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254 Cards in this Set
- Front
- Back
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proteoglycans consist of:
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core protein binding many GAGs, and a link protein that binds hyaluronic acid. GAGs are highly sulfated and consist of repeating disaccharide units of a *hexosamine* (e.g.N-acetylglucosamine, N-acetylglucosamine) and a *uronic acid* (e.g. glucuronic acid)
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examples of glycosamioglycans
examples of glycoproteins |
GAGs: hyaluronic acid, chondroitin sulfate, keratan sulfate, dermatan sulfate, heparan sulfate
glycoproteins: fibronectin, laminin (both basal lamina), chondronectin (cartilage), osteocalcin, osteopontin, bone sialoprotein |
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collagen
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hydroxyproline, hydroxylysine, glycine L-handed helix
synthesis includes: hydroxylation by peptidyl proline hydroxylase and peptidyl lysine hydroxylase (vit. C) intracellularly, and cleavage of procollagen to form tropocollagen and self-assembly/cross linking (lysyl oxidase enzyme) into fibers |
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elastic fibers
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consist of elastin surrounded by fibrillin. Elastin contains 2 unique amino acids, *desmosine and isodesmosine*, which are involved in cross-linking
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macrophages are activated by:
macrophage granules (endolysosomes) contain: |
activated by: lipopolysaccharides, gamma interferon
granules contain: acid hydrolases, aryl sulfatase, acid phosphatases, and peroxidases |
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macrophages secrete:
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IL-1 (stimulates mitosis of T cells)
IL-6 (stim differentiation of B cells) pyrogens TNF-a GM-CSF (granulocyte-macrophage colony-stimulating factor |
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Mast cells
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important in type I anaphylactic reactions, inflammation, and allergic reactions.
have IgE receptors, cause classic wheal-and-flare reaction. 1) heparin, 2) histamine, 3) leukotrienes, 4) eosinophil chemotactic factor |
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homocystinuria
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also known as Cystathionine beta synthase deficiency. AR, leads to deficits in connective tissue
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amyloidosis
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a group of disorders that have in common the deposition of amyloid in the intracellular space of various organs. amyloid is an eosinophilic, amorphous substance composed of nonbranching fibrillar proteins and a glycoprotein called P component (pentagonal in shape)
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primary amyloidosis
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aka. immunocyte dyscrasias with amyloidosis - most common form of amyloidosis, associated with the amyloid light chain protein.
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secondary amyloidosis
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aka reactive systemic amyloidosis, occurs as a secondary complication to chronic inflammation (ex. rheumatoid arthritis, regional enteritis, ulcerative colitis) and is associated with amyloid-associated protein.
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hemodialysis-associated amyloidosis
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associated with the beta-2 microglobulin protein
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senile cerebral amyloidosis
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occurs in patients with alzheimers disease and is associated with the beta-2 amyloid protein
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endocrine amyloid
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occurs in patients with type 2 diabetes and is associated with islet amyloid polypeptide deposition in the pancreatic islets
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3 types of cartilage
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hyaline (articular), elastic (pinna of ear), and fibrocartilage (annulus fibrosus of intervertebral disk, meniscus of knee joint)
Type 1 collagen is found in fibrocartilage, while Type II collagen is found in elastic and hyaline cartilage |
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chondrocytes
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live in lacunae, form isogenous groups that are surrounded by a territorial matrix that stains basophilic because of the high local concentration of chondroitin sulfate. chondrocytes may undergo mitosis
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chondrogenesis: occurs in the embryo when mesodermal cells aggregate to form centers of chondrification. 2 main ways:
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a. interstitial growth: occurs by mitosis of preexisting chondrocytes. **bone cannot grow this way!
b. appositional growth: occurs by differentiation of chondrogenic cells in the perichondrium into chondroblasts. |
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hormonal influences on cartilage growth:
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1. GH --> somatomedin C (aka IGF-1) in the liver, which stimulates cartilage growth
2. T3, T4, testosterone stimulate cartilage growth 3. estradiol, cortisone, hydrocortisone inhibit growth |
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cartilage repair
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in the adult, damaged cartilage shows limited repair (esp. articular cartilage, which lacks a perichondrium on the surface of articulation) and may form scar tissue instead of cartilage. Greater possibility for repair exists in young children.
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ground substance in bone
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proteoglycans containing chondroitin sulfate and keratan sulfate (same as cartilage), glycoproteins (ex. osteonectin, osteocalcin, and osteopontin), hydroxyapatite, citrate, and carbonate. **weak acid demineralizes bone
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osteoid
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osteoblasts secrete osteoid, which is unmineralized bone matrix.
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bone mineralization
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osteoblasts secrete osteocalcin and alkaline phosphatase, which hydrolyze phosphate-containing substrates as well as calcium-beta-glycerophosphate to release calcium and phosphate. in addition, osteoblasts release matrix vesicles which concentrate calcium and phosphate and are the most important factor for mineralization
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osteoblasts
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secrete IL-1, which actigates osteoclasts. do not undergo mitosis. have PTH and vitamin D receptors. secrete osteoid.
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osteocytes
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live in lacunae and canaliculi, communicate via gap junctions, supplied by haversian systems in compact bone
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osteoclasts
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derived from granulocyte-monocyte progenitor cells - *NOT* mesodermal! these are multinucleated cells that live in Howship's lacunae and secrete lysosomal enzymes and collagenase.
osteoClasts have the Calcitonin receptor, while osteoblasts do not. |
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clinical markers for osteogenesis or bone repair:
clinical markers for bone resorption: |
osteogenesis: serum alkaline phosphatase, serum osteocalcin
bone resorption: urine hydroxyproline, urine pyridinoline cross links, serum N-telopetide |
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osteogenesis
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intramembranous ossification (flat bones of skull) vs. endochondral ossification (long bones) - both types can create both cortical and spongy bone.
**these are both examples of appositional growth. |
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zones of epiphyseal plate:
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a. zone of reserve of chondrocytes
b. zone of proliferation c. zone of hypertrophy d. zone of calcification e. zone of ossification (here osteoprogenitor cells become osteoblasts, depositing bone to form a mixed spicule consisting of calcified cartilage and bone. |
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repair of a bone fracture
*woven bone in the adult is ALWAYS pathologic! |
a. hematoma formation
b. soft tissue callus (procallus) c. immature woven bone deposited d. mesenchymal cells in procallus form hyaline cartilage at periphery which undergoes endochondral ossification e. now called bony callus f. woven bone is remodeled into mature lamellar bone characterized by a regular arrangement of collagen |
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hormonal influences on bone: GH, PTH, calcitonin, thyoid hormone
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GH --> somatomedin C (aka IGF-1) in liver, promotes bone growth/remodeling
PTH causes bone resorption (increased blood Ca++) calcitonin acts directly on ostoclasts in inhibit bone resorption, lowering blood Ca++ T3, T4 stimulate endochondral ossification and linear bone growth |
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actions of PTH on bone
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PTH --> osteoblasts --> secrete macrophage colony-stimulating factor (M-CSF) and express RANKL. M-CSF causes macrophages to express RANK. interaction btw. RANK and RANKL induces differentiation into ostoclasts. osteoclasts increase bone resorption, elevating blood Ca+ levels
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hormonal effects on bone: androgens, estrogens, cortisol, 1,25-(OH) vitamin D
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androgens and estrogens result in closure of epiphyseal plate (ref. precocious sexual development, gonadal hypoplasia)
cortisol inhibits bone formation active vitamin D acts directly on osteoblasts to secrete IL-1, stimulating osteoclasts to increase bone resorption, elevating blood Ca++ (so to activate the Clasts, you go through the Blasts - in both vitamin D *and* PTH!) |
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primary osteoporosis
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can be senile (GH) or estrogen (postmenopausal). low estrogen --> high IL-1. can also be a consequence of chronic glucocorticoid use
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osteosarcoma
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malignant tumor that *produces* bone. usually found in teenagers around the knee. retinoblastoma and p53 mutation genes (Li-Fraumeni syndrome) are implicated
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Paget disease
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uncontrolled osteoclast activity, followed by rapid osteoblast formation of woven bone. the net effect is paradoxically an increase in bone mass that is architecturally unsound.
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osteomalacia (adults) and rickets (children)
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a lack of minerals within osteoid, resulting from vitamin D deficiency.
physical signs includ bowed legs, scoliosis, increased fracture in adults and craniotabes (elastic skull recoil), pigeon-breast, and rachitic rosary (excess osteoid at chonstochondral junction) in children |
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acromegaly
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thick bones as a result of excess GH
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vitamin A excess and bone
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an excess of vitamin A causes a premature closure of the epiphyseal plate, resulting in a person of short stature
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Degenerative joint disease (osteoarthritis)
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progressive erosion of articular cartilage *without* a prominent inflammatory rxn. chondrocytes produce IL-1, initiating bone breakdown, and TNF-a and TNF-b stimulating release of lytic enzymes from chondrocytes. considered a disease of cartilage.
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rheumatoid arthritis
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erosion of articular cartilage and ankylosis of the joint resulting from chronic proliferative synovitis. an autoimmune disease, typically begins at the proximal PIP joint and MP joints of the hand. women affected 3-5x more than men.
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muscle fiber types
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red fibers (type I) - small, slow twitch
white fibers (type IIa/b) - large, fast twitch |
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muscle cross striations
ZIAH |
A band (dark band) - both thick and thin filaments, this is the only band that doesn't change size with contraction!
I band (light band) - thin (actin) filaments H band - thick (myosin) filaments Z disk - bisects the I band, composed of alpha-actinin |
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components of thin myofilament
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F-actin
tropomyosin (blocks active site actin) troponin C |
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components of thick myofilaments
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myosin - can be cleaved by trypsin into *light meromyosin* and *heavy meromyosin*, which contains myosin heads.
titin - anchors myosin to Z disks |
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skeletal muscle triad
*this is only in skeletal muscle - cardiac muscle has a diad! |
consists of a single transverse tubule flanked by two terminal cisternae (dilated sacs of SR)
The T-tubule contains the L-type Ca++ channel (dihydropyridine receptor), while the terminal cisternae contain a fast Ca++ release channel (ryanodine receptor) |
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tubocurarine, pancuronium, vecuronium, atracurium
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nondepolarizing competitive nAChR antagonists.
reversed by acetylcholinesterase inhibitors tubocurarine can cause histamine release --> bronchospasm, hypotension |
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succinylcholine
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depolarizing competitor for ACh - maintains open Na+ channel, eventually causing skeletal muscle relaxation and paralysis. Cannot be reversed by acetylcholinesterase inhibitors.
may cause malignant hyperthermia (treat with dantrolene, which blocks Ca++ release from SR) |
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Botulinus toxin
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produced by clostridium botulinus bacteria, inhibits the release of ACh
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motor unit
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*a motor unit is the functional contractile unit of a muscle - not a muscle fiber! can contain anywhere from 5-150 muscle fibers innervated by a single alpha-motorneuron
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effects of skeletal muscle denervation
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if a nerve to a muscle is severed, fasciculations occur caused by release of ACh from degenerating axon. Several days later, fibrillations (spontaneous repetitive contractions) occur due to a supersensitivity of the muscle to ACh as nAChRs spread out over the entire cell membrane
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skeletal muscle repair
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regeneration is limited. skeletal muscle fibers develop embryologically from rhabdomyoblasts. After injury or extensive exercise, satellite cells fuse to form new skeletal muscle fibers. Adult skeletal muscle fibers do not undergo mitosis
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muscle spindles
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activate the strech reflex, and consist of nuclear chain and bag fibers. these use group Ia and group II afferent neurons, and are innervated by gamma-motorneurons that set the sensitivity of the muscle spindle. After spinal cord transection, hyperactivity of gamma-motorneurons plays a role in spasticity and hypertonia!
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golgi tendon organ
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activates the stretch reflex. consists of a bundle of collagen fibers within the tendon that transmit sensory information to group Ib afferent neurons
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Single unit smooth muscle
Multiunit smooth muscle |
single unit: found in the respiratory, genitourinary system, and GI tract. APs superimposed on spontaneous slow waves, has gap junctions. Activity modulated by: (para)sympathetic NS, hormones (oxytocin, EPI, CCK)
Multiunit: dilator and sphincter pupillae muscles of the iris and ciliary muscle of the lens. Highly innervated, no gap junctions. |
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smooth muscle contraction cycle
**note that unlike skeletal/cardiac muscle, smooth muscle regeneration rates are high! PERICYTES give rise to new cells, and mitosis is possible. |
intermediate filaments connect dense bodies in the cytoplasm and dense plaques beneath the cell membrane.
Ca++/Calmodulin --> activation of myosin kinase contraction halted by myosin phosphatase |
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hemicholium
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blocks uptake of choline from the synaptic cleft into the synaptic terminal - depletes ACh stores.
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neuronal inclusion bodies:
1) Lewy bodies 2) Negri bodies 3) Hirano bodies 4) Neurofibrillary tangles 5) Cowdry Type A |
1) round, eosinophilic inclusions - seen in Parkinson's disease
2) pathognomonic of rabies 3) rodlike, eosinophilic - seen in Alzheimer's disease 4) seen in Alzheimer's disease 5) intranuclear inclusions, found in herpes simplex encephalitis |
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axonal transport
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fast anterograde (vesicles): kinesin
slow anterograde (cytosolic and cytoskeletal components) 1-5mm/day fast retrograde (nerve growth factor, tetanus toxin, polio/rabies/ herpes simplex virus: dynein travel on microtubules |
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tetraethylammonium
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(a poison) - a potent K+ channel blocker
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CNS stimulants
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caffeine: adenosine receptor antagonist
nicotine: nAChR agonist at low doses, mAChR agonist with no response at nAChR at high doses ("nicotinic escape") amphetamines, methylphenidate: stimulate dopamine release cocaine: prevent DA, NE, 5HT reuptake |
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Drugs of Abuse:
1) LSD, psilocybin, mescaline 2) PCP, "angel dust" 3) Ketamine |
1) these interact with 5-HT receptors
2) NMDA receptor antagonist 3) NMDA receptor antagonist - CNS depressant, dissociative aesthetic, used as "date-rape" drug |
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Drugs of Abuse
4) Marijuana (dronabinol) 5) MDMA (ectasy, XTC) 6) y-hydroxybutyrate (GHB, G) 7) Rohypnol and clonazepam (flunitrazepam, roofies) |
4) THC prob. has its own receptors
5) causes damage to 5HT neurons 6) CNS depressant, sedative or euphoric effect, used by bodybuilders (stimulates GH release) and as a date-rape drug 7) similar to other benzodiazepines, sedative, muscle relaxant, amnesia - "date rape" drug |
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pharmacology of migraine headaches
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sumatriptan (imitrex), rizatriptan, naratriptan, zolmitriptan, almotriptan, and eletriptan are 5-HT receptor agonists that reduce sensory activation at the periphery, nocioceptive transmission in the brainstem trigeminal nucleus, and vasoconstriction of blood vessels, opposing the vasodilation thought to be involved in migraine attacks
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astrocyte markers
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asterocytes undergo hypertrophy and hyperplasia in reaction to CNS injury, and contain glial fibrillary acidic protein (GFAP) and glutamine synthetase. These are good markers for astrocytes
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choroid epithelial cells
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these cells are a continuation of the ependymal layer that is reflected onver the choroid plexus villi, and they *secrete CSF* by selective transport of molecules from blood.
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CSF characteristics and colors
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normally clear, a yellow color (xanthochromia) indicates previous bleeding (subarachnoid hemorrhage) or increased [protein]. A pinkish color is caused by a bloody tap, while turbidity is caused by leukocytes
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CSF normal values
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CSF pressure: 70-80 mmH20
CSF cell cound: <6 lymphocytes/cc, while the presence of ANY neutrophils is always pathologic CSF [protein]: 20-45 mg/dL (serum proteins generally too large to cross blood-CSF barrier) CSF [glucose]: 40-70 mg/dL |
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CSF characteristics in acute bacterial meningitis
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cloudy CSF, increased pressure/neutrophils/[protein], decreased [glucose]
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Tanycytes
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these bad boys are modified ependymal cells that mediate transport between ventricles and the neuropil. they project to hypothalamic nuclei that regulate GnRH
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Blood Brain Barrier is absent where?
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median eminence, neurohypophysis, lamina terminalis, pineal gland, and choroid plexus.
**infarction of brain tissue destroys the blood-brain barrier and results in vasogenic edema |
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PNS nerve degeneration and regeneration
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Anterograde (Wallerian) degeneration of axon and myelin distal to injury site. macrophages infiltrate. see chromatolysis (loss of rER, movement of nucleus to periphery) and muscle fasciculations occur.
during regeneration, schwann cells form a cord penetrated by the growing axon. during this time, muscle fibrillations occur |
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CNS nerve degeneration and regeneration
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degeneration: microglia phagocytose myelin and injured axons. glial scars (astrogliosis) form.
regeneration: effective regeneration does not occur in the CNS!! |
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stereocilia
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stereocilia are long microvilli found on hair cells of the inner ear
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zonula occludens
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the gatekeeper of the paracellular pathway, the zonula occludens can be rapidly formed and broken (e.g. during leukocyte migration across endothelium).
made up of occludin and claudin proteins |
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zonula adherens
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extends around the entire perimeter of the cell, made up of actin filaments (cytoplasmic) linked by alpha-actinin and vinculin to a transmembrane protein called E-cadherin (aka. A-CAM)
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macula adherens (desmosomes)
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made up of tonofilaments, desmoglein, desmocollin, and desmoplakin
occur at small, distinct sites |
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Bullous pemphigoid
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an autoummune disease in which antibodies against desmosomal proteins are formed, resulting in widespread skin and mucous membrane blistering as desmosomes fall apart
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slow cardiac action potentials (SA, AV nodes)
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caused by the presence of slow (funny) Na+ channels
1) Ca++ influx through long-lasting L-type Ca++ channels 2) K+ efflux 3) Ca++ influx through transient T-type Ca++ channels and Na+ influx through slow (funny) Na_ channels. |
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fast cardiac action potentials (atrial/ventricular myocytes bundle of His, Purkinje myocytes)
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caused by fast Na+ channels
1) Na+ influx - fast Na+ channels 2) inactivation of fast Na+ channels and K+ efflux 3) Ca++ influx through L-type Ca++ channels ("trigger" Ca++) 4) inactivation of Ca++ channels and K+ efflux 5) high K+ efflux, removal of excess Na+ by Na/K ATPase |
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myocardial endocrine cells
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found in the left and right atria, and secrete *atrial natriuretic peptide*
ANP is secreted in response to increased blood volume or increased venous pressure (e.g. atrial distention caused by left atrial failure). ANP increases natriuresis, inhibits ADH/aldosterone/renin secretion as well as causing generalized vasodilation |
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role of calcium in cardiac myocyte contraction
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the calcium influx that occurs at the cell membrane and T tubule through L-type calcium channels is *not* sufficient to cause contraction, but acts as a "trigger" calcium that stimulates the release of a large pool of calcium stored in the terminal cisterna/SR though the ryanodine receptor
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standard ECG waves/intervals and their meanings
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P wave: atrial depolarization
QRS: ventricle depolarization QT interval: represents entire period of ventricle depolarization and repolarization ST segment: period when entire ventricle is depolarized T wave: ventricle repolarization |
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tunics of blood vessels
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tunica intima - endothelium, basal lamina, loose connective tissue, and internal elastic lamina
tunica media - smooth muscle, type III collagen, elastic fibers, and an external elastic lamina. many factors influence smooth muscle Tunica adventitia: fibroblasts, type I collagen, some elastic fibers |
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1) Elastic arteries
2) Muscular arteries 3) Arterioles 4) Metarterioles **arteries in general have a thicker tunica media, while veins have a thicker tunica adventitia |
1) prominent elastic component of tunica media
2) prominent internal elastic lamina, thick tunica media 3) 1-2 layers of SM in tunica media 4) precapillary sphincter controls blood flow to capillary beds |
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Arteriovenous anastamoses (AVA)
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constriction of the arteriolar component directs blood to the capillary bed, causing depletion of body heat.
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types of capillaries
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continuous: contain zonula occludens, found in lung, muscle, and brain
fenestrated with diaphragm: contains fascia occludens, found in endocrine glands, intestine, kidney fenestrated without diaphragm: only in kidney glomerulus discontinuous (sinusoids): liver, bone marrow, spleen |
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plasma vs. serum
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plasma contains: albumin, gamma globulins, beta globulins (transport lipids, metals, hormones) and fibrinogen.
*plasma without fibrinogen is called serum! |
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Rh factor
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clinically important in pregnancy if mother is Rh- and fetus is Rh+. Affects second pregnancy with an Rh+ fetus, causing Rh-hemolytic disease of newborn (erythroblastosis fetalis). Give mother recombinant Rh immune globulin within 72hrs after pregnancy of an Rh+ baby to prevent erythroblastosis fetalis during subsequent pregnancies
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Kernicterus
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a pathologic deposition of bilirubin in the basal ganglia, may develop as a result of the jaundice from the RBC hemolysis
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Hydrops fetalis
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most severe form of alpha-thalassemia and causes severe pallor, generalized edema, and massive hepatosplenomegaly, and invariably leads to intrauterine fetal death
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beta-thalassemia major
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most severe form of beta-thalassemia, causes a severe transfusion-dependent anemia. most common in mediterranean countries and southeast asia.
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carbon monoxide (CO) poisoning
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carboxyhemoglobin gives blood a characteristic cherry-red color.
causes a left-shift Hb dissociation curve patients are given 100% O2 as treatment |
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platelets
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derived from megakaryocytes
contain PDGF, factor V, fibrinogen, and live 9-10 days |
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pharmacology of antiplatelet drugs
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aspirin: irreversible cyclooxygenase inhibitor
ticlopidine: inhibits ADP-induced binding of fibrinogen to the platelet membrane dipyramidole: increases adenosine levels, inhibiting platelet aggregation. used clinically to prevent thromboemboli in patients with a prosthetic heart valve |
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red bone marrow - main site of B lymphocyte formation, removes aged RBCs, main site of hematopoesis
consists of: |
stromal (1%), myeloid (granulocytes, 65%), erythroid (RBC, 20%) components.
**The myeloid:erythroid (M:E) ratio is 3:1 to 5:1 normally |
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bronchiolar mucosa
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the epithelium is a simple ciliated columnar epithelium with goblet cells and Clara cells.
the lamina propria consists of collagen and elastic fibers. Clara cells secrete a component of surfactan, secrete Clara cell protein |
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Clara cell protein (CC16)
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used as a marker of pulmonary function in bronchopulmonary lavage fluid and serum.
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surfactant components
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cholesterol (50%), dipalmitoyl phosphatidylcholine (DPPC; 40%), and surfactant proteins (10%) SP-A, SP-B, SP-C
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elastance
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the collapsing force that develops in the lung as the lung expands.
E = 2T/radius large alveoli have low elastance and are easy to keep open |
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the medium-sized bronchi are the main site of airway resistance - factors that alter vasoconstriction
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bronchoconstrictors: parasympathetic stimulation, leukotrienes, prostaglandin F (PGF), thromboxane (TXA)
bronchodilators: sympathetic stimulation, PGE, beta-adreergic agonists (terbutaline, albuterol, metaproterenol, salmeterol) |
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infant respiratory distress syndrome
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caused by surfactant deficiency (prolonged intrauterine asphyxia, premature birth, diabetic mothers)
thyroxine and cortisol treatment RDS can lead to hyaline membrane disease |
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inner nuclear envelope
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intermediate filaments (lamins A,B,C)
these guys are taken down by lamin kinase during prometaphase |
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regulators of apoptosis
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reminder: apoptosis can be caused by intracellular or extracellular signals. cytochrome c release into the cytoplasm activates Apaf-1 which in turn activates caspases.
Bcl-2, IAP-family proteins are apoptosis inhibitors, while Bad, Bax, and Bak are all apoptosis promoters |
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nucleolus general features
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rRNA transcription. RNA pol I catalyzes formation of 45S rRNA within the nucleolus, while another set of rRNA genes outside the nucleolus are transcribed by RNA pol III to form 5S rRNA. The nucleolus also contains snoRNAs
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euchromatin
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dispersed chromatin, associated with acetylation of H2A, H2B, H3, H4 histones
acetylation of histones activates the associated DNA! |
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histones general features
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these are small proteins containing a high proportion of lysine and arginine - these are very basic (positively charged) proteins!
activated by histone acetyltransferases (HATs), inactivated by histone deacetylases (HDACs) |
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30 NM chromatin fiber
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the 10nm nucleosome fiber is joined by H1 histone proteins to form the 30nm chromatin fiber.
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depurination
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most common type of DNA lesion, when N-glycosyl bond btw purine and deoxyribose sugar phosphate is broken. repaired by AP endonuclease nick deoxyribose sugar-phosphate, phosphodiesterase excises sugar-phosphate, DNA polymerase and DNA ligase correct sequence
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deamination of cytosol to uracil
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if the U is not corrected back to C, upon replication U-A instead of C-G pairing will occur.
Corrected by uracil-DNA glycosidase - does not remove thymine b/c of methyl group on carbon 5 |
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pyrimidine dimerization
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caused by sunlight. uvrABC enzyme excises 12-residue oligonucleotide including the dimer
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xeroderma pigmentosum
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hypersensitive to sunlight, patients lack an nucleotide excision repair enzyme.
problems in XPC, ERCC, DDB2, XPV genes |
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Atexia-Telangiectasia (AT)
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autosomal recessive, affected individuals are hypersensitive to ionizing radiation.
cerebellar ataxia with depletion of Purkinje cells; progressive nystagmus; slurred speech; occulocutaneous telangiectasia. Caused by genetic defects in DNA recombination repair enzymes. |
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Fanconi's Anemia
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most common form of congenital aplastic anemia.
short stature, cafe-au-lait spots, hypogonadism, microcephaly, hypoplastic thumbs, renal malformation - FA-A gene |
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Bloom Syndrome
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autosomal recessive, affected individuals are hypersensitive to a wide variety of DNA-damaging agents.
long, narrow face; erythema with |
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Telangiectasia
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Telangiectasias are small dilated blood vessels near the surface of the skin or mucous membranes. These are "spider veins"
Sclerotherapy is the "gold standard" |
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Cell cycle control: general features
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Cdk-cyclin complexes: cyclins and cyclin-dependent protein kinases.
cyclins regulate Cdks and are so named because, well, they cycle! The ability of Cdks to phosphorylate target proteins is dependent on the particular cyclin that complexes with it. |
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important Cdk-cyclins in cell cycle control
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Cdk2-cyclin D and Cdk2-cyclin E: mediates G1-->S phase at the G1 checkpoint
Cdk1-cyclin A and Cdk1-cyclin B: mediate G2-->M phase at the G2 checkpoint |
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ribosomes
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40S (small) subunit, 60S (large) subunit
peptidyl transferase activity lives on the 60S subunit |
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Phase I vs. Phase II reactions in the sER
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Phase I: cytochrome P450 mono-oxygenase rxns (hydroxylation, de-alkylation, oxidation, reduction)
Phase II: drug detoxification using glucuronyl transferase - the conjugation of glucuronic acid to a variety of drugs using UDP-glucuronic acid |
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Leber's hereditary optic neuropathy
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progressive optic nerve degeneration
involves the ND4 gene located on mtDNA, missense mutation arg->his. encodes protein for subunit 4 of NADH dehydrogenase complex in the ETC. As a result, demands of a very active neuronal metabolism cannot be met. |
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Kearns-Sayre syndrome
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opthalmoplegia (degeneration of motor nerves of the eye), pigmentary degeneration of the retina, complete heart block, short stature, cerebellar ataxia
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Myoclonic epilepsy with ragged red fibers syndrome
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myoclonus (muscle twitching), seizures, cerebellar ataxia, mitochondrial myopathy, esp. causing an irregular shape and blotchy red appearance in skeletal muscle.
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adrenoleukodystrophy
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a genetic disease that involves mutation of genes for various peroxisomal enzymes used in fatty acid beta-oxidation.
results in abnormal accumulation of lipid in the brain, spinal cord, and adrenal gland. Leads to dementia and adrenal failure |
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centrosome
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the microtubular organizing center (MTOC) of the cell is called the centrosome. At the center of the centrosome are two centrioles that are organized perpendicular to each other.
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Chediak-Higashi syndrome
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genetic disease, neutropenia and impaired phagocytosis of bacteria, results from a defect in microtubule polymerization that impairs lysosomal function of leukocytes. see large abnormal lysosomes in the cytoplasm of leukocytes in people with this syndrome
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Colchicine
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M phase specific drug (anti-mitotic) that inhibits microtubule assembly. Used in the treatment of acute and chronic gout by reducing the activity of leukocytes (anti-inflammatory)
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vinblastine/vincristine vs. paclitaxel
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these are all M-phase specific drugs (anti-mitotic) that bind tubulin.
vinblastine and vincristine inhibit microtubule assembly, while paclitaxel inhibits microtubule disassembly |
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hemosiderosis vs. hemochromatosis
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during iron overload, iron accumulates within the cell as hemosiderin in *hemosiderosis*. Hemosiderosis can be observed in patients with increased iron absorption, impaired iron utilization, hemolytic anemia, and blood transfusions
The more extreme accumulation of iron is *hemochromatosis*, which is associated with liver and pancreas damage. |
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glycogen general facts
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1,4 glycosidic bonds, synthesized by glycogen synthase, degraded by glycogen phosphorylase to glucose-6-phosphate, which is catalyzed to free glucose by glucose-6-phosphatase
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glycogen storage diseases:
1) Von Gierke disease (type 1 glycogenosis) 2) McArdle disease (type V glycogenosis) |
1) glucose-6-phosphatase deficiency, causing enlarged liver and severe hypoglycemia
2) glycogen phosphorylase deficiency, causing exercise-induced muscle pain and cramps |
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components of the cell membrane (lipid portion)
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a) phosphatidylcholine, sphingomyelin (outer leaflet)
b) phosphatidylethanolamine, phosphatidylserine (inner leaflet) the gradient is maintained by flippase, and observing phosphatidylserine in the outer leaflet, for example, is a sign of cell damage. |
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cholesterol and fluidity
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at physiologic temperatures and phospholipid contents, **CHOLESTEROL DECREASES FLUIDITY!!
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Glycolipids: types
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1) cerebrosides contain a single sugar
2) other glycolipids (ex. RBC antigens) which contain many sugars 3) gangliosides (e.g., ganglioside GM1), which contain many sugar moieties and negatively charged N-acetylneuraminic acid (or sialic acid) |
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production of eicosanoids
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1) injury or inflammation --> phospholipase A2 or C breaks down lipids to arachidonic acid
2) lipoxygenase converts AA to the straight-chain eicosanoids leukotrienes 3) COX(I/II) convert AA to the cyclical eicosanoids prostaglandins, prostacyclin, and thromboxane. (COX I = "good COX", COX II = "bad COX") |
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ABC transporter superfamily
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contains two ATP-Binding Cassettes; this family contains a variety of transporters, including multidrug resistance (MDR) proteins, the chloroquine transporter, the CFTR, the multispecific organ anion trnasporter (MOAT), BAT, and flippase
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Multidrug resistance (MDR) proteins
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MDR1 = transports cholesterol into the bile canaciculus in hepatocytes
MDR2 = transports phospholipds (mainly lecithin) into the bile canaciculus in hepatocytes **both of these proteins are expressed by human cancer cells and confer resistance to chemotherapeutic drugs by transporting the hydrophobic drugs out of the cancer cell. |
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chloroquine transporter
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expressed by plasmodium falciparum, confers resistance to chloroquine
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multispecific organ anion transporter (MOAT)
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transports bilirubin glucoronide (bile pigment) and glutathione into the bile canaliculus in hepatocytes
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Biliary acid transporter (BAT)
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transports bile salts (cholic acid and chenodeoxycholic acid) into the bile canaliculus in hepatocytes
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strata of keratinocytes
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basale (hemidesmosomes, mitotically active)
spinosum (desmosomes, tonofibrils, lamellar bodies, postmitotic) granulosum (keratohyaline granules, lamellar bodies, filagrin) lucidum (highly refractive) corneum (keratinocytes devoid of nuclei, involucrin, loricrin, keratin/filaggrin complexes |
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nonkeratinocytes found in the epidermins
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1) melanocytes: clear cells in basale, neural crest derived
2) merkel cells: mechanoreceptors in basale, also neural crest derived 3) langerhans cells: APCs in spinosum, bone-marrow derived (mesoderm), become dendritic cells in lymphatic system, contain Birbeck granules |
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melanocytes - melanin synthesis
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melanocytes are neural crest derived and their differentiation is dependent on the c-kit receptor (a TKR)
tyrosinase converts tyrosine --> dopa --> melanin the completed melanosome is called a melanin granule |
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Eccrine sweat glands
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clear cells (water, Na+, Cl-, K+, urea, NH4+) and dark cells (glycoprotein by merocrine secretion)
excretory duct consists of cuboidal cells, opens onto skin as sweat pores. these sweat glands regulate body temp and emotional sweating |
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Apocrine sweat glands
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found in axilla, mons pubis, and anal regions. secretory portion = merocrine secretion. excretory portion (duct) opens into pilosebaceous canal of a hair shaft
influenced by androgens/estrogen modified apocrine glands in eyelids = *glands of Moll* and external auditory meatus = *ceruminous glands* |
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sebaceous glands
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secretes sebum via holocrine secretion.
duct opens into pilosebaceous canal under influence of androgens (increase activity) and estrogens (reduced activity) |
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malignant melanoma
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dysplastic nevi are precursors of malignant melanoma. characterized by oval cells that breach the basement membrane and grow in nests within the dermis
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vitiligo vs. albinism
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vitiligo = autoimmune loss of melanocytes
albinism = melanocytes are *present*, but lack the enzyme tyrosinase |
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psoriasis
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recurrent eruptions of red or silvery plaques.
epidermal hyperplasia (acanthosis) resulting from abnormal proliferation, retention of nuclei in keratinized surface cells (parakeratosis), and elongation of dermal papillae |
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parenchyma of the spleen - general features
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the paranchyma is divided into the *white pulp* (small, pale islands of lymphoid tissue) and *red pulp* (large numbers of RBCs.
The splenic artery, splenic vein, and efferent lymphatics are found at the *hilus* |
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functions of the white pulp of the spleen
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the white pulp immunologically monitors the BLOOD (unlike lymph nodes, which monitor lymph), where T and B cells interact to form a boatload of plasma cells that migrate to the red pulp and produce Igs. The white pulp consists of mature (virgin) B cells organized into lymphatic follicles closely associated with the central artery and mature T cells organized in a sheath around the central artery called the periarterial lymphatic sheath (PALS), which is a thymic-dependent zone similar to the inner cortex of a lymph node
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Marginal zone
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located between the white pulp and red pulp, the marginal zone is the site where the immune response is initiated and where lymphocytes exit the bloodstream to repopulate the spleen. The marginal zone consists of *macrophages* and *antigen-presenting cells*
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functions of the red pulp of the spleen
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the red pulp removes banged up RBCs and particulate matter from the circulation by macrophages. The red pulp also stores platelets and is the site of Ig production released from plasma cells. The red pulp is organized into *splenic cords* that are separated by *splenic venous sinusoids*.
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splenic cords consist of:
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1. macrophages
2. plasma cells 3. lymphocytes 4. RBCs 5. fibroblasts (secrete type III reticular collagen fibers that form a stromal network. |
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blood flow of the spleen
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splenic artery --> trabecular arteries --> central arteries --> radial arterioles --> penicillar arterioles --> splenic venous sinusoids --> trabecular veins --> splenic vein
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congestive splenomegaly
**aside: Howell-Jolly bodies are found after splenectomy, and represent nuclear fragments that are normally removed from RBCs as they pass through the splenic sinuses |
usually a result of portal hypertension caused by cirrhosis. The spleen is frequently covered by a "sugar-coated" capsule and focal areas of fibrosis containing iron and calcium called *Gandy-Gamna nodules*.
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Parietal cells secrete the following:
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1. HCl (through carbonic anhydrase, H+/K+ ATPase on basolateral membrane, and CFTR on apical membrane
2. Intrinsic factor (loss --> pernicious anemia from no B12) 3. HCO3- into the bloodstream ("alkaline tide" |
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Chief cells
G cells EC cells D cells |
Chief cells secrete pepsinogen. G cells secrete gastrin - found in antrum of stomach, so in ulcers the antrum can be resected to ease symptoms. EC cells secrete serotonin (increases gut motility) and histamine (increases HCl secretion). D cells secrete somatostatin, which inhibits HCl release
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Zollinger-Ellison syndrome and secretin
- note - other causes of elevated serum gastrin include use of H2 blockers, and atrophic gastritis |
a secretin test is confirmatory for a gastrinoma (secretin administration results in an elevation of gastrin levels in patients with a gastrinoma - usually secretin kills gastrin!)
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general features of small intestine - mucosa, submucosa, muscularis externa, serosa
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mucosa (consisting of an epithelium, glands, lamina propria, muscularis mucosae)
submucosa (connective tissue containing blood vessels, nerves, and Meissner plexus) muscularis externa (smooth muscle arranged as an inner circular layer and outer longitudinal layer containing the Myenteric plexus between the two layers) |
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enterokinase
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secreted from enterocytes, enterokinase converts the inactive form [e.g. trypsinogen] of pancreatic enzymes to the active form.
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small intestine absorption of carbohydrates
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glucose and galactose enter enterocytes by secondary active transport using the Na+/glucose cotransporter (SGLT-1). Fructose enteres enterocytes by facilitated diffusion using GLUT5. All 3 sugars exit enterocytes into the portal blood via GLUT2.
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small intestine absorption of proteins
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proteins are digested to amino acids, dipeptides, and tripeptides. Most of these enter enterocytes by secondary active transport using Na+/amino acid contransporters. *****There are 4 separate cotransporters for neutral, basic, acidic, and aromatic amino acids. Cytoplasmic peptidases in the enterocyte break down any di- and tri-peptides to amino acids.
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small intestine absorption of triacylglycerols
Short- and medium-chain FAs and glycerol enter the enterocyte DIRECTLY by diffusion (no micelle), exit the enterocyte by diffusion (no chylomicron), and are delivered to the portal blood instead of the lymph via lacteals. |
long-chain FAs (>12 carbons), monoacylglycerols, cholesterol, and fat-soluble vitamins are packaged into micelles and enter enterocytes by diffusion assisted by *fatty acid-binding proteins (FABPs). Within the enterocyte, resynthesis of triacylglycerols occurs in the *SER*. Subsequently, the triacylglycerols, cholesterol, and vitamins are packaged by the Golgi with *apoproteins* into *chylomicrons*.
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absorption of water-soluble vitamins in the small intestine
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water-soluble vitamins enter the enterocyte by diffusion, although some require a Na+-dependent cotransporter. Vitamin B12 is absorbed in the ilium and requires intrinsic factor. Calcium is absorbed and requires 1,25(OH)2 vitamin D, which is produced by the kidney. Fe2+ enters the enterocyte as heme iron or free iron. Free iron is released into the blood and circulates in the blood bound to transferrin
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Paneth cells in the intestinal glands (crypts of Lieberkuhn)
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Paneth cells are found in the base of intestinal glands and secrete a) lysozyme, b) TNF-alpha, and c) defensins (cryptidins)
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I cells
S cells K cells L cells |
I cells secrete CCK, which stimulates enzyme secretion from the pancreas and stimulates bile release. S cells secrete *secretin* (called nature's antacid) in response to H+ in the gut lumen. Secretin stimulates release of HCO3- from the pancreas. K cells secrete gastric-inhibitory peptide (GIP). GIP stimulates insulin secretion (why oral glucose causes more insulin secretion than IV glucose). L cells secrete glucagon-like peptide-1 (GLP-1), which stimulates insulin secretion and inhibits glucagon. GLP-1 is treatment for type II diabetes
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3 critical stimuli for insulin secretion from the islet cells of the pancreas:
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1) glucose
2) gastric-inhibitory peptide (explains why oral glucose causes more insulin release than IV glucose) 3) glucagon-like peptide-1 (GLP-1) stimulates insulin secretion in the presence of hyperglycemia and inhibits postprandial glucagon secretion. The drug *Byetta* (which is GLP-1) is an incretin-mimetic and is a good treatment for Type II diabetes. -- note - this kinda sucks - glucagon-like peptide I doesn't act like glucagon at all! |
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Gut-associated lymphatic tissue (GALT; Peyer patches)
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Peyer's patches are lymphatic follicles found in the intestinal mucosa and submucosa that are covered by an epithelial lining containing M cells (APCs with microfolds on luminal surface).
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secretory IgA
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M cells in Peyer patches display antigen to virgin B cells, which differentiate into plasma cells and secrete IgA into the lamina propria. This IgA binds to the poly-Ig receptor on the basal enterocyte to form an IgA+poly-Ig receptor complex that is endocytosed and transported across the enterocyte. At the apical domain the complex is cleaved such that IgA is released into the lumen joined with the *secretory piece* of the receptor, and is known as secretory IgA
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Crohn disease
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a chronic inflammatory bowel disease usually affecting the ileum. Abundant lymphocytes form a granuloma within the submucosa. Neutrophils infiltrating intestinal glands destroy them, leading to ulcers. The ulcers coalesce into long, serpentine ulcers (linear ulcers). A classic feature of CR is the demarcation between diseased bowel segments directly next to normal bowel and a *cobblestone appearance*. Findings of diarrhea, weight loss, and weakness. Complications of strictures of lumen, formation of fistulas, and perforation
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cholera toxin
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cholera toxin is an enzyme that catalyzes ADP ribosylation of the alpha5 chain of Gs protein. This effectively raises cAMP levels that activate Cl- channels of enterocytes to secrete Cl- into the lumen.
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what 3 features distinguish large bowel from small bowel?
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1. teniae coli
2. haustra (aka sacculations) 3. appendices epiploicae |
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actions of enterocytes of the large bowel
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these enterocytes absorb Na+, Cl-, and H20 by faciliated diffusion using ion channels under the regulation of aldosterone. **Aldosterone increases the number of Na+ ion channels, thereby increasing the amount of Na+ absorbed. ****Sedatives, anesthetics, and steroids are also absorbed, which is clinically important when medication can't be delivered orally
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Upper anal canal
all smooth muscle, so under autonomic control |
venous drainage by superior rectal vein --> portal vein. Varicosities of the superior rectal vein are called *internal hemorrhoids*. Tumors will drain to DEEP lymphatic nodes (not palpable!). Sensory innervation is for stretch sensation - no pain sensation is present, so internal hemorrhoids or tumors in this area will NOT be accompanied by pain!
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Lower anal canal
motor innervation involves voluntary control of the external anal sphincter (skeletal muscle) |
venous drainage by inferior rectal veins --> IVC. Varicosities of the inferior rectal vein are called *external hemorrhoids*. Tumors will drain to SUPERFICIAL lymph nodes (palpable!). Sensory innervation is for pain, temperature and touch - so external hemorrhoids or tumors in this area are painful!
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cholestasis
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a general term that defines the impaired production and semisecretion of bile at the level of hepatocyte (intrahepatic cholestasis), or a structural blockage, or a mechanical blockage (e.g. cholelithiasis [gallstones])
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lymphatic drainage of the liver
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lymph flows from the space of Disse to lymphatic vessels in the portal triad --> lymphatic vessels that parallel the portal vein --> thoracic duct.
so, lymph flows in the same direction as bile! |
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exocrine pancreas
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functional unit: acinus. The secretion of digestive enzymes is stimulated by CCK.
the ducts of the exocrine pancreas (intercalated and intralobular) secrete HCO3- under the influence of secretin |
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pancreatitis and specific cell injury
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pancreatitis is almost always associated with acinar cell injury. Chronic pancreatitis --> pancreatatic calcifications (pathognomonic), while acute pancreatitis --> increased levels of amylase in pleural fluid (pathognomonic). About 80% is due to biliary tract disease or alcoholism
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alpha cells of the pancreas
beta cells of the pancreas delta cells of the pancreas |
alpha cells secrete glucagon (20%)
beta cells secrete insulin (75%) - note that preproinsulin (contains signal sequence, C peptide) --> proinsulin (contains C-peptide) --> insulin (hexamer associated with Zn++ in secretory granule) delta cells secrete somatostatin |
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Insulin receptor and signal transduction
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Insulin --> IRS-1, IP3K, MAPK, phosphoprotein phosphatase
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type 1 diabetes - HLAs, immune antibodies
note - infiltration of islets by CD8+ cytotoxic T lymphocytes |
HLA-DR3, HLA-DR4
Glutamic acid decarboxylase (GAD), insulin, and tyrosine phosphatases IA-2 and IA-2b autoantibodies may play a role |
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Adenohypophysis subdivisions
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three subdivisions: pars distalis, pars tuberalis, and pars intermedia
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Somatotrophs and functions of growth hormone
note - hyposecretion of GH --> dwarfism, while hypersecretion of GH --> gigantism |
GH release is induced by GHRF and inhibited by somatostatin. In muscle, GH decreases glucose uptake and increases protein synthesis. In adipose tissue, GH decreases glucose uptake and increases lipolysis. In hepatocytes, GH increases gluconeogenesis, increases glycogen degradation, and stimulates release of IGF-1 (somatomedin C)
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functions of IGF-1 (somatomedin C)
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IGF-1 increases protein synthesis in *chondrocytes* at the epiphyseal growth plate and therefore causes linear bone growth (pubertal growth spurt).
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regulation of prolactin secretion
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mammotrophs secrete prolactin (PRL) under the control of TRF and prolactin-inhibiting factor (*dopamine!*)
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functions of prolactin
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prolactin binds to a receptor tyrosine kinase, and has the following effects:
a. promotes milk secretion b. promotes growth of mammary gland c. **inhibits release of GnRH, and thereby prevents ovulation or spermatogenesis!!! |
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ACTH, beta-endorphin, gamma-LPH, beta-melanocyte-stimulating hormone:
derivation from POMC |
these are all derived from pro-opiomelanocortin (POMC). POMC is cleaved to form ACTH and *beta-lipotropic hormone (b-LPH)*.
beta-LPH is further cleaved to beta-endorphin and gamma-LPH - which is further developed into beta-MSH, which explains the hyperpigmentation seen in Addison disease. |
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functions of ACTH
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1. stimulates the mitochondrial enzyme *desmolase* that converts cholesterol to pregnenolone, a key step in the synthesis of all steroids
2. stimulates the zona fasciculata and zona reticularis to secrete cortisol, androstenedione, and DHEA |
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functions of FSH and LH
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In women, FSH grows secondary follicles --> Graafian follicles. In men, FSH promote spermatogenesis and stimulates synthesis of androgen-binding protein (ABP) in Sertoli cells.
In women, LH promotes ovulation (LH surge), luteinization, and progesterone secretion. In men, LH stimulates testosterone secretion from Leydig cells |
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Pars Tuberalis
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the pars tuberalis surrounds the median eminence and infundibular stem of the neurohypophysis. The pars tuberalis contains the portal venules of the hypophyseal portal system
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components of the hypophyseal portal system:
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1. primary capillaries (fenestrated) - formed by the superior hypophyseal artery, located in the median eminence, where releasing factors are secreted into the blood.
2. Portal venules are located in the pars tuberalis - transport releasing factors to the pars distalis. 3. secondary capillaries (fenestrated) live in the pars distalis. Releasing factors leave the bloodstream to chat with the adenohypophysis |
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neurohypophysis
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receive axonal projections from the supraoptic and paraventricular nuclei. Oxytocin causes milk ejection and uterine contraction during childbirth. ADH (aka. AVP) increases water reabsorption in the kidney.
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Leukotrienes:
1) LTB-4 2) LTC-4 3) LTD-4 |
1) LTB-4: stimulates leukocyte chemotaxis
2) LTC-4: bronchoconstrictor, slow-reacting substance of anaphylaxis 3) LTD-4: bronchoconstrictor, slow-reacting substance of anaphylaxis |
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cyclooxygenase products (prostaglandins, prostacyclins, thromboxane)
1) PGE-1 2) PGE-2 3) PGF-2a 4) PGI-2 5) TXA-2 |
1) PGE-1: vasodilator, inhibits gastric HCl, stimulates gastric bicarb and mucus
2) PGE-2: vasodilator, bronchodilator, contraction of uterine smooth muscle at parturition, inhibits platelet aggregation, potentiates inflammation 3) contraction of uterine SM 4) vasodilator, inhibits platelet aggregation, potentiates inflamm. 5)potent vasodilator, stimulates platelet aggregation |
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misoprostol
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a PGE-1 analogue, Misoprostol is used with mifepristone (RU-486; a progesterone receptor blocker) to induce therapeutic abortion. Misoprostol is also used to treat peptic ulcers, because it stimulates the release of gastric bicarbonate and inhibits gastric HCl
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products of arachidonic acid
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lipoxygenase converts AA to leukotrienes, while cyclooxygenase I and II make prostaglandins, prostacyclins, and thromboxanes.
COX-II is the "bad COX" |
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NSAIDS
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Aspirin irreversibly inhibits COX, while Ibuprofen, Indomethacin and Naproxen (Aleve) reversibly inhibit COX.
note - Indomethacin is used to treat acute gout, ankylosing spondylitis, and promote closure of the ductus arteriosus |
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ectopic cardiac pacemakers
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ectopic pacemakers are present in the *normal* heart, and their added activity may induce continuous rhythm disturbances, such as *paroxysmal tachycardias*. When the ectopic pacemaker stops functioning, the SA node may remain quiescent for a period of time (called the SA node recovery time). In patients with *sick sinus syndrome*, the SA node recovery time is prolonged with a period of asystole and loss of consciousness
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first degree heart block
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abnormally long delay at the AV node. The delay between the start of the P wave (atrial depolarization) and the QRS complex (ventricular depolarization) occurs at the AV node.
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Wolff-Parkinson-White Syndrome
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a congenital disorder in which an accessory conduction pathway between the atria and ventricles exists. Normally asymptomatic. However, a re-entry loop may develop in which impulses travel to the ventricles via the normal conduction pathway but return to the atria via the accessory pathway, causing a *supraventricular tachycardia*
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tunica of blood vessels
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tunica intima (endothelium, basal lamina, loose connective tissue, internal elastic lamina)
tunica media (smooth muscle, type III collagen, elastic fibers, external elastic lamina) tunica adventitia (fibroblasts, type I collagen, and some elastic fibers) |
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endothelial cells and anticoagulant activity
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NORMALLY, endothelial cells act as potent anticoagulants by: 1) expression of anticoagulant cell surface molecules (GAGs, thrombin-thrombomodulin-protein C system, and plasminogen-plasmin activator system), 2) secretion of prostacyclin and EDRF, and 3) secretion of tissue plasminogen activator (TPA) and urokinase
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endothelial cells and procoagulant activity on injury
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on injury, endothelial cells secrete *tissue factor*, *von Willebrand factor*, *factor V*, *plasminogen activator inhibitors*, *IL-1*, *TNF*, and *endothelin-1* which affects smooth muscle cells of the tunica media and causes vasoconstriction.
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extrinsic pathway for hemostasis (blood clotting)
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damaged tissue releases *thromboplastin*, which initiates a cascade involving factor VII, X, and V and prothrombin activator (converts prothrombin --> thrombin)
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intrinsic pathway for hemostasis (blood clotting)
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RBC trauma or RBC contact with subendothelial collagen initiates a cascade involving factors XII, XI, IX, VIII, X, and V and prothrombin activator
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vitamin K
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essential for hemostasis - acts as a cofactor for an enzyme involved in the posttranslational carboxylation of glutamic acid forming *gamma-carboxyglutamate* residues in certain blood factor proteins. These residues have high affinity for Ca++. Vitamin K deficiency rare in adults; can result in hemorrhage
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anticoagulants:
Heparin vs. Warfarin |
Heparin stimulates the proteolytic activity of *antithrombin III*, which inactiates thrombin. **heparin is used during pregnancy b/c heparin doesn't cross the placenta. Warfarin inhibits the synthesis of vitamin K, and is contraindicated during pregnancy because it crosses the placenta
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thrombolytics:
streptokinase vs. tissue plasminogen activator (TPA) and urokinase |
streptokinase is an *indirect* thrombolytic drug that combines with plasminogen to form an activator complex that converts plasminogen to plasmin. TPA and urokinase are *direct* thrombolytic drugs that directly convert plasminogen to plasmin
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thrombocytopenia
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most common cause of abnormal bleeding. petechiae and purpura (small reddish-purple blotches in the skin) are apparent
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idiopathic thrombocytopenic purpura (ITP)
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antibody-mediated destruction of platelets. The acute form is associated with viral infection in children and resolves spontaneously, while the adult form is chronic, occurs particularly in women of child-bearing age, and may be associated with other autoimmune diseases
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thrombotic thrombocytopenic purpura (TTP)
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platelet consumption syndrome that usually affects young women and has a viral prodrome. Characterized by the presence of hyaline thrombi in arterioles (without inflammation) leading to microvascular disease.
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Hemophilia A (factor VIII deficiency)
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x-linked recessive disease; the procoagulant portion of the factor VIII protein is deficient
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von Willebrand diseaes (vWD)
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autosomal dominant disease; both the procoagulant and antigenic portion of factor VIII are deficient.
**affects both men and women |
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thyroid follicular cells
note that T3 (more active form) and T4 function like steroid hormones! |
oxidize iodide (forming I2) using the enzyme thyroid peroxidase and iodinate tyrosine residues in thyroglobulin.
note that the conversion of T4 to T3 largely occurs peripherally in the liver and kidney. |
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secondary hyperthyroidism
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relatively uncommon, caused by a TSH adenoma in the adenohypophysis (anterior pituitary)
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Hashimoto Thyroiditis
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the most common cause of *goitrous* hypothyroidism, Hashimoto Thyroiditis is an autoimmune disease that produces thyroid peroxidase autoantibodies.
note that you don't always get a goiter with Hashimoto |
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secondary hypothyroidism
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relatively uncommon, most usually iatrogenic resulting from destruction of the anterior pituitary
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estrogen effect on thyroid hormon
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Estrogen effect: the use of oral contraceptive pills or the use of diethylstilbestrol for treatment of prostate cancer increases synthesis of TBG
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Diffuse nontoxic (simple) goiter
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most commonly due to a deficiency of iodine in the diet. Wherever endemic goiter is prevalent, endemic cretinism occurs
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When would thyroid binding globulin be high or low?
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TBG is high when you're hypothyroid, and low when you're hyperthyroid.
Also, TBG is increased with excess estrogens, and decreased with excess androgens |
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tell me about the T3 resin uptake test
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The T3 resin uptake test is not a measure of serum T3 levels; rather, it measures the percentage of free T4. This test evaluates TBG levels via a competition assay between a resin and TBG for radioactive T3. If TBG levels are low, then more radioactive T3 will bind the resin. TBG has an inverse relationship to T3 resin uptake
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Thyroiditis
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inflammation of bacterial or viral origin. Note that while T4 is high, Iodine uptake is LOW for thyroiditis!
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parathyroid hormone
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PTH acts not only to increase kidney reabsorption of calcium, but also increases the synthesis of 1-alpha hydroxylase in the kidney (increases active vitamin D levels) AND acts directly on osteoblasts to secrete M-CSF and to express RANKL. RANK on macrophages interacts with RANKL on osteoblasts to cause the differentiation of macrophages into osteoclasts.
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1,25-(OH) vitamin D
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it's important to remember that while PTH acts as an *acute* regulator of blood calcium levels, active vitamin D is the *chronic* regulator of body calcium.
Vitamin D acts not only to increase calcium uptake from the gut, but also directly on osteoblasts to secrete IL-1, which stimulates osteoclasts to increase bone reabsorption. |
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primary hypoparathyroidism
(e.g., accidental surgical removal, DiGeorge syndrome, autoimmune destruction) |
leads to hypocalcemia (if sudden, may be life-threatening). Chronic renal failure and vitamin D deficiency also lead to hypocalcemia. Chvostek sign (tapping facial nerve elicits spasm of facial muscles), Trousseau phenomenon (inflated BP cuff on arm elicits carpel tunnel spasm), cataracts, tetany, may occur
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pseudo-hypoparathyroidism
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a rare condition characterized by abnormal PTH receptors, leading to hypocalcemia although there are high PTH levels
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primary hyperparathyroidism (e.g., adenoma, hyperplasia, MEN syndromes)
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excessive PTH leads to hypercalcemia. Findings include osteitis fibrosa cystica (bone softening and painful fractures), urinary calculi, abdominal pain (caused by constipation, pancreatitis, or biliary stones), depression or lethargy, and arrhythmias. Think "painful bones, kidney stones, belly groans, mental moans"
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Malignant tumors and PTH
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lung, breast, or ovarian carcinomas may secrete a PTH related protein, leading to hypercalcemia
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adrenal cortex: GFR, ACD
**The regulation of the glomerulosa is INDEPENDENT of the fasciculata/reticularis!! |
glomerulosa: aldosterone
fasciculata/reticularis: cortisol/androgens the reticularis contains lots of lipofuscin; DHEA and androstenedione are metabolized by the liver to 17-ketosteroids; urine levels of these 17-ketosteroids are used for diagnostic purposes |
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effects of cortisol
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*overall, the most important metabolic effect of cortisol is the conversion of fat and muscle protein to glucose. Cortisol also inhibits bone formation and stimulates surfactant production in the fetus.
at high levels cortisol is antiinflammatory by inhibiting: phospholipase A2, IL-2 production, and histamine/serotonin release from mast cells |
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primary hyperaldosteronism
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commonly caused by an aldosterone-secreting adenoma (Conn syndrome) within the zona glomerulosa. Characterized by HTN, hypernatremia, hypokalemia
treatment is by surgery or spironolactone, which is an aldosterone receptor antagonist |
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Cushing Syndrome vs. Cushing Disease
- treatment of Cushing syndrome include aminoglutethimide, metyrapone, and ketoconazole |
Cushing *sydrome* is high levels of cortisol (often iatrogenic). Strictly speaking, an ACTH-secreting adenoma is Cushing Disease (75% of cases). The remaining 25% is caused by an adrenal cortical adenoma.
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treatment of female infertility with clomiphene
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clomiphene is an estrogen receptor antagonist in the hypothalamus and adenohypophysis, which blocks feedback inhibition by endogenous estrogens, causing increased FSH and LH secretion so that ovulation occurs.
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polycystic ovary syndrome
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increased LH secretion from the adenohypophysis stimulates excessive production of androgens by the theca interna cell of secondary and Graffian follicles, resulting in numerous atretic or cystic follicles
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the Secretory (Luteal) Phase: Days 15-25
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characterized by the secretory activity of the endometrial glands. This phase is controlled by *progesterone* secreted by granulosa lutein cells of the corpus luteum. The endometrial glands become modified to convoluted endometrial glands with secretion product within their lumen
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Asherman syndrome
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end-organ disease of the uterus, in which the basal layer of the endometrium has been removed by repeated curettages
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bleeding after progesterone withdrawl: 3 conditions in which there is *not* bleeding after progesterone withdrawl
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Anorexia nervosa, ovariectomy, Asherman syndrome
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nipple secretion
**a nipple discharge that is green, milky, yellow or brown, not spontaneous, bilateral, and affects multiple ducts is usually a benign situation. |
exfoliated duct cells, alpha-lactalbumin, immunoglobulins, lactose, cholesterol, cholesterol, steroids, and fatty acids, along with ethanol, caffeine, nicotine, barbituates, pesticides, and technetium
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Sertoli cells
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Sertoli cells surround the developing spermatogenic cells, extend the full thickness of the germinal epithelium, form the blood-testes barrier through tight junctions, secrete *inhibin* (inhibits release of FSH), secrete mullerian inhibitory factor, synthesize androgen-binding protein, possess FSH receptors
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Meiosis and the primary spermatocytes
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MEIOSIS OCCURS ONLY IN THE OVARY AND TESTES!
the primary spermatocyte remains in prophase for 22 days! |
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congenital adrenal hyperplasia: differentiating 21-hydroxylase deficiency from 11-beta-hydroxylase deficiency:
note that both conditions give excess androgens and female virilization or male macrogenitosomia |
In 21-hydroxylase deficiency you've got no aldosterone OR cortisol, so you get salt loss and volume depletion. By contrast, in 11-beta-hydroxylase deficiency you have hyper-aldosterone but no cortisol, so you get salt retention and hypertension.
**HTN IS KEY CLINICAL CLUE! |
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primary adrenal insufficiency (Addison disease)
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Addison disease is caused by autoimmune destruction of the adrenal cortex. Characterized by fatigue, anorexia, weight loss, hypotension, skin pigmentation (high MSH), hyponatremia, hyperkalemia (may lead to fatal cardiac arrhythmia)
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secondary adrenal insufficiency
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reduced secretion of ACTH due to a hypothalamic or pituitary problem. It is clinically very similar to Addison disease, **Except there is no hyperpigmentation of the skin!
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blood supply to the adrenals
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the adrenal arteries end up in medullary venous sinuses; this means that aldosterone, cortisol, androstenedione, and DHEA leave the adrenal cortex by first percolating through the adrenal medulla. Activation of the enzyme PMNT, a key enzyme in the synthesis of Epi by chromaffin cells, is dependent on high levels of cortisol!
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neuroblastoma
associated with opsoclonus, a neuroblastoma contains small cells arranged in Homer-Wright pseudorosettes. Increased urine VMA and metanephrine levels are found. |
neuroblastoma is a common extracranial neoplasm containing primitive neuroblasts of neural crest origin. Neuroblastomas occur mainly in children. They are found in extra-adrenal sites, usually along the sympathetic chain ganglia (60%) or within the adrenal medulla (40%). They metastasize widely.
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opsoclonus
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rapid, irregular movements of the eye in horizontal and vertical directions; "dancing eyes"
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Histology of a lymph node
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Outer cortex: Mature c(virgin) B cells in follicles, follicular dendritic cells, macrophages, fibroblasts (type III collagen reticular fibers).
Inner cortex: Mature T cells, dendritic cells, macrophages, fibroblasts. Medulla: lymphocytes, plasma cells (*a major site of IG secretion!), fibroblasts, macrophages |
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Flow of lymph through a lymph node
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afferent lymphatic vessels --> cortex --> subcapsular (marginal) sinus --> cortical sinus --> medullary sinus --> efferent lymphatic vessel at the hilum
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Flow of blood through a lymph node
**blood enters AND leaves at the hilum! |
artery enters at hilum --> capillary network within the cortex --> high endothelial venules within inner cortex --> veins that leave at the hilum.
**lymphocytes enter nodes via HEV's, and leave them via efferent lymphatics! |
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Kuppfer cells
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macrophages in liver! secrete:
TNF-alpha (causes cholestasis) IL-6 (synthesis of acute phase proteins) TGF-beta (causes synthesis of type I collagen by hepatic stellate cells) |
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Hepatic stellate cells (Fat-storing cells; Ito cells)
Portal Triad: |
these cells are found in the perisinusoidal space (of Disse). They contain fat, store and metabolize vitamin A, and secrete type 1 collagen.
A portal triad consists of: hepatic arteriole, portal venule, and bile ductule |
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Conjugation of bilirubin:
*(bilirubin - water insoluble - is derived from the breakdown of hemoglobin by macrophages. |
Bilirubin travels in the blood bound to albumin (note - free bilirubin is toxic to the brain - kernicterus), is endocytosed by hepatocytes, and conjugated by UDP-glucuronyl transferase in the sER. In the colon, bilirubin-glucuronide is broken down and reduced to urobilinogen and excreted in feces.
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1) Crigler-Najjar disease
2) Dubin-Johnson syndrome |
1) loss of UDP-glucuronyl transferase - inability to conjugate bilirubin.
2) failure to release bilirubin-glucuronide into bile canaliculi |
