Glossary of Block V, Week I

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What are two major differences between necrosis and apoptosis?
1. Necrosis results in loss of a large area of cells, whereas apoptosis results in loss of specific, individual cells. (Necrosis is messy, Apoptosis is neat)
2. Necrosis results in an inflammatory response, Apoptosis does not.
Define Cell Stress
a broad group of agents or conditions that elicit pressure on normal homeostastis.
When a cell undergoes stress, what are the possible outcomes of the situation?
1. adaptation
2. recovery (reversible cell injury)
3. cell death via necrosis or apoptosis. (irreversible cell injury)
Give some examples of types/classes of agents that elicit cell injury. (7 total)
1. Physical agents (ie. temperature)
2. Chemical agents (ie. chemotherapy, acetaminophen)
3. Hypoxia
4. Infectious agents (virus)
5. Immunologic rections
6. Genetic defect or susceptibility
7. Nutritional imbalance (starvation OR excess lipid intake)
1. Define hydropic swelling.
2. What would it look like?
1. a reversible increase in cell volume
2. pale cytoplasm, swollen ER cisternae and mitochondria. number of organelles is unchanged.
What are the three mechanisms leading to hydropic swelling?
1. increase in plasma membrane permeability to Na+
2. downregulation of the Na/K/ATPase
3. Reduction of ATP supply
1. What do cellular proteins look like in necrosis?
2. What would this look like under the microscope?
1. cellular proteins are denatured
2. the cytoplasm would be more eosinophilic (denatured proteins have incr. affinity for eosin)
Describe pyknosis
a process during necrosis in which the nucleus becomes smaller and stains deeply basophilic as chromatin clumping continues.
When the rate of dissolution of cells is greater than the rate of repair, it is called ____________ necrosis.
What is the pathophysiology behind liquefactive necrosis.
polymorphonuclear leukocytes appear in a bacterial infection and produce rapid cell death - they then digest the dead cells completely. this frequently results in an abscess.
What portion of the body does fat necrosis specifically occur? Causes?
occurs in and around the pancreas and small intestine. Caused by acute pancreatitis or trauma to the area.
Pathophysiology behind fat necrosis?
1. ruptured pancreas/small intestine releases activated digestive enzymes.
2. phospholipases and proteases attack the plasma membrane of adipose cells, releasing triglycerides.
3. pancreatic lipase hydrolyzes the TAGs producing free fatty acids.
4. free fatty acids precipitate as calcium soaps.
What would fat necrosis look like under a microscope?
basophilic deposits at the periphery of islands of necrotic adipocytes
Caseous necrosis is most often caused by?
destruction of a mycobacterium (TB or leprosy - "waxy" coat bacteria)
what does caseous necrosis look like on a gross level?
granulomatous lesion resembling clumpy cheese
What is the mechanism behind caseous necrosis?
1. granuloma is formed on a platform of dead mononuclear cells,mycobacterium and cell debris.
2. Due to the waxy cell walls of the mycobacterium the necrotic debris is not removed. Forms a greyish-white lesion.
Fibrinoid necrosis refers to an alteration of ___________.
injured blood vessels
How are apoptotic cells disposed of?
they are phagocytosed by surrounding cells or macrophages.
1. what happens to the cell size during apoptosis?
2. what about chromatin?
1. Shrinks
2. Chromatin condenses
this type of necrosis occurs in the brain following artery occlusion.
liquefactive necrosis. (mechanism unknown)
What is the most characteristic feature of apoptosis?
chromatin condensation
what is an apoptotic body and how is it formed?
apoptotic body is formed by a "blebbing" which resulted in a separation from the apoptotic cell. These bodies are membrane bound and contain cytoplasm and packed organelles.
What happens to the apoptotic bodies?
they are phagocytosed by resident macrophages or adjacent parenchymal cells.
What would the cytoplasm of an apoptotic cell look like under the microscope?
it would be intensely eosinophilic.
what is a DNA ladder?
DNA in the apoptotic cell is cleaved in specific areas by a calcium dependant endonuclease. these fragments are all approx. the same length and appear as a ladder in an electrophoretic gel.
What role does transglutaminase have in apoptosis?
transglutaminase crosslinks cytoplasmic proteins and forms a shell under the plasma membrane. In this way it mediates cell shrinkage and body formation.
What do these 3 genes have in common: caspases, Bcl gene family, Apaf-1?
they are all genes that are essential in the control of cell death via apoptosis.
What is so special about caspase-3?
caspase-3 is a terminal caspase: once it is activated the cell will undergo apoptosis.
How is the Bcl-2 family involved in apoptosis?
the balance between pro and anti-apoptotic family members controls the decision on whether to undergo apoptosis or not
describe (in general) the pathobiology of apoptosis. (4 steps)
1. protein cleavage
2. protein cross-linking
3. DNA breakdown
4. phagocytosis
DNA cleavage during apoptosis is mediated by?
TNF-a and fas ligand are great examples of what kind of apoptosis?
receptor mediated apoptosis
Where is TNF-a found vs. where fas is found?
TNF-a is found as a free cytokine.
fas is found in the plasma membrane
How do TNF-a and fas ultimately mediate apoptosis?
they activate the caspases
how do killer lymphocytes mediate apoptosis?
CTL recognizes a cell as foreign.
It binds to the cell membrane and uses a perforin to punch a hole in the plasma membrane.
It then releases granzyme-B into the cell, granzyme goes on to activate the caspase-8.
Where do proteins of the Bcl family reside and why is this crucial?
They reside in the mitochondrial inner membrane. When balance leans towards the pro-apoptotic members they activate the caspase cascade inside the mitochondrion. Damage to the mitochondrial membrane for sure results in cell death.
1. mitochondria can mediate apoptosis by releasing what?
2. What is a classic activator of mitochondrial mediated apoptosis via this pathway?
1. cytochrome-c, once released, activates Apaf-1, which activates caspase-9.
2. ROS
1. What is the function of p53?
2. what happens when there is a mutation in p53?
1. p53 functions to identify mutations in DNA. If the mutation cannot be repaired p53 signals the cell to undergo apoptosis.
2. defective p53 drives the development and progression of cancer
What are four mechanisms that always result in cell death?
1. oxygen and ROS
2. intracellular Ca++
3. ATP depletion
4. defects in membrane permeability
How does increased intracellular [Ca++] lead to cell death?
Ca++ activates:
1. phospholipases (destruction of cell membrane)
2. proteases
3. ATPases (causes ATP depletion)
4. endonucleases
Activation of...
1. ATPases
2. Phospholipases
3. proteases
4. endonucleases
...results in?
1. ATP depletion
2. loss of plasma membrane integrity
3. disruption of membrane and cytoskeletal proteins
4. nuclear chromatin damage
How does hydrogen peroxide form free radicals?
via the Fe2+ catylized Fenton reaction
How is the superoxide anion generated?
mainly via leaks in the electron transport chain
What is dangerous about the superoxide anion?
It goes on to create other ROS
How is the hydroxy radical generated? (3 ways)
1. radiolysis of water
2. from H2O2 via the Fe2+ catalyzed Fenton rxn.
3. from H2O2 via the Haber-Weiss rxn.
How is peroxynitrite generated?
generated from the reaction of superoxide with nitric oxide (NO).
How are lipid peroxide radicals generated?
these radicals are produced during lipid peroxidation
What ROS is generated by macrophages and neutrophils during respiratory burst accompanying phagocytosis?
Hypochlorous acid (HOCL). Dissociates to yield hypochlorite radical (OCl-)
1. What is the most reactive ROS molecule?
2. What are the 3 ways it damages a cell?
1. Hydroxyl radical
2. lipid peroxidation
protien alteration
DNA damage and repair
What are four cellular defenses against ROS?
1. superoxide dismutase
2. catalase
3. glutathione peroxidase
4. vitamins E, C and retinoids
What makes reperfusion so devastating in an I/R injury?
reperfusion results in an excess of oxygen - this results in lots of ROS.
What is the role of hypoxanthine/xanthine in ischemic conditions?
formation of a superoxide anion
Which ROS can the (NO radical) be converted to? What is "special" about this one?
peroxynitrite (ONOO) - a major mediator of tissue damage with high oxidative power.
I/R injury leads to the release of cytokines. What do these cytokines do? (3 things)
1. promote vasoconstriction
2. stimulate adherence of inflammatory cells and platelets to endothelium.
3. produce a systemic effect.
Prokaryote or Eukaryote?
1. Bacteria
2. Fungi
3. Protozoa
1. prokaryote
2. eukaryote
3. eukaryote
What type of ribosomes do prokaryotes have?
What about eukaryotes?
prokaryotes - 70S
eukaryotes - 80S (70S within organelles, suggests prokaryotic origins)
What would brightfield microscopy look like and what is it used for?
dark objects against a bright background. Most common type of microscopy. Used for general morphology, stained specimens.
What would darkfield microscopy look like and what is it used for?
bright objects against a dark background. use to see motility, objects too small or thin for brightfield (ie. spirochetes).
What would phase contrast microscopy look like and what is it used for?
dark objects against a bright background. Used for morphology and some inner structures of unstained (living) bacteria, fungi, parasites.
In electron microscopy, transmission EM is used to ______________, whereas scanning EM is used to ___________.
TEM - used to view internal structures
SEM - used to view surface structures
The Acid-fast staining method is most often used to identify _________?
If you wanted to see endospores, flagella, cell walls or capsules, you would need to use this type of stain.
Structural stains
If I wanted to see a virus what kind of microscopy would I have to use?
Bacteria shape:
1. a coccus is ___________.
2. a bacillus is ___________.
3. A fusiform bacillus is __________.
4. A coccobacilli is __________.
5. A spirillum is ____________.
6. A spirochete is ____________.
7. A vib
1. round
2. rod shaped
3. rod shaped with tapered ends
4. short rod shaped
5. corkscrew shaped
6. flexible, undulating
7. curved and corkscrew
Where does electron transport take place in a bacterium?
on the cell membrane
What types of molecules would you see on the cell wall of a gram positive bacteria? (2)
1. techoic acids
2. lipotechoic acids
What types of molecules would you see on the cell wall of a gram negative bacteria?
1. lipopolysaccharides
2. an outer membrane
What is the function of lipotechoic acid in the gram positive cell?
anchors the cell wall to the cell membrane.
In a gram negative bacteria, what anchors the outer membrane to the peptidoglycan layer?
What is clinically important about lipopolysaccharide?
contains lipid-A, a very toxic compound. If this cell ruptures and end even minute amounts are released, shock and fever will occur.
In what type of bacterium would you see a periplasmic space and an outer membrane?
gram negative cells have a periplasmic space and an outer membrane.
A bacterium with an endoflagella is also known as a ___________.
describe the movement of the flagellum in a bacterium.
Rotates. (doesn't whip like euk. flagella)
What are the four uses of pili?
1. Conjugation (Only DNA donors have the pili)
2. Attachment
3. Antiphagocytic
4. Antigenic switching
A capsule is normally made of _____________. exception?
HMW polysaccharide
exception: Bacillus anthracis
What are three functions of the capsule?
1. Inhibits phagocytosis
2. protects from dehydration
3. attachment to surfaces
The cytoplasm of a bacterium may contain storage granules. What could be found inside these? (3)
1. glycogen
2. polymetaphosphate
3. PHA
describe the DNA of bacteria.
single circular chromosome (haploid)
1. Describe an endospore
2. Are endospores reproductive?
3. Give two examples of bacteria which sporulate.
1. a metabolically inactive form of certain bacteria.
2. NO.
3. Bacillus and Clostridium are species which sporulate.
Regarding temperature, how can bacteria be classified? (4)
1. psychrophiles (4-20) deg.C
2. Mesophiles (15-48)
3. Thermophiles (42-68)
4. Extreme thermophiles >68
What is a microaerophilic bacteria?
Bacteria that require just a small amount of oxygen.
What is a "fastidious" bacteria?
difficult to grow
When bacteria grow, cell division is by _____________________.
transverse fission
What are the four methods of measuring bacterial growth?
1. Direct count
2. viable count (live only)
3. Turbidity (both living and dead)
4. Filtration
Estrogens are C___
Androgens are C___
Progestins are C___
C18 - estrogens
C19 - androgens
C20 - progestins
1. What is the primary source of estrogen in women?
2. What are other sites of estrogen synthesis in women? (6)
1. the granulosa cells of the ovary
2. adipose, liver, brain, kidney, skeletal muscle (placenta)
1. What is the role of estrogens in puberty?
2. What is the effect of estrogens on LDL and HDL?
1. development of secondary sex characteristics and reproductive organs
2. increases HDL, lowers LDL
What are the carcinogenic actions of estrogen?
- DES specifically encourages vaginal and cervical cancer
- high postmenopausal estrogen levels encourage endometrial cancer
1. What is DES used for?
2. which is more potent: DES or ethinyl estradiol?
3. Where does the primary metabolism of estrogen preparations occur?
1. chemotherapy for breast cancer
2. ethinyl estradiol is 20x more potent than DES
3. liver
Name some of the therapeutic uses of estrogen in menopause...
used to treat:
chills, sweating
muscle cramps
palpitations and dizziness
atrophic vaginitis
What are some other indications for prescribing estrogen therapy?
delayed puberty
Name some side effects of estrogen therapy
1. GI upset(nausea, vomiting)
2. Cancer (breast, uterine, testicular, bone, renal)
What is significant about children of women who were treated with DES during their first trimester of pregnancy?
These women developed vaginal/cervical cancer
what type of cancer are postmenopausal women that are treated with estrogen prone to? What can we do to counteract these effects?
endometrial cancer
Progesterone will decrease the carcinogenic effects.
A woman who uses oral contraceptives may have an increased risk of which type of cancer?
breast cancer
1. What is the source of progestins in a woman?
2. What stimulates the secretion?
1. progestins are secreted by the corpus luteum during the luteal phase of the menstrual cycle.
2. Secretion is stimulated by LH.
What happens when progesterone levels decrease?
Menses occurs
What is the function of progestins during pregnancy?
Progestins supress uterine contractility during pregnancy
Which hormone is responsible for mammary preparation of lactation?
Both estrogens and progestins help prepare for lactation
Which hormone is thermogenic and hence responsible for the change in BBT during ovulation?
____________ promotes differentiation, while _________ promotes growth.
progestins - differentiation
estrogens - growth
By what molecular means does progesterone increase estrogen clearance?
progesterone increases the activity of 17-OH steroid dehydrogenase and estrogen sulfotransferase: both of which increase estrogen clearance
Why is native progesterone ineffective orally?
the 1st pass metabolism (hepatic) gets it. synthetic progestins are less susceptible to hepatic metabolism
What are some therapeutic uses of progestins?
1. oral contraceptives
2. dysfunctional uterine bleeding
3. dysmenorrhea (used w/estrogens)
4. endometriosis
5. threatened spontaneous abortion
What is a major contraindication for progesterone use?
Congestive Heart Failure
in an oral contraceptive that has both estrogen and progesterone, what is the role of each hormone?
estrogen: promotes endometrial development, prevents breakthrough bleeding
progesterone: withdrawal promotes initiation of menses
Which type of estrogen is most commonly seen in oral contraceptives?
ethinyl estradiol
Which types of progestins are most commonly seen in oral contraceptives?
Give a few examples of progestin-only long term contraceptives.
1. Norplant (5yr) Levonorgestrel
2. Depo-Provera (3mo)Medroxyprogesterone
3. Progestasert (annual)Progesterone IUD
1. Which hormones are found in the contraceptive patch? (OrthoEvra)
2. What about the Nuva-Ring?
1. Estrogen and Progesterone
2. Same as above
Via which route is estrogen replacement therapy administered?
via transdermal patch or gel
In general, what is the MOA of a combined estrogen/progesterone pill?
prevents ovulation by suppressing the hypothalamo-pituitary axis. Estrogen inhibits FSH, Progesterone inhibits LH.
In general, what is the MOA of a progestin only pill?
Produces an unfavorable endometrium and a viscous cervical mucous.
What is the mechanism of the "morning after pill?"
altered gamete transport by enhanced uterine and/or oviductal motility
List some non-serious side effects of oral contraceptive use.
nausea, vomiting, dizziness, headache, weight gain, breakthrough bleeding, mood changes, libido changes, amenorrhea
List some serious side effects of oral contraceptive use.
cardiovascular complications, jaundice, bladder disease, ocular changes, dermal changes, alopecia
1. Describe some adverse hemodynamic changes due to oral contaceptives.
2. What other circulatory system changes are observed?
1. decreased flow to lower extremities, stasis, Na+ retention
2. decreased tone and elasticity of peripheral veins, altered clotting mechanisms
What role do FSH and LH have in androgen synthesis?
They stimulate androgen synthesis
What role do estrogens, inhibin and androgens have on androgen synthesis?
They inhibit androgen synthesis (negative feedback)
Which part of the body synthesizes and secretes testosterone?
Leydig Cells of the Testes
1. Leydig cells are stimulated by __________?
2. Function of sertoli cells?
1. LH
2. establish blood-testis barrier, produce estrogen and inhibin
1. How are androgens transported in the blood?
2. How are androgens metabolized and excreted?
1. Via Androgen Binding Proteins (ABP), albumin and CBG
2. metabolized via liver, excreted in urine
In an androgen, can androgenic and anabolic effects be separated for pharmacological purposes?
NO (at least not in humans)
1. What type of androgen is orally active? What is it's drawback?
2. How does native testosterone need to be administered? advantages?
1. 17a-alkylated androgens (methyl testosterone). It is hepatotoxic
2. transdermally, it is less toxic
what is the most effective method to administer testosterone and keep relatively constant therapeutic levels?
transdermal gel (transdermal patch is close behind)
Why is androsteinedione considered an "anabolic' steroid?
It is a precursor to testosterone
1. testosterone, when acted upon by 5a-reductase, is converted to__________?
2. testosterone, when acted upon by aromatase, is converted to__________?
1. DHT
2. estradiol
What is the effect of androgens in utero? (3)
-prevents cyclic release of GnRH by hypothalamus
-differentiation of male reproductive system
-supression of female reproductive system
What are the effects of androgens in the male during puberty?
1. increase libido, agression
2. induce secondary sex characteristics
3. increase retention of N, Na,K,P,S,Cl,H20
4. reduce subcutaneous fat, increase muscle and bone mass
5. induce epiphyseal plate closure
5. enhance facial, body and pubic hair
What would be the effects of an androgen deficiency:
1. in utero
2. at puberty
3. after puberty
1. ambiguous genitalia
2. eunochoidal, hypogonadal male
3. hypogonadal male
There are 12 pharmacological uses of androgens. List as many as you can...
1. hypogonadism
2. Anemia
3. Enhance N balance and muscle development
4. athletic abuse
5. hereditary angioneurotic edema
6. tx. for certain female breast cancer patients
7. osteoporosis
8. burn patients
9. endometriosis
10. short stature
11. cryptorchidism
12. increase libido in women
There are 9 side effects of androgen therapy. List as many as you can...
1. excessive masculinization
2. early onset of puberty
3. fluid retention/edema
4. jaundice/hepatic carcinoma
5. azoospermia
6. steroid fever, stomatitis
7. urinary obstruction secondary to prostate enlargement
8. priapism
9. gynecomastia
contraindications and cautions of androgen therapy? (4)
1. prostate cancer or breast cancer in males.
2. pregnancy
3. hepatic, renal, cardiac disease
4. premature epiphyseal plate closure
What are the two natural antiandrogens?
estrogen and progesterone
Therapeutic uses of antiandrogens?
Antiandrogens are used to treat:
1. prostate cancer
2. hirsutism
3. male pattern baldness
Therapeutic use of gonadal suppressive agents?
1. reduces gonadal steroidogenesis.
2. tx. for prostate cancer

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