2.03 + 2.04

Question 1

Osteoporosis medication

Answer 1

Inhibitors of bone resorption
Bisphosphonates (Risedronate (oral) , alendronate(oral) , zoledronic acid) - kill osteoclasts (if you miss out on 25% of dose, 65% efficacy gone)
Strontium Ranelate
RANKL-inhinibtors
PTH + Vit. D
MRONJ - bisphosphonates, denosumab

Question 2

Other bone disorders

Answer 2

Achondroplasia (Mutation of FGF23 —abnormal cartilage synthesis and decreased epiphyseal bone formation)
Osteogenesis imperfecta (type 1 collagen defect)
Osteomalacia/Rickets - Vit. D insufficiency (osteoid formed)
Paget’s - localised areas with increased/irregular bone turnover DUE to increased alkaline phosphatase in plasma
- Mostly affect pelvis, tibia, femur, LS spine, skull (max over mandible)—hypercementosis of teeth and gross enlargement of alveolar processes

Question 3

What is osteoarthritis?

Answer 3

Progressive disease representing the failed repair of joint damage

Question 4

What is osteoarthritis?

Answer 4

Progressive disease representing the failed repair of joint damage. A consequence of excessive load and joints inability to account for excessive load (synovial inflammation is a common problem) + cartilage breakdown all joint tissues are involved.

Question 5

Diagnostic criteria for osteoarthritis

Answer 5

Knee: knee pain + old age, stiffness, crepitus, bony tenderness + enlargement, no palpable warmth
Hand: Hard tissue enlargement of 2 or more DIP (distal inter-phalangeal) joints, fewer than 3 swollen MCP (metacarpophalangeal) joints, deformity of 1 of 10 selected joints
Hip: hip pain + 2/3 - ESR<20 mm/hour
Radiographic femoral or acetabular osteophytes
Radiographic joint space narrowing (superior, axial, and or medial)

Question 6

Synovial joints features

Answer 6

Cavity - filled with synovial fluid
Articular cartilage - covers articular surfaces, hyaline
Capsule - blends with periosteum, encloses
Synovial membrane - lines inner surface of capsule, serous, produces mesothelial cells, produces synovial fluid
Synovial fluid - lubrication, nourishment, reduces friction, has hyaluronic acid (produces viscosity)

Question 7

Other synovial joint structures (fat pad, bursae, menisci)

Answer 7

Fat pad - space filler
Menisci - fibrocartilage, shock absorber
Bursae - reduce friction (11> around knee joint)

Question 8

Knee and hip joint articular surfaces

Answer 8

Knee - patellar surface of femur (modified hinge joint)

Hip - acetabulum (ball and socket) (look at ligaments diagram)

Question 9

Hand joints + carpal tunnel

Answer 9

Interphalangeal - between sections of fingers
Metacarpophalangeal - meeting of palm and bottom of finger
Carpometacarpal - joint of thumb
Carpal tunnel syndrome - median nerve neuropathy

Question 10

What are aggrecan’s and ADAMTS

Answer 10

Aggrecan—proteoglycans—structure—compression resistance –elastic padding material - gives cartilage its strength
ADAMTS—enzyme breakdown aggrecans - aggrecan depletion in arthritic diseases

Question 11

Is osteoarthritis wear and tear?

Answer 11

NO - progressive, multifaceted disease

cartilage breakdown, synovial inflammation, extrinsic factors (obesity, smoking, age), subchondral bone sclerosis

Question 11

Is osteoarthritis wear and tear?

Answer 11

NO - progressive, multifaceted disease

cartilage breakdown, synovial inflammation, extrinsic factors (obesity, smoking, age), subchondral bone sclerosis

Question 12

Signs of osteoarthritis

Answer 12

Mechanical pain
Tenderness over the joint line
Crepitus with movement of the joint
Bony enlargement of the joint
Reduced range of motion 
Joint swelling
Joint deformity
Instability/laxity of joint

Question 13

What management for certain fracture’s

Answer 13

Reduction - aim for normal alignment (open/closed)
Continuous traction - femoral fractures in children
Cast splintage - plaster of paris - not too tight > compartment syndrome
Functional bracing:
Internal fixation - wires/plates/screws, when you can’t treat externally, pathological fractures
External fixation - high energy trauma/infection, pelvis

Question 14

What is Rheumatoid arthritis

Answer 14

Chronic inflammatory disease driven by failure of self-tolerance leading to immune response against self-antigens in joint (autoimmune)

Question 15

Aetiology of RA

Answer 15

Genetic cause - variations in human leukocyte antigen (HLA) genes , especially the HLA-DRB1 gene. HLA genes help the immune system distinguish the body’s own proteins from proteins made by foreign invaders
Also: anti-CCP (aids in autoimmunity), B and T cell variations, mannose binding, cytokines,

Question 16

Acute pathogenesis of RA

Answer 16

Acute changes of RA in joints:
Increased vascular flow, oedema, fibrin (rice bodies) – quite large collections occur
Endothelial cell activation – increased adhesion molecule expression on endothelium surface, allows leukocytes to adhere and migrate into inflamed tissues
Vascular proliferation - high endothelial venules
Replication of Type B Synoviocytes—fibroblastic
Replication of Type A—macrophages
Fusion of both into giant cells (IFN-g, IL3, GMCSF)

Question 17

Chronic pathogenesis of RA

Answer 17

Pannus formation
Tissue degradation
Reduced apoptosis of synoviocytes
Erosion of cartilage and bone

Question 18

RA epidemiology

Answer 18

Increase risk in women, high risk of onset post-partum, remission during pregnancy, early menopause increased risk, conflicting data with OCP, HRT, estrogen-inhibits T suppressor cells
Genetic: HLA-DRB1 0404 and 0401

Question 19

Clinical features of RA

Answer 19

Early morning stiffness, exclusion of other diseases, synovitis in 3> joints, distribution: hand joints, wrists, elbows, shoulders, knees, ankles, hips
Formation of a pannus
RA affects body elsewhere aswell
Nodules - seropositive - RF, anti-CCP, common - 30%
Eye disease - sclera inflammation, dry eyes
Lung disease - pericarditis
Vasculitis, Felty’s syndrome - splenomegaly

Question 20

RA investigations (ESR etc)

Answer 20

RF and antiCCP (PREDICTOR)
- Anti CCP
- Up to 10 years before diagnosis
- 60-80% sensitivity
Inflammatory markers (monitor disease) - ESR (increases as disease progresses), ferritin, ANAEMIA
X-ray - cartilage loss
Ovr: 
- ESR and or CRP elevated
- Multiple joints with synovitis
- RF and or CCP +
- Symptoms over 6 weeks
- Other disease excluded

Question 21

RA treatment

Answer 21

Analgesics, anti-inflammatory, NSAIDs and COX-2 inhibitors, corticosteroids, DMARDS (target immune cells, Methotrexate, Leflunomide)

Question 22

Other rheumatic conditions

Answer 22

SLE (Systemic Lupus Erythematosis) - systemic autoimmune disease, damage to blood vessels/organs, females, mean age - 30, arthritis 90%, butterfly rash, alopecia, pericarditis, anaemia, renal diseases
Sjogren’s disease - lymphocytic infiltration in exocrine glands, xerostomia, dry eyes, caries, salivary gland enlargement, elevated ESR, anaemia, RF
Gout - build up of uric acid, crystal arthropathy (monoarthritis), acute joint swelling, 50% in big toe
Psoriasis - Hyperproliferation of epidermal keratinocytes, gene HLA-Cw6, mean age - 28, flaking, scaly lesions, inadequate release of lipids is cause

Question 23

Types of muscle fibres

Answer 23

Type 1 - slow twitch → Very fatigue resistant and capable of producing repeated, low-level contractions. Produce large amounts of ATP through aerobic metabolism

Type IIa: Fast twitch oxidative → Produce fast, strong muscle contractions but prone to fatigue. Produce ATP at a FAST rate via anaerobic and aerobic metabolism

Type IIb: Fast twitch glycolytic → Produce short bursts of power but fatigue quickly. Produce ATP SLOWLY via anaerobic metabolism

Question 24

Contractile unit of muscles

Answer 24

Sarcomere - composed of regular thick and thin filaments Thin actin filaments joined together at z-lines Thick myosin filaments in between actin filaments Cross-bridges are myosin heads which produce force or shortening Interaction of components of sarcomere's is what allows contraction Isotonic contraction (muscle maintains the same tension as it shortens)

Question 25

What is excitation-contraction coupling

Answer 25

Excitation-contraction coupling is the series of events involving production of an electrical impulse to the contraction of muscles 1. Action potential propagates from NMJ along sarcoplasm and into T-tubules 2. Action potential depolarises voltage sensors on T-tubules 3. Voltage sensors on T-tubules are coupled with adjacent Ca2+ channels on the sarcoplasmic reticulum 4. Ca2+ channels release Ca2+ into sarcoplasm, open SR channels triggering release and contraction

Question 26

Cross-bridge Cycle

Answer 26

→ Repeated cycle of myosin heads on thick filaments binding with thin filaments and producing force Steps: 1. Ca2+ binds to troponin, tropomyosin changes shape, and exposes myosin bind site 2. Myosin head binds to actin; ADP released 3. Power stroke pulls z-lines together 4. ATP binds to myosin; myosin head releases actin 5. ATP→ADP causes myosin to reset conformation 6. Go to step 2

Question 27

Actinomycin

Answer 27

→ Complex of parallel threads of actin and myosin that slide past each other during contraction

Question 28

Tropomyosin

Answer 28

→ Protein that coils around actin filament and covers myosin binding sites

Question 29

Troponin

Answer 29

→ Protein that binds tropomyosin to actin filament; binding site for Ca2+ regulation When Ca2+ binds to troponin, the tropomyosin’s conformation changes and myosin can bind with actin

Question 30

Pathology of excitation-contraction coupling

Answer 30

Myotonia – Failure to relax at the end of voluntary contraction, abnormal ion channels cause hyperexcitability, voluntary contraction leads to extended forces Myasthenia Gravis – Autoimmune disease leading to weakening of voluntary muscle contraction, antibodies block nicotinic ACh receptors on muscle end plate, muscle depolarization due to single ACh vesicle release decrease, AP doesn’t initiate on muscle Malignant Hyperthermia – Release of Ca2+ in all muscles cause contraction and raise in temp, mutation in sER release channel, triggered by anaesthesia – halothane opens sER cannels

Question 31

ATP pathologies

Answer 31

McArdles disease—lack of myophosphorylase, enzyme which breaks down glycogen—can perform oxidative phosphorylation slowly on glucose or fatty acids. Normal strength, rapid painful fatigue—gentle exercise is OK Mitochondrial myopathies - Very poor exercise tolerance Severe metabolic acidosis—lactic acid Histologically fibres show multiple damaged mitochondria—ragged red fibres

Question 32

Muscle repair process

Answer 32

Muscle Repair: 1. Satellite cells border muscle fibers 2. Satellite cells activated from muscle damage 3. Satellite cells differentiate into myoblasts that divide and fuse to myotubules 4. Myotubules repair and replace damage region of muscle cell

Question 33

Role of dystrophin

Answer 33

Dystrophin acts as a membrane stabilizer during muscle contraction to prevent contraction-induced damage (over/under stretched) It is a cytoskeletal protein that connects contractile proteins to the cell membrane If missing: more susceptible to tear damage Tears in sER allow Ca2+ release Tears in T-tubules allows leak of enzymes out of muscle fiber Satellite cells cannot keep up with required muscle repair

Question 34

What is osteomyelitis

Answer 34

Osteomyelitis – infection of the bone caused by pyogenic bacteria or myobacteria, sub classified on the basis of duration, causative organism, anatomic location of infection Can be spread via direct penetrating trauma, haematogenous spread or by direct spread from adjacent infection SEEN in - Tibia, humerus, vertebrae, maxilla and mandible

Question 35

Causative agent of osteomyelitis

Answer 35

Causative agent - 50% Staphylococcus Aureus and coagulase-neg (related to prosthetic material 25% - Strept, enterococci, Gram negs—(pseudomonas and Enterobacter) Anaerobes—bacteriodes Rare - TB bacteria (non TB as well), brucella, salmonella

Question 36

Prevalence of osteomyelitis

Answer 36

Associated with aging, diabetes and peripheral vascular disease Post-traumatic (50%) Vascular insufficiency (30%) Hematogenous seeding (20%)