Penicillins & Cephalosporins (Lesse) Gram positive (secretes beta-lactamase into ECM) vs.

Gram negative (secretes beta-lactamase into periplasmic space) Penicillins irreversible binds to the transpeptidase enzyme to inhibit peptidoglycan cross-linking thus, only active on replicating organisms (thus, not active against bacteria in static or stationary phase) resistance mechanisms:  -lactamases: enzyme produced by bacteria to inhibit penicillins (encoded on plasmids so easy transfer to other bacteria that dont have such resistance)  alteration of penicillin-binding proteins (like the transpeptidase enzyme) so penicillin can no longer bind to it & thus no longer inhibit it MRSA & streptococcus pneumoniae classified into: natural, anti-staphylococcal, amino, & extended spectrum given orally: penicillin V, ampicillin, amoxicillin, cloxacillin, dicloxacillin these need no dose adjustment if renal dysfunction since they are excreted via biliary system: nafcillin, oxacillin, cloxacillin, dicloxacillin drugs are lipophilic side effects: allergy, methicillin-allergic interstitial nephritis, electrolyte disturbance, leukopenia (for nafcillin), seizures, c. diff infection Natural Penicillins Penicillin G drug of choice if it is still actually active against the bacteria staph aureus strains) are resistant Benzathine penicillin limited to syphilis and prophylaxis

but most (such as 95% of

Antistaphylococcal Penicillins nafcillin, oxacillin previously drug of choice for staph & strep infections till methicillin-resistance (MRSA) arose MRSA means they are resistant to not just methicillin but all antistaphylococcal penicillins:  nafcillin / oxacillin (IV) vs. cloxacillin / dicloxacillin (oral) Aminopenicillins ampicillin, amoxicillin Amoxicillin has greater oral absorption, serum levels and half life compared to ampicillin no additional activity against staph than natural penicillins do (>95% also resistant to these abx) good for enterococcal, strep, haemophilus influenzae (but 25% carry -lactamase plasmid) Extended Spectrum Penicillins piperacillin gram-negative rods, including pseudomonas often given with -lactamase inhibitors (suicide inhibitors that destroy the bacterial enzyme) to expand their spectrum of activity even farther used for staph, klebsiella, E.coli, Neisseria, haemophilus influenza, branhamella, bacteroids, etc. Cephalosporins 1

similar to penicillins in that it inhibits the transpeptidation rxn from occurring to cause failure in cross-link formation resistance mechanisms:  special -lactamases (cephalosporinases) mostly plasmid mediated o except the following which are chromosomally mediated SPICE: serratia, providential, indole-positive proteus, citobacter, & enterobacter side effects: those allergic to penicillin often allergic to these, anaphylaxis (severe allergic rxn) Classification by generations, each generation gets better activity against gram-negative rods:  1st good for both staph & strep: cefazolin (IV) vs. cephalexin (oral)  2nd with Haemophilus activity (cefuroxime) or with anaerobic activity (cefoxitin)  3rd without pseudomonas activity (ceftriaxone) or with pseudomonas activity (ceftazidime)

Antibiotics II (Lesse) Vancomycin a glycopeptide antibiotic inhibits cell wall synthesis but via diff. mechanism than -lactam drugs by binding to the terminal D-Ala-D-Ala complex (via charge attraction H-bonding) to block transpeptidation rxn resistance: drug not susceptible to -lactamases so bacteria must use other means:  alteration of the terminal complex so it can no longer bind to it o substitution of lactic acid for D-Ala since its unable to bind to complex if lactic acid used  must carry an entire gene cluster to encode for a 2 mechanism of cell wall synthesis agent of choice for MRSA great gram positive (aerobic & anaerobic, including c. diff) Cleared by the kidney no oral absorption, yet there is still a pill form why? to treat infections in the gut (like pseudomembranous colitis) given IV for systemic tx thus, used for: MRSA, if allergic to penicillin, or given orally for pseudomembranous colitis side effects: nephrotoxicity; Red Man Syndrome (severe histamine rxn) if given rapidly (must administer at <1dose/hr) Recent outbreaks in hospitals of vanco resistant enterococci Vanco is not as bacteriosidal as beta-lactams Daptomycin a lipopeptide antibiotic alters ion flux in bacterial membranes very potent, rapid bactericidal more active against MRSA than vanco thus, drug of choice if MRSA cant be cleared by vanco Bound by surfactants can not use to treat pneumonia Usage concerns: my cause rhabdomyolosis Linezolid an oxazolidinone antibiotic inhibits protein synthesis by binding to 50S ribosome & thus bacteriostatic active against staph, strep, enterococci, gram+ anaerobic cocci, corynebacteria, listeria monocytogenes also good for MRSA & vanco-resistant enterococci 2

side effects: bone marrow suppression (thrombocytopenia, neutropenia), abnormal LFTs

Quinupristin-dalfopristin a streptogramin antibiotic inhibits protein synthesis by binding to 50S ribosome used as a vanco substitute active against gram+ cocci: multidrug-resistant strains of strep, staph, pneumoniae, & E. faecium (but not E. faecalis) I.V. only Inhibits Cytochrome P450 (although it is not necessary for its metabolism) affects metabolism of other drugs Tigecycline a glycylglycine antibiotic inhibits protein synthesis by binding to 30S ribosome given IV only watch out for severe N&V (esp. in otherwise healthy people rather than the old) resistance: inefficiently pumped out of bacterial cells by multidrug transport pumps, alteration of 30S ribosomal binding site used: where MRSA, vancomycin-resistant enterococcus (VRE), & other gram+s are likely to infect (like post-operative wounds) Erythromycin a macrolide antibiotic bacteriostatic, inhibits protein synthesis by binding to 50S ribosome growing resistance, plasma incoded (esp. Grp A strep, staph, & pneumococci) by modification of binding site (ribosomal protection via a methylase) or efflux of drug out of cell or production of esterases that hydrolyze macrolides  Staph resistance to this drug in Buffalo > 40% used as a penicillin substitute (for those allergic) staph, strep, pneumococci (if not resistant) side effects: GI problems, inhibits cyt P450 enzymes which can serum []s of other drugs Destroyed by gastric acids, requires enteric coating and foods interfere with its absorbtion Clarithromycin a macrolide antibiotic inhibits protein synthesis by binding to 50S ribosome identical to erythro, just better activity against Haemophilic, moraxella, & mycobacterium avium also less GI problems & less frequent dosing but more expensive those resistant to erythromycin are also resistant to this Azithromycin a macrolide antibiotic inhibits protein synthesis by binding to 50S ribosome identical to clarithro, just less active against staph/strep & more active against H. influenza active against chlamydia very slowly released from tissues & thus long half life (3 days) once daily dosing & shorter duration of tx Does not interfere with cytochrome P450 like Erythro or Clarithro Telithromycin a ketolide antibiotic inhibits protein synthesis by binding to 50S ribosome 3

given once daily but never for myasthenia gravis since it makes it worse active against erythro-resistant S. pneumo side effects: significant hepatotoxicity (causing it to be much less used & probably wont be around much longer), GI problems, prolonged QT interval, visual disturbances Contraindicated for M. Gravis patients

Clindamycin a lincomycin antibiotic inhibits protein synthesis by binding to 50S ribosome Activity against strep, staph, pneumococci, gram+s (both aerobic & anerobic) just not c. diff.  uses: CA-MRSA (esp. kids), pt. with penicillin allergy, severe anaerobic infections (like Bacterioides) side effects: antibiotic-induced colitis (from presence of c. diff toxin) Neuromuscular Disease I (Heffner) Approach to neuromuscular diseases Clinical  muscle weakness: if proximal or generalized (myopathy) vs. if distal (neurogenic)  presence or absence of muscle atrophy or wasting  high serum muscle enzymes (like CK) highest in fiber necrosis Pathologic recall histochemistry of muscle is placed on fresh frozen tissue (not fixative)  instead of the normal polygon in cross-section: if rounded (myopathy) vs. if angular (ie, one diameter larger than the other denervation)  instead of peripheral nuclei: if internal nuclei (think limb girdle muscular dystrophy or MyD)  ATPase stain: brown stain (Type II will be dark) best for distinguishing between fiber types  Oxidative enzyme stains (SDH) stain for Type 1 fibers Muscular Dystrophies genetic disorders often with family hx early onset but not at birth progressive course severe muscle weakness types: duchenne, limb girdle, central core, & nemaline Duchenne muscular dystrophy (DMD): Most common type 1/7,000 births Onset 2-5 y/o always in boys, poor prognosis (death by mid-20s) fibers formed normally, then destroyed diagnostic calf pseudohypertrophy: calf is as big as the thigh proliferation of CT/fat (much weaker than the original muscle itself) that happens naturally when muscle wasting occurs) most have deletion in dystrophin gene (sex-linked recessive) encodes a membraneassociated protein that attaches -DG & actin to stabilize the sarcolemmal membrane

mutation causes tears in membranes (delta lesions) to occur more easily, allowing Ca to flood in & activate proteases which breakdown the muscle fibers Gowers maneuver: patient attempts to overcome muscle weakness by climbing up his legs to get off the floor biopsy shows: necrotic fibrosis, cardiac fibrosis, pre-necrotic hyaline fibers (hyper-contracted fibers with more pronounced lacunae), fiber regeneration, and fiber loss

Limb Girdle muscular dystrophy More often recessive presents as floppy infant syndrome (weakness, quiet cry, low tone, low movement) weakness of the arms and legs pseudohypertrophy in 1/3 of cases much less progressive than DMD longer life span fibers are formed normally from the beginning (like DMD) (defects in scarcolemmal proteins) Diagnosis: internal nuclei, moth-eaten fibers in SDH stain (lack of homogeneity of sarcoplasm), & hypertrophy with splitting Central Core Disease autosomal dominant inheritance (Chr 19q13 RYR1 ryanodine receptor aka DHP) made abnormally from beginning (unlike LGMD and DMD) diagnosed central pale cores in SDH stain loss of sarcomere architecture there weakened ability to contract (explaining source of muscle weakness) can get progressively worse or progressively better (if core doesnt get any bigger) Nemaline Myopathy more common in girls(autosomal dominant) with clusters of subsarcolemmal rods (which mimic Z lines) seen in RTC stain loss of sarcomere Genetics: NEM1 -tropomyosin or NEM2 nebulin similar to central core disease but with facial dysmorphism (long jaw & droopy eyes ptosis, high-arched palate) The Structure and Physiology of Skeletal Muscle (Pendergast) Function: force development length of muscle fiber converts chemical energy into mechanical energy shortens

Voluntary muscle contraction skeletal muscle after 40 y/o, the force muscles are able to make significantly decline with each passing decade genetic predisposition (85% sets upper limits but not lower limits) vs. environmental factors (15% exercise, diet, disease, altitude, etc.) upon contraction, H zone & I band shorten as the Z lines converge toward each other, but the A band remains the same length twitch: muscle response from one single stimulus Systemic Muscle Recruitment 5

primarily via alpha motorneurons bulk of muscle contraction  but gamma motorneurons (or spindle) tells brain the extent of muscle length during contraction & is also involved in fine motor control large motor units (large with many fibers that are type II, fast conduction, high force) vs. small motor units (small with few fibers that are Type I, slow conduction, low force)  small recruited first so energy is not wasted with the large for small jobs large only recruited if small is incapable of performing the work itself its the size of the fibers, not the number of fibers that matter Type I larger fibers, Type II shorter fibers

Excitation-contraction coupling fast twitch (Type II) vs. slow twitch (Type I weaker peak tension, longer time to reach peak tension, longer relaxation time ie, longer time for muscle to recover) excitation: 1. Action potential is elicited & spreads down T-tubule, changing the membrane potential from positive to negative 2. DHP (dihydropyridine receptor aka ryanodine receptor the voltage-sensitive receptor on the T tubule membrane) senses the change in charge & becomes activated Ca released from sarcoplasmic reticulum (since DHP is mechanically attached to Ca channels on SR)  if DHP receptor hyperactive sustained Ca levels sustained contractile state hypertrophy heart failure (since enlarged muscles take up too much O2) & eventual atrophy (since over-expression of muscle leads to down regulation of protein synthesis) 3. Ca binds to troponin on actin to expose myosin heads 4. Myosin heads execute power stroke (ie, the myosin head attached to actin rotates from 90 to 45, moving actin with it, to cause a contraction)  Contraction force will as Ca (summation) till all possible binding sites on actin are exposed & any further Ca additions will not cause a stronger contraction (ie, tetanus achieved prolonged contraction of muscle fibers) 5. Myosin head is detached ( requires ATP)  cross-bridge cycling is just this process repeating itself: relaxed state contractile state binding state product release state ATP binding dissociation relaxation: 1. Action potential stops Ca channels to close 2. Ca is pumped back into SR ( requires ATP) 3. Ca pops off troponin & myosin head returns to ready state (ie, relaxed but ready to reattach to the first free actin binding site it comes it contact with) Time course in relation to Ca++ concentration: 1. Contraction initiated by action potential 2. Ca++ in myoplasm Ca++ binding of troponin myosin/actin excute cycling 3. Twitch tension develops in proportion to bound Ca++ and [Ca++] of the myoplasm 4. Relaxation takes place but Ca++ in myoplasm because it is taken up by SR Effects of Ca++ 1. [Ca++] in binding 6

2. As in Ca++ binding in force 3. As troponin sites saturate no more in force Muscle Fiber Types percentage is variable (explains why some are born faster than others) Type I: slow twitch fibers (50%), red, oxidative, small fibers, low force but long duration tonic  ex: soleus (posture endurance) Type IIb: fast twitch fibers (40%), white, glycolytic, fatigueable (since it depends on anaerobic glycosis), larger fibers, high force but short duration phasic  ex: latissmus dorsi (rapid, powerful movements) Type IIa: fast twitch fibers (10%), red, oxidative, moderate size  ex: mixed with vastus lateralis (medium endurance) Muscle Contractions Muscle contraction force can be sustained by repeated stimuli o stimuli frequency incomplete recovery Ca bound binding sites, cross bridge cycling and force Summation o If stimuli enough such that all binding sites are engaged sustained contraction [=] tentani 3 types: isotonic (force > resistance movement) vs. isometric (force resistance contraction but no movement) vs. isokinetic (force > resistance, but controlled velocity to measure torque)  isometric pressor test: used clinically shows linear relationship of cardiac output from O2 consumption high heart rate/bp (thus, assesses patient risk level in doing isometric exercise) Force of contraction dependent on: number/types of fibers recruited, frequency of action potentials, number of cross-bridges/binding sites activated, [Ca] o   o Force per unit cross sectional area is constant 3 kg/cm2 o Cross sectional variable based on fiber type (Type I ~2000 m2, Type II ~5000 m2) Velocity of contraction dependent on: resistance, number/types of motor units, number of cross-bridges formed, rate of cross-bridge cycling (ATPase), length of muscle fibers  length-tension diagram: dictated by initial length of muscle force as muscle length but: o short length overlap (stretched to little that it cant generate force) & long length separation (stretched too far that it cant generate force)  velocity: max at zero resistance, decreases hyperbolically as resistance increases muscle fatigue: Type I (fatigue resistant since no summation ie, no build up of Ca to elicit contraction since more or less tonic) vs. Type II (fatigueable since follows summation of Ca)  normal muscle is a mix of both so it is the average of both extremes  fatigue due to build up of metabolites, like: P, lactic acid, low pH, ADP, etc. products of glycolysis Effect of Chronic Muscle Contraction hypertrophy of all types of fibers occur after maximal neural recruitment & high resistances 7

sustained heavy use of fast twitch coupled with disuse of slow twitch (like steroid use) leads to hypertrophy of only fast twitch with atrophy of slow twitch fibers

Energetics most energy for muscle movement supplied by oxidation (aerobic metabolism) energy increases as work increases (ie, as velocity & force increase) efficiency: measures the effectiveness of the muscles use of energy ie, low efficiency may include use of high energy (for unusual activities or altered motor unit recruitment) with little gain energy sources: ATP, phosphocreatine, anaerobic glycolysis, oxidation of carbohydrates/fats  slow (use carbs/fats for energy) vs. fast twitch fibers (use glycolysis)  energy deficit: ATP & creatine phosphate (CP) splitting compensated by anaerobic glycolysis including lactic acid synthesis  energy recovery: resynthesis of ATP & CP from oxygen consumption anaerobic (high power, low capacity, short duration) vs. aerobic (low power, high capacity, long duration) Pharmacology of Neuromuscular Blocking Agents (Berman) Neuromuscular junction blocking agents muscle relaxants ( opposite of anti-AChEs) by inhibition at the neuromuscular junction via binding to the -subunits of the Ach receptor causes flaccid paralysis (by blocking the binding & action of ACh at nAChR on skeletal muscle rapid onset, given parentally (IV) Two types of NMJ blockers: d-tubocurarine (dTC): a nondepolarizing blocker a pure competitive inhibitor; binds to the AChR & causes it to be locked in its closed state so no depolarization can occur to elicit a muscle contraction  the more innervated the muscle is, the more sensitive it is to dTC thus, there is a sequence in the drug effects seen: o first (small, rapid moving muscles eyes, ears, fingers, face, mouth) o next (limbs, neck, trunk) o last (diaphragm, intercostals muscles necessary for breathing) o recovery is in reverse order  longer duration 30 mins (eliminated by urine)  used for: intubation, with ECT, with anesthesia, ventilator control  side effects: prolonged paralysis, histamine release ( bronchoconstriction, hypotension, increased bronchial secretion, etc.) succinylcholine (SCh): a depolarizing blocker binds to the AChR & causes it to be locked in its open state (thus it activates the receptor (causing fasciculation ie, muscle twitching) before it inactivates it)  has a similar sequence of action to dTC, but brief fasciculations in chest/abdomen seen first  short duration 5 mins (just gets broken down by the cholinesterase) 8

used for: intubation, with ECT, short procedures (like diagnostic tests endoscopy) can cause intense skeletal muscle contractions ( muscle pain during recovery, fractures, tearing, etc.): o thus, not for pts. with current M/S problems o also: intense contractions K leakage into blood hyperkalemia cardiac arrythmias  use with caution in pts. with: o glaucoma (since it can increase intra-ocular pressure & the intense contractions can cause further ocular damage) o extensive soft-tissue trauma/burns (since the K loss can then be life-threatening) o no longer indicated in children <8 y/o o low pseudocholinesterase (since they will be unable to degrade SCh rapidly persistent paralysis for hours)  not for pts. with can trigger malignant hyperthermia: characterized by consistent muscle rigidity from a genetic defect in the ryanodine receptor very high metabolic rate very high, life-threatening systemic temperature) o tx: ice to cool patient & sodium-dantrolene (blocks the ryanodine receptor) Drug Interactions increased effects on relaxation seen when both of these blockers given with general anesthetics, antibiotics, & Ca blockers (since they all also block the release of ACh) But! mixed results seen when given with anti-AChEs:  if with dTC (decreased relaxation effects since ACh can overcome the dTC competitive block when the esterase is inhibited)  if with SCh (increased relaxation effects since more SCh will be available with the esterase inhibited since it is also susceptible to enzymes degradation just like ACh is) Low Back Pain (Paroski) Low Back Pain most expensive benign condition, most common cause of activity limitation & job related disability risk factors: obesity, high physical labor, high levels of body vibration (like truck drivers or Joes moms Magic Bullet), etc. Recall Anatomy of the Back: vertebrae: 7 cervical, 12 thoracic, 5 lumbar, 5 fused sacral all with 4 articular facets: 2 superior & 2 inferior ligaments: posterior longitudinal ligament (along anterior wall, attaching at midline of each disc) vs. ligamentum flavum (from one lamina above to the lamina below) muscles: erector spinae, transversospinalis intervertebral discs: annulus fibrosis (tough outer, nerve endings but no substance P so no pain) vs. nucleus pulposus (gelatin inner, no nerve endings gradual in water content with age) Disc herniation 9

 

not painful in itself, pain only when the disc compresses a nerve or nearby structures most back pain is not due to this but needs to be ruled out simian gait: patient tend to flex forward spontaneously while walking relieved by hyperextension of back & laying down pain worsens with sitting, standing, or Valsalva maneuvers (coughing, sneezing, bearing down when taking a poo) most commonly at L4-L5 & L5-S1 can have pain/numbness in dermatomal distribution of affected nerve root (radiculopathy):  L4: medial aspect of lower leg, weak knee extension, weak hip flexion/adduction  L5: lateral aspect of lower leg & medial dorsum of foot (incl. medial 3 toes), weak extension of great toe, foot dorsiflexion, & hip flexion/abduction  S1: posteriolateral aspect of lower leg, lateral foot, weak plantar flexion, knee flexion, hip extension lab work up: MRI/CT scan (for evidence of herniation with nerve compression) or EMG/NCS (for radiculopathy) tx: acute (lower physical activity, ice then heat, pain relievers, muscle relaxants, PT) vs. chronic (NSAIDs, TCAs, oxycontin (if severe pain), surgery, etc.)

Neuromuscular Diseases II (Heffner) Myotonic Dystrophy DMPK gene mutation (trinucleotide CTG repeats) encodes for myotonin protein kinase  autosomal dominant but variable penetrance (not all disease manifestations may be present in one case) 1/8,000 births distal atrophy ( indicative of a nerve issue), frontal alopecia (baldness), Hatchet face (long & sad-looking with ptosis), myotonia (involuntary sustained muscle contraction after percussion or voluntary contraction ex: hand may stay in contraction when opening a door knob; on EMG sustained contraction w/ rapid in discharge rate over time)  thus disease involves muscles of both the face and the extremities is a systemic disease not just skeletal muscle: smooth muscle atrophy, testicular atrophy, myocardial fibrosis ( heart failure) 3 histological features: selective Type I atrophy, internal nuclei, & ring fibers (myofibrils wrap around rather then running along the entire length of muscle, oriented 90o on wrong direction) Inflammatory Myopathies often infectious or immune mediated thus rapid onset (unlike slowly progressive dystrophies) Examples:  dematomyositis (see above)  polymyositis: o generalized muscle weakness with systemic symptoms o 35y/o midlife peak onset (rather than infancy as in dystrophies) o T-cell mediated (unlike B-cell mediated dermatomyositis) CD8+ expressed; MHC-1 antigen expressed (which is atypical for T-cells to express) o histo: lymphocyte infiltration, abnormal MHC1 expression 10

inclusive body myositis (IBM): o 60y/o late-life peak onset M>F o asymmetric, distal weakness (such as a weak grip) violates rule! (ie, this disease is not neurogenic) o unlike the other inflammatory myopathies: progresses more slowly & resistant to steroid tx o histo: lymphocyte infiltration, fiber hypertrophy with splitting, characteristic nuclear inclusions (made of amyloid filaments rimmed vacuoles)

Metabolic Myopathies McArdles Disease defect in glycogen metabolism  due to autosomal recessive inherited mutation of PYGM gene loss of phosphorylase (thus, glycogen can be made but not broken down to be used (in muscle, liver glycogen processing is fine) & thus unable to make lactic acid)  diagnosed by the ischemic forearm test (shows extent of lactic acid made when exercising nl. person will have a large spike in lactic acid produced but these pts. show only tiny spike)  histo: PAS+ glycogen blebs off sarcolemma, negative phosphorylase rxn Acid Maltase Deficiency o Autosomal recessive inheritance (w/ a # of mutations disclosed) o Deficiency in lysosomal enzyme cleaves -glycosidic linkages @ pH 4.5 o 2 forms: infantile form ( absence of enzyme) or late onset ( amount of enzyme does not correlate w/ disease) CPT Deficiency defect in lipid metabolism  CPT transports long-chain fatty acids into mitochondria for them to undergo -oxidation o CPT I (aka CAT I outer membrane, linking fatty acid to carnitine) vs. CPT II (inner membrane, releasing fatty acid from carnitine) o thus, if deficient lipid accumulation in sarcoplasm  caused by recessive inheritance of CPT II gene  histo: vacuoles full of fat globules  typically in males (85%), episodic attacks following exercise Molecular Genetics & Pathophysiology of Muscular Dystrophies (Ettinger) Muscular Dystrophies progressive muscle weakness & muscle wasting (muscle replaced by fat & CT) usually most symptomatic in skeletal muscle diagnosis now made using algorithm based on molecular defects Types:  X-linked: Duchenne (DMD) & Becker Muscular Dystrophy (BMD) o highest incidence since mutn rate in dystrophin gene is so high since protein is so large o 2/3 of all muscular dystrophy cases  autosomal o Limb-Girdle (LGMD) recessive or dominant o Congenital (CMD) recessive only 11

all types differ clinically by: severity, age of onet, rate of progression, & life expectancy:  DMD: early onset by 3y/o, wheelchair-confined by 12, death by 20  BMD: later onset, slower progression, still not wheelchair-confined at 16 but! cardiomyopathy more common  LGMD: varies from mild to severe  CMD: most severe earliest onset, quickest progression, are never able to walk at all

Dystrophin-Glycoprotein Complex (DGC) DGC bridges actin inside cell thru dystrophin to the basal lamina outside cell thru dystroglycan dystrophin: a cytoskeletal protein that binds to actin in cytoplasm & -dystroglycan ( -DG) on cell membrane  large, dumbbell shaped, fibrous protein with homologus domains to spectrin (which maintains RBC biconcave shape & flexibility)  found in skeletal muscle, heart, and brain, explains risk of cardiomyopathy & IQ in DMD/BMD -dystroglycan ( -DG): an extracellular peripheral membrane protein that binds to -DG on membrane & merosin (aka laminin 2 a muscle specific basal lamina protein) in the ECM sarcoglycans (SGs): integral membrane proteins that bind to each other and -DG on membrane Dystrophin protein cloned from female carrier (women can have DMD if X-inactivation of normal gene o In experiments anti-Dystrophin Abs brought down entire complex If the distrophinopathies (DMD/BMD) both have a deficiency in dystrophin, how are they different? amount of dystrophin DMD (very little if any more severe) vs. BMD (some less severe) genetic defect DMD (large deletion with frameshift) vs. BMD (small deletion w/o frameshift) Pathogenesis of DMD: lack of dystrophin in muscles mechanically weak sarcolemma with increased susceptibility to tears (esp. when muscle is stretched) y entire DGC collapses with lack of dystrophin since it causes large in both DGs & SGs (but not merosin) focal separation of sarcolemma from basal lamina y focal tears at these fragile site Ca flood in & activate proteases inside muscle cells, causing muscle cell necrosis (and thus releasing CK which becomes increased in serum) y adipocytes & fibroblasts proliferate in response to necrosis pseudohypertrophy (enlarged from fat/CT replacing muscle tissue) y So why most symptom-free till 3/yo? they still have the focal tears but are able to repair muscle better using utrophin (dystrophin-like homologue), but eventually regeneration is just exhausted  mdx mice: muscular dystrophic X-linked mice have no muscular dystrophy till much later in life because the utrophin surrogate effect lasts longer in mice than humans Limb Girdle Muscular Dystrophy

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presents the same as DMD or BMD initial involvement in shoulder and pelvic girdle but! not X-linked & not due to dystrophin deficiency y have normal dystrophin levels but defect in a specific sarcoglycan skeletal muscle specific secondary in other SGs entire DGC collapse  these do not bind directly to dystrophin but dystrophin is required for their assembly / maintainence of sarcolemma SGs are essential for the proper function of dystrophin  SGs have extracellular domains that interact with the ECM, which is also affected in LGMD  In sacroglycoprotienopathies normal dystrophin levels, low in specific SG, secondarily low in other SGs y calpainopathy: a form of LGMD  defect in calpain 3 a cytoplasmic, muscle-specific, Ca-activated protease involved in titin processing (a very large fibrous protein that enables the elasticity of skeletal muscle)  increase in serum CK levels, calf hypertrophy, weak pelvic girdle, ambulatory til 40s (classic LGMD features) y Classic CMD most severe (despite no effect on brain or IQ) (30% of CMDs) due to defect in -2 chains of merosin hypotonia at birth, never ambulatory (ie, can never walk)  loss of merosin loss of muscle development & regeneration after injury since it is the anchor of the whole DGC normal levels of dystrophin, SGs, & DGs, no effect on IQ Dystroglycanopathies since DG is the integral membrane protein that connects the extracellular to the intracellular, a deletion in the DG-gene causes early embryonic development abnormalities spontaneous abortion, hypogycosylation of DGs CMD Mystery Case (Brownie/Heffner) McArdles Disease (Type V Glycogen Storage Disease) Pt. presentation (symptom free w/o physical exertion, muscle pain accompanied by muscle cramps following physical activity)  Pt has no family history of disorder autosomal recessive disease  NO testable muscle weakness (all 4 extremities are 5/5) and sensation/ deep tendon reflexes are normal  Dark brown urine following exercise (myoglobinuria) caused by muscle breakdown  Elevated serum creatine kinase (differentiates from carnitine palmitoyltransferase deficiency) Non-Ischemic Forearm Test measures energy metabolism in muscle w/o damaging the patient w/ cramps, pain or muscle injury  Preferred lactate forearm test and relies upon sampling the plasma lactate and ammonia concentration at baseline and w/in the first two minutes following exercise (which consist of one second handgrips every other second for one minute)  Ammonia levels same as normal, Lactate lack of elevation

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Why measure ammonia? Monitoring ammonia concentration tells us weather oxidative metabolism can be normal Ammonia is a byproduct in purine nucleotide cycle which implements TCA cycle intermediaries Pathogenesis: Myophosphorylase involved in breakdown of glycogen to glucose in muscle removes 1,4 glycosyl residue and adds phosphate to form glucose-1-phosphate Response to glucagon infusion normal, since liver metabolism is normal Response to epinephrine little or no increase in lactate Second Wind phenomena can use fatty acid oxidation pathway as fuel in muscle y

Mystery Case 2 The Sleepy Student (Heffner) Motor End Plate (MEP) Diseases y MEP excitable region of muscle fiber plasma membrane responsible for initiating AP across muscles surface leading to contraction of muscle  Ach Receptor is composed of 5 subunits: 2 (the most impt), , ,  Muscle specific kinase (MuSK) is adjacent to AchR y MEP diseases: Autoimmune (Myasthenia Gravis (MG) and Eaton Lambert syndrome and Congenitial (presynaptic, synaptic or postsynaptic) [not covered] Myasthenia Gravis (MG) y An autoimmune disease, Ab mediated with circulated Abs to post-synaptic membrane (AChR or MuSK), initial triggering event is still unknown y 14/100,000 ppl and F>M, 20-30 y.o y First notable sign ocular muscles affected ptosis o Myasthenic sneer = facial mm. too weak to smile, when attempt to smile appears as a sneer y Sxs get worse in the day y Immunopathogenesis: Anti-AchR Abs bind to the -1 subunit leads to complement cascade and complement-mediated lysis o No macrophages or T-Cells seen at the MEP y EMG: MAP amplitude becomes smaller w/ repetitive stimulation (Decrement) y Pathology: Type 2 fiber atrophy seen; EM abnormal motor point, MEP is simplified w/ fewer functional folds and a widened synaptic cleft y Thymus is implicated, 2 possible pathologies: Thymic hyperplasia (increased size and lymphoid follicles w/ B-cells (should be T-Cells)) or Thymomas o In either case, Tx: is thymectomy y Early treatment is essential, 70% mortality w/o treatment Eaton-Lambert Syndrome y Autoimmune presynaptic disease, Abs against voltage gated Ca++ channels in presynaptic terminal Ca++ evoked neurotransmitter release Ach release y Associated w/ neuroendocrine tumors (esp small cell cancers) y M>F y Effects proximal limb muscles and ocular muscles tend to be spared, strength after few secs of voluntary contraction, autonomic dysfunction (dry mouth, sweating)

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y y

Pathology: NO type 2 atrophy (as apposed to MG), MEP is more complex freeze fracture shows active zone particles (which are voltage gated Ca++ channels) EMG: increased response w/ repetitive stimulation

Workbook Cases III (Heffner/Severin) Clavicle Fracture y Most common fracture, common caused by fall on the shoulder, outstretched upper extremity or direct blow to clavicle y Middle break most common due to shape of the clavicle, 2 curves (bend is the weakest point) y After fracture of the clavicle, the sternocleidomastoid muscle elevates the proximal fragment of the bone. The trapezius muscle is unable to hold up the distal fragment owing to the weight of the upper limb, and thus the shoulder droops. The adductor muscles of the arm, such as the pectoralis major, may pull the distal fragment medially causing the bone fragments to override. (wiki) y Tx: sling, no surgery Cuboid Syndrome y Common in ballet dancers overuse or repetitive injury y Presentation: sudden lateral foot pain, side to side; a shallow depression is seen on dorsal foot y Caused by subluxation of cuboid bone cuboid bone slips out of joint Disc Disease y Back pain is most common symptom (60-90% of population will have back pain during their lifetime) y Risk factors: age(wear and tear), heavy physical work, genetics, obesity, work dissatisfaction o Peak age 30-50, rare before 20 and less common after 60; M>F y Nucleus pulposus herniates towards spinal cord (posterior lateral direction because in front is the anterior longitudinal ligament which is strong prevents anterior rupture, the posterior ligaments is much weaker) y Mechanical compression and chemical irritation (body treats discs contents as a foreign body) inflammation y Symptoms: sudden in onset and episodic; associated with lifting and twisting o Relief when laying down no load on back, vs. standing gravity is acting on back y Lumbar disc asymptomatic disc common, pain often present (worse: standing, walking, Valsalva maneuver) o 2/3 pts L4-L5 disc (L5 root): weak toe extensors, numb on dorsal foot, pain in posterior lateral thigh o 1/3 of pts L5-S1 disc (S1 root): weak plantar flexion, cant tiptoe, numb on lateral foot, pain in posterior calf, weak ankle jerk y Diagnosis: Passive straight leg raising (more pain b/w 30o and 70o), MRI (very specific test, but high false positives cant really only on MRI, symptoms must match findings) EMG to document denervation 15

Rx: most improve w/in 3-4 wks, modify activity, lying down often improves pain, physical therapy, NSAIDs, steroids, Surgery (only successful in select pts)

Achilles tendon most common tendon to rupture, usu when running presents as severe calf pain o Over time pain resolves but pts limps due to gradual degeneration associated with age tear occurs 5-7 cm from insertion on the calcaneus PE: calf swelling early on, palpable defect where tendon should be, Thomson test: pt. kneels & doctor squeezes calf normally foot should plantar flex but instead it does nothing when tendon is torn Tx: surgical repair for complete tear, delayed rx fixed mm. contraction Plantar Fasciitis inflammation of the plantar fascia of foot caused by gradual degeneration at fascia origin at the medial tubercle of the calcaneus most common cause of adult heel pain, W>M, 40 y.o Symptoms: onset insidious but pain becomes chronic, pain worst with the first steps of morning since it wasnt stretched all night PE: pain w/ palpitation of medial tubercle and no pain w/ side to side compression of clacaneous heal spur osteophytes common on X-ray (50% of cases) do not remove, not cause and removal may worsen condition Tx: rest, nsaids, stretching of Achilles tendon Hallux valgus aka bunion medial deviation of 1st MTP joint actual big toe to be laterally deviated valgus (distal part points out knock kneed) vs. varus (distal part points in role of proper shoe ware Musculoskeletal Infections & Gram-Negative Rods (Russo) Anatomical Classification of M/S infections: cellulitis (skin, most superficial) fasciitis (underlying fascia) myositis (muscle) osteomyelitis (bone, deepest)& lymphadenitis MRI used to determine depth of inflammation (MRI is best) pathogens response: mostly gram positives (like strep/staph) but significant minority: gramnegative rods (more common in lower body) Cellulitis ecthyma gangrenosum: presents in cancer patients undergoing chemotherapy, most commonly caused by pseudomonas, involves bacteremia & neutropenia hot tub folliculitis: infection of hair follicles most often caused by pseudomonas in hot tub water that has not been kept up bite associated cellulitis  pasteurella multocida: most common bacteria from an animal bite (often cat but also 50% of dogs) that causes rapid cellulitis

bow legged)

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human bites are not really worse than animal bites it is a presentation bias: whenever we get bit by an animal we run to the hospital to ensure no rabies but if we get bit by a human, we never go to the hospital unless a severe infection develops tx: ampicillin-sulbactam (IV) vs. clavulanate (oral)

Fasciitis life threatening infection a medical emergency, usually fulminant & rapid progression most often caused by Grp A strep (the flesh-eating bacteria), but also others pain can occur if nerves are involved, but often stops spontaneously when infection kills the nerve itself, leading to possible paralysis Need MRI to differentiate b/w fascittis and cellulitis, if unknown tx: antibiotics not enough requires additional surgery or amputation Myositis necrotizing myositis: life-threatening infection often caused by clostridium septicum (which is endogenous from the gut but infection often not due bacteremia from trauma to GI tract instead, usually due to colon cancer) tropical-temperate myositis: not as serious as necrotizing myositis myositis from direct inoculation think steroid use Osteomyelitis: often hematogenous spread: bone infection secondary to contiguous focus (most common), penetrating wound, or hematogenous spread:  in adults: bacteremia that initially spreads to disc space, then into vertebral bodies & eventually into spinal cord paraplegia, cord compression (a surgical emergency)  in kids: within long bones Cat-scratch Disease caused by bartonella henselae mostly found in young people (85% <21y/o) with normal immune systems infection usually mild & self-limited but possibly: papule/pustule (3-5 days after scratch) tender regional adenopathy (1-2 weeks after scratch) tx with non-usual agents for cellulitis (quinolones, doxycycline, macrolides) MRSA/ Gram Positive Infection (Lesse) CA-MRSA these Staph are resistant to all currently available -lactams, worldwide problem Waves of resistance: Penicillin resistance rapid, Methicillin resistance slower, MRSA IV rapid again (circa 1995)  Prior to 1995, MRSA was hospital problem became a community problem Mechanisms: Staphylococcal cassette chromosomal (SCCmec) codes for a PBP2a and carriers other resistance markers  8 Major types: CA- MRSA are type IV and V and also have a marker, Panton-Valentine leukocidin (PVL) PVLs pathogenesis still in question (Current US strain USA300)

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The CA-MRSA cassette size is much smaller than that of hospital acquired MRSA (delay in resistance was due to: hospital was initially spread of strain from pt. pt. but smaller cassette allowed from spread of cassette from pt. pt.)  Type can be determined by sequencing or PCR not done clinically Epidemiology: ~70% of all CA-staph infections are CA_-MRSA  Groups at risk: Athletes, prisoners and guards, gays, children in day care  Crossover in hospitals settings to CA-MRSA, taking over hospital MRSA Clinical Syndrome: Skin and soft tissue necrotizing (Pruritic (itching) is a strong sign, note: these abscesses must be treated surgically, antibiotics are not enough), Necrotizing pneumonia (destroys the lungs), Musculo-skeletal (necrotizing fascittis, osteomyelitis, septic arthritis) Management algorithm for patients w/ skin infection in age of MRSA  Sx: Redness, Swelling, Warmth, Pain, Complaint of insect bit  Yes fluctuance(palpable fluid filled cavity), yellowish center, head, pus  Yes drain lesion, send drainage for culture; No possible cellulitis w/o abscess, provide antimicrobial therapy and maintain close followup Tx: Clindamycin (primarily given to children, tests should be given to id inducible resistance, may lead C. dif. Related illness) Trimethoprim/sulfamethaxole (given only to adults, no coverage for group A strep a common cause of cellulitis, causes developmental problems cant give to kids or pregos, requires a greater dose than clindamycin)

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