Biology Basic Science- Miller review Flashcards
What is a DNA topoisomerase?
unwinding of DNA for transcription
Topoisomerase-1 (scl-70) antibodies are seen in scleroderma and crest
what is translation?
building of a protein out of amino acids from mRNA template.
Antibodies to tRNA synthetase (anti-jo-1-antibiodies) are seen in dermatomyositis
what are centromeres?
they link the sister DNA
anticentromere antibodies are seen in Crest Syndrome
What does tumor supressor gene P53 do?
prevents entry into S phase (synthesis)
losing it opens the gate to synthesis
implicated in osteosarcoma, rhabdomyosarcoma dn chondrosarcoma
pRB-1 Retinoblastoma protein
undergoes progressive cell cycle regulated phosphorylation
targets E2f: a transcription factor that regulates genes important for cell cycle control
Agarose Gel electrophoresis
Northern Blot: detects RNA
Western Blot: detects Protein
Southern Blot: Detects DNA
cytogenic analysis is used to dtect chromosomal translocations
t(x;18) synovial sarcoma
t(11;22) Ewings Sarcoma
t(2;13) Rhabdomyosarcoma
t(12:16) myxoid liposarcoma
t(12;22) in clear cell sarcoma
what is silencing RNA?
Blocks transcription of mRNA in order to study results of genes loss of function.
How does the innate system recognize pathogens?
Pathogen-associated molecular patterns (PAMPs) on microbes are recognized by TLRs on innamte immune system cells (macrophages and dendritic cells)
There is an upregulation of NF_KB transcription factor, resulting in release of immune mediators (PRP enzymes)
Arachadonic acid is released from cell membtanes making prostaglandins and leukotrienes
What is the immununology term for anyphylaxitic shock?
IgE-type 1 hypersensitivity reaction
What are some disease examples of autoimmunity, where the epitopes are “self”?
Anti-SM- Lupus
Anti-RNP-mixed connective tissue
Anti-Scl-70-scleroderma
Anti-dsDNA-lupus/nephritis
anti-histone- drug induced lupus
anti-RO and anti LA–sjogrens
HLA gene on chromosome 6
can be rearranged to make an antigen specific receptor on APCs for a billion or more different epitopes
associated with (PAIR)
Psoriasis
AS
Inflammatory bowel
Reiters Syndrome
Type 1 hypersensitivity
Mediated by IgE
mast cell degranulation-histamine
Food and drug allergies
Type II hypersensitivity
Mediated by IgM or IgG
cytotoxic, antibody mediated response
Heparin induced thrombocytopenia
Rheumatic Fever
Myasthesia Gravis
Type III hypersensitivity
Immune complex mediated ) antigen/antibody
SLE
RA
Type IV hypersensitivity
cell-mediated (no antibodies)
helper T-cells activate cytotoxic cells and macrophages to attack tissue
delayed response
TB/PPD test
Type 1 diabetes
MS
type iV response to orthopedic implants
IL-1
initiates acute phase response
induces bone loss through activation of osteoclasts via RANK/RANKL pathway
IL-6
induces synthesis of acute phase proteins from liver
is key to growth and survival of multiple myeloma cells
what makes staph resistant to PCN?
b-lactamase bla gene
what gene makes staph MRSA
penicllin-binding protein 2a
mecA gene
FNB gene
fibronectin in staph increased adhesions to titanium
what is the technical name for biofilm?
glycocalyx-biofilm-slime-pollysachride capsule
what is the cytotoxin for ca MRSA?
Panton-Valentine leukocidin cytotoxin (PVL)
pore forming toxin specific to neutrophils
list some clinically relevant bacterial toxins?
Endotoxin-gram negative lipopolysaccharide
Exotoxin-Clostridium perfringens-lecithinase-tissue destroying alpha toxin
accounts for the myonecrosis and hemolysis of gangrene
Clostridium tentani toxin
tetanospasmin–blocks inhibitory nerves
lockjaw or muscle spasm
Clostridium botulism
blocks acetylchonine release
floppy baby
botox
Superantigens
activate 20% of T-cells
massive cytokine release
Group A strep_ M protein
S. auress-TSS toxin 1
MRSA
HA-
mecA gene
located on staphylococcal chromosome cassette mobile element-Carry IV
SCCmecIV
encodes for penicllin-binding protein 2A, which has low affinity for b-lactam antibiotics
Community acquired MRSA
Bacteris have smaller SCCmec genetic elements
almost all have PVL cytotoxin
gamma-hemolysin-a pore forming toxin that can lyse PMNs
At risk grous are athletes, IV drug abusers, homelss, military recruits, prisoners
Erysipelas
INfection of dermis and lymphatics
Group A streph
peau de orange
tx with PCN or erythromycin
SSI risk
more than 10^5 CFUs need in normal host to cause infection
need only about 100 cfus if a foreign object is present
Human bites
Strep viridans
Eikenella Corrodens
get xrays
Cat bites
Pasteurella Multocida
50% require surgery
puncture wounds to tendon/joints
Dog bites
P. multocida
Pasteurella canis
Marine Injuries
Mycobacterium marinum
Erysipelothrix rhusiopathiae (GP bacillus)
Vibrio Vulnificus (GN rods)
What is the anatomic classification of osteomyelitis?
I. medullary
- Superficial
- localized
- diffuse
what is a sequestra
dead bone nidus with surround granulation tissue
involucrum
periosteal new bone forming later
What are the treatments for osteomyelitis
Newborn to age 4-
S. aureus, gram negative baciili, group B strep
Nafcillin or oxacillin PLUS third gen Cephalosp
Children age 4 or older
S. aureus, Group A Strep
Nafcillin or oxacillin vs Vanco (MRSA)
Adults
S. Aureus
Nafcillin or oxacillin versus vancomycin (MRSA)
osteomyelitis and sickle cell
salmonella
pseudomonas osteomylelitis
iv drug abuse
medial/lateral clavicile
puncture wounds
P. acnes
gram positive anaerobic rod that flouresces under UV light
Bite table
Antibiotics mechanism of action table
Beta-lactam Antibiotics
PCN, cephalosporins
inhibit crosslinking of polysaccharides in the cell wall by blocking transpeptidase enzyme
Aminoglycosides
Gentamycin, tobramycin
Inhibit protein synthesis by binding to cytoplasmic 30S ribosomal unit
Clindamycin and macrolides
clindamycin, erythromycin, clarithromycin,azithromycin
inhibit the dissoation of peptidyl-transfer RNA from ribosomes during translocation
50S ribosomal unit
Tetracycline
inhibit protein synthesis
binds to 50S ribosomal unit
Rifampin
inhibits RNA polymerase F
Quinolones
Ciprofloxacin, levofloxacin
inhibit DNA gyrase
Oxazolidinones
linezolid
inhibit protein synthesis
50S ribosomal unit
Antibiotic indications and Side Effects
Soft tissue Infections table:
Innate Immunity and adaptive immunity
Mendelian Inheritance table:
x-linked dominant
Mendelian inheritance table:
x-linked recessive
Mendellian Inheritance pattern:
Autosomal Recessive
Autosomal Dominant
What DMARDS target IL-1?
Anakinara
what DMARDs target TNF-Alpha
etanercept
infliximab
adalimumab
Describe the skeletal muscle anatomy
Describe the sarcoplasmic reticulum:
Multiple nuclei: typically located adjacent to sarcolemma
Sarcoplasmic reticulum (SR)
Smooth endoplasmic reticulum that surrounds the individual myofibrils
Stores calcium in intracellular membrane–bound channels.
Ryanodine receptors (e.g., RYR-1) regulate the release of calcium from the SR and serve as a connection between the SR and sarcolemma-derived transverse tubule.
Abnormality of ryanodine receptors is implicated in persons susceptible to malignant hyperthermia.
Dantrolene decreases loss of calcium from the SR.
Characterize the sarcomere
Sarcomere: basic functional unit of muscle contraction
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Myofibrils
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Set of sarcomeres parallel to axis of cell
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(1–3 μm in diameter and 1μ2 cm long)
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Sarcomere organization causes the banding pattern (striations) seen in skeletal muscle (Table 1.23; see Fig. 1.40).
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Costamere connects the sarcomere to the sarcolemma at the Z disc.
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Z disc (or line) represents terminus of sarcomere
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Contains desmin, α-actinin, and filamin
A-band (or dark band) represents thick filaments.
Thick filaments composed of myosin
Also contains myosin [H-band], M protein, C protein, titin, and creatine kinase
I-band represents thin filaments.
Primarily composed of actin
Also contains
Troponin: has binding site for Ca
Tropomyosin: prevents myosin-actin interaction
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Attach to Z disc
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Involved in delayed-onset muscle soreness (DOMS)
Describe the gross anatomy of the muscle
Fascia (tough connective tissue) covers muscle and allows sliding.
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Epimysium (more delicate) surrounds bundles of fascicles.
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Perimysium surrounds individual muscle fascicles (hundred of muscle fibers).
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Endomysium surrounds individual myofibers.
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Stretch receptors
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Muscle spindles: located within muscle, transmit muscle length to CNS, control muscle stiffness
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Golgi tendon organ: located at musculotendinous junction, helps prevent excess tendon lengthening
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Myotendinous junction
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Often the site of tears with eccentric contraction (forced lengthening of the myotendinous junction during contraction), which places maximum stress across this area
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Myofilament bundles are linked directly onto collagen fibrils, with sarcolemma filaments interdigitating with the basement membrane (type IV collagen) and tendon tissue (type I collagen).
Describe the Motor Unit
The α-motoneuron and the myofibers it innervates
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Each myofiber is innervated by a single axon but an axon can innervate multiple myofibers
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Smaller and more delicate muscles have fewer myofibers per motor unit (<5 fibers per unit in extraocular muscles but as many as 1800 fibers per unit in gastrocnemius muscle)
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Contraction
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Response to mechanical or electrochemical stimuli generated at the motor end plate (neuromuscular junction) where the axon contacts an individual myofiber (Fig. 1.42).
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Depolarization reaches motor neuron axon terminal, and acetylcholine (ACh) is released from presynaptic vesicles.
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ACh diffuses across the synaptic cleft (50 nm) and binds to postsynaptic receptors on sarcolemma, which begin depolarization.
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Myasthenia gravis is due to IgG antibodies to the Ach receptor. Manifests initially as ptosis and diplopia. Weakness worse with muscle use.
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Botulinum A injections reduce spasticity by blocking presynaptic acetylcholine release. Commonly used for spastic muscles in cerebral palsy.
What are the types of muscle contractions?
Review muscle physiology
Muscle cross-sectional area is a reliable predictor of the potential for contractile force.
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Muscle tension is determined by the contractile force generated.
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Muscle contraction velocity is determined by fiber length.
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A well-conditioned muscle may be able to fire more than 90% of its fibers simultaneously.
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At any velocity, fast-twitch (type II) fibers produce more force.
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Isokinetic exercises produce more strength gains than do isometric exercises (see Table 1.25).
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Plyometric (“jumping”) exercises, the most efficient method of improving power, consist of a muscle stretch followed immediately by a rapid contraction.
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Closed-chain exercise involves loading an extremity with the most distal segment stabilized or not moving, allowing for muscular cocontraction around a joint and minimizing joint shear (e.g., less stress on the ACL).
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Open-chain exercise involves loading an extremity with the distal segment of the limb moving freely (e.g., biceps curls).
What are the types of muscle fibers?
Type I
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Slow-twitch, oxidative, “red” fibers (mnemonic: “slow red ox”)
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Aerobic
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Have more mitochondria, enzymes, and triglycerides (energy source) than type II fibers
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Low concentrations of glycogen and glycolytic enzymes (ATPase)
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Enable performing endurance activities, posture, balance
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Are the first lost without rehabilitation
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Type II
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Fast-twitch, glycolytic, “white” fibers
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Anaerobic
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Contract more quickly and have larger, stronger motor units (increased ATPase) than type I fibers
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Less efficient than type I but with large amount of force per cross-sectional area, high contraction speeds, and quick relaxation times
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Well suited for high-intensity, short-duration activities (e.g., sprinting)
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Rapid fatigue
Low intramuscular triglyceride stores
Two subtypes:
Type IIA is intermediate.
Type IIB is most fatigable and has highest anaerobic capacity.
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What is the areobic system?
Aerobic oxidation of glycogen and fatty acids through Krebs cycle
Sustained exercise such as distance running
General muscle fitness pearls
Training
Specific training can selectively alter fiber composition.
Endurance athletes—higher percentage of slow-twitch fibers
Sprinters and athletes in “strength” sports—higher percentage of fast-twitch fibers
Endurance training—decreased tension and increased repetitions
Induces hypertrophy of slow-twitch fibers
Increases capillary density, mitochondria, and oxidative capacity
Increases resistance to fatigue and cardiac output
Improves blood lipid profiles
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Strength training—increased tension and decreased repetitions
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Induces hypertrophy (increased cross-sectional area) of fast-twitch (type II) fibers
Denervation
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Causes muscle atrophy and increased sensitivity to acetylcholine
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Leads to spontaneous fibrillations at 2–4 weeks after injury
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Immobilization
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Accelerates granulation tissue response
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Immobilization in lengthened positions decreases contractures and maintains strength.
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Atrophy results from disuse or altered recruitment.
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Muscles that cross a single joint atrophy faster (nonlinear fashion).
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Sarcomeres at the myotendinous junction are especially affected
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Electrical stimulation can help offset these effects.
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Muscle strains
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Most common sports injury
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Most occur at the myotendinous junction.
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Occur primarily in muscles crossing two joints (hamstring, gastrocnemius) that have increased type II fibers
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Initially there is inflammation, and later, fibrosis mediated by TGF-β occurs.
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Immobilization or rest for 3–5 days followed by progressive stretching and strengthening
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Muscle tears
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Most occur at the myotendinous junction (e.g., rectus femoris tear at anterior inferior iliac spine).
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Often occur during a rapid (high-velocity) eccentric contraction
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Satellite cells act as stem cells and are most responsible for muscle healing.
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Alternatively, the defect can heal with bridging scar tissue. TGF-βstimulates proliferation of myofibroblasts and increases fibrosis.
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Surgical repair of clean lacerations in the muscle midbelly usually results in minimal regeneration of muscle fibers distally, scar formation at the laceration, and recovery of about half the muscle strength.
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Prevention of tears—muscle activation (through stretching) allows twice the energy absorption before failure.
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DOMS
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This phenomenon occurs 24–72 hours after intense exercise.
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Associated with eccentric muscle contractions
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Most common in type IIB fibers
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Caused by edema and inflammation in the connective tissue, with a neutrophilic response present after acute muscle injury
May be associated with changes in the I band of the sarcomere
NSAIDs relieve DOMS in a dose-dependent manner.
Other modalities (ice, stretching, ultrasonography, electrical stimulation) have not been shown to affect DOMS.
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Induces myofibrillar muscle protein synthesis (MPS)
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Improves neural activation
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Both endurance training and strength training delay the lactate response to exercise.
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A significant decline in aerobic fitness (“detraining”) occurs after only 2 weeks of no training.
What are the three stages of tendon healing?
Three stages of tendon healing
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Inflammation
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Hematoma formation following by resorption
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Type III collagen is produced at the injury site by tenocytes.
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Weakest stage of repair
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Proliferation: maximal type III collagen production
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Remodeling:
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Begins at 6 weeks
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Decreases cellularity
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Type I collagen predominates
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Two mechanisms:
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Intrinsic: recruitment of local stem/progenitor cells from endotenon and epitenon
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Extrinsic: cells from surrounding tissue invade damaged area.
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Faster but primary source of adhesions
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Achilles, patellar, and supraspinatus tendons are prone to rupture at hypovascular areas.
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Achilles tendon is hypovascular 4–6 cm proximal to calcaneal insertion.
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Responsive to different cytokines and growth factors
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PDGF genes transfected into tenocytes show collagen formation.
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VEGF genes transfected into tenocytes show TGF-β upregulation and adhesion formation.
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When exposed to PMNs (as with inflammation), tenocytes upregulate genes for inflammatory cytokines, TGF-β, and MMPs while suppressing type I collagen expression.
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Surgical tendon repairs: weakest at 7–10 days
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Maximum strength achieved at 6 months, reaching two-thirds of original strength.
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No evidence in favor of a trough (exposing tendon to cancellous bone) over direct repair to cortical bone.
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Motion and mechanical loading have beneficial effects on tenocyte function.
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Immobilization decreases strength at tendon-bone interface.
What are the mechanical properties of tendons?
Anisotropic: properties vary depending on direction of applied force
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Viscoelastic: properties vary depending on rate of force application
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Creep: increasing deformation under constant load
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Stress relaxation: decreasing stress with constant deformation (elongation)
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Hysteresis: during loading and unloading, the unloading curve is different from the loading curve. The difference between the two represents the amount of energy that is lost during loading.
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Stress-strain curve
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Rest: collagen fibers are “crimped.”
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Toe region: flattening of crimp; nonlinear; tendon stretched easily
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Linear region: intermediate loads
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Failure
What is the structure of tendons?
Composition
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Water: 50%–60% of total tendon weight
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Collagen: 75% of dry weight
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95% type I collagen, also type III collagen
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Elastin: 1%–2% of dry weight
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Highly elastic protein that allows tendon to resume its shape after stretching
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Also responsible for “toe region” of stress-strain curve
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Proteoglycans
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Decorin—most predominant proteoglycan in tendons. Regulates tendon diameter and provides cross-links between collagen fibers. Also shown to have antifibrotic properties via inhibition of TGF-β1.
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Aggrecan—present at points of tendon compression
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Biglycan
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Tenocytes (fibroblasts):
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Derived from mesoderm
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Function to synthesize ECM, collagen, and proteoglycans
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Assemble early collagen fibrils and produce matrix-degrading enzymes (MMPs)
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Detect strain during tendon loading though deflection of cell cilia
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Tenocyte production of collagen increases tendon healing and reduces repair ruptures.
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Role in tendinopathy (due to inflammatory mediator production)
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Tenocytes produce type III collagen in response to rupture.
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Greater proportion of type III collagen, naturally seen in Achilles tendon, predisposes tendons to rupture.
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Structure
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Strands of collagen (triple helix of two α1 chains and one α2 chain) organized into microfibrils, which in turn make up fibrils, fascicles, and tendon
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Fascicles surrounded by endotendon (contiguous with epitendon covering entire tendon)
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Carry the neurovascular and lymphatic supply of tendons
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Composed of type III collagen
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With aging, more type I collagen strands interdigitate between type III collagen strands.
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Covered by paratenon (Achilles, patellar tendons) versus synovium (digital flexor tendons)
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Higher vascularity of paratenon leads to increased healing.
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Sheathed tendons
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Vincula (extension of synovium) carry blood supply to one tendon segment (Fig. 1.45).
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Some nutrition from synovial fluid (found between the two layers of the synovial sheath) via diffusion
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Myotendinous junction
Actin microfilaments extend from the last Z line
These are linked to the sarcolemma, which in turn connects to the collagen fibril–rich matrix of the tendon.
Bone-tendon junction (direct vs. indirect)
Direct (fibrocartilaginous) insertion
Usually in areas subject to high tensile load
Four layers: tendon, fibrocartilage, mineralized fibrocartilage, and bone
Indirect Insertion
Fibers insert directly into periosteum through Sharpey fibers
how do tendons get their blood supply?
Millers Entire review section on ligaments:
Characteristics
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Originates and inserts on bone
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Stabilizes joints and prevents displacement of bones
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Contains mechanoreceptors and nerve endings that facilitate joint proprioception
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Like tendon, displays viscoelastic behavior
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Structure and composition
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Composition
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Similar to that of tendon
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Water: 60%–70% of total weight
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Collagen: 80% of dry weight
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90% type I collagen; also types III, V, VI, XI, and XIV collagen
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More collagen type I is seen at the origin and insertion, with collagen III seen midsubstance.
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Elastin (1% dry weight)
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Proteoglycans (1% dry weight)—function in water retention and contribute to viscoelastic behavior
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Fibroblast
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Primary cell, oriented longitudinally
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Functions to synthesize ECM, collagen, and proteoglycans
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Epiligament
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Similar to that in epitenon; carries the neurovascular and lymphatic supply of tendons
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Compared with tendon
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Less total collagen but more type III collagen
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More proteoglycans and therefore more water
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Less organized collagen fibers that are more highly cross-linked and intertwined
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“Uniform microvascularity”—receives supply at insertion site by the epiligamentous plexus
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Insertion
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Similar to that of tendon
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Direct (fibrocartilaginous) insertion
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Four layers: tendon, fibrocartilage, mineralized fibrocartilage, and bone
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More common
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Deep fibers attach at 90-degree angles
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Indirect
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Superficial fibers insert into the periosteum and deep fibers insert into bone via Sharpey fibers (perforating calcified collagen fibers).
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Injury
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Knee and ankle ligaments are most commonly injured
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Ligaments do not plastically deform.
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They “break, not bend.”
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Midsubstance ligament tears are common in adults.
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Avulsion injuries are more common in children.
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Typically occurs between unmineralized and mineralized fibrocartilage layers
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Healing
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Increased number of collagen fibers but
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Fewer mature cross-links (45% of normal at 1 year)
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Decrease in mass and diameter
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Three phases, as in bone
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Inflammatory—early acute mediators (PMNs and then macrophages), with production of type III collagen and growth factors
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Proliferative—around 1–3 weeks, with replacement of type III collagen by type I collagen (Think of macrophages as weakening the structure—weakest point.)
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Remodeling and maturation
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Factors that impair ligament healing
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Intraarticular ligamentous injury
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Old age, smoking, NSAID use
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Diabetes mellitus
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Alcohol use
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Local injection of corticosteroids
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Factors that improve ligament healing experimentally
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Extraarticular ligamentous injury
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Compromised immunity
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IL-10 (antiinflammatory)
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IL-1 receptor antagonists
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Mesenchymal stem cells
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Scaffolds (such as collagen–platelet-rich plasma hydrogels)
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Neuropeptides
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Calcitonin gene–related peptide
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Immobilization
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Adversely affects ligament strength: elastic modulus decreases
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In rabbits, breaking strength reduced dramatically (66%) after 9 weeks of immobilization.
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Effects reverse slowly upon remobilization.
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Prolonged immobilization disrupts collagen structure, which may not return to normal within insertion sites.
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Exercise
Improves mechanical and structural properties
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Increases strength, stiffness, and failure load
What is Decorin?
most predominant proteoglycan in tendons. Regulates tendon diameter and provides cross-links between collagen fibers. Also shown to have antifibrotic properties via inhibition of TGF-β1.
What are Sharpey’s Fibers?
Fibers insert directly into periosteum
Describe the anatomy of Intervertebral discs
Allow spinal motion and stability
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Also function as cushioning for axial loads on the spine
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Two components
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Central nucleus pulposus
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Derived from notochord
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Hydrated gel with compressibility
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Low collagen (type II)/high proteoglycan (and glycosaminoglycan) content
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Proteoglycans make up higher percentage of dry weight.
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With time, the nucleus pulposus undergoes loss of proteoglycans and water (desiccation).
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Surrounding annulus fibrosis
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Derived from mesoderm
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Extensibility and increased tensile strength
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High collagen (type I)/low proteoglycan content
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Proteoglycans make up lower percentage of dry weight.
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Superficial layer contains nerve fibers.
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Composition:
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Water (85%)
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Proteoglycans
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Type II collagen (20% of dry weight) in the nucleus pulposus
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Type I collagen (60% of dry weight) in the annulus fibrosis
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Neurovascularity
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Dorsal root ganglion gives rise to the sinuvertebral nerve, which then innervates the superficial fibers of the annulus.
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Avascular—nutrients and fluid diffuse from the vertebral end plates. This diffusion is impaired by calcification with aging.
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Aging disc
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Early degenerative disc disease is an irreversible process, with IL-1βstimulating the release of MMPs, nitric oxide, IL-6, and prostaglandin E2(PGE2).
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Decreased water content and conversion to fibrocartilage
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A result of decreased hydrostatic pressure due to fewer large proteoglycans (aggrecan)
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Fibronectin cleavage or fragmentation is also associated with degeneration.
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Increase in keratan sulfate concentration and decrease in chondroitin sulfate
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Increase in relative collagen concentration, with no change in absolute quantity
Receptors table
Summary of Spinal Reflexes
Types and Characters of Nerve fibers
The nucleous polposus is derived from…
derived from the notochord
annulos fibrosis derived from
the mesoderm
