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135 Cards in this Set

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how can mitochondrial dysfunction lead to both apoptosis and necrosis?
apoptosis: release of cytochrome c
necrosis: inability to generate ATP, increased intracellular pH, loss of Na/K pump activity
what ion is a major cause of necrosis?
increased intracellular Ca

leads to enzyme activation (membrane and nuclear damage)
increases mitochondrial permeability (bad!)
at a cellular level, what are the mechanisms of REVERSIBLE cell injury?
loss of ADP
increased cell pH
loss of membrane transport (edema)
membrane detachment
glycogen depletion
at a cellular level, what are the mechanisms of IRREVERSIBLE cell injury?
membrane damage (phospholipases, ROS)
release of lysozomal enzymes
large Ca influx
coagulation necrosis: characteristics
cell outlines preserved
can be ischemic or hemorrhagic types
without nuclei
liquefactive necrosis
liquefaction by lysozomal enzymes or neutrophils
caseous necrosis
variant of coag necrosis: acellular cheese like material
(TB and Histoplasma)
fat necrosis:
unique to the adipose around pancreas
pancreatic lipase saponifies TGs
Fibrinoid necrosis
limited to small vessels
deposition of fibrous material inn vessel wall
what are the 3 possible nuclear changes in a NECROTIC cell?
karylosis (fading of nucleus)
pyknosis (shrinkage of nucleus)
karyorrhexis (nuclear fragmentation)
how do viruses inhibit apoptosis?
they express caspase inhibitors
what is the difference between intrinsic and extrinsic apoptosis?
intrinsic: controlled by Bcl-2, lead to mitochondrial release of cyt c

extrinsic: Fas and TNF receptor activation.

they converge on executioner caspases
how does Bcl-2 work?
it prevents the formation of Bax/Bak pores in the mitochondria which allow release of cytochrome c.

net result: Bcl-2 is anti-apoptotic (there are antagonists of bcl-2!)
how is acute inflammation differentiated from chronic inflammation?
acute: neutrophil invasion

chronic: lymphocyte and/or monocyte invasion
what is the difference between an exudate and a transudate?
transudate: extravascular fluid due to increased hydrostatic pressure (low protein content)

exudate: extravasc fluid due to increased vascular permeability (high protein content) with inflammatory cells
serous exudate:
lowest protein content (of exudates)
fibrinous exudate:
with fibrin and other proteins
purulent exudate:
exudate with neutrophils
what are the 2 vasoactive substances increasing vascular permeability?
histamine and serotonin
what are the components of a granuloma?
core of highly activated macrophages (with lots of cytoplasm: so they're called "epithelioid cells", may fuse to become multinucleate "giant cells")

rim of lymphocytes

possibly fibrotic ring and necrotic center
leukocytes exit the blood stream at...
post capillary venules
what is the function , mechanism, and location of the selectins?
they mediate ROLLING

they all have N terminal lectin binding domains (they bind CHO)

L selectin is on leukocytes, P and E selectin are on endothelial cells
what is the funciton and location of Integrins?
They are responsible for strong adhesion and integration into tissue

Mac-1 is on monocytes and neutrophils

LFA-1 is on lymphocytes

both Mac-1 and LFA-1 bind ICAM-1 (on endothelial cells)
how is integrin activity controlled?
The Ig cell adhesion molecules (principally ICAM-1) expression is controlled by CYTOKINES

binding affinity of the Integrins with ICAM is inc reased by CHEMOKINES on endothelial surface binding chemokine receptors on rolling leukocytes
IL-8 is chemotactic for...
neutrophils
CCL5 is chemotactic for...
lymphocytes
IFN-gamma is a cytokine increasing
phagocytosis and killing (macrophages)
what is the difference between resolution and restitution?
resolution: complete reduction of inflammatory processes

restitution: return only to normal fx level
restitution requires...
regenerative capacity of the tissue (
what is the major stimulatory molecule for angiogenesis?
VEGF
what is the major stimulatory molecule for fibrogenesis?
TGF-beta
what is granulation tissue
the sub-terminal tissue in scar formation
fibroblasts secreting collagen
highly vascularized (numerous small tissues)
what is the difference between
fibrinous:
fibrous:
fibrinous: containing fibrin (insoluble protein made from fibrinogen...i.e. clots)

fibrous: containing fibrobasts and collagen
proliferation of endometrium during menstrual cycle is an example of...
physiologic hyperplasia
hypertyroidism and post-surgical adhesions are examples of...
pathologic hyperplasia
cardiomegaly is an example of
pathologic cell hypertrophy
loss of wolffian ducts during embyogenesis of female fetuses is an example of...
physiologic ATROPHY (they persist even though they're tiny)
muscle wasting as a result of denervation is an example of
atrophy
hypoplasia is...
incomplete development of an organ
agenesis/aplasia is:
failure of an organ to develop at all
atresia is:
failure of the hollow portion of an organ to form (esophagus, trachea, fallopian tube without lumen)
dysplasia is:
disorganization of normal cellular uniformity (pre-neoplastic sign)
what are the two components of neoplasms?
parenchyma (the neoplastic cells of origin)

stroma (the desmoplastic fibroblasts, this is what you feel in a lump)
how do the appearance of individual cells vary between benign and malignant neoplasms?
benign: well differentiated (look like cell of origin)

malignant: poorly differentiated (variable appearance)
the suffix -oma refers to
benign neoplasms

(except for lymphoma, which is malignant)
when do benign neoplasms become concerning?
compression of vital organs (meningioma)
interference with normal fx (leiomyoma of uterus)
hormone production (insulinoma)
malignant potential (adenomatous polyp in colon)
at a cellular level, what features strongly suggest malignant neoplasm?
pleomorphism of nuclei/cells
bizarre mitotic figures
hyperchromatic nuclei
carcinoma:
malignant neoplasm of epithelial origin
sarcoma:
malignant neoplasm of mesenchymal origin
carcinomas most often metastasize by traveling through...
lymphatics
kidney and colon cancers most often metastasize by traveling though...
hematogenous path
what is the difference between tumor grade and tumor stage?
grade: an expression of the differentiation of the tumor

stage: an expression of the extend of spread of a tumor
asbestos exposure puts a person at high risk for...
mesothelioma (cancer of pleural lining, encases lung, BAD!!) and bronchogenic carcinoma
arsenic exposure puts a person at risk for what type of cancer?
skin cancer
aniline dye exposure puts a person at risk for what type of cancer?
bladder cancer
unopposed estrogen puts a person at risk for what type of cancer?
endometrial cancer
exposure to Epstein-Barr virus puts a person at risk for
Burkitt's lymphoma
exposure to H. Pylori puts a person at risk for...
gastric lymphoma
exposure to Hepatitis B/C virus puts a person at risk for...
hepatocellular carcinoma
Carcinoembryonic antigen (CEA):
marker for-
sensitivity and specificity-
marker for: GI cancers (also can be breast, liver, lung cancers)
can use to follow disease progression

limitation: low specificity
Alpha-fetoprotein (AFP)
marker:
marker for: hepatocellular carcinoma
germ cell tumors of yolk sac-differentiation
CA 125
marker:
marker for: ovarian carcinomas
(also benign and malignant uterine tumor)

can have helpful or misleading values if tracked post-op
CA19-9
marker for:
pancreatic cancer
(also elevated in colorectal carcinoma, gastric carcinoma)
Prostate Specific Antigen
sensitivity and specificity
great sensitivity

moderate specificity
(also elevated in prostatitis, benign prostatic hyperplasia)
why is PSA good as a screening agnet?
although it has moderate specificity, it has great sensitivity

also, prostate cancer usually begins peripherally and patients won't experience urinary retention until late in disease process
what are normal PSA levels?
0-4 ng/mL
when taking a FNA on a palpable mass, what is an easy indicator of metastatic squamous carcinoma?
just 1 giant squamous cell is diagnostic of metastatic squamous carcinoma
why is histology better than cytology?
it allows you to grade, stage, and characterize neoplasms
on histology, how can you ID a sarcoma?
usually spindle cells without intercellular bridges (desmosomes) like carcinomas have
what are teh advantages of IHC in ID of neoplasms?
can ID cell of origin (espcially for hematopoietic origin)

can also inform pharm treatment by specific markers
a cancer becomes detectable at how many cells?

kills you at how many cells?
10^9 cells

10^12 cells
which gene type is never a cause of a familial cancer syndrome?
oncogenes. They are + function genes, you only need one for activity. It doesn't hold with the loss of heterogeneity mechanism of familial cancer syndromes
mutations in p53 are associated with...
Li-Fraumeni syndrome (very high risk for all sorts of cancers)
mutation in APC gene are associated with...
Familial adenomatous polyposus and colon cancer
what are the 7 characteristics of cancer cells?
1. genomic instability
2. self sufficiency of growth signals
3. resistance to growth inhibition
4. limitless replication potential
5. resistance to apoptosis
6. sustained angiogenesis
7. tissue invasion and metastasis
what is the function of the normal BRCA1 protein?
DNA repair
what is the function of the Rb gene?

what controls it
it is a strong inhibitor of the transition between G1 and S.

transition allowed when Rb is inhibited by phosphorylation by CDK4/Cyclin D
how does HPV lead to cancer?
its proteins are oncogenic
E6: inactivates p53
E7: inhibits Rb
what are protooncogenes?
genes of signal transduction pathways, anti-apoptosis factors, transcription factors
HER2: function and role in cancer
it is an epidermal growth factor overexpressed in many breast cancers

herceptin inhibits it
what is the function of the bcr-abl protein?
it is an unregulated tyrosine kinase induces cell growth

inhibited by gleevac
what is the mutation associated with burkitt's lymphoma?
c-myc mutation, heavy chain promoter translocated in front of myc protein (a growth transcription factor)
Ras is a...
oncogene
overactivated by a point mutation
JAK2 is a...
oncogene
overactivated by a point mutation
what are the two most important tumorigenesis sensors?
p14 and p16 (both located on the Ink4 gene locus)

when p14 and p16 are activated, they activate p53 and Rb, respectively.
what is the function of MDM-2?
p53 acts as a transcription factor for its transcription

when there isn't DNA damage MDM-2 protein proteolyzes p53 when there is DNA damage, MDM-2 is phosphorylated (inactivated)
normal cells become senescent after how many doublings?
~60
what is the cause and consequence of acute promyelocytic leukemia?

trx?
cause: translocation to make a PML retinoic acid receptor

consequence: DIC because the dying cells cause coagulation

trx: all-trans retinoic acid induces terminal differentiation of leukemia cells
loss of what gene greatly increases likelihood of metastasis?
loss of E-cadherin (it allows cells to slough and move away)
which HPV subtypes are the high risk types?
HPV16 and HPV18
people with humoral immunodeficiency are susceptible to...
infection by encapsulated bacteria
sinopulmonary disease
people with cellular immunodeficiency are susceptible to...
low grade opportunistic fungi, viruses
growth retardation
increased change of cancer malignancy
what is the best source for information on primary immune deficiencies?
"Primary Immune deficiencies"
updates from the
International Union of Immunological Societies Expert Committee
Published in J of Allergy and Clin. Immunology
what mutations cause SCID?
all of the interleukin receptors have a common gamma chain, without activity at all the IL receptors you have SCID

also, loss of adenosine deaminase leads to toxic buildup of adenosine...very toxic to T cells in particular
what is the cause of Hyper IgM?
mutation in CD40L
B cells are present, produce lots of IgM but can't class switch so all of the other types of Ig are not present
what is the cause of X-linked agammaglobulinemia?
mutation in gene for a cytoplasmic tyrosine kinase (btk)
B cells and Ig markedly decreased
infections with pyogenic bacteria
what are the characteristics of common variable immunodeficiencies?
decrease in at least 2 Ig types
IgM =< normal

recurrent pyogenic bacterial infection
what are the symptoms of DiGeorge syndrome?
agenesis of thymus
huge decrease in CD-8 T cells
susceptible to fungal and viral infections
what is the cause of Wiskott-Aldrich Syndromme
mutated X linked gene leads to decline in T cells and platelets

IgM down
IgA and IgE up
what is the cause of APECED?
defect in deletion of self-reactive T cells- autoimmunity
what are the disorders of phagocytes?
CGD: defect in respiratory burst
LAD: Leukocyte adhesion deficiency (delayed cord separation and infection)
deficiencies in "early" complement components lead to...
SLE like syndromes, rheumatoid like disease, and infections
deficiencies in "late" complement components leads to...
SLE like diseases
susceptibility to neisseria meningitidis infection
what is responsible for HIV binding to T cell?
gp120: binds CCR on T cell
what is responsible for HIV's ability to penetrate the T cell membrane?
gp41
how does HIV get access to T cells?
it binds APCs and "hitches a ride" to T cells
what components are necessarily for HIV to infect T-cells?
gp120 to bind to CD4
CCR5 on T cell as a co-receptor
gp41 for entry into T cells
what neoplasms are associated with AIDS?
Kaposi sarcoma (skin papules)
B cell non-hodgkin lymphoma
brain lymphoma
uterine cervical cancer
mutations at what gene provide protection against HIV infection?
CCR5 (it is the co-receptor for HIV T cell entry)
how can an HIV infected patient keep the infection at bay?
CD8 T cells can produce a factor called Cellular Anti-viral Factor (CAF) that blocks HIV replication in CD4 cells without killing the CD4 cells
how does amyloid appear on staining?
fibrils form misfolded linked beta sheets
pinkish
takes up Congo reddish orange
apple green with polarized light
where is the best play to take a biopsy to diagnose an amyloidosis?
fat biopsy
what are some of the main causes of secondary amyloidosis?
chronic inflammation
rheumatic autoimmune diseases
what should you always consider on ddx of unexplained organ failure or unexplained organomegaly
amyloidosis
type I hypersensitivity rxns
IgE antibody mediated huge release of histamine. Anaphylaxis
type II hypersensitivity rxns
antibody mediated
cytotoxic: opsonization/complement deposition

non-cytotoxic: against ECM proteins (pemphigus) or against receptors (Myasthenia Gravis)
type III hypersensitivity rxns
Ag-Ab complex deposition. Serum sickness.

fever, urticaria, renal dysfx
type IV hypersensitivity rxns
delayed type cell mediated. TB skin test
Acute transplant rejection and GVHD
what is the process of thymic T cell selection?
all cells have MHC I, dendritic cells and macrophages have MHC II

T cells that react too strongly to MHC are deleted (negative selection), T cells that reaction somewhat to MHC are selected (positive selection)
what 2 mechanisms prevent selection of self reactive CD8 T cells?
chronic stimulation of T cells favors apoptosis

MHC presentation without co-stimulatory signals (by normal host cells) to an unactivated T cell causes anergy of the T cell
a loss of what part of the apoptotic pathway can cause autoimmunity?
Fas or FasLn (can cause autoimmune lymphoproliferative syndrome)
which complement components can cause autoimmunity, and how can that happen?
C2 and C4 especially

seems paradoxical!
but...early complement is important for opsonization of apoptotic bodies. without clearance, the apoptotic bodies are immunogenic and lead to autoimmunity
what is Chronic Discoid Lupus?

how is it diagnostically different
a subtype of SLE
Skin manifestations ONLY

has ANA but no anti-dsDNA-Abs
what kind of antibodies do you get in Drug-induced lupus?
anti-histone Abs

DO NOT have anti-dsDNA-Abs
what are the important diagnostic tests for RA?
Rheumatoid factor: an autoantibody against denatured IgG
good sensitivity, not great specificity

anti-CCP Ab: not great sensitivity, great specificity
what are the main symptoms of scleroderma?
CREST

Calcinosis (thickening of skin and vasculature)
Raynaud's phenomenon (vasospasm in hands)
Esophageal dysmotility
Sclerodactyly
Telangectasia
what is the pathogenesis of systemic sclerosis (Scleroderma)?
fibrosis of skin, vasculature, GI tissues
what are the diagnostic autoantibodies of systemic sclerosis (scleroderma)
anti-Scl-70 Ab

Anti-centromere Abs
what is the pathogenesis of Sjogren's syndrome?
T cell infiltration of lacrimal and salivary glands. Xerostomia and keratoconjunctivitis sicca
what is the difference between raynaud's phenomenon and raynaud's syndrome?
phenomenon: small artery vasospasm leading to discoloration of hands due to cold or stress

disease: cryglobulins that agglutinate and gel at cold temperatures leading to the same phenomenon
anti-ANCA antibodies are present in which two conditions?
wegener's granulomatosus
microscopic polyangitis
what are the symptoms of Kawasaki disease?
MI
Fever
Swollen hands and feet with desquamating rash
eye redness
strawberry tongue
what are the symptoms of polyarteritis nodosa?
microaneurysms of small-med vessels
skin, joint, heart, sometimes renal involvement
how does polyarteritis nodosa differ from Microscopic Polyangiitis?
MPA has renal and pulmonary involvement (always) and anti-ANCA
cerebral infarction causes what type of necrosis?
liquefactive because it activates autocatalytic enzymes