Microanatomy

Bone development and growth Bone formation appositional growth Intramembranous bone formation flat bones (calveria, scapula, sternum) Occurs in the richly vascularized mesenchymal tissue Groups of mesenchymal cells differentiate and cluster together to form a 1o ossification center Osteoblasts differentiate and secrete osteoid (organic bone matrix); when they become trapped in this matrix, they become osteocytes Spicules of bone trabeculae spongy bone Undifferentiated mesenchymal cells surrounding the trabeculae differentiate into bone marrow stromal cells; hematopoietic cells later populate this tissue Endochondral ossification long and short bones Before birth During fetal development, vascularization of the perichondrium in the diaphysis (shaft) of the hyaline cartilage model causes chondrogenic cells to differentiate into osteoprogenitor cells, which in turn differentiate into osteoblasts Osteoblasts lay down osteoid, which mineralizes to form a bone collar around the diaphysis Formation of the bone collar triggers apoptosis of resident chondrocytes in the diaphysis, which are replaced by the newly-formed osteoblasts primary ossification center Osteoblasts in the primary ossification center secrete more osteoid, which progressively replaces the original cartilage model trabecular bone + marrow cavity After birth Vascularization of the epiphyses begins after birth secondary ossification centers Proliferation and hypertrophy of chondrocytes within epiphyseal plates, followed by calcification, leads to an increase in bone length Zone of rest (reserve cartilage, nearest epiphysis) small, scattered chondrocytes Zone of cell proliferation larger chondrocytes, arranged like a stack of coins Zone of cell maturation and hypertrophy columns of large chondrocytes Zone of calcification dead chondrocytes + calcified bone matrix Zone of ossification newly formed bone Bone deposition on the outer surface of the bone collar + resorption of bone on the inner surface results in a progressive increase in the diameter of the diaphysis

Bone remodeling resorption by osteoclasts + deposition by osteoblasts Remodeling occurs in response to weight-bearing and mechanical forces, or to blood calcium levels (via PTH and calcitonin). Activation of osteoclasts resorption reversal formation. Bone fracture repair 1. Formation of fracture hematoma Vessels in periosteum, osteons, and medullary cavity rupture when the bone is fractured, and a clot forms around the injury site Lack of circulation causes death of osteocytes + inflammation migration of PMNs, macrophages, and osteoclasts 2. Formation of cartilaginous callus Fracture hematoma is reorganized into granulation tissue Fibroblasts and osteoprogenitor cells from the periosteum and bone marrow produce fibrous CT between the ends of the bone Some osteoprogenitor cells become chondrogenic cells and produce a hyaline cartilage callus 3. Formation of bony callus Osteoprogenitor cells in cartilaginous callus produce bony trabeculae by way of intramembranous bone formation As the blood supply to the callus improves, endochondral ossification will occur in the cartilaginous callus, forming a bony callus of primary (woven) bone 4. Bone remodeling Joints Synarthoses joints where bones are closely bound together with minimal movement Diarthroses joints that permit a wide range of free movement synovial joints

Muscle Physiology
Functional aspects of muscle Movement proportional to length of muscle fibers parallel-fibered muscles Force proportional to cross-sectional area of muscle fibers pennate muscles Tendons In parallel-fibered muscles, replacing muscle w/ tendon reduces muscle length less movement In pennate muscles, replacing muscle w/ tendon reduces the number of fibers less force

Skeletal muscle plasticity and adaptations to exercise Types of muscle fibers Classification Type I slow and fatigue resistant red With increasing High capillary density stimulus strength, I is High amount of myoglobin activated first (lowest Numerous mitochondria threshold), then IIa, Type IIa fast but fatigue-resistant (fast oxidative glycolytic) then IIb (reserve Less myoglobin and fewer mitochondria than type I capacity) Type IIb fast fatigable (fast glycolytic) No myoglobin Limited # of mitochondria greatest anaerobic capacity Fiber type adaptations with exercise Genetics largely determines the distribution and proportion of I and II fibers cant convert from 1 type to the other Weight lifters and power athletes show enlargement of type II fibers Both endurance athletes and weight lifters may convert IIb to IIa fibers Fiber type adaptations with aging Progressive decrease in # and area of type II fibers No barrier to training adaptations of muscle fibers Strength peaks between 20 and 40 (largest cross-sectional area) Concentric strength begins to decline first Eccentric strength begins to decline at a later age and progresses more slowly

Enhancing skeletal muscle force production Neuromuscular adaptations account for most initial gains in strength (hypertrophy hasnt yet occurred) Increased motor unit recruitment to a particular stimulus Increased firing rate of recruited motor units Increased motor unit synchronization Increased activation of synergist muscles Increased inhibition of antagonist muscles Hypertrophic factors Increase in cross-sectional area of muscle fibers (particularly type II) greater capacity to produce force Increased area is coupled directly to increases in number of myonuclei and synthesis of cellular components, particularly protein filaments that constitute the contractile elements Hyperplasia minimal contribution to force production Endurance adaptations in skeletal muscle Resistance training little impact on cardiovascular fitness or body fat Aerobic training mitochondrial volume and # mitochondrial enzymes capillary density Exercise-induced muscle damage Delayed-onset muscle soreness Microscopic tears in muscle tissue or damage to contractile elements release of CK or TnI Osmotic pressure changes cause fluid retention in surrounding tissue Muscle spasms Overstretching and tearing of connective tissue membranes Acute inflammation Altered calcium regulation (due to changes in pH, ionic balance, temperature, etc.) entry of Ca2+ release of enzymes degradation of contractile and noncontractile structures pain Role of the satellite cell Fusion of satellite cell nuclei and their incorporation into existing muscle fibers enables the fiber to synthesize more proteins to form additional myofibrils This likely contributes directly to muscular hypertrophy and may stimulate transformation of existing fibers from one type to another Improving mass and strength Anabolic steroids protein synthesis, protein degradation Myostatin negative regulator of muscle mass myostatin, muscle mass

Physiology of skeletal muscle Cellular anatomy of skeletal muscle fibers Thick filament = myosin Thin filaments Actin Troponin Tropomyosin

Excitation/contraction coupling and the sliding filament model of contraction 1. Binding of Ach to nAChR on the motor end plate causes a local potential, which is conducted electrotonically to adjacent regions of membrane (with many Na channels), where an action potential is initiated 2. Action potential is conducted along sarcolemma and into the myofibrils by the T-tubules 3. Ca2+ release channels (ryanodine receptors) in the SR are mechanically opened, and Ca2+ is released into the sarcomere 4. Binding of Ca2+ to troponin C causes a conformational change that exposes binding sites on actin 5. Myosin heads bind to actin, forming a crossbridge total force generated is proportional to the number of cross-bridges formed 6. Hydrolysis of ATP by the ATPase in the myosin head pulls the thin filaments toward the M line of the sarcomere = muscle contraction 7. The muscle relaxes when Ca-ATPases pump Ca2+ back into the SR, calcium dissociates from troponin, and tropomyosin resumes blocking the myosin binding site on actin Mechanics of muscle contraction Types of contraction Isotonic contraction causes a change in muscle length Eccentric muscle lengthens (force < load) Concentric muscle shortens (force > load) Isokinetic muscle shortens at a constant rate during isotonic contraction Isometric contraction causes no change in muscle length (force = load) Isotonic contractions and force-velocity curve As load increases: contraction velocity distance shortened duration of contraction lag time between action potential and contraction (harder to overcome load to generate concentric contraction) Maximum power output is obtained when a muscle moves against a load that is 1/3 of max
Distance shortened

light load intermediate load heavy load

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Time

Isometric contractions and the length-tension curve Maximum force is generated near resting length As the muscle is stretched, the resistive force (passive tension) increases

Summation of contractions Because the action potential is very short, the absolute refractory period for skeletal muscle is very short. It is therefore possible to generate a second action potential before the muscle has relaxed (i.e. there is still Ca2+ in the sarcomere). increasing frequency of stimulation results in an oscillating pattern of tension, in which the force generated by the muscle increases

Orthopaedics
Orthopaedic soft tissue injuries Injured tissues Meniscus Ligaments L ~ 10% failure of ligament Parallel collagen fibers resist tensile forces but not compressive forces, and must offer very little resistance to motions whose magnitude is in the physiological range but offer strong resistance to motions outside that range Knee (ex. ACL) 6 weeks to revascularize after ligament transplant Shoulder (ex. Inferior GH ligament) operate on pts. between 20 and 40 years old Tendons Collagen bundles tighter in tendons than in ligaments greater tensile strength Rotator cuff tear (mostly supraspinatus) associated with pain at night Rehab Phase I recovery Phase II motion Phase III strengthening

Mechanics of the cervical and lumbar spine Anatomical structures of the cervical and lumbar spine Ligaments Posterior longitudinal ligament, interspinous ligament, and supraspinous ligament resist flexion Anterior longitudinal ligament restricts extension Intertransverse ligaments connect neighboring transverse processes to each other and have connections to deep paraspinal back muscles Capsular ligaments, working along with facet joints, restrict axial rotation in the lumbar spine Ligamentum flavum connect the laminae of adjacent vertebrae

T2-T10 at higher risk for neural injury (smallest ratio of canal size to cord diameter)

Facet joints

Cervical spine 45o coronal/axial flexion, extension, lateral bending, rotation

Thoracic spine some lateral bending, some rotation

Lumbar spine 45o coronal/saggittal flexion, extension, some lateral bending Intervertebral disks **Anulus = type I collagen **Nucleus = type II collagen provides resistance to compressive spinal loads by generating hydrostatic pressure

Disk degeneration Typically begins in 2nd decade of life in men, and 3rd decade in women Thickening of annulus collagen fibers takes up space initially occupied by nucleus pulposis Nucleus decreases mucopolysaccharide and proteoglycan content and therefore becomes less effective at retaining water Osteophytes form at vertebral margins, and disk height decreases decrease in space available for exiting spinal nerve roots (foraminal stenosis) leg pain, weakness, numbness in a dermatomal distribution Degenerative changes of the disk are usually accompanied by degeneration of the facet joints spondylosis (disk degeneration + facet arthritis) Facet osteophytes encroach the spinal canal central canal and lateral recess stenosis neurogenic claudication (pain, numbness, weakness in lower limbs during walking) Disk herniation Tissue from nucleus pulposis protrudes through a defect in the annulus fibrosis mechanical impingement on spinal nerves + chemical irritation back and leg pain **Important mediators of inflammation include matrix metalloproteinases, nitric acid, PLA2, PGE2, and IL-6 **Disk herniation affects the spinal nerve of the vertebra below (i.e. L4-L5 bulge affects L5 spinal nerve)

Back pain The development of a lordotic lumbar curve, which made humans able to stand upright and walk on two legs, predisposes us to back pain. Leg pain nerve compression Back pain problem with disk or facet Common sources of back pain **Muscle or ligamentous strain (usually from acute injury) pain does not radiate Herniated disk particularly L4-L5 (affects L5 spinal nerve) or L5-S1 (affects S1 nerve) Usually presents with pain that radiates into the leg Pain is usually continuous and may radiate throughout the dermatome served by the compressed nerve root If herniated disk impinges on a nerve and causes incontinence or weakness/paralysis, urgent treatment is essential Disk degeneration Spinal stenosis Osteoarthritis Vertebral fracture or collapse (particularly in older people with osteoporosis) Psychosocial factors depression, anxiety, hypochondriasis, acute remunerative back pain Less common but more serious causes Neoplasm metastatic cancer, multiple myeloma, primary tumor, lymphoma Age over 55 or under 20 History of cancer Presents with constitutional symptoms (ex. fever, chills, weight loss) Patient uncomfortable in any position and unable to find relief Pain is worse in supine position, particularly at night Infection epidural abscess, vertebral osteomyelitis, septic disk, Potts disease Associated with IV drug use or immune suppression Similar presentation as neoplasm Cauda equina syndrome Saddle anesthesia Recent onset of bladder and/or bowel dysfunction Severe or progressive neurological deficit in lower extremity Major motor weakness quadriceps, ankle plantar flexors, evertors, and dorsiflexors Metabolic problems osteoporosis, osteomalacia, hemochromatosis Extrinsic diseases (ex. aortic aneurysm)

Clinical overview of the hand Congenital differences Etiologies 10% environmental 30% genetic 60% unknown

Embryology **Upper limb develops between 4th and 8th weeks of fetal growth this is also when the viscera and other internal organs develop, so children with congenital hand abnormalities should be evaluated for other congenital problems Syndactyly = failure in separation of the fingers Simple only soft tissue involved Complex bone is also involved need to correct earlier if border digits (ex. thumb and index finger, which grow at different rates) are involved Trauma Fractures **Extraarticular no rotational deformity can be accepted Intraarticular need to maintain normal joint architecture Bennett fracture occurs at the base of the 1st metacarpal Flexor tendons Lacerations in Zone 2 (where flexor digitorum superficialis tendons split around the tendons of the flexor digitorum profundus) are especially difficult to treat because of the potential for scar formation in the flexor sheath Infections Necrotizing fasciitis destroys skin and fascia but spares muscle Infectious flexor tenosynovitis Diffuse swelling of finger Tenderness along flexor sheath Finger held in a slight flexed position Excrutiating pain with passive extension of the finger

Four Signs of Kanavel

Vascular occlusion Most people have collateral circulation to the hand, so injury to either the radial or ulnar artery usually does not threaten digit viability. Allens test to assess collateral circulation Occlude both radial and ulnar arteries releasing 1 side should restore circulation to all digits Repeat for other side Nerve injury See carpal tunnel syndrome (below)

Carpal tunnel syndrome Carpal tunnel syndrome is caused by compression of the median nerve within the carpal canal, secondary to narrowing or crowding the nerve. It can occur at any age, but is most often encountered in patients > 30 years old, and occurs more frequently in women. Signs and symptoms Numbness and tingling of the thumb and fingers at night or while driving Decreased sensation in median nerve distribution
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Thenar nerve atrophy + Tinels Sign (nonspecific tests for irritation of the nerve) tapping over volar center of wrist evokes tingling fingers + Phalens Test (specific to CTS) holding wrist in full flexion for seconds evokes numbness/tingling of thumb or fingers due to increased pressure in carpal tunnel + Compression test pressure applied directly over carpal canal evokes symptoms EMG and nerve conduction studies distal median sensory latency time distal median motor conduction time in the wrist Differential diagnosis Cervical radiculopathy Peripheral neuropathy Thoracic outlet syndrome Occlusive vascular disease Causes / risk factors Space-occupying lesions Recent or old wrist fractures Infection Local edema Foreign body Lipoma or other neoplasm Systemic conditions Pregnancy (fluid retention) Obesity Diabetes Thyroid dysfunction Arthritis Amyloidosis Overuse syndromes Forced flexion or extension of wrists (ex. typing) Constricting bands or clothing around the wrist Treatment Conservative treatment Wrist splint to limit flexion/extension (which compress the carpal canal) NSAID Steroidal injection Surgical decompression used when conservative treatment doesnt work or if there is pronounced thenar atrophy

Biomechanics of fractures Fractures occur when forces applied to a bone exceed its ultimate strength. Determinants of bone strength Metabolic Osteomalacia Ca2+ in bone matrix Osteoporosis quantity of bone Structural When young, bones have small cross-sectional diameter + thick walls = strong Aging causes bones to lose wall thickness thinner cortex but increased diameter, as the bone tries to compensate for reduction in strength Modality of the force applied Bone is weaker in tension than compression Rapid force application fracture Slower force application ligament failure Bone remodeling Wolfs law If a constant force is applied to a bone over a long period of time, the bone will re-organized to make itself stronger to resist that force Factors affecting bone healing Metabolic Nutrition Smoking PO2 NSAIDs need inflammation to produce granulation tissue for callus formation Local biology blood supply from surrounding soft tissue; deprived blood supply can cause necrosis Femoral neck fracture causes loss of blood supply to head of femur Talus neck fracture causes loss of blood supply to head of talus Mechanical factors Primary bone healing rigid stabilization to prevent all motion bone heals by remodeling Callus formation need some motion, but not enough to cause non-union Fatigue failure of internal fixators if fracture doesnt heal quickly enough, implant may fail Bone healing failures Mis-union bone doesnt join correctly Non-union caused by arrest in healing process additional time will not yield union Hypertrophic callus on both ends (elephant foot appearance), but healing is not complete Atrophic (avascular) bone doesnt grow back Complications of fractures ARDS can lead to multi-system organ failure Fat embolus, pulmonary embolus Compartment syndrome accumulation of fluid cause increased pressure compromised vascularity pain, pressure, paralysis, pulselessness, pallor Nerve injury Tibial fractures injury to common fibular nerve Humerus factures injury to radial nerve

Vascular injury Distal femur fracture injury to superficial femoral artery Shoulder fractures injury to axillary nerve Knee dislocation injury to popliteal artery Injury to surrounding tissues Goals of fracture treatment Achieve union in shortest time proper joint alignment Restore function to pre-injury state Knee pain Ligaments protect the menisci Menisci protect articular cartilage Ligament and meniscus injuries
Injury ACL* Precipitating event hyperextension, twisting, quick stop, varus or valgus stress twisting, quick stop -- but can still play direct blow laterally direct blow medially force on anterior knee Mechanical symptoms Snap/pop at time of injury Buckling thereafter Snap/pop at time of injury Locking, clicking, catching, buckling thereafter Tests + Lachman, + Pivot shift, + Anterior drawer, - Posterior drawer + McMurray, joint line tenderness valgus stress test, pain over medial condyle of femur varus stress test + Posterior drawer

Meniscus*

MCL LCL PCL

*ACL and meniscus injuries are usually associated with swelling patient comes in with leg in flexion Knee conditions that can mimic ligament or meniscus injuries Patellofemoral problem Loose bodies can cause locking, clicking, catching, buckling Bursitis Tendonitis Iliotibial band friction syndrome Treatment options Conservative treatment PT +/-brace. Arthroscopic repair/excision/reconstruction, followed by PT (+/- brace)

Surgical treatment of arthritis and joint disorders Categories of surgical treatment for arthritis Osteotomy corrects joint malalignment Debridement better if there are specific lesions to be addressed (ex. meniscal tears, loose bodies) Remove inflamed synovium Smooth irregular articular surfaces Arthrodesis (fusion) eliminates motion at the joint Arthroplasty replaces articular surfaces

Contraindications to total joint replacement Absolute contraindications Active infection in the joint to be replaced No arthritis in the joint to be replaced (ex. referred hip pain from arthritis in spine) Relative contraindications Morbid obesity Neuropathic joints Progressive neurological disease History of IV drug use Non-compliance Non-ambulation Total hip arthroplasty Indications now include younger patients with multiple etiologies Long term results most never need revision Complications DVT Leg length difference Total knee arthroplasty Requires a functioning extensor mechanism More difficult rehab than hip replacement (more range of motion, ligament balance to work on) Long term results most never need revision Complications Infection Palsy of common fibular nerve

Foot pathophysiology and mechanics Ankle sprains most common injury presenting to ER Usually caused by inversion with the ankle plantar flexed Physical exam findings Edema Tenderness Ecchymosis over lateral ankle ligaments Possible tenderness medially or above ankle Initial treatment Relative rest weight bearing ok, but often with braces/casts to limit inversion Ice Compression Elevation re-evaluate 3-4 weeks after injury to assess instability and instruct in rehab Bunions (hallux valgus) Bunion = prominent medial eminence (deviated 1st metatarsal) History Pain with closed toe shoes, particularly with heels No pain with bare feet or tennis shoes
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Treatment Conservative wide shoes, low heels, stretch leather over bunion Surgical treatment only indicated for pain, not for cosmetic reasons or phophylacticaly Diabetic foot ulcers Ulcers develop secondary to excess pressure, neuropathy, and vasculopathy often present with no pain, because the patient didnt feel the inciting injury **Calluses are an indication of underlying damage Treatment Debride calluses and nonviable tissues Total contact casting to decrease pressure and shear across ulcer site After ulcer heals, custom orthotics Plantar fasciitis most common source of disabling foot pain Injury is caused by inflammation and microscopic tearing of plantar fascia Clinical presentation Pain during the first few steps after waking, which gradually improves Pain happens again after starting to walk after sitting for a long time Most patients are overweight Most have tight calf muscles Treatment Calf stretches Judicious use of steroid injections never on first visit NSAID Heel orthotic

Impingement syndrome rotator cuff pathology General principles Symptoms result from rubbing of a rotator cuff tendon (most often the supraspinatus tendon) under the surface of the arch formed by the coracoids, coracoacromial ligament, and anterior acromion. They are often related to repetitive overhead activity. Sudden onset suggests a mechanical injury; insidious onset suggests a degenerative disease or inflammatory process. Involvement of the hand may suggest a neurovascular or neurological pathology. Signs and symptoms of impingement syndrome due to supraspinatus pathology **Pain on lateral aspect of upper arm and inferior to acromion May radiate distally Worse at night, disrupting sleep Worse with reaching overhead Muscle wasting (disuse atrophy) Markedly limited internal rotation Tenderness over greater tuberosity of humerus

Elbow pain Medial epicondylitis golfers elbow pain results from resisted wrist flexion and pronation Lateral epicondylitis tennis elbow Results from repeated stress on or near lateral epicondyle by wrist extensor muscles, particularly the extensor carpi radialis brevis Mild tenderness to palpation over and distal to the lateral epicondyle Decreased grip strength + pain gripping objects Normal range of motion No visible swelling Morning stiffness and aching throughout the day

Bone and joint infections Synovial membranes In diseases like RA, the synovial lining can become abnormal, with disease characteristics. Antibiotics can diffuse across the synovial membrane. After surgical excision, the synovial lining usually regenerates within 4-6 weeks. Portals of entry Hematogenous local infiltration of bone (most common) Bacterial seeding takes place through nutrient or metaphyseal vessels and localizes in the venous sinusoids of the metaphysis Acute exudative inflammation + increased vascularity edema + PMN infiltration Within 2-3 days, thrombosis and obliteration of the vessels ischemia, necrosis Intramedullary abscess forms, and edema and purulent exudates are forced through the Haversian and Volkmann canals Periosteum is stripped from the bone, further isolating cortical bone from nutrition and producing more necrotic tissue Pus may re-enter the medullary canal through the cortex at a distance, may perforate the periosteum and enter soft tissue, or extend into neighboring joint Direct inoculation via penetration wounds, surgery, injections, etc. Septic arthritis Clinical signs and symptoms Fever and chills Irritable joint painful, with limited motion Synovitis Effusion Xray soft tissue swelling joint narrowing and destruction Blood tests **Elevated CRP and sed rate (CRP is elevated earlier) Blood cultures positive 40-50% of the time WBC not generally elevated Synovial fluid changes Opaque, mixed coloration (vs. normal clear and colorless) Decreased viscosity, decreased sugar content Increased cellularity (esp. PMNs) Gram stain may reveal organisms absolute diagnosis
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Complications Cartilage and joint destruction by proteolytic enzymes relased from bacteria and WBCs Avascular necrosis Subluxations and dislocation Degenerative arthritis Pain and loss of function Treatment Antibiotic therapy TB isoniazid, rifampin, pyrazinamide, ethambutol Coccidioidomycosis fluconazole, amphotericin B Double refractile wall with enclosed endospores Granuloma reaction, but no caseation necrosis

Surgical drainage Osteomyelitis Anatomical classification Type I medullary Type II superficial ulcer with exposed bone Type III localized cortex and medullary canal involvement Type IV diffuse cortical involvement with extension through medullary cavity

Osteomyelitis may cause septic arthritis Treatment of infected fractures Control infection Debride all nonviable bone and soft tissue Culture specimens for aerobes, anaerobes, fungus, and TB Stabilize fracture Soft tissue coverage muscle transfer 3-7 days after first debridement **Only transfer healthy muscle Bone grafting Local antibiotic delivery antibiotic beads, spacers, etc. Advantages Higher local concentrations much higher than can be achieved by systemic administration Lower side effects
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Disadvantages Foreign body May cause resistant organisms Antibiotic elution related to: Dosage Surface area minibeads > beads > spacers Fluid environment Rate of fluid turnover Antibiotic vehicle porosity Antibiotic type tobramycin > vancomysin

Pediatric orthopaedics Pediatric trauma considerations Differences from adults Cortex more porous, so bones may bend and retain a distorted shape Healing is fast nonunions are rare Weak link in bone-ligament-tendon complex is the cartilaginous attachment of the tendon or the growth plate overuse injury (traction apophysitis) Osgood-Schlatter disease at tibial tubercle Calcaneal aponeurosis at heel Little leaguers elbow at medial epicondyle **Injuries commonly involve the physis (growth plate) injured by shearing force Tenderness along the bone (1-2 cm from joint) physeal fracture need to cast (but faster healing than long bone shaft fracture) Tenderness along the soft tissue (right at joint) not physeal fracture Fractures can compress the cortex Developmental dysplasia of the hip hip does not fully form, but doesnt impact walking Clinical variants Femoral head subluxation incomplete contact with acetabulum Femoral head dislocation out of acetabulum clunk [click/snap is associated with soft tissue moving over bone not found in hip dysplasia] Risk factors Breech presentation First-born Females > males Left > right Physical exam findings Asymmetric abduction Asymmetric thigh or buttock folds + Barlow test (dislocates on adduction) + Ortolani test (dislocates on abduction) Imaging Ultrasound best or first 6 months (femoral head doesnt ossify until then, so xray not useful) Avoid imaging for first 3 weeks, since there is more ligamentous laxity overdiagnose

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Treatment Between 3-6 months, bracing is appropriate Pavlik harness 24/7 for 6-8 weeks to abduct thigh After 6 months, can only treat surgically Slipped femoral capital epiphysis epiphyseal plate slips off femoral head ** this is a medical emergency Clinical presentation Usually occurs in obese teenagers Pain may be in hip, thigh, or knee Endocrine causes bilateral symptoms Limited hip abduction Imaging need AP and frog-lateral xray of pelvis Kleins line Treatment Stable (pt. can walk) single percutaneous pin in situ Unstable (pt. cant walk) surgical reduction + 1-2 pins 50% risk of avascular necrosis Complications Avascular necrosis of femoral head Chondrolysis Degenerative arthritis as an adult

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Rheumatology
Inflammatory and noninflammatory skeletal muscle disorders Assessing stiffness Non-inflammatory joint diseases morning stiffness lasts for < 30 mins Inflammatory joint diseases more severe and prolonged muscle stiffness History Associated with significant morning stiffness ( > 45 mins) Insidious onset of pain Pain often better with movement Physical exam Swelling, erythema, warmth, detectable joint fluid Weakness in muscles surrounding the affected joint Focal neurological abnormalities Lab studies ESR C-reactive protein Assay for autoantibodies Organ specific tests to determine if internal organs are involved Duration of symptoms is important for diagnosis < 6 months may be early rheumatic disease 1 year diagnostic clinical signs and lab abnormalities are usually present > 2 years abnormalities almost always present Causes of musculoskeletal pain Inflammatory causes Rheumatoid arthritis Lupus Polymyositis/dermatomyositis Proximal muscle weakness May have characteristic skin involvement (particularly mantle/shawl distribution of rash) Scleroderma/eosinophilic fasciitis Polymyalgia rheumatica Age > 60 Proximal muscle myalgias and stiffness without specific muscle weakness High ESR Anemia Temporal arteritis Often predated by polymyalgia rheumatica Headache, scalp tenderness, visual changes, jaw claudication Needs immediate treatment with prednisone! Fibromyalgia Fatigue, pain, stiffness, headaches, sleep disturbances, irritable bowel/bladder syndrome, depression/anxiety Dx at least 3 months of widespread tenderness 80-90% female onset often during child-bearing years Aerobic fitness is a protective factor 1

Endocrine causes **Thyroid dysfunction (esp. hypothyroid often associated with elevated CKs) Parathyroid dysfunction Adrenal disease Diabetes Acromegaly Drug reactions statins, AZT, ethanol, clofibrate, cyclosporine, penicillamine, prednisone

Rheumatoid arthritis Rheumatoid arthritis a chronic, inflammatory, systemic disease that primarily targets synovial joints Prevalence ~1% of general population; increases with age Affects women more commonly than men Decreases life expectancy by ~10 years Genetics often associated with HLA-DR4 antigen Etiology believed to be a combination of genetic susceptibility + triggering infection Pathogenesis Synovium shows edema, cell proliferation, vasodilation, and infiltration by T cells, B cells, plasma cells, and monocytes/macrophages IL-1 and TNF produced by synovial macrophages As disease progresses, granulation tissue forms at edge of synovial lining (forming the pannus), with extensive angiogenesis and production of MMPs Synovial fluid increases in volume, with increased #s of cells, oxygen radicals, immune complexes prostaglandins, and lysosomal enzymes **Rheumatoid factor (anti-Ig) and citrullinated peptide are found in serum in most pts NET: thickened synovium, synovial fluid, tissue damage, bony erosion, joint fusion Clinical presentation Symmetrical joint involvement, with sparing of DIPs of fingers, IPs of toes, and lumbar spine Synovial thickening + inflammation swelling, pain, decreased ROM, morning stiffness Joint deformity (ulnar deviation of fingers) C-spine instability Tendon rupture Stress fractures (due to osteopenia or osteoporosis) Extra-articular manifestations Anemia of chronic disease Muscle atrophy due to disuse or rheumatoid myopathy Rheumatoid nodules (granulomas) in pressure areas signify more severe disease Vasculitis Pleuropulmonary manifestations Carditis due to deposition of circulating immune complexes Peripheral nerve compression Ocular inflammation Feltys syndrome RA, hypersplenism, leukopenia, some thrombocytopenia Useful diagnostic tests Sed rate, C-reactive protein nonspecific tests for inflammation Anti-CCP and anti-RF more specific to RA (though other diseases produce RF) 2

Therapy NSAIDS Disease modifying anti-rheumatic drugs (DMARDs) require 1-6 months for effectiveness Methotrexate (1st choice) Hydroxychloroquine, gold, cyclosporine, cyclophosphamide, other cytotoxic drugs Biologic drugs (target IL-1 and TNF) cytokine receptor antagonists or monoclonal antibodies Corticosteroids short-term control of flare-ups, bridge to DMARDs PT Joint replacement Juvenile rheumatoid arthritis (onset < 16 years old) Modes of onset Polyarticular (40-50%) like adult disease, but RF is less frequently present Mono- or oligoarticular (30-40%) Systemic / acute febrile (10%) Clinical presentation Joint involvement High fever **Rash Hepatosplenometaly Carditis may be life-threatening Lymphadenopathy Growth abnormalities (premature epiphyseal closure)

Seronegative (HLA-B27 associated) arthritides Seronegative arthritides contrasted with RA High incidence of spinal joint involvement Asymmetrical lower extremity joint involvement Men are involved much more frequently than women High frequency of HLA-B27, especially with spinal arthritis RF is usually absent Anklyosing spondylitis chronic, inflammatory, systemic disease major target is SI joints & spine Prevalence occurs mainly in young men; over 90% of patients are HLA-B27 positive Clinical presentation Low back pain and stiffness of >3 months duration, unrelieved by rest Limited motion of the lumbar spine (particularly flexion) Reduced chest expansion, with reduction of vital capacity Bilateral sacroiliitis Squaring of vertebrae Eventually, 40% of patients develop peripheral arthritis, mainly in hips, shoulders, and knees, with synovium that is pathologically similar to that of RA **Characteristic outcome is ankylosis (fusion) of joints in flexed position + ossification of paraspinal ligaments loss of lumbar lordosis, kyphosis of thoracic spine, compensatory hyperextension of cervical spine, and flexion contractures of involved peripheral joints 3

Extra-articular manifestations Acute iritis (inflammation of anterior chamber of eye) Upper lobe pulmonary fibrosis Aortic regurgitation, conduction defects Cauda equina syndrome Therapy (none is definitive) NSAIDS Methotrexate Anti-TNF Physical therapy Postural exercises to prevent kyphosis Breathing exercises to maintain lung capacity Hip or spine surgery Reiters syndrome (reactive arthritis) secondary to exposure to infectious agents in HLA-B27+ people Prevalence More common in men Endemic (post-venereal) form is associated with Chlamydia or mycoplasma Epidemic form is associated with shigella, salmonella, or yersinia Clinical manifestations Arthritis Mainly lower extremity joints Usually asymmetrical but self-limited Sausage toes Urethritis Infectious diarrhea Conjunctivitis Mucocutaneous lesions on penis Psoriatic arthritis Clinical manifestations Occurs after psoriasis DIP joints commonly involved Nail involvement is very frequent Sausage toes or fingers Remissions tend to be more frequent than in rheumatoid arthritis **Pencil-in-cup, whittling, periostitis, nonmarginal spinal syndesmophytes features on xray

Lupus Epidemiology Predominantly affects young women of child-bearing age More prevalent in African Americans and Asians Etiology caused by disturbance in immune regulation exaggerated production of autoantibodies Genetic influences HLA-DR2 and DR3 are increased in Caucasian lupus patients Environmental triggers Infectious agents act as adjuvants or co-stimulators for autoreactive T cells Sunlight cellular injury alters expression of self antigens Breakdown of tolerance multi-system tissue injury Failure to clear apoptotic debris inappropriate processing of self-antigens by APCs + failure of Tregs + failure of inhibitory FcR receptors + failure to eliminate self-reactive T and B cells IMMUNE AUTOREACTIVITY Organ system involvement not all are affected simultaneously cyclical disease syndrome Skin **Butterfly (malar) rash on face Hydropic degeneration of basal zone of epidermis Mononuclear infiltration Musculoskeletal Symmetrical polyarthritis similar to RA Myalgia, myositis, proximal muscle weakness Renal Glomerulonephritis (focal or diffuse) due to deposits of Ig, complement, and ANA Edema Nephritic syndrome Hypertension RBC, WBC, casts in urine Hematological Anemia chronic disease, blood loss, autoimmune Lymphopenia Autoimmune thrombocytopenia Circulating autoantibodies to coagulation factors (lupus anticoagulant) Respiratory Pleuritis fever, chest pain, cough Fibrosis or pneumonitis of lung parenchyma Pulmonary hypertension Cardiovascular Pericarditis, myocarditis, endocarditis (ex. Libman Sacks endocarditis due to vegetations) Vasculitis of coronary arteries Accelerated atherosclerosis Neuropsychiatric Disturbance in mental function (memory loss, trouble concentrating, etc.) Seizures 5

Autoantibodies Non-organ specific autoantibodies form immune complexes, deposit in tissues complement deposition chemotaxis and inflammation tissue destruction Antinuclear antibody (ANA), particularly anti-Smith and anti-dsDNA Lack of ANA doesnt rule out lupus Other forms of ANA can be caused by RA, scleroderma, and many other conditions Rheumatoid factor Organ specific autoantibodies (anti-RBC, anti-WBC, etc.) cause cell lysis, premature removal of cell from circulation, or impair cell function Causes of death Early deaths related to SLE and opportunistic infections Late deaths cardiovascular complications Drug-induced lupus May result from procainamide and other medications +ANA, but no anti-dsDNA or anti-Smith antibodies Discontinuation of the medicine will result in improvement and disappearance of symptoms

Systemic sclerosis (scleroderma) Epidemiology More common in females Peak age 35-65 More common in African Americans and Choctaw Native Americans Etiology Overproduction of collagen by fibroblasts due to TGF and other cytokines; unknown trigger Autoantibodies (including ANA, hyper-Ig, immune complexes) Histopathology Atrophy and thinning of epidermis Thickening of dermis due to increase in collagen fibers Scarcity of blood vessels Loss of dermal appendages (hair follicles, sweat glands) Focal collections of lymphocytes (mainly T cells) in deep dermis Organ system involvement Skin Sclerosis Changes in skin pigmentation **Sclerodactyly loss of skin folds in fingers **Raynauds phenomenon paroxysmal vasospasm, often precipitated by cold **Telangiectasias macular skin lesions characterized by dilated and tortuous blood vessels blanch on pressure, fill from center when pressure is removed Musculoskeletal Symmetric polyarthritis and polyarthralgia Synovium pathology fibrin deposits, mild chronic inflammation and fibrosis 6

 Squeaks and leathery rubs over tendinous areas Myopathy Renal occurs in pt with rapidly progressing diffuse skin disease (see below) Intimal hyperplasia Fibrinoid necrosis of blood vessels GI tract Replacement of muscularis layer by collagen Replacement of submucosa and serosa with fibrosis Inflammation in blood vessels Dilation of lower esophagus Small bowel stasis, associated with bacterial overgrowth and malabsorption Pneumatosis cystoides intestinalis = pockets of air in intestine Large bowel pseudodiverticula Pulmonary Interstitial fibrosis Hyperplasia and sclerosis of pulmonary artery branches pulmonary hypertension Aspiration pneumonia Cardiovascular Myocardial fibrosis Conduction defects, arrhythmias Pericarditis Clinical subtypes of scleroderma Diffuse cutaneous Diffuse, symmetric skin thickening Early onset of skin disease following Raynauds phenomenon Significant visceral disease lung, heart, GI, kidney Associated with anti-topoisomerase antibodies (anti-SCl 70) Limited cutaneous Symmetric skin thickening Raynauds phenomenon begins more than 2 years before skin changes CREST calcinosis, Raynauds, esophageal dysmotility, sclerodactyly, telangiectasis Visceral disease occurs late Associated with anti-centromere antibodies Localized (including morphea and linear subtypes) Fibrosis confined to skin No visceral involvement

Osteoarthritis Disease classification Primary OA no identifiable cause Secondary OA has an identifiable cause unusual location, patient < 50 yo Structural abnormalities Old fracture Meniscectomy Congenital abnormalities 7

 Avascular necrosis Infection Articular inflammation Hypermobility syndromes (ex. Ehler-Danlos) Mucopolysaccharidosis Metabolic disorders Acromegaly Alkaptonuria Gout Hemochromatosis Chondrocalcinosis Ochronosis causes pigmentation of eyeball, skin, and urine Marfans syndrome Clinical presentation Morning stiffness > 30 minutes Crepitus No inflammation, non-inflammatory synovial fluid Bony enlargement or tenderness Bouchards node affects PIP joint Heberdens node affects DIP joint 1st C-MC joint (since thumb is involved in most hand motion) Risk factors Aging accumulation of mechanical damage + decreased viscosity and elasticity in synovial fluid Obesity Quadriceps weakness Joint overuse/injury Developmental abnormalities Genetic susceptibility DIP involvement more likely in females Familial OA occurs with point mutation in cDNA for type II collagen Inverse relationship between OA and osteoporosis Pathogenesis

Normal cartilage + abnormal loads Abnormal cartilage + normal loads

Crystal-induced arthropathy Crystal species and associated clinical disorder

Clinical disorder Gout Crystal monosodium urate Crystal characteristics negative birefringence yellow when parallel blue when perpendicular positive birefringence yellow when perpendicular blue when parallel

Pseudogout

calcium pyrophosphate

Calcific periarthritis

Apatites Tricalcium phosphate Octacalcium phosphate

Gout caused by altered metabolism of uric acid deposition of monosodium urate into tissues Uric acid metabolism and gout Overproduction of purines via de novo pathway uric acid buildup Associated with ethanol, myeloproliferative disorders, hemolytic disorders Most cases of gout result from faulty renal excretion of uric acid, rather than overproduction Associated with lactic acidosis, cyclosporine, low dose aspirin, hypertension Pathogenesis Hyperuricemia results in deposition of monosodium urate in joints, cartilage, and kidneys Urate crystals are phagocytosed by synoviocytes, which then release crystal-induced chemotactic factor, LTB4, IL-1, TNF, and other chemotactic mediators Neutrophils and macrophages migrate into the joint space and amplify the inflammatory process Lactic acid production favors a local decrease in pH that promotes further deposition of uric acid Clinical presentation Acute gouty arthritis Intermittent attacks of severe joint inflammation (swelling, redness, warmness and stiffness) with marked pain that lasts several days Most initial attacks will be in 1st MTP joint (great toe) After attack subsides, patient is fine until next occurrence Systemic symptoms (fever, chills) often present Chronic gouty arthritis (tophaceous gout) due to untreated acute gout Buildup of tophi in connective tissue multiple joint involvement + joint destruction Patient is no longer pain-free between attacks Laboratory features Most patients with hyperuricemia do not have gout; most gout patients have hyperuricemia Visual conformation of crystals in joint fluid Inflammatory synovial fluid Peripheral WBC may be elevated during attack ESR elevated during acute episodes Pseudogout Clinical presentation Gout-like attacks lasting 3-14 days, but caused by deposition of calcium pyrophosphate First attack is often in the knee joint Asymptomatic between attacks **Deposition of crystals in cartilage = chondrocalcinosis associated with hyperparathyroidism and hemochromatosis 9

Calcific periarthritis Clinical presentation More periarticular symptoms than gout or pseudogout Large joint destruction arthritis Calcinoma cutis = calcium deposits in skin often seen in patients with scleroderma

10

Pathology
Musculoskeletal tumors of mesenchymal origin General concepts Frequency of mesenchymal tumors Benign are much more common than malignant Adults carcinoma >> sarcoma Children sarcoma > carcinoma Clinical presentation of sarcoma Incidence generally increase with age More common in males Initially usually painless, eventually becoming painful Present usually with rapid growing mass Often metastases are present at diagnosis lungs, liver, brain Soft-tissue tumors
NAME Lipoma AGE RANGE adulthood (very common) adulthood SITE trunk, limbs deep soft tissue (thigh, retroperitoneum) volar aspect of forearm, trunk, back prox. extremities, retroperitoneum (present as painful mass) head and neck (embryonal type) or lung (alveolar type) extra-adominal, intra-abdominal, abdominal PROGNOSIS good poor in retroperitoneum GROSS encapsulated soft, yellow mass mucoid, graywhite to yellow MICRO looks like normal adipose tissue; may involve other cell types (ex. angiolipoma) myxoid, variable lipoblasts with triangular nuclei nuclear scalloping whirls, fascicles, myxoid background, prominent nucleoli, mitotic figures pleomorphic cells in a whirling storiform pattern; multiple bizarre cell types (incl. giant cells) elongated myoblasts (strap cells) with cross-striations fascicles of fibroblasts infiltrating adjacent tissue

Liposarcoma Nodular fasciitis (benign reactive lesion) Malignant fibrous histiocytoma Rhabdomyosarcoma (very aggressive)

young adults

good poor infiltrates bone, common metastasis moderate (6580% survival rate) infiltrative, recurring, but no metastasis

circumscribed

adults (very common) children and adolescents

hemorrhage, necrosis infiltrative, hemorrhagic, necrotic rubbery, poorly demarcated

Desmoid tumors

teens to 30s

Cartilage-forming tumors
NAME Chondroma (enchondroma) AGE RANGE 20-50 SITE metaphyseal region of tubular bones (esp. hands and feet) central portion of skeleton PROGNOSIS benign GROSS circumscribed mass of mature hyaline cartilage lobulated, necrosis, hemorrhage MICRO hyaline matrix, irregularly scattered neoplastic chondrocytes varies according to grade of lesion

Chondrosarcoma

40-60

good

Bone-forming tumors
NAME Osteoid osteoma AGE RANGE teens or twenties SITE lower extremity -painful due to PGE (responds to aspirin) spine, hands, feet; tumor is achy, does not respond to aspirin metaphyseal areas of long bones (knee, humerus) PROGNOSIS good GROSS >2 cm MICRO Central nidus of osteoblasts producing osteoid Central nidus of osteoblasts producing osteoid haphazard osteoid, pleomorphism, sometimes cartilage or fibrous tissue present

Osteoblastoma

teens or twenties

good

< 2 cm

Osteosarcoma

75% in teens; 25% in elderly

frequent lung metastasis

hemorrhage, necrosis, cystic degeneration

Miscellaneous
NAME AGE RANGE 10-15 yo -present with mass + systemic symptoms SITE medullary cavity of long bones, may penetrate periosteum and invade adj. tissue PROGNOSIS GROSS hemorrhage, necrosis MICRO small, primitive, uniform, closely packed round cells; few nucleoli; glycogen

Ewing sarcoma

moderate

Non-neoplastic diseases of bones, joints, and connective tissue Osteoblasts are rich in alkaline phosphatase Increase in new bone formation increased alkaline phosphatase levels Congenital diseases of bone Osteogenesis imperfecta 4 major forms most are autosomal dominant Abnormal type I collagen production abnormal osteoid bones are thin and ill-formed Fractures begin early in life and heal improperly Short stature Abnormal collagen affects other structure blue sclera, lax ligaments, teeth, deafness Marfan syndrome Autosomal dominant inheritance increased risk with increased paternal age Caused by mutation in fibrillin Skeletal abnormalities tall stature, long fibers Ocular changes ectopia lentus (displaced lens) Cardiovascular lesions mitral valve prolapse, dilation of aorta from cystic medial necrosis Osteopetrosis defect in osteoclastic reabsorption dense, brittle bone with little marrow space Achondroplasia defect in cartilage synthesis short stature Infections of bone Acute pyogenic osteomyelitis Most common in children and young adults Symptoms fever, pain, limp in children Usually caused by bacteria (especially staph aureus); fungus may also be a cause Pathology Acute infection in bone causes bone necrosis (sequestrum) Intraosseus abscess formation Infection may rupture out into periosteal space or joint Reactive sleeve of new bone (involucrum) may develop between periosteum Therapy antibiotics + surgical drainage Chronic osteomyelitis results from untreated acute osteomyelitis Patients may develop secondary amyloidosis from prolonged inflammatory response Can also develop squamous cell carcinomas at the site of draining sinuses

Tuberculosis of bone Clinical onset is insidious with low-grade fever and weight loss extensive bone destruction Predilection for immunocompromised patients **Pott disease = TB of spine
3

Metabolic diseases of bone Osteoporosis total mass of bone w/ micro-architectural deterioration pain + susceptibility to fracture Caused by dysregulation of osteoclast formation/function Primary osteoporosis related to aging Secondary osteoporosis bone loss occurs from immobilization, endocrine disorders, drugs, malnutrition, malabsorption Affects all bones of body, but symptoms occur in areas of extreme weight bearing/stress Normal lab values of Ca, P, alkaline phosphatase Osteomalacia/Rickets Defective mineralization of osteoid peripheral seams of uncalcified osteoid bones are soft and weak, with tendency to fracture Caused by vitamin D deficiency in kids (rickets) or adults (osteomalacia) Bone diseases of unknown cause Paget disease Disease may involve 1 bone (monostotic) or multiple bones (polyostotic) Pathogenesis Lytic phase osteoclasts resorb bone radiolucency Mixed phase irregular new bone formation (highly vascular) Sclerotic phase osteoblast activity > osteoclast activity, bones become thickened **NET = bone thickening increased skull size, bowing of long bones in leg + fracture susceptibility Marked increase in alkaline phosphatase values due to marked osteoblast activity Complications Hemodynamic abnormalities hypervascular bone shunts blood from regular circulation **Secondary sarcoma most osteosarcoma in adults is due to underlying Paget disease [trabeculae are enlarged]

Fibrous dysplasia Characterized by abnormal proliferation of benign fibrous tissue 70% monostotic 30% polystotic craniofacial involvement, endocrine abnormalities Ground glass appearance on xray Pathology Lesions expand the medullary bone and lave a shell of intact cortex at the periphery Secondary cysts and hemorrhage are often present Mature fibrous tissue with admixed, irregular, curved trabeculae of woven bone Complications fractures, deformity, rare secondary sarcoma

Joint infections
Pyogenic arthritis* Tuberculous arthritis Presentation pain, tenderness, warmth, erythema + fever, chills, leukopenia swelling, pain, no warmth or erythema Synovial pathology hyperplasia, acute inflammatory infiltrate hyperplasia, acute/chronic inflammation, granulomas

*Most common organisms are staph aureus, neisseria, streptococci, H. influenza, and other gram Inflammatory arthritides Immunologic joint diseases Rheumatoid arthritis Juvenile RA Anklyosing spondylitis Lupus Scleroderma Crystal-induced joint disease Gout due to deposition of urate crystals in connective tissue Primary gout affects elderly men Secondary gout caused by rapid cell destruction that releases uric acid

Tumors of Mesenchymal Origin

Malignant Fibrous Histiocytoma Fibrohistiocytic tumor Middle-aged to elderly most common (but any age possible) Most common soft tissue sarcoma in adults Proximal extremities or retroperitoneum 50% survival at 5 years Large tan-white mass with areas of hemorrhage/necrosis Plump, pleomorphic, large, round spindle cells arranged in a whirling (storiform) pattern. Some cells may resemble lipidladen histiocytes Rhabdomyosarcoma Skeletal muscle tumor Under 20 years old Chondrosarcoma Cartilage-forming tumor 30-50 years old Osteosarcoma Bone-forming tumor Teens or twenties Ewing Sarcoma Neurectodermal tumor Under 20 years old

Category Age

Prevalence

Typical Site

Prognosis Gross Appearance

Microscopic Appearance

Most common soft tissue sarcoma in children and adolescents Head, genitourinary region, or retroperitoneum Cure in 65-80% of children under 10 Soft, friable, graywhite infiltrative mass with hemorrhage/necrosis Undifferentiated, small, round or spindle-shaped, immature striated muscle cells with abundant eosinophilic cytoplasm (rhabdomyoblasts) in a variably myxoid stroma

Second most common primary malignant bone tumor Central skeleton: pelvis, proximal long bones and ribs 80-90% survival at 5 years (for low grades) Bulky, gray-white tumor with gelatinous and ossified areas distributed lobularly Irregular chondrocytes with hyperchromatic forms and multiple chondrocytes in the same lacuna

Most common primary Second most common malignant bone tumor bone sarcoma in children Around knee and proximal humerus medullary cavity of femur and flat bones of pelvis

Bulky, gray-white, gritty tumor, with some hemorrhage/necrosis Osteoid is laid down in a haphazard fashion, stains eosinophilic. Highly pleomorphic cells with large, hyperchromatic nuclei and increased mitotic activity

Soft, gray to white tumor often with hemorrhage and necrosis Small primitive, uniform, closely packed round cells with scant, clear cytoplasm and indistinct boundaries. Special stains for glycogen (like PAS) are classically positive.

Pharmacology
Muscle relaxants Centrally acting spasmolytics GABA-A postsynaptic GABA agonists/analogues (-motor neuron) Benzodiazepines GABA-B presynaptic GABA-A agonists (Ia afferent neuron) Major side effect is sedation Baclofen (Lioresal) GABA-B agonist Opens K+ channels and closes Ca2+ channels neurotransmitter release is inhibited Produces less sedation than diazepam Progabide (Gabrene) GABA-A and B agonist Metabolized to GABA Gabapentin (Neurontin) Structural analog of GABA but has no activity at GABA receptors Blocks Ca2+ channels no NT release Other CNS-acting drugs Tizantidine (Zanaflex) Increases presynaptic and postsynaptic inhibition and excites analgesic efficacy Adverse effects include drowsiness, hypotension, and dry mouth Riluzole (Rilutek) blocks release of Glu Peripherally active spasmolytics Dantrolene blocks Ca2+ release from sarcoplasmic reticulum muscle contraction is inhibited Cardiac and smooth muscle are largely unaffected (no SR) Adverse effects include muscle weakness and sedation Effective for treating malignant hyperthermia (excess Ca2+ release stimulates extreme muscular contraction, which generates a lot of heat) Locally-acting spasmolytics Botulinum toxin blocks release of ACh paralysis Cyclobenzaprine (Flexiril) blocks 5HT2 relief of local muscle spasm (may cause hallucination)

Local anesthetics Lidocaine most widely used local anesthetic (particularly for cardiac arrhythmias) Bupivacaine can cause cardiotoxicity Benzocaine topic anesthesia; can cause methemoglobinemia Mechanism Block Na+ channel from the inside of the cell neuron cannot depolarize Uncharged base form (lipophilic) is able to cross the plasma membrane to access the binding site less absorption in acidic tissues At physiological pH (7.4), charged form cation predominates ion = active blocking agent

Pharmacodynamics Differential blockade based on susceptibility of different types of fibers Larger diameter more drug needed (higher Cm) Myelination more drug needed (higher Cm) Repetitively stimulated nerve less drug needed (lower Cm) Potency correlates with lipid solubility Time course of regional anesthesia 1. Block of sympathetic nerves vasodilation 2. Loss of pain and temperature sensation (A and C fibers) 3. Loss of touch sensation and deep pressure 4. Loss of motor function

Hypokalemia and hypercalcemia antagonize blockade

Pharmacokinetics Absorption Rate of absorption is proportionate to vascularity of the site of injection Local anesthetics that are highly tissue-bound are more slowly absorbed Duration of action associated with protein binding Distribution Strong protein binding tends to retain anesthetic in blood High lipid solubility facilitates tissue uptake Highly protein-bound drugs have minimal levels in fetus First pass effect through lungs Metabolism Esters metabolized by pseudocholinesterase Amides metabolized by CYP **Co-administration with a vasoconstrictor (ex. epinephrine) decreases the rate at which drug is removed from injection site faster onset prolonged local action decreased systemic toxicity Toxicity CNS effects depression of inhibitory centers in brain increased CNS excitability convulsions Cardiac effects arrhythmias, hypotension (due to direct effects of Na+ channel blockade) most common with bupvacaine Allergic reactions skin rashes, asthmatic attack highest risk with ester-type local anesthetics NSAIDs analgesic, anti-inflammatory, antipyretic effects due to blockade of COX COX 1 widely distributed Gastric cytoprotection due to PGE2 and PGI2 ( secretion of mucus and bicarbonate) Platelet aggregation COX 2 inflammation COX2 inhibitors cause lower gastric irritation, but allow platelets to aggregate Drugs Celecoxib (Celebrex) and Rofecoxib (Vioxx) Clinical uses OA, RA, acute pain, dysmennorhea, familial adenomatous polyposis 2

Common side effects of NSAIDS Inhibition of platelet aggregation (COX-1 inhibition) **At low doses, aspirin selectively inhibits platelet COX 1 Hypersensitivity (COX-1 inhibition) Alteration in renal function (COX-2 inhibition) PGs inhibit reabsorption of Cl- and increase glomerular filtration blockage results in edema Renal toxicity in patients with CHF or hepatic cirrhosis Effect on reproductive tissues (COX-2 inhibition) PGs are needed for ovulation blockage decreases fertility PGs stimulate uterine contraction blockage prolongs labor Displacement of other drugs from albumin (doesnt occur with ibuprofen or naproxen) CNS disturbances tinnitus, decreased hearing, vertigo Non-aspirin NSAIDs at anti-inflammatory doses, they inhibit LOX & COX Indomethacin Most potent inhibitor of COX Causes CNS side effects Used to treat patent ductus arteriosus in neonates and to halt the progression of labor Sulindac Sulfoxide prodrug is not a good inhibitor of COX Reduced form sulfide is a strong inhibitor of COX, but is inactivated before excretion safe for patients with kidney problems Ibuprofen fewer GI complications; equally potent as aspirin Naproxen 20x more potent than aspirin; also inhibits leukocyte migration Aspirin Pharmacokinetics Hydrolyzed by esterases to salicylate (which has same effects as aspirin but less potency) Excreted by kidney Mechanism irreversible blockage of COX no prostaglandins Pain receptors are not sensitized Reset temperature control within hypothalamus to facilitate heat dissipation Side effects Metabolic acidosis uncoupling of oxidative phosphorylation produces compensatory glycolysis Hyperventilation respiratory alkalosis secretion of HCO3- (worsens metabolic acidosis) Reyes syndrome in children caused by virus-host reaction Therapy for aspirin poisoning Urine alkalization to cause ionization less reabsorption in kidney HCO3 to correct metabolic acidosis Acetominophen analgesic, antipyretic / not anti-inflammatory Mechanism unknown Pharmacokinetics Rapid absorption 90% conjugated by liver Remainder is converted by CYP to quinoneimine toxic

Side effects Since acetaminophen doesnt inhibit COX, it has different side effects from NSAIDs Acute hepatotoxicity due to depletion of cellular glutathione cannot detoxify quinoneimine delayed hepatic necrosis (exacerbated by agents that induce CYP) Little chronic toxicity Antidotes for acetaminophen toxicity goal is to glutathioine via cysteine administration N-acetylcysteine Methionine (slower) Cysteamine (produces GI and CNS toxicity)

Drugs for rheumatoid arthritis Glucocorticoids Drugs Prenisone causes retention of Na Dexamethasone more potent, less Na retention Mechanism Inhibit phospholipase A by way of lipocortin/lipomodulin Suppress expression of COX2 Side effects Long term use causes adrenal suppression, growth retardation, peptic ulcers, susceptibility to infection, osteoporosis, myopathy, cataracts, and hyperglycemia Large doses of prednisone can cause fluid and electrolyte imbalance Clinical use intra-articular injection for relief of flare-ups Disease-modifying antirheumatic drugs Methotrexate Mechanism Low concentrations anti-inflammatory agent (causes release of adenosine) High concentrations inhibits dihydrofolate reductase immunosuppresion Side effects GI disturbances Mild alopecia Myelosupression Pneumonitis Liver cirrhosis Toxicity if patient also taking NSAID (displaces methotrexate from albumin) 4

Leflunomide Mechanism Inhibits dihydroorotate dehydrogenase, the rate limiting enzyme for de novo synthesis of pyrimidine nucleotides inhibits clonal expansion Since resting lymphocytes and other cells get their pyrimidines from salvage pathway, they are not affected Side effects Diarrhea Elevate liver enzymes Teratogenic Hydroxychloroquine Mechanism Interferes with functioning of lysosomes and prevents release of hydrolytic enzymes Inhibit DNA and RNA synthesis Clinical use RA, SLE combined with methotrexate Sulfasalazine Mechanism metabolized to sulfapyridine and 5-aminosalicylic acid, which inhibit IL-1 & IFN Side effects Sulfa allergy reactions Nausea, vomiting, headache, diarrhea TNF inhibitors etanercept, infliximab Side effects Serious infections Drug-induced lupus

Pharmacology of gout Drugs for acute attacks of gout Non-aspirin NSAIDs indomethacin In gout, leukotrienes play a greater role than prostaglandins Since acute treatment is only needed for several days, high-dose indomethacin can be used to inhibit LOX, without having to worry about its side effects Aspirin cannot inhibit LOX, and is contraindicated in gout because it inhibits uric acid excretion At high doses, indomethacin inhibits LOX Colchicine used to prevent acute attacks of gout occurring during 1st month of chronic therapy Mechanism inhibition of leukocyte migration, phagocytosis, and secretion of enzymes Inhibits production of crystal-induced chemotactic factor Prevent tubulin polymerization Adverse effects Damages proliferating epithelial cells in GI tract diarrhea, nausea, vomiting Can cause transient leukopenia Toxic doses produce severe bone marrow depression Drugs that decrease hyperuricemia (long-term therapy for tophaceous gout) Uricosuric agents probenecid, sulfinpyrazone Mechanism compete with uric acid for organic acid transporter impaired reabsorption Adverse effects Renal stone formation due to increased urate excretion 5

 Acute gouty attacks during initial days of treatment Contraindications Uric acid overproducers (use allopurinol instead) Kidney problems Use of aspirin (siacylate interferes with renal function) Allopurinol Mechanism inhibits xanthine oxidase reduced uric acid synthesis Clinical use indicated when uricosuric drugs are contraindicated Drug interactions Uricosuric agents reduce reabsorption of alloxanthine (allopurinol metabolite) Inhibition of CYP increases levels of uricosuric drugs Increase toxicity of 6-mercaptopurine by inhibiting its oxidation by xanthine oxidase