OMK: week 12 PLO, LO, lecture

LO: Using pedigree charts, determine (a) the possible genotypes of an individual, (b) calculate the probability an individual will be a carrier for a disease allele, and (c) calculate the probability an individual will present with a disease (Dr. Becker)

(do practice questions)

LO: Calculate allele, carrier and disease frequency using the Hardy-Weinberg equation

(go practice)

LO: Describe the measures commonly used in systematic reviews

(idk what he asking for...clearly it was not in the slides) -formulate questions/PICO -make hypothesis -conduct literature search using keywords -assess bias/accuracy -confidence intervals (reject if the tested group has CI within 95% CI of control group -summarize empirical evidence using rigid protocol

LO: Based on a clinical scenario and the pharmacologic properties of the drug; employ the most appropriate drug 30 yo construction worker sustained bilateral crush injuries to LE (skeletal muscle trauma), requiring immediate surgery. A junior resident administers succinylcholine to intubate and prep for surgery. What is site of action of Succ? Effect of Succ? Adverse effects on this patient?

-Nicotinic receptors (Nm) of muscle end plate -succ binds Nicotinic receptors, causing 1 time depolarization, and remains there blocking ACH binding -causes malignant hyperthermia (stiffness), hyperKalemia =Dantrolene, to stop Succ-induced malignant hyperthermia *DO NOT USE succ in skeletal muscle injury pt, or burned patients!

LO: Summarize how to review a published meta-analysis and use the results to solve a clinical problem

-after systematic review.... 1. check if questions/methods clearly stated 2. make a preset protocol for selection articles (set definitions/question) 3. check publication bias 4. cochrane collaboration (grades used to rank the studies)

How to decide which NMB drug to use?

-dependent on available NM receptors -in pt with Myasthenia gravis (damaged/reduced receptors), will likely have higher NM blockade effect with nondepolarizing NMBD → needs lower dosage -in pt with severe burns (increase receptors, and sensitivity) -will likley have lower NM blockade effect →needs higher dose *in pt with BCHe deficiency (cannot breakdown succ), will have prolonged succ NMBD induced paralysis→ need to adjust dose accordingly -we can test their BCHe percent by injecting dibucaine to a blood sample, dibucaine number needed to inhibit succ breakdown is indicative of BCHe amount in blood *hyperkalemia is common in burn-patients if given succinylcholine

LO: Compare the strengths and weaknesses of a standard versus a network meta-analysis

-standard/pairwise= strong comparision btn 2 drugs since you are literally take studies specifically comparing those 2 treatments, limited studies with those 2 specific drugs -network= larger pool of studies to take from, weaker connection btn 2 treatments

PLO: Explain the mechanism by which an action potential arriving at a presynaptic terminal leads to the release of acetylcholine (Ach)

7 steps mechanism of action potentials to skeletal muscle contraction: 1. AP at synpase, depolarization causes 2.V-gated Ca+ channels 3. Ca+ stimulates NT ACH release from docking protein 4. NT diffuses across cleft to post-receptors ------POST CELL------ 5. activated ACH-ligand gated receptors cause depolarization (Na channels open) 6. EPP generated, activates voltage gated L channels (DHP-RR complex) 7. releasing intracellular Ca+ to bind troponin>myosin head>actin filament>contraction

LO: Define confidence interval and explain how confidence intervals can be used to determine whether a relative risk or odds ratio is statistically significant

=% confidence that our interval contains the mean -95% CI means results are replicable 95% of time -used to determine how precise the data set is -CI values are estimated ranges of the actual outcome -if CI range includes 0 or 1, it is not significant *rule of thumb=if the estimated probility for experimental group is within 95% CI of control group, it means your drug likely "makes no difference"

LO: Describe the difference between correlation and causation (Dr. Ferland)

=Correlation - a measure of an association between two variables (in a linear relationship) -not indicative of causation ex. found via survey studies ======================================= =Causality - relationship that directly impacts 2 variables - relationship must meet 3 criterias: ➊cause is related to effect at individual level ↳individual case control study, establish relation) ➋cause precedes the effect ↳cohort, find common exposure prior to effect ➌changing case, changes effect ↳random case trials, establish relation ex. tested via experimental or case controlled studies

PLO: Understand the assumptions made in the Hardy-Weinberg equation

=[p2 + 2pq + q2]= 1 Assumptions: Organisms are diploid Generations are non-overlapping Population must be large No immigration or emigration No mutation in the gene of interest No natural selection occurs (individuals reproduce at equal rates) Mating is random Equation: p2 + 2pq + q2 = 1 Frequency of dominant allele = p Frequency of recessive allele = q All frequencies must equal 1, therefore: p+q=1

LO: Describe the molecular basis of cross bridge cycling that generates force in skeletal muscle fibers; explain the role of ATP in this process.

=cross bridge cycling generates repeated power strokes pulling actin over myosin filaments 1. in presence of Ca+, troponin deactivated, and actin unlocked... 2. ATP hydrolysis by myosin ATPase (rate limiting step) provides ADP to energize myosin head 3. ADP+myosin bends head 90* and binds actin (forming cross bridge) 4. followed by powerstroke 45* 5. pulling actin filament to slide closer (seen as contraction) 6. ADP released, ATP unlocks myosin head from actin (detaching the bridge) 7. this process repeats in the present of Ca+, and adequate ATP *in the lack of ATP, myosin ATPase stops hydrolysis, no ATP to detach the bridge, cross bridging remains

LO: Describe the impact of incomplete penetrance on disease frequency

=incomplete penetrance occurs in autosomal dominant disorders * Penetrance= (%diseased/total carriers)

LO: Identify the indication, mechanism of action, and adverse effects of dantrolene

=treatment for Succinylcholine inhalation-caused-malignant hyperthermia (stiff patient) -gas succ increases metabolism, LOT Ca+ release, and heat overproduction -blocks ryanodine receptors (RYR1) -prevent Ca+ release -no contraction, no heat

LO: Predict the effects of autonomic ganglionic blockade on tissues (Table 10.2)

ACH affects muscles and ganglions, the following drugs blocks ACH to ganglion activation.. ■Depolarizing Ganglion blockers ●Nicotine (lipid-soluble analog of ACH) →crosses skin, BBB, placenta →causes vasoconstriction, EPI/NORE/DOPA release from adrenal medulla →Low dose nicotine: stimulates both sympathetic/parasympathetic (+ BP, +DOPA/ +Gi metabolism) →High dose nicotine: causes neural ganglion & neuromuscular blockade *nicotine withdrawal=tx with varenicline *Fetal circulation is 15% more sensitive to nicotine =========================================== ■NON Depolarizing Ganglion blockers →limited to research, unpredictable effects ●Hexamethonium ●trimethaphan ●mecamylamine

PLO: Describe codominant and incomplete dominant inheritance patterns and how they contrast from classic Mendelian inheritance patterns

Codominant: an inheritance pattern in which the heterozygous individual expresses BOTH alleles E.g. Blood types! Individuals who have AB blood exhibit codominant inheritance because they express A and B blood groups on RBCs. Incomplete Dominance: an inheritance pattern in which the heterozygous phenotype is a mixture of the dominant and recessive phenotypes

Drugs that decrease/increase ACH activity at NMJ:

Decrease ACH activity: -Botox (block ACH receptors, causing stiff muscles, no wrinkles? lol) -NMB drugs (succ, cisa-atra, RoVe) -ACHe analogs *Dantrolene (tx succ hyperthermia) is actually also a ACh blocker like succ but has better affinity Increase ACH activity: -Nicotine -ACHe inhibitors (Neostigmine>pyrdostigmine>Edrophonium) *RoVe is on steroids, needs to be on Sugar instead

LO: Differentiate the concepts of heterogeneity and homogeneity

Heterogeneity (P<5%): Like comparing apples to oranges -hetero studies are NOT good for combined studies -heterogenous results are significantly by chance (less than P<5%) -WE DO NOT WANT hetero studies Caveat: absence of statistical significance does NOT mean homogeneity, as the tests used tend to have low power Homogeneity (P>5%): Comparing apples to apples; we want homogeneity *homogenous studies (P> 5%, very similar, unlikely random) can be combined into meta-analysis

PLO: Identify the receptor type and subtype found in the neuromuscular junction

In skeletal NMJ, there are mostly nicotinic receptors (Ach ligand-gated Na channels)... ■Nn→ neuron autonomic ganglion ■Nm→ muscle NMJ

LO: In clinical problems, calculate relative risk, odds ratio, attributable risk, relative risk reduction, absolute risk reduction, number needed to treat, and number needed to harm

Just go practice on his slides/practices

LO: Differentiate between prospective and retrospective study designs

Prospective= predicts future risk/effects -ex. cohort studies for predictive risk factors restrospective= trace back into past -ex. case studies trace back in time to find cause

LO: Summarize the main features and strengths and weaknesses of RCTs and observational studies considering Methods, Assignment, Assessment.

Randomized control trials: ↳features= randomization in assigned groups -parallel design, compares intervention to outcome -cross over design, compares intervention to outcome, then swap placebo group and repeat (best with wash out period) ✅double blind assignments prevents bias, best for testing drugs, finds causation expensive, time consuming, potential volunteer bias (in it for money), ethical issues Observational studies: ↳features=cohort, case controlled, cross sectional studies ✅ethically safe, more convenient, cheaper, establish correlation of events recall bias, cohort effect, confounding variables, cannot find causation ●Cohort studies=best to find predictive risk factors ●Case-studies=best for rare diseases ●cross sectional study= best for prevalence of disease at a specific point in time (but on diff people)

LO: Differentiate between a standard meta-analysis and a network meta-analysis (as well as to other study designs)

Standard meta-analysis=compares interconnected studies ex. 2 drugs that have been DIRECTLY tested in 1 study Network meta-analysis= compares indirectly related studies ex. compares 2 drugs that been indirectly studies against each other

LO: Describe how X-inactivation, haploinsufficiency, and compound heterozygosity relate to disease

X-inactivation: -females have X (Xi), Xi becomes an inactive barr body -generally extra Xs are not lethal coz only 1 X is activated while the rest is inactivated -X inactivation leads to mosaicisms in females (calico cats, which the fur coat color gene is still active) (ex. 21 trisomy down syndrome, klinefilter XXY think male calico cats) haploinsufficiency: -mutation that deletes one of the gene alleles -one copy of gene is not enough to produce the needed gene (ex. GLUT1 deficiency syndrome) compound heterozygosity: -2 different mutations inherited that result in disease phenotype (ex. cystic fibrosis)

PLO: Identify patterns of autosomal dominant, autosomal recessive, X-linked dominant, X-linked recessive, Y-linked, and mitochondrial inheritance in pedigree charts and family histories (Dr. Becker)

Y-linked: only males affected. Affected father will pass to all sons. Mitochondrial: Affected mothers will pass to all children while affected fathers pass to none. Autosomal dominant: doesn't skip a generation. All affected individuals will have affected individuals will have affected parents. Autosomal recessive: skips generations. Two unaffected individuals can produce affected offspring X-linked dominant: affected father will produce 100% affected daughters (father passes Xd to daughter) X-linked recessive: more males will be affected. Affected females will have affected father and sons. (affected Xd,Xd mom will have 100% affected sons)

LO: Define attributable risk, relative risk reduction, absolute risk reduction, number needed to treat, and number needed to harm

attributable risk (AR) -risk difference, fraction of risk that is actually due to risk factor -(% exposed- %unexposed) relative risk reduction (RRR) -proportion of relative risk that is due to drug exposure as compared to control absolute risk reduction (ARR) -difference of risk of unexposed group minus risk of exposed group - (% unexposed-% exposed) number to treat=number of subjects who must be tested/treated for 1 person to benefit from treatment (1/ARR) number to harm=number of subjects who must be exposed to risk factor to cause harm in one subject (1/AR)

LO: Describe expressivity, pleiotropy, epistasis and anticipation on disease phenotype

expressivity= degree to which trait expression differs among individual (ex. polydactylyl: how many toes difference? pleiotropy=one gene affecting more than 1 trait (ex. Marfan syndrome) Epistasis= the amsking of allels by allic combination of another gene anticipation=progressive earlier onset of disease in successive generations with increasing severity within family (ex. Huntington's disease)

PLO: Characterize and trace acetylcholine synthesis, storage, release, and signal termination (Dr. Scully)

synthesis= like most other small amino acids, it is made directly at nerve terminals from (acetyl+choline group via O-acetyltransferase) storage=stored in vesicles at axon terminals release= binding of Ca+ releases ACH vesicle across synpase signal termination= after hydrolytic breakdown by ACHestase *not via reuptake

Non depolarizing steroid derivatives:

→Rocuronium (intermediate) →Vecuronium (intermediate) →pancuronium (long acting) ⚠️Adverse: -elevated histamine -interacts with inhaled anesthetics= suppresses CNS

Non depolarizing isoquinolines derivatives:

→cisatracurium (more potent, intermediate acting, Hofmann elimination) →atracurium (intermediate acting, Hofmann elimination) →(Mivacurium, tubocurarine, both not in USA) ⚠️Adverse: -Hoffman breakdown to laudanosine poison→seizures -interacts with inhaled anesthetics= suppresses CNS

PLO: Define dystrophin and learn how it contributes to structural integrity of a skeletal muscle fiber

→large rope-like protein with low abundance that forms a dystrophin-glycoprotein complex →anchors sarcolemma (plasma membrane) to cytoplasmic actin →prevents contraction induced injury

PLO: Explain the ionic mechanisms by which Ach depolarizes the post-synaptic membrane; explain the differences between a depolarizing (excitatory) motor end-plate potential (EPP) and an action potential; learn the role of acetylcholinesterase in regulation of depolarization of the post-synaptic membrane

■ACH on post synaptic membrane →binds ACH ligand gated Na channels →causing small depolarizations on sarcolemma membrane known as EPP (graded potentials, that eventually reach AP, above -55mv). →AP propagated down the T tubules →activates L channels (DHP receptor-rynaodine complex) →releasing intracellular Ca+>myosin head cycling>contraction ■ACHe → found in synaptic cleft → breakdown ACH, inhibits depolarization *causes relaxation of muscles instead

What do all NM blocker drugs have in common?

■ALL NMB Drugs: -elevates histamine -interacts with antibiotics (aminoglycoside, tetracyclines) to prolong NM/Ca+ blockade -interacts with cholinesterase inhibitors: -ACHe inhibitors enhance succ -ACHe inhibitors inhibits non-depolarizing blockers *caution to pt taking abx: aminoglycosides= streptomyosins/myosins tetracyclines= doxycycline/cyclines

LO: Define excitation-contraction coupling and explain depolarization-induced Ca2+ release; learn the role of ryanodine receptors and dihydropyridine receptors in this process. (Dr. Morganelli)

■Excitation-Contraction Coupling →AP>ligand gated Na inflex>depolarizes T tubules> activates DHP-RR channel complex>release intracellular Ca+>contract muscles →thus, AP excitation induces contractions ■depolarization-induced Ca2+ release (DICR) →depolarization down T tubule →activates L channels (DHP receptors) to fuse with ryanodine receptors forming DHPR-RR complex →complex directly releases stored Ca+ from SR *in sense, the depolarization DIRECTLY stimulates SR Ca+ release *CICR= depolarization opens L channel, extracellular Ca diffuses into cell as 2nd messenger>then bind RR *DICR= does not require extracellular Ca+ to diffuse in, no second messenger **Skeletal muscles use the DICR pathway : T-tubule depolarization activates DHPRs, causing them to fuse to ryanodine receptors directly releasing intracellular Ca+

LO: Characterize myasthenia gravis and Lambert-Eaton myasthenic syndrome (LEMS); apply the appropriate diagnostics and pharmacologic intervention(s)

■Lambert Eaton myasthenic syndrome (LEMS) autoimmune attack on Voltage Ca+ channels - age 35-60 - absent tendon reflexes, autonomic dysfunction - bilateral weakness (lower to upper spread) -strength improves for few minutes during exercise before worsening -dx with auto-antibody to VGCC ■ Myasthenic gravis (MG) autoimmune attack on ACH muscaric receptors - age 35-50 (younger) - droopy eyelids - unilateral weakness (upper to lower spread) - normal reflexes, and autonomic function - worsen with exercise -dx with auto-antibody to ACh muscaric receptors or MuSK *LCAB=lambert, Ca+ inhibition, absent reflexes, bilateral *GAUD=Gravis, ACH inhibition, unilateral, eyes droopy "el CABbage is gaud"

PLO: Identify and characterize the cholinergic receptors (nicotinic and muscarinic)

■Muscarinic →located on smooth muscles, visceral organs/vessels, brain →uses GPCR (metabotropic, indirect, 2nd messenger) located primarily on →responds to muscarine and acetylcholine ■Nicotinic →located on skeletal muscles, NMJ/motor end plates, brain →uses Na+/K+ ion channels (ionotropic, direct) →responds to nicotine and acetylcholine

PLO: Learn the structural and molecular elements of the neuromuscular junction (NMJ) involved in neurotransmitter release and stimulation of skeletal muscle fibers

■NMJ →synapse btn motor neuron and skeletal muscle fiber, also called motor-end plate →chemical transmissions: ACH release across synaptic cleft →NO electrical transmissions (no gap junctions in skeletal muscle) ■NT release →AP in presynpatic neuron →opens voltage Ca+ channels →Ca+ influx binds and releases ACH vesicles →ACH release across synapse ■stimulation of skeletal muscle fiber →ACH binds motor end plate's receptors →opens ACH ligand gated Na channels →depolarization across sarcolemma>T tubules →stimulates release of Ca+ from SR (activates DHPR-RR complex, which is a channel for Ca+) →Ca+ unlocks troponin complex →allows myosin heads to bind and pull actin filaments →sarcomere shortening, is seen as contraction *in skeletal muscles, uses Ca+ to unlock tropinin, but in smooth muscles Ca+ is used to activate MLCKinases

PLO: Define motor unit and learn how the size of a motor unit varies depending on the function of a particular muscle

■motor unit=consist of single somatic alpha motor neuron AND innervated muscle fibers. Has 3 sizes for motor units... ➊Small (type1)= →<100 muscle fibers →slow, fine motor control (hands, postural muscles), →more easily activated due to low threshold ➋Medium Motor units=Type 1/2 ➌Large (type2)= → >2000 muscle fibers, →fast, power (quadriceps, biceps) →high threshold, needs strong stimuli

LO: Define prevalence rate, incidence rate, mortality rate, describe their usage, and their effects on each other

■prevalence= ALL cases/total population ■iNcidence= new cases over time period/total population ■mortality rate= deaths/population *used to assess population epidemiology and disease control

LO: Differentiate between randomized controlled trial and quasi-experimental study designs and describe their advantages and disadvantages.

■Randomized controlled trials →establishes causality, true experiment design →double blind, randomized groups, has control group →design types includes: ●parallel design (compares drug->outcome) ●crossover design (2 part time, compares drug->outcome, then retest with swapped control group) ■Quasi-experimental study →tests some causation →no randomization, has control group (assigned groups by self section/natural grouping/administrator selection →design types includes: ●Non-equivalent group designs (NEGD)=tx group gets baseline pre-test ●double pretest design=both groups get baseline pre-test (use to compare baseline of both treated/untreated group) ●proxy pretest design=similar to NEGD, except you don't tell the patient it is pre-test (use only when no pre-test avail) ●Multiple time series design=several tests before and after drug given (use to track multiple changes) ●switching replication quasi experimental design= pretest, give drug, post test, THEN swap controls and retest (similar to cross over RCT), both groups treated fairly *rules out confounding variables that were present since the start of trials

LO: Explain the mechanism by which a rise in intracellular calcium leads to cross bridge formation; learn the mechanisms that restore intracellular calcium to resting (non-contractile) conditions.

■Rise in intracellular calcium →contraction of all muscle types (skeletal, smooth + cardiac muscle) requires activation of DHPRs (on T tubules), and increase of intracellular free Ca2+ →Ca2+ unleashes troponinC →allows high energy myosin head(with ADP) to bind actin forming cross bridge formation, followed by contraction ■Ca+ removal: -Ca+ usually stored inside SR, bounded by calreticulin, calsequenstrin -post contraction elevated intracellular Ca+ is removed by: 1. SERCA pump= constantly pumps Ca+ back into SR, maintains resting baseline 2. Na/Ca exchanger= exports Ca+ out of cell 3. Ca+ pumps= constantly pumps Ca+ out of cell *pumps=uses ATP and are always active, necessary for muscle relaxation

LO: Define skeletal muscle wave summation that occurs for unfused and fused tetanic contractions; learn the biochemical mechanism responsible for this phenomenon.

■Wave summation= synergistic effect from collection of graded EPP occurring one after another. If a skeletal muscle receives a second stimulus while a previous twitch is still occurring, the second twitch will be stronger. ■UNFUSED tetanic contractions -incomplete tetanus which APs drive increasing force development (until it reaches max/fused tetanus which force development is platued) ■FUSED tetanus -complete/fused tetanus which force development is maxed out, no more AP can further increase it - intracellular [Ca2+] and cross bridge cycling is maximized -contraction can continue uninterrupted until the muscle fatigues and can no longer produce tension. *The longer intracellular Ca2+ remains elevated above baseline, the longer the period of cross bridge cycling. (force summation due to repetitive stimulation)

LO: Identify the methods of reversal of nondepolarizing neuromuscular blockade (2 reversal agents)

■cholinesterase inhibitors ●MOA: +ACH, to flood out drug →neostigmine (first choice) →pyridostigmine (long acting) →edrophonium (short acting) ⚠️neo= causes allergic rxn, arrhythmias, SLUDGE (neo-slimey symptoms) ■selective chelating agents ● +elimination/chelating of drugs →Sugarmmadex (ONLY for rocuronium, vecuronium; Sugar for Rove) ⚠️eliminates oral contraceptives, anaphylaxis *you cannot reverse succ coz it is so strongly bond, will have to let it diffuse off before adding BCHe to break it down, you CAN however treat succ-induced hyperthermia with Dantrolene

LO: Name and Identify the mechanism of action and adverse effects of depolarizing and non-depolarizing neuromuscular blocker drugs (Dr. Scully)

■depolarizing NM blockers ●succinylcholine (Short acting, metabolized by BCHe after diffusion) ●MOA: phase 1→Succ binds NM receptor causing sustained depolarization, muscle fasciculation, flaccid paralysis phase 2→Succ hogs channel causing membrane repolarized, and desensitization ⚠️Adverse: -hyperkalemia, -malignant hyperthermia especially with inhalation (tx with Dantrolene) -post op pain due to prolong muscle fasciculation (avoid in pt with asthma, cardiac arrest, kids, severe skeletal muscle trauma) ================================================= ■nondepolarizing NM blockers (2 curare derivatives) ●MOA: →ACH competitive antagonist ●isoquinolines →cisatracurium (more potent, intermediate acting, Hofmann elimination) →atracurium (intermediate acting, Hofmann elimination) →(Mivacurium, tubocurarine, both not in USA) ⚠️Adverse: -Hoffman breakdown to laudanosine poison→seizures -interacts with inhaled anesthetics= suppresses CNS ●steroids →Rocuronium (intermediate) →vecuronium (intermediate) →pancuronium (long acting) ⚠️Adverse: -elevated histamine -interacts with inhaled anesthetics= suppresses CNS =================================================== ■ALL NMB Drugs: -elevates histamine -interacts with antibiotics (aminoglycoside, tetracyclines) to prolong NM/Ca+ blockade -interacts with cholinesterase inhibitors: -ACHe inhibitors enhance succ -ACHe inhibitors inhibits non-depolarizing blockers *caution to pt taking abx streptomyosins/myosins, or doxycycline/cyclines *BCHe= butyrylcholinesterase *curare=very large, ionizes and hydrophilic, does not cross GI lining *ACt-on-the-RVsP

LO: Define the length-tension and force-velocity relationships for intact skeletal muscles and learn their role in the regulation of active force development

■length-tension= -decrease length, increase velocity -more shortening means more contraction (more tension made) -F=W/d (smaller distance, increases force) *max force development=when sarcomere goes from resting length to full contraction ■force-velocity= -increase force, decrease velocity of contraction -the more force made, runs out of cross bridges thus slows down -F=MA (increase force, decrease acceleration and velocity) ■regulation of active force development -max resting length, will yield the most active force development (larger magnitude in contraction) -the more stretch out it is, the more it can contract later *both relations are inverse!

PLO: Define the load on a muscle and active muscle tension or force; define isometric and isotonic contraction of an intact skeletal muscle

■load=force exerted on a muscle by an object →increase load, increases demand for more force, increases rate of cross cycling ■active muscle tension →force produced by cross-bridge cycling regardless if muscle shortens/not ■isotonic contraction →muscle length shortens →peak tension is always constant (u cannot go beyond the max) →low resistance to change ■isometric contraction →muscle length constant →peak tension is constant (sustained) →high resistance to change) *think: it's already at it's max stretch, cannot further stretch anyways *afterload= is the max load, at this point it pulls on the muscle so much that it prevents contraction/shortening

PLO: Define a skeletal muscle twitch and learn its different phases; describe the ionic basis of a skeletal muscle fiber action potential

■skeletal twitch →momentary muscle fiber contract caused by 1 stimuli (activates 1 muscle fiber, not the while muscle) →3 phases: -lag phase (before AP) -contraction (increase Ca+, excitation-contraction coupling) -relaxation (cross bridge cycle, tension) ■skeletal muscle AP →cause by opening of ACH-ligand gated Na channels on sarcolemma membrane making graded potentials (EPP) →eventually depolarizes membrane causing AP (seen as spike in Na+) →AP travels down T tubules opening DHP -ryanodine receptors →influx Ca+>troponin>cycling>contraction *EPP=excitatory end plate potentials

PLO: Learn why skeletal muscle is defined as striated muscle; define muscle fiber, sarcolemma, myofibril, myofilament, sarcomere, T-tubule, and sarcoplasmic reticulum (Dr. Morgnaelli)

■striated= due to many organized sarcomeres units lining up uniformly to form dark bands →muscle fiber=1 looong skeletal muscle cell that has bundled fibrils →sarcolemma=plasma membrane around the striated muscle fiber cell (where L channel/DHPR are) →myofibril=rods inside the cell, sectioned with sarcomere units →myofilament= myosin/actin filaments inside the sarcomere →T tubules= invagination of sarcolemma, carries AP down T tubules>SR>to stimulate release of Ca+ →triad=area of exchange btn T tubules, SR, cisternae (contains A→I band junction) →sarcoplasmic reticulum (SR)= releases intracellular Ca+ when its Ryanodine receptors activated by NMJ depolarization *Titin= protects myosin thick filaments from over contraction during high stress (muscle damage)

PLO: Explain how the structural elements of a sarcomere are organized; learn the protein composition of thick and thin filaments; learn how the structural elements of a sarcomere change during active muscle shortening

■structure=contractile units of thin/thick filaments →thick=bundle of myosin molecules each with 2 heads which has myosin ATPase and regulatory light chains attached. →thin= G-actin filaments with 2 strands of tropomyosin (at rest, blocks myosin binding sites, needs Ca+ to bind TnC subunit to unlock it) ■sliding filament theory →thin actin filaments slide over thick myosin filaments →HI bands and Z-Z distance shortens, thus whole sarcomere shortens →collectively seen as muscle contraction BONUS: I band - Lighter band; thin filaments plus Z-disk Z-disk - attachment site of thin filaments; are anchored to cytoskeleton A band - darker band; region of overlap of thin and thick filaments (myosin) H-band - thick filaments only M-band - proteins that anchor thick filaments to cytoskeleton *H i, I am thick, she is light, but we ALL overlap in other places

LO: Describe the principles for evaluating meta-analyses and systematic reviews

■systematic reviews -use before meta-analysis if avail -identify and critique relevant studies -form new conclusions ■meta-analysis -collection of studies from published researches -limited to certain pre-existing questions that the original studies have set -least bias, due to tests being repeated thousands of times and is highly inclusive

LO: Describe different types of study designs used in randomized clinical trials (n-of-1, parallel, crossover, etc.)

▶RCT: ●N-of-1 -randomized, multiple crossover study performed in a single individual -Can balance patient needs with methodological rigor -several tests at the same time -useful for understanding rare diseases ●parallel design (compares drug->outcome) ●crossover design (2 part time, compares drug->outcome, then retest with swapped control group) ========================================== ▶Cross-Sectional Study Design: -finds correlation of a disease and the prevalence of risk factors - can be measured at a single point in time, across large population -no longitudinal time course thus association is weaker than in other study designs

nondepolarizing NM blockers (2 curare derivatives)

●MOA: →ACH competitive antagonist ●isoquinolines →cisatracurium (more potent, intermediate acting, Hofmann elimination) →atracurium (intermediate acting, Hofmann elimination) →(Mivacurium, tubocurarine, both not in USA) ⚠️Adverse: -Hoffman breakdown to laudanosine poison→seizures -interacts with inhaled anesthetics= suppresses CNS ●steroids →Rocuronium (intermediate) →vecuronium (intermediate) →pancuronium (long acting) ⚠️Adverse: -elevated histamine -interacts with inhaled anesthetics= suppresses CNS

LO: Describe characteristics of a strong randomized controlled study design for a research study

●Randomization groups= chance determines what group a subject may be in ●Double blind= Ideally both the subjects and the investigators are not aware of which group they are in --> Double-blind

LO: Explain the appropriate use of clinical case reports and case series as evidence in medical practice

●clinical case reports/case studies PROS: - help recognize rare disease, unusual presentation - introduces new treatments/methods CONS: - not representative of population - author bias - no causation, no inference made *use with caution

LO: Define relative risk, odds ratio, and hazard ratio and describe their usage

●relative risk →probability of event occurring in exposed group/ probability of the event occurring in non-exposed group. →is a percentage out of TOTAL possibility (1/4 chance) =(% truly exposed / % truly not exposed) *best to find relative risk not absolute ====================================== ■odds ratio → (odds of having risk if condition is present/odds of having risk if condition is absent) →is a ratio comparing against OTHER possibilities (1:3 ratio) =(product of 2 extremes/ product 2 nonextremes) *best for retrospective case-controlled studies, to find risk for particular outcome, case controlled studies ==================================== ■Hazard ratio -(hazard rate when exposed/hazard rate when unexposed) -best to show relative risk OVER TIME for prospective studies

Depolarizing NM blocker (only 1):

●succinylcholine (Short acting, ACH analog) ●MOA: phase 1→Succ binds NM receptor causing sustained depolarization, muscle fasciculation, flaccid paralysis phase 2→Succ hogs channel causing membrane repolarized, and desensitization *removal= needs to be diffused off receptor before BCHe can break it down ⚠️Adverse: -hyperkalemia, -malignant hyperthermia especially with inhalation (tx with Dantrolene) -post op pain due to prolong muscle fasciculation *avoid in pt with asthma, cardiac arrest, kids, severe skeletal muscle trauma