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SPM (ARSH) > PBL > Flashcards

PBL Flashcards

1
Q

What is the inheritance pattern of cystic fibrosis?

A

autosomal recessive

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2
Q

What chromosome is the CFTR gene located on?

What is the most common mutation and what does it lead to?

A
  • Genetic Mutation: CFTR gene located at chromosome 7
    • Most Common Mutation: delF508, which is deletion of phenylalanine at 508-position
    • Leads to misfolding and degradation
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3
Q

What is the epidemiology of cystic fibrosis?

  • Which two populations have the highest incidence?
  • What disease is present in high incidence populations?
A
  • Epidemiology: Ashkenazi Jewish has highest (1/24), followed by Whites.
    • High presence of cholera in high incidence populations. With half functional CFTR you do not die from dehydration when infected with cholera because of the ability to retain more chloride ions & therefore water than those who are not carriers.
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4
Q

What are the limitations of genetic screening exams?

A
  • Limitations of Genetic Screening Tests for CF: multiple mutations, all of which are not deleterious
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5
Q

What does the CFTR gene encode for?

What is the role of the CFTR protein in epithelial cells?

A
  • CFTR is a chloride channel located on the apical membrane of epithelial cells of different organ systems
  • Mucous lubricates lining of airways, digestive system, reproductive tract, etc.
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6
Q

How does a normal CFTR protein function biochemically?

A
  • Normal CFTR: increases the secretion of chloride ion via active transport and reduces the passive reabsorption of sodium ions “via regulation of epithelial Na channel”
    • CFTR has direct inhibition of the Na channel → with chloride efflux, Cl- ions negatively inhibits sodium influx
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7
Q

How does a mutated CFTR protein function biochemically at the membrane?

A
  • Mutated CFTR: decreases the secretion of chloride ion and augments the reabsorption of sodium ion (with passive water reabsorption)
    • Hyperconcentrated, “dehydrated” mucous
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8
Q

How do defects in CFTR proteins translate to dysfunction in sweat glands?

A
  • CFTR actively transports chloride ions out of sweat gland lumen into surrounding tissue
  • In sweat, sodium follows chloride ions out of the sweat gland lumen
  • Improper CFTR leads to increased NaCl released out of sweat gland lumen onto skin
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9
Q

How do defects in CFTR proteins translate to dysfunction in intestines/pancreas/lungs?

A
  • Mutated CFTR channels → chloride is not actively transported into the lumen → ENaC (sodium channel) is not negatively inhibited → increased sodium reabsorption → increased water reabsorption → dehydrated mucous layer of lumen (muconeum ileus – obstruction of small intestines in neonates)
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10
Q

How does the sweat chloride test determine the presence of cystic fibrosis?

A
  • Cl- conductance is virtually abolished because CFTR is the only outlet for chloride.
  • When Na+ attempts to flow out of a CF duct through remaining sodium-selective pathways, it is unaccompanied by Cl- and so it creates an excess of negative charge in the duct that attracts Na+ and prevents its further absorption.
  • The net result is that very little NaCl is reabsorbed, resulting in a high salt content in CF sweat.
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11
Q

What defects and symptoms occur in the respiratory tract due to CFTR dysfunction?

A
  • thick and sticky mucous (assoc. with CF) clogs the tubes that moves air in and out of your lungs
    • Symptoms: wheezing, breathlessness, lung infections
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12
Q

What defects and symptoms occur in the pancreas due to CFTR dysfunction?

A
  • Pancreatic Insufficiency: The thick mucus can also block tubes that carry digestive enzymes from your pancreas to your small intestine. Without these digestive enzymes, your intestines aren’t able to completely absorb the nutrients in the food you eat.
    • Symptoms: failure to thrive, CFRD (CF related diabetes)
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13
Q

What defects and symptoms occur in the reproductive system due to CFTR dysfunction?

A
  • Reproductive System: vas deferens and fallopian tubes filled with thick mucous
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14
Q

What are three multi-organ system based treatments for cystic fibrosis?

A
  • Enzymes to allow for digestion of food
  • Shaking Vest to breakup mucous in lungs for easier breathing
  • Antibiotics to fight off infections caused by ineffective mucous
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15
Q

What are the six classes of CFTR mutations, their functional consequences, and their treatments?

A
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17
Q

What is the inheritance pattern of G6PD deficiency and what are some causes of genetic selectivity?

A
  • Inheritance pattern: X-linked recessive
    • Males are hemizygous – one mutant gene leads to full blown deficiency
    • Females are mosaic – x-link deactivation leads to differing levels of deficiency
  • Causes of Genetic Selectivity: Carriers offer resistance to a deadly form of malaria called plasmodium falciparum
    • Falciparum targets mature red blood cells
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18
Q

What are some of the most common mutations associated with G6PD deficiency that may alter protein structure/enzyme activity?

A
  • Missense point mutations (change in one nucleotide that could alter AA) at Xq48
  • Most abnormal alleles result in a functionally normal enzyme but have a shortened life span within the red cell
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19
Q

What is the role of G6PD in the hexose monophosphate shunt pathway and how can oxidative stress tip the balance of NADP-NADPH in the erythrocyte?

A
  • G6PD oxidizes G6P while reducing NADP+ to NADPH
  • NADPH can then reduce oxidized glutathione, in order to reduce H2O2
  • G6PD is involved in the only pathway in RBCs that can reduce oxidants
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20
Q

In the G6PD case, oxidative stress was caused by…

A

Oxidative stress is caused by…

  • Fava beans
  • Bactrim (has a FR, which oxidizes GSH back to GSSG)
  • Severe infections
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21
Q

What are the consequences of oxidative stress (think the G6PD case)?

A
  • Oxidizes Fe2+ to Fe3+, changing hemoglobin to methemoglobin, which cannot bind O2
  • Denatures cytosolic and membrane proteins → hemolysis → heme breakdown → bilirubin (toxic) → juandice
  • Denatured hemoglobin → Heinz’s bodies → Bite cells after macrophages eat Heinz’s bodies
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22
Q

Explain how the imbalance between NADP-NADPH causes hemolysis. How does jaudice come from this?

A
  • Decreased [NADPH] → decreased [GSH] → increased [ROS] → oxidation of Fe2+ to Fe3+ → hemoglobin converted to methemoglobin → increased [ROS] denatures cytosolic and membrane proteins → hemolysis → hemoglobin breakdown → heme exposed → porphorin ring exposed → formation of bilirubin (toxic) → increased blood [bilirubin] → juandice
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23
Q

What is the structure of hemoglobin and some characteristics?

A
  • Hemoglobin
    • Tetramer – each monomer is called globin
    • Each monomer has a heme center that holds Fe2+ that binds an O2 molecule to transport to tissues
    • Cooperative binding – when one O2 binds to one globin, binding affinity increases for other globins
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24
Q

Relate the concepts of oxygen saturation, partial pressure of oxygen and the hemoglobin-oxygen dissociation curve.

  • What factors affect the oxygen binding cuve and how does it move?
A
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25
Q

What is the interrelation of Fe2+ and Fe3+?

A
  • Interrelation of Fe2+ and Fe3+
    • Fe2+ is oxidized to Fe3+ → hemoglobin is converted to methemoglobin → can no longer bind oxygen
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27
Q

Describe four factors that can acutely change in a patient that will alter a drug’s volume of distribution and clearance.

A
  • Dehydration – affects filtration rate of blood → less drug is filtered out
  • The metabolism rates
    • Children have an increase in metabolism, resulting in higher drug metabolism
    • The elderly are affected due to diminished cellular function, receptor function and drug elimination difficulty.
  • Renal Function affects the drug clearance and reabsorption.
  • Liver diseases affect the biotransformations and absorption.
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28
Q

What are the steps of a normal NMJ?

A

Steps of Normal NMJ

  1. Depolarization of pre-synaptic nerve
  2. Voltage-gated Ca++ channels open at synapse
  3. Ca++ dependent vesicle binding
  4. Neurotransmitter (ACh) release
  5. Two ACh molecules bind to post-synaptic receptor (MuSK clusters AChR to post-synaptic membrane)
  6. Receptor opens allowing Na+ to flow into cell
  7. Depolarization of post-synaptic muscle
  8. Acetyl-cholinesterase terminates response
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29
Q

What are two problems that can occur at the NMJ in myasthenia gravis?

A
  • Antibody binds to AChR → diminished end plate potential
    • Binding – antibodies may initiate an inflammatory reaction that destroys them
    • Blocking – antibodies prevent acetylcholine from binding to active site
    • Modulating – increased endocytosis of receptor
  • Antibody binds to MuSKR → diminished end plate potential
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30
Q

What makes diagnosing myasthenia gravis so challenging?

A
  • Complaints are non-specific (i.e. tiredness, weakness)
  • Other treatable conditions closely resemble MG
  • Difficult to catch early due to slow progression of disease
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31
Q

What are the mechanisms of the three main tests used to diagnose myasthenia gravis?

A
  • Injection of Edrephorium– inhibits Acetyl cholinesterase → increase in ACh activity
    • Tensilon Test bad because it was non-specific acetyl cholinesterase inhibitor, causing heart arrhythmias (atropine is required to reverse effects)
  • Nerve Stimulation Test – consistent nerve stimulation leads to decreased and delayed nerve response
    • Amplitude of response remains same in normal individuals
  • Serum AChR-AB Assay Blood Test – checks for AChR ABs are present
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32
Q

What is the relationship between the thymus gland and myasthenia gravis?

A
  • Thymus is the site of production for helper T-cells, which help stimulate the B-cells that produce antibodies against the ACh receptor.
  • Thymus cells are the only known cells to express intact AChR outside of muscle.
    • These can be recognized as foreign and can start an autoimmune response to AChR throughout the body.
  • Thymoma can lead to an overexpression of certain antibodies by causing an infiltration of more B cells
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33
Q

What are the four main treatments for myasthenia gravis?

A
  • Predisone: immunosuppressant
  • Pyridostigmine: AchE inhibitor
  • Azothioprine: immunosuppressant
  • IVIG: non-specific immunoglobin that boosts immunity by attacking ABs and foreign objects
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34
Q

What is the cellular mechanism of glucose transport from the gut to the pancreas?

A
  • From Gut to Pancreas: Carbs are broken into monosaccharides → glucose → transported to SGLT2 on the apical surface from lumen to cell (Na+/Glucose transporter with NaATPase maintaining gradient) → GLUT2 on basolateral surface from cell to blood → blood → to pancreas
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35
Q

What is the cellular mechanism of glucose transport from the pancreas in beta cells?

A
  • From Pancreas: GLUT-2 transporters bring glucose into pancreatic B-cells → metabolized to produce ATP via aerobic respiration → increase in [ATP] closes ATP-sensitive K+ channels → cell depolarization → voltage-gated Ca2+ channels open → Ca2+ triggers the release of insulin → tyrosine kinase receptors
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36
Q

What is the cellular mechanism of insulin trysoine kinase receptors in the periphery?

A
  • From Tyrosine Kinase Receptors in Periphery: increase in blood [insulin] → insulin binds to tyrosine kinase receptor → cross-phosphorylation of dimer → tyrosine kinase receptor recruits GLUT4 in skeletal tissue to PM → GLUT4 allows passive diffusion of glucose into cell
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37
Q

What is the interplay of insulin and glucagon secretion, how does the regulation work, and what are the tissue recceptor sites?

A

Liver

  • Fed State (Insulin from beta cells)
    • Increase Glycolysis
    • Increase Glycogen synthesis
    • Increase Cholesterol synthesis
    • Increase fatty acid synthesis
    • Increase triglyceride synthesis
    • Inhibits glycogenolysis
    • Inhibits gluconeogenesis
  • Fasted State (Glucagon from alpha cells)​
    • Increase gluconeogenesis
    • Increase glycogenolysis
    • Increase ketogenesis
    • Increase amino acid breakdown

Adipose

  • Fed State (Insulin from beta cells)
    • Increase triglyceride synthesis
    • Decrease lipolysis
  • Fasted State (Glucagon from alpha cells)
    • ​Increase lipolysis via beta-oxidation

Skeletal Muscle

  • Fed State (Insulin from beta cells)
    • Increase protein synthesis
    • Increase glycogen synthesis
    • Inhibits proteolysis
    • Inhibits glycogenolysis

Fasted State (Glucagon from alpha cells)

  • Glucagon has no effect on skeletal muscle
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38
Q

What is the epidemiology of diabetes mellitus II?

A
  • Epidemiology: thrifty gene hypothesis that genes for fat deposition were advantageous when we were hunter/gathers
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39
Q

What are three risk factors of diabetes mellitus type 2?

A
  • Inheritance Factors: some genetic component that makes some individuals more insulin insensitive
  • Behavioral Factors: eating habits, exercise habits
  • Environmental Factors: socioeconomic status
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40
Q

Define diabetes and list the criteria required to diagnose diabetes mellitus and pre-diabetes?

A
  • Diabetes Mellitus – “sweet urine”
  • Criteria to Diagnosis:

DMII

  • Fasting Glucose: > 126 mg/dL
  • Glucose-Tolerance Test: > 200 mg/dL
  • A1C: > 6.5%

Pre-Diabetes

  • Fasting Glucose: 115-125 mg/dL
  • Glucose-Tolerance Test: 140-199 mg/dL
  • A1C: 5.6-6.5%
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41
Q

What is the mechanism of deregulated glucose homeostasis that leads to diabetes mellitus type 2?

  • Consider: insulin deficiency, insulin resistance, metabolic responses to eating and glucose toxicity
A
  • Decreased insulin sensitivity → decreased glucose reuptake → increased blood glucose → increased beta-cell secretion of insulin → increased lipid/cholesterol synthesis → increased fat deposition on VAT (visceral adipose tissue) on organs
    • For example, increased fat deposition on heart causes increase in HR and BP
    • Fat deposition on VAT instead of SAT (subcutaneous adipose tissue)
  • After years of increased insulin secretion, cells lose sensitivity to insulin becoming insulin resistant exacerbates cycle
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42
Q

What is the metabolic syndrome and what are the health consequences of it?

A

Group of conditions that increase your risk of heart attack and stroke. Chronic state of inflammation:

  • High blood pressure
  • High blood sugar
  • Excess body fat around the waist
  • Abnormal cholesterol and triglyceride levels
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43
Q

What are the seven symptoms of hyperglycemia and what are their mechanisms?

A
  • Polyphagia (increased hunger): glucose is unable to enter the cells
  • Polydipsia (increased thirst): result of dehydration from polyuria
  • Polyuria (increased urination): increased blood glucose causes osmotic diuresis
  • Weight loss resulting from dehydration and proteolysis
  • Blurred vision: water is drawn out from eye
  • Chronic fatigue due to lack of cells ability to uptake and use glucose
  • Acanthosis nigricans: increase in circulating insulin results in increase in IGF which results in increased keratinocyte and fibroblast proliferation which results ultimately in increased melanin
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44
Q

What is the Class/Action/Side Effects/Elimination/Drug Interactions of Metformin?

A
  • Class: Biguanide
  • Mechanism of Action: decreases hepatic glucose production by activation of AMPK leading to more GLUT4 going to cell surface, decreases glucose absorption from intestines, increases insulin sensitivity
  • Side Effects: Not good for people with liver damage, lactic acidosis, hypoglycemia
  • Elimination: Renally
  • Drug Interactions: Other renally eliminated drugs
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45
Q

What is the Class/Action/Side Effects/Elimination/Drug Interactions of Glipizide?

A
  • Class: Sulfonylurea
  • Mechanism of Action: Increase insulin release from beta cells by binding to K+ channels, causing depolarization of the cell, opening of Ca2+ gated ion channels, Ca2+ influx, release of insulin into blood
  • Side Effects: Can cause hypoglycemia because lowers hepatic glucose production
  • Elimination: Hepatic biotransformation, urine and feces
  • Drug interactions: Diuretics
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46
Q

What are the major steps in the biosynthesis of cholesterol?

A
  1. AAs, FAs, Glucose → Acetyl CoA
  2. Acetyl CoA → HMG-CoA
  3. HMG-CoA → Mevalonate via HMG-CoA Reductase
  4. Mevalonate →→ Cholesterol
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47
Q

What is the major regulatory step in the biosyntheis of cholesterol?

A

HMG-CoA Reductase Is Rate-Limiting Step of Cholesterol Synthesis

  • Inhibited by: high cholesterol, phosphorylation of AMP dependent-kinase (senses high [AMP], glucagon, epinephrine, statin (HMG-CoA Reductase is phosphorylated)
  • Stimulated by: insulin
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48
Q

Disciss how the SCAP/SCREBP/INSIG complex regulates cholesterol levels.

A
  • High [cholesterol] → SCAP (SREBP cleavage-activating protein) binds to cholesterol, SREBP (sterol regulatory element binding protein), and an INSIG protein at the ER Membrane → inactive state
  • Low [cholesterol] → SCAP (SREBP cleavage-activating protein) and SREBP (sterol regulatory element binding protein) complex unbind from the INSIG protein at the ER Membrane → SCAP/SREBP transported to Golgi → SREBP is cleaved by S1P and S2P (two proteases) at two different locations, resulting in transcription factor → transcription factor travels to nucleus → increase in cholesterol synthesis
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49
Q

Describe the processes that lead to cholesterol turnover and elimination from the body, including the role of bile acids.

A
  1. Fats ingested
  2. Bile salts emulsify fats, forming micelles
  3. Intestinal lipases degrade triacylglycerols into glycerol and free FAs
  4. Free FAs taken up by mucosa and converted back into triacylglycerols in intestinal epithelial cells
  5. Triacylglycerols, cholesterol, and apolipoproteins form chylomicrons
  6. Chylomicrons move through lymphatic system and bloodstream to tissues
  7. Lipoprotein lipases is activated by apoC-II in capillaries releases FAs and glycerol
  8. FAs enter cells
  9. FAs are oxidized as fuel or converted back to triglycerides for storage
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50
Q

What are the two transport mechanisms and what major liproteins are included in each one?

  • Describe the role of each lipoprotein
A

Delivery Transport Mechanism (ApoB containing lipoproteins)

  • Chylomicrons (biggest and highest [lipid])
    • Can go to the liver – directly drop off FFAs for energy use or membrane rigidity
    • Can go to the adipose – directly drop off FFAs for storage and then chylomicron remnants go to liver for recycling
  • VLDL
  • IDL
  • LDL
    • ApoB containing lipoproteins slowly give away their FFAs to cells and get denser and denser

Reverse Cholesterol Transport (ApoA1 containing lipoproteins)

  • HDL (smallest and highest [protein])
    • Picks up ApoB proteins that dissociated
    • Interacts with ApoB containing lipoproteins to exchange its cholesterol for TAGs
    • HDL is returned to the liver
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51
Q

What is the role of oxidized LDL in the formation of arthersclerosis?

A
  • LDL leaks between endothelial cells into the wall of the artery → LDL contents (TG, cholesterol) become oxidized → monocytes migrate into wall to clear the oxidized LDL → oxidation of macrophage → macrophage becomes a foam cell → attract more monocytes → creates fatty streaks → inflammatory response → cells pushed into lumen → increase in blood pressure
  • Foam cells also release IGF → migration of smooth muscle cells from media layer to intima layer → produce collagen → plaque (fibrous cap) → loss of elasticity
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52
Q

What are two therpaies/drugs used to lower blood cholesterol?

A

Statins and Evolocumab

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53
Q

What is the Class/Action/Side Effects/Elimination/Drug Interactions of Statins?

A
  • Class: Statin
  • Action: HMG-CoA reductase inhibitor (competitive) in cholesterol synthesis pathway.
  • Side effects: mevalonate derivatives will also be decreased (quinones), rhabdomyolysis (muscle degradation), hepatic failure (low enzymes), renal dysfunction due to proteinuria
  • Elimination: Liver, modified in liver by CYPs, renal excretion
  • Drug interactions: CYP inhibitors (slow breakdown), lipid-lowering drugs
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54
Q

Draw the Urea Cycle and define what its function is.

A
  • Definition of Urea Cycle: Method of excreting urea, a metabolite of protein catabolism.
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55
Q

What are the possible enzyme defects that occur in the urea cycle?

List:

  • Disorders are associated with them
  • Where the enzyme is located
  • What product accumulates
A
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56
Q

How does evolocumab function to reduce cholesterol?

A
  • Taken in conjunction with statin
  • PCSK 9 normally binds to LDL receptor and degrades the receptor. Evolocumab actively binds to PCSK 9, increasing the number of LDL receptors. More LDL is taken from the blood into the liver. Therefore, LDL and cholesterol levels decrease.
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57
Q

What are the ACC/AHA CV Risk guidelines to assess coronary heart disease?

A

How to calculate ACC/AHA CV Risk

  • Variety of factors to predict risk in the next 10 years
  • Age, gender, race, history of hypertension, smoking, diabetes, current BP, total cholesterol, HDL level, BMI
  • Plug factors into calculator to give percentage
  • Treatment recommended for greater than 10% with statin
  • Only accurate for people between 40-80 yo and total cholesterol of 320 or more.
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60
Q

What occurs to the urea cycle during times of starvation (negative nitrogen balance)?

A
  • Starvation/fasting → protein catabolism → amino acid degradation → elevated ketones and ammonia
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61
Q

What regulates the urea cycle and what acts as the rate-limiting step?

A
  • Regulation: N-acetylglutamate is an allosteric activator of carbamoyl phosphate synthase
  • Rate-Limiting Step: carbamoyl phosphate synthase
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62
Q

What are the physiological consequences associated with hyperammonemia and what symptoms are associated with these symptoms?

A
  • Excess ammonia → converts alpha-KG to glutamate → glutamate to glutamine → depletes alpha-KG → inhibition of TCA cycle
  • Leading to symptoms of lethargy (inhibition of TCA), vomiting (toxicity), seizure (NMDA activation by glutamate), cerebral edema (excess glutamate changes osmolality differences across BBB)
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63
Q

What are the two sources of ammonia in the blood?

A
  1. Protein Catabolism
  2. Gut Bacteria
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64
Q

What are the six different treatments associated with the urea cycle and with what enzymes do they correlate (if they do)?

A
  • Hemodialysis:
    • Removes all the ammonia in the blood
  • Low-Protein Diet
    • Any enzyme deficiency requires a low-protein diet because protein catabolism produces ammonia
  • L-Arginine
    • Arginosuccinase deficiency - L-arginine bypasses the arginosuccinase step and allows for the urea cycle to produce urea and then pick up new NH3 to excrete as argininosuccinate
  • Glucose
    • Ensures that the patient does not starve.
  • Sodium Benzoate/Sodium Phenylacetate
    • Provides a method of excretion for high ammonium levels
  • Liver Transplant
    • Provides normal enzymes for urea cycle
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65
Q

What are the four ethical considerations for newborn screening?

A
  • Reliable diagnostic test
  • Treatments are available
  • Early interventions have positive effects
  • All tests can be avoided on religious basis
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66
Q

What is the general pathway of the BCKD complex and what metabolites are formed?

A
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67
Q

What are the six state mandated newborn screening tests?

A
  1. Congenital adrenal hyperplasia (CAH)
  2. Galactosemia
  3. Hemoglobin diseases
  4. Maple syrup urine disease (MSUD)
  5. Phenylketonuria (PKU)
  6. Primary congenital hypothyroidism
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68
Q

What are the two routes that convert methemoglobin to hemoglobin?

A
  • Two Routes of Converting Methemoglobin to Hemoglobin
    • Cytochrome b5 Reductase: uses NADH produced from glycolysis
    • Methemoglobin Reductase: converts methylene blue to leukomethylene blue using NADPH → leukomethylene blue reduces Fe3+ back to Fe2+
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69
Q

How is the BCKD regulated?

A
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70
Q

What is the general mechanism of the BCKD complex or any other dehydrogenase complex?

A
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71
Q

Where is the branched-chain ketoacid dehydrogenase found?

A
  • BCKD complex is found in the inner membrane of the mitochondria
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72
Q

What are the branched chain amino acids and what pathway to their metabolites feed into?

A

3 BCAAs (L, I, V - essential) → ketoacids → metabolites of TCA cycle

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74
Q

What are the four classes of amino acids mutations and where do the mutations occur?

A
  • “Classic” MSUD (Class 1a): Mutation in gene encoding for E1 alpha subunit
  • “Intermittent” MSUD (Class 1b): Mutation in gene encoding for E1 alpha subunit
  • “Thiamine responsive” MSUD (Class 2): Mutation in gene encoding for E2
  • Class 3: Mutation in gene encoding for E3
    • Extremely rare
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75
Q

What cofactors does the BCKD utilize?

A
  • Utilizes 5 cofactors
    • Tender Loving Care For Nancy
      • TPP (B1 – thiamin)
      • Lipoic Acid
      • FAD (B2 - Ribloflavin)
      • NAD+ (B3 - Niacin)
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78
Q

How is Hardy-Weinberg used to calculate carrier frequencies in local Mennonite populations and the population at large?

A
  • Mennonite Population
    • p2 + 2pq + q2 = 1
    • q2 = 1/176 q = 0.0754
    • p + q = 1 p = 1 – 0.0754 = 0.9256
    • Carrier Frequency = 2pq = 13.9%
  • Population at Large
    • p2 + 2pq + q2 = 1
    • q2 = 1/185000 q = 0.00232
    • p + q = 1 p = 1 – 0.00232 = 0.998
    • Carrier Frequency = 2pq = 0.46%
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79
Q

What is the founder effect - colony effect?

A
  • Decreased genetic variation due to lack of reproduction outside of a particular community
  • All members have roots in the same small group of ancestors
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80
Q

What is the newborn screening used for MSUD?

A
  • (+) newborn screening using tandem mass spectrometry-based amino acid profiling…
    • Confirmed with:
      • Quantitative plasma concentration amino acid analysis to rule out hydroxyprolinemia
      • GC/MS - on urine samples detects presence of BCKAs
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81
Q

What are the clinical presentations of MSUD?

A
  • Initial Presentation in an infant
    • increased sweet-smelling ear wax within 12-24 hours
    • Sweet Smelling urine within 5-7 days
  • Lethargy - vomiting - decreased oral intake - ataxia -
  • Urine with a syrup odor (sotolone)
  • Ketoacidosis - keto-acid buildup
  • Neuro Sx: developmental delay and cerebral edema
    • Particularly due to Leucine toxicity; Leu can cross BBB
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82
Q

What are the treatments associated with MSUD?

A
  • Special diet of purified amino acids (limit the ones he cannot breakdown but enough for proper growth and development)
    • Goals: reduce toxic metabolites; achieve plasma concentrations of branched-chain amino acids, especially leucine; support normal growth; and preserve intellectual function and development.
  • Thiamine (50 to 200 mg/day) should be given for four weeks to all patients with MSUD
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83
Q

What may exacerbate MSUD symptoms?

A
  • Any additional stress on the body leads to protein degradation and in turn a build up of the branched amino acids due to the deficiency of the BCKAD enzyme. Stressors include but not limited to:
    • Infection
    • Trauma
    • Surgery
    • Extended fasting
    • Strenuous exercise
    • Failure to adhere to diet
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84
Q

Define Collagen.

Describe the 4 types?

A
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86
Q

Describe the compostion of collagen.

A

Repeating sequence -GLY-X-Y- (X mainly proline, and Y mainly hydroxyproline)

3 alpha helices in triple helix

Every third amino acid should be a glycine

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87
Q

What are some important structural feature of collagen?

Think H-bonds.

A

Proline important for hydroxylation → forms H-bonds → strengthens collagen structure

Hydrogen bonds between hydroxyl groups on external amino groups are weakened due to kink

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88
Q

What happens if a glycine in a collagen strucutre is substituted for another AA?

A

Substitution of glycine for another amino acid creates a kink in structure → unfolded protein (this is due to the relative flexibility of glycine when compared to other AAs)

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89
Q

Steps (7) of post translational modifications of collagen?

A

Translation of mRNA creates prepro-a-chains on RER

Steps of Post-Translational Modifications

  1. Hydroxylation: Proline and lysine can be hydroxylated, requiring O2, Fe2+, and Vitamin C).
    1. Enzyme: lysyl hydroxylase
  2. Glycosylation: Hydroxyl group of the hydroxylysine can be glycosylated, attaching glucose and galactose (ER)
  3. Assembly: Formation of the triple helix with H-bonds and disulfide bonds, forming procollagen (ER)
  4. Exocytosis: Procollagen moves through the Golgi and packaged into secretory vesicles, which is secreted into the ECM
  5. Proteolysis: specific procollagen peptidases cleave N and C terminus with disulfide bridge by N- and C-procollagen peptidases, making tropocollagen (insoluble)
  6. Cross-Link Formation: Lysine and hydroxylysine covalently bond, forming staggered tropocollagen molecules making fibrils
    1. Enzyme: lysyl oxidase

Formation of Fibers: Inter cross-links between fibrils form collagen fibers.

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90
Q

Describe the role of vitamins in collagen formation.

A

Vitamin C

  • Necessary for lysyl hydroxylase/prolyl hydroxylase.
  • Deficiency causes anemia due to poor blood vessel formation (collagen is necessary for vessels)

Copper

  • Necessary for lysyl oxidase
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91
Q

What is the most common unheritance pattern for OI?

What gene is mutated?

What are some less common genes involved with OI?

A

Most common gene affected in OI

  • Autosomal dominant mutation in COL1A1 or COL1A2 affecting alpha chains of type I collagen
  • Autosomal dominant Gly to Val mutation hinders proper triple helix formation in ½ of the procollagen. This consequentially leads to the unfolding of procollagen and a significant decrease in type 1 collagen within bone.

Other autosomal recessive gene mutations can occur that affect the hydroxylases, oxidases and folding machinery

  • CRTAP
  • LEPRE1
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92
Q

What are some example of collagen diseases that are not OI?

A
  • Ehler’s Danlos - collagen type 3 (1 and 5 may also be affected); stretchy skin; problem with crosslinking; most affected - skin, gi, blood vessels.
  • Marfan’s Syndrome - tall, thin, large bones. Defect in fibrillin 1. Major risks - mitral valve prolapse, aortic aneurysm
  • Epidermolysis Bullosa - dermis and epidermis are not linked together, lots of tearing and blistering.
93
Q

Discuss how DNA testing is used to confirm an OI diagnosis.

A

DNA testing shows mutations in COLA1 and COLA2 genes

94
Q

Describe the treatments available for OI.

A
  • Goal: Reduce fractures and pain and maximize mobility (physical therapy)
  • Cure: None
  • Bisphosphonates: Inhibit osteoclastic bone resorption by attaching to the hydroxyapatitte binding sites on bony surfaces, especially those undergoing active resorption.
  • Hormonal Therapies (Teriparatide): PTH (takes Ca from bone and other sources to increase serum Ca levels) intermittent exposure leads to increased bone formation
  • Supplementation: Vitamin C, Vitamin D, Calcium
95
Q

Define X-inked inheritance.

A

X-linked Inheritance: any mutation that lies on the X-chromosome, and therefore is more likely to be present in males

96
Q

Define anticipation.

A

Anticipation: The signs and symptoms of some genetic conditions tend to become more severe and appear at an earlier age as the disorder is passed from one generation to the next.

97
Q

What is X-inactivation?

How does it relate to Mosaicism?

A

X-Inactivation: One chromosome can be inactivated in a way that it has heterochromatin – an inactive form of DNA.

  • Condensing of on X chromosome into barr bodies that are not expressed
    • Mosaicism
      • Xist RNA inactivates the X chromosome via methylation
      • Inactive X chromosomes can be at least partially reactivated in vitro by administering 5-azacytidine, a demethylating agent.
      • Skewing favors the wild type over the defective
98
Q

Explain dosage compenstation.

A
  • Dosage compensation – most gene products coded by the X chromosome are present in equal amounts in males and females,
    • Males have one X chromosome
    • Females have two X chromosomes - one of which is inactivated.
99
Q

Describe how females can manifest an X-linked disorder.

A
  • Each cell in a female will inactivate or turn off one of its two X chromosomes.
  • If a large proportion of the cells turn off the X chromosome with the Fragile X mutation, then most of the cells will have an active X chromosome that can produce FMRP. As a result, the impact of Fragile X syndrome will be limited.
  • If a large proportion of the cells turn off the X chromosome with the working FMR1, then there will be few cells able to produce FMRP. As a result, the impact of Fragile X syndrome will be more pronounced.
100
Q

Descibe the symtpoms of Fragile X?

A
  • Symptoms in Full Penetrance Individual
    • Intellectual disability/autism
    • Large testes, ears, jaw, face
    • Mitral Valve prolapse
    • Seizures
101
Q

Describe the sympotms who carrier the premutation for Fragile X.

A
  • Symptoms in Pre-mutation
    • Premature menopause in women who are carriers (Fragile X related ovarian insufficiency)
    • Tremor/Ataxia (Fragile X Ataxia-Tremor Syndrome) - histone acetylation
102
Q

What protein is involved with Fragile X?

What is that protein’s normal function?

A
  • The FMR1 gene codes for the FMRP protein which is important for synaptic plasticity and brain development.
    • FMRP also acts as an mRNA chaperone → regulation of translation
103
Q

What is the mechanism of mutation for Fragile X?

A

Genetic Mechanism: DNA polymerase slips due to the number of CGG repeats and a loop of unreplicated DNA forms

Fragile X syndrome is due to hypermethylation of 5’ UTR of DNA due to trinucleotide repeats (CGG)

More repeats = more methylation

104
Q

Define the terms pre-mutation and full mutation and describe the range of phenotypes and genotypical differences associated with these mutations.

A

Pre-mutations: less triplets of a triplet expansion disease

50-200 repeats = pre-mutation

Full-mutation: large number of triplets causing silencing of gene in triplet expansion disease

>200 repeats = gene silencing

105
Q

What gene is affected in DMD and BMD?

What is the function of the protein it codes for?

A

Dystrophin is a cytoskeletal protein that binds actin filaments inside sarcomeres to a protein complex at the sarcolemma, which in turn bind glycoproteins and collagen. It acts as a cohesive protein, connecting the cytoskeletons of skeletal muscle cells to help keep structure. N-terminus binds actin, cytoskeleton. C-terminus binds extracellular matrix.

DMD gene.

106
Q

Why do mutations in DMD casues muscle wasting phenotype?

A

The muscle membrane is susceptible to damage and muscle fiber deterioration occurs, resulting in cycles of regeneration and degeneration that result in fibrosis and fatty replacement of muscle.

107
Q

Why does elevated serum creatine phosphokinase indicate muscle damage?

A

Creatine phosphokinase is very concentrated within muscle cells and should remain inside the cytoplasm of myocytes. When the membrane is damaged, CPK may leak out of the cell and into the blood. Phosphocreatine is used in muscle as an ATP reserve for short term storage to buffer the levels of ATP present in the muscle. If not present in the blood, probably a neurological problem.

108
Q

Difference between DMD and BMD?

A

Duchenne is a quantitative issue, no dystrophin is transcribed due to a frameshift mutation. Beckers is a qualitative issue, the dystrophin made retains some function due to an inframe mutation, typically a premature stop codon.

109
Q

How is muscle damage caused DMD?

A
  1. Dystrophin – connects extracellular matrix with sarcolemma membrane and associated cytoskeleton
    1. Defect in Dystrophin gene causes MD
    2. X-linked disease
  2. Ca++ entry from extracellular fluid causes proteolysis – inducing muscle damage
  3. Creatine Kinase – muscle breakdown causes leak out of muscle and becoming elevated in the blood
  4. Myofibrils are replaced with fatty tissue. Therefore, muscles are not fully repaired.
110
Q

How is repair of muscles affected in DMD?

A

MD patients cannot go through muscle regeneration repair fast enough

  • Pts with MD lack to ability to completely repair the muscle fibers. It is thought that the satellite cells are either unable to repair the muscle fibers or are not fast enough to repair it.
111
Q

Define atrophy.

A

Atrophy is the decrease in muscle strength due to a decrease in muscle mass, or the amount of muscle fibers. Can be due to diseases, starvation, or disuse.

112
Q

Define hypertrophy.

A

Hypertrophy is an increase in the size of a muscle through an increase in the size of its component cells. Hypertrophy can occur through increased sarcoplasmic volume or increased contractile proteins. Can be due to strength training or anaerobic training. Changes occur due to adaptive responses to increase ability to generate force or resist fatigue

113
Q

Name some disease asscoited with Ashkenzi Jews.

A

CF, Tay-Sachs

114
Q

What are the most common molecular genetic defects associated with Tay-Sachs? What protein does the HEXA gene encode?

A

Beta-hexosaminidase A, encoded by HEXA, plays a critical role in the brain and spinal cord (central nervous system). Within lysosomes, beta-hexosaminidase A forms part of a complex that breaks down a fatty substance called GM2 ganglioside.

115
Q

What is the differenece between different LSDs?

A
116
Q

What are gangliosides?

A
  • Gangliosides are sialic acid-containing glycosphingolipids that are most abundant in myelin of the nervous system. The hydrocarbon motif embeds in the cell membrane and the rest is exposed to the cell surface. On the cell surface, they participate in cell-cell recognition, adhesion, and signal transduction.
  • They are continually synthesized and broken down. The sugars cause water to come in so if it is not broken down the cells can swell - causes brain problems.
118
Q

What are symptoms of Tay-Sachs?

A
  • Cherry red spot on macula
  • Startle Response
  • Seizures
  • Hypotonia
  • Normal at birth but progress to a vegetative state with early death between around 2 yo
119
Q

Explain heritable versus non-heritable retinoblastoma.

A
  • Non-heritable form: Unilateral RB → two sporadic mutations
  • Heritable form: Bilateral RB → loss of heterozygosity (“second hit” after germline mutation)
120
Q

What is the difference in frequecy between inherited Rb to somatice Rb?

A
  • The frequency of RB in an inherited Rb proband will be higher than in a somatic Rb proband.
121
Q

Outline the testing for Rb.

A
  • Testing
    • Ophthalmic Exam: Complete visualization of the retina and identification of multifocal tumors; Can detect leukocoria
    • WBC Analysis: In heritable forms of retinoblastoma, molecular testing of peripheral white blood cells can identify the germline mutation in 90 to 95 percent of cases
      • More likely to get metastatic form of the cancer
122
Q

Expliain the inheritance pattern (recessive/dominat) of Rb?

What is the two hit hypothesis?

A
  • Tumor suppressor genes are recessive, loss of function
  • Retinoblastoma exhibits haploinsufficiency, only requires one mutated allele + loss of heterozygosity (only one WT allele left)
  • Retinoblastoma is dominant because one allele can lead to the disease (“second hit”), but it is genotypically recessive
  • Two-Hit Hypothesis: In a tumor suppressor gene, a mutation in one allele will cause genomic instability. This can lead to a mutation in the second allele and ultimately “two-hits”.
123
Q

How do these classes of drugs target the cell cycle in cancer cells?

DNA Damage

Inhibition of DNA synthesis

Inhibition of Microtubule Function

A
124
Q

What is the transcriptional control of the cell cycle?

A

Transcriptional Control:

  • Rb attaches to E2F (a transcription factor)
  • When Rb is phosphorylated by Cdks → E2F is active
  • p21/p16/p27 deactivate cyclin → dephosphorylating Rb → E2F is inactive
    • p53 transcribes p21
  • [Cdk] stays constant. [Cyclin] varies.
125
Q

What cyclin controls each checkpoint?

A

G1/S Checkpoint

  • Cyclin E

S/G2 Checkpoint

  • Cyclin A

G2/M Checkpoint

  • Cyclin B

M/G1 Checkpoint

  • Cyclin E

G0 Checkpoint

  • Cyclin D
127
Q

Explain why the risk for additional cancers is higher in retinoblastoma patients.

A

Children with germline mutations have a higher risk for other types of cancer. This is due to the fact that the body has an abnormal RB1 tumor suppressor gene, which would normally stop some of these cancers from forming. This is not true for non-hereditary.

128
Q

What is the inheritance pattern of BCRA1/2?

What type of cancers are these proteins related to?

A
  • Most inheritance is due to germline mutations in BRCA1 or BRCA2, which is inherited as an autosomal dominant fashion.
    • Mutations in BRCA1/BRCA2 often cause breast cancer in women and can possibly cause prostate cancer in men.
  • These genes produce tumor suppressor proteins → help in repair of damaged DNA
129
Q

What is the molecular function of BRCA1 and 2?

A

Overall, BRCA1 makes sticky ends and BRCA2 localize RAD51 to resected DNA and work as homologous recombination (HR) transcription factors. In BRCA-deficient cells, non-homologous end-joining (NHEJ) takes over as the primary form of double stranded break repair, which is faulty and can result in mistakes/somatic mutations that lead to mutations, genomic instability, and transformation.

130
Q

When is Tamoxifen used?

What does it do?

A
  • ER-positive breast cancer drug
  • Competitively binds to estrogen receptor at the ligand binding site → Preventing estrogen molecules from binding → doesn’t change receptor’s shape so coactivators are unable to bind → genes that stimulate cell proliferation can’t be activated
  • Antagonist on breast tissue; agonist at uterus, bone
131
Q

When is Anastrozole used?

What does it do?

A
  • aromatase inhibitor that inhibits synthesis of estrogen by binding reversibly to aromatase enzyme through competitive inhibition
  • inhibits conversion of androgens to estrogens in peripheral tissues
  • ONLY for postmenopausal women (postmenopausal women the ovaries are no longer making estrogen. This is why anastrazole is used in these women.)
132
Q

Explain the significance of HER2/neu (her 2 or c-erbB2) overexpression in breast cancer, and its relevance for breast cancer therapy.

A

HER2/Neu Receptor binds to a partner receptor to form a dimer with tyrosine kinase domains. The partner receptor can come from the EGFR family of growth factor receptors, and HER2 has high affinity for all monomers. HER2 has no specific ligand. HER2/Neu overexpression will cause it to competitively bind to EGFR family monomers, causing cell proliferation and cell cycle disregulation through PI3K activation.

133
Q

Explain the rationale for using PARP inhibitors for treating BRCA-mutant tumors.

A

PARP is important in SSB repair. If BRCA1/2 is mutated, tumor cell is dependent on PARP for all DNA repair. PARP inhibitors prevent this DNA repair in cancer cells and since BRCA 1 cannot help the cell undergo homologous recombination → apoptosis occurs

134
Q

How does radiation and chemotherapy work as cancer treatments?

A

Radiation - causes more mutations helping lead to apoptosis

Chemotherapy: combination of different drugs to treat different classes of breast cancer

135
Q

What are the STAGES of breast cancer?

A
  • Stage 0: Noninvasive cancers
  • Stage I: The tumor is small, and the cancer has not spread to the lymph nodes under your arm or to other sites beyond your breast.
  • Stage II: The tumor is a little larger, or the cancer has spread to the lymph nodes under your arm. Stage I or II cancers may be called early-stage cancers.
  • Stage III: This is a more advanced cancer, but it is still confined to your breast, surrounding tissues, and lymph nodes.
  • Stage IV: Cancer has spread or metastasized
136
Q

Correlate drug therapies with the different classes of breast cancers.

PARP, Trastuzamab, Lapatinib, Anastrozol, Tamoxifen, Fulvestrant

A

BRCA1/2 (+) – PARP Inhibitors

HER2/Neu (+) – Trastuzamab (antibody)/Lapatinib

ER/PR (+) Post-Menopausal – Anastrozole (aromatase inhibitor)

ER/PR (+) Pre/Post-Menopausal – Tamoxifen (SERMS → modulates receptor) Fulvestrant (SERD→ degrades receptor)

137
Q

What are the four clinical presentations of Lynch Syndrome?

A
  • 3 or more relatives with Lynch Syndrome
  • 2 or more successive generations affected
  • 1 or more cancers in the first degree relative before the age of 50
  • Presence of different types of cancers
138
Q

What are the two diagnostic techniques used in diagnosing Lynch Syndrome?

A
  • Microsatellite Instability Testing
    • MSI testing is performed using polymerase chain reaction (PCR) to amplify a standard panel of DNA sequences containing nucleotide repeats
  • Immunohistochemistry
    • The mutations in the MMR genes that cause Lynch syndrome typically result in a truncated or lost MMR protein that can be detected as loss of staining of the protein on tumor IHC testing
      • Then need to make sure there is no methylation by checking for BRAF-V600E. This is not considered Lynch Syndrome because it is an epigenetic modification
139
Q

What are the two genetic characteristics of Lynch Syndrome?

  • What five genes are affected?

What percentage of CRCs are caused by Lynch Syndrome?

A
  • Genetic Characteristics
    • Loss of Heterozygosity - genotypically recessive, but inherited in an autosomal dominant fashion
    • Mutations in any of the MMR genes causes LS:
    • MSH2, MSH6, MSH3, MLH1, PMS2
  • Epidemiology
    • 2-3% of all colorectal cancers
140
Q

What is the step-by-step mechanism of MMR?

A
  1. MSH2 dimerizes with MSH6 to form hMutSα, which scans the double strand DNA for mismatches
  2. Once mismatch is located, MLH1 and PMSC will dimerize (forms hMutLα) and join hMuTSα
  3. Activates Helicase and recruits exonuclease 1 that recognizes nicks on lagging strand and removes long strand of DNA nucleotides containing mismatch
  4. DNA polymerase will then use leading strand as template to create correct sequence fragment
  5. Ligation by Ligase
141
Q

For DNA repair mechanisms, what are the:

  • Causes
  • Effect (Damaged Caused)
  • Relevant Proteins Involved
A
142
Q

What is the normal function of DNA MMR and what happens in Lynch Syndrome?

A
  • Normal Function: DNA mismatch repair allows for repair of mismatches and DNA loops
  • Lynch: A MMR gene is mutated, so cannot properly repair
    • Gut epithelial cells have a high turnover rate. So mismatches/loops accumulate and lead to cancer
143
Q

Define microsatellites and microsatellite instability.

A
  • Microsatellite Instability: common areas of hypermutation due to DNA polymerase slippage
    • MSI can inactivate tumor suppressor genes resulting in cancer.
  • Microsatellite is a tract of repetitive DNA in which certain DNA motifs (ranging in length from 2–13 base pairs) are repeated, typically 5–50 times as a result of DNA slippage
    • Similar to Insertion and Deletion loops (IDLs)
    • Normally, MMR would removes these microsatellites
144
Q

Describe in general terms the common components and the rationale of the AJCC staging system for patients with cancer.

A

Remember: M1 = Stage IV

145
Q

Describe epigenetic modification of DNA and its role in Lynch Syndrome.

A
  • In the tumor, MLH1 promoter is methylated, thus it does not get transcribed. This often happens in endometrial cancers and sporadic colon cancer tumors. Most microsatellite instability (MSI) cancers are caused by MLH1 methylation (~75%)
  • MSI is also associated with BRafV600E mutation, which is associated with non MMR mutation, so this would not be part of the Lynch Syndrome.
147
Q

List the two major classes of genotoxic carcinogens in tobacco smoke and describe how they form DNA adducts and induce mutagenesis and carcinogenesis.

A
  • PAH - polycyclic aromatic hydrocarbon → BPDE creates mutations in p53 & Kras by forming guanine adducts
    • Main type: Benzo(A)pyrene
    • Activated by AHH and EH (types of cytochrome p450)
  • Nitrosamines (NNK) - burning of nicotine forms NNK
    • N-nitrosamines, as alkylating agents, act directly on DNA bases to induce cross-linking → adducts
148
Q

Outline the stages of the metastatic cascade and the obstacles that tumor cells overcome to form metastases.

A
149
Q

Describe the biochemical pathways by which tobacco carcinogens are metabolically activated and metabolically detoxified.

A
  • Activation: cytochrome p450s
  • Detoxification: glutathione-S-transferases (GSTs) - glutathione reduces ROS
151
Q

Provide an example and mechanism of action of one drug from each of the following classes of chemotherapeutics: alkylating agent, topoisomerase inhibitor, small molecule tyrosine kinase inhibitor.

A
  • Etoposide (Topoisomerase II Inhibitor)
    • Forms ternary complex with DNA and topoisomerase type II, trapping complex in the cleavable state
  • Cisplatin (Alkylating Agent)
    • Platinum-based chemotherapeutic
    • Forms monoadducts and bis adducts with guanine
    • Non-specific nucleophilic attack damages all macromolecules, but damage to DNA is the most crucial
    • Severe side effects: anemia, GI problems, hair loss
  • Erlotinib (RTK inhibitors) (-nib = tyrosine kinase inhibitor)
    • Selective and competitive EGFR inhibitor
    • Competes for the ATP binding site of EGFR
    • Typically used after failure of 1 prior chemotherapy
152
Q

Describe the cytotoxic mechanism of radiation and explain the concept of chemotherapeutic agents as “radiation sensitizers”.

A
  • Cytotoxic Mechanism of Radiation
    • Causes ds breaks by direct (breaking of phosphate bonds) and indirect (formation of oxygen radicals that act on the DNA)
    • Destroys all cells in the area
  • Chemotherapeutic agents that are highly responsive to ionizing radiation and enhance the effectiveness of radiation treatment are termed radiation sensitizers
    • This is possible by interfering with DNA repair mechanisms and checkpoints
153
Q

Describe (in general) the usefulness and limitations of surgery in the treatment of malignancy.

A
  • Inoperability
    • Age-related issues
    • Encroaching on nearby critical structures - not encapsulated
    • Comorbidity issues (obesity, heart failure)
  • Surgical resection is the first-line treatment in non-small cell lung carcinoma (NSCLC), as chemotherapy typically is not effective as it is on SCLC.
155
Q

Discriminate between Phase I, II, and III clinical trials.

A

Phase

Purpose

Phase 1

  • Find a safe dose
  • Decide appropriate route of administration
  • How treatment affects the human body
  • How treatment fights cancer

Phase 2

  • Determine if treatment has effect on specific cancer
  • How treatment affects the human body
  • How treatment fights cancer

Phase 3

  • Compare the new treatment with current treatments

Phase 4

  • Evaluate side effects not apparent in phase 3 trials
156
Q

What tests is used for community acquired penumonia and how does it work?

A
  • Community Acquired Pneumonia Diagnostic Tests: Urinary antigen test
    • Detecting the C-polysaccharide antigen of Streptococcus pneumoniae (leading cause of CAP)
157
Q
  • Define blood glucose levels and the hemoglobin A1C test and what they measure.
  • Define the normal and diabetic levels of A1c.
  • What can cause a false normal A1C level in a diabetic patient?
A
  • Blood glucose: instantaneous measure of glucose in the blood
  • The hemoglobin A1c test measures the percentage of red blood cells with a sugar coating over a three month period (~life cycle of a RBC)
    • Normal: 4-5%
    • Diabetes: >9%
  • However, in reality this is a false statement in this case due to his hemolytic anemia. As a result, it can how normal HgA1c levels if there is a high rate of RBC hemolysis
    • Alternative: Fructosamine Test - measures glycosylated albumin over a 3 week period
158
Q

Define the causes, physical exam findings, labs, and treatment for DKA.

A
  • Causes: stress, infections, insulin noncompliance anything that increases glucose, epinephrine, cortisol, or adrenaline
  • Physical Exam: Delirium/psychosis, Kussmaul respirations (rapid/deep breathing), abdominal pain, nausea, vomiting, diarrhea, dehydration, fruity breath odor (due to acetone)
  • Labs: hyperglycemia, rise in H+, decrease in HCO3, increase in free fatty acids, increase in ketones, large anion gap, high blood glucose
  • Treatment: IV fluids, IV insulin, and potassium to replete intracellular stores, glucose as needed
159
Q
  • What are the signs/sx of uncontrolled diabetes type I?
  • How is managed (what are the two types of insulin)?
  • How is it monitored?
A
  • Signs and Symptoms of poorly controlled Diabetes Type I: neuropathy, nephropathy, retinopathy, edema of lower extremities
  • Management
    • Glargine: long acting insulin
      • Same amount of base insulin throughout
    • Lispro: short-acting insulin
  • Monitoring: monitor blood glucose, pump insulin as needed
160
Q
  • What allows for the crossover of diabetes and Celiac Disease?
A

HLA Types of Diabetes and Celiac Disease: HLA-DQ2 & HLA-DQ8 (MHC II types)

161
Q
  • What do the HLA Types of Diabetes and Celiac Disease: HLA-DQ2 & HLA-DQ8 present?
A

o Present the gliadin or transglutaminase (TTG) peptide

162
Q

What group is most at risk for Celiac? Name three diagnostic tests for Celiac and which is the most definitive?

A
  • People with HLA-DQ2 and HLA-DQ8 are more likely to have Celiac Disease, but they are not guaranteed the disease
  • Diagnostic tests:
    • Transglutaminase Antibody
    • Gliadin Antibody
    • Duodenum biopsy (definitive)
163
Q

What is the step-by-step process of how Celiac is presented and how the immune system responds? Also, where does dermatitis herpetiformis fit into this process?

A
  1. Gluten is digested → broken down into gliadin
  2. Gliadin is picked up by IgA in lumen → crosses mucosal epithelial layer
  3. Gliadin is released and deaminated by transglutaminase
  4. APCs pick up modified gliadin and present these antigens via MHC IIs
  5. CD4+ cells recognize these antigens as foreign and release interferon gamma and TNF-alpha
  6. Release of cytokines → causes damage to epithelial layers and recruits B-cells
  7. B-cells make more antibodies against gliadin and transglutaminase → circulated throughout the body including epidermis layer→ dermatitis herpetiformis
  8. CD8+ (recruited by cytokines) cells cause further damage to epithelial layer
  9. Damages causes → villous atrophy
164
Q

What vitamin deficiencies may Celiac patients have and why does this occur? What effect do these deficiencies have?

A
  • The atrophy of villi in the duodenum (small intestine) makes it harder for celiac patients to absorb both fat-soluble and water-soluble vitamins
  • Fat soluble: vitamin D deficiency → osteoporosis
  • Water soluble: B12 deficiency → macroblastic anemia
  • Minerals: deficiency in iron → anemia. Zinc → required for immune system.
165
Q
  • What does dapsone treat and what is the normal pathway?
  • What can be a side effect of dapsone in prolonged use? Describe that pathway.
  • What drug can counteract this effect while maintaining therapeutic effect?
A
  • Normal pathway to treat dermatitis herpetiformis: sulfonic antibiotic/potent inflammatory → treats dermatitis herpetiformis
  • Side effect: Dapsone → N-hydroxy dapsone (ROS) via CYP450
    • Oxidizes hemoglobin(Fe2+) → methemoglobin (Fe3+)
    • NADPH correction (G6PD) pathway: reduces methemoglobin → hemoglobin
      • Overwhelming of G6PD pathway causes a buildup of ROS → oxidative stress → cell lysis
  • Cimetidine acts on CYP450s to inhibit Dapsone → N-hydroxy dapsone
    • Dapsone still has therapeutic effects for dermatitis herpetiformis
167
Q

Compare and contrast the following anemias (including their blood stain appearances):

  • Folate deficiency
  • Iron deficiency
  • Hemolytic anemia

How can all of these occur at the same time?

A
  • Folate deficiency - B12:
    • Macrocytic, pernicious (neuro) anemia
    • Impaired DNA synthesis → buildup of macromolecules inside cell → inability to divide → macrocytic anemia
  • Hemolytic anemia - ROS:
    • Overwhelming of G6PD pathway → decrease in NADPH levels → increase in ROS → lysis of RBC → hemolytic anemia
    • Release of hemoglobin into blood stream → bilirubin → secondary jaundice
  • Iron deficiency:
    • Deficiency in iron → heme is unable to bind iron → decreased binding of O2 → anemia
    • Secondary tiredness due to lack of O2 to tissues
  • All three at the same time: Celiac patients have folate and iron deficiencies, and if taking dapsone, they will also be prone to hemolytic anemia
    • Blood stain: Macrocytic (folate), Heinz bodies and bite marks (hemolytic anemia), and microcytic, hypochromic (iron deficiency)
168
Q

What is the general epidemiology of TB?

A
  • Epidemiology of TB worldwide
    • Prevalence of latent infection: ⅓ of global population (2 billion)
    • Incidence of disease: 10 million new cases per year (out of the 2 billion) and 1.5 million of the 10 million die
  • Epidemiology of TB in United States
    • Prevalence of latent infection: ~11 million latently infected people
    • Incidence of disease: ~10,000 cases per year
169
Q

How is TB transmitted and how can it be prevented?

A
  • Person-to-person transmission through the air via droplet nuclei
    • Singing, talking, coughing from infected individuals
    • This is special because it can spread much farther than typical infections (i.e. influenza)
    • Particles are suspended in the air for a long period of time
  • Preventing transmission
    • Negative air pressure rooms, allowing air to flow into the room but not out of the room
    • N95 mask and PAPR mask
170
Q

What are three phases of TB?

A
  • Exposure
  • Infection
  • Disease
171
Q

Define TB exposure.

A
  • Exposed: sharing air space with infected individual
    • A small percentage of individuals exposed become infected
172
Q

Define primary TB infection and what occurs in an infetion. Discuss the following possibilities post-infection: latency and primary TB pneumonia.

A
  • Primary Infection: this small percentage that inhale bacteria which reach peripheral part of airways, multiply, and drain to the hilar lymph nodes (towards center of lungs)
    • This collective peripheral multiplication of the bacteria and the draining lymph nodes are called the primary or Gohn complex
    • Types:
      • Latent: Macrophages are recruited as primary immune response, and form a granuloma and contains infection.
        • At this point the patient is infected but not ill or contagious
        • Can persist for years until immune system can no longer control infection
      • Primary TB pneumonia: symptomatic TB immediately following exposure
        • Most likely cause of miliary TB (dissemination of bacteria in blood throughout body)
173
Q

Define secondary TB disease and what can cause it? How can one become contagious again?

A
  • Secondary Disease: reactivation of bacteria after the bacteria escapes the granuloma (also called a tubercles) and can reactivate
    • Due to anything that causes immunosuppression (i.e. HIV, smoking, diabetes)
    • Upon reactivation, it leads to caseating necrosis making the patient symptomatic and infectious (only if the necrosis is in the lung)
174
Q

What are the four principal sx of TB?

A
  • Weight loss
  • Night sweats
  • Cough
  • Hemoptysis
175
Q

What are the three diagnostic tests for TB? Define what is done in each test

A
  • PPD Skin Test
    • Take a purified protein derivative (PPD), injected intradermal
    • If they have a delayed type IV hypersensitivity reaction, they are considered to have a positive test
    • Detects that your body has created memory T cells in response to M. tb infection
  • IGRA (IFN-gamma release assay)
    • Measures how much IFN-gamma T cells releases in response to exposure of three cloned proteins that only exist in M. tb
  • Acid Fast Stain
    • Sputum culture staining
176
Q

What is the treatment for latent infection and the treatment for active TB? Provide drug name(s).

A
  • Treatment for latent infection (9 months)
    • Isoniazid (INH): inhibits synthesis of mycolic acid allowing immune system to attack cell wall
  • Treatment for active TB
    • Cocktail of 4 drugs: Rifampin (always combine), Isoniazid, Pyrazinamide, and Ethambutol (RIPE)
177
Q

What type of vaccine is the BCG vaccine, what is its effect on the PPD skin test and why is not given in the USA?

A
  • BCG vaccine
    • Attenuated version of Mycobacterium bovus
    • Vaccination wanes over time and does not affect PPD skin test
    • Not given in the United States because PPD test is method of testing
    • Countries with high prevalence
      • 90% of newborns will be given vaccine across the globe
178
Q

What mosquito transmits malaria?

A

· Anapholes mosquitoes

179
Q

What is the detailed life cycle of malaria? Include the two stages.

A

Life Cycle

  1. Infected female anopheles mosquito bites a human. Mosquitoes infect human with sporozoites.

Hepatic Stage, steps 2-3 (P. vivax and P. ovale can hide in the liver as hypnozoites for weeks to years; individual can relapse)

  1. Sporozoites travel to liver and infect liver cells. Parasites divide many-1000-fold (1st stage of multiplication).
  2. Infected hepatocytes rupture and release merozoites into blood stream.

Erythrocytic Cycle, steps 4-6

  1. Merozoites invade RBCs and multiply approximately 30-fold(2nd stage of multiplication)
  2. RBCs rupture and release more merozoites.
  3. Released merozoites invade other RBCs.
  4. Some merozoites are able to form gametocytes.
  5. Mosquito bites individuals and gametocytes are ingested by mosquito. The gametocytes sexually reproduce in midgut producing sporozoites. (cycle back to step 1 with a different individual)
180
Q

What is the basic epidemiology of malaria? Where is it most prevalent?

A
  • 5th leading cause of death in the world
    • 98% of deaths from malaria occur in Africa
    • 2nd leading cause of death in Africa after HIV
181
Q

What are the 5 species of plasmodium and describe key charactersistics of each type (including most severe, fever patterns, possibility of relapse, and types of malaria associated if any)?

A
  • P. falciparum (most common)
    • Most severe and much more likely to kill you
    • During the life cycle, it makes adhesion molecule that clogs of blood vessels
    • Variable fever pattern, cannot relapse
    • Cerebral malaria
  • P. malariae
    • Very unlikely to be fatal
    • 72 hr fever pattern
  • P. ovale (stay dormant in liver because they form hypnozoites)
    • Very unlikely to be fatal, can relapse
    • 48 hr fever pattern
  • P. vivax (stay dormant in liver because they form hypnozoites)
    • Very unlikely to be fatal, can relapse
    • 48 hr fever pattern
  • P. knowlesi
    • Very unlikely to be fatal
    • 24 hr fever pattern

*Cyclical fever is due to synchronized lysis of blood cells, suggesting malaria. If fever happens every 48, hours, individual has tertian fever, is due to P. ovale, P. vivax and P. falciparum. Quartan fever, every 72 hours is due to P. malariae.

183
Q

What is the gold standard diagnostic modality of malaria?

A

Blood smear is the gold standard

  • Thick blood smear shows parasitemia.
  • Thin blood smear shows the presence of specific ring formation.
    • The parasite can be identified through examining a patient’s blood smear, specimen is stained by giemsa stain, giving the parasites a distinctive “headphone” appearance. Below shows P. falciparum.
185
Q

What is the innate and adaptive response to malaria?

A
  1. Innate:
    • When TLRs are engaged, macrophages and dendritic cells produce Th1 cytokines such TNF-alpha and IL-1 and IL-12
    • IL-12 stimulates T cells and NK cells to produce interferon (IFN)-gamma, which stimulates macrophages to phagocytize infected RBCs in the liver and spleen
    • Activates all 3 complement pathwa
  2. Adaptive:
    • IL-4 from CD4→ Th2 activation → Phagocytosis of Merozoites
    • CD8+ T cell response directed against infected hepatocytes
    • Short-lasting adaptive response. Still at risk when revisiting a malaria-infected region
186
Q

What are the sx of malaria?

A
  • Fever, chills, anemia
  • Hypotension
  • More severe: jaundice, seizures, coma, death
188
Q

What mosquito avoidants are available and what chemoprophylaxis (4 drugs) are available?

A

Mosquito Avoidance - while traveling

  • Bug repellant
  • Bed nets

Chemoprophylaxis - begin before travel, and for a duration after traveling. The time frames differ between drug types.

  • Chloroquine (unless travelling to a geographic region with Chloroquine resistance)
  • Atovaquone plus Proguanil (Malarone)
  • Doxycycline
  • Mefloquine
189
Q

What are 4 drugs used in treatment of malaria?

A
  • Clindamycin
    • Bind to 50S subunit and inhibits protein synthesis
    • Used with quinidine (IV) for P. falciparum infections
  • Quinidine
    • G6PD - contraindications
  • Chloroquine
    • Variable sensitivity. Use quinidine
  • Primaquine targets hypnozoites (P. vivax/P. ovale)
190
Q

What two diseases provide immunity against malaria and describe how this takes place?

A
  1. Sickle Cell patients have a differently structured RBC that lack a receptor for the “duffy” antigen presented from the parasite. The lack of the receptor protects the RBC from being infected.
  2. G6PD deficiency make parasite-infected Erythrocytes more susceptible to dying from oxidative stress
    • Plasmodium oxidizes RBC NADPH from the Pentose Phosphate pathway for its metabolism

*These diseases ward off malaria infection and confers a natural selection advantage in “Malaria Heavy” regions

191
Q
  • What is the general strucutre of the influenza virus?
  • What type of nucleic acid does it have?
  • Does it have an envelope? If so, what are the glycoproteins and their functions?
A

Structure:

  • They have segmented negative sense ssRNA
    • There are 8 pieces in influenza A and B
      • Each of the 8 codes for a different protein
    • Influenza C has 7
  • It has an envelope that contains 2 glycoproteins hemagglutinin (HA) and neuraminidase (NA).
    • NA helps with virus release
    • HA binds to sialic acid (sugars) residues on upper respiratory epithelial cell surface glycoproteins.
192
Q

What is the DETAILED process of replication of the flu virus?

A
  • Replication:
    • Influenza binds to the membrane of the host cell via HA.
      • HA binds to sialic acid (sugars) residues on upper respiratory epithelial cell surface glycoproteins.
    • The virus is then endocytosed
    • The acidic environment of the endosome causes a conformational change in the virus → fusion of envelope with endosome membrane
    • Nucleocapsid is released into the host cytoplasm.
    • The nucleoplasm travels to the nucleus
      • THIS IS UNUSUAL FOR AN RNA VIRUS (most undergo replication in the cytoplasm)
    • The negative RNA strand is transcribed into the positive RNA strand via transcriptase
    • The positive strand is translated into protein
    • M1, M2, HA, and NA are transported to the cell membrane of the host and stick to it. The virion uses the cell membrane to form its envelope.
      • HA keeps the virus in the cell
      • NA clips the host sialic acids on the host membrane to let the virion out
193
Q

What are the symptoms of influenza and when do they appear (see image)?

A

Non-productive cough, myalgias, fever, chills, sweats

194
Q

Distinguish between antigenic drift and antigenic shift.

A

Antigenic Drift:

  • Causes new strains (i.e. H1N1 #12)
  • A gradual change in antigenicity that results from continually occurring point mutations in the NA or HA genes of type A or B

Antigenic Shift:

  • Causes new subtypes (i.e. H1N1 to H7N9)
  • When more than 1 influenza A virus (especially if one is from an animal) infect the same cell, reassortment of the segmented genome can result in new subtypes, causing a rare but dramatic antigenic shift in 1 of the surface glycoproteins and leading to pandemics due to lack of immunity in the population.
195
Q

What is the epidemiology of influenza, including seasons, pandemics, and animal strains?

A
  • Birds are natural hosts of influenza A.
  • Pigs are considered a mixing vesicle. Pigs have receptors for both avian flu and human flu.
  • Between 1 in 20 and 1 in 5 people worldwide will get influenza yearly.
    • 3-5 million of those will be severe leading to about 500,000 deaths worldwide.
    • US: 200,000 are hospitalized per year.
    • Death usually due to other infections.
      • Grouped with pneumonia deaths
    • Timing: more prevalent in the winter
      • People spend more time indoors and are exposed to a higher concentration of the virus
      • Nasal passages are dry as well
      • Southern Hemisphere: has opposite seasons (prevalent May to Sep)
196
Q

How is influenza transmitted and what is the incubation period?

A
  • Transmitted when an infected person coughs or sneezes within 6 feet.
  • Sxs begin within 1-4 days (after incubation) and they are the most infectious at the beginning of sx onset (roughly the end of 4 days).
  • A person can be infectious up to 5-7 days after sx onset
197
Q

What is the immunopathogenesis?

A

Immunopathogenesis

  • Flu: establishes in upper respiratory ciliated epithelial cells
  • When the flu escapes these cells they are destroyed
    • Causes a lot of sxs
  • When you inhale bacteria it cannot be expelled from these cells because they are damaged
  • This cells release interferons and cytokines which triggers the immune system
  • Escape: virus leaves the apical surface and escapes back into the airway. This is how it promotes spread and transmission to other people
  • APCs have MHCII and MHCI which activates Th and CTL response, respectively
    • Th lead to antibody production.
    • Abs are important for future protection
      • Specific for NA and HA
199
Q

How is influenza diagnosed and treated (what drugs)?

A
  • Nasopharyngeal swab (halfway through the head) until first patient in community is found → PCR assay → flu diagnosis
    • Once patient zero is in community, diagnosis made based on symptoms.
  • Treatment
    • Amantadine and rimantadine act on Influenza A
    • Oseltamivir and zanamivir (Neuraminidase inhibitors) can make a healthy person get better 1 day faster if started in the first 48 hours, and can reduce deaths of hospitalized patients.
200
Q

What is the importance of vaccines? What types of vaccines are available?

A
  • Though anti-flu drugs can prevent the flu, vaccination is the major way to save lives. Vaccination is safe but is needed every year to account for antigenic drift and because immunity from flu vaccines only lasts several months. Tetravalent vaccine.
  • Types
    • Inactivated - injected IM
    • Attenuated - mist in nose
201
Q

What is the HIV retrovirus life cycle?

A
  1. Binding: gp120 fuses with the surface of the T-cell, macrophage, and dendritic cells via a CD4 receptor and
    1. In early stages, binds a CCR5 coreceptor/chemokine receptor on macrophages or dendritic cells
    2. In late stages, binds CXCR4 on CD4+ T-cells
  2. Fusion: The virus’s core (capsid, genome, proteins, enzymes) then enters the cell.
  3. Reverse Transcription (cytoplasm): The shell of the capsid disintegrates and the HIV protein called reverse transcriptase transcribes the viral ss, + sense, linear RNA into one copy of ds linear DNA.
  4. The viral DNA + integrase is transported across the nucleus.
  5. Integration: HIV protein integrase inserts the HIV DNA into the host’s DNA.
    1. At this point, individuals have HIV permanently integrated into genome - you have infection
  6. Transcription of viral genome using host machinery (nucleus)
    1. Makes ss + sense RNA, which can act as mRNA or for packaging of new viruses
  7. Translation (cytoplasm): mRNA gets translated into polypeptides
  8. Packaging (cytoplasm): the new viral RNA and HIV proteins move to the surface of the cell, where a new, immature HIV virion form.
  9. Budding: the immature non-infectious virus is released from the cell (has long polyprotein chain with all proteins/enzymes)
  10. Release: the HIV protein called protease cleaves newly synthesized polyproteins to create a mature infectious virus.
202
Q
  • What is the structure of HIV?
  • What type of nucleic acid, containing what genes?
  • What enzymes does it have/require?
  • What surface glycoproteins does it have?
A
  • 2 + single stranded RNA molecules, containing gag, pol and env.
    • Gag - capsid protein p24 (structural proteins)
    • Pol- reverse transcriptase, integrase and protease. (all enzymes)
  • Env- gp120 (attachment to the host, surface gp) and gp41 (diffusion and entry into the cell, transmembrane gp)
203
Q

Name the antibodies.

A
204
Q

In detail, describe the immunopathogenesis of HIV?

A
  • With initial infection, dendritic cells present HIV antigens to CD4 cells in lymph nodes, causing immune activation. Widespread dissemination of virus occurs to lymphoid organs, as well as bone marrow and the brain, with progressive CD4 cell depletion, particularly in gut-associated lymph tissue. Depletion of CD4 lymphocytes (T-helper cells) is key because these cells are the “conductor of the immune orchestra.”
  • The immune response to HIV is substantial, but inadequate. The high levels of antibodies against HIV are typically non-neutralizing. High levels of virus replication and thus mutation lead to constant evolution of different species with altered antigens and reduced recognition by antibodies that have been made up to that point.
  • Additionally, mature memory T cells, which appear normal to immune effector cells, serve as a reservoir of virus even after decades of complete pharmacologic control of viral replication.
205
Q
  • What groups are most likely to get HIV?
  • What are risk factors?
  • What are modes of transmission and rank the most likely to transmit?
A
  • Prominent in Homosexual males → African Americans → latinos
    • Respectively
  • Risk Factors for HIV
    • Sexually Active, Homosexuals, heroin (needle-stick) users
  • Modes of Transmission
    • Unprotected sex (mostly anal, but also vaginal & oral)
    • Contaminated blood transfusions or hypodermic needles
    • Mother-to-child – pregnancy, delivery, or breastfeeding
    • Probability:
      • Blood transfusion > non-medicated perinatal transmission > receptive anal > insertive anal > vaginal fluid exposure
206
Q

Differntiate between the three phases of HIV and what occurs in each phase?

A
  • Acute infection: people have a flu-like syndrome, during which HIV viremia is transiently very high
    • Virus shifts from a CCR5-tropic non-syncytia-forming → CXCR4-tropic syncytia-forming predominance, the viral load significantly rises, and rate of CD4 decline becomes more rapid.
  • Latent: Patients are then asymptomatic, but still make 10 billion new virions every day
    • CD4 count gradually declines.
    • Persistent generalized lymphadenopathy (PGL).
  • When the CD4 <200 cells/uL = AIDS
    • Risk for opportunistic infections
207
Q

What are diagnostic tests for HIV?

A
  • Antigen tests (for p24 capsid)
  • Antibody tests (EIA with confirmatory western blots) are specific and sensitive.
  • Patients are monitored by CD4 T-helper cell counts, and PCR for plasma viral load.
208
Q

What are the classes of HIV drugs (5 big classes) and what are the mechanisms of actions and toxicities associated with each one?

A
  • Protease inhibitors - Prevent virally encoded proteins from cleaving proproteins into mature proteins to complete maturation of the virion
    • Toxicities: lipodystrophy
  • Nucleoside reverse transcriptase inhibitors -Prevent the transcription of ssRNA into dsDNA for integration into the genome by using by acting as nucleoside analogs, must be phosphorylated to be incorporated and active (chain terminators)
    • Toxicities: lactic acidosis, fatty stool, Type IV hypersensitivity reaction
  • Non-nucleoside reverse transcriptase inhibitors - Direct inhibition of RT with a different binding site and do not require phosphorylation to be active
  • Fusion inhibitors - Interfere with binding, fusion, and entry of an HIV virion into CD4 cells
    • Enfuvirtide: blocks gp41 conformational change
    • Maraviroc: acts as CCR5 antagonist
  • Integrase inhibitors - Block the integrase-mediated insertion of viral DNA into the host genome
210
Q

What are primary immunodeficiencies?

A
  • Primary
    • Hereditary/genetically determined
    • Deficiencies in: Humoral immunity, cell-mediated immunity, innate immunity, and complement proteins
    • Example: hyper-IgM Syndrome
      • Not an immediate concern following birth because children have their mom’s IgG antibodies transferred through placenta with half-life of one month
211
Q

What are secondary immunodeficiences?

A
  • Secondary
    • Acquired, often from external sources
    • Possibly from: Diabetes, HIV infection, immunosuppressive treatments, prolonged illness, hospital stay.
212
Q

Describe the epidemiology of X-linked hyper-IgM syndrome and autosomal recessive hyper-IgM syndrome.

A
  • X-linked hyper-IgM Syndrome
    • All forms of hyper-IgM syndrome are rare.
    • Loss of CD40L on T-cell, required for activating class-switching
  • Autosomal Recessive hyper-IgM Syndrome
    • Mutations in AID
213
Q

Explain the underlying genetic, molecular (e.g. CD40L), and cellular defects that are responsible for hyper-IgM syndrome and the consequence of these defects on the immune system of an individual who is afflicted with hyper-IgM syndrome.

A
  • Loss of CD40 ligand on T-helper follicular cells → Decreased naive B-cell to T-helper follicular cell binding → Decreased class switching → Decreased IgG, IgA, IgE antibodies
    • Naive B-cells natively express IgM
    • IgM has a short half-life compared to other immunoglobulin subtypes
214
Q

Describe the molecular basis of heavy chain isotype (class) switching and the role that CD40-CD40 ligand (CD40L) interactions play in this process.

A

CD40L to CD40 receptor binding releases AID → ds breaks in V(D)J area (MD Gea) → class switching (changes of constant regions of the heavy chain) → formation of immunoglobulin subtypes

215
Q

Predict the immunological-based tests that are used in the diagnosis of hyper-IgM syndrome.

A
  • CD40 Ligand Flow Cytometry
    • Functional test that determines whether CD40 ligand protein is expressed on the surface of activated T cells
  • Quantitative Ig Test
    • Detects the number of each Ig subtype
    • Decrease in IgA, IgG, IgE with a normal or slightly elevated IgM indicate possible hyper-IgM syndrome
  • Antigen-specific Antibody Titers
    • Used to determine presence of antibodies against certain antigens.
216
Q

Explain the relationships that exist among hyper-IgM syndrome, susceptibility to infectious pathogens, and the generation of protective immunity via vaccination.

A
  • IgG is especially useful for attacking encapsulating bacteria and viral and infections. He lacks IgG, so he will be vulnerable to those infections.
  • Antibodies against T-cell–dependent antigens, such as antibodies to tetanus-toxoid, diphtheria-toxoid, and protein-conjugated H influenzae type b antigens, are absent.
  • Avoidance of live, attenuated vaccinations is recommended because he cannot make long-lasting antibodies against them.
  • Patients with hyper-IgM are able to take killed/inactivated vaccines, but it is important to take a series of these vaccinations to maintain immunity.
217
Q

Identify the indications for kidney transplantation including the common diseases that lead to end-stage renal disease.

A
  • ESRD damage is irreversible; need dialysis or will have blood toxicity
    • Eligible for transplant if GFR < 15
    • Only cure is kidney transplant
  • Risk factors for ESRD: Focal segmental glomerulosclerosis (scarring of kidney), Hypertension, diabetes (both types)
218
Q

Describe the different types and sources of organ transplants.

A
  • Allograft - between two non-identical individuals
  • Isograft - from an identical individual
  • Autograft - from self, one part of the body to another
  • Xenograft - foreign species (animal)
219
Q

What are the immune-based tests that are used to determine transplant compatibility and how genetics contributes to this compatibility.

A
  • PRA: Test patient’s serum against lymphocytes of all donors that represent the potential HLA makeup
    • PRA - % of population that wouldn’t be able to donate to you. 1-19% PRA - low probability of rejection
    • High # = high chance or rejection; Low # = low chance or rejection
  • Cross reactive testing
    • Testing to see if a specific individual can be a donor.
    • Positive = not compatible. Negative = compatible
    • Mixing recipient and donor’s serum to see if there’s a reaction
220
Q

What are the HLA types?

A
  1. MHC Class I - Chromosome 6
    1. HLA-A
    2. HLA-B
    3. HLA-C
  2. Main MHC Class II HLA Types (each has an alpha and beta chain) - Chromosome 6
    1. HLA-DP
    2. HLA-DQ
    3. HLA-DR (This has one alpha chain, and four beta chains)
221
Q

Percentage match between siblings?

A

Each person has two sets of HLA haplotype clusters. One haplotype cluster (i.e. A, B, C) is inherited from each parent. Therefore, with any sibling, there is a 25% chance of a exact HLA match.

222
Q

Compare and contrast hyperacute, acute, and chronic graft rejection.

A
  • Host vs. Graft (Recipient attacks donor)
    • Hyperacute rejection - humoral response
      • Immediate response usually during surgery - thrombosis and occlusion
      • Occurs due to wrong blood type or cross-contamination of blood type
      • Can have pre-made HLA antibodies
    • Acute rejection - cell-mediated and humoral response
      • Response in weeks to months
      • Antibodies made after transplantation
    • Chronic rejection
      • Response in months to years
      • Slow degradation of organ over time from T-cell mediated responses
223
Q

Graft vs. Host

A
  • Graft vs. Host (Donor transplant attacks recipient tissue)
    • Donor T-Cells in the graft proliferate and attack the recipient’s tissue. Common in bone marrow transplants.
224
Q

Transplant: Desensitization therapy?

A
  1. Desensitization therapy
    1. Rituximab
  2. Fab domain of rituximab binds to the CD20 antigen (NFAT) on B-lymphocytes, and the Fc domain recruits immune effector functions (NK cells) to mediate B-cell lysis
  3. Can’t make antibodies (No humoral response)
225
Q

Calcineurin Inhibitors

A
  1. Calcineurin Inhibitors -
    1. Stop Calcineurin from dephosphorylating (activating) NFAT which is a transcription factor that activates the expression of genes involved in T expansion → prevents IL-2 transcription
    2. Side effects: nephrotoxicity, neurotoxicity, HTN, and DM
    3. Types
      1. Tacrolimus - Binds FKBP12, creating a complex that inhibits calcineurin

Cyclosporine - Binds to cyclophilin, inhibiting calcineurin

226
Q

Block lymphocyte proliferation drugs?

A
  1. Azathioprine - metabolized to 6-mercaptopurine in the body blocks de novo purine synthesis (which lymphocytes depend heavily on) and prevents lymphocyte proliferation
    1. Nonspecific to the immune system
    2. Side effects – leukopenia, anemia, thrombocytopenia

Mycophenolate mofetil - prevents guanine nucleotide synthesis in lymphocytes, inhibiting de novo purine synthesis and preventing lymphocyte proliferation → Specific to immune system,

227
Q

Inhibits B & T cell responses to IL-2 drugs?

A
  1. Rapamycin (Sirolimus) - inhibits mTOR (important for translation), a kinase which is required for T cell responses to IL-2, a cytokine growth factor involved in T cell activation
    1. Side effects – NOT nephrotoxic, causes anemia, thrombocytopenia, leukopenia, insulin resistance, HLD
      1. Has lower toxicity to kidneys than calcineurin inhibitors
228
Q

Predict the side effects associated with treatments that are used to prevent allograft rejection.

A
  1. Increased risk of infection (neutropenia)
  2. Increase risk of cancer from oncoviruses.
  3. Nonspecific immunosuppression

SPM (ARSH) (5 decks)

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