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108 Cards in this Set
- Front
- Back
Every day mammalian cells incur over ____________ damaging events
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100,000
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What kind of damaging events happen in mammalian cells?
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Replication errors, base decay, attack by reactive oxygen species, or ionizing radiation
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What are repair pathways dependent on?
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The cell cycle (have to occur in specific sequences for them to act appropriately)
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What are enzymes relied upon to do?
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- remove unwanted or damaged components
- insert correct base(s) or sequence - reunite the phosphate backbone of the helix |
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Base Excision
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- repairs individual bases
- proofreading polymerase identifies mutation, endonuclease removes it, use opposite strand as template, DNA polymerase inserts correct base, DNA ligase ties everything back together |
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Nucleotide Excision
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Removes dimers
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Single Strand Repair
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- if no bases are missing, simple ligation of helix is made
- w/ missing bases, DNA polymerase replaces them & DNA ligase ties everything back together |
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Double Strand Repair - Homologous Recombination
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- intact sister chromatid acts as template in repair
- only time a sister chromatid is usable: after S phase, all the way through mitosis (anaphase is stopping point where fix can get done) - less mutations |
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Double Strand Repair - Nonhomologous End Joining
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- no guarantee that what we're repairing is what should've been there int he first place, no guarantee that it fixed what was lost
- can get complete deletions, translocations, or sequences than can be lost |
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Crosslink DNA Repair
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DNA strand break linked to another molecule (protein)
- lethal if not repaired |
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Mismatch DNA Repair
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- Replication errors
- Single Base --> hopefully proofreading polymerase fixes it - Small Sequence Insertions --> sometimes an entire wrong sequence is put in, becomes a question of which side is correct |
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Operational Classifications of DNA Damage - Lethal Damage
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Irreparable; cell dies
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Operational Classifications of DNA Damage - Potentially Lethal Damage (PLD)
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- damage that usually produces cell death if no repair occurs
- through repair cell has opportunity to survive - repair is highly dependent on environmental conditions |
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Operational Classifications of DNA Damage - Sublethal Damage (SLD)
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- under normal conditions repair is made (w/ ideal environment conditions)
- dependent on cell cycle phase & cell cycle synchrony |
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PLD Repair
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- if a cell goes to 1st checkpoint marker in G1 & doesn't have proper condition to go into S phase, that delay will allow more time to repair (suboptimal conditions)
- radiation therapy implications - cell survival increase |
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SLD Repair
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- repair that occurs between fractionated doses
- less time between doses = lower survival fraction (more than 2 hours = end of window for repair) - 3 Intervals: Repair, Reassortment, Repopulation |
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SLD Repair - Repair
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Occurs promptly
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SLD Repair - Reassortment
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- progression through cell cycle
- results in cell synchrony through multiple irradiation events - if it's timed appropriately, can kill off more cells (ex. tumors) |
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SLD Repair - Repopulation
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Surviving fraction divides & grows
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SLD repair mechanism is dependent upon...
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Ability to repair DSB's
- multiple DSBs are bad - purpose is to reduce formation of lethal lesions |
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Repair vs. Radiation Quality
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- dependent on amount of SLD produced
- much less recovery potential for neutrons than x-rays b/c of the difference of mass (neutrons are high LET) - in high LET there's more multiple DSBs, deletions, complete breakage of chromosomes |
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Dose-Rate Effect
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- potential for cell survivability when we take given doses & spread them over time
- as dose rate is lowered & exposure time is increased, the effect of radiation is decreased - as dose rate is decreased, curve flattens out b/c more cells start surviving |
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Acute Administration
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A single high dose rate over a short period of time; creates more damage than can be repaired
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Inverse Dose-Rate Effect
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- decreased dose-rate causes increase in cell killing
- block is implemented at G2 (radiosensitive), survivability decreases - any other dose outside the range of 1.54-0.37 Gy/hr will produce expected results |
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Brachytherapy
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- implanted low dose rate radioactive sources placed close to tumors
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Intracavity Brachytherapy
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- radioactive material actively placed within a cavity in body that will help retain material so it will interact w/ tumor
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Interstitial Brachytherapy
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- encapsulated implants into or around tumor ("wires" or "seeds")
- continuous dose of radiation over time - temporary or permanent |
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Radiolabeled Immuoglobin Therapy
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- monoclonal antibodies: labeled antibody delivers radioisotope to tumor cell
- diagnostic, therapeutic |
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Exposure to oxygen at the time of irradiation __________ (increases/decreases) the damaging effect
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Increases
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Oxygen Enhancement Ratio (OER)
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- ratio of doses administered under hypoxia to aerated conditions needed to produce the same biological effect
- effects were identified in 1940s by Gray |
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The OER is dependent on....
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LET
Low LET produce HIGHER opportunity for OER High LET produces greater damage |
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Indirect Action of Oxygen Effect
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- production of ion pairs along charged particle tracks produce free radicals
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Free Radicals
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- break chemical bonds, make chemical changes
- in presence of oxygen, these react w/ DNA |
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DNA radical can be quickly restored to normal through...
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Reaction w/ SH group
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Formation of RO2 makes damage...
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Semi-permanent (repairable only through DNA repair mechanisms)
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Hypoxic conditions _________ (enhance/reduce) RO2 production
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Reduce; less oxygen present for free radicals to combine with
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What determines hypoxia?
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Diffusion of oxygen through tissues
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Cells that are further away from oxygen source are ___________ (more likely/less likely) to be chronically hypoxic
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More likely
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Acute Hypoxia
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- occurs when blood flow is interrupted in a small blood vessel
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Chronic Hypoxia
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- causes cells to not repopulate or metabolize in the same manner
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How do tumors avoid hypoxia?
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- create their own blood supply
- structural integrity of blood vessels isn't normal (not strong enough to hold vessel open all the time) |
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Reoxygenation
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- loss of cell numbers in localized areas can lead to this
- cell killing through radiation exposure treatment reduces cell numbers to increase oxygen diffusion in tissue (aerated cells die, hypoxic cells live) - cells that survive become more radiosensitive |
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How does hypoxia play a role in tumor malignancy?
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Through the opportunity for cells to recognize that they aren't getting oxygen they need
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Linear Energy Transfer (LET)
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- energy transferred through unit length of path traveled / expression of energy put down over a certain length of path
- units = keV/μm - linear energy transfer (L) of charged particles in a medium is the quotient of dE/dl where dE = average energy locally imparted on the medium by a charged particle of specified energy in traversing a distance of dl |
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LET vs. Energy
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LET is lower between 10 MeV protons & 150 MeV protons b/c as energy increases, the potential for this proton to transmit through tissues is decreased
Going to get to a point where the energy will have less of an effect on the amount of damage done b/c they transmit all the way through |
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Relative Biological Effectiveness (RBE)
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- comparison of biological effect of different radiation types
- uses the effect of 250 keV x-rays as the standard |
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National Bureau of Standards of RBE
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The RBE of some test radiation (r) compared with x-rays is defined by the ratio
D250/Dr where D(sub)250 & Dr are, respectively, the doses of x-rays & the test radiation required for equal biological effect |
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Factors that Determine RBE
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Radiation Quality
Dose (cell survival curve) Number of dose fractions Dose Rate Biological system or endpoint |
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Neutron curve will be __________ (steeper/less steep) than an electron curve
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Steeper; less shoulder on neutron curve (energy of neutrons much higher than electrons)
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RBE _______________ (increases/decreases) with fractionation of dose
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Increases
Low LET x-rays allow for repair between doses; increases total dose required to get to that point |
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If mean lethal dose (LD50) for 250 keV x-rays is 8 Gy for an immortalized cell line & for neutrons is 4 Gy, RBE = ?
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2 (8/4)
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RBE as a Function of LET
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As LET increases beyond 10 keV/μm, RBE increases rapidly until 100 keV/μm then decreases rapidly
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What does the point at 100 keV/μm at which the ionization events are separated coincide with?
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The diameter of the DNA double helix
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Radiation Weighting Factor (WR)
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- quality factor of radiation
- used to calculate equivalent dose - convert rad to rem, Gy to Sy |
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What does the radiation weighting factor help identify?
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Amount of dose being imparted to tissues based on the LET of the radiation in question
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Acute Radiation Syndrome
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- effect of high radiation exposure received in a single dose
- shortens life span depending on the dose & chance for recovery (5% for each 100 rads) - expectation is a shortening of lifespan dose |
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Median Lethal Dose (LD50/60)
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- specifies the lethal effect of radiation
- dose will cause 50% of the population to die within 60 days |
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Immediately lethal doses cause death prior to how long?
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60 days
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LD50/60 is influenced by...
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Health, presence of bacteria, age, sex, environment
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3 Pathologic Processes caused by Radiation
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1) Necrosis/cell death
2) Hemorrhage 3) Infection |
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Necrosis
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- occurs in most radiosensitive cells/tissues (lymph nodes, bone marrow, gonads, GI epithelium, skin)
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Hemorrhage
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- occurs mainly due to suppression of platelet formation
- damage to capillary walls is also evident which allows bleeding into other tissues ex. skin (petechia), GI tract, respiratory system |
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Infection
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- lack of body defense system
- occurs due to: loss of lymphocytes, immune system suppression, cell death, hemorrhage, anemia |
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What are the 4 whole body syndrome stages?
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Prodromal Stage, Latent Stage, Manifest Sage, Recovery or Death Stage
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Prodromal Stage
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- happens right after dose is taken away
- Symptoms: malaise, nausea/vomiting (higher doses), fright |
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Latent Stage
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- body seems to recover from exposure, won't exhibit any symptoms
- may last hours to days to weeks |
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Manifest Stage
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- S&S of syndrome will be manifested
- progression of symptoms will occur - at higher levels the symptoms of more than 1 syndrome may be apparent |
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Recovery or Death Stage
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- dependent on 2 things: total exposure (REM) & treatment availability
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Subclinical Syndrome
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- occurs in ranges of 50-200ad (0.5-2 Gy)
- only PRODROMAL stage occurs - less than 25 rads = no effect - 20-100 Rad effects will occur in production of leukocytes |
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Hematopoietic Syndrome
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- exposure ranges 250-500 Rad (2-5 Gy)
- death 2-3 weeks or up to 2 months |
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Hematopoietic Syndrome - Prodromal Stage
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- can last 2 hours to 2 days
- nausea |
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Hematopoietic Syndrome - Latent Stage
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- bone marrow & lymph nodes depleted of cells
- anemia occurs b/c of loss of RBC precursors |
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Hematopoietic Syndrome - Manifest Stage
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- sore throat, fever, malaise, diarrhea
- LD50/60 is at 400 Rad exposure level - have opportunity w/ good health care to overcome |
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GI Syndrome
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- whole body exposures from 600-1000 R
- average survival = 6 days |
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GI Syndrome - Prodromal Stage
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- occurs within hours
- watery diarrhea |
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GI Syndrome - Latent Stage
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- may or may not occur depending on exposure dose (higher dose = less likely to occur)
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GI Syndrome - Manifest Stage
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- may come directly here from prodromal
- S/S: nausea, vomiting, prostration & elevated body temp - epithelium of bowel lining flakes off & is removed - death within 2 weeks w/ no treatment |
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CNS Syndrome
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- very high exposures, 1000+ R
- onset of nausea & vomiting within minutes - convulsions, brain edema happen due to cerebellum cell damage - death within a few days |
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Delayed Radiation Effects - Deterministic Effects
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- threshold is seen
- increased dose increases severity of effect |
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Delayed Radiation Effects - Stochastic Effects
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- non-threshold
- increased dose increases probability of effect - can appear to occur randomly within a population |
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Sigmoid Dose-Response Curve
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- applies to most patients having radiation therapy
- characterized by S-shaped curve - starts out w/ no effect until a certain dose is reached, then trends upward; will peak & effect will decline (even as dose is increased) |
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Why does the effect decline as dose is increased on the Sigmoid Dose-Response Curve?
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Because at a certain point, we'll get to a quantity of dose where patients start dying
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Characteristics of Sigmoid Dose Response Curve
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Has dose-rate effect, has threshold, has deterministic effect
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Dose-Response Carcinogenesis
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- proposed by Gray who said that radiation-induced malignancy produces a bell shaped curve
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Linear Dose-Response Curve
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- ALL DOSES HAVE AN EFFECT
- most accepted version of application of radiation w/ expected effects - |
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What is the linear dose-response curve used to estimate?
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Upper limit effects, genetic effects, leukemia, & radiation induced cancers
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Damage itself may not be seen, but there is an expectation of...
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Damage occurring
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Characteristics of Linear Dose-Response Curves
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- no threshold (see effect as soon as dose applied)
- response is proportional to dose - no dose-rate effects - stochastic effects |
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Linear-Quadratic Dose-Response Curve
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- sharp contrast between effects of doses at high vs. low level
- high level doses have a quadratic (squared) response - low level doses have a linear relationship |
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Characteristics of Linear-Quadratic Dose-Response Curves
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- no threshold
- low exposures = linear, high exposures = quadratic - stochastic effects |
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Carcinogenesis
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- increased frequency in exposed population
- stochastic effect (not everyone in population will get cancer) - long latent periods for solid tumors |
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What sources of human data have been used for radiation effects?
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Occupational exposure, atomic bomb survivors, medical exposure, fallout accidents in Pacific testing grounds
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Typical study performed to determine Radiation Induced Cancer Incidence
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- control group = general population (expected incidence of cancer)
- experimental group = irradiated population (incidence of cancer) - calculating the irradiated population risk factor & expressing it as a rate Rate = # of cancer cases/# exposed people (yr/rem) |
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Problems with studies performed to determine Radiation Induced Cancer Incidence
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- no 2 health statuses are alike in experimental group
- number of people in general population w/ cancer compared to the total number of people in population is small fraction |
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What are the most common carcinogenic effects of radiation?
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Leukemia, Breast / Thyroid / Lung / Bone / Stomach Cancer
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Breast Cancer (Carcinogenic Effects of Radiation)
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- Life Span Study: Hiroshima Survivors
- Nova Scotia & Massachusetts Studies (induced pneumothorax & fluoro) - Rochester Study (acute postpartum mastitis w/ fluoro) |
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Skin Cancer (Carcinogenic Effects of Radiation)
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- occurred in physicians & dentists holding patients during x-ray exposures
- usually either basal cell or squamous cell carcinoma (basal cell 4x more likely) |
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Bone Cancer (Carcinogenic Effects of Radiation)
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- found in radium watch dial painters; ingested radium, which deposited into bone
- children treated for tinea capitis (fungal infection of skin) |
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Liver Cancer (Carcinogenic Effects of Radiation)
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- thorotrast: contrast agent that contained thorium used for liver radiography & angiography
- patients have shown increased incidence of cancer - caused by alpha particles released as thorium decayed |
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Lung Cancer (Carcinogenic Effects of Radiation)
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- uranium miners inhaled radon gas & radioactive dust; high incidence of cancer in bronchial epithelium (higher than atomic bomb survivors)
- 8x more likely to have cancer from job; 20x more if they also smoke |
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Leukemia (Carcinogenic Effects of Radiation)
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- seen in Japanese atomic bomb survivors
- Ankylosing Spondylitis (used x-rays to treat, 12x higher rate of leukemia) |
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Thyroid Cancer (Carcinogenic Effects of Radiation)
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- radiation therapy for thymus enlargement
- sometimes have 10 year latent period - non-aggressive cancer |
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Radiation Therapy Induced Carcinogenesis
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- secondary malignancies produced from exposure from treatment
- factors such as lifestyle & age have a higher chance of causing additional malignancies |
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Who are at highest risk for radiation induced cancer?
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Nuclear industry workers, radiologists (used to be), children in utero
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Life Span Shortening
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- stochastic & non-specific shortened lifespan a result of other specific causes
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Theories on Life Span Shortening
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1) Radiation will cause normal aging at a faster rate
2) Radiation will cause an individual to be more sensitive to specific diseases 3) Life span shortening is due to point mutations of the genes & chromosomal rearrangements |
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Radiation Hormesis
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- frequent low level radiation exposure produces a protective effect (school of thought)
- impact it has on cell/DNA repair mechanism |
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Decreasing Incidence of Radiation Induced Cancer
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- increased knowledge of effects of radiation
- strict regulations - radiation no longer utilized as treatment for everything |