PBL Flashcards

Question

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

Answer 1

* 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.

Answer 2

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

Answer 3

* 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

Answer 4

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

Answer 5

* 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

Answer 6

* 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

Answer 7

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

Answer 8

* 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

Answer 9

* 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

Answer 10

* 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

Answer 11

**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

Answer 12

* Epidemiology: thrifty gene hypothesis that genes for fat deposition were advantageous when we were hunter/gathers

Answer 13

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

Answer 14

* 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%

Answer 15

* 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

Answer 16

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

Answer 17

* **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

Answer 18

* 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

Answer 19

* 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

Answer 20

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

Answer 21

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

Answer 22

* 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

Answer 23

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

Answer 24

**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

Answer 25

* 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

Answer 26

Statins and Evolocumab

Answer 27

* 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

Answer 28

* Definition of Urea Cycle: Method of excreting urea, a metabolite of protein catabolism.

Answer 29

* 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.

Answer 30

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.

Answer 31

* Starvation/fasting → protein catabolism → amino acid degradation → elevated ketones and ammonia

Answer 32

* Regulation: N-acetylglutamate is an allosteric activator of carbamoyl phosphate synthase * Rate-Limiting Step: carbamoyl phosphate synthase

Answer 33

* 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)

Answer 34

1. Protein Catabolism 2. Gut Bacteria

Answer 35

* 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

Answer 36

* Reliable diagnostic test * Treatments are available * Early interventions have positive effects * All tests can be avoided on religious basis

Answer 37

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

Answer 38

* 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+

Answer 39

* BCKD complex is found in the inner membrane of the mitochondria

Answer 40

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

Answer 41

* “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

Answer 42

* Utilizes 5 cofactors * **T**ender **L**oving **C**are **F**or **N**ancy * TPP (B1 – thiamin) * Lipoic Acid * FAD (B₂ - Ribloflavin) * NAD+ (B₃ - Niacin)

Answer 43

* 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%

Answer 44

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

Answer 45

* (+) 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

Answer 46

* 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

Answer 47

* 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

Answer 48

* 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

Answer 49

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

Answer 50

Proline important for hydroxylation → forms H-bonds → strengthens collagen structure Hydrogen bonds between hydroxyl groups on external amino groups are weakened due to kink

Answer 51

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)

Answer 52

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.

Answer 53

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

Answer 54

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

Answer 55

* **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.

Answer 56

DNA testing shows mutations in COLA1 and COLA2 genes

Answer 57

* **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

Answer 58

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

Answer 59

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.

Answer 60

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

Answer 61

* 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.

Answer 62

* 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.

Answer 63

* Symptoms in Full Penetrance Individual * Intellectual disability/autism * Large testes, ears, jaw, face * Mitral Valve prolapse * Seizures

Answer 64

* 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

Answer 65

* 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

Answer 66

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

Answer 67

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

Answer 68

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.

Answer 69

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.

Answer 70

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.

Answer 71

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.

Answer 72

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.

Answer 73

**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.

Answer 74

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.

Answer 75

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

Answer 76

CF, Tay-Sachs

Answer 77

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.

Answer 78

* 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.

Answer 79

* 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

Answer 80

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

Answer 81

* The frequency of RB in an inherited Rb proband will be higher than in a somatic Rb proband.

Answer 82

* 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

Answer 83

* 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”.

Answer 84

**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.

Answer 85

**G1/S Checkpoint** * Cyclin E **S/G2 Checkpoint** * Cyclin A **G2/M Checkpoint** * Cyclin B **M/G1 Checkpoint** * Cyclin E **G0 Checkpoint** * Cyclin D

Answer 86

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.

Answer 87

* 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

Answer 88

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.

Answer 89

* 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

Answer 90

* 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.)

Answer 91

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.

Answer 92

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

Answer 93

Radiation - causes more mutations helping lead to apoptosis Chemotherapy: combination of different drugs to treat different classes of breast cancer

Answer 94

* 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

Answer 95

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)

Answer 96

* 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

Answer 97

* 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

Answer 98

* 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

Answer 99

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

Answer 100

* 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

Answer 101

* 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

Answer 102

Remember: M1 = Stage IV

Answer 103

* 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.

Answer 104

* 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

Answer 105

* Activation: cytochrome p450s * Detoxification: glutathione-S-transferases (GSTs) - glutathione reduces ROS

Answer 106

* 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

Answer 107

* 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

Answer 108

* 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.

Answer 109

**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

Answer 110

* Community Acquired Pneumonia Diagnostic Tests: Urinary antigen test * Detecting the C-polysaccharide antigen of *Streptococcus pneumoniae* (leading cause of CAP)

Answer 111

* 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

Answer 112

* 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

Answer 113

* 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

Answer 114

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

Answer 115

o Present the gliadin or transglutaminase (TTG) peptide

Answer 116

* 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)

Answer 117

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

Answer 118

* 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.

Answer 119

* 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

Answer 120

* 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)

Answer 121

* 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

Answer 122

* 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

Answer 123

* Exposure * Infection * Disease

Answer 124

* Exposed: sharing air space with infected individual * A small percentage of individuals exposed become infected

Answer 125

* 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)

Answer 126

* 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)

Answer 127

* Weight loss * Night sweats * Cough * Hemoptysis

Answer 128

* 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

Answer 129

* 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: **R**ifampin (always combine), **I**soniazid, **P**yrazinamide, and **E**thambutol (**RIPE**)

Answer 130

* 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

Answer 131

· Anapholes mosquitoes

Answer 132

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) 2. Sporozoites travel to liver and infect liver cells. Parasites divide many-1000-fold (1st stage of multiplication). 3. Infected hepatocytes rupture and release merozoites into blood stream. Erythrocytic Cycle, steps 4-6 4. Merozoites invade RBCs and multiply approximately 30-fold(2nd stage of multiplication) 5. RBCs rupture and release more merozoites. 6. Released merozoites invade other RBCs. 7. Some merozoites are able to form gametocytes. 8. 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)

Answer 133

* 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

Answer 134

* 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.

Answer 135

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.

Answer 136

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

Answer 137

* Fever, chills, anemia * Hypotension * More severe: jaundice, seizures, coma, death

Answer 138

**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

Answer 139

* 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)

Answer 140

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

Answer 141

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.

Answer 142

* 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

Answer 143

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

Answer 144

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.

Answer 145

* 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)

Answer 146

* 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

Answer 147

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

Answer 148

* 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.

Answer 149

* 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

Answer 150

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.

Answer 151

* 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)

Answer 152

* 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.

Answer 153

* 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

Answer 154

* 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

Answer 155

* 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.

Answer 156

* 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

Answer 157

* 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

Answer 158

* Secondary * Acquired, often from external sources * Possibly from: Diabetes, HIV infection, immunosuppressive treatments, prolonged illness, hospital stay.

Answer 159

* 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

Answer 160

* 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

Answer 161

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

Answer 162

* 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.

Answer 163

* 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.

Answer 164

* 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)

Answer 165

* 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)

Answer 166

* 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

Answer 167

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)

Answer 168

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.

Answer 169

* 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

Answer 170

* 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.

Answer 171

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)

Answer 172

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

Answer 173

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,

Answer 174

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

Answer 175

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

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