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Pathology 5001
Dr. Weber

Make sure to read "Pathology 5001" handout.

The text used in the past is Kumar, Cotran, and Robbins' "Basic 
Pathology" 1992 edition. The prolem is that a new edition is coming out 
in about 8 weeks, after this course is over. So, you should probably not 
buy the book. Try to borrow it or buy it at a very cheap price. The first 
81 pages in the book cover the first half then 170-215 is neoplasia. One 
option would be to xerox 1-81 and 170-215. (oh yeah? Isn't that a 
copywright violation or something?) he recommends buying the NEW edition, 
even though it's after this class is over, 'cause it will be useful in 
the future.

Computer assisted learning:
<a href="http://phl.vet.upenn.edu/cal95">Cal 95</a> Pathology descriptive 
terminology and glossary should be very helpful. Thanks to Jenny Cromwell 
:)
Make active use of this resource!

Now, looking at course schedule- the "seminar/lab" things will be in 
different places. Sometimes we start in rm 13 so they can show the 
kodachromes, but that's still part of the lab. The gross demos- class 
divided into 6 groups meeting in 11 or 12 or PMR, VHUP.

Our instructors are all VMD/DVM/PhD types. They're very experienced. 
Don't worry about whether or not they know their stuff; they do.

Q: how is lab stuff tested? see p1 of handout, paragraph 3. "a small 
portion of the final exam may well include evaluation of a gross specimen 
and histopathological material." Eg, you'll have to describe a gross 
specimen, look at kodachromes of histological prep of the specimen, and 
draw conclusions. Lab stuff isn't on the midterm.

Dr. Goldschmidt will now talk to us about descriptive pathology - he's 
chief of the biopsy service and very knowledgable ;). he's giving out a 
handout that hopefully will make it back to me....

he says he's going grey and bald from stress of teaching first years all 
the time :)

he also says to check out the cal95 stuff :)

so. WHY pathology?
we learned anatomy and histology so we'd know normal stuff
now we need to learn gross pathology, ABNORMAL anatomical changes, and 
microscopic pathology, abnormal histologic changes. If we learn all this 
we should be good clinicians. good clinicians interpret the changes that 
occur from the normal grossly, histologically, and biochemically. SO we 
need to concentrate on these areas. If we can understand this stuff, next 
year's systemic pathology course will be easy. general pathology is the 
FOUNDATION for everything else.

RECORDING OBSERVATIONS?
why do we do this? because there are lawyers who need to make a living as 
well. last week Dr G was on post-mortem rm duty and had two posts with 
possible legal consequences. when dealing with that kind of situation, 
you HAVE to be able to describe what you see, either on post mortem, or 
biopsy, or exploratory,, or whatever. So you need to know the right 
terms. 

reports should be concise, MUST be precise, and must be grammatically 
correct. this is very important. you must be able to use English 
competently and adequately or you will not be thought of as adequately 
prepared to be a vet in private practice. you need to be able to use 
correct language with your clients. use of language extremely important.

RULES:
use present tense. if there is a lump on side of dog, say "there is a 3 
cm mass on the side of this 9 yr old male castrated dog."
organize thoughts before writing them down.
omit unnecessary phrases. be specific. do NOT say "there appears to 
be..." - that's wishy-washy. say "there IS.." so you sound like you know 
what you are doing. avoid unnecessary terms like "it is red IN COLOR" - 
just say "it is red."
use simple declarative statements - noun, verb, object. 
avoid analogies! say "caseous" not "like cottage-cheese." say "3 mm mass" 
not "pea sized mass." Peas can vary in size. Don't say "cauliflower-like" 
- not everyone EATS cauliflower! don't say "tomato-soup consistency" - 
some is thick, some is thin, some folks are allergic to tomatoes! don't 
use SPORTS analogies. "tumor size of basketball" - not everyone plays 
basketball. use common sense. MEASURE The mass! BTW, for a mere 50 cents 
you can get a see through, plastic, flexible ruler. bring one to lab!
don't inject INTERPRETATION into the descriptive report. you could be 
WRONG. at this stage, we WILL be wrong :). we don't know anything yet. so 
don't interpret!

need to measure the size of lesions and of entire organs. shoudl be two 
or three dimensions. use cm and mm, not inches and feet.

also WEIGH the organ. if you think something is enlarged, you need to 
prove it. say a cat dies and you post it. you weigh the cat, and get TBW 
(total body wt). open chest - collect 250 mL of clear fluid from thorax. 
Look at heart - LOOKS enlarged. how do you know it is enlarged? dissect 
it out, and weigh it. write down heart wt= 25.6 grams. heart wt/TBW = 
%TBW that heart equals. If that's > 0.2% of total body wt, then we know 
it's enlarged. you can do this with any organ. so weigh everything.

external appearance and color. there are HUGE numbers of colors of paint 
out there - we aren't interested in those. we are interested in primary 
colors and modifiers eg pale, dark eg pale pink, dark red, etc. not 
chartreuse, mauve, etc.

consistency- terminology very variable from one person to another. one 
person may think of something being rubbery, another may thing only 
slightly firmer than normal.

remember the parts of the specimens most affected by pathologic process. 
think of a kidney. you have cortex, medulla, and hilus/pelvis. say there 
is an abcess (collection of PMNs) and it's in the cortex. so you write 
that there is a 1.5 cm diameter abcess in the cranial pole of kidney 
within the cortex, and when cut a large amt of yellow, sl smelly material 
exuded from cut surface. don't say "yogurt like" or "custard like" etc.

finally: MORPHOLOGIC DIAGNOSIS is made.
an MD incorporates what you've seen. 
-severity: mild, moderate, severe, very severe (hardly ever say very 
severe)
-time course: recent=acute (up to 48 hrs), not so recent = subacute 
(48hrs-6days), chronic = 6 days - life.
-lesion: abscess, tumor, etc
-anatomical site: eg cranial cortex of left kidney, or whatever.

so for the kidney abscess:

acute, focal (distribution of lesion can be focal, multifocal, diffuse), 
moderate abscess (or necrotizing inflammation) within cranial renal 
cortex.

then someone else can understand this. we'll be making morphologic 
diagnoses in lab. this can be difficult and controversial. people argue - 
is it multifocal or diffuse?

some important definitions we will know by the end of this week:

pathology: science and study of disease, especially as relates to cause 
and development of abnormal condition

lesion: abnormality or alteration in tissue or in cell. seen grossly or 
microscopically. a pathologic change.

pathogenesis: process of events leading up to pathologic changes. 
sequence of events underlying a disease or morbid process.

etiology: causative agent (eg, a bacterium, virus, parasite, protozoa, 
foreign body, congenital, trauma, chemical, UV radiation, etc etc)

prognosis: prediction of outcome of the pathologic process or disease

p 3 handout: a variety of shapes to look at and try to remember.
eg, circle, sphere, reniform, linear, fusiform, etc.

prefixes/suffixes:

a- without
homeo - similar
epi- outside
read them. if you studied latin and greek, no problem :) (thank god i 
did!)
if you only had latin, kinda harder
if you didn't have either, sorry...
dia - through, eg, diarrhea, flowing through (the bowel).

this stuff is all clinically applicable. you need to learn this to 
communicate.

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Donna Dambach: CELL INJURY AND DEATH
handout "Cell Injury and Death" 18 pgs, comprehensive. use this handout 
as a reference or throw it out.

textbooks...Cellular and Molecular Pathogenesis - a really cool book. 
This book covers things well. Dr Dambach has read chaps 1 and 4 or 5 and 
copied them and they're in the library. If you listen to lecture, and go 
to library and read chapters, shouldn't have a problem. At least read 
chap 1. examples should be helpful. It's on reserve in the library.

lectures - lots of word slides, because we have to learn a lot of words. 
the whole reason we're here is because of pathology. this is all we are 
going to deal with - preventing and curing disease and abnormal 
processes. like it or not, you gotta deal with it. 

dr dambach ALSO says to look at the website...

PERSPECTIVES:

what is pathology? 

study of disease. why do we study it? it bridges the basic and clinical 
sciences. if you understand a disease process, you will be a better 
clinician. think of parvovirus. if you understand pathogenesis and 
clinical manifestations, you can recognize it and figureout how to stop 
it or treat it. 

in pathology, you can take time to understand disease processes whereas 
in private practive, you're rushed.

different disciplines:
clinical pathology- looking at peripheral blood, bone marrow, bloodwork 
serology, etc. overseeing clinical lab. impression smears. 
anatomic pathology - necropsy, autopsy, biopsy, impression smears, 
aspirates
necropsy service here sees about 1/4 of the animals that die in the 
hospital. 
surgical pathology: just biopsies. biopsy of surgically removed specimen. 

experimental pathology: researchers and pathologists who attempt to use a 
model of disease. people working on HIV using monkeys, mice - 
experimental pathology. using a defined system to answer defined 
questions in a controlled way. not a clinical discipline. the clinical 
stuff is more randomized.

how does the CELL fit in?
most important part! believe it or not, everythign starts at the cellular 
level. the only reason you see pathology is because cells were affected. 
sunburn: cells are injured, some die and slough, some get swollen, some 
live and get tan...you see sunburn. pain. solar radiation attacks cells 
and causes this pathology. 
cells make up bodies and they act in concert. there are different cell 
types in different organs...epithelial cells, fibroblasts, etc etc. if 
you damage one cell it may affect other cells. if you damage enough cells 
in one organ, you damage the organ, which may affect the system...

core of pathology:

etiology: all diseases have a cause, or etiology. 

pathogenesis: all diseases have a progression or mechanism, eg 
pathogenesis

morphologic changes: all diseases manifest in some way - via cellular 
changes, aka morphologic changes that we can see visually. 

clinical disease.

eg, 6 mo old depressed dog with projectile vomiting and diarrhea.
intestine bloody with white flocculent film. dog dehydrated. 
how did this happen? what caused it?

etiology can be acquired: sunburn, trauma, virus, etc
can be inherited/genetic: cleft palate, polydactylism
can be congenital: in this case, is either inherited or acquired, but 
maybe you don't know which.... eg, could be cyclopia due to dam eating 
plant or due to genetic problem.
idiopathic: unknown etiology.

now, when describing things, imagine you're on the phone with grandma, 
who is a famous pathologist, and you have to describe what you see 
without interpreting.

case example: parvoviral enteropathy (a morphologic diagnosis)

etiology: parvovirus
pathogenesis: oronasal exposure...viral infxn of epithelial cells and 
lymphocytes...spread of virus with lysis of lymphocytes (LEUKOPENIA one 
of first changes we see clinically)..infxn of rapidly dividing cells of 
intestinal tract, the crypt epithelium...viral replication...viral lysis 
of cells...death of the epi cells and attempts by remaining cells at 
regeneration (LESIONS SEEN AT LIGHT MICROSCOPIC LEVEL or possibly at 
gross level if really bad)...severe malabsorptive and bloody diarrhea 
with secondary dehydration/electrolyte imbalance and possible death 
(CLINICAL DISEASE).

slide: gross appearance of severe parvoviral enteropathy, with 
pseuomembrane or "diptheritic" membrane. small intestinal mucosa is 
diffusely red. covering it is a flocculent (puffy, tan) membrane.

slide: histologic appearance of severe parvoviral enteropathy - no 
crypts! lumenal surface is covered with fibrin exudate. crypts/villy 
gone. they're collapsed. a few are there, dilated, lined with big cells - 
body attempt to regenerate crypt cells. so these changes are pathognomic 
for parvovirus or irradiation. so parvo is often called "radiomimetic" 
virus. now, since body is trying to repair, we know this has been going 
on for some time. long enough for body to try to recreate homeostasis.

definition of cell injury and adaptation:

homeostasis: equilibrium at which body functions optimally. 
cells job is to maintain homeostasis.

injury can be reversible - eg, sunburn

 or irreversible - leading to cell death, irreversible injury.

if you injure yourself, not all cells die - eg, liver damage will cause 
some hepatocytes to die, not all...
now, if you kill neurons, the won't regenerate. but if you kill 
hepatocytes,they have good regenerative capability.

exact point of "irreversible injury" is unknown. see p 2 handout for 
diagram. cells adapt to injury, migrate, or die. most cells can't 
migrate, so they adapt or die when they are injured. you should live your 
life that way...

TIME course of injury. everything happens on time continuum.

first thing you see are biochemical changes. when people have heart 
attacks, the first thing MDs due is draw blood and check CPK. when heart 
muscle is damaged, it leaks, and CPK will increase. if someone has an MI 
and drops dead, heart will look histologically normal, because cells 
havne't had a chance to demonstrate changes. but bloodwork would show 
rise in these enzymes...occurs in seconds.....these changes are early 
indicators of disease. you can also see ultrastructural changes (eg, 
electron microscopy) which happen in minutes. light microscopic changes 
take hours to days, and gross changes take days to weeks.

eg, that parvo slide had to be subacute or chronic, or we wouldn't have 
seen those changes. fibrin leakage can be acute (less than 48 hrs). 

injury categories:

dammit list. degenerative, acquired, metabolic, nutritional, etc.

hypoxia: decreased oxygen at cellular level. note that ISCHEMIA means 
"lack of blood" so that would mean there is NO oxygen delivery. as a 
result of ischemia, cells become profoundly hypoxic.

infectious agent- viruses, bacteria, parasites

physical agent- sunburn, radiation, septa bus, pencil

chemical agent- alcohol, CCl4, food.

immunological reaction- immune mediated dz, lupus, AIHA

genetic derangement- functional (enzyme defect) or structural (conal 
truncal defects where heart doesn't form well)

nutritional/metabolic derangement- some genetic enzyme deficiencies...eg, 
phenylketonuria.

neoplasia- tumors. cause injury via compression/mass, and changing 
metabolism

aging/degenerative changes- changes that occur over time, cause 
regression of things. 

iatrogenic- our fault. induced by clinician.
eg, iatrogenic cushing's dz due to overmedication with pred or something.


4 CELLULAR SYSTEMS VULNERABLE TO INJURY

plasma membrane: inside and outside will mix and that's bad. nothing will 
work. sodium and water will get into cell....cell can lyse...etc

aerobic respiration: energy. you need this. mammalian cells tend not to 
work well anaerobically. we are not yeast.

synthesis of proteins: without protein synth, can't repair, can't have 
enzymatic processes to maintain homeostasis, bad news.

genetic apparatus: if cell can't replicate new enzymes or proteins, it 
will break down. 

every type of injury affects these four things.

antioxidants are supposed to help maintain these four systems and inhibit 
cell injury. that's why people take them. who the hell knows.

COMMON MECHANISMS OF CELL INJURY AND DEATH:
of all those 10 mechanisms that can attack the four systems..they do it 
via these five methods:

free radical injury: radiation injury, heart attack, etc. hypoxemic 
injury causes free rad injury.

hypoxemic/ischemic injury- lack of oxygen.

virus induced injury- cell destruction or taking over cells.

chemical toxicity- lead for example will bind proteins. also, chemical 
metabolites can produce free radicals...

physical trauma- hit by bus, arm through meat grinder, etc. if you rip 
cells apart they will die. 

FREE RADICAL INJURY:
what are free radicals (FRs) and how do they cause injury? no, they are 
not people in berkeley who have demonstrations.
-stabilizing combinations
-autocatalytic
-reperfusion injury - related to low oxygen and FRs. 
- FR formation is a common final pathway of many agents. this is because 
they attack everything - membranes, proteins, DNA. they cause disruption 
because, in the 60s, they were jailed, and now they are free, and...oh 
wait, no. sorry. they have an unpaired electron, they're unstable, so 
they wanna BIND. they want some stability, that's all. they don't care 
what they hook onto. Well, H is their favorite, but they'll take what 
they can get. now, if they hook onto your membrane, it willthen start 
leaking and stuff, and that's bad. so, they wanna glom onto things, and 
they change the structure and stability of the things they glom onto, so 
they perpetuate the FR state, because the thing they glom onto becomes an 
FR, and gloms onto something else - so it's autocatalytic in this way.
believe it or not, FR production is a normal part of homeostasis and dz 
control in the body. the body has ways to detoxify and stabilize them. 
normally, when macrophages and PMNs have oxygen burst, they do it via FR 
production. if this gets out of whack, there's a problem. a major 
perpetuation of inflammation is formation of FR by inflammatory cells.

reperfusion: when homeostasis returns, the neutrophils are stimulated to 
release FR that formed due to anaerobic respiration.

P450 system (ARGH!). major detoxifying system in liver, works via FR 
formation. that's why chemicals often cause hepatic damage. CCl4 is a 
hepatotoxin because of FR formation. 

radiotherapy- ionizing radiation - forms free radicals.

carcinogenesis...like CCl4 problem.

H2O2, superoxide, OH* 

OH* is the WORST.

these are intermediates between oxygen and water (fully reduced). they 
are normally produced in cells by enzymatic and non enzymatic reactions. 
problems occur when they get out of control.

ROBBINS pathologic basis of disease- first 5or 6 chaps are recap of small 
red path book.

respiration produces FR in mitochondria
peroxisomes make FR
p450
NADPH oxidase in macrophage

enzymes and binding agents in cells try to bind up the FRs
superoxide dismutase - now available in pill form (prolly doesn't work, 
though).
glutathione reductase - cats don't have enough. that's why they get liver 
failure, and that's why you can't give them acetominophen. 

white muscle dz- nutritional myopathy of lambs. selenium/vit E 
deficiency. causes necrosis or death of muscle cells because they can't 
detoxify their FRs.
-common sources of FR include:
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