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256 Cards in this Set
- Front
- Back
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What are the different ways in which genes can regulate patterning along an axis? (2)
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Varied expression of genes along the axis
Concentration gradient expression of single gene along an axis |
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In human development, what happens at:
Week 1? Week 2? Week 3? Weeks 4-8? Weeks 9-birth? |
Week 1: Fertilization, implantation
Week 2: Bilaminar embryonic disc Week 3: Trilaminar (mesoderm) embryonic disc Weeks 4-8: Tissues, organs, body form (patterning) Weeks 9-birth: Fetal period (growth) |
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What is a homeotic gene?
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Determines the fate or identity of each body segment
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How do HOX genes work?
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Encode a DNA-binding homeodomain
Act as transcription factors Can be expressed at different times, in different places = specific functions! |
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What is spatial colinearity? Temporal?
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Spatial:
The order of genes maps an axis in the developing embryo Temporal: The order of genes reflects their temporal expression during development |
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What is the "posterior dominance" of HOX genes?
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When one or more HOX genes are expressed in a given segment, the HOX gene whose expression pattern is the most posterior defines the phenotype of that segment.
Ex. from lecture: lack of b4 → becomes atlas |
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What is synpolydactyl?
What is its inheritance pattern? What gene is involved? |
Webbing of digits with extra digits
Autosomal dominant, incomplete penetrance HOX D13 |
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What gene regulates notochord signalling for the neural plate to form?
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Sonic Hedgehog
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What does it mean that the notochord is an organizing center?
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Sonic Hedgehog affects development of adjacent areas (sclerotome/somites, dermomyotome)
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What is the cascade of signalling for hedgehog genes?
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Inctivates Ptc (which is inhibitory))
→ Disinhibition (activation) of GLI1/2/3 (+/-) |
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What does a mutation in sonic hedgehog cause?
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No induction of signaling
Holoprosencephaly - Small eyes - Microcephaly |
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What does a Ptc mutation cause?
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Pathway always on (doesn't inhibit like it's supposed to)
Nevoid basal cell carcinoma syndrome (NBCCS), aka Gorlin syndrome - Large head - Wide eyes - Retardation **Extreme septation - can see calcified falx cerebri |
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What does a GLI mutation cause?
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Greig cephalopolysyndactyl syndrome
- Pathway abnormality in extremities - too many fingers/toes |
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What is the gene dosage effect?
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Heterozygotes typically have 50% enzyme activity relative to homozygous normal.
ie. one copy of the gene works, one doesn't |
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What is the purpose of activator with GM2 → GM3 + GalNac conversion?
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Creates interface between enzyme and substrate (lipid/water) - micelle!
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Why is it hard to diagnose the AB variant of HEX <i>in vitro</i>?
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Enzymes will cleave GM2 in the presence of detergent, which is used <i>in vitro</i> instead of activator.
→ looks like normal |
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In what population is Tay-Sachs prevalent?
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Ashkenazi Jews
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Which mucupolysaccharidosis is NOT autosomal recessive?
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Hunter (type II) - X-linked recessive
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What is responsible for the variations in severity of mucupolysacchiridoses?
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Allelic heterogeneity
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What is responsible for similar phenotypes of mucopolysaccharidosis but different enzyme mutations?
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Locus heterogeneity
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If two cell types with MPS did NOT cross-correct each other, what type of mutation did they have?
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Allelic mutations
(same enzyme deficiency, different phenotypes) |
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What is the pathology of I-cell disease?
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UDP-GlcNac transferase deficiency = mannose not phosphorylated = enzymes not transported to lysozome
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What are the 3 lysozomal storage diseases?
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1. Tay-Sachs
2. Mucopolysaccharidoses 3. I-cell disease |
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What are the precursors to propionyl CoA?
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VOMITS
Valine Odd-chain fatty acids Methionine Isoleucine Threonine Side chain of cholesterol |
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What is the difference between late onset and early onset multiple carboxylase deficiency?
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Early onset: holocarboxylase synthetase deficiency (can't make holocarboxylase)
Late onset: biotinidase deficiency (can't recycle biotin) → treat with ↑ biotin in diet |
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What are the four carboxylase enzymes?
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Pyruvate
AcCoA Propionyl CoA β-methylcrotonyl |
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What is haploinsufficiency?
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One copy of the gene is NOT enough
(sort of opposite of gene dosage) |
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What genotype causes xanthoma and xanthelasma in familial hypercholesterolemia?
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Homozygous dominant
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What are the steps of collagen synthesis?
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1. Synthesized in RER (ribosomes)
2. Lots of modification of aas 3. Associate to form triple helix, then secreted 4. N-propeptide and C-propeptide and cleaved 5. Associate to form fibrils |
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Is it better to have reduced amounts of normal collagen or normal amounts of abnormal collagen?
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Reduced, but normal
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What is the mechanism for development of secondary sexual characteristics in boys?
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LH secreted from pituitary
Binds Leydig cells Leydig cells make testosterone |
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Why aren't girls affected by LH receptor constitutive activity?
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Puberty in girls depends on other hormones as well as LH
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What is the structure of a chromosome?
What are the 3 types? |
Centromere
Long arm, short arm Metacentric (equal) Submetacentric Acrocentric |
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What are the parts of acrocentric chromosomes? What is unique about them?
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Stalk
Satellite Both are very redundant, so mutations in either don't do much. |
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What is the only factor that predisposes to chromosomal abnormality?
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Maternal age
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What are the results of first division meiotic non-disjunction?
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Trisomic
Monosomic |
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What are the results of second division meiotic non-disjunction?
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Trisomic
Monosomic Euploid |
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What is a fragile site? How does it appear?
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Satellites at the end of the long arm of chromosome X
Looks like a gap at Xq27.3 |
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How many repeats of CGG in FMR1 are required before individuals show the phenotype?
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>200
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When do trinucleotide repeats expand in FMR1?
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Premutation (50-200): meiosis in oogenesis
Mutation (>200): meiosis in oogenesis, mitosis |
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What is anticipation?
Non-penetrance? |
Anticipation - appearance of a genetic trait at an earlier age or with greater severity in successive generations
Non-penetrance - females have 2 X chromosomes, so one is randomly inactivated in cells; if it's the mutated one, they'll be fine |
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Why are daughters of transmitting males of Fragile X normal?
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Transmitting males have premutation, but it only expands in oogenesis, so their daughters will also have premutation.
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What does a longer repeat length in Friedriech's Ataxia mean?
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Earlier age of onset
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What are the two diseases affecting androgen receptors?
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Complete Androgen Insensitivity Syndrome (CAIS) - loss of function
SBMA - gain of function |
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What are the principles of teratogens? (4)
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1. Specific
2. Dose-effect relationship 3. Timing! (stage of development) 4. Genotype of mother/fetus |
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What is the result (generally) of teratogenic exposure at:
• First 2 weeks after conception • 2-8 weeks • > 8 weeks |
• All-or-none
• Organogenesis defects • Growth defects (but malformation is unlikely) |
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What are the two common maternal illnesses that can lead to teratogenic effects?
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1. DM
• 3x increase in malformations (related to poor glucose control) • Caudal regression syndrome (underdevelopment of lower extremities)... 2. PKU • Exposure of fetus to high levels of phenylalanine • Mental retardation, microcephaly, heart defects |
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What is the effect of ionizing radiation at 0-2 weeks, 2-5 weeks, >5 weeks?
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• 0-2 weeks: all-or-none
• 2-5 weeks: CNS damage • >5 weeks: growth retardation |
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What is the effect of thalidomide on fetuses?
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Phocomelia
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What is Fetal Warfarin Embryopathy?
What enzyme is likely to be involved? What disease does it present similar to? |
When exposed b/w weeks 6-9:
• Calcification of of cartilagenous epiphyses • Shortening of distal phalanges • CNS, cardiac abnormalities Arylsulfatase E X-linked recessive Chondrodysplasia Punctata |
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What is the difference between major and minor anomalies?
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Major - compromise survival
Minor - no functional significance, usually cosmetic |
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What are the 3 types of anomalies?
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1. Malformation: poor formation of tissue
2. Deformation: unusual forces on tissue 3. Disruption: breakdown of normal tissue |
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What are the 3 flavors of malformation?
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1. Incomplete: common
2. Redundant: uncommon (polysyndactyl) 3. Aberrant: rare (mediastinal thyroid) |
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What is the major cause of congenital malformations?
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Idiopathic (unknown)
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What are the types of deformations?
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1. Extrinsic mechanical
2. Intrinsic • Malformational (ex. spina bifida leads to club foot) • Functional (ex. neurological or muscular damage) |
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Which anomalies can be corrected spontaneously or by posture?
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Deformations
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Which anomalies will occur during organogenesis? Which will occur during the fetal period?
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Malformations
Deformations, disruptions |
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What is a sequence?
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Collection of anomalies that occur together
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What is the Robin sequence?
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Malformation (mandibular hypoplasia)
OR Deformation (mandibular constraint) leads to failure of tongue descent leads to cleft palate ------ Malformation: Treacher-collins Deformation: Pierre-Robin *recall that deformation can see spontaneous correction - better prognosis |
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What is the significance of minor anomalies?
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Often associated with major anomalies
Can aid in diagnosis (i.e. sequences) |
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What are the goals of gene therapy?
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1. Alter/supplement function of mutated gene
2. Directly alter/repair mutated gene 3. Provide a gene that adds missing function of or regulates another gene |
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What determines success of gene therapy?
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1. Delivery to appropriate cell
2. Proper expression |
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What are important factors to consider when creating a gene therapy?
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1. Short/long-term
2. Tissue specificity 3. Regulation of expression 4. Quantity of cells to hit 5. Ex vivo or in vivo? |
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What is pseudo-typing?
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Changing the viral envelope protein to change tropism
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What are the 5 primary types of receptors?
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1. Intracellular (e.g. steroid)
2. Trasmembrane, intrinsic enzyme activity (e.g. EGFR) 3. Trasmembrane, auxiliary enzyme (e.g. cytokine R) 4. Ligand- or voltage-gated ion channel (e.g. ionotropic glutamate) 5. GPCR (β-adrenergic) |
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What is positive and negative allosterism?
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Positive allosterism - enhance agonist-mediated response but do not independently activate receptor
Negative allosterism • Agonist-dependent: reduce agonist-mediated signalling • Agonist-independent: like inverse agonist |
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What is the therapeutic index?
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Toxic ED<sub>50</sub>/Good EC<sub>50</sub>
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What are the properties of competitive antagonists? Non-competitive antagonists?
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Competitive:
• Bind irreversibly to same site as agonist • ↓ potency • Efficacy unchanged • Effect depends on [agonist] and [antagonist] Non-competitive: • Bind irreversibly to same site as agonist OR to allosteric site • Potency unchanged • ↓ efficacy |
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How are agonist-dependent non-competitive antagonists described?
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Inhibition-response relationship: measure response while varying concentration
Look for IC<sub>50</sub> |
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How are agonist-independent non-competitive antagonists (~inverse agonists) described?
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Schild analysis
• Plot [agonist] vs. response • Dose ratio = ↑ [agonist] required to give same response with certain [inverse agonist] |
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What are spare receptors?
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Maximum physiologic response can be achieved without 100% binding of receptors.
Commonly observed with receptors that do not mediate the DIRECT effect ie. GPCR, but not voltage-gated ion channel |
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What happens if there are spare receptors and you give a low concentration of non-competitive antagonist?
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Looks like competitive antagonist.
Keep increasing [ ] and THEN Effect<sub>max</sub> will drop. |
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What are inverse agonists?
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Drugs that reduce activity of <b>constitutively active</b> receptor
Competitive/Non-competitive |
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What are the properties and types (6) of intracellular receptors?
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Lipophilic ligands
Receptors are transcription factors 1. Thyroid hormone receptor-like 2. Retinoid X receptor-like 3. Estrogen receptor-like 4. Nerve growth facter 1B-like 5. Steroidogenic factor-like 6. Germ cell nuclear factor-like E.g. tamoxifen (SERM) |
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What are the properties and types (6) of enzyme-linked receptors?
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Ligands - extracellular proteins
Slow! 1. Receptor tyrosine kinases • Growth factors often ligands 2. Tyrosine kinase-associated receptors • Cytokines • Dimerization required 3. Receptor like tyrosine phosphatases • Unknown ligand 4. Receptor serine/threonine kinases • TGF-β, BMP, activin 5. Receptor guanyl kinases (cGMP) • Natriuretic peptides 6. Histidine kinase-associated receptors • Bacterial chemotaxis |
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What are some ligands for receptor tyrosine kinases (RTKs)?
How are receptors activated? |
Insulin, EGF, IGF, PDGF, VEGF...
1. Ligand binds 2. Receptor dimerizes 3. Kinase phosphorylates tyrosines 4. Downstream signalling |
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What receptors must dimerize to signal?
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RTKs
Tyrosine kinase-associated receptors |
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What are the properties and types (3) of ligand/voltage-gated ion channels?
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Receptors have semipermeable channels
Ligands are small molecule NTs 1. Cys loop receptors • Pentameric • GABA<sub>A</sub>, GABA<sub>B</sub>, glycine • Nicotinic AChR, 5-HT<sub>3</sub> (serotonin) 2. Glutamate receptors • Tetrameric • AMPA, NMDA, kainate 3. ATP receptors • Trimeric • P2X |
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How does memantine work?
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Uncompetitive antagonist - binds in the ion pore, so requires it to be active first.
Thought to prevent some excitotoxicity in neurons from constitutively open NMDA receptors. |
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What are some channelopathies?
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1. Cystic fibrosis - CFTR transporter
2. Long QT - KCNQ1, other K Also epilepsy, migraine, hyperekplexia |
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What are the properties and types (3) of the GPCRs?
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Much slower signalling than ion channels
1. Family A (Rhodopsin-like) • Rhodopsin • Biogenic amine receptors • Olfactory receptors 2. Family B (secretin-like) • GI peptides • Corticotropin releasing hormone (CRH) receptor 3. Family C (metabotropic) • mGluRs • GABA<sub>B</sub> • Calcium-sensing Rs |
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Give an example of tachyphylaxis.
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β-adrenergic receptor
- β-arrestin binds, prevents association with Gs = Loss of receptor function (receptor-dependent) |
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What's the different between pharmacodynamics and pharmacokinetics?
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Pharmacodynamics - what drug does to the body
Pharmacokinetics - what body does to the drug |
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What are dialyzing membranes?
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Most capillaries, renal glomerules
Fenestrated! |
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What are the transporters of primary active transport? What are the properties?
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ATP-binding cassette (ABC) transporters
Unidirectional efflux Saturable Can be inhibited by metabolic inhibitors |
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What is MDR?
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Multidrug resistance - p-glycoprotein, modulates drug permeability
1. Prevents GI absorption 2. Role in BBB 3. Excretion in bile, urine Can be overexpressed in cancers |
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How is secondary active transport different from primary?
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Doesn't use ATP
Couples transport of one solute going uphill with another going downhill. Ex. SLC5A - Na-dep Gluc symporter SLC8 - Na/Ca exchanger |
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What type of transport is targeted by SSRIs?
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SLC6A4 - secondary active transport
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What is vectorial transport?
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Transferring solutes/drugs from one side of cell membrane to the other in polarized cells (e.g. endothelial, epithelial)
Often polarized expression of transporters! (e.g. SLC5A brings in glucose against [], SLC2A2 takes it downhill on other side) |
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What are the two types of endocytosis?
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Fluid-phase - like pinocytosis
Receptor-mediated - clathrin-coated pits |
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What are some proteins involved in intercellular junctions? Which are involved in paracellular transport?
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Claudins
Occludins Zo proteins JAMs (junctional adhesion molecules) Claudin-5 - BBB, <1nm pore Claudin-2 - ~5nm pore in other tissues for paracellular transport |
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What is the Hendersen-Hasselbach equation?
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log([base]/[acid]) = pH - pKa
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What are the parenteral and non-parenteral routes of administration?
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Parenteral:
• IV • IM • SubQ Non-Parenteral: • Oral • Rectal • Inhalation • Topical |
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How does food affect drug absorption? Give 2 examples.
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Food increases gastric emptying time (longer gastric residence)
1. Didanosine Acid-labile: take without food to decrease residence time 2. Nitrofurantoin Delayed absorption prolongs dissolution time = ↑ bioavailability (but ↓ Cmax) so take with food |
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What is the major metabolizing enzyme in the gut?
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CYP3A4
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How does grapefruit juice affect drug absorption?
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1. Inhibits CYP3A4 (irreversible)
2. Inhibits OATP (organic anion-transporting polypeptide) -Reversible |
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How do we know that grapefruit juice only affects GI drug metabolism?
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Felodipine study: IV + grapefruit juice = no change, but PO + GFJ = ↑ F
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How much first-pass metabolism is present with rectal dosage forms?
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~50% (some bypasses liver)
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What determines initial distribution of drugs? Final distribution?
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Initial: blood flow - brain, heart, liver, kidneys
Final: affinity of drug for tissue • Lipid - all organs, adipose • Ionic - plasma, interstitial compartments |
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What 2 protein subfamilies of ABC transporters make up the biochemical barrier of the BBB?
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Pgp (MDR/ABCB1)
Multidrug resistant associated protein (MRP1, ABCC1) |
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Why can intrathecal injections be used to treat brain infections?
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There is no good brain-CSF barrier (no tight junctions)
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Why is albumin important in distribution?
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Drugs bound to albumin are pharmacologically inactive and can affect transport to tissues.
Must adjust for albumin level |
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How can redistribution be dangerous (ie. thiopental, propofol)?
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Gets stored in fat cells, released when drug is no longer given - can OD.
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Why are lipid drugs hard to excrete renally?
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They are reabsorbed after being filtered in the glomerulus
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What is the major mechanism of excretion of ionized drugs (especially anions)?
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Tubular secretion (proximal tubule)
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What are the transporters in renal secretion?
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Pgp
MRPs OATs Solute carrier transporters: 1. Weak bases (histamine) - Procaine - Quinine 2. Weak acids (uric acid) - Penecillin - Probenecid ex. give probenecid - ↓ secretion of penicillin! |
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Where does reabsorption occur? What happens to ionic drugs?
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Distal tubule
Ion trapping - ionic drugs excreted in urine |
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How can renal excretion of a weak base like amphetamine be increased?
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Acidify the urine with arginine-HCl! Makes the charged form more prevalent (ion trapping)
Works for weak acids too - alkalinize urine! |
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How do drugs enter the bile?
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Lipid diffusion
Small molecules through fenestrae Transporters |
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What is the enterohepatic cycle? What is it's effect on elimination?
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Glucuronides formed in liver
Enters bile (MW >500, esp.) Glucuronides can be cleaved in colon, some drug reabsorbed Delays drug excretion, prolongs drug action E.x. birth control + anbitiotic - disrupts cycling, lower plasma levels, unexpected pregnancy! |
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What is cometabolism?
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Enzymes that metabolize endogenous agents also metabolize xenobiotics
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What are the types of drug metabolism?
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Phase I: functional group
• Hydrolysis • Oxidation • Reduction Phase II: Conjugation to make more polar • Sulfation • Acetylation • Glucuronidation • Glutathione-idation • Methylation |
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What does caffeine do at low doses? High doses?
*boards question |
Adenosine antagonist
Inhibits phosphodiesterase = ↑ cAMP |
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What is one of the reasons alcoholics have many metabolic disorders?
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NADH excess! (from dehydrogenase activity)
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Why is ingesting foods with tyramine (cheese) with MAOIs a bad idea?
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Tyramine releases NE which is inactivated by MAO. If inhibited, hypertensive crisis.
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Which CYP enzyme has many polymorphisms? What is the distribution?
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CYP2D6
Trimodal: poor, extensive, ultraextensive metabolizers |
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How should you adjust the dose of codeine in an Ethiopian patient with CYP2D6 ultraextensive metabolism?
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DECREASE dose - metabolism of codeine is to activate it to morphine!
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What are the two polymorphisms involved in ethanol metabolism?
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Alcohol dehydrogenase overactivity
Aldehyde dehydrogenase underactivity |
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Fast and slow acetylators
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Just know they exist.
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Glutathione null genotypes
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Mu
- Linked with cancers Theta - Adverse effects with cancer chemotherapeutics |
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What is the mechanism responsible for the increased toxic effects of acetaminophen in the presence of alcohol?
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EtOH uses and INDUCES CYP2E1, which is responsible for the toxic metabolites of acetaminophen
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What can happen to a patient on oral contraceptives who also takes St. John's Wort?
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SJW induces CYP3A4 = can get preggo!
Also induces CYP2E1 |
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What are the results of non-instantaneous drug distribution?
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1. Termination - may be fast or slow, depending on when effect is terminated (rapid distribution phase or slow elimination phase)
2. Bolus, infusion only appropriate for drugs with high margin of safety (initial volume < Vd) 3. Accumulation during continuous administration (effect of infusion duration and distribution) |
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What is the mechanism of inactivation of effect of IV anesthetics?
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Redistribution to lean and fat tissues.
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Why is thiopental typically a short-acting drug? How does increasing its dose make it a long-acting drug?
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Falls below min effective conc (MEC) during rapid distribution.
If you increase dose, it will hit slow elimination phase and take a long time to fall below MEC |
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How does drug distribution change with redistribution of cardiac output (ie. hemorrhage)?
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Ex. in hemorrhage, decreased blood flow to muscles, GI, increased to brain
Different distribution = different effects |
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What is hysteresis with pharmacodynamics?
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There is a lag time between plasma concentrations and pharmacologic effect.
→ delay in onset and offset Use biophase model to adjust and collapse hysteresis loop |
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Which of the β-lactams can you give orally?
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Penicilin V (1)
Oxacillin (2) Amoxicillin (3) Cephalexin (1st) Cefadroxil (1st) Cefaclor (2nd) |
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Clavulonic acid cannot inhibit WHICH β-lactamase? Why?
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Type B - is a Zn enzyme that does not form a penicilloyl enzyme complex.
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Why is vancomycin useful against staphylococcal enterocolitis or GI superinfection?
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Not absorbed orally!
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Describe the steps of bacterial protein synthesis.
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1. Initiation
• mRNA binds 30S + F3 • fMet-tRNA binds + F1, F2 • 50S binds, F1,2,3 released 2. Elongation • aminoacyl-tRNA + elongation factors binds • Peptide bond formed • Translocation 3. Termination |
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How are penicillins and aminoglycosides synergistic?
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Penicillins degrade cell walls, allowing aminoglycosides to enter
= bactericidal! |
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What are the two fluroquinolones NOT excreted renally?
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Moxifloxacin
Trovafloxacin |
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Which drug inhibits mammalian CYP450 most?
Fluconazole Itraconazole Ketoconazole |
Flu < Itra < Keto
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What does Nifurtimox treat?
Piperazine? |
Trypanosoma cruzi
Ascaris lumbricoides |
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What is damaged non-dividing tissue replaced with?
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Scar tissue (collagen)
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How do stem cells hold on to tritiated-thymidine?
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Stem cells retain the maternal strand
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What determines the fate of stem cells?
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Tissue microenvironment
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What is the main function of:
1) TGF 2) VEGF 3) HGF 4) EGF 5) FGF 6) Prolactin |
1) TGF - epithelial cells, liver regen
2) VEGF - angiogenesis 3) HGF - liver growth and function 4) EGF - epithelium proliferation 5) FGF - mitogen for fibroblasts and epithelium 6) Prolactin - proliferation/differentiation of breast epithelium |
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What is a metaplasia?
Dysplasia? Neoplasia? |
Metaplasia - change in differentiation from one type to another (reversible)
Dysplasia - abnormal hyperplasia, propensity for malignancy (sometimes reversible) Neoplasia - uncontrolled growth and cellular autonomy (irreversible) |
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What are some examples of metaplasias?
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1. Squamous metaplasia: glandular to squamous
- pseudostratified ciliated columnar to squamous (in respiratory tract) 2. Glandular metaplasia: Squamous to glandular (e.g. Barrett's esophagus - stratified squamous of esophagus to columnar intestinal) |
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What are the cellular responses to stress?
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1. Ignore - quiescence
2. Adapt 3. Divide and differentiate 4. Die (necrosis, apoptosis) |
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What is coagulative necrosis?
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Trigger: Ischemia, toxins
Scarring and removal (time-dependent) |
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What is liquefactive necrosis?
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Form of coagulative necrosis
Necrotic area rapidly liquefied (extensive lysis) BRAIN vascular injury → cells digest dead tissue but it's not scarred, refills with cysts and fluid |
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What is caseous necrosis?
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Associated with caseating granulomas
Center of lesions undergoes liquefaction Think TUBERCULOSIS Caseous = cheese |
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What is fat necrosis?
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Often fatty tissue after trauma; often tissue near pancreas
Pancreatic damage → acinar cells leak enzymes → digest fat (saponification) to FAs which chelate metal ions (esp Ca2+) Can become hypocalcemic! (tetany, death) |
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What is tumor necrosis?
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1. Poor blood supply
2. Bad angiotic factor production 3. Apoptotic factor produced by dying tumor cells 4. Therapy |
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What factors indicate irreversible cell injury?
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Mitochondrial densities
Blebbing Spilling of lysosomal enzymes Rupture of plasma membrane |
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What are the main causes of necrosis?
|
1. ATP depletion
2. Loss of Ca2+ homeostasis (influx → activates degrading enzymes) 3. Free radicals (and DNA/protein damage) 4. Loss of membrane permeability |
|
|
What are clinically important proteins released during necrosis?
|
Cardiac:
cTNI - 4-6hr of MI Lactic dehydrogenase (LD): 1 = cardiac, 2 = skel muscle If LD1 > LD2 = cardiac necrosis Liver: ALT/AST Pancrease: Amylase |
|
|
What is a major difference morphologically between apoptosis and necrosis?
|
Necrosis - swelling and explosion
Apoptosis - shrinking, controlled; no inflammation! |
|
|
What are the two pathways of apoptosis?
|
1. Intrinsic:
• p53-triggered → Bax/Bak • Cytochrome c release from mitochondria • Activation of caspases (9, then 3,6,7) 2. Extrinsic • Triggered by pro-apoptotic receptors: Fas, TNF • Fas-assocated death domain (FADD) • Caspases 8, 10 → 3,6,7 |
|
|
What is fatty liver?
|
Too many FAs produced by liver - can't cope - puts them into droplets (accumulates)
Alcoholic Obesity - metabolic syndrome DM Can see Mallory bodies REVERSIBLE! |
|
|
What are the 6 ways FA concentration in the liver can increase?
|
1. ↑ FA uptake
2. ↑ FA synthesis 3. ↑ triglyceride synthesis 4. ↓ FA oxidation 5. ↓ Apoprotein synthesis 6. ↓ Lipoprotein secretion |
|
|
What is the unfolded protein response (UPR)?
|
Response for misfolded proteins in the ER (unlike ubiquitination in cytoplasm)
Detector: BiP, recognizes mutant proteins and binds sensors Sensors: IRE1, ATF6, PERK - signal Effectors - UPR • Fast feedback: shut down ribosomal translation • Slow feedback: kinases, transcription factors Effector: ERAD • If protein can't be refolded correctly, ERAD sends them to proteosome • May also get rid of foreign agents in ER Effector: Apoptosis • Follows prolonged UPR response |
|
|
What is lipofuscin?
|
Seen during aging process
Undigested cellular material accumulating in endstage liposomes |
|
|
What are two other pigmented substances that can deposited in cells?
|
Melanin
Hemosiderin • Bruising • Poor vascular perfusion (nutmeg liver) • Hemochromatosis (mutation) - body takes in too much iron = heme deposition |
|
|
What is the result of precipitated uric acid?
|
Gout, hyperuremia
|
|
|
What are exogenous accumulations?
|
Anthracosis - Carbon particles in airway, lung (ie. smoker, coal miner)
• Anthracotic pigment • Can lead to cell death, fibrosis, cancer Tattooing: increased risk of HBV, HCV, HPV |
|
|
What are the characteristics of calcification?
|
1. Dystrophic
• Calcification in dead and disease tissue (due to net negative charge in dead cells) • Normal serum levels • Psammoma bodies - tombs for cancer cells ex. atherosclerosis 2. Metastatic • Calcification in normal tissues with hypercalcemia • Prefers net negative charge: lung, kidney, stomach |
|
|
What is pathological ossification?
|
Myositis ossificans
Metaplasia following trauma - Deposition of cartilage or bone on skeletal muscle |
|
|
What is the Hayflick limit?
|
Point at which cells stop growing and senesce.
Eventually will either die or become malignant. |
|
|
What are telomeres?
|
Caps on the end of all DNAs.
3-10kbp Preserves DNA upstream from damage in replication Shorten with age - RNA primer on lagging strand gets degraded = shorter telomere → seen as biologic clock |
|
|
What cells' telomeres do not shorten?
|
Stem cells
Reproductive cells (ie. spermatogonia) Controlled by telomerase enzyme Can see increase in telomerase in cancer |
|
|
What is Werner syndrome?
|
Defective DNA helicase
= defective DNA repair = faster aging! |
|
|
What are the methods of immune tolerance (ie. specific inhibition of the immune response to self)?
|
Central:
• Clonal deletion - in thymus of T/B-cells that are self-reactive • Clonal anergy - T-cell that is not co-stimulated (by B7) is turned off = anergic Peripheral: • Clonal anergy • Sustained activation of T-cells = apoptosis • Suppression (Th2) - IL-4, IL-10, <b>TGF-β</b> |
|
|
What are the pathologic mechanisms of autoimmunity (4)?
|
1. Immunologic -
• Upregulation of B7 • Defective Fas-FasL apoptosis • ↓ Th2 suppression activity • Polyclonal B-cell activation • Cross-reactive antigens • Cryptic, sequestrated antigens 2. Genetic - prevalence of certain diseases in certain HLA haplotypes (incl. complement def.) 3. Viral - mitogens (B-cell activation), neoantigens (like haptens), T-cell suppression 4. Hormonal - female predilection, pregnancy |
|
|
What is the likely effect of testosterone on autoimmune disease?
|
Inhibits! (mice experiments...)
|
|
|
Graves' Disease
• Pathophysiology? • Symptoms |
1. Endocrinopathy
• Hyperthyroid - thyroid stimulating Igs (TSIs) bind TSH receptor → increase cAMP → make T3, T4 • Anti-TPO, anti-thyroglobulin sometimes present as well 2. Ophthalmopathy • Edema, wide eyes 3. Dermopathy • Non-specific edematous thickening Increased metabolism = sweating, tachycardia, etc. *Loss of Th2 suppressor activity |
|
|
Hashimoto's Disease
|
1. Hypothyroid
2. Hurthle cells • Degenerated thyroid cells 3. Autoantibodies • anti-TPO • anti-thyroglobulin • anti-colloid • anti-TSH receptor (block) Slowed metabolism = fatigue *Loss of Th2 suppressor activity |
|
|
Myasthenia Gravis
|
1. Anti-nAChR autoantibody
2. Associated with thymic disorders 3. Fatigue with descending paralysis/weakness Edrophonium test - give anticholinesterase = improvement! |
|
|
Pernicious Anemia
|
1. Decreased B12 absorption
• Bone marrow defective maturation of DNA of RBCs = megaloblastic anemia • Spinal cord - myelin degeneration 2. Autoantibodies • sIgA against parietal cells = achlorhydria (↓ HCl in stomach) • Against intrinsic factor (IF) = blocks binding of IF-B12 = can't absorb B12 OR binding Ab = binds IF-B12 complex = not absorbed **B12 required for DNA synthesis Megaloblast - large nucleus (RBCs in bone marrow) |
|
|
What are the transitions on the way to fibrinoid necrosis in an artery?
|
Inflammation
Exudation Dissolution Necrotizing → Results in fibrin-like material = fibrinoid The result of autoantibody or immune-complex trapping in blood vessel wall |
|
|
Systemic Lupus Erythematosus
|
1. Skin rash, joint pain!! (see below)
2. Autoantibodies - ANA! • anti-dsDNA • anti-ssDNA • anti-histone • Extractable Nuclear Antigens (ENAs): anti-Sm, anti-nRNP, anti-SSa, anti-SSb 3. Symptoms • Butterfly rash; atrophy of epidermis • Arthritis • Proteinuria • Raynaud's • Pleuritis, pericarditis, endocarditis • Anemia, leukopenia, thrombocytopenia • Vasculature: onion skin appearance 4. Kidney • Various forms of lupus glomerulonephritis • Diffuse proliferative - BAD prognosis • Membranous nephritis - better prognosis Remissions, relapses Late stage: disfigured face like a wolf = lupus |
|
|
What is unique about anti-Smith antibody?
Which other antibody is specific for SLE? How are they detected? |
Titer does not fluctuate with progress/state of disease
Specific for SLE, found in 20-30% of patients. Speckled IF anti-dsDNA also specific for SLE. Peripheral IF. Crithidia luciliae test |
|
|
What is the crithidia luciliae test?
|
Protozoan, has kinetoplast rich in dsDNA
Used to test for anti-dsDNA Ab |
|
|
What are the patterns of immunofluorescence for nuclear antigens?
|
Homogeneous - DNA, histones, nRNP (not specific)
Peripheral - dsDNA, soluble NP (specific for SLE) Speckled - ENA, partially specific for SLE; hallmark of mixed CTDs Nucleolar - RNA - scleroderma, polymyositis-dermatositis |
|
|
Which has a better prognosis: diffuse proliferative (nephritic state) or membranous nephritis (nephrotic state)?
|
Membranous nephritis
|
|
|
What is the diagnostic feature of progressive systemic sclerosis?
|
Scl-70 (anti-DNA topoisomerase I)
|
|
|
What is the pathophysiology of PSS, and what are some of the symptoms?
|
Lymphokines stimulate collagen production systemically (delayed-type hypersensitivity)
S<sub>x</sub> • Loss of elasticity (mouth, skin) • Vasospasm, vasculitis • Honeycomb lung • Systemic HTN (↓ RBF) • ↓ GI absorption, peristalsis |
|
|
What is CREST syndrome?
|
Calcinosis
Raynaud's syndrom Esophageal dysfunction Sclerodactyl (hardening of digits) Telengiectasia (capillary dilation) |
|
|
What is Sjorgen's Syndrome
a) Pathophysiology? b) Symptoms? |
a) SSa, SSb autoAb (ENA)
b) Painful, but can't cry • Infiltrates in secretory glands |
|
|
What is polymyositis-dermatositis
Patho and Sx? |
a) Anti-myoglobin, anti-tRNA synthetase autoAb
b) Inflammatory/degenerative disease of muscle/skin |
|
|
What is characteristic of Mixed Connective Tissue Disease (MCTD)?
|
Often female with multitude of symptoms
Anti-ribonucleoproteins: + Anti-DNA, Anti-Sm: - (if positive, then SLE) Speckled immunofluorescence |
|
|
What is Polyarteritis Nodosa?
a) Pathophysiology? b) Symptoms? |
Males!
a) P-ANCA Perinuclear-AntiNeutrophil Cytoplasmic Antibody Anti-MPO (found in PMNs) in microscopic form b) Nodosa = nodules = aneurysms of large arteries Fibrinoid necrosis, immune complexes in all 3 layers of artery |
|
|
What is karyorrhexis? When do you see it?
|
Fragmentation of nuclear material.
Specific to lupus |
|
|
What is the pathophysiology of Raynaud's phenomonon?
|
Cryogenic Igs precipitate in cold
= cyanosis in fingers + vasospasm (endothelin) |
|
|
Where do immune complexes typically deposit in nephritic (diffuse proliferative) and nephrotic (membranous nephritis)?
|
Nephritic = subendothelial
Nephrotic = subepithelial |
|
|
How does discoid lupus differ from SLE?
|
Localized form in skin
|
|
|
What are some drugs that cause lupus?
|
NAT slow acetylators:
Procaineamide Hydralazine Diphenylhydantoin |
|
|
What is the triad of symptoms in Wagener's Granulomatosis?
|
Nasopharyngeal granuloma (nasal septum destruction)
Vasculitis (microscopic) Necrotizing glomerulonephritis |
|
|
What is the cause of Wagener's?
|
C-ANCA
Cytoplasmic-Anti-Neutrophil Cytoplasmic Antibody anti-PR3 (proteinase 3) in PMNs |
|
|
How is Wagener's differentiated from Polyarteritis Nodosa, immunologically?
|
Wagener's: C-ANCA
PAN: Both C- and P-ANCA |
|
|
What is the pathophysiology of Amyloidosis?
|
Stach-like deposits in various organs
MECHANICAL disturbances, NOT inflammatory |
|
|
What does the starch-like deposit of amyloidosis contain?
|
1. Fibrillary proteins (eg. AA, AL, ATTR, Aβ<sub>2</sub>m, etc)
2. Serum amyloid-P component (SAP) 3. Proteoglycans 4. Sulfated GAGs |
|
|
What are the classifications of amyloidosis?
|
1. Systemic
• Primary - myeloma • Secondary - chronic infections, hemodialysis • Hereditary - familial mediterranean fever 2. Localized • Endocrine • Senile • Atrial • Cutaneous |
|
|
What is the reason for precipitation of fibrils (amyloid)?
Where do AA and AL precipitate? |
Limited proteolytic cleavage
AA - liver AL - plasma cells |
|
|
What is the difference between sago and lardaceous spleen?
|
Sago - amyloid around arterioles
Lardaceous - amyloid in sinusoids (looks like fat = lard) |
|
|
What does congo red stain for?
|
Amyloid! Causes birefringence due to β-pleated sheet of amyloid protein
|
|
|
What is the length of fibrils to be considered amyloid?
|
8-10 nm
|
|
|
What are the characteristics of benign vs. malignant tumors? Include nomenclature.
|
Benign:
• Resemble tissue of origin • ↓ mitosis • Expansive with encapsulation "cell of origin" + "-oma" • Adenoma = glandular epithelium • Papilloma = squamous epithelium Malignant • May/may not resemble tissue of origin • ↑ mitosis • Infiltrative, invasive "cell of origin" + "-sarcoma" • Rhabdomyosarcoma = striated muscle • Leiomyosarcoma = smooth muscle For epithelium: "cell of origin" + "-carcinoma" • Adenocarcinoma |
|
|
What are the exceptions to the nomenclature rules?
|
Melanoma = malignant (benign = nevus)
Lymphoma = malignant Teratoma = benign (totipotent stem cells) |
|
|
What is differentiation?
|
Extent to which parenchyma of tumor resembles normal cells
Well-differentiated = typically benign |
|
|
What is anaplasia? What are some characteristics?
|
Lack of differentiation
Pleomorphism = multiple cell types, sizes, shapes Hyperchromatic ↑ nuclear:cytoplasmic ratio Abnormal mitosis Loss of polarity |
|
|
What is dysplasia?
|
Disordered growth - loss of architectural orientation
|
|
|
What is "carcinoma in situ"?
|
Dysplasia affects entire epithelium but confined to basement membrane
|
|
|
What is desmoplasia?
|
Extensive collagen produced in stroma (like in breast adenocarcinoma)
|
|
|
What affects tumor growth? How is it related to differentiation?
|
• Doubling time
• Fraction of tumor cells in replicative pool • Rate of apoptosis Growth α 1/differentiation (well-diff. = slow growing) |
|
|
What are the steps for invasion of tumor cells?
|
1. Loosening of intracellular junctions (E-cadherins)
2. Degradation of ECM - MMPs (proteolytic) 3. Changes in attachment of tumor cells to ECM proteins 4. Locomotion and migration - ratcheting mechanism |
|
|
What is metastasis? What are the 3 pathways?
|
Spread of malignant tumor clels to distant site
1. Direct seeding of body cavities/surfaces (peitoneal, pericardial, pleural, etc.) 2. Lymphatic 3. Hematogenous - affects liver, lungs especially (thin vessels) |
|
|
What is tumor grading?
|
Degree of differentiation of tumor cells.
I → IV (well-diff. → not well) |
|
|
What is tumor staging?
|
Degree of spread and size
UICC: T = primary tumor N = regional lymph nodes M = metastasis |
|
|
What is the monoclonal origin of tumors?
|
Derived from a <u>single cell</u>!
|
|
|
What are the types of oncogenes? Give an example of how each can lead to cancer.
|
1. Extracellular growth factors
• PDGF overexpression 2. Growth Factor Receptors • Erb2 (her2/neu) expression • EGFR - 80% of squamous cell carcinoma of lung 3. Signal transducing proteins • RAS: codes for p21 GTP-binding proteins, turned off by GTP-ase activating protein (GAP) → mutant p21 always on, resistant to GAP 4. Non-receptor tyrosine kinase • c-ABL - chromosomal translocation in CML 5. Nuclear transcription factors • C-myc: translocated adjacent to Ig heavy chain = dominant clone of B-cells (Burkitt's Lymphoma) due to oversupply of c-myc transcription factor • N-myc: neuroblastoma 6. Cyclins and CDKs • Overexpression of Cyclin D • Amplification of CDK4 • In charge of G1→S transition |
|
|
What is a tumor suppressor gene (TSG)? What is the inheritance?
|
Genes that code for proteins that STOP cell proliferation (anti-tumor)
Each cell MUST have both alleles knocked out. But if organism if heterozygous, there is a much higher chance to lose second allele in an individual cell. → Susceptibility is dominant inheritance |
|
|
Retinoblastoma
|
Malignant tumor from immature retinal neurons
Leukocoria - appearance of a white pupil (white mass = tumor) Susceptibility is autosomal dominant (see TSG flashcard) • Homozygous normal requires 2 mutations (one in each Rb allele) |
|
|
What is the normal function of Rb?
|
Prevents transition to S phase
Sequesters E2F Phosphorylation (*by Cyclin D/CDK4) releases E2F...S phase! |
|
|
What are the possible mutations in the G1/S checkpoint?
|
1. Rb
2. Cyclin D 3. CDK4 4. P16/Ink4a - CDK inhibitor |
|
|
What is Li-Fraumeni syndrome?
|
1 defective p53 gene
|
|
|
What does p53 do?
|
Senses DNA damage
Upregulates p21 (CDK inhibitor), GADD45 (DNA fixer), bax (apoptosis) Activates transcription of mir34 (miRNA) - inhibits growth promoting genes (myc, CDK4), anti-apoptosis genes (BCL-2) |
|
|
What are BRCA1 and BRCA2?
|
TSGs in breast, ovarian cancer
Transcriptional gene regulation, DNA repair |
|
|
What is adenomatous polyposis coli (APC)?
|
TSG
Seen in Familial Adenomatous Polyposis - defective APC allele - metric fuckton of polyps Promotes degradation of β-catenin, which can activate genes involved in proliferation (c-myc, Cyclin D, etc.) |
|
|
What is WT-1?
|
Wilm's Tumor (TSG)
WT-1 gene essential for normal urogenital development Can get renal tumors |
|
|
What is NF-1?
|
Neurofibromatosis type 1 (TSG)
Neurofibromin - same as GAP, inactivates RAS-GTP |
|
|
What is Von Hippel Lindau (VHL)?
|
TSG
Ubiquitin ligase - regulates hypoxia response genes in angiogenesis |
|
|
What is Smad4?
|
TSG
90% of pancreatic adenocarcinomas, many colon adenocarcinomas too Mediates TGF-β suppression of epithelial cell growth |
|
|
What genes regulate apoptosis?
|
Bcl-2 - anti-apoptotic → overexpression in many B-cell lymphomas
Bax - "death gene" Ratio of bax + bad/Bcl-2 + Bcl-xL = determines apoptosis |
|
|
What is Hereditary NonPolyposis colon cancer (HNPCC)?
|
Inherited predisposition to colon cancer
Defects in DNA mismatch repair genes (MSH2, MLH1, PMS1, PMS2) Usually heterozygous - second hit occurs in colonic epithelium |
|
|
What is xeroderma pigmentosum?
|
Autosomal recessive
Mutation in one of several nucleotide excision repair (NER) genes Extreme photosensitivity, SUPER HIGH risk of skin cancer |
|
|
What is ataxia telengiectasia?
|
Hypersensitivity to ionizing radiation
Cerebellar degeneration Oculocutaneous telengiectasia Immunological abnormalities Predispose to cancer |
|
|
What % of cancers are environmentally induced?
|
85-90%
|
|
|
What is initiation in carcinogenesis?
Is it sufficient to produce tumorigenesis? |
Irreversible DNA damage in a critical target gene (oncogene, TSG, etc.)
NO |
|
|
What is promotion in carcinogenesis?
Is it reversible? |
Process by which initiated cell is selected for and amplified into benign tumor/preneoplastic condition
Reversible initially |
|
|
What is progression in carcinogenesis?
|
Benign → invasive potential (carcinoma in situ)
Then, subpopulation of these cells selected for ability to metastasize |
|
|
What is the electrophilic theory of carcinogenesis?
|
Direct-acting carcinogens - already electrophilic - bind DNA, RNA, proteins
Indirect-acting carcinogens must be metabolically activated into electrophilic species |
|
|
What is a mutagen?
|
An agent that can permanently alter genetic constitution of the cell
Most carcinogens are mutagens, and vice versa |
|
|
What is the Ames test?
|
Test for chemical carcinogens
Uses S. typhimurium that CANNOT produce histidine (can't grow on normal agar) If agent causes bacteria to make histidine (mutated) = mutagen! |
|
|
What is an example of a direct-acting chemical carcinogen?
|
Nitrogen mustard
Found in chlorambucil, melphalan (anti-cancer drugs) |
|
|
What are some examples of indirect-acting chemical carcinogens?
|
Polycyclic aromatic hydrocarbons
• Incomplete combustion of organic material • Benzo(a)pyrene Aflatoxins • B1 - one of the most potent liver carcinogens • Aspergillus flavus - more common in Africa, Asia • Produces p53 point mutation ("footprint") in HCC - not seen in HCC in USA Nitrosamines • Implicated in GI cancers • Nitrates (food) + acid = nitrosamines |
|
|
What are some promoters in human cancers?
|
Cigarettes
UV Hormones Viral infection High fat diet |
|
|
What are the events that occur in colonic mucosa that result in adenocarcinoma?
|
1. APC gene mutation
2. K-Ras point mutation 3. p53 mutation SMAD mutation Telomerase overexpression, hypermethylation |
|
|
What 3 cancers are caused by UV exposure?
|
Melanoma
Basal cell carcinoma Squamous cell carcinoma |
|
|
What cancers are associated with asbestos exposure?
|
Malignant mesothelioma
Lung cancer |
|
|
What cancers does HPV cause?
How does it do this? |
Papilloma (benign squamous cell cancer)
Cervical carcinomas (often with high-risk HPV - 16, 18) E6 expression - binds and degrades p53 E7 - binds Rb (displaces E2F) |
|
|
What cancers are associated with EBV?
|
(E. Thomas) Hodgkin disease
Burkitt's Lymphoma Very Nasopharyngeal carcinoma |
|
|
How does HBV cause cancer?
|
Mutation-favored environment from hyperplasia from chronic liver injury
X protein - binds p53 |
|
|
What cancer is linked to H. Pylori infection?
|
Gastric lymphomas of MALT ("Maltomas")
Gastric adenocarcinomas |
|
|
What are paraneoplastic syndromes?
|
Effects not attributable to invasion or metastases (not local effects):
• Fever • Weight loss (cachexia) • HyperCa (parathyroid hormone-related protein secreted by tumor) • Hypercoagulable state • Neurologic symptoms |
|
|
What is the difference between edema and inflammatory edema?
|
Transudate (low in protein)
vs. Exudate (high in cells) |
|
|
What is Virchow's triangle?
|
Factors promoting thrombosis:
Endothelial injury Abnormal blood flow Hypercoagulable state |
|
|
What is a paradoxical embolus?
|
One that starts in the venous system and gets systemic (often through septal defect or PDA)
|
|
|
Why can't a group A patient get a group O organ?
|
Organ anti-A will react with patient's A antigen (like graft-vs-host)
|
|
|
What is Neonatal Alloimmune Thrombocytopenia?
|
Mother's IgG antibodies against fetal platelets
Human Platelet Antigen (HPA) 1a = most common (on GPIIIa) |
|
|
What is Hemolytic Disease of the Newborn?
|
Maternal IgG against fetal RBCs
Antigens: • A, B - mild • Kell, Duffy, Kidd, ... = severe alleles in each one • D in Rh system = most severe Rh(D-) mom with Rh(D+) baby • 15% chance of anti-D in mom each time Treat with anti-D IVIG |
|
|
Does ABO incompatibility matter in newborns receiving heart transplants?
|
NO!
Too early to produce antibodies But...may require careful monitoring, immunosuppression Don't really start making anti-A/B antibodies even after they grow up |
|
|
What are some strategies to deal with ABO incompatible organ transplants?
|
1. Donor exchanges
2. A<sub>2</sub> subgroup = milder 3. Japan method: • Remove ABO antibody • Immunosuppression • Inhibit antibody production • Monitor |
