have to kinds of water:
Obligated water: Obligated to go out with every Na, Cl, K ---> 20ml of
water has to go out
Free water: ADH causes Na-K-Cl pump to produce free water
Obligated water: 1 Na reabsorbtion = 20ml + 1 K reabsorbtion = 20ml
+ 2 Cl reabsorbtion = 40ml ---> 80ml of water ; Na-K-Cl pump
Blocked by lasix (Loop diuretic)
Type 2 pneumocytes: 1) Produce surfactant, 2) Repair cells, even
replace type 1.
Astrocytes: can proliferate (stable cell), cause gliosis = increase in
protoplasmic processes (reaction to injury in the brain) ---> analogous
to fibroblast laying down type-3 collagen in wound.
Walerian degeneration: When a big nerve cut into half ---> Schwann
cells myelinate PNS axons.
Oligodendrocytes myelinate CNS axons.
Schwannoma = acoustic neuroma (if involves VIII nerve), seen in
neurofibromatosis (autosomal dominant)
IgG and/or fibrinogen increased ---> ESR Increased (acute and chronic
inflammation)
Negative charge normally keeps RBC away from sticking to each other
together ; IgM, cryoglobulin cause RBC to stick (cold agglutination
---> Raynauds phenomenon).
Raynauds phenomenon: Cold weather ---> nose, tips of finger, ears
turns blue ; warm ---> pink
IgM antibodies produce cold agglutinins causing RBC to agglutinate
---> ishemia ; Blood Warms up ---> IgM cannot work they fell apart.
High association of Hep.C with cryoglobulin.
IgG ---> Multiple Myeloma most common
IgM ---> waldenstrom macroglobulinemia most common
IgG and IgM both increases ESR.
Greater than 10% band neutrophils is left shift.
Acute inflammation: absolute increase in neutrophils, toxic granulation
(azurophilic granules), left shift.
Left shift: assuming myeloblast on the left ---> series of divisions --->
forms segmented neutrophils on the right ; We normally go from left
to right in maturation ; by defination greater than 10% dense ???
neutrophils considered as left shift ; Even presence of 1 myelocyte or 1
metamyelocyte ---> consider it as left shift.
Azurophilic granules: Red granules, lysozomes, increased in acute
inflammation ---> we have more myeloperoxidase to kill bugs (Toxic
granulation).
--------------- The End Inflammation ---------Fluid and hemodynamics
Post 12: (Dated: Jan 22 - 2009) 5 (min30)
Edema: Excess fluid in interstitial fluid (extracellular space)
Non pitting edema: exudate (increase vessel permeability with pus) >
3g/dl protein
Pitting edema: transudate (right heart failure) < 3g/dl protein
increased blood to Right heart (We don't want veno-dilation ---> pool
in legs), ---> Increase in force of contraction due to action on BAdrenergic receptors ---> SV increased little bit + increases the heart
rate; Arterioles on the systemic side ---> B-receptors of smooth
muscles gets stimulated.
Diastolic pressure due to amount of blood in arterial system while
heart is filling up in diastole; Peripheral resistance arterioles controls
the amount that is the arterial system ---> maintains the diastolic
pressure; When arterioles constricted ---> very little blood going into
tissues (Compromised) but instead diastolic pressure is up ---> Its
good because coronary arteries get blood by this; All done by
catacholamines ---> stimulates the renin angiotensin aldosterone
system ---> renin ---> angiotensin 2 ---> vasoconstrictor of peripheral
resistance arterioles (helping along the catacholamines); Angiotensin 2
---> stimulates of 18-hydroxylase ---> converts corticosterone in to
aldosterone ---> reabsorbs salt and water ---> raised CO.
SV decreased ---> blood flow to kidney decreased ---> activation of
renin-angiotensin aldosterone system ---> receptors located into JGApparatus in afferent arterioles, have sensors (modified smooth
muscles that sense blood flow); ADH will be released ---> increase in
pure water.
Normal saline (0.9%) is plasma without the proteins, it stays in the
ECF.
CO decreased ---> renal blood flow decreased ---> peritubular
hydrostatic pressure decreases ---> peritubular oncotic pressure
increased ---> reabsorption increased (isotonic solution); Any type of
shock same type of mechanisms.
The tonacity of fluid reabsorbed from proximal tubules ---> roughly
isotonic; ADH contributes pure water ---> adds 2 lit in to ECF; Tonacity
becomes ---> little bit hypotonic; This mechanism normally happens,
kidney reabsorbs when ever there is decrease in CO.
SV and arterial Volume increased: Absolute reverse of above
mechanism; The baroreceptors going to be stretched (innervated by
9th and 10th nerve) ---> parasympathetic system ---> fluid overload
---> ADH or renin-angiotensin aldosterone not activated; Peritubular
hydrostaticpressure is increased in cappilaries ---> even if salt is
reabsorbed ---> it does't get in to blood stream instead it comes out in
DKA: Osmotic diuresis ---> hypotonic urine (little bit more H2O than
salt); hypovolemia --->give normal saline (around 6-8 liters until BP
stable); High Glucose means nothing; After initial Rx ---> 0.5% NS +
Insulin.
When ever Hypovolumic ---> 1st Step in mannagement; NS to get BP
normal then decide according to the cause; if Sweating (hypotonic)--> Hypotonic salt solution; Adult Diarrhea (isotonic) ---> NS.
Diabetes Insipidus: Lets say 165 Serum Na, BP stable, pt is lucid --->
Rx: Water; If there is a problem of aspiration ---> 5% (50 gm of
glucose) Dextrose water I/V which is close to pure water
Loss of salt ---> Hypovolemic shock (CO dec, cold skin, TPR inc, MVOC
dec, BP dec, pulse inc, LVEDP dec)
MI ---> cardiogenic shock (everything like hypovolemic except LVEDP
inc)
E. coli (urinary catheter) ---> septic shock (CO inc, warm skin, TPR
dec, MVOC inc)
Gram negatives: have Endotoxins (lipopolysaccharide) in cell wall;
Gram positive dont have endotoxin.
Fluid and Hemodynamics
Post 18: (Dated: Feb 01 - 2009)
Hypovolumic and Cardiogenic shock: Skin ---> Cold and clamy due to
vasoconstriction of peripheral vessels; EAVD, sV, CO ---> decreased
due to Catacholamines and Angiotensin 2 etc ---> Constricts blood
vessels in skin and redirect the blood flow to more important organs
like brain and kidney; BP decreased, Pulse raised.
Poiseuille law: TPR referred to ur arterioles = viscosity of blood in
numerator / raduis of vessels to the 4th power; Therefore main factor
controlling TPR is radius to 4th power; Viscosity of blood is controlled
by Hb ---> anemia (Viscosity decreased), Polycythemia (Viscosity
increased).
Septic Shock: Endotoxins are released ---> First they activate
alternate system and cause release of C3a and C5a (Anaphylotoxin)
---> stimulate mast cells to release histamine ---> peripheral
resistance arteriolar dilation ---> skin feels warm; Endotoxins also
damage the endothelial cells;histamine ---> vasodilation of arterioles.
white spots ---> becomes extensive and grow over the eye and get
softening of cornea (keratomalacia)---> blindness (2nd most common
cause).
Vit. A deficiency: Eye ---> Bitots spots; Failure to thrive; follicular
hyperkeratosis; night blindness (nictalopia), squamus metaplasia --->
bronchogenic carcinoma.
Number 1 cause of global blindness is trachoma(chlamydia
trachomatis); but in USA DM.
You can be non-smooker, and can get sq.metaplasia of mainstem
bronchus ---> Bronchogenic ca.
Vit A toxicity (bear hunters, who eat bear livers): severe liver toxicity,
cerebral edema with papilledema --->headache.
Retinoic acid: for treatment of Acne and acute progranulocytic
leukemia
A young lady on Isoretinoic acid for cystic Acne, check her Liver
enzymes + any headaches --->may produce papilledema and cerebral
edema.
Vit D: mostly from sunlight, not food (hardly in breast milk).
Cholesterol: is the main component of cell membranes
- is the starting point for bile salts and bile acids
- is the first compound used in the synthesis of steroid hormones in
adrenal cortex
- 7-dihydrocholesterol in skin is photoconverted to Vit.D.
Breast milk: hardly have Vit.K or Vit D ---> needs supplements.
- Vit D. is reabsorbed in jejunum ---> has to go through 2
hydroxylation steps; 1st one in Liver (25-Hydroxylated); 2nd in Kidney
(1-25-Hydroxylated) in proximal tubules by PTH ---> Active Vit D;
- Active vitD, main job is mineralizing bone and cartilage --->
reabsorbs Ca and Phosphorus from jejunum.
PTH is responsible for the synthesis of 1-a-hydroxylase, which is in the
PT.
vitamins) ---> gets bleeding gums while brushing his teeth ---> scurvy
(Vit C. defeciency); Vit c. ---> hydroxylates proline and lysine in golgi
apparatus (post translational modification) ---> week tensile strength
of collagen as you cannot form cross bridges ---> blood vessels
rupture, gums bleed (type1 collagen weakens leads to inflammation)
while brushing teeth, hemarthrosis (complications of severe
Hemophilia A).
- Peri-follicular hemorrhage (rupture of vessels around hair follicles
looks like ring around follicles), glossitis (tongue; smoothness and
hurts), kelosis along the angles of mouth.
Ring sideroblasts: Nucleated RBC, has too much iron in mitochondria.
Excess of vit c. common in USA, 6-8 gm/day ---> renal stones (uric
acids and others as well) .
Vit C is theraputic drug for Ancillary treatment of met-Hb Anemia;
reducing agent, a great scavanger hunter for free radicals, knocks of
free radicles.
Water soluble vitamins are mainly co-factors for biochemical reactions;
Vit C. is a co-factor for making catacholomines (converting norepi to
epi.)
Thiamine is a cofactors for many important reaction like; Transketolase
reactions which are involved in the HMP(Pentose Phosphate shunt);
Pyruvate dehydrogenase (all those dehydrogenase reactions in
biochemistry), a-ketoglutrate dehydrogenase, a-ketoacid
dehydrogenase ---> all of these reactions reactions require Thiamine
as a cofactor.
Pyruvate dehydrogenase is the main enzyme that converts pyruvate in
to Acetyl-Coa (pyruvate can also be converted into oxaloacetic acid
with a carboxylase enzyme); when Acetyle-CoA combines with
oxaloacetate ---> citrate forms in TCA cycle; In case of thiamine
defeciency, if its involved in Pyruvate dehydrogenase reaction --->
decreased Acetyl-Coa, decreased Citrate, decreased ATP; so the
problem with Thiamine defeciency is ATP depletion; From Pyruvate to
Acetyl Coa ---> 2 NADH generated in mitochondria and gets 6 ATPs;
TCA-cycle ---> 24 ATPs generated; 6+24 = 30 ATPs; The total ATPs
generated from glucose to metabolised is 38 ATPs; Thiamine
defeciency leads 38 ATP depletions.
Dry Beri-Beri: Peripheral neuropathies (wernicke's and korsakoff
Ans: uterus and the most common tumor is leimyoma (smooth muscle
tumor).
Term fibroid - "Oid" means looks like fibrous tissue, but its a smooth
muscle. It becomes so hard they look like scar tissues; No
transformation to leimyosarcoma.
The most common benign tumor in a man, "Yellow", around elbow,
Lipoma; Most common in womens, Leimyoma of uterus.
Benign tumors of glands = Adenomas
Adenomas of adrenal: Thinness of adrenal cortex, which must be
functioning, making cortisol (Cushings)---> ACTH suppressed --->
Fasciculata and Reticularis undergo atrophy.
If the tumor is producing mineralocorticoid = Conn syndrome (atrophy
of zona glomerulosa).
GFR = Glomerulosa (salt), Fasciculata (glucocorticoids), Reticularis
(sex hormones)
Tubular adenoma: Precursor lesion for Colon cancer, looks like a
strawberry on a stick.
Carcinoma is the malignancy of epithelial tissues (squamous,
glandular, transitional).
In Squamous Carcinoma: Little swirls of increase redness called as
Squamous Pearls
Glandular carcinoma: Glands, looks like round and have something in
the middle ---> Adenocarcinoma (things inside the glands)
Transitional cell Ca: Comes from genitourinary tract (bladder, ureter, or
renal pelvis)
Malignant Melanoma: Rx Excision; malignancy of melanocytes;
Benign form is Nevus, The most rapidly increasing cancer in USA.
S100-Antigen positive, APUD tumors (A - means precursor of bcarboxylation decarboxylation) which have neurosecretory or
neurocrest origin. On EM, they have neuro secretory granules.
S100 Antigen which is used for staining things with APUD origin or
Neurocrest origin, most of them do not take stain.
Cystic teratoma of the ovaries Qs: 16 year old girl with onset of right
lower quadrant pain (always make right lower quadrant pain making
confusion with appendicitis, Crohn disease, ectopic pregnancy or
follicular cysts). X-rays showed some calcification in the pelvic area->
cystic teratoma; calcifications could be bones or teeth.
Germ cell tumors: They have tendency of staying in the mid line.
Ovaries are reasonably in midline. Ant.Mediastinum is right in the
midline. So teratoma is commonly developed there in the Pineal gland,
which is in midline. Therefore these are midline tumors the teratomas
which are Germ cell tumors.
Leukemia and Lymphomas:
Auer rod in a myeloblast ---> Leukemia
Hypersegmented neutrophils ---> B12, folate deficiency
Leukemia: Malignancy of stem cells in bone marrow. Like all cancers
they can metastasize out of it and always do. They have generalized
lymphadenopathy, and hepato splenomegaly.
Malignant Lymphomas arise from lymph nodes. Because they are all
malignant, can metastasize where ever they want including bone
marrow.
The most common site of body where lymphoma are not developing in
the lymph nodes is stomach.
Most of them are extra nodal (outside lymph nodes), primary
lymphomas occurs in stomach; H.Pylori can produce primary
lymphomas. The second most common location is in Peyers patches of
terminal ileum.
Mixed tumors Vs Teratoma
Leukemia Vs Lymphomas
Follicular B-Cell Lymphoma, knocks off apoptosis gene. It is a
translocation(14;18) of a heavy chain, B-Cells makes Bcl2 end product
which inactivates the apoptosis gene in the B-Cell. The cells become
immortal. Therefore it is the inactivation of apoptosis gene, common of
all the lymphomas.
Trophoblastic tumors: We see in pregnancy. Males can get as well
which are non-gestational.
Hydatidiform Mole: Looks like bunch of Grapes. Which presents in 1st
black except that lucency??? down over there ---> its metastasis and
the women is with breast cancer.
Most common bone metastasis is to is vertebral column, higher
vertebral column (acromioclavicular area).
We have metastasis that are lytic and blastic
Lytic: They break bone down.
Multiple myeloma ---> punched out lessions ---> all malignant Plasma
cells have IL-1 (osteoclast activating factor) in them ---> pathologic
fractures + Metabolic abnormality (hypercalcemia).
Some cancers go into bones and induce osteoblastic response. Bone
becomes dense ---> alkaline phos. elevated ---> Males with prostate
cancer which is almost always osteoblastic (which is making bone and
releasing Alk.Phos); Most common location for metastasis is lumbar
vertebrae.
Qs: 80 year old man with lower lumbar pain with point tenderness.
First step in management?
a- Bone scan
b- PSA
c- Transrectal U/S
Ans: Digital Rectal exam. Its stage 4 disease which means that
prostate definitely will be palpable. Then any other test.
X- rays:
Lytic metastasis ---> vertebrae collapse ---> lucencies
Blastic ---> Densities
CT scan of liver: If you see a gross specimen an x ray, CT, MRI etc
---> Multiple lessions in it ---> Ans- metastasis (dont pick abscess or
whatever). Dont pick primary cancer which is usually in one area or
the other but not all over the place. Just find out where that choice
deals with metastasis, never pick benign ever.
Brain: Most common cancer ---> metastasis.
Most common killer in man and women ---> Lung cancer; therefore
the most primary site for cancer in brain ---> lung cancer.
Lung: most common cancer of the lung ---> metastasis; most
common primary ---> breast.
Oncogenesis:
First step in malignancy is initiation that means mutations.
2nd step - Promotion: you make multiple copies of that mutation;
G1 to S phase, you got a mutation there and cell enter cell cycle --->
bad news ---> cell making multiple copies --->promotion.
Progression: In charged of whole thing ---> progressed --->
3rd step ---> different kinds of cancer cells have different functions
(community of malignant cells that has one purpose --->kill you).
Culturing cancer cells: Like Melanomas ---> tumors placed in the
culture medium and disk with different chemotherapy agents ---> you
can see who kills them ---> they can give you exact chemotherapy
agent that can kill them; Cannot do this for every cancer.
Stage1: Initiation ---> mutation
Stage2: Promotion ---> Dividing (multiple copies)
Stage3: Progression ---> sub specialization
When we have two sets of genes that are involved in cancer. They are
involved in the growth process and involved with cell cycle related
things. Those kind of genes monitor and suppress things, so we have
group of cells that are involved in normal growth cycle and then we
have other types of genes that are involved in suppression called
Suppressor Genes. Those are the two big sets of genes.
Things involved in trying to get cell to divide: Growth factors eg,
Epidermal derived growth factor.
Protoncogenes: these are cancer genes. But normally, when not
activated, they are actually serving normal function in the normal
growth process. Thats why called as protoncogenes. When they
become oncogenes it means that they are bad, they are cancer
producing genes.
So we have certain protoncogenes that are "Co-"??? to growth factors,
eg Cis-protoncogenes whose only function is to make growth factors.
All factors have to hook into receptors just like all hormones have to
hook into receptors like insulin hooks in to tyrosine kinase receptor on
adipose in muscle.
We have certain protoncogenes whose main job is to make receptors.
Erb-2 protoncogene, a classic one from breast cancer who calls for
receptors;
Ret-protocogene, of MENI and MenII.
Therefore protoncogenes are involved in receptors not the growth
hormones, thats their speciality. We have to send the message to the
nucleus.
We have another whole set of protoncogenes whose job is to send the
message like telegraph system.
Some of them are located in the cell membrane ---> Ras
Qs: Disease with radiation, what would you be? AnsNeuropathologists as they are dealing with brains and the prions.
Basal cell carcinoma: picture: Multifocal; Non ionizing radiation
(ionizing is the bad stuff of radiation); UV-B light (B = Bad).
UV-A: Superficial dermatophytes, shagreen patches in tuberous
sclerosis ---> Rx Black Light (UV-A).
UV-B: Protects from skin cancers like Basal cell Ca. most common, Sq
cell Ca 2nd most common, malignant melonoma; by mechanism of
Thymine dimers.
Precursor lession for certain cancers that are commonly seen in sun
exposed area, which you can scrape it off and it comes black --->
Actinic keratosis (solar keratosis) ---> predisposes to Sq. cancer --->
Pearly grayish white and looks like somebody just scraped it off.
Actinic keratosis: Only 3-4% of Actinic keratosis becomes squamous
cancers;
Heavy metal - Arsenic; Country - Bangladesh (probably water supply
which is contaminated with Arsenic related cancers are increasing).
Arsenic related cancers: Skin cancers, lung cancers, and angiosarcoma
of the liver.
Kid with white eye reflex ---> retinoblastoma, chromosome 13.
Qs - How many mutations does it takes for sporadic to become
retinoblastoma? Ans; 2 separate ones ---> You have to knock one
from One chromosome 13 and from another one.
Qs - How many mutations in autosomal dominant genetic inheritance?
Ans- 1; You are born with one already and activated, so you need one
more mutation on the other chromosome only.
White eye reflex is most commonly caused by congenital cataracts
(congenital infections like CMV or Rubella etc.) ---> shinning a light on
newborn eye ---> its white ---> retinoblastoma.
Qs - Why would a patient with Cushings have cataracts? AnsCorticosteroids, predispose to cataracts
Neoplasia 3
The sun exposed area would be predisposed to all the skin cancers
(basal cells, Sq Cells and melanomas).
Xeroderma pigmentosa: Autosomal recessive disease. Defect in the
DNA repair enzymes.
Group of diseases which are also DNA repair enzyme defects --->
BRCA1, BRCA2, P-53.
Chromosomal Instabillity syndrome: Wiskott aldrich syndrome, Bloom
syndrome, Ataxia telangiectasia, Fanconi's syndrome ---> All of them
have problems with DNA repair.
Upper Lip: Basal cell.
Lower Lip: Squamous cell.
Sq Cell Ca: burns, develops in the draining sinus, also doesn't heals
with antibiotics, constant irritation in the division of cells ---> greater
risk of cancer because you are dealing with squamous epithelium not
glandular epithelium
Lungs: Scar-cancers related to Old TB scar are adenocarcinoma not
squamous (related mostly to skin)
Only bacteria associated with the cancer ---> H.Pylori --->
Adenocarcinoma and Low Grade Malignant lymphoma.
Grade of the cancer ---> what's it look like.
If you can identify what it is because it is doing something like making
keratin, glands and is well differentiated ---> Low Grade.
Its anaplastic and high grade, fully differenciated ---> you cant tell by
looking at it under Microscope what it is. Grade term
Slide: Sq cancer ---> Keratin pearls (you can identify it ---> low
grade)
Slide: Gland like spaces ---> Adenocarcinoma ---> (you can identify it
---> low grade)
Stages of tumor:
T - Toy ---> Size of the Tumor (<2 sonometers it generally has the
chance to metastasize)
N - Nancy ---> Nodes
M - Machine ---> Metastasis outside the nodes.
Most common staging system which goes from least important to most
important.
Scenario: Breast Cancer ---> Low axillary nodes are involved ---> You
think that its the worst part but instead it the end part of TNM --->
Worst part when it is out side the lymph nodes likes bones, lungs, or
liver.
Most important prognostic factor is stage!
In staging the most important thing is Metastasis.
Qs: Which is the worst prognosis in prostate cancer?
a Limited to prostate
b Went into seminal vesicles
c Went into wall of the bladder
d went into lymph nodes around the bladder
e went into the bones (Correct)
Slide: Colon Cancer ---> Lymph nodes. Which one is important size of
the tumor or lymph node involvement? Ans- Lymph node; Simillar
focus of cancer in the liver ---> then liver is the most important
prognostic factor.
Host Defenses: The most important is Cytotoxic CD8-T cells (No 1
most imp. host defense sys. we have got); We have other things --->
Macrophages, NK cells, Antibodies (Type2 HSN).
Cyt-CD8 T cells: They rounds every day looking for altered class I
antigens ---> when ever neoplastic cells those class 1 antigens --->
Cyt CD8 T cells they get interested in that cell to kill that cell ---> put
perforin which is the signal to Caspases (proteases ---> start breaking
down the nucleus, screwing up the mitochondria) to start apoptosis.
Cachexia: Cause is TNF ---> irreversible. Once you see the pt with
disseminated cancer just beginning to go into the catabolic state, you
can get them total parenteral nutrition ---> they will not get their
muscle mass due to TNF-alpha.
Hematologic causes of anemia are present in malignancy. Most
common anemia in malignancy is the anemia of chronic disease.
Colon cancer: Left side obstructs and the right side bleed ---> if you
have the right sided colon cancer ---> then iron deficiency will be more
common; Metastasis to bones and replaced all the bone marrow --->
anemia.
Chemotherapy drugs that are cell cycle specific or non specific --->
you wipe out the marrow.
Autoimmune mechanisms with certain types of cancers; But overall is
the anemia of chronic disease.
Most patients that have the disseminated cancers are hypercoagulable
(tendency of forming clots)
Qs: Pt that has the painless jaundice, left supraclavicular nodes, light
colored stools, he has this peculiar lession in the vein which jumps
from one part of the body to the next? Ans-Trousseau sign, superficial
migratory thrombophelibits of the patient with carcinoma of the head
of the pancreas.
Pancreatic cancers also likes to go to left supraclavicular nodes.
Disseminated cancers - Thrombocytosis: An elevated platelet count.
Labs: We need to work up the cause of thrombocytosis --->
hematology slip; Iron deficiency, scar over here (left abd --->
splenectomy), if TB; No obvious cause of thrombocytosis that rule out
the Myeloproliferative dissease or stuff like that.
40% of all disseminated cancers have thrombocytosis.
Most of the time Colon cancer is missed due to presence of black stool.
Stool guaiac is important
Fever: Most common cause of fever in malignancy is gram (-)
infection. Usually gram (-) is hospital acquired.
E.Coli - Indwelling catheter
Pseudomonas Aeruginosa - Repirator
Staph Aureus (gram +) - Indwelling catheter in vein.
Most common cause of death in cancer is infections.
Paraneoplatic syndromes: These are the signs which shows that there
may be some underlying cancer. They are kind of clues, tells that
something going on in the patient, so you can actually find that cancer
before it get metastasized.
Most common Paraneoplastic syndrome is hypercalcemia.
Qs:There are 2 mechanisms behind hepercalcemia in malignancy.
1) It has metastasized to bones ---> produce some kind of chemical
like IL-1, PGE2 that activates osteoclasts ---> produces lytic lesions in
bones ---> Hypercalcemia.
2) It can be Cal??? cancer like a renal adenocarcinoma or sq.
carcinoma of main stem bronchus which makes paratharmone like
peptide and cause hypercalcemia. It acts like pth
Which one is the paraneoplastic? Ans- 2nd one.
Slide: Two lessions that are black here. Both of these are phenotypic
markers for same cancer, the gastric adenocarcinoma. The black
lession under the arm is acanthosis nigricans; This is called as
seborrheic keratosis (beningn). If they develope all of a sudden, called
Lesser-Trlat sign, you get multiple outcroppings of these things --->
phenotypic marker of gastric adenocarcinoma.
Acanthosis Nigricans: Also associated with other things like Insulin
receptor deficiency related to DM, also with MEN syndromes. So its
phenotypic marker for lots of things but most commonly gastric
adenocarcinoma.
Clubbing: Hypertrophic osteoarthritis ---> Inflammation underlying
bone, periostitis, thats stimulates increase in soft tissues development
producing clubbing; Clubbing also associated with bronchiectasis,
inflammatory bowl disease, but in case of malignancy it would be
mostly associated with primary lung cancer.
Dermatomyositis: Least common collagen vascular disease which is
most commonly associated with underlying cancer, and with elevation
of serum CK, raccoon eyes (heliotrope eyes), inflammation of skin and
muscles. High association with Leukemias, lung cancers, lymphomas
etc, and Goytrans patches over the knuckles.
Man:
No 1 Cancer: Prostate
No 2 Cancer: Lungs
No 3 Cancer: Colon
2nd most Common cancer and cancer killer in man and women
and Alcoholics)
Normocytic Anemias: Low Retic count (Aplastic anemia, Renal
disease).
Corrected Retic count increased: Hemolytic anemia, Spherocytosis,
sickle cell, G6PD deficiency, autoimmune hemolytic anemia,
microangiopathic anemia.
Correcting the Retic count next to Complete blood cell count is your
first step in a work up of any anemia.
Reticulocyte: A young red blood cell. In 24 hours a reticulocyte
becomes a mature RBC with biconcave disc.
In case of anemia the retic count becomes important because it tells
you where the problem is, either in bone marrow in making the RBC or
is it a problem outside the bone marrow causing the problem.
If Bone Marrow was the problem, retic count would not be good --->
inappropriate response ---> you got a marrow that has RBC
hyperplasia ---> BM making lots of RBC and gonna put some of those
reticulocytes out a little bit prematurely ---> that means its working
and doing something, trying to correct the anemia.
In case of blood loss, it takes 5-7 days before it begins getting retic
count increased. Kinda like the kidney dealing with HCO3 in acid base
disorder.
If there is nothing wrong with bone marrow then there should be a
good reticulocyte response (No need of bone marrow exam), if there is
something wrong, it there won't.
You have to correct the retic count to the degree of anemia.
The Corrected retic count is the hematocrit of the patient divided by 45
which is considered as normal (for both male and females) multiply by
retic count that you have been given.
Scenario: The pt hematocrit is 15% (severe anemia). Retic count 9%
(increased, any thing over 3% is considered increased); If you did not
corrected, it looks like bone marrow responding appropriately because
its 9% but you have to correct it according to the degree of anemia;
So 15 over 45 is 1/3 - Divided by 9 = 3, so actually when we correct
Qs: Pt got 5gm of Hb, was given 3 units of Packed RBCs, the following
day Hb is 6, Hematocrit is 18, is that a appropriate response? Ans - Hb
8 with Hematocrit of 24; Why it wasn 't 8? Ans- Pt had GI bleed, the
most common of anemia is iron deficiency and the most cause of iron
deficiency is GI bleeding overall.
Most common reason why the Hb and Hematocrit do not go up after
the transfusion of RBC, you are loosing blood most commonly in GI
tract; If you are thinking Hemolysis - its 1 in 250,000 chance.
Hb Electrophoresis is mainly used to detect different kinds of
Hemoglobinopathies.
MCV: Either Small dude,Normal dude, Big dude. Machine takes
average size of the cells. Its the best way of classifying the anemias.
If normal is 80-100. If average MCV is <80, then it is microcytic --->
play odds its iron deficiency; If its between 80-100 and have an
anemia, then it would be normocytic anemia; If greater >100, then its
Macrocytic anemia.
In case of Small cells and large called Dimorphic RBC population --->
Normal MCV ; Kinda like those blood gases, m.acidosis and m.alkalosis
---> Normal PH.
Iron deficiency anemia and Folate deficiency: They are reabsorbed
---> Iron in duodenum, Folate in Jejunum, B12 in terminal ileum, it
means that you have small bowel disease like celiac disease, you have
malabsorption that effects different areas of small bowel.
Celiac disease: most common cause of Malabsorption ---> duodenum
and Jejunum ---> deficiency iron and folate ---> small cells and large
cells; lets say its involving jejunum and terminal ileum ---> deficiency
of B12 and Folate.
So its possible to have 2 anemias at the same time and normal MCV.
Red Blood Cells Distribution Width (RDW): Its basically, the machine
looking at the RBCs that are coming to the machine, are they
uniformly small, normal, macrocytic or tremendous difference in size.
RDW can detect the change in the size and reports it as a Number.
Qs: Microcytic anemia, RDW increased? Ans- different size in
microcytic cells, difference in the sizes, may be got some small ones
Signs of anemia:
Spoon nail: Sign of iron defeciency ---> also called as Koilonychia.
Hematology
Post 37: (Dated: March 01 - 2009)
Cheilosis: Cracking (many things produces it like iron deficiency or
riboflavin but not specific).
Palor of conjunctiva: 6 gm or less Hb.
You look in the palmar crease (caucasians): Dont see red in them --->
Anemic.
Slide: Lead line; Discoloration ??? margin ---> lead poisoning.
Neurological Exam is very important in B12 def. because you knock off
the posterior columns and lateral corticospinal tract --->
proprioception abnormalities and decreased vibratory sensation;
Lat.Cort.Sp.Tract have babinski.
Normal Serum Iron = 100 (same with Alveolar O2).
Ferritin: Circulating soluble form of iron storage. It also represents the
amount of iron stored in the bone marrow.
So if you have to pick one test for diagnosing iron deficiency, Anemia
of chronic disease, or iron overload disease ---> it would be serum
Ferritin which is the best screening test.
TIBC: Carrying protein for iron? Ans- Trans = Carry, Ferrin = iron --->
protein carries iron.
All proteins made in liver. Transferrin or TIBC are same.
There is a relationship between the iron stores in the bone marrow
with the transferrin synthesized in the liver. When the iron stores in
bone marrow are difficient ---> iron defeciency ---> it is the signal to
liver to make more transferrin ---> increase TIBC; So low iron stores,
increased transferrin synthesis = increased TIBC ---> kinda like
inverse relationship like hormones ---> T4 increased / Tsh decreased =
iron stores decreased / Transferrin , TIBC increased or vice versa.
Percent sat.: Its a calculation. Serum iron divided by total iron binding
capacity; Normaly serum iron is 100; Normaly TIBC is 300; Normal
but you cant get it out. Good news, you are keeping it away from bugs
so they cannot reproduce. Bad news, keeping it away from the RBC so
you have decreased Hb synthesis. Unlike iron defeciency where there
is no iron in macrophages but in this case piles of iron
in the macrophages but its like a safety deposit box and you are the
only one who have the keys.
Sideroblastic anemia: Sidero means Iron like Ferro.
Reaction Locations:
Biochemical reactions in inner mitochondrial membrane: oxidative
phosphorylation.
Mitochondrial matrix: Beta oxidation of FA (TCA cycle) in Cytosol and
mitochondria.
Gluconeogensis starts in mitochondria and ends ups in cytosol.
Urea synthesis: Starts in mitochondria, goes into cytosol and back into
mitochondria.
Heme synthesis: parts in mitochondria, parts into cytosol and parts
into mitochondria again.
First part of heme or porphyrin synthesis, begins in mitochondria; The
first reaction - succinyl-CoA (in TCA cycle, substrate for
gluconeogensis) ---> put together with glycine.
Glycine: Simplest AA, an inhibitory neurotransmitter of muscles,
blocked by tetnus toxin causing opisthotonus, risus sardonicus, and all
those tetanic contractions of muscles; Every 3rd AA in collagen is
glycine and we can see that its also involved in heme synthesis.
Rate limiting enzyme in heme synthesis, porphyrin synthesis ---> ALA
synthase (cofactor - pyridoxine); delta amino levulinic acid, other
enzymes ---> they go to porphobilinogen, uroporphyrin ??? back into
mitochondria.
Protoporphyrin + iron, put together by chelating agent
(Ferrochelatase) ---> combines iron together with protoporphyrin to
form heme.
Heme has the feedback mechanism as do all rate limmiting enzymes
with ALA-Synthase; heme increased ---> Inhibits ALA-Synthase; Heme
is decreased ---> enhances ALA-Synthase.
Rarest of all microcytic anemias, sideroblastic anemia. Three main
causes:
Pt with dementia, must get TSH to rule out hypothyroidism and B12 to
rule out B12 deficiency.
They are reversible causes of dementia.
B12 is an animal product. So you cannot be pure vegan and get B12.
Scenario: Comparing pure vegan to ovo-lacto vegetarian. If you are an
ovo-lacto vegetarian, you are taking dairy products as an animal
products, you wont have to be on B12 supplements. But if you are
pure vegan, you are taking pure vegetable products and no dairy or
meat products, you would require B12.
The very first thing you do when you are chewing, B12 binds to RFactor in saliva. The purpose of R-Factor is to bind the B12 to protect it
from getting distroyed by acid in stomach.
Intrinsic factor is made by parietal cells, located in body fundus (two
thing acid and intrinsic factor).
Intrinsic factor is't distroyed by acid so it does't need anything to
protect it. So the B12-R-factor complex goes into the duodenum where
the intrinsic factor is waiting for it ---> functioning pancrease that
cleave off the R-Factor ---> Intrinsic factor + B12 ---> complex takes
a long route to terminal ileum, where there are receptors for intrinsic
factors and get reabsorbed, its the same place for reabsorbtion of bile
salts and crohns disease.
So when you have crohn disease, you have Bile salts and B12
deficiency.
Duodenum: Iron country
Ligamentum triad - beginning of jejunum: Thats Folate country
The most common cause of all this stuff is pernicious anemia,
autoimmune disease with destruction of the parietal cells. There are
autoantibodies against parietal cells and intrinsic factors. Parietal cells
gets knock off and you get atrophic gastritis of the body andfundus, no
parietal cells no acid (achlorhydria) and no intrinsic factor.
Atrophic gastritis of the body and fundus with no acid ---> predispose
to cancer. Achlorhydria
B12 deficiency, you give a radioactive B12 by mouth. They swallow it,
you collect the urine for 24 hrs and see if any of it comes out in the
urine. If Nothing comes out ---> proves they are having a problem
because they are reabsorbing B12.
Shilling Test:
1)Radioactive B12 + Intrinsic factor: Collected urine for 24 hrs --->
piles of B12 in urine = pernicious anemia; if did't work ---> you
exclude pernicious anemia.
2)10 days of broad spectrum antibiotics: Come back in 10 days, you
give radioactive B12 ---> piles of B12 comes out = Bacterial
overgrowth, you have knocked out those bugs that were eating B12; If
that did't worked ---> last thing left, pancreatic extract.
3)Pancreatic Extract: you give couple of pills, you gave radioactive
B12, 24 hrs latter ---> radioactive all over the place = chronic
pancreatitis; If that did't worked could be crohns disease or worms.
Normocytic anemias: When you do the corrections for the anemias,
turns out that its polychromasia, and the correction is <2 % ---> Not
good, normocytic anemia and BM is not responding correctly.
Hematology
Post 41: (Dated: March 15 - 2009)
The first 2 things that you will see here is early iron deficiency and
anemia of chronic disease. You have to have a normotcytic anemia first
before you become microcytic, so you still have to have differential
diagnosis of a normocytic anemia with corrected retic count <2%. You
still have to get a ferritin thats totally ligitimate.
Iron deficiency stages: First thing happens is that ferritin levels goes
down. The next thing iron decreased, TIBC increased, %Sat decreased
---> You still dont have anemia. In fact all the iron studies are
abnormal before you even have any anemia in iron deficiency, then
you get a mild normocytic anemia then eventually microcytic anemia.
Blood loss
Aplastic anemia: No Marrow. All the hematopoietic cells are destroyed
in the marrow ---> in peripheral blood ---> pancytopenia. You have
normocytic anemia, thrombocytopenia, Neutropenia.
Slide: So this was the kid with sickle cell disease with dactylitis. They
X-ray the hand and the reason why those bones looked all washed out,
they were all white, and were infarcted.
Because whats happening is, bone infarction occuring due to sickling in
the BM and is infarcting the bone. It hurts so much. X-ray shows, kid
also have lead poisoning with sickle cell.
Dactylitis usually does't come till 6-9 months because HbF inhibits
sickling.
Osteomylitis: Sickle cell pts are very succeptible to osteomyelitis, not
the usually caused by staph aureus but salmonella. One reason for
that is dysfunctional spleen. Salmonella is destroyed by macrophages,
not by other mechanism. Thats why salmonella (75% of the times its
salmonella species) is the more common cause of osteomyelitis in
sickle cell disease. Next most common one is staph aureus.
Rx: Hydroxyurea ---> decrease in the incidence of vaso occlusive crisis
---> increases HbF synthesis.
Slide: Howell jolly body. G6PD deficiency. Sex linked recessive; Inborn
errors of metabolism like PKU, albinism, homocysteinuria ---> majority
of those are autosomal recessive, so that means that you gotta 1 in 4
chance with carriers having a kid with the disease.
Sex Link recessive: G6PD deficiency and lesch nyhan syndrome.
Lesch nyhan syndrome: Purine metabolism problem. Kids are mentaly
retarded, self mutilation, increase in uric acid, HGPRT deficient.
G-6-Phosphate: Use to make glutathione, and also Ribose 5-Carbon
sugars for making DNA from this pathway. Also you can make
glycogen from G-6-P, which is converted to G-1-P ---> UDP-Glucose
and glycogen; G-6-P can be the substrate used for making glutathione
and other substrates.
Here is an enzyme, you are gonna be able to make NADPH, which is
the major factor for anabolic types of biochemical reactions in our
body like steroid synthesis etc. NADPH will reduce oxidized-glutathione
to glutathione ---> neutralizes peroxides into H2O (Catalyzed by
Vitamin Riboflavin, enzyme - glutathione peroxidase, trace metal selenium).
Every living cell makes peroxide as an end product, just normal end
product to normal metabolism. Thats why every living cell has to have
some way of handling it. Catalase is present in all cells except RBCs
and it can neutralize peroxide, stored in peroxisomes. The other way of
neutralizing peroxide is with glutathione which is the only thing
available to RBCs which dont have catalase. So when you are deficient
in glutathione, peroxide increases to a point where you start
hemolyzing like you have infection, certain oxidizing drug (sulfa or
nitro drug) ---> you will be getting lots of peroxide ---> not gonna be
neutralized if we are deficient in that enzyme ---> peroxide gonna do a
job on Hb ---> causes it clump up and called Heinz bodies + damages
the RBC membrane so much that the primary mechanism for
destruction is intravascular (little bit extravascular as well).
Hematology
Post 42: (Dated: March 16 - 2009)
Two drugs most important: Primaquine and Dapsone.
Primaquine: Pt got Malaria, recieved a drug, 2-3 days later developed
Hb-Uria, chills and Hemolytic anemia.
Dapsone: For Rx of leprosy. Every person thats in the leprosarium,
before they put him on Dapsone they do a screen for G-6-PD because
of high incidence of producing hemolysis. Its a normal screen test for
pts of leprosy before they put them on Dapsone; Pretty much same
with Beta-thal, gotta be black, greek or italian population. So BetaThal and G-6-PD deficiency are two things in same group of people.
Heinz bodies: This is what a smear look like when someone is actively
hemolysing your RBC. Special stain ---> Blue clumps all over the
place, some ones are right on the membrane, called heinz bodies. This
goes into the cords of billroth and the macrophages will see this big
thing and will take a big bite out of the membrane and some times its
just a small bite, so cell can get out in the peripheral blood and just a
piece of its membrane missing like some thing took a bite out of it and
hence the term Bite Cells. Very characterstic finding in peripheral blood
in G6PD deficiency.
You need special stains to find out these Hienz bodies thats why its
called Hienz body anemia.
The pts that are greeks or italians have the most severe forms of
G6PD deficiency. They can eat just Fava beans and precipitates
hemolysis of cells. Fava beans present in salads. Also called as Favism.
Slide: This is peripheral smear from a 49 year old man. 150,000 WBC
count, 1% myeloblast in peripheral blood and BM, Gen. non-tender
lymphadenopathy, hepatosplenomegaly, thrombocytopenia,normocytic
anemia: Diagnosis - Chronic myelogneous leukemia.
Hematology
Post 45: (Dated: March 23 - 2009)
Right age bracket, right % of blasts ---> what test? Ans- Philadelphia
chromosomes study; Philadelphia chromosome t(9 ABL; 22 BCR). ABL
has non-receptor tyrosine kinase activity.
Translocation from 9 to 22 fuses with great cluster region on the fusion
gene thats the Philadelphia chromosome.
CML test: Leukocyte alkaline phosphatase, which is a Stain; We will
take the smear and overlay the stain on it and see which neutrophils in
the smear gonna take up the stain for alkaline phosphatase. Mature
neutrophils all have alkaline phosphatase in them but neoplastic
neutrophils donot. So in this test we look for staining ---> segmented
neutrophil with out stain (if it was benign it would have taken up the
stain). So you grade from 0 to 4 by counting the neutrophils --->
Score called Leukocyte Alkaline phosphatase score ---> always low in
Chronic Myelogneous leukemia.
Therefore confirmatory test for CML: Philadelphia chromosomes study
and Leukocytes alkaline phosphatase score which is low, usualy "0".
Slide: Tear drop; Hematopoeitic cells moves from BM to spleen.
Extramedullary Hematopoiesis ---> in which hematopoiesis takes place
other then bone marrow usually spleen. Spleen is huge, some of the
biggest spleen you will ever feel in disease called Agnogenic myeloid
metaplasia.
Some of the hematopoeitic cells wants to go back to marrow. While
some of the megakaryocytes lay down collagen through out the
marrow so nobody can go back ---> Fibrosis of entire BM, old term to
this is Myelofibrosis Myeloid Metaplasia and now called as Agnogenic
myeloid metaplasia.
10% of the cells never get the message and donot move to spleen
---> hang around even in the fibrotic marrow and do their things; like
RBCs, to get out into sinusoids they have to move through the strands
of fibrous tissues which damages their membranes. Plus it hurts --->
they cry! ---> while coming through all the barbwires (fibrous tissues)
and getting into the sinusoids ---> finally makes their way to
peripheral blood ---> they cry and become identifiable cells the "Tear
Drop".
Slide: Too many platelets. This is the myeloproliferative disease. This is
essential thrombocythemia. Thats a neoplastic stem cell that wants to
make too many platelets.
Slide: This is the pt 4 years old that presents with sternal tenderness,
fever, gen.non-tender lymphadenopathy, hepatpsplenomegaly,
normocytic anemia, 50000 WBC many of which are abnormal
appearing cells like these. Diagnosis? Ans- Acute Lymphoblastic
leukemia (ALL), the most common cancer in kids.
ALL: Most common type. Common ALL antigen, Bcell leukemia --->
the "cALLa"-antigen. The cluster designation of CALLA antigen = 10.
So its CD10+, CALLA antigen positive, B-Cell= ALL.
Slide: This is the peripheral blood from 65 year old man, gen.nontender lymphadenopathy,hepatpsplenomegaly, normocytic anemia,
thrombocytopenia and 90000 WBC almost all those cells resembling
these cells. There are couple of "Smudge cells". This pt also have
hypogammaglobinemia, because these are neoplastic B-Cell and
cannot tranformed into plasma cells to make the gammaglobulin --->
death due to infections related to hypogammaglobulinemia.
Slide: This is the 62 yrs old pt, hepatosplenomegaly, huge spleen.
These are Weird old cells with projections of cytoplasm, stained by
tartrate resistant acid phosphatase (TRAP).
Hematology
Post 46: (Dated: March 24 - 2009)
Slide: Continue... And wat cancer? Ans- Hairy cell leukemia.
Slide: Thats the Auer rods. This is a peripheral smear from a pt that is
35 who has 50000 WBC count with many abnormal cells, 70% blast in
BM, Anemia, thrombocytopenia ---> Acute Myelogenous leukemia.
Auer rods: Abnormal lysosomes. Looks like little red splinters in the
BM.
All you need to know is How Auer rods looks like, leukemia likes to
infiltrate gums (Acute monocytic leukemia - M5), and this one you
need to know:
This one over here is so full of them (Auer rods) does't have any
cytoplasm left. Some may even get into the blood ---> Acute
progranulocytic leukemia, M3, they always have DIC. So in all the
leukemia this is the numero ono in DIC. It has translocation t(15;17).
You treat it with retinoic acid (vit.A) ---> it causes blasts to mature
into benign cells.
Slide: This is the lymph node. If you have a lymphadenopathy that
hurts its never malignant, means you have some kind of inflamation.
Does't always means infection. You have gen. lymphadenopathy in
lupus but its painful adenopathy becasuse you are stretching the
capsule ---> its an inflammatory condition that produces pain.
When you have nontender lymphadenopathy, always think malignant.
The first thing is metastatis and 2nd primary lymphoma.
You have localized and generalized lymphadenopathy.
Generalized painful lymphadenopathy means systemic inflamatory
disease. So in HIV, EBV, SLE, they all have gen.lymphadenopathy. But
exudative tonsillitis, goes into local nodes and gonna hurt. Breast
cancer goes into local regional nodes and gonna hurt.
Slide: This is the lymph node:
Bruton's Agammaglobulinemia: The area would be ABSENT, the
germinal follicle (B-Cells gone).
Digeorge Syndrome: Paratrabecular got screwed up which is the Tcell
country.
Histiocytosis X: which means Hand-Schuller-Christian Disease,
Letterer-Siwe Disease, which is a true histiocytic CD1+ tumor. Seen in
sinuses.
Severe Combined Immunodeficiency: due to adenine deaminase
deficiency. You would have histiocytes, thats a combine B and T
lymphocytes.
When macrophages process antigens, they deliver it to Bcells that
what causes these germinal follicles. These are Bcells that are in the
process of division ---> the end product come out of the follicle is
Because its just one clone of plasma cells, you get most of the time
IgG. It makes lots of immunoglobulin, lots of light chains and the light
chains get into the urine ---> bence jones proteins.
Scenario: A person 25 yrs, non-smoker, emphysema of lower lobes
and protein electrophoresis showed, this peak was gone, no alpha-1
peaks. Diagnosis? Ans- Alpha-1 antitrypsin.
Multiple myeloma is a horrible disease, usualy incurable unless BM
transplant. Over 50 yr, Women>men. Most common type is Ig-Kappa
type of MM. Remember that Plasma cells have IL-1 (osteoclast
activating factor).
Slide: Skull, lots of lytic lessions. Pretty much round. Pagets disease of
bone also have lytic areas but very fussy looking.
IL-1 activates osteoclasts, they bore hole through the BM and produces
lytic areas. If this lytic lession is in ribs and when you cough --->
pathologic fractures, extremely common.
Scenario: Elderly women, who coughs and develops severe pain. She
comes in and you see there is a point tenderness over the Rib. Xray
showed a lytic lession with pathological fracture ---> MM.
Slide plasma Cells: Bright blue cytoplasm, nucleus eccentrically
located, right next to nucleus is clear area. Electron microgroscopy - in
cytosol shows, layers of RER, sheaths and sheaths as constantly
making proteins. Important to know how Plasma cells looks on WrightGiemsa stain, and EM.
EM: This is amyloid, non-branching linear compound that has a hole in
center of it.
Amyloidosis: Always seems to end up in the DD, for multisystem
disease. Amyloid is a protein, and many different kinds of proteins are
converted into it. So its a unique protein and many different kinds of
proteins are transformed in it. eg. Pre-albumin can be converted into
amyloid. Calcitonin (tumor marker for meduallary Ca. of thyroid) can
be converted into amyloid.
Light chains in MM can be converted. Trisomy 21, chromosome 21
codes for beta-amyloid. So if you have 2 chromosome-21 ---> gonna
make little bit more beta-amyloid (toxic to neurons).
So now the platelets sticks called platelets adhesion ---> it causes the
platelets to release chemicals ---> most important chemical is
Adenosine diphosphate (ADP) ---> potent aggregating agent --->
causes platelets to begin sticking together ---> forms a thrombus in
little injured vessel ---> begins to stop the bleeding ---> but its not
enough to do the whole thing. So this is called the Release Reaction.
We need one more chemical to stop the bleeding. ASA that platelet has
that release reaction, it begins synthesizing its own unique substance
---> Thromboxane A2 (TXA2). Its the only cell in the entire body that
has Thromboxane synthase. It converts PGH2 ---> TXA2.
TXA2: Potent vasoconstrictor. It is important to stop bleeding because
when you slow up the rate of blood flow it makes easier for platelets to
stick together. They dont get washed away.
PGE2: Vasodilator. Platelets cant stick.
TxA2, as a matter of fact it causes vasoconstriction of coronary artery
in prinzmetal angina.
Its also a bronchoconstrictor ---> has some activity in asthmatics --->
gonna help LT- C4,D4,E4 alot. So its a vasoconstrictor,
bronchoconstrictor and platelets aggregator; It block up the lumen of
injured vessels ---> bleeding time has just ended.
TXA2 synthesis: Platelets have 2 interesting things; First platelets have
release reaction for the chemicals, that were already made in it, were
released; Second it makes its own unique chemical called TXA2 a lil bit
latter.
Mast Cells: 2 IGEs, next juxta-post to each other in polen kinda bridge
the gap like an electrical circuit ---> mast cells have release reaction
of preformed chemicals like histamine, serotinin, eosinophil
chemotactic factor ---> start the process of inflammatory reaction in
TypeI-HSR ---> mast cells (? in-)activated the released arachidonic
acid from its membrane, we ended up making PGs and leukotrienes,
they were released 30 minz to an Hour latter ---> gonna further
enhance that inflammatory reaction, which we associate with TypeIHSR.
So release reaction of preformed elements ---> make you ??? PGs and
leukotrienes as a latter effect. The platelets kinda do the same thing.
They have a release reaction too. They make TxA2 a lil bit latter.
That little plug is very temporary. Its a bunch of platelets stuck
together and held together by fibrinogen ---> enough to stop &
prevent bleeding ---> Stops bleeding.
Prolong bleeding time: Most common cause is thrombocytopenia. You
have low platelet count, <90,000 platelets ---> prolong bleeding time.
vWF Adhesion molecule disease: Most common genetic hereditary
disease ---> Autosomal dominant. 1 in 250 people have vWF disease.
Aspirin: Most common cause of prolong bleeding time ---> Aspirin
blocks platelets cyclooxygenase (COX) (TX-synthase is blocked by
dipyramidole); Endothelial cells have COX too.
Aspirin did't inhibit endothelial COX from making PGI2; The platelet
COX Vs endothelial cells COX reacts differently with aspirin --->
basically different compounds reacts differently to non-steroidals. Its a
9:1 ratio, with 9 times inhibition of platelets COX when you take
aspirin and non-steroidal Vs inhibition of the endothelial cells COX.
Therefore Aspirin and NSAIds inhibits platelets COX predominantly not
COX of endothelial cells.
Aspirin: Irreversible
NSAIDs: Reversible, 48 hrs.
You took one Aspirin for any reason: Gonna work on every single
platelet ---> if you cut yourself shaving this morning ---> not gonna
stop bleeding in 9 minutes, may be 15-20 minutes.
So aspirin works by blocking platelets COX and preventing them from
aggregating. If There is no TXA2 there ---> Its not gonna work and
you continue bleeding.
It also helps in understanding the signs and symptoms of a platelets
deficiency vs coagulation factor deficiency.
Reminder: We release tissue thromboplastin and activated the
extrinsic system ---> activate the Hageman factor XII because the
collagen being exposed ---> activates the intrinsic system ---> end
product of coagulation system ---> Thrombin, converts the fibrinogen
to fibrin.
We have piles of platelets stuck together and draped over them is
fibrinogen ---> these things gonna happen just a little bit latter after
the bleeding time is over; Thrombin which is generated from ext. & int.
sytem will convert the fibrinogen thats holding the platelets together
loosely into fibrin ---> makes a stable platelet plug in there that it
wont be able to dislodge.
Whose gonna remove the platelet plug from the vessel? AnsPlasminogen will be activated.
Plasmin will be formed, drill a hole through it ---> recanalize, and our
vessels looks normal.
Hematology
Post 51: (Dated: April 01 - 2009)
So in other words we do the bleeding time, the bleeding time goes up
to the formation of temporary hemostatic plug. We have piles of
platelets stuck together with fibrinogen ---> stops the bleeding time
but it very unstable. But when the coagulation system makes its
thrombin or converts the fibrinogen, thats draping it together,
converted to fibrin ---> strong platelet plug forms.
Platelet problem: Bleeding time = Prolong. If cut small vessels --->
continue to bleed.
Bleeding from superficial scratches or cuts. You cant form the
temporary hemostatic plug. In addition you screw up the integrity of
the small vessels when ever you screw around with platelets ---> you
get petechia (pinpoint areas of hemorrhage; only seen in platelets
abnormality), echymoses or purpura (little greater area of hemorrhage
in to the tissues), epistaxis (nose bleed).
None of the things like petechia, echymoses or purpura, epistaxis or
bleeding from superficial scratches, occurs in coagulation deficiencies.
Hemophilia A: Deficient in Factor-A, Bleeding time = Normal. Run into
late rebleeding. eg, Appendectomy, you woke up and start to move
around and the massive amounts of blood starts to come out ---> you
bled to death. The only thing that was really holding in small vessels
together were sutures and temporary hemostatic plugs.
If you have a coagulation factor deficiency, you cant convert the
fibrinogen into fibrin and that little platelet things gonna fall away. So
you get late rebleeding.
You can handle superficial scratches and superficial cuts with no
problems. But they are not gonna hold that vessel closed for too long,
they gonna be dislodged ---> rebleeding.
Scenario: Best question to ask a person to see, if they have
coagulation factor deficiency.
Q- Do you have ever molar tooth removal or wisdom tooth removal?
A: yes they have.
Gonna find out whether she has a coagulation factor deficiency.
Q- Do you have any problem with bleeding with it?
A: No
Just checked off a coagulation factor deficiency.
If you dont have a bleeding problem after extracting a wisdom tooth,
that actually imposes to greatest hemostatic stress on your system
that exist. Its even worst than thoracotomy, or other types of surgical
procedures.
Scenario: If you had your wisdom tooth extraction today. A dude over
there and got numbed up, and got epinephrine to help vasoconstrict.
They gonna pack a little bit. If you have Hemophilia-A, mild case. No
problem in hemostasis control. The only thing holding little vessels,
little temporary platelet plugs held together by fibrinogen. They always
tells you to rinse your mouth out. Preferably little salt and bit of
peroxide there ---> all those temporary hemostatic plugs are gone
---> bleed to death, lots of people choke to death on their own blood.
Factors deficiency: Menorrhagia - more of a feature of coagulation
deficiency than platelet problem; Potentential for hemarthrosis
depends on how severe the factor deficiency is. Hemarthrosis is the
bleeding in close spaces. Totally different from platelet problems.
Epistaxis, petechia, echymosis, bleeding from sperficial scratches vs.
late rebleeding, menorrhagia, GI bleeds and potential for
hemarthrosis; So both of them are different in terms of sign and
symptoms. All based on knowing what normally happens when you
screw up small vessels when you are injured.
Test for platelets abnormalities: Platelets count, bleeding time and vWF
test.
How many Platelets we have?. You took an aspirin or NSAIDs, you still
have normal number of platelets, but they dont work.
Bleeding time: Good test for platelet function.
vWF test: Called ristocetin co-factor assay. If you are missing vWF,
ristocetin cant cause the platelets to clump. Most sensitive test for
diagnosis of vWF disease.
Qs: Old Pt with chronic headaches, osteoarthritis went into prostate
transurethral resection surgery. Bleeding to death after that. PT
normal, PTT normal, platelet count normal. Whats your treatment?
Ans- You have osteoarthritis, you probably on pain medication like
NAIDs. Since PT, PTT are coagulation factors test. Platelets are also
normal but due to NSAIDs, stops them to clump (?). Rx- Platelet
packed transfusion. When you gave them platelets from a donor they
are able to work, the pt's platelet cant work but donor units of
platelets can work and it will stop the bleeding.
Case: Pt had 20 units of blood. PT normal , PTT normal, bleeding time
normal. Guy was bleeding to death. He was on NSAIDs. Rx- 5 units of
platelets.
In case of Major surgery, you are bleeding to death. The only Rx is
normal platelet.
Extrinsic system has Factor VII.
Intrinsic system: Four dudes in it, XII, XI, IX and VIII.
Both systems share the same final common pathway.
Common pathway also shared by other systems like complement
system. You have classical pathway, alternative pathway and they
have final common pathway (C3), what you call MAC - Membrane
Attack complex, unit.
Very similar with this, you have extrinsic and intrinsic. They both uses
the final common pathway except it has "factor-X", not "C3".
So what we have left, we have used VII and we have used XII, XI, IX,
VIII. We have X, V, II (prothrombin), I (fibrinogen) ---> clot.
Warfarin or Heparin:
Platelet count = N
Bleeding time = N
PT & PTT = P
For warfarin ---> PT
For Heparin ---> PTT
Blood group-O: Most common one. You have anti-A IgM and anti-B
IgM, antibodies. Also anti-AB IgG.
Blood group-A: Anti-B IgM
Blood group-B: Anti-A IgM
Blood group-AB: Nothing
New Born: Nothing. Dont begin synthesizing IgG until they are born.
Those are IgM antibodies.
After 2-3 months they begin synthesizing IgG, so dont have isohemaglutinins.
Old Men or Women: Hardly any.
Scenario: An old person. Who is blood group-A and by mistake recieve
group-B blood and did't develope the hemolytic transfusion reaction.
Why? Ans - Their levels of antibodies are so low when you get older
that they don't have anything around to attack those cells.
Associations:
Gastric cancer ---> group-A
Duodenal ulcers ---> group-O
Universal donor ---> group-O; they have no A or B antigen. Can get
only from group-O.
Universal recepient ---> group-AB; No antibodies to attack those cells.
Rh +ve: There are five Rh antigens ---> D, C, c, E, e. When you say
you are Rh+, you are +ve to one of them ---> ie. D = Dork.
Rh -ve: D-Antigen -ve.
Duffy antigen: Is missing in Black population. Not likely to get
plasmodium vivax malaria ---> antigen that p.vivax needs to parasitize
the RBC with Duffy antigen. So if you dont have it on your RBC --->
p.vivax cant get into it.
Alphas, Beta-thals, sickle cells, G6PD: Protects black population from
Falciparum ---> all of those anemias have RBCs that have shorter life
span ---> malaria parasites cant live out their cycles in RBCs --->
protected from getting Falciparum.
Cross Match: While giving blood, the Major cross match ---> gonna
take the pt's blood-serum in a test tube with the blood of the donor
unit that they are supposed to get and mix the two together ---> So
its the pt serum with the donors RBCs, mix them together to see if
they are compatible. Any thing in pt serum gonna attack antigens in
the donor RBC ---> basic purpose of Major Cross match.
Antibodies in a pt serum, is another part of the work up for cross
matching people is to do the antibody screen ---> Indirect coomb test
---> thats -ve 99.99% of the time. When you do the major cross thats
compatible because what it really detecting is whether there is an
antibody in the pt serum, thats gonna attack the donor RBCs. So they
have to do a SEPARATE cross match for every unit of blood.
Its that gonna prevent you from getting hemolytic transfusion reaction
= No
Its that gonna protect you from developing antibodies ??? = No
There is zero chance of having same antigenic makeup on RBC in
different individuals.
So if a Group-O person , gave blood to Group-O person---> dont have
all the same antigens ---> gonna develope antibodies against it --->
every unit of blood that you give a person ---> increase the risk of
developing antibodies. Thats means thats when times comes up to get
the another transfusion, they have to find units of blood that are -ve to
that antigen to which you have antibodies which increases cost and
time it takes to cross match you.
Moral of the story: Dont transfuse unless its absolutely necessary.
Answer to some kinda Question:
Because they are only involved in IgG antibodies against those
particular cells. Everything in Lupus is not Type III.
Post streptococcal disease is not type III either. eg. post streptococcal
A pt with HIV and you accidentally stick your finger with a needle.
Chances of getting HIV +ve? Ans- 1/300. Rx- You go on a therapy as if
you were HIV +ve ---> Triple therapy, 2 reverse transcriptase
inhibitors, AZT and protease inhibitors for 6 months. You get constant
checks, may be PCR test looking for RNA virus (Most sensitive test),
and ELISA screen.
In fact the most common mechanism for medical personal to get HIV
is accidental needle stick.
Reminder: Dont transfuse anything into a person unless they are
symptomatic from what ever they are deficient of.
If a person have 10 gm of Hb and it has no symptoms ---> dont
transfuse.
If 10 gm of Hb + COPD, starting to have angina related to that 10gm
of Hb ---> transfusion.
If you have 50,000 platelets count. If you are not having epistaxis --->
Dont treat. But if they have, treat them.
Every blood product is dangerous. As You can get infections from it.
FFPs: Should never be used like Isotonic saline, raising the pt BP. You
run the risk of transmitting disease. (Extremely contraindicated)
We use FFPs predominantly for multiple coagulation factors
deficiencies. eg, DIC, Warfarin over anti-coagulation but they were
bleeding to death we wont be using I/M Vit.K as it take 6-8 hrs to
reverse it ---> but FFPs reverses immediately.
Heparin overdose: Protamine Sulphate ---> works immediately.
So FFPs are pretty much limited to multiple factor deficiencies; Like
Cirrhosis, as most of the factors are made in liver so they are deficient
in factors ---> bleeding significantly.
Allergic reaction: Most common Transfusion reaction. With Itching like
Hives, potentially get anaphylaxis related to it and it would be Type IHSR.
You have got a unit of blood and in the plasma of that person, he has
something to which you are allergic to, may be it was penicillin --->
When they ask that you been on any medications - NO. They got your
blood and you are allergic to penicillins, and you got that pts blood and
you end up with allergic reaction.
Hematology
Post 57: (Dated: April 08 - 2009)
You just treat with benadryl (antihistamine) in most of the cases.
2nd most common one is the febrile reaction, which is due to HLAAntibodies. The pt has HLA-antibodies against leukocytes from the
donor units. So when that unit of blood is transfused in pt --->pt's
antibodies will react against it ---> destroy those cells and release the
pyrogens from the neutrophils ---> Fever.
Qs: If a person never been transfused, should he have anti-HLA
antibodies against any of them? Ans- No.
Qs: Who is most at risk for having a febrile reaction with transfusion?
Ans- A women because she has been pregnant. So every women that
has given birth to a baby, that had a feto-maternal bleed. So of the the
baby's leukocytes goes into the mommys blood stream and develope
anti-HLA antibodies.
So the more pregnancies a women has, the more anti-HLA antibodies
she is gonna develope because of her previous pregnancies. Thats also
true for spontaneous abortions, you can still get HLA-Antibodies of that
baby.
We should not have anti-HLA antibodies in our blood stream unless we
been exposed to human blood.
So its Type II-HSR. Thats IgG antibody-anti ALA antibody.
Where as the allergic reaction is type-I.
Transfusion reactions are very rare. A person who is group-A and got
group-B blood ---> got anti-B IgM. Since IgM is the most potent
compliment activator. That RBC gonna last for a millisecond.
ASA that RBC hits the circulation the anti-B IgM gonna attack it --->
CI to CIX, intravascular hemolysis, anaphylotoxins released --->
shock.
A pt that has antibody against an antigen on the RBC in unit. Instead
of major cross match thats compatible and means that there are't any
antibodies ---> unfortunately some antibodies are not present; but
you have been exposed to (antigen), and you have memmory B-cell.
If a person got blood 30 years ago from a car accident, say there were
anti-CALLA antibodies ---> probably after 30 years there would be no
antibodies, what so ever ---> because they would have gone away, but
do have memmory B-Cells of the event ---> so the person will be have
normal cross match and -ve antibody-screen. On transfuion of CALLA
+ve unit ---> The memmory B-Cells who were sleeping for 30 years
---> wakes up, start dividing in germinal follicles and eventually turn
into plasma cells ---> gonna make anti-CALLA IgG antibodies. Some
times it can occur in few hours or take a week or so, depends on the
antibody ---> delayed hemolytic transfusion reaction.
Scenario: A women postpartem, had very difficult delivery with
abruptio placenta ---> she was transfused 3 units of blood. When she
left the hospital her Hb=10, and she was fine. One week latter she
looked into the mirror and sees jaundice and feeling little tired and
week. She goes to doctor ---> she has an unconjugated
hyperbillirubinemia and Hb=8 ---> Delayed hemolytic transfusion
reaction. You will get Coombs test ---> prove that antibodies are
coating the pts RBCs.
Moral of story: You have been transfused, you have a certain level of
Hb. A week latter you have jaundice and a drop in Hb ---> delayed
hemolytic transfusion reaction.
ABO-Rh incompatibility: Babies only compatibility are Rh-compatibility.
Blood group-O women: If they have baby, they will be the one gonna
have problem with ABO-incompatibility because they already have an
antibody that can cross the placenta.
Reminder: Old people are anti-A IgM and anti-B IgM and anti-AB IgG
normaly ---> if there was placenta ---> it would cross it and attack A
or B RBCs.
So ABO-incompatibility, the very first pregnancy you can have a
problem.
Scenario: Mommy Blood group-O -ve, Baby blood group-A -ve.
Incompatibility of blood groups = Yes
RH groups = No
Mommy gonna have anti-AB IgG antibody ---> cross the placenta. The
A-part of mommy's IgG antibody gonna attach to baby's A-Cells --->
baby's macrophages in spleen destroys it ---> Type II-HSR, mild
anemia, unconjugated bilirubin derived from that macrophages ---> in
utero, mommy's liver take care of it and no problem with kernicterus,
or jaundice; Baby is born ---> mild anemia and in first 24 hrs they will
develop jaundice.
The MCC of jaundice in newborn baby is ABO incompatibility. Not
physiologic jaundice thats day 3.
The baby developed jaundice because its liver system for conjugating
is't good as adults --->has to handle all that unconjugated bilirubin on
its own now ---> bilirubin builds up.
UVB-Light: Its converts the bilirubin into di-pyrol, which is water
soluble, harmless and they pee it out.
The hemolytic anemia is very mild. Mainly because its not strong
antigen, and does't host a very brisk hemolytic anemia by antibodies
---> little problem with jaundice but with no problem. The coomb test
on baby's RBC would be +ve, as some of the RBC are covered by IgG
antibodies.
Always old mommys with blood group-A and with group-A or B baby.
There could be problem from very first pregnancy. Its not like RHsensitization with the first pregnancy, but it can be from any pregancy.
So you are group-O, your baby is A = problem, B = problem, and O =
no problem.
Rh-Incompatiblilty: Mommy is Rh -ve, and baby is Rh +ve ---> or
comparatively Mommy is group-O -ve and Baby is group-O +ve. So
they are not ABO-incompatible but Rh-incompatible.
First pregnancy: Mommy delivers the baby there is a feto-maternal
bleed. Some of the baby's O- +ve cells goes into the blood stream
---> not good and develop anti-D antibodies against it ---> The
mommy is sensitsized, got antibody against that D-Antigen; An year
later mommy is preganant (O-negative, anti-D,), with O-postive baby
---> as its IgG antibody gonna cross the placenta and attach to baby's
D-Antigen +ve cells ---> worst hemolytic anemias ---> baby will be
more severely anemia with Rh than ABO-incompatibility.
Baby's macrophage start phagocytosis ---> Anemia, mommys liver
gonna work little bit harder ---> when the baby is born ---> bilirubin
levels will be way higher, anemia will be way worst ---> 99% chances
of exchange transfusion ---> gonna take all of their blood out and so
getting rid of all the bilirubin and sensitized RBCs and also do the
transfusion because they are anemic.
Remember: In first pregnancy the baby is not affected that when you
get sensitized. Future pregnancies the baby gonna have problem.
Prevention: Mommy Rh-negative ---> when she comes in she will have
antibody screen = negative.
Around 28th week they are gonna give Rh-Immunoglobulin (anti-D)
thats a prophylactic; The anti-D comes from women that was
sensitized and was re-treated (?), cant cross the placenta ---> staying
inside the mommy ---> given on 28th week because often time
mommy get feto-maternal bleed before you actual delivery ---> may
get into car accident or fall and some baby blood can get into
circulation and you have some anti-D antibodies there that sits on DPositive cells and destroy it, so the mommy dont get sensitized (thats
probably the reason); Now at birth the baby is Rh-positive, they have
to do ??? test ---> take some of the mommy's blood and do a special
stain ---> can identify the fetal RBCs, if there are any in her circulation
---> they can count them and can accurately say that there is 10 ml,
or 20 ml of bleed from baby to mommy ---> depending on that, gonna
count how many vials of Rh-immunoglobulins should be given to
protect her further.
So anti-D from Rh-immunoglobulins are up to 3 months ---> gonna
give more at birth if you find the baby Rh-postive.
If the mommy is O-negative and the baby is A-positive. Two problems
---> ABO-imcompatible and Rh-Incompatible ---> no problem with
sensitization because while delivery some of the baby's A-cells gonna
enter the blood of mommy ---> gonna live for millisecond because
mommy is bood group-O and have anti-A IgM antibodies ---> gonna
destroy those cells so fast and in majority of cases (not all), they are
all gone ---> no oppotunity for the mother to develope antibodies
against D-Antigen.
Literature says: ABO-incompatibility protects against Rh-sensitization.
Slide: This is a kid with Erythroblastosis fetalis and has Rhincompatibility. They are died by heart failure. Severe anemia
decreases viscosity of blood and so that get a high out put failure, LHF
first and RHF 2nd. Actually we dont get the pitting edema but there
would be pitting edema in this pt. The liver is huge because they have
extramedullary hematopoiesis in it---> they are severely anemic --->
so basically they die of heart failure and secondary to severe anemia.
Slide: CS of brainstem from kid. What was the cause of color change.
These are kinda yellowish, its kernicterus. The baby probably had RhIncompatibility. Its Unconjugated hyperbilirubinemia because its a
hemolytic anemia and it realtes to unconjugated which is lipid soluble.
The baby's blood brain barrier is immature, so this lipid soluble
unconjugated bilirubin gets into the lipid rich brain ---> basal ganglia,
or other areas of the mid brain and its very toxic and you end with
severe debiltating disease or death from kerniterus.
---------------End Hematology ----------Cardiovascular
Post 58: (Dated: April 10 - 2009)
Jugular venous pulse: Its usually on the right side where we examine
the pt. The best way of finding out is when systole occurs ---> when
1st heart sound occurs, then you can clearly identify the waves. The CWave corresponds with the first Heart sound, which is the begining of
systole.
There are 3 positive waves: A, C, V
Two Negative waves: X and Y
A = Rt atrial contraction in late diastole. That is to get the last bit of
blood out to fill up that Rt ventrical. When it does that the last
contraction, lots of the blood goes into the Rt ventricle, little bit backs
up and the venous pulse creates a +ve A-wave. So A-wave due to late
atrial contraction and the ventricle.
As the tricuspid valve closes in systole and there is contraction --->
blood goes up to PA, and some of it will hit against the Tricuspid valve
and bulge it out a little bit into the Rt atrium ---> Creates a C-Wave.
Make a picture: Systole occured, Rt ventricle contracted and triscup
valve is closed and bulge out initially. Blood going right up to PA an
creates a little negative pressure behind it and sux the valves down a
little bit ---> x-waves which is negative.
V-Wave: Is the filling up of Rt atrium with blood in systole. The
tricuspid valve is still closed, systole occuring, blood going out the PA
but your Rt atrium has to fill up again. So v-waves actually
corresponding with the actual begining of Diastole, the S2 heart sound.
Regular-Irregular Pulse: Its Mitral stenosis ---> A-wave is disappeared,
because thats atrial contraction. Whats been discribed here is atrial
fibrillation.
If this heart sound was present but usually it is't. What heart sound
would be absent? Ans- S4.
It relates to atrial contraction against the increase resistance. So you
will have an absent A-Wave if you have A-Fib and if you have S4, you
will loose it because it deals with atrial contraction.
Tricuspid stenosis (TS): The atrium had to contract against a valve that
did't wanted to open ---> A-wave become huge called Giant A-wave.
Tricuspid regurgitation (TR): Systole occured and lots of blood went
into the Rt atrium and some went up to PA --->you will get Giant C-Vwave.
So giant A-wave is TS and giant C-V-wave is TR.
When you have turbidity of plasma ---> its due to only triglyceride not
cholesterol.
There are 2 fractions that carry triglycerides:
Chylomicrons from the triglyceride you eat at Mc Donalds which is
saturated fat, which are long chain fatty acids and they are being
broken down in your gut with the help of lipases and reassembled in
small intestine and stuck in chylomicrons. So its exogenous or diet
drived triglycerides. In order to find the acurate triglyceride levels
thats telling you about the pts real triglyceride level, you must fast for
12 hrs otherwise any kind of fatty food, that would be in chylomicron
---> falsely increase the triglyceride.
You dont fast for an accurate cholesterol and you can go to Mc Donalds
if you want ---> get HDL and cholesterol level and it wont be affected
by it at all ---> <3% cholesterol present in chylomicrons ---> you dont
have to fast to get an accurate cholesterol and HDL (for cholesterol
measuring).
But you have to fast to get triglycerides levels because there will be
chylomicrons related to the crap that you ate.
What is it called that the triglyceride we make ---> VLDL, what we
make in liver from glyerol 3 phosphate which came from glucose and
its increased among all alcoholics, because of all that NADH, pushing
the DHAP to glycerol 3 phosphate.
VLDL are more dense than chylomicrons because of little protein in it.
Chylomicrons hardly have any proteins so it floats.
So you see this kinda white with yellow, its chylomicron. When you see
this pinkish turbidity below thats called the Infernate, thats VLDL.
1. In the respiratory lectures, during the fungal infections, he says that
Crypto looks like a "mickey mouse" and is a narrow based bud. He
then says the treatment for it is Actynomycin. I think he confused
crypto with blasto.
He apologized for this last statement in the renal section the next day,
saying the treatment is Anphotericin B.
2. Still in respiratory, while describing Sarcoidosis as a common cause
for Restrictive Lung Disease, he says it's the 2nd MCC of
Pneumoconiosis.
3. In heme or cardio, I don't exactly recall, he says that Chagas
disease is a Leishmanial disease, when in fact, the agent is
Trypanosoma.
4. When describing chronic renal failure, he says the definition is a
BUN/Cr ratio of 10:1 for more than 3 months. (Normally, we should
always have that ratio)...He forgot to mention that it's actually the
BUN and Cr being elevated for more than 3 months what defines the
disease, while keeping the normal BUN/Cr ratio.
So far it's the one's I've found. I'm still going through day 5, so I'll
check for more and post up.
KEEP ROCKIN' GIK!
Cardiovascular
Post 59: (Dated: April 12 - 2009)
So a simple tube placed in the refrigerator at 4 degrees and you can
tell what lipid fractions are responsible for your elevated triglycerides.
So this pt is combination of excess chylomicrons probably because he
did't fast and increase in VLDL.
The Lumen is very narrow. When ever we have lots of pink staining
stuff with some tissue, we always use the term Hyaline.
Hyaline arteriolosclerosis: its a small vessel disease. Diabetes and HTN
produces this kind of small vessel disease but with different
mechanisms.
Diabetes is by non-enzymatic glycosylation; Hb-A1c = glycosylated
Hb; So glycosylation is glucose attaching to Amino acids and proteins.
In terms Hb-A, it is glucose attaching to Amino acids in Hb-A, it means
that it gets glycosylated. Hb-A1c levels correlates with 6-8 weeks what
your blood glucose levels were. So its the absolute best way of seeing
long term glucose management.
So if <6%, you are diabetic ---> you are in normal glucose range.
All the damgage due to diabetes is purely related to glucose and
nothing else. So you have two pathologic processes ---> nonenzymatic glycosylation of small blood vessels including cappilaries in
kidney, and osmotic damage.
Osmotic damage: Those tissues that contains aldose reductase (lens,
pericytes in the retina, schwann cells) ---> convert glucose into
sorbitol, which is osmotically active ---> sucks the water into it and
those cells die ---> you get cataracts, micro-aneuryms in the eyes
because the pericytes are destroyed and they are weakened so the
retinal vessels get aneuryms and you get peripheral neuropathy
because your shwann cells are destroyed.
Non-enzymatic glycosylation: Causes the BM of the small vessels,
becomes permeable to proteins ---> so the proteins in the plasma
kinda leaks into the BM and goes into the vessels wall and produces
the hyaline change and narrows that lumen; Similarly in nonenzymatic glycosylation of glomerular BM ---> render it permeable to
proteins ---> proteins in urine called microalbuminuria, which is the
first change that one sees in diabetic nephropathy, a little bit trace
amount of albumin that should't be there.
HTN: Does't use that system to produce this disease, it just uses brute
(?) force ---> it just drives because of the increase in diastolic
pressures ---> it just the proteins right through the BM there and
produces that effect.
When we look at the kidneys in HTN, its shrunken and got the
cobblestone appearance on the surface ---> because they have hyaline
arteriolosclerosis of the little arterioles in the cortex ---> the schemia
and basically its just wasting away with fibrosis and atrophy of tissue.
So it has a significant component to the pathology of HTN ---> lacunar
strokes, with tiny areas of infarction that occured in internal capsular
area, its a hyaline arteriolosclerosis problem related to HTN. So much
of the pathology of HTN and diabetes are related to that disease.
Slide: Hyperplastic arteriolosclerosis ---> We see this with malignant
HTN. blacks > whites, mainly because HTN is more common in blacks
than whites. The BP- 240/160, you have papilledema, this is the kinda
vessel changes you see in kidney. Mainly its the vessels disease we see
in malignant HTN.
Slide: You see Two kidneys, Aorta, bifurcation and you see the
aneurym.
Aneurysm: Its an area of out pouching of a vessel due to weakening of
a vessel wall.
Whats causing the weakening the vessel wall causing it to out pouch?
Ans- Atherosclerosis.
Terms related to Weakening and Outpouching:
In lungs ---> bronchietasis, its due to cystic fibrosis with infection,
destruction of elastic tissue. You get out pouching and dilatation of the
bronchi.
GI ---> Divertucular disease, you have a weakening and outpouching
of mucosa and submucosa through the area of weakening.
Physio: law of Laplace, wall stress increases when radius increases. It
means that ones you start dilating it, it does't stops because when you
dilate someting and increase the radius ---> increases the wall stress
---> it just keeps on getting. So in other words all aneuryms will
rupture, its just a matter of when.
Why its the most common location for aneuryms? Ans- No vasavasorum ---> blood supply to the aorta below the renal arteries. So
That means that aorta can only get O2 and nutrients from the blood
thats in its lumen ---> so the peripheral part furthest from it, gets
screwed. So because of the fact that its not getting enough O2 and
properly ---> some of the blood gonna drip back. So you gonna have
more volume of blood in your Lt ventricle, some one with Aortic
regurgitation ---> Frank starling gonna be working, since you strectch
cardiac muscles, you increase the force of contraction. So you have a
120 ml of blood in Lt ventricle and get out 80 ml normally. So the E.F
is 80/120 = 0.66.
Lets say you have 200 mls of blood in here because of the blood
drifting back in ---> Frank starling ---> they get out 100. Actually its
not all that efficient because a normal person gets out 80/120 = 0.66;
This is a 100/200 = 0.5 ---> the frank starling is not a normal
physiologic process, it occurs in pathologic conditions.
So when you have 100 ml of blood coming out of aorta ---> your
heads gonna be going like this (?) ---> the mouth shows the uvula
pulsating. The nails have underneath pulsating vessels. stethoscope
over the femoral artery, press down ---> Duroziez's sign. They have
water hammer pulse; All of this because of increased stroke volume
coming out related to the fact that there is more blood in the left
ventricle; Classics ones of syphillitic aneurysm in the aorta.The left
recurrent laryngeal nerve goes around this arch ---> it streches it --->
hoarseness.
Most common complication of aneyrysm ---> rupture.
Slide: This is syphilitic aortitis. This is the dissecting aortic aneurysm.
Article says: The key factor that causing the tear in the aorta is HTN.
This imposes stress on the wall of the vessel. There is a weakening of
the elastic artery as well ---> elastic tissue fragmentation. Plus there
is a cystic medial necrosis, that kinda where glycosaminoglycans
mixed together and have muciny crap there, little cystic pockets.
You can almost see the walls of the aorta rubbing on itself and the
middle is like nothing in there ---> fragmented elastic tissue ---> little
bit of HTN ---> tears.
Cardiovascular
Post 61: (Dated: April 15 - 2009)
Slide: This is where the tear was in this person. This is the aortic
valve, the tear is right over here near the arch of vessel. So what
happens is, where ever the area of weakness is in the elastic artery,
the blood will dissect. In this pt you can see that it was't distally, but
its proximally, its out side of the aorta - thats the linning of aorta. Here
is blood ---> the paricardial sac attaches to it ---> blood goes into the
heart (pericardium) ---> pt dies of cardiac tamponade. This is called a
Proximal dissection which happens to be the most common one.
Because of the fact that most of the tears are up in the arched vessel
---> absent pulse; Very common in dissection thats proximal when
that dissect close off the lumen of the subclavian artery, usually on the
left ---> absent pulse.
Pain: You will have tearing pain, retrosternal, and radiating to back.
The pulse on the left diminished vs the one the right. Tropinin -ve, EKG
not shows any signs of acute changes. CXR ---> widening of the aortic
knob ---> dissecting aortic aneurysm.
CXR: Excess blood in here, you do the chest xray. The diameter of the
proximal aorta is gonna be expanded ---> 85% sensitive so its the
screening test of choice.
Confirmation: Trans-esophageal ultrasound, and angiography.
Lots of diseases can predispose to dissection.
Slide: This is Marfans syndrome. The height from the pelvic rim to the
feet > pelvic rim to the head. Arms span > height. This guy had an
appendectomy, this pt already had operation for his dissection.
In marfans which Autosomal dominant, chromosome 15, defect in
fibrillin which is the component in elastic tissue ---> lens dislocation,
and dissecting aortic aneurysm. The MCC of death in marfans is MVprolapse or TCV-prolapse ---> sudden death because of conduction
defects.
More Causes: Ehler Danlos, defects in collagen ---> the MCC of death
Pregnancy: The most common catastrophic disease of aorta in
pregnancy ---> dissecting aortic aneurysm ---> because there is twice
the plasma volume during pregnancy (2 RBC mass by 1) ---> Hb
concentration decrease; Normally all pregnant women have 11.5 as
cutoff point for anemia and for non-pregnant women its 12.5 ---> in
pregnancy usually its due to dilutional effect of excess of plasma
volume.
Excess of plasma volume for 9 months ---> in some women can cause
weakening and you get dissections.
Slide: This guy was smoker with primary lung cancer. Now complaining
of headache and blurry vision. So you are looking at his retina, he has
retinal vein engorgement, its congested ---> superior vana caval
syndrome ---> Its usually due to primary lung cancer knocking off the
superior vena cava and you get back up of venous blood into the
jugular system into the dural sinuses ---> the pt usually dies. Rx with
radiation to shrink down the amount of tumor so that they can get
some good blood flowing here.
Superior vena caval syndromes confusing with pancoast tumors which
are associated with Horner syndrome. SVC syndrome is just knocking
off the SVC and nothing to do with horner syndrome.
Slide: This is sturge weber syndrome. Its vascular malformation in the
face. This is in the trigeminal distribution. On the same side of brain
there is a AV malformation there as well ---> predisposes to bleeding.
Also these pts are little bit mentally retarded.
Slide: This is the osler weber rendu disease showing some of the
telengectasia in the GI tract.
If you press this end, these little tentacles will go away ---> Spider
angiomas; Normal in pregnant women, due hyperestrinism. Other
ther than pregnant women, spider angioma means cirrhosis ---> MCC
of cirrhosis is alcohol --->can't metabolize estrogen and it builds up
---> gynecomastia, gonna have warm skin - palmar erythema and
gonna have spider angiomas related to hyperestrinism.
Hyperestinism: No metabolism of 17-keto-steroids ---> gonna
aromatize those in adipose into estrogen. So there are 2 ways that you
get hyperestrenism in cirrhosis.
Qs: How does this looks different from a petechia? Ans- It looks
different for one but if you press that in, this would blanch because its
an AV-fistula, in other words you are going from arteriole directly to a
venule and bypassing capillaries.
Slide: Picture of a child with red lession, B/L white eye reflex, This kid
does't have retinoblastoma.
They show you a kid with a red lession on the face. They are gonna
say:
A- Surgically removed
E- Leave that alone ---> Yes
So infarction is what you see with muscular artery vasculitis like PAN,
W.Granulomatosis, Kawasaki's.
When you knock off elastic arteries then you start dealing with Arched
vessels and you are gonna get pulseless disease thats takayasu
arteritis. The vasculitis will block off the lumen of one of the arch
vessel ---> you get strokes, because it may knock off the part of
internal carotid.
Palpable purpura = small vessel vasculitis Infarction = Muscular
vasculitis
Pulseless or stroke = Elastic arteries (far east young lady with absent
pulse = Takayasu's arteritis)
Slide: This guy has headache; History ---> It hurts right here doc, i
cant see at this side. I have aches and pain all over my body. When I
chew it hurts ---> Dx- Temporal arteritis.
Temporal arteritis slide: Its a granulomatous (multinucleated giant
cells). It can involve other portions of the artery including the
opthalmic branch and produce blindness. Thats sedimentation rate is
the only screen from temporal arteritis, its not specific for this but if
this is an arteritis (an inflammation), Sed.rate should be elevated but
if it was not then you can think about TIA or some other thing; Since
screen takes time, to take a biopsy and look for these things and the
pt can go blind, so you have to put them on corticosteroid on just
history alone.
Cardiovascular
Post 62: (Dated: April 17 - 2009)
Polymyalgia rheumatica: Muscle aches and pains. Commonly
associated with this as well. There is no elevation serum CK where as
polymyositis is the inflammation of muscle and you have elevated
serum CK.
Slide: This pt smoked. Buergers disease, also called as
thromboangiitis obliterans or smokers disease. Usually males, young,
they get digital vessels thrombosis. They get autoinfarction of their
fingers and toes. Does't go away usually by quitting smoking.
Story: Stuffy nose ---> look for amputated finger.???
Scenario: 14 year old boy. URTI 1 week ago, presents with
polyarthritis, joint pain, hematuria, RBC casts, and palpable purpura of
buttocks and lower extremity ---> Dx- henoch schonlein purpura. The
most common vasculitis in children. Its an immune-complex, as are all
small vessel vasculitides, its an anti-IgA immunecomplex and the RBC
cast is glomerulonephritis.
Scenario: This pt with saddle nose deformity and it aint congenital
syphillis. Also have problems with sinus infections and problems with
URTI, lungs problems with nodular masses and also even a rib ???
glomerular disease ---> Dx - Wegener's granulomatosis. MCC of saddle
nose deformity in USA. Its a granulomatous inflammation and
vasculitis involving U.airways, lungs, kidneys and its an antibody thats
associated with it, highly specific antineutrophil cytoplasmic antibody
(c-ANCA). TOC: cyclophosphamide ---> C = C (c-ANCA).
cyclophosphamide can cause hemorrhagic cystitis and blader cancer.
Hemorrhagic cystitis is prevented by Mesna.
Polyarteritis nodosa (PAN): A male dominant disease and involves
musclar arteries so infarction is part of this thing. Also have antineutrophil cytoplasmic antibody but its p-ANCA. PAN is highly
associated with Hbs-Ag.
Scenario: IV drug abuser with chronic Hep.B who has a nodular
inflammed mass on the lower extremity, hematuria (kidney infarct).
Diagnosis? Ans- PAN.
Slide: This is vessel in Rocky mountain spotted fever. Rickettsial
organism infects endothelial cells. The spots are in fact petechia.
Unlike other Rikettsial diseases with rash, this starts on extremities
and goes to the trunk where as the other ones goes from the trunk to
the extremities. The vector is Tick.
Tick borne diseases:
Lyme disease = Borrelia burgdorferi; where as Borrelia recurrentis =
relapsing fever with antigenic shifts (means it can shifts in terms of
antigenicity).
Spirochetes: Leptospira, also Syphillis, Borrelia, and Treponema
pallidium.
Slide: This is a fungus. Its wide angle non-septate. This pt with DKA
and there is cerebral abcess related to this fungus. Dx? Ansmucormycosis.
HTN: Main organs that HTN affects and most common cause of death
in HTN:
1- MI
2- Stroke
3- Renal failure
Essential HTN: highest incidence in HTN in black population. The
genetic thing associated with it is Multifactorial inheritance or Polygenic
inheritance.
Gout is multiple factorial inheritance.
When you ask people if they have family histroy of a coronary disease
they say YES. So the coronary artery disease is mulifactorial.
Multifactorial: Diabetes-II, affective disorder, congenital pyloric
stenosis, Essential HTN It means that you have a tendency but not
necessarily get it.
So you are black and have family history ---> to prevent it from
getting E.HTN ---> cant change the genetics like cant get rid of salts in
urine ---> retaining too much salts which is the basic mechanism of
E.HTN in black population + old people. But can control 2 things like
weight (since there is a direct correlation with HTN) and reduce salt
intake + excercise ---> reduces risks for developing HTN because
those are the other factors which can produce the disease.
Gout: If there is a family history of Gout. Prevention ---> avoid red
meat, and absolutely no alcohol which keeps the purine metabolism
down.
Type II diabetes Prevention: Weight ---> lean and mean. When you
loose adipose you upregulate insulin receptors synthesis.
Some thing you cant do, that will decrease the chance that you can
get the multifactorial inheritance:
HTN: like You retain salt ---> retained in ECF ---> plasma volume
increases ---> stroke volume increase. So excess salt which likes to go
into smooth muscle cells in peripheral resistance arterioles ---> Na+
enter muscles it opens up certain channels for Ca+, which goes in --->
causes the contraction of smooth muscles ---> peripheral resistance
arterioles, constricted.
helping the left ventricle push blood out of the heart ---> abnormal
Heart sounds and murmurs increases in expiration.
Scenarios: Left, Right or middle. Heart sounds
E.HTN ---> Left
MR ---> Right
MS ---> Middle
Stenosis means problem in opening the valves.
Regurgitation or insufficiency means that there is a problem in closing
the valves.
In stenosis murmurs when the vavle is opening, thats when the
murmur gonna occur.
For Regurgitation murmur all you have to know when the valve is
closing.
Who is opening in systole? Ans- Aortic and Pulmonic valve ---> so the
murmurs of AS and PS occur in systole. They have to push the blood
through a narrow orifice.
Picture of aortic stenosis: Left ventricle contracts, it encountering some
great resistance ---> the intensity of the murmur initially going up
---> "Shhhheeeeeeeeee" pushing pushing pushing ---> goes to a peak
and "Shheewww" ---> diamond shape configuration thats why its
called an ejection murmur.
When you get to bone pathology, he says the most common B9 tumor of the cartilage/
Exostosis (osteochondroma) and then he says that the multiple form of it is Ollier's dis
When in fact Ollier's is the multiple form of Enchondromas.
Side note: Marfucci's is Ollier's + hemangiomas.
So basically, he's saying that Osteochondromas and Enchondromas are the same thing
Cardiovascular
Post 64: (Dated: May 20th - 2009)
So E.Murmur like Aortic stenoisis has crescendo decrescendo
appearance.
Valves heard best:
The ant. leaflet of M.V ---> is actually one side of the outflow tract out
into the aorta ---> the murmur called Austin flint murmur; When you
have AR and you have austin flint murmur ---> you call you cardiac
surgeon, thats the time to remove the valve because if you have that
murmur then you are significantly dripping back in here, that valve has
to be replaced.
Scenarios: Left and Right sided heart failure.
This is section through lungs ---> Lf
Liver ---> Rt
Paroxysmal nocturnal dyspnea ---> Rt
Left Heart Failure: Its forward failure or your left ventricle is failed. It
has to push against and after load, it fails; it has to deal with an
excess volume it fails; you have so many infarcts that the left ventricle
no longer muscle and its fibrous tissue so the contractility is
decreased.
Cardiovascular
Post 65: (Dated: May 29 - 2009)
So that means that your EDV gonna increased because you cant get all
the blood out or you cant push it out. With that pressure the volume
gonna go back in to the LA and back into the Pulmonary Vessels --->
increase the hydrostatic pressure ---> Pulmonary Edema.
When you have chronic LHF ---> you have hemmorhage with alveolar
macrophages that phagocytose the RBC ---> rusty colored sputum
---> you do cytology and see Heart failure cells, those are alveolar
macrophages that have phagocytose the RBC and its broken down into
hemosiderin.
LHF is the diagnosis of symptoms ---> "Doc 'm having trouble in
breathing"
RHF is the diagnosis of signs ---> Since its the problem in the RT heart
getting blood through the Pulmonary vessels to the left heart. So if it
fails ---> blood builts behind it ---> its backward failure --->
hydrostatic pressure will increase in the venous circuit ---> you have
neck vein distension; painful hepatomegaly called as Nutmeg liver
because the increased pressures in the vena cava gonna be
transmitted to the hepatic vein which empties into it and back into the
liver into the central vein and you are gonna get the little dots all
around it and looks like a Nutmeg.
C3a, C5a, Nitric oxide ---> increases venous return in the heart.
Poiseles Law: Viscosity over radius to the 4th power. So if you vasso
dilate the PRA ---> decreased TPR ---> more blood comes back to the
right heart, left heart has to deal with it ---> you run the risk of high
output failure.
Beside septic shock another cause of vassodilatation is thiamine
deficiency.
Since the problem in thiamine deficiency is ATP depletion ---> smooth
mucle cells in the PRA need ATP ---> decreased ATP ---> vassodilation
of the PRA ---> HOF.
Graves disease: Thyroid hormone increases synthesis of Beta
receptors in the heart ---> increased in force of contraction ---> there
is more blood, systolic pressure are higher ---> HOF.
AV-Fistulas: If you are stabbed in leg ---> develop AV-malformation
---> arterial blood bypassing microcirculation goes directly in the
venous circulation ---> blood will be coming faster than normal --->
bruit over the mass, pulsatile, if you press the proximal portion of it
the heart rate will slow (branham sign).
Fetal circulation: Baby is not exchanging blood with O2 in our lungs.
The Pulmonary vessels in fetus look like they have P.Hyp ---> they are
so thick that is extremely hard to get blood through the P.A into the
left ventricle. Therefore you need PDA in order to get it out of there.
The O2 in fetus is coming from the chorionic villous dipping into the
lake of blood which drives from mommy's spiral arterioles. Its not a
good O2 source as lungs. So you need high affinity hemoglobin to able
to get O2 ---> HbF which has high affinity for O2. The bad thing is that
it does't wanna give it up. This produces tissue Hypoxia so EPO is
released ---> 18 gm hemoglobin is present normaly. Newborns have
polycythemia.
Therefore HbF has high affinity ---> you have more RBCs with more
Hb in it.
Cardiovascular
Post 67: (Dated: July 17 - 2009)
So the blood O2 goes through syncytiotrophoblast of chorionic villous
---> cytotrophoblast ---> myxomatous stroma of the chorionic villous
---> goes into the blood vessels of the chorionic villi ---> umbilical
vein which has the highest O2 concentration ---> goes up to liver and
there are 2 ways it can go ---> (1) In to hepatic sinusoids, and
through hepatic vein and gets dumped into IVC or (2) They can select
the ductus venosus and goes into right IVC, ---> Right side of the
heart.
Picture this: Foramen ovale is opened. Oxygenated blood is coming up
from IVC ---> right atrium ---> foramen ovale ---> left atrium --->
left ventricle ---> aorta.
The SVC blood goes through tricuspid valve ---> right ventricle --->
since pulmonary vessels are too thick, blood goes through the patent
ductus arteriosus (kept opened by PGE2 made by placenta, a
vasodilator) ---> Right-left-shunt ---> dumped into the aorta.
When the baby is born: baby breaths ---> pulmonary vessels gets
opened in milli seconds ---> blood goes through them; Patent ductus
begins functionally closing and eventually closes and forms the
ligamentum arteriosum.
When the blood goes out the Aorta: it goes into 2 umbilical arteries;
there is one umbilical vein. The vessels with the least amount of O2
are the umbilical arteries, where as the most O2 is in the umbilical
vein.
If you have left-right-shunt and you have Oxygenated blood going into
un-oxygenated blood ---> Step up of O2 saturation on the right side.
If you have right-left-shunt with unoxygenated blood going into left
side ---> step down.
The O2 saturation of the blood on the right side of the heart, returning
from the body is 75%.
The O2 saturation on the left side is 95%.
Slide ASD: Normally there is a membrane in this portion of the
septum. Its not just all muscles going straight up there; Notice the
close relationship of aortic valve leaflet in that septum.
The left ventricle is stronger then right ---> direction of shunt is leftright ---> Oxygenated blood dumped into the right ventricle ---> Step
up; also its gonna pumped out of the pulmonary artery ---> step up.