MSK Learning Objectives Lecture 1 Skeletal Muscle Growth and Function Dr. Ruth Wood, May 1, 2012 1.

. Review the cell structure of skeletal muscle.

2. Discuss muscle development

Mesoderm: migrate from myotomes Myoblasts: mitotically active Myotube: fusion of myoblasts, differentiations Muscle fiber (immature): growth Muscle fiber (mature): future growth

3. Diagram a muscle spindle and describe how it senses muscle length. Muscle spindles are in the belly of the muscles and consist of specialized intrafusal fibers, together with sensory and motor nerve endings. Sensory nerve fibers in the spindle fire in response to changes in muscle stretch. Gamma motor neurons maintain tension on the intrafusal fibers. The muscle spindle reflex provides sensory feedback to regulate muscular contraction.
-Nuclear chain fibers, static bag fiber: respond to stretch -Dynamic nuclear bag fiber: respond to changes in the rate of stretch

4. Describe the location and function of the Golgi tendon organ. Golgi tension organs are free nerve endings at the junction with tendons and provide sensory input on muscle strain. Golgi tendon reflex protects the muscle from excess heavy loads by causing the muscle to relax and drop the load. Lecture 2 Connective Tissue III: Bone Development Dr. Ying, May 1, 2012 1. Be able to distinguish the difference between intramembranous and endochondral bone formation and describe the steps involved in each. Intramembranous Bone Formation Endochondral Bone Formation Within a layer of condensed mesenchymal cells Within cartilage model, Cartilage replaced by bone Occur in flat bones (like skull, scapulae, sternum) Occur in long bones
1. Aggregation of mesenchymal cells 2. Differentiation into osteogenic cells, then osteoblasts which produce osteoid 3. Bony spicules are initially produced and fused to form trabeculae 4. Other mesenchymal aggregates form bone marrow 5. Primary Bone is replaced by lamellar bone 1. Periosteal bone collar is formed first: Chondrocyte prolif, hypertrophy, calcification, BV sprouting 2. Periosteal bud forms the 1 center of ossification (cavity): Periosteal collar extends along diaphysis 3. 2 ossification centers and epiphyseal growth place form 4. Epiphyseal plate replaced by an epiphyseal line, except articular surface: BVs from diaphysis and epiphysis intercommunicate

2. Be able to explain how bones grow in length and width.

Proliferation and hypertrophy of chondrocytes within the epiphyseal place, followed by calcification of the cartilage matrix, leads to an increase in bone length Bone deposition on the outer surface of the bone collar and resorption of bone on the inner surface results in progressive increase in diameter of the diaphysis.

3. Be able to outline the sequence of events in repair of bone fractures.

1. Formation of fracture hematoma: broken blood vessels clot, inflammation occurs, bone fragments begin the gradual resorption by osteoclasts 2. Cartilaginous callus formation: fibroblasts survive and replicate, fracture hematoma is changed into granulation tissue, a hyaline cartilage callus is formed around the ends of the bone 3. Bony callus formation: periosteal cells distal to the fracture gap develop into osteoblasts which form woven and bony trabeculae 4. Bone remodeling: primary replaced by secondary bone

4. Be able to describe the basic structure of synovial membranes.

The synovial membrane is a layer of squamous-to-cuboidal epithelial cells. There are 2 types of cells: Type A (phagocytic) and Type B (fibroblast-like). The synovial membrane secretes a colorless, viscous fluid rich in hyaluronic acid and proteins.

Lecture 3 Musculoskeletal Tumors Tumors of Mesenchymal Origins Dr. Pinsky, May 3, 2012 1. Define and use in context these words and roots:
Actin: structural intracellular molecule that works in muscle contraction, common to skeletal and smooth m Angio-: related to blood vessels Chondro-: related to cartilage Desmin: cytoskeletal element common to skeletal and smooth m Fibro-: related to fibroblasts Histio-: related to immune cells Leio-: related to smooth muscle Lipo-: adipose-related Mesenchyme: undifferentiated tissue derived from embryologic mesoderm Myoglobin: O2 carrying protein present only in skeletal muscle Osteo-: related to bone Osteoid: secreted by osteoblasts to create bone Pluripotential: capable of differentiation into more than one tissue type Rhabdo: related to skeletal muscle Sarcoma: malignant tumor of mesenchymal origin Tumor grade: Grade 1 (low, benign) III (high, malignant, more mitoses), grade by histological type, cellularity, nuclear pleomorphism and mitotic activity Vimentin: an intermediate filament common to mesenchymal tissues

2. Delineate the typical age range, site, prognosis and gross and microscopic appearances (where given) and recognize clinically and histologically each of the following *starred* mesenchymal tumors/tumor-like lesions: See separate page for chart

Lecture 4 Physiology of Skeletal Muscle Dr. Robert Farley, May 3, 2012 1. Describe the cellular structure of a skeletal muscle fiber. See Right 2. Know the difference between Type I and Type II skeletal muscle fibers Type 1: Red fibers rich in mitochondria, Hb, Mb, and cytochromes, give a slow-twitch response to stimulation, more resistant to fatigue, most efficient for generating sustained forces Type 1I: White fibers relatively depleted in mitochondria, energy from glycolysis, fast twitch response, fatigue easily, most efficient for quick, intermittent movements. 3. Name the major protein components of the thick and the thin filaments Thick filaments: myosin (two isozymes Type 1 myosin hydrolyzes ATP more slowly than Type II) Thin filaments: actin, tropomyosin, and troponin 4. Explain the sliding filament model of muscle contraction, including the relationship between crossbridge formation, force generation, and ATP hydrolysis. Describe the role of calcium contraction.
Thin and thin filaments interdigitate and overlap part of their lengths and increase this overlap during contraction. This occurs through breaking and reformation of crossbridges between myosin heads on thick filaments and actin molecules on this filaments. Myosin cross bridges attach to actin at 90 and swivel to about 45. The energy for this process comes from hydrolysis of ATP by the myosin ATPase. Myosin is 1-200x more efficient in ATPase action while bound to actin, so Ca2+ facilitates this interaction as Calcium binds troponin C, releasing actin for myosin binding.

5. Distinguish between isotonic and isometric contractions Isotonic: change in muscle length Isometric: no change in muscle length 7. Describe the force-velocity relationship for an isotonic contraction The rate and extent of muscle shortening and duration of contraction decrease as the size of load increases. Power is maximal when the load is 1/3max. 8. Explain the length-tension curve for an isometric contraction No work is done in an isometric contraction As the muscle is strength, resistive force increases After the muscles maximum, it can no longer stretch safely, and tension decreases

9. Describe the mechanism whereby force of contraction can be increased by increasing the frequency of motor nerve firing The action potential is short (~5msec) compared to the duration of the twitch (10-100msec), and it is possible to generate a second AP before the muscle has relaxed, which would release more calcium and generate even more force. Lecture 5 Skeletal Muscle Plasticity and Adaptions to Exercise Dr. Schroeder, May 3, 2012 1. Describe muscle fiber type characteristics and adaptations to exercise and aging.
Type I: slow twitch, endurance Type IIa: fast shortening speed, moderately well-developed capacity for energy transfer from both aerobic and anaerobic sources, represent fast-oxidative-glycolytic (FOG) fibers Type IIb: possesses greatest anaerobic potential and most rapid shortening and most rapid shortening velocity, represents true fast-glycolytic (FG) fibers.

2. Explain the neuromuscular and hypertrophic adaptations that are responsible for enhancing skeletal muscle force production.
Hypertrophic factors: hypertrophy, proportion of Type II/Type I fibers, myofilament packing

Neuromuscular factors: #motor units recruited, firing rate (freq) of MU, MU synchronicity, activation of synergist muscles, inhibition of the antagonist muscles (first 4-6 wks of training)

3. Describe the process of exercise induced muscle damage and the importance to muscular adaptation.
Once a muscle fiber is injured large amounts of calcium may enter the cell, which is cytotoxic. Changes in pH, intramuscular high E phosphates, ionic balance, or T with unaccustomed exercise produce major alterations in the sarcoplasmic reticulum structure/function. This depresses the rates of Ca2+uptake and release and free Ca2+concentration. Ca2+ may then move into the cytosol of the damages fiber, contributing to the autolytic process that degrades both contractile and noncontractile structures, leading to reduced force capacity and muscle soreness. The muscle damage acts as a stimulus for initiation of the repair process and adaption. The greater the magnitude of muscle fiber damage the greater the compensatory adaption

4. Discuss several of the important factors that contribute to improving muscle mass and strength.
Genetics myostatin, androgens Nervous system activation Physical activity progressive resistance training Nutritional activity Endocrine influences Environmental factors

Lecture 18 X-Rays and Other Imaging to See Kids Bones Dr. White, May 15, 2012 1. Know advantages and disadvantages of radiographs, CT and MRIs
Advantages Radiographs
First modality obtained Differential dx of osseous lesions (bony lesions, dislocations, subluxations, erosions, ST edema, calcifications, effusion) Many benefits including joint space narrowing/erosions Multiple plane visualization Minute details within slices, subtle fractures 3D reconstruction Matrix mineralization Good for image guided injection, arthrogram, bone/doft tissue biopsies guided RF ablation Excellent for soft tissues ligaments, cartilage, solid or cystic soft tissue masses RF: detected by overlying coil T1: anatomy T2/STIR: pathology PD: cartilage Routine study depending on indication MR arthrogram, MRI w/o and w IV contrast

Disadvantages
Not good and showing soft tissues Ionizing radiation: avoid repeat, protect pt

CT

Adverse rxn to IV contrast agent Dose of radiation more than radiographs (esp in children)

MRI

Subtle calcifications may not be apparent avulsion, subtle calcific tendonitis Correlate with radiographs

Lecture 23 Non-neoplastic Diseases of Bones, Joints, and Connective Tissues Dr. Cosgrove, May 16, 2012 1. Define and use in context the following terms: Arthritis: swelling of the synovium Arthralgia: joint pain Effusion: escape of fluid Involucrum: new bone resorption Monostotic: one bone involved Osteoblasts: mononuclear, secrete procollagen, alkaline phosphate rich Osteoclast: multinucleate, resorb bone Osteocyte: mononuclear cells in lacunae Osteoid: type 1 collagen lay down by osteoblasts Osteopenia: low bone mineral density
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Osteophyte: new bone Osteoporosis: Decrease in total bone mass w/ microarchitectural deterioration Pannus: marked hyperplasia causing flap Pathologic fracture: fracture due to erosion or other pathology Polyostotic: multiple bone involvement Rheumatoid nodule: central necrosis, palisading histiocyte, chr. inflam Sequestrum: bone necrosis Synovitis: swelling of the synovium Tophus (pl. tophi): soft tissue depositing that occurs in gout

2. Identify the (most common) etiology, and discuss the significant clinical and pathologic features for each of the following disease states:
Etiology Congenital Diseases Defective synthesis/ Osteogenesis secretion of pro-collagens Imperfecta
4 forms: AD most common, AR more rare/lethal

Clinical Features
Fractures early in life Improper healing Short statures Abn collagen affects sclera (blue), ligaments, teeth Short, curled bones Dwarfism, normal dev of ribs/skull, but long bones fail to elongate Nerve compression, marrow impingement with anemia, tcp, susceptibility to inf. Tall stature, arachnodactyly, lax ligaments, ectopia lentos, mitral valve prolapse, cystic medial necrosis of aorta Fever, pain, limp

Pathologic features Abn osteoid matrix

Achondroplasia AD, dwarfism

Pt mutation in FGFR3 Suppressed cartilage production at epiphysis Rare Decreased osteoclastic reabs Bones enlarged but brittle AD, risk w paternal age Mutation in fibrillin gene FBNI, affects tissue with high elastic content Children, young adults, previously healthy Related to trauma Bac: S. aureus, Some fungal, salmonella in sickle cell pt Enter via blood, contiguous spread or trauma Complication of acute osteomyelitis

Osteopetrosis

Enlarged, dense vertebra on Xray Aorta, CT degenerating

Marfan Syndrome

Infections of Bone

Acute Pyogenic Osteomyelitis

Acute inflammation: Abscesses Bone necrosis: Sequestrum Reactive new bone: Involucru m Acute and chronic inflammation Involucrum and Sequestrum Draining sinuses to skin 2 amyloidosis, Squamous Cell CA Necrotizing granulomata, chronic inflam AFB stain oft (+) Thinned cortical and trabecular bone, normal structures, changes often subtle Bone trabeculae with thick seams of periph. osteoid

Chronic osteomyelitis

Ulceration and necrosis

TB of bone

Immunosuppressed pts, developing nations

Gradual onset, fever, weight loss Spine commonly effects (Pott dz) X-Ray: Bone destruction, soft tissue masses 1: aging, females, whites, idiopathic 2: Immobilization, endocrine d/o, drugs, malnutrition, malabsorption All bones affected, sx in weight-bearing bones Fractures, height, deformity, pain Soft, weak bones, fracture easily Soft weak bones, fracture easily Deformities due to epiphyseal disruption

Metabolic Bone Disease in total bone mass w/ Osteoporosis

microarchitectural deterioration Bone loss that produces sx

Osteomalacia Rickets

Structural abn of bone due tp defective osteoid min. due to Vit D deficiency Osteomalacia in children

Etiology Bone Diseases of Unknown Cause Anglos, 3-10% of US pop, Pagets over 40yo Disease
Monostotic or Polyostotic

Clinical Features
Pain, deformities, fractures Serum alkaline phosphatase Enlargement, deformity of aff. bones Stages: 1.Lytic: Irreg. bone resorption 2.Mixed: Irregular bone form active osteoblasts/clasts very vascular bone 3.Sclerotic: bone enlarges. osteoblastic act. Monostotis: 70%, single bone aff, incidental X-ray finding, pain, deformity, fractures Polystotis: 30%, multiple bones, with craniofacial involvement, pain, disfigurement, deformity, fractures, 510% with assoc abn (ex. Albright syndrome) Single, large joint Pain, warmth, erythema Fever, chills, high WBC Synovial fluid: PMNs, gram stain +, culture s. aureus usual cause Single, large joint, swelling, pain, minimal warms/erythema Synovial fluid: PMNs, lymphs, +AFB

Pathologic Features Irregular, thick trabeculae, prominent cement lines

Fibrous Dysplasia

Replacement of localized bone areas by abn prolif of fibrous tissue and irregularly arranged woven bone

Radiologic: well-demarcated, lucent, ground glass lesion Gross: expansion of medullary space by grey-tan tissue, cortex intact Histo: mature fibrous tissue w/ admixeds woven trabec.

Joint Disease Pyogenic arthritis

Hyperplasia, acute inflammation of synovium

TB Arthritis

Developing countries

Rheumatoid Arthritis

Auto-immune disease

Hyperplasia, acute chornic inflammation, granulomata, necrosis, +AFB Synovium: Marked hyperplasia (pannus), lymphs, plasma cells, M0, lymphoid follicles, fibrin
Rheumatoid nodules: central necrosis, palisading histiocyte, chr. inflam

Crystalinduced arthritis Osteoarthritis

Gout, old mine, increased serum Uric Acid

Acute: MSU crystal deposit in synovium, sudden, severe attacks of pain, Fluid has PMNs, needle-shaped crystals Chr: large masses of MSU, tophi in soft tissue.

Primary: aging Secondary: trauma, congenial anomalies

Aff. weight bearing joints, fingers (Herberden nodes) Synovium: Mild hyperplasia, chr inflammation Early: fissures, clefts, uneven loss and prolif of chondroc. Late: cartilage loss, osteophyte formation, deformities

3. List the major microbiologic agent(s) responsible for acute pyogenic osteomyelitis, infectious arthritis, and Lyme disease and Pott disease. APO: S. aureus, fungus in immunosuppressed Inf arthritis: S. aureus, Neisseria, strep, H. influenza, and other gram (-) Lyme: Borrelia burgdorferi Pott dz: Tuberculosis 4. Presented with an image and appropriate background information, identify the gross and/or microscopic appearance of the following conditions: See above chart Acute pyogenic osteomyelitis Osteoarthritis (DJD) Pott disease Fibrous dysplasia Paget disease Rheumatoid arthritis Lecture 27 Bone and Joint Infections I Dr. Holtom, May 18, 2012 1. Understand the pathophysiology of infectious arthritis.
Enter the joint from the bloodstream, from a contiguous site, or from direct inoculation (trauma, surgery) The course of infection: 8

Organisms enter joint space, adhere to cartilage Neutrophils enter joint space and synovial membrane Damage to cartilage within 48h - pressure, bacterial toxins, leukocyte proteases and inflammatory cytokines, invasion of cartilage by bac/inflam cells Cartilage destruction leads to joint space narrowing, further erosive damage to cartilage, possible extension to bone and soft tissue

2. Know the common microbiologic causes of infectious arthritis.

Common Bacteria: 50% S. aureus, 20% Strep (mainly pyogenes), 5% H. influenza, 4% E. coli, 3% Neisseria gonorrhea (rare in practice) Less common: TB (common worldwide), B. burgdorferi (Lyme dz), Treponema pallidum, and brucella Fungal: Coccidioides immitis, sporothrix schenckii (rose thorns), candida, Cryptococcus Viral: Parvo B19, rubella, HIV, HTLV-1

3. Know the appropriate antibiotic therapy for infectious arthritis.

Debridement followed by systemic 3rd gen cephalosporins +Vancomycin for 2-4wks

4. List the common microbiologic causes of osteomyelitis.

Its always Staph aureus, really depends on etiology (Salmonella in sickle cell pts)

5. Understand the principles of antibiotic therapy for osteomyelitis.

Depends on clinical situation and cultures, generally give antibiotics for 4-6wks

6. Be familiar with the clinical findings, microbiologic causes, and therapies of special types of OM.
Vertebral OM Clinical findings Non-specific back pain Low grade fevers Prolonged illness (several months) Adjacent vertebral bodies affected Fever +acute, several. sacral pelvic pain OM of adjacent bones + Blood cultures Distal tibia w/ single lesion, <25yo Acute, subacute fever, pain) or chronic (afebrile, chronic dull pain) Microbiological Cause S. aureus (50% Enterics (E. coli) 25% IVDA: MRSA, P. aeruginosa, Serratia spp Mycobacteria TB Potts Dz S. aureus Gram (-) bacilli in IVDA Therapies Antimicrobials for 4-6wks No debridement unless epidural abscess found Spine stabilization as needed IV Antibiotics for 4-6wks Surgery usually not necessary

Sacroiliac joint infection Brodies Abscess

S. aureus

Lecture 28 Bone and Joint Infections II Dr. Zalavras, May 18, 2012 1. Understand the diagnostic features and treatment of septic arthritis
History of predisposing factors, fever and chills, painful, swollen, red joint with limited motion, and joint effusion. Imaging studies show early soft tissue swelling and later joint narrowing which signifies cartilage destruction. Laboratory Exams include CRP (most reliable), sed rate, WBCs (50%), (+) blood cultures (50%). Synovial fluid analysis shows thick and cloudy fluid with PMNs and (+) cultures. 2. Know the complications that occur from septic arthritis. Cartilage destruction, pain and loss of function, degenerative arthritis, avascular necrosis of femoral head, subluxation and dislocation, and recurrent infections

3. Explain the adverse role that biofilm plays in infections.

Biofilm protects the organism from antibiotics and host defense mechanisms including AB formation and phagocytosis. It allows the infection to exist in a subclinical state and to recur.

4. Describe the anatomic and physiologic classifications of osteomyelitis

Anatomical: Type I - medullary Type II - superficial Type III - localized Type IV diffuse (bone unstable) Physiological: A Host normal B Host Immunocompromised (systemic or local) C Host Treatment not indicated

5. Understand the diagnostic features and treatment of osteomyelitis.

Acute exudative inflammation, increased vascularity, pain of the bone, edema, PMNs. Lab values: WBC, ESR and CRP, + blood cultures, bone aspiration/biopsy, X-rays show periosteal elevation after 7-10d, and late cortical and marrow destruction.

6. Describe the principles of debridement, local antibiotic therapy, soft tissue coverage, and bone grafting.
Surgical debridement to remove all necrotic bone and soft tissue Culture specimens of pus, soft tissue and bone + Systemic and/or local antibiotic therapy Fracture stabilization if necessary Soft tissue coverage, as vascularity improves healing Bone grafting to provide scaffold for new bone

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