YEAR 2 MSS BLOCK

CONTENT

As of 2020-2021 M25 Year 2 Teaching Schedule…

Code Lesson Name Professor Notes Teacher’s

page note
number available?
MSS01 Upper limb bones and joints ALM Cheung 4 Yes
MSS02 Lower limb bones and joints ALM Cheung / Yes
MSS03 Introduction to degenerative joint disorders PKY Chiu 16
Introduction to inflammatory joint HY Chung 21
MSS04 disorders
Introduction to radiology of the Vardhanabhuti 24
MSS05 musculoskeletal system
MSS06 Biochemistry of cartilage and bone D Chan 28
Infections of the soft tissues and PL Ho 34 Yes (SSY
MSS07 musculoskeletal system Wong)
MSS08 Drugs used in the management of arthritis SWS Leung 37
MSS09 Upper limb muscles ALM Cheung / Yes
MSS10 Lower limb muscles ALM Cheung / Yes
MSS11 Neuromuscular junction and motor unit CW Lee 40
Physiology and regulation of skeletal CW Lee 45
MSS12 muscle contraction
MSS13 Gait MKT To 49
Neuromuscular blocking agents and local MKM Leung 52
MSS14 anaesthetics
Pathology of inflammatory and JM Nicholls 54 Yes
MSS15 degenerative joint disorders
MSS16 Brachial plexus and nerve distributions ALM Cheung / Yes
MSS17 Lumbosacral plexus and nerve distribution ALM Cheung / Yes
MSS18 Vascular supply of the limbs ALM Cheung / Yes
MSS19 Bone structure, remodeling and repair J Yang 58
MSS20 Introduction to musculoskeletal trauma C Fang 62
Drugs for the management of gout and SWS Leung 64
MSS21 osteoporosis
MSS22 Anatomy of the spine R Liu 68
Introduction to spinal cord/ nerve JPY Cheung 72 Yes
MSS23 compression disorders
MSS24 Non-opioid analgesics SWS Leung 74
Molecular and genetic aspects of skeletal D Chan 76
MSS25 disorders
Molecular mechanism of bone D Chan 79
MSS26 development
MSS27 Experiencing chronic illness and disability WWT Lam 85
Health and wealth: opportunity cost and D Vackova /
MSS28 productivity in low back pain
MSS29 Development of the musuloskeletal system ALM Cheung / Yes
MSS30 Muscle disorders JD Huang 87
Basic physiology of skin and mechanisms MWM Chan 91
MSS31 of skin diseases

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 MSS32 Peripheral nervous system J Yang 93
MSS33 Somatic and autonomic reflexes CW Ma / Yes
Human reflexes, electrophysiology and CW Ma / Lab manual
MSSLPh clinical examination
Infections of the skin, soft tissue, bone, and PL Ho / Lab manual
MSSLM joint
MSSLP Diseases of bone, cartilage and joints JM Nicholls 100 Lab manual
MSSPH Public Health Practical I KYL Hon 103
MSS Exam Focus 107
Key: MSSL means Practical / Laboratory class.
Comments:
 Before using notes, you can check whether the same teacher is still teaching that lecture.
Often there are substantial differences in teaching content when a different professor is
teaching.
 Suggest using Teacher’s notes when it is available, often they are good. If not, you may use
my notes.
o Some teacher’s notes were only published in older years (e.g. ALM Cheung, SSY
Wong) and not anymore now. Yet, they should still be accessible in Medical
Society’s google drive (‘MBBS Preclinical resources’)
 (If you have a problem locating those files, you can email me directly. I’d be happy to reply.)
 Sorry I haven’t written notes for all the lectures. Do check out seniors’ notes from other
years.
o Note that a few anatomy / dissection practicals were not listed in the table above
 ‘Exam focus’ provides additional resources for revision.

Total pages: 117

2
INTRODUCTION

Set of notes on Musculoskeletal system block lectures (based on M25 Year 2 2020-2021
curriculum)

SYMBOLS AND ABBREVIATIONS

: Important / Needs memorize

: Special point to note
 Italianized / in Grey: Likely not important / Reference reading
 Bold / Underlined / Highlighted: Important
 > is equivalent to an arrow pointing towards right, not ‘more than’
 D, M, Y: Day, Month, Year

CONTACT

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THANK YOU!

Great thanks to my classmates and PBL groupmates for their support towards the production of
this set of notes. They provided many valuable feedback, spotted errors, and made suggestions.

Many teachers made good PowerPoint slides and even prepared lecture notes for us, of which this
set of notes is largely based on, and hence I owe them lots of credits. The disknotes published by my
seniors kept me afloat; my notes are nothing compared to theirs. Finally, thanks to the disknotes
admins for keeping all these resources tidy and accessible to all.

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MSS01 UPPER LIMB BONES AND JOINTS

OVERVIEW

1. Basic concepts
2. Pectoral girdle
a. Clavicle
b. Scapula
c. Joints (Including Synovial joints)
d. Movements
3. Bones of the arm, forearm, and hand
a. Humerus
b. Radius and Ulnar
c. Bones of hands
4. Shoulder and elbow joints
a. Shoulder joints
b. Elbow joints
5. Radioulnar joints, wrist joint and joints of the hand

BASIC CONCEPTS

The form of limbs adapts to their functions:

Limb Function Form
Upper Holding objects More mobile but less stable; Pectoral girdle has large range of
movement
Lowe Walking, bearing Less mobile but more stable; Pelvic girdle fixed to vertebral
r weight column
 Outline of: Upper limb regions
o 4 parts: Shoulder, Brachium, Antebrachium, Manus
o Associated structures: Cubital fossa, Wrist, Digits (Pollex, Index, Middle, Ring,
Digitus minimus; Or I, II, III, IV, V simply)
o Anatomical position: Thumb faces out (Naturally 90 degrees to other fingers)

4
PECTORAL GIRDLE

 Outline of: Pectoral girdle and upper limb bones

o Pectoral girdle: Clavicle, Scapula.
o Upper limb bones: Humerus, Radius, Ulna
o Assorted bones of the hands

Supplementary box: Learning Objections (Sectional)

 Identify the bones that make up the pectoral girdle
and describe their bony features.
 Know the anatomical factors that help stabilize
synovial joints.
 Classify the sternoclavicular and acromioclavicular
joints, and know the movements of the pectoral
girdle.

CLAVICLE

 Function: Holds upper limb away from body

 Important anatomical note:
o S shaped: Medially convex, laterally concave (goes anterior)
o Sternal end round, acromial end flat
o Superior smooth, Inferior rough
 Clinical note: Most commonly fractured

Structures:
 Sternal end, Acromial
end
 Superior Smooth,
Inferior rough (Because
of the attachment
points: Trapezoid line,
Conoid tubercle;
Groove for subclavius,
Costal tubercle)
 Note in this picture,
you've viewing
downwards & upwards,
not laterally!

SCAPULA

 Function: Attachment of muscles for movement of the girdle

5
  Descriptor:
o Triangular plate bone
o 3 angles: Superior, Inferior, Lateral (Glenoid fossa: Socket of shoulder)
o Protrusions: Acromion, Coracoid process, Supraglenoid tubercle, Infraglenoid
tubercle, Spine
o Other structures: Supraspinous fossa, Infraspinous fossa, Scapular notch

JOINTS AT THE PECTORAL GIRDLE

OVERVIEW: SYNOVIAL JOINT

 Structures:
o Basic: Fibrous capsule, Articular cartilage, Synovial membrane, Synovial cavity
o Others: Bursa. Fibrous capsule discontinues and synovial membrane bulges. For
lubrication when uplying muscle contracts.
 Most joints in limbs are synovial joints (for movement)
 Factors of stability:
o Static:
 Congruent articular surfaces (Articular cartilage reduces friction)
 Strong capsules and ligaments
o Dynamic: Muscle tone of muscles

STERNOCLAVICULAR JOINT
 The only join attaching the pectoral girdle to axial skeleton
 Types: Synovial saddle joint, Double plane joint
 Stabilized by the articular disc, costoclavicular ligament, anterior &
posteriorsternoclavicular ligaments, and interclavicular ligament

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 Right: Important diagram showing
structures of sternoclavicular joint,
description see above
Up: The sternoclavicular joints
allow movements in various plants
of the clavicle. This alongside other
structures allows wide angle of
movement in upper limb.

ACROMIOCLAVICULAR JOINT
 Type: Synovial plane joint
 Movements: slight gliding
movements
 Stabilized by
coracoclavicularligament (strong)
and acromioclavicular ligament
(weak)
 Functions: Holds clavicle & scapula
together, but allows the scapula to
adjust to the shape of the thorax
during movement of the pectoral
girdle.

MOVEMENT

 Clavicle and scapula move together as a unit

 Movement: Elevation, Depression, Protraction, Retraction, Rotation (Upward vs.
Downward)

7
THE UPPER LIMB

BONES OF THE UPPER LIMB

Supplementary box: Learning Objections (Sectional)

 Identify the bones that make up the skeleton of the free upper limb.
 Describe the main bony landmarks and features of these bones.

HUMERUS (RIGHT)
 The Humerus, just as any typical long bones, has 2 heads and one shaft (Medial
supracondylar ridge)
 Structures at the Humerus:
o At the head: Head, Neck, Greater and lesser tubercle, Surgical neck (Common
fracture point)
o Tuberosities: Deltoid tuberosity (for deltoid muscle)
o Body: Intertubercular groove (Bicipital groove, for bicipital muscle attachment);
Deltoid tuberosity (for deltoid muscle attachment)
o The other end (Head?): Trochlea, Capitulum, Lateral and Medial epicondyle, Radial
and coronoid fossa, Lateral and Medial condyle, Lateral supracondylar ridge and
medial supracondylar ridge, Olecranon fossa (posterior)
o Nerve grooves: Ulnar nerve, Radial nerve (aka. Spiral groove)

RADIUS AND ULNAR (RIGHT)

 Points to note:
o Feel your hands to understand pronation and supination. In anatomical position,
they shouldn’t cross (2nd picture)
o Differentiate ulnar from radius: Radius close to thumb
 Structures
o Radius: (Proximal  Distal) Head, Neck, Bicipital tuberosity
o Ulna: (Distal  Proximal) Head , Coronoid process, Trochlear notch, Olecranon

8
 o Styloid process present at both Ulna and Radius distally.
o Interosseous membrane for load sharing and force transmission

BONES OF THE HANDS

Structures: Carpals, Metacarpals,
Phalanges (2 in thumb, 3 in other
digits)
Sesamoid bones at the metacarpals

Note: Palms are naturally concave

(longitudinally and transversely),
due to tubercles of the scaphoid
and trapezium on the radial side,
and the pisiform and the hook of
hamate on the ulnar side.

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JOINTS AT THE UPPER LIMB & MOVEMENT

SHOULDER (GLENOHUMERAL) JOINT

 Type: Synovial ball-and-socket joint
 Structures:
 Mind you:
o The glenoid fossa is small and shallow. The head of humerus that fits into it is 4x
that of it
o Because of this, the glenoid labrum (fibrous cartilage acts as an extension to
increase the area)
o This arrangement (Head > Capsule) allows wide range of movements

Movements of shoulder joint

 Flexion & Extension, Abduction (two limbs moving away) & Adduction, Medial / Lateral
Rotations, Circumduction (Combination of these movements)
 Note: Full abduction involves rotation of scapula (Abduction stops when greater tubercle
contacts glenoid labrum)

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Joints capsules and ligaments
 Loose fitting (for movement)
 Proximal attachment at glenoid labrum;
Distal attachment at neck of Humerus
(Slightly inferior at surgical neck)
 Gap allowing slight freedom of movement
 Structures:

Stability of shoulder joint

 Inferiorly week, very unstable, but very mobile
 Stability mainly by Coracoacromial ligament, and Rotator cuff (4 muscles)

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ELBOW JOINT
 Type: Synovial hinge joint
 Anatomical point: Synovial cavity continuous with proximal radioulnar joint
 Structures:

Movements of elbow joint

 Flexion & Extension only (a hinge joint)
 Other random points: Carrying Angle, Relationship between Epicondyles and Olecranon

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Joint capsule and collateral ligaments:

RADIOULNAR JOINTS, WRIST JOINT AND JOINTS OF THE HAND

Supplementary box: Learning Objections (Sectional)

 Classify the radioulnar joints, wrist joint and joints of the hand.
 Describe their anatomy and movements.

PROXIMAL AND DISTAL RADIOULNAR JOINT

 Type: Synovial pivot joint (Two components: A central cylinder + surrounding ring. The
cylinder can turn around.)
o Movement: Supination and pronation
 Easy to remember / Orientate: Supination vs. pronation
 Supination is the movement when you play your violin (left
hand). And violin is the 'superior instrument' (sorry viola), so
violin hand for supination.
 Pronation is the movement when you play the piano (P for piano)
 Non-piano players: Pronation is the position when you type notes
on computer, this makes you more 'pro' too.
 Proximal radioulnar joint
o Sometimes considered part of elbow joint.
o A synovial pivot join: Annular ligament forms the ring, head of radius forms pivot.
 Quadrate ligament (named according to shape) re-enforce the inferior
aspect of joint capsule [See small image on left]
o Clinical relevance: Pulled elbow in children. Sometimes you pull their hand to hard
and quickly that the radius just slips out of the annular ligament.
 Distal radioulnar joint
o A synovial pivot joint: This one doesn't have such a complete ring. The head of ulnar
fits in the ulnar notch (in radius). The articular disc (aka. triangular fibrocartilage)
separates head of ulnar to wrist joint and helps bind radius and ulnar together.

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WRIST JOINT

 Type: Synovial ellipsoid joint. One surface oval and concave (formed by radius). The other is
oval and concave (formed by wrist bones).
 Ulnar does not participate in formation of wrist joint. It is separated by the triangular
cartilage. Hence, the wrist joint is aka. radiocarpal joint (with no ulnar inside this word).
o Easy to orientate: Convex vs. concave. Concave is cave, so its 凹.
 Stabilized by the collateral ligaments: one of each side. Radial collateral ligament (attaches
to scaphoid) and Ulnar collateral ligament (attaches to pisiform & triquetral bone.)

MOVEMENTS OF WRIST JOINT

1. Extension (700) & Flexion (900). Midcarpal joints also participates in this movement, hence
allows greater degree of movement
a. Extension angle smaller, this is because of shape of lower end of radius.
2. Abduction (150) & adduction (450)
3. Circumduction, but NO ROTATION (since this is not a ball & socket joint! You can try on
your own hands, and you’ll realize you can’t rotate)

JOINTS IN THE HAND

The name gives information, e.g. intercarpal refers to all the joints between the carpal bones.
Carpometacarpal means between carpal and metacarpal. So no need to be scared of the names.

 Condylar: Can do Flexion & Extension, Abduction & adduction

 Hinge joints: Flexion & extension.

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MOVEMENTS OF THE DIGITS

Axial line of hand is in the 3rd metacarpal. The thumb is not moving in the same plane as the fingers,
so note position of thumb: abduction the thumb moves away from palm, vise versa for adduction.
Flexion means bend fingers, extension means straighten them, and the thumb moves away.

 The special movement: opposition

o Only at the Carpometacarpal joint of thumb (1st CMC joint); Saddle joint.
o Means: Thumb touches pad of fingers. A combination of flexion, abduction, and
medial rotation.

Thumb opposition Saddle joint A saddle

15
MSS03 INTRODUCTION TO DEGENERATIVE JOINT DISORDERS (OSTEOARTHRITIS)

OUTLINE

1. Background
2. Clinical features
3. Pathology
4. Management

BACKGROUND

 Loss of cartilage. A cartilage:

o Layers: Superficial tangential layer, middle zone, deep zone, calcified zone,
subchondral bone
o Composition: Water, Structural macromolecules (Type 2 Collagen, Proteoglycan,
glycosaminoglycan), Chondrocytes (make ground substances, intense interaction
with ECM)
o Features: avascular, aneural, alymphatic (hence limited capacity to repair; a = no)
 Degeneration is different from ageing.
o Aging: Stable structural changes, decreased water content, increased cross-linking
in collagen.
o OA: Progressive structural changes, increased water content, disruption of
organization (see image)
 Types: Primary vs. Secondary
o Primary: Mostly weight bearing joints (Hips and knees), sometimes not (e.g.
Interphalangeal joints)
 Factors: Systemic (Age, sex, nutrition, and metabolic factors), Local
mechanical (Joint deformity / Malalignment, Obesity, Joint injury), Genetics
o Secondary: Injury, infection, Endocrine (e.g. hypothyroidism), Neurological
(neuropathic arthropathy)
 Epidemiology:
o Osteoarthritis in knee: More common in Chinese women
o Osteoarthritis in Hips: Low prevalence in Chinese

Supplementary box: Joint Malalignment

 Basic introduction on Hip and knee joints:
o Hip: Ball and socket
o Knee: Modified hinge joint (allowing rotation)
 Ideal architecture: Centers of hip, knee and ankle falls on the same line (mechanical axis) 
Both knees, both malleolus touch
 If not, part of the knee may be loaded more than the other
parts: Knock knee (genu valgum), Bow leg (genu varum)
 Mnemonic (See right diagram)

CLINICAL FEATURES

 Diagnostic guidelines: EULAR (3 symptoms + 3 signs), ACR

 Symptoms:

16
 o Pain:
 Mild form: Increase in activity (Triphasic: Increase when starting to walk,
decrease after a while, increase after long walk)
 Severe form: Pain at rest and at night, need painkillers and walking aids,
quit hobbies and job
o Stiffness ('gelling'): After prolonged immobility (e.g. wake up).
 Hip: may complain cannot put on socks, cut toenails
 Knee: may complain cannot squat
o Crepitus on PE: ‘Oon’ movements (Sounds / feel with hands)
o Bony enlargements: Due to osteophyte formation
o Deformity (e.g. Genu varum / valgum)
o Limping: i.e. abnormal gait
 Staging: Kallgren Lawrence Staging. From swelling cartilage > Thickness defect (Partial >
Full) > Eburnation (Exposure of subchondral bone, cartilage is gone) [will come back later]

PATHOLOGY

THE BIG 4 PATHOLOGICAL CHANGES

1. Articular cartilage damage

2. Osteophyte formation
3. Subchondral sclerosis
4. Subchondral cysts

BIOMECHANICAL PERSPECTIVE (FOR REFERENCE)

 Main point: Bears a lot of weight cumulatively

 Many steps in a lifetime + Bears much force
o Hip joint: The joint bears the weight of both the body parts + forces of the muscles
used in balancing
o Knee joint: 3X body’s weight in ground walking, even more in other cases (e.g. stairs,
single legged). Medial (70% force and area), Lateral (30% force and area). Although
force: area ~ 1:1, still usually the medial side have problem first.
o Patellofemoral joint: bears much weight 2X in descending stairs

PATHOLOGICAL IMAGES (FOR REFERENCE)

Deformed joints. Arthroscope: Surface not Eburnation Osteophyte at Subchondral cyst

smooth. (surgery) margin: Body’s
attempt to ↑SA to
reduce contact
pressure

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INVESTIGATIONS

 Investigation summary: Plain X-ray. Others to rule our DD.

 Imaging:
o Plain X-ray
o MRI (for unusual situations).
o Findings: Kallgren Lawrence Staging [Macroscopic (Arthroscopy / Surgery). From
swelling cartilage > Thickness defect (Partial > Full) > Eburnation (Exposure of
subchondral bone, cartilage is gone)]  The 4 big Pathological signs: Narrowing of
joint space (loss of cartilage), Osteophyte (marginal growth), Subchondral sclerosis,
Subchondral cyst, Bony contour change/defect)
 Blood test: Only to rule out DD e.g. Inflammatory / Infective (ESR, CRP); Rheumatoid /
Septic arthritis, Mineral count e.g. Ca, P, ALP
 Joint aspiration. OA indicative: Clear straw color, Low total cell count, Bacterial test (e.g.
gram, culture) negative

Supplementary box: Kallgren Lawrence Staging

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MANAGEMENT

 Education & Modify risk factors (e.g. Weight loss, Lifestyle (reduce stair walking), walking
aids
 Physical Exercise: Strengthen muscle (e.g. Quadriceps, trunk, and abdomen muscles)
 Pharmacological: Not as effective as Physical therapy
 Cartilage supplements: Lack evidence
 Intra-articular injections (Visco-supplementation: for lubrication. It only 2/3 work, not
always):
o Usually Hyaluronate, seldom steroids (unless strong inflammatory element, it's bad
for cartilage)
o Other lack-of-evident injections:
 Plate rich plasma: due to anti-inflammatory effects
 Stem cells: can be used in sports injury but immature technology for OA
 Surgical:
o Arthroscopy:
 Trim away unhealthy parts.
 Proven to be ineffective (i.e. = Surgical placebo), hence now only for loose
bodies or meniscal tear.
o Osteotomy (Joint-preserving surgery):
 Realign bones around joint to shift loading to affected side to healthy side
('Redistribute stress)', by taking out a wedge of bone.
 The patient can then use the knee / hip joint for many years more.
 Not for end stage osteoarthritis (It is called joint-preserving surgery, if
whole joint diseased, then there’s no healthy joint to preserve.
o Joint replacement: If whole joint diseased. Metallic replacement.

IMPORTANT POINTS

EMQ
Which of following best match clinical scenario for diseases of bones and joints?

A. Osteomyelitis B. Ankylosing spondylitis C. Giant-cell tumor of tendon

sheath
D. Osteoarthritis E. Pigmented villonodular F. Gout
synovitis
G. Pseudogout H. Rheumatoid arthritis I. Septic arthritis

118. A 5-year-old boy, 3-day history of fever and right hip pain. Aspiration of joint fluid reveals
increased number of neutrophils.

119. A 76-year-old man has a known history of degenerative joint disorder. He complains of
pain in his right knee. X-ray shows calcification of meniscus.

120. A 40-year-old woman presented with bilateral wrist swelling with a flexion deformity. A
biopsy of synovium reveals villous synovium with an increased number of plasma cells and
lymphocytes.

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Ans: I G H

OSTEOARTHRITIS (PLEASE KNOW)

LOSS sign Cause
Loss of joint space Cartilage mechanical erosion
Osteophyte formation Eburnation exposes subchondral bone, osteophyte formation as
attempt to increase SA to reduce pressure
Subchondral sclerosis Osteocyte attempts to repair / Fibrous scar
Subchondral cyst Cartilage erosion  Large intra-articular pressure  Synovial fluid
forced into subchondral bone

20
MSS04 INTRODUCTION TO INFLAMMATORY JOINT DISORDERS

OUTLINE

1. Rheumatoid arthritis
2. Gout
3. Spondylarthritis
4. Other inflammatory causes of Joint pain

RHEUMATOID ARTHRITIS

 Characteristics:
o Systemic autoimmune disease
o Inflammatory polyarthritis, but distal interphalangeal joint usually
spared
o Proliferative changes in synovium.
 Pathological changes:
o Gross: Swan neck, Boutonniere, Mallet finger
o X-ray: Subluxation
o Extra-articular features (∵Systemic autoimmune): Lung fibrosis,
Hematological (Felty's syndrome), Ocular (Episcleritis, scleritis),
Vasculitis, Rheumatoid nodule, Amyloidosis
 Treatment:
o Principles: Suppress inflammation, prevent further joint damage,
Minimize complications
o Pharmacological: (Details refer to coming Pharmacology lecture)
 Symptom modifying: NSAIDs, COX II
 Disease modifying: DMARDs
Note: Drugs not useful if joints already damaged.
o Other therapy: Physiotherapy, Occupational therapy (esp. hands),
Surgery (if joint already badly damaged)

Rheumatoid synovium: Proliferative changes Subluxation of finger joints in X-ray

21
GOUT

 Background information
o Inflammation caused by urate acid.
o Rapid onset, usually affect the metatarsal phalangeal joint (Big toe of
foot), Usually monoarticular / Podagra
 Stages: 1 (Asymptomatic), 2 (Intermittent i.e. comes and goes), 3 (Exacerbation)
 Pathogenesis: Uric acid becomes less soluble in cold environment (e.g. morning,
night) > deposit at distal joints e.g. fingers
 Triggers: Alcohol, diet (high uric acid intake e.g. shellfish, sardines, meats, fructose which
would become urate), pathologies (infections, bleeding, trauma, etc.)
 Clinical presentation: Fever + joint pain (Mimic with other conditions e.g. septic arthritis)
 Investigations: Arthrocentesis and check for uric acid level (this is to rule out septic arthritis,
which is a medical emergency as it can cause very distorted joints afterwards)
 Treatment: (Similar to Osteoarthritis) Stop gouty attack with painkillers, prevent future
attack by lowering serum uric acid level

SPONDYLARTHRITIS

 Genetics-related
 Characteristics:
o Inflammation, characterized by spinal bone formation and ankylosis
o Clinical
 Asymmetrical involvements (Different from Rheumatoid arthritis),
Psoriasis, Dactylitis (Sausage finger), Enthesitis at Achilles Tendon)
 Extra-articular: Anterior (Not posterior or others) uveitis, aortic
regurgitation, apical fibrosis [All starting with 'a']
 Investigations: X-ray (usually good enough for diagnosis, if not ±MRI)
o Findings: Sacro-iliac SI joint fusion (MRI hyperintense indicating inflammation,
characteristic 'bamboo spine' from ankylosis)
o Diagnosis also depends on types of Spondylarthritis: Non-radiographic vs.
Radiographic
 Sacroiliitis (X-ray visible for Radiographic type; MRI hyperintense for non-
radiographic type)
 + HLA-B27 antigen for non-radiographic type
 Treatment: (Similar to Osteoarthritis) NSAIDs, DMARDS (Axial: biological; Peripheral:
conventional), physiotherapy, surgery

Supplementary box: Differentiating between several joint problems

 OA vs. RA:
o OA: Polyarthritis | Symmetrical | Early morning stiffness, Bony feeling in palpation
o RA: Polyarthritis | Symmetrical | Bulgy feeling in palpation (synovium)
 Diagnosis by number of arthritic joints:
o Monoarthritic: Gout, & Pseudogout, OA, Septic arthritis
o Oligoarthritis: Spondylarthritis
o Polyarthritis: Rheumatic, OA

22
Characteristic Bamboo spine appearance Left: No joint space between sacrum and ilium, Patient:
irregularities due to ankylosis. Right (MRI): Cannot see
Hyperintensity shows inflammation. sun.

Acute arthritis, asymmetrical Psoriasis (Poor demarcation) Dactylitis/ Sausage finger (of one
involvement (different from particular finger)
Rheumatoid arthritis)

Enthesitis Non-radiographic SpA. MRI in SI joint Radiographic SpA. X-ray shows

reveals hyperintensity (inflammation) sacroiliitis.

OTHER CAUSES OF JOINT PAIN

 Osteoarthritis: Elderly prevalent, see another lecture. Preserved bone density.

 Systemic Lupus Erythematosus
 Certain infections (e.g. hepatitis, parvovirus)
 Septic arthritis (medical emergency)
 Fibromyalgia

23
MSS05 INTRODUCTION TO RADIOLOGY OF THE MUSCULOSKELETAL SYSTEM

OUTLINE

1. By modality
o Plane X-ray
o CT
o Ultrasound
o MRI
o Radionuclide (Nuclear scan)
o Summary
2. By pathology

BY IMAGING MODALITY

PLANE X-RAY

 Can visualize: Bones, no good for soft tissue

 Advantages: Cheap and readily available
 Disadvantages: Soft tissue, not good for complex anatomy (e.g. Appendicular skeleton
good, pelvis no good)
 Application: Trauma, Bone tumors, Infection and inflammation, Spinal column pathology
(but not for neural, or disc details)

CT

 Essentially a rotating X-ray beam

 Recent advancements: multi-slice helical reconstruction (Thinner slices, faster, more details
'sub-mm coverage', smoother multiplanar reconstruction)
 Can visualize: bones, some soft tissues
 Advantages: Complex anatomy (e.g. pelvis), Calcification
 Disadvantages: Ionizing radiation higher, imaging not as good as MRI still
 Application: Trauma (Complex anatomy), Tumor (Guide biopsy, calcification), Infection and
inflammation (not in arthropathy), Spinal (only if MRI contraindicated)

ULTRASOUND

 Advantages: Superficial imaging good (Excellent resolution, real time examination). No

ionizing radiation, inexpensive
 Disadvantages: Only superficial, can only see bone cortical surface but doesn't penetrate
bone (hypoechoic), Operator dependent with long learning curve
 Application: Mass and cyst, Real time examination, Guide biopsy

MRI

 Advantages: Good imaging quality (esp. soft tissue differentiation, bone marrow changes),
Different sequences to look at different things, No ionizing radiation
 Disadvantages: Not readily available, very expensive, note contraindication, takes 30-45
mins and may not be tolerated in some patients (e.g. unstable patients in trauma)

24
  Application: Staging (not diagnosis) of tumor, infection and inflammation, Spinal column
(esp. disc protrusion ,spondylodiscitis, cord / nerve compression). Less for trauma

RADIONUCLIDE (NUCLEAR SCANS)

 Inject tractor to release gamma waves which will be detected

 Types:
o Bone scan: Very sensitive to marrow changes (but not sensitive with diagnosis, e.g.
tumor, infection, fracture)
o Other applications: Specialized scans (Whole body scan for abscess location)
o Positron emission tomography (Cancer)
 Advantages: Early detection of pathology, Specific radionuclide for problem solving (e.g.
WBC scan for abscess localization)
 Disadvantages: Poor structural information (Can't pinpoint where exactly), not specific for
cause (tumor vs. infection vs. fraction looks same), Expensive

SUMMARY (TEACHER’S)

PART 2: BY PATHOLOGY

TRAUMA

 Plane X-ray: For simple cases

 CT For:
o Complex anatomy (e.g. pelvis, foot)
o For severe trauma in multiple areas

25
 o To exclude cervical spine injury
o For patients requiring, minimal mobilization to protect spine
 MRI: For spinal trauma with potential neural damage
 Others: e.g. Marrow edema, Injured soft tissue (e.g. ligaments)

BY PATHOLOGY

SPINAL PATHOLOGY

 Plane X-ray + Dynamic flexion extension studies: usual case

 CT: Complex bone deformities e.g. scoliosis
 MRI: Vertebral discs (e.g. disc protrusion), Neural involvement, soft tissues (e.g. paraspinal
soft tissues)

SOFT TISSUE PATHOLOGY

 Ultrasound: Superficial soft tissue pathology excellent, can guide biopsy

 MRI: Excellent for soft tissue pathology (esp. intra-articular structures, and extensive area of
involvement)
 Pathological cases:

Cystic structures, checking Rheumatoid arthritis: Juxta-articular erosion, periarticular

content: Hyperechoic, edema, tenosynovitis)
Hyperintense if fat content

LEARNING OBJECTIVES

 Recognize the different imaging modalities that are used for imaging musculoskeletal
disorders
 List the pros and cons of the different imaging modalities in musculoskeletal imaging.
 Select the most appropriate imaging investigation for different musculoskeletal disorders

26
IMPORTANT POINTS RECAP
Question
Pick imaging modality:
Superficial soft tissue mass
Septic arthritis features
Application of MRI
Answer Remarks
Ultrasonography (USG) /
Ultrasound more useful for Repeated question in older
diagnosis (Aspirate) years PP
(1) Neural involvement e.g. sciatica, (2) Soft tissue / Disk,
(3) Spondylodiscitis (Note: For spinal pathology you can use CT
too, but certainly wouldn’t be most sensitive.)
27
MSS06 BIOCHEMISTRY OF CARTILAGE AND BONE

OUTLINE

1. Background: Extracellular matrix

2. Bones
a. Collagen
b. Glycoprotein
3. Cartilage
a. Glycosaminoglycan
b. Proteoglycan
c. Adhesive glycoprotein
4. Cellular interactions
5. ECM and Cell function
6. Clinical application: Intervertebral disk

BACKGROUND: EXTRACELLULAR MATRIX

 A complex mixture of proteins, produced by cells, and surrounds cells

 Consists of insoluble fibers, soluble fibers, and adhesive molecules
 Function: Withstand stress & maintain shape; communication with cells
 Form of extracellular matrix adapts to the function. E.g. Transparent in cornea, mat-like in
basal lamina, Rope-like in tendon, Resilient in skins and artery, shock absorbing in cartilage,
hard in teeth and bone
 The type of fiber, amount, arrangement dictates the forms to suit the functions
o E.g. Articular cartilage. Collagen: Proteoglycan=1:1 (Need both tensile strength and
compressive resistance)
o Bone: Mostly collagen (Needs mineralization)
 Clinical relevance: ECM degenerative skeletal diseases. E.g. Osteoporosis, Osteoarthritis,
Intervertebral disc degeneration, etc.

BONE

 Types: Compact, Spongy.

o Formation (i.e. fibril organization) is directed by the level of mechanical function at
the site.
 Dense matrix: 70% inorganic, 30% organic (of which mostly collagen)
o Inorganic: Ca phosphate (in forms of hydroxyapatite crystals)
o Organic: Collagen (Type 1) mostly, some proteoglycan and glucosamine

COLLAGEN

 Formation: GlyXY repeats  Alpha chains  Procollagen  Collagen (By cleaving

propeptides) fibrils  Self arranged in pattern with gaps (Typical pattern in
electronmicroscopy).
 Notable properties:
o Insoluble
o Heterotypic: Other types of collagens may intermingle or attach to fibril surface

28
Formation of collagen fibers (From leftmost to right). Descriptions see above. Middle picture:
Note typical electromicroscopic appearance of collagen, have gaps. Right: see intermingle
different types of collagen fibers; surface attachment of some other types of collagens.

GLYCOPROTEINS

 Notable properties:
o Anionic / negatively charged, rich in acidic amino acids (see types by AA below)
o Involved in calcification process: When local ion concentration (e.g. Ca, P) increase
Reduced mineralization inhibitors and more mineral nucleators. Mineral
nucleators + Collagen fibrils support hydroxyapatite deposition at hole zones
Continual accrual of hydroxyapatite. (+ Regulators from osteoblasts.)
 Types: Osteopontin (Aspartic residues), Bone sialoprotein (Glutamic residues), Osteocalcin
(γ-Carboxyglutamic acid)

CARTILAGE

 3 zones by cartilage matrix components and locations:

o Pericellular: Closest to chondrocytes, produced mostly by 1 chondrocyte. Syndecan,
fibronectin, integrin, etc.
o Territorial: Mostly produced by 1 chondrocyte (See diagram below). Collagen II,
fibromodulin, decorin, COMP, etc.
o Inter-territorial: Produced by several chondrocytes. Hyaluronic acid, etc.

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  Comprised of 2 big classes of soluble polymers (Same for articular cartilage and
intervertebral discs): Glycosaminoglycans (GAGs), Proteoglycans.

GLYCOSAMINOGLYCAN

 Glycosaminoglycans: Hyaluronic acid + Protein core (e.g. Chondroitin sulphate)

 Background:
o Linear polymers of repeating disaccharide units
o Highly negatively charged, hydroxyl group can be sulphated to further increase
negative charge
 Hyaluronic acid
o An unsulphated glycosaminoglycan that is not attached to a protein core, but is
huge due to repeating units
o Forms clear and viscous liquid for: Lubricantin synovial fluids and joints, resist
compressive forces in cartilage, Space filler
o Special relationship between Hyaluronic acid and protein core: forms huge
aggrecan
 Protein core. 2 parts components:
o One end: N-acetylglucosamine (NAG), or N-acetylgalactosamine
o Another part: D-glucuronic acid, or L-iduronic acid

PROTEOGLYCANS

 A core protein + GAG attached covalently (These are usually

much shorter than hyaluronan)
o GAG occupies a greater fraction and is the site of
biological function
o GAGs are highly negatively charged (due to sulphate
and carboxyl groups)
 Negative charge = high affinity for cations =
hydrophilic = can swell
 Chemical group forms hydrogen bonds and
allows electrostatic interaction readily
 Components: Hyaluronic acid binding, GAG chains, other
o Types: Large (e.g. Aggrecan), Small (e.g. Perlecan), Membrane bound (e.g.
Syndecan)
o Large proteoglycans can have lots of GAG chains, whereas small proteoglycans only
have a few ('short leucine repeating proteoglycans, SLRPs')

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ADHESIVE GLYCOPROTEINS

 Function: Interacts with cells and other molecules in matrix, promotes cell adhesion, cell
migration, differentiation
 Examples: Fibronectin
o Allows disulfide bonding  stabilizes fibrillar matrix
o Binds to assorted collagen etc. fibers, as well as integrin receptors and RGD (Arg-
Gly-Asp; RGD motif)

CELLULAR INTERACTIONS

 Receptors: Mainly integrins, also Discoidin domain receptors (DDRs)

 Integrins. Special features:
o Sequence specific (RGD: Arginine-Glycine-
Aspartate) transmembrane signaling
transducers.
o Dimeric/ Heterodimers: Single Beta chain can
interact with multiple alpha chains to bind
with different ligands. Enhanced specificity
through multiple interactions
o Interacts with cytoskeleton: Focal adhesions
for hundreds of weak cell-matrix interactions,
allows signaling to cell nucleus

ECM AND CELL FUNCTION

 Cell produce ECM, ECM signals cell

 Maintenance and homeostasis by matrix assembly and matrix turnover. Imbalance leads to
degenerative diseases
 Enzyme turnover by:
(1) (Major) Matrix metalloproteinases, including (a) Secretion of MMPs, (b) Cleavage at
specific sites since it is produced as a proenzyme, (c) TIMPs (Tissue inhibitors)
(2) (Minor) Other degradative enzymes: E.g. hyaluronidase, Chondroitinase, elastase

CLINICAL APPLICATION: INTERVERTEBRAL DISK

 Aggrecan (Hyaluronic acid) swells in fixed boundary to resist compression

 Degradation by MMPs and other proteinase; Proteolytic fragmentation increases with age
 MMPs plays a role in rheumatoid arthritis, intervertebral disc degeneration, etc.
 Sequestration of pathogenesis:
o Interplay between cells and ECM (E.g. External irritant provokes cell changes, cell
changes produce ECM changes, which changes cell, which changes ECM.
o Additional interplay by cell and ECM signaling, e.g. integrin, DDRs (DNA-damage
response?); receptors detect ECM components (e.g. collagen), ECM degradation
produces, leading to loss/ gain of signaling

31
Changes in aggrecans, see debris in Degenerate Interplay between cells and ECM in
24 years-old (haha, us already old.) d disk. pathogenesis process.

LEARNING OBJECTIVES

 Basic components of the extracellular matrix and function

 Key matrix molecules contributing to the structural properties of bone and cartilage
 Cell-matrix communication in the regulation of tissue homeostasis
 Concepts applicable to other tissues and organs

IMPORTANT POINTS RECAP

Question
Molecules that hold water
Cartilage. Collagen: Proteoglycan:
Elastin.
Main enzyme responsible for
Aggrecan cleavage
Collagen type found in fibrocartilage
vs. hyaline cartilage.
Biochemical composition of Bone
Biochemical composition of
Cartilage
Answer Notes
Hyaluronic acid / Collagen: Tensile strength
Aggrecan, Proteoglycan: Hold water /
Proteoglycans (due to Lubrication
negative charge) Elastin: Elastic force
1:1: small amounts
MMP Not ‘serine protease’
1 vs. 2 Fibrocartilage quite important, often
examined. Fibrocartilages are the ones in
tendons. (3 types of cartilage: Hyaline (T2,
our case); Elastic (Elastic fiber rich, T2);
Fibrocartilage (Tendons & Bones, T1)
Collagen I, Osteopontin (glycoprotein), Osteocalcin
(glycoprotein)
Why no proteoglycan? Because bones no need much water.
Collagen II, Aggrecan (a proteoglycan), Fibronectin (a
glycoprotein) [Note: Collagen: Aggrecan = 1:1]

SAQ
Question
Post-translational
modifications for collagen
synthesis
MMP classes example
MMP activity regulation
Using cartilage as an example,
state the functions of:
Collagen, Proteoglycan,
Glycoprotein
Answer
At RER: Signal peptide cleavage, prolyl hydroxylation
Extracellular: Proteolytic processing, fibril assembly and cross-
linking
Collagenase, Stromelysin (membrane bound)
Production, activation of proenzyme, TIMPs
(1) Collagen: Type 1 in fibrous cartilage (the bones), Type 2 in
Hyaline cartilage; for tensile strength. (2) Proteoglycan
(Aggrecan): Absorb water to swell to withstand compressive
force. (3) Glycoprotein (Fibronectin): Cellular attachment and
communication with ECM

32
Cell-matrix interaction
examples
Organization of collagen
Properties of GAG
How does ECM regulate IHH
level (ECM & Cell interaction)
(1) Integrins: Binds with transmembrane protein with focal
adhesions; (2) Syndecan: Binds to collagen and fibronectin
Triple helical structure, Glycine at every 3rd residue (Gly-X-Y),
Stabilized by interchain H bonds
(1) Highly negative charge: attract cations; (2) Hydrophilic:
Supports swelling pressure
(1) Aggrecan act as selective sieves to regulate traffic of
molecules; (2) Binds to signaling molecules

***
As a student I found this lecture quite confusing. I’ve tried to summarize the key points in the final
section ‘Exam Focus’. Hope it helps!
***

33
MSS07 INFECTIONS OF THE SOFT TISSUES AND MUSCULOSKELETAL SYSTEM

OUTLINE

1. Background information
2. Epidermis
3. Dermis
4. Multiple layers
5. Infective arthritis

BACKGROUND INFORMATION

 Layers of the skin: Epidermis, Dermis, Subcutaneous tissue, Deep fascia, Muscle tendons
bones joints
 Resident skin flora:
o Mostly Gram +ve: Staphylococcus, Corynebacterium, micrococcus,
Propionibacterium
o Less Gram-ve (Acinetobacter) and Yeast (Candida)
 Defense at skin: Normal integrity, Rapid cell turnover, Sebum, Normal flora
 Reasons of infection: Breach of normal integrity, altered normal skin flora (e.g. prolonged
hospitalization), changes in tissue (e.g. hematoma, foreign body), exogenous microbial
flora (e.g. dog bite)

EPIDERMIS
Infection Key points
Dermatophytosis All molds (Trichophyton, Microsporum, Epidermophyton). Diagnosis: KOH
wet mount, culture
Paronychia (Nail fold infection) Acute (Staphylococcus aureus) vs. Chronic (Candida)

(UP TO) DERMIS

 Collectively known as Pyoderma (Pus forming: Epidermis to subcutaneous)

 Mostly Streptococcus pyogenes (except for Folliculitis & Impetigo: Staphylococcus aureus)

34
  Treatment directions: Drain collections, Antibiotics (Beta lactam with reference to
sensitivity, e.g. MSSA (Amoxicillin clavulanate), MRSA (Non-beta lactam antibiotics)
 Note: CA-MRSA (Furuncles, Panton-Valentine leucocidin > Necrotizing pneumonia) vs. HA-
MRSA

Infection Key points

Impetigo Commonly in children
Folliculitis Abscess around hair follicles, Staphylococcus aureus
Abscess Furuncle: Small subcutaneous abscess.
Carbuncle: Large contiguous group of furuncles, common at the back of
immunocompromised
Cellulitis Unclearly defined margins although cardinal signs apply
Erysipelas Distinct red boarder

MULTIPLE LAYERS (DERMIS, SUBCUTANEOUS FAT, DEEP FASCIA, MUSCLE)

NECROTIZING SOFT TISSUE INFECTIONS (EMERGENCY)

 2 important emergencies: Clostridial myonecrosis, Necrotizing fasciitis

o Clostridial Myonecrosis (Gas gangrene for Clostridium difficile)
 Due to Clostridium perfringens spores from foreign body / coagulative
necrosis of muscles
 Lab diagnosis: Lots of bacteria, few leukocytes
o Necrotizing fasciitis (Anesthetic / loss sensory in affected area, grey to black color).
 Types: Type 1 (Mixed, bowel surgery complications, uncommon nowadays),
Type 2 (Streptococcus pyogenes), Type 3 (Vibrio vulnificus, water contact)
 Cyanotic skin / dark / black, tender at lesion edge but aesthetic in center
 Both: Surgical emergency (Surgical debridement, antibiotics)

OTHERS

Pyomyositis: Abscess in muscles (Staphylococcus aureus) Psoas abscess

OSTEOMYELITIS
 Routes of infection: Hematogenous, Contiguous; Prosthetic related (introduced in
operation, sometimes hematological. This is an important complication of joint
replacement surgery)
 Pathogenesis: Acute inflammation & Increase bone pressure  Obliteration of vascular
channels, Ischemia and necrosis i.e. Sequestrum & abscess  Subperiosteal extension of
infection & new bone formation  Sinus tract drainage
 Mostly: Staphylococcus aureus
 Other types
o Vertebral: Mostly hematogenous (Segmental arteries bifurcates at disk, disk RIP
first). Due to Trauma, operations, open fractures, metabolic e.g. DM
o Mycobacterial: Mycobacterium tuberculosis (Hematogenous spread),
mycobacterium marinum (seawater)
o Chronic: From improperly treated Acute. Bone loss (sequestrum resulted), sinus
tract. Can be very clinically mild.

35
  Diagnosis:
o Imaging: CT or MRI (Not Plain X-ray: 2-week lag)
o Microbial: Blood culture, bone biopsy (Not sinus tract ∵ not reliable)
 Treatment: Surgical debridement of sequestrum, prolonged antibiotics.

OTHERS
Surgical wound infection: Depending on type of operation.
 Abdominal e.g. E. coli, proteus, Klebsiella)
 Ortho and neuro (S. aureus from skin)
 Hospital acquired (Pseudomonas, Acinetobacter), skin flora (Streptococcus,
Staphylococcus)

INFECTIVE ARTHRITIS

 Acute, Chronic
 Routes: Hematogenous, Inoculation
 Mostly staphylococcus aureus, unless indicative: Infants & Children (Streptococcus
agalactiae, Hemophilus influenzae; resp.), Sexually active (Neisseria gonorrhoeae), IV users
(S. aureus, Pseudomonas aeruginosa)
 DD: Autoimmune (RA), Crystal induced (Gouty, Pseudogout), Trauma, hemarthrosis,
osteoarthritis, tumor
o Differentiate from gout and pseudogout (Microscopy + Bacterial studies, since they
can superimpose)
o Blood culture, Synovial fluid aspirate (Leukocyte count, Gram stain, crystals,
culture), synovial biopsy
 Treatment: Surgical drainage, antibiotics

IMPORTANT POINTS RECAP

DISEASE & CAUSATIVES

 Epidermis:
o Dermatophytosis: Trichophyton, Epidermophyton, Microsporum
 Onychomycosis: Trichophyton
 Scalp: Microsporum
o Paronychia (S. aureus).
 Dermis:
o Folliculitis: S. aureus
o Impetigo: S. aureus
o Abscess incl. furuncle & carbuncle; Cellulitis, Erysipelas: S. pyogenes
 Multiple layers:
o Necrotizing:
 Gas gangrene: Clostridium perfrenges
 Necrotizing fasciitis: S. pyogenes, Vibrio vulnificus
o Others. Osteomyelitis, Infective arthritis: S. aureus

Recall IASM content for S. aureus and fungus (e.g. treatment)!

36
MSS08 DRUGS USED IN THE MANAGEMENT OF ARTHRITIS

BACKGROUND INFORMATION

INTRODUCTION TO ARTHRITIS

 2 types: Degenerative (Osteoarthritis), Inflammatory (e.g. Rheumatoid arthritis, Gout,

Spondylarthritis)
 Medications of Arthritis:
o Symptom-relieving
 Analgesia:
 Paracetamol (1st line)
 NSAIDs
 Anti-inflammatory:
 NSAIDs (Bridge)
 Glucocorticoids
o Reduce joint problem progression:
 DMARDs (conventional synthetic, biological, targeted synthetic)
 Glucocorticoids
 General approach for Rheumatoid Arthritis (Not important)
o Analgesia: Paracetamol, if not NSAIDs; +
o Triple therapy (Methotrexate, Sulfasalazine, Hydroxychloroquine)  1st line. If not
working:
 Milder: Conventional synthetic DMARDs
 Severe: Biological DMARDs / Targeted synthetic DMARDs

DRUG LIST

See next page.

LEARNING OBJECTIVES

 Identify the rationale behind the selection and the regimen of analgesic and anti-
inflammatory drugs in the management of joint disorders
 Describe the risk for chronic usage of anti-inflammatory steroids
 Describe the different categories of DMARDs
 Explain the pharmacological differences between non-biological and biological DMARDs
 Recognize the benefits and the risks associated with the use of non-biological and biological
DMARDs

37
GENERAL APPROACH IN ARTHRITIS

Class Examples Mechanism Effects Side effects; Contraindications Notes

(1) Analgesics
Paracetamol (Acetaminophen) See other lectures - Skin rash, minor allergic reactions.
- Liver & kidney damage (at toxic dose of 4g/day; but may increase
with CYP enzyme or GSH depletion, e.g. heavy alcoholic, fasting,
malnutrition; Antidote by N-acetylcysteine)
- No anti-inflammatory effect (Only for osteoarthritis)
(2) Anti-inflammatory drugs
NSAIDs Traditional (Ibuprofen, Inhibit COX activity > Less prostanoids > Effects: NSAIDs: Little / See other lectures
(Also has Naproxen); Selective COX2 (1) Less vasodilation and vascular permeability > Less Glucocorticoids:
analgesic inhibitors (Celecoxib) edema, swelling and redness  Suppresses Glucocorticoid functions: Response to threat,
effects) (2) Less sensitization to pain nerve endings > Analgesic Permissive (i.e. regulatory) effects. Specifically:
(3) Lower hypothalamic thermoregulatory set point > ~On Glucose: Gluconeogenesis, Reduced glucose uptake and
less fever (antipyretic effect) utilization (i.e. similar to Glucagon) > Increased BGL > Fat
Gluco- Short to intermediate -[Pro-drugs: Cortisone, Prednisone: Becomes translocation to trunks + DM prone
corticoids acting: Hydrocortisone, hydrocortisone and prednisolone at liver via 11β- ~On Amino acid: Promote proteolysis > Muscle wasting
Prednisolone HSD1] ~On Lipid: Lipolysis (Due to lipase and insulin from high BGL)
Pro-drug: Cortisone, -Glucocorticoid binds to receptor > Receptor ~On Calcium: Reduced absorption of GIT and kidney excretion
Prednisone translocate to nucleus to interfere with transcription > (along with water excretion) > Osteoporosis
Long acting (Topical only): New mRNA to produce new proteins (e.g. enzymes) ~Vasoconstriction (Indirect), CNS (Mood elevation, Euphoria,
Betamethasone, for effects: insomnia, restlessness)
Dexamethasone 1. Inhibits cyclooxygenase 2 > less prostanoids ~Suppressed response to infection (esp. Peptic ulcers), general
(Prostaglandin, Thromboxane) wound healing
2. Stimulates Lipocortin (Annexin-1) production > Less ~Side effects increases with dose and duration, lowest possible dose
Phospholipase A2 activity > Less arachidonic acid > by gradual lowering (2W interval follow-up) / Intermittent
Less arachnoid (Leukotrienes, Prostaglandins, administration with alternate day schedule (prevents adrenal
Thromboxane) function suppression)
3. Inhibit pro-inflammatory cytokines (TNF, IL) ~Typical presentation: Buffalo hump, Moon face
-Effects of 1, 2, 3: Less inflammation ~Contraindication: Children, Chronic use, Pre-existing condition of
I: Vasodilation, Vascular permeability, the above side effects that may cause exacerbations
II: Diapedesis and Antigen presentation > Less WBC
activities, cytokine production, cell adhesion
Clinical note:  On drugs:
~Supplementary dose when stressed (e.g. surgery, ~Takes time (i.e. days) because: (1) Need time for protein to be
trauma) to prevent adrenal insufficiency (life produced; (2) Need time for old protein to degrade
threatening shocks, hypoglycemia). ~Contraindicated in hepatic dysfunction
~Gradual withdrawal, not sudden. May take 2M to 1Y
(Individual differences)

38
ADDITIONAL DRUGS FOR RHEUMATOID ARTHRITIS
Class Examples Mechanism Effects Side effects; Contraindications Notes
(1) Conventional synthetic DMARDs
Cytotoxic antifolate Methotrexate, 1. Inhibit AICAR transformylase and thymidylate synthetase -Cell turn-over: GID, mucosal ulcers Triple therapy:
Leflunomide > Increase AICAR -Cytotoxic: Hematological, Hepatic Methotrexate (if not
2. Inhibit AMP deaminase > AMP increase > More -Hypersensitivity tolerated:
extracellular adenosine Contraindicated in pregnancy Leflunomide),
3. In immune cells binds to adenosine receptors to activate (Cytotoxic!) Sulfasalazine,
cAMP and PKA Supplement with folic acid to reduce Hydroxychloroquine
4. Inhibit proliferation, cytokine release; stimulate apoptosis side effects
Sulfasalazine
Antimalarial drugs Chloroquine, Hydroxychloroquine
Immunosuppressant Cyclosporine, Mycophenolate mofetil
s
(2) Biological DMARDs (All biological, cannot oral)
T-cell co-stimulation Abatacept CTLA-4 (Cytotoxic T-lymphocyte antigen-4) binds to CD80 -Intravenous infusion (30 mins every 2W to 1M)
modulators and 86 of APC > T cell cannot bind to APC > No T cell -Hypersensitivity, Immunosuppression (So, don’t multi-therapy)
activation -Screen for TB before treatment
TNF-α blocking (X-mab) etanercept, infliximab, adalimumab, golimumab, certolizumab
agents
B-cell cytotoxic Rituximab
agents
IL-6 inhibitors Tocilizumab, sarilumab
IL-1 inhibitors Anakinra, rilonacept, canakinumab
(3) Targeted Synthetic DMARDs
Janus-activated Tofacitinib, Binds to ATP receptor of JAK > Inhibit JAK > Less signaling Adverse effects: Immunosuppression Orally bioavailable,
kinase inhibitors baricitinib by interferon and IL6 (esp. Herpes, need vaccination), skin indicated when
cancer risk, raised ALT AST LDL HDL, inadequate
more immunosuppression (Anemia, response to
leukopenia, neutropenia, DMARDs
thrombocytopenia, etc., since many Drug interaction
hematopoietic growth factors signaled with CYP
through JAK)

39
40
MSS11 NEUROMUSCULAR JUNCTION AND MOTOR UNIT

OUTLINE

1. Neuromuscular junctions: Background understanding

2. Pathological perspective: Myasthenia gravis
3. Electromyography

NEUROMUSCULAR JUNCTIONS: BACKGROUND UNDERSTANDING

 Neuromuscular junctions are adapted to suit their function: Presynaptic, Postsynaptic

differentiation
o Presynaptic: Clusters of synaptic vesicles containing ACh
o Postsynaptic: ACh Receptors (AChR) clustering at crest of junctional folds (Slightly
Important feature)
 Clustering of AChR is induced by innervation (and they do not need to be
activated in order to do so)
 Process: Agrin (in ECM, in minutes) activates LRP4 and MuSK (muscle-specific
kinase)  AChR phosphorylation & clustering (in next few hours)
 Summary (Slightly important): Nerve innervation of muscle fibers induce AChR
clustering via agrin-Lrp4-MuSK signaling pathway.
 3 components of a neuromuscular junction: Muscle, Motor neuron, (Perisynaptic) Schwann cells

BIOCHEMICAL PERSPECTIVE: ACETYLCHOLINE CYCLE

 Production:
o Acetyl of Acetyl CoA binds with Choline via Choline
acetyltransferase.
o Acetylcholine is packed in vesicles.
 Release:
o Upon action potential, increase in intracellular Ca level stimulates
fusion of vesicles to axolemma to release ACh to synapse.
o ACh diffuse across synapse and bind to ACh Receptors clustering
at crest of junctional folds
 Recycling: ACh is rapidly broken down by acetylcholinesterase (AChE) to acetate and choline.
Choline is reabsorbed by axon via transporter and re-used to make more ACh.
 Activation: Binding of ACh molecules to AChR causes conformational changes in ion channel
that results in big influx of Na and small efflux of K  Membrane depolarization & muscle
contraction

41
PATHOLOGICAL PERSPECTIVE: DISORDERS OF NEUROMUSCULAR JUNCTIONS
-- MYASTHENIA GRAVIS

 Background:
Commonest NMJ disease, due to genetics but non-inherited
Progressive symptoms (Muscle weakness)
 Onset: Ocular (Eyelid drooping, Double / blurry vision, due to weakness of
muscles controlling eyeballs); Oral symptoms
 Progression: Generalized (Head, arms, legs)
 Others: Thymic tumor
 Cause: Autoimmune antibodies destroying AChR. 3 important ways of pathogenesis in NMJ
disorder:
1. Attract MAC  NMJ structure destroyed (e.g. junctional folds gone)
2. AChR dimerized and cross linked  AChR Endocytosed  AChR density decrease
[Myasthenia gravis]
3. Inhibited AChR channel property ( cannot signal for muscle activation)
 Mostly Seropositive (Attacking known receptors / complexes, e.g. AChR, LRP4, MuSK), some
seronegative (attacking unknown)
 Serological diagnosis: ELISA (Color), RIPA (Radioactive), Cell-based (Fluorescence)
1. Enzyme linked immunosorbent assay (ELISA, Color detection): Measuring serum IgG
autoantibodies
2. Radioimmunoprecipitation assay (RIPA or RIA, Radioactive signals): Radioactive α-
bungarotoxin to indicate the presence of pathogenic autoantibodies against AChRs
3. Cell-based assay (CBA, Fluorescence signals): Heterologous cell express AChR or MuSK
to test the binding of pathogenic autoantibodies
Unimportant note: different assays measure different kinds of myasthenia gravis (different
by what they attack)
 Treatment:
1. Anticholinesterase therapy (AChE inhibitors e.g. Tensilon/ Edrophonium,
Pyridostigmine):
o Effect: Reduce degradation, increase time in synapse
o Disadvantage: Effect wears off in a few hours
2. Immunosuppressant therapy (Corticosteroids)
o Effect: Suppress immune system attack
o Disadvantage: Immunocompromised (not for patients with chronic disease)
3. Other therapies: e.g. Intravenous immunoglobulins

42
ELECTROMYOGRAPHY

BACKGROUND

 Motor units (Quick recall)

o Definition: All the muscle fibers innervated by a single motor nerve
o Muscle fibers intermingled, contract at same time
 Recruitment:
o Definition: Successive activation of the same or additional motor units with increasing
strength of voluntary muscle contraction
o Ways (Can happen concurrently, i.e. both at the same time)
 Spatial recruitment: More motor units
 Temporal recruitment: Increase firing frequency

ELECTROMYOGRAPHY (EMG)

 Function: Diagnostic procedure to access health of muscles and motor neurons

 How: Convert Electrical signals between muscle neurons and muscles to graph/sounds
o EMG signals will be decomposed into Motor unit action potential (MUAP, i.e. electrical
signals from one single motor neuron) for analysis
 Types: Surface EMG, Intramuscular EMG
o Surface: Non-invasive but limited assessment (superficial muscles only)
o Intramuscular: Needle, common diagnostic procedure
In both cases, patient needs to contract muscle (minimal, then increasing strength).
Hence, patient needs to be cooperative and cannot be paralysis
 Analysis of motor unit demonstration :

43
LEARNING OBJECTIVES

 Describe the molecular mechanisms underlying the formation of neuromuscular junctions.

 Explain the pathophysiology of NMJ disorders.
 Explain the relationship between EMG signal and motor unit activation

IMPORTANT POINTS (FOR MORE SEE EXAM FOCUS)

MCQ
Question
Common drug for myasthenia gravis
& effect
Type of ACh receptors in muscles
Changes in ion permeability when
ACh binds to AChR in muscle fibers?
Answer
Tensilon (Edrophonium), acetylcholinesterase inhibitor
(increase ACh level at motor end plate)
Nicotinic (that's why they always stress on Conformational
change. Muscarinic replies on secondary ion transport)
Sodium (Not K and don't mix up with Ca)

SAQ
Question
3 phases of muscle twitch + brief
description
Incomplete vs. Complete tetanus
Explain the pathogenetic
mechanisms of myasthenia gravis
What happens when muscle
constantly depolarized (e.g.
neuromuscular poisons SARIN)?
ACh: Production, Release,
Recycling, Activation
How is ACh produced (Substrate,
Enzyme)
How is ACh degraded (Enzyme,
Products)
Answer
Latent period (for 1. AP propagation; 2. Ca release from SR);
Contraction phase, Relaxation phase
Reduced vs. Eliminated relaxation phase
(initially) Binding of autoantibodies to nicotinic cholinergic
receptors that alters function; (progressively) stimulates AChR
endocytosis hence reduced AChR density. (Late events) Lower
end plate potential  only motor units with less power
activated + less motor units recruited  muscle weakness with
less force
Prolonged depolarization  Zone of electrical inexcitability
around endplates  Flaccid muscle paralysis, decreased motor
response
Refer to above
AcetylCoA(- CoA)+Choline=Acetylcholine; Choline
acetyltransferase
Acetylcholinesterase; Acetate, Choline (recycled)

OTHERS
Questions Answers
3 pathogenic mechanisms of (1) Attract MAC  NMJ structure destroyed (e.g. junctional folds
NMJ diseases gone); (2) AChR dimerized and cross linked  AChR Endocytosed 
AChR density decrease [Myasthenia gravis]; (3) Inhibited AChR
channel property ( cannot signal for muscle activation)
3 serological tests of NMJ ELISA (Color), RIPA (Radioactive), Cell-based (Fluorescence)
diseases

44
Presynaptic & postsynaptic Clustering of vesicles, clustering of AChR (Agrin-LRP4-MuSK)
adaptation of NMJ
Spatial vs. Temporal More motor units vs. increased firing frequency
recruitment
Sarcomere bands A (Thick), H (Thick only), I (Thin only)
Contraction cycle proteins Actin (thin), Myosin (Thick); Troponin (Ca binding), Tropomyosin
(unblocks actin). Titin (Elasticity), Nebulin (aligns actin)
Ca release and uptake Release (DHP+Ryanodine; small external influx), Uptake (SERCA,
small external outflow)

45
MSS12 PHYSIOLOGY AND REGULATION OF SKELETAL MUSCLE CONTRACTION

OUTLINE

1. Important (but old) concepts recap: muscle contraction

2. Sliding filament theory
3. Different types of muscle contractions
a. Types by summation
b. Types by changing lengths
4. Performance capabilities
a. Muscle fibers
b. Physical conditions in training
5. Pathological associations: Exercise associated muscle cramps

IMPORTANT (BUT OLD) CONCEPTS RECAP: MUSCLE CONTRACTION

1. Neural control:
a) Neuromuscular junction
b) Graded and action potential
c) Release of neurotransmitters
2. Excitation-contraction coupling
a) Propagation of action potential
b) Calcium release
c) Actin-myosin interaction
3. Tension production
a) Threshold and maximal stimulation
b) Twitch, summation, tetanus

SLIDING FILAMENT THEORY

 Proteins of sarcomere:
o Main: Actin (Thin filament), Myosin (Thick filament)
o Others: Troponin, Tropomyosin, etc.
o New:
 Nebulin (Within actin): Helps align actin
 Titin (From Z to M line; i.e. collinear with Nebulin): Acts like springs to allow
stretching of sarcomere, stabilizes the myosin core
 Zone of overlap and force of contraction
o Optimal sarcomere length:
 Optimal sarcomere length: Large zone of overlap, largest tension
 Shorter than this: Large zone of overlap, but passed across sarcomere’s center
interfere with normal orientation ∴ less tension
 Longer than this: Reduced zone of overlap, reduced cross-bridge formation ∴
less tension
o In muscle contraction, zone of overlap increases due to power stroke

46
 An unimportant but fancy
diagram… just know the
shape perhaps (a hill with
optimal value)

DIFFERENT TYPES OF MUSCLE CONTRACTION

TYPES BY SUMMATION

 Twitch
o Twitch: Contraction and relaxation by single, isolated stimulus (Independent latent
period; contraction, and relaxation phase)
o Summation leading to unfused tetanus (incomplete tetanus): Reduced relaxation phase
o Summation leading to fused tetanus (complete tetanus): Eliminated relaxation phase
 Latent period: Between stimulus and onset of twitch. For 2 things to happen:
1. Time needed for conduction of action potential
2. Release of Ca ions from sarcoplasmic reticulum

TYPES BY CHANGING LENGTHS

 Types of muscle contraction by changes in length: Isotonic, Isometric

o Isotonic: Muscle length changed (Muscle pulls weight, weight moves). Further classified
into 2 types: Concentric, Eccentric
 Concentric: Muscle length shortens
 Eccentric: Muscle elongates
o Isometric: Muscle length unchanged (Muscle pulls weight, weight doesn't change
because not enough force)

47
One relaxed Isotonic Isotonic Isometric
chilling boi (Concentric) (Eccentric)
Understand: Iso = same, metr* understood as length. Isometric
= length doesn’t change.

PERFORMANCE CAPABILITIES

 Performance capabilities. 2 aspects: Muscle performance, Endurance

o Muscle performance: Maximum amount of tension
o Endurance: Maximum amount of time. 2 subtypes: Aerobic, Anaerobic
 Aerobic endurance: Maximum time supported by glycolysis and existing energy
reserves, e.g. Creatine phosphate.
 Can be increased by frequent, brief and intense workout
 Increased anaerobic endurance accompanied with hypertrophy
 Aerobic endurance: Maximum time supported by mitochondrial activities
 Not associated with hypertrophy
 (A little bit important) Factors determining performance capabilities:
1. Type of muscle (+distribution, +size of muscle fibers)
2. Physical condition or training

TYPES OF MUSCLES

 (old) Classification: Fast (I) vs. Slow (IIB) vs. Intermediate (IIA) TCA cycle, Oxidative phosphorylation
o Type 1 (Slow oxidative): Slow-twitching Fatigue-resistant, TCA+OP (Mitochondria,
Myosin, Capillaries), stained Dark; Postural muscles, Marathon Runners
o Type 2B (Fast glycolytic): Fast-twitching Fatigue-prone, Glycolysis (Rich Glycogen
storage), stained Pale; Fine motors, Bicep and Triceps, Sprinters
o Type 2A (Fast oxidative glycolytic): Fast-twitching
Note: proportion of these muscle fiber type can change with physical conditioning (e.g. athletic
training, e.g. increase intermediate to fast fibers ratio)

Le capillaries

Type I Type IIB 48

PHYSICAL CONDITIONS IN TRAINING

Changes in muscle fibers: Hypertrophy, Atrophy

 Hypertrophy: Increased muscle size
o Mechanism: Increased satellite cell fusion (more myonuclear) + increase protein
(more synthesis, less proteolysis, i.e. protein synthesis per myonuclear)  Increase
fiber size
o Method: Repeated stimulation to produce near-maximal tension (e.g. bodybuilder)
 Atrophy: Reduced muscle size, tone, and power
o Method: Muscle is not regularly stimulated (e.g. spinal cord injury, neuromuscular
disease, e.g. before and after wearing a cast)
o Treatment: Physical therapy, electric stimulation if muscle paralyzed

The more accurate way of understanding it. Additional information.

PATHOLOGICAL ASSOCIATION: EXERCISE ASSOCIATED MUSCLE CRAMPS

 What: Sudden and involuntary contraction; mechanism unknown

 Causes: Inadequate blood supply, nerve compression, mineral depletion
 Prevention: Electrolyte supplementation and hydration, Stretch muscles

LEARNING OBJECTIVES

 Explain what is meant by the sliding filament theory of contraction.

 Compare the different types of muscle contraction
 Relate the types of muscle fibers to muscle performance.

49
MSS13 GAIT

OUTLINE

1. Background
2. Beyond-the-basic backgrounds
a. Prerequisites of normal gait
b. Gait cycle
c. Gait evaluation
3. Abnormal gait patterns
4. Dr. To's conclusion

BACKGROUND

 Basic definitions:
o Gait: Pattern of movement during locomotion
o Limp: Difficulty during walking (irrespective of cause, e.g. muscles, bones, joints, pain
etc.)
 Neurophysiology of gait: involves CNS, PNS, MSS (Many systems)

BEYOND THE BASIC BACKGROUNDS

PREREQUISITES OF NORMAL GAIT

1. Stability in stance: Good stable foot to balance body

2. Sufficient foot clearance during swing: Can lift up leg properly (vs. dragging on the floor)
3. Appropriate swing phase pre-positioning of foot: Ankle lands on foot
4. Adequate step length: le reasonable distance (for efficient walking)
5. Energy conservation: We try to save energy (vs. stiff knee, stroke, energy needed to balance
themselves)

GAIT CYCLE

50
  2 phases: Stance, Swing
o Stance: Double support I, Single support, Double support II
 Double support I: Initial contact, Loading response
 Single support: Mid stance, Terminal stance
 Double support II: Pre-swing
o Swing: Initial, Mid, Terminal
 Note: Stance to Swing phase proportion changes in different activities
o Walking: Stance 60%, Swing 40%
o Running: Stance 40%, Swing 60%, + Double float (both off ground)

GAIT EVALUTION

 Purpose: Gait evaluation  Identify gait pattern (e.g. intoeing)  Work out cause
 History taking (May produce certain gait pattern)
o CNS: Stroke, Cerebral palsy (e.g. birth suffocation), Parkinson’s, Cervical myelopathy
o PNS: Peripheral neuropathy, Injury
o MSS: Muscle weakness, joint contracture, bone deformity
 Physical examination. 2 directions: Kinematics, Kinetics
o Kinematics: Motion (regardless of cause) e.g. Stride
length, Step length, Stride width, Cadence
o Kinetics: Effects of force, torques
 Motion analysis via Gait laboratory

ABNORMAL GAIT PATTERNS

OVERVIEW: TYPES OF ABNORMAL GAIT

 Neurological: Hemiplegic (Unilateral weakness), Spastic diplegic (Spastic lower limbs),

Neuropathic (weakness, e.g. dropfoot), Parkinsonian (Smol steps, stiffness), Choreiform
(Huntington's), Ataxic (Cerebellar disease, just like people who are drunk)
 Others: Antalgic gait (avoiding pain), Myopathic (e.g. Trendelenburg), Short limb gait
 Focus of this lecture: Antalgic gait, Trendelenburg gait, short limb gait

GAIT PATTERNS OF FOCUS

Gait pattern Descriptor
Antalgic Shortened stance phase to avoid pain
Trendelenburg Unilateral weakness of hip abductors (e.g. left gluteus medius)  Shift weight to
contralateral side (e.g. right)  Body swings to the other side (e.g. left) to compensate
(pelvic drop in CONTRAlateral side)
Short limb Compensation for both cases: Long limb (knee bending, Circumduction), Short limb
(Tiptoe)
Cerebral palsy  Cerebral palsy: Due to pre-natal brain trauma; non-progressive
 Common problem: Muscle spasticity  Tiptoeing, Soft tissue contracture  Crouching
 Common gait patterns: Jump knee, Recurvatum knee, Stiff knee, Crouch knee

51
TO’S CONCLUSION
 Movement of the body is a complex process involving multiple systems
 Gait evaluation helps to understand the underlying pathology
 Advances in technology helps with evaluation and treatment for patients with gait
abnormalities
LEARNING OBJECTIVES
 Basic neurophysiology of gait and gait cycle
 Assessment of gait
 Common gait abnormalities
 Gait modifying surgeries in cerebral palsy
IMPORTANT POINTS
Question
Prerequisites of normal gait (5)
What is stride length, step length, and step
width?
Explain abnormal gait patterns esp.
compensations (Antalgic, Trendelenburg, Short
limb, Cerebral palsy
What are the 2 phases of gait cycle
6 Determinants of gait
Changes in CG during gait cycle (Highest, lowest,
curve)
Increase in energy expenditure in wheelchair
For more, please see Exam Focus.
Answer
Stance stability, foot clearance, swing phase
prepositioning e.g. ankle landing, Step length,
Energy conservation
See notes
Antalgic (Shortened stance phase to avoid pain),
Trendelenburg (Weakened hip abductors lead to
dropping pelvis on CONTRAlateral side), Short
limb (Knee bending & circumduction at long
limb; Tiptoeing at short limb), Cerebral palsy
(Muscle spasticity lead to tiptoing' soft tissue
contracture lead to crouching)
Swing, Stance
Horizontal pelvic rotation, Frontal pelvic tilt,
Stance knee flexion, Knee ankle motion, foot
motion, Lateral displacement of pelvis
Highest when single support, Lowest when
double support; Changes: Sine wave vertically &
horizontally
None (i.e. same)
52
MSS14 NEUROMUSCULAR BLOCKING AGENTS AND LOCAL ANAESTHETICS

LEARNING OBJECTIVES

1. When to use neuromuscular blocking agents (NMB) in medical practice

2. How to administer NMB safely
3. How to monitor patients who have received NMB
4. When to use local anesthesia (LA) in medical practice
5. How to administer LA safely
6. How to monitor patients who have received LA
7. Identify LA toxicity and know how to manage it.

NEUROMUSCULAR BLOCKING AGENTS

INTRODUCTION

 When to use neuromuscular blocking agents (NMB) in medical practice: Surgery, Intensive care
(e.g. intubation)
 Types of NMB: Non-depolarizing muscle relaxant (NDMR), Depolarizing muscle relaxant (DMR)
 Pharmacokinetics of NMB
o Drug properties: Highly water soluble, Highly polar  Poor oral bioavailability (i.e. need
IV)
o Doesn't cross BBB, only works on Skeletal muscles (not cardiac, not smooth)
o Patient remains conscious afterwards, only their skeletal muscles relaxes
 Clinical note: Accidental Awareness during General Anesthesia (Uncommon yet severe
traumatic), please monitor patient after NMB [See more later]
 NMB can KILL, DO NOT ADMINISTER if you are not familiar with it (Call an anesthetist)
 2 big types: Non-depolarizing muscle relaxant (NDMR), Depolarizing muscle relaxant (DMR)

NON-DEPOLARIZING MUSCLE RELAXANT (NDMR)

 Examples: Pancuronium, Vecuronium, Rapacuronium, Rocuronium, Atracurium, Tubocuarine,

Mivacurium
 Mechanism: Competitive antagonist of ACh (the other binding site can't open channel)
 Metabolism: (1) Wait (Diffuse from NMJ), (2) Increase ACh (with AChE inhibitors), (3)
Encapsulation by sugammadex
 ACh inhibitors: Neostigmine, Pyridostigmine

DEPOLARIZING MUSCLE RELAXANT (DMR)

 Examples: Succinylcholine (Suxamethonium)

 Mechanism: Binds to Na channels to depolarize  Patient fasciculate, then relaxed
 Plasma cholinesterase / PAChE (Butyrylcholinesterase) [Only 10% reaches NMJ, Neostigmine
decreases PAChE activity profoundly]
 Metabolism: Diffusion (from NMJ)

53
  Side effects: Various (Systemic e.g. HyperK, Bradycardia, Increased intra-ocular, -gastric, -
cranial pressure)

LOCAL ANAETHESIA

 Examples: -caines. Esters (Cocaine, Procaine, Tetracaine, Benzocaine); Amides (Lidocaine,

Prilocaine, Mepivacaine, Ropivacaine, Bupivacaine, Etidocaine)
 When to use: Small & larger surgeries (e.g. dental, Awake brain surgery), invasive procedures
(e.g. lumbar puncture, blood taking, aspiration), even ointments and sore throat lozenges
 Mechanism: (drug hydrogenized after crossing membrane to be trapped) > binds to Na
Channel, No depolarization and AP propagation > Interrupts flow of pain from periphery to
brain
 Metabolism: (1) Plasma absorption, redistributed to inactive sites for excretion (2) Altered pH
(infected = acidic = less effective)
 Side effects: Motor block, Neurotoxicity, Methemoglobinemia (for prilocaine), LAST (See
below. This depending on dose & site of injection, e.g. if you inject in circulation, then RIP).
Please follow LAST guidelines for immediate actions (Symptom monitoring + Lipid emulsion
bolus)
 Notes:
o Small & myelinated fibers blocked more readily (i.e. sensory)
o +Adrenaline (constricts local vessels > increase duration of action BUT avoid giving at
end-arteries e.g. digital. Otherwise Ischemia.)
 Local anesthetic systemic toxicity (LAST)
o Factors for risk: LA-related (Type, Dose), Block-related (Route, Location, Infusion),
Patient related comorbidities (e.g. liver, kidney, pregnancy, pediatrics)
o How to administer safely: All LA carry risk of LAST, so always be aware of LAST: start
from low dosage and cautiously monitor symptoms), Calculate Max dose & choose
injection site wisely (e.g. USG guided if necessary).

54
MSS15 PATHOLOGY OF INFLAMMATORY AND DEGENERATIVE JOINT
DISORDERS

OUTLINE

 Quick recall: Anatomy and Physiology of Synovium and Cartilage

1. Osteoarthritis
2. Rheumatoid arthritis
3. Ankylosing spondylitis
4. Gout
5. Pseudogout
Note. Additional resources:
 Fielding’s notes have many well-organized details for extra read-up

QUICK RECALL: ANATOMY AND PHYSIOLOGY OF SYNOVIUM AND CARTILAGE

SYNOVIUM

 2 types of cells: Type A, Type B

o Type A: Macrophage like
o Type B: Produce ECM

CARTILAGE

 Composition: ECM (Collagen, Proteoglycan) + Chondrocytes

 Property: Compressive stiffness. Hence, chondrocytes produce these substances:
o Stiffness (Framework): Collagen
o Compressible (Spring): Aggrecans (GAG + Hyaluronic acid)
 Functions: Distribute weight over bone surface, lubrication to reduce friction
 Layers of articular cartilage (in zones; out to in):
1. Lamina splendens: Resists tension and substance exchange (Glucose
goes in, but hyaluronic acid cannot escape)
2. Tangential zone: Flat chondrocytes
3. Transitional and radial zones: Normal chondrocytes with stacking
4. Tidemark: Boundary between transitional and calcified layer
5. Calcified cartilage: Chondrocytes with dark staining matrix
6. Subchondral bone

55
OSTEOARTHRITIS

 Background
o Nutrition for chondrocytes and cartilage maintenance: Avascular ∴ depends on synovial
fluid diffusion. Pressure pushes nutrients into cartilage:
 Increased pressure / weight (Overloading) on joint: Nutrient goes in, but
metabolites can't leave  Breakdown > Synthesis  Chondrocyte death
 Reduced pressure/ weight (Underloading in abnormal weight distribution):
Nutrients cannot go in  Breakdown > Synthesis Splitting of cartilage
(Fibrillation: related to Stromelysin!)
 Risk factors: Overweight, poor posture, trauma, occupation
 Pathogenesis of Osteoarthritis:
1. Abnormal loading leading to poor nutrient supply (overload, underload; due to risk
factors: Overweight, poor posture, trauma, occupation)
2. Disturbed regulation of matrix formation by Stromelysin (a type of MMP): Degradation
more than synthesis
3. Repair process that fails to restore the balance
o Remodeling to adapt to abnormal weight (Loss of cartilage, Osteophyte formation,
Subchondral sclerosis, Subchondral cyst; See another chapter for pathological
explanations of the 4 big signs (LOSS) of Osteoarthritis

RHEUMATOID ARTHRITIS

 Pathogenic steps (Quite important):

1. Some sort of virus (unknown mechanism) that triggers immune response
2. Synovial cell triggered by virus to hyperplasia, extroversion of lymphocytes and plasma
cells
3. Fibrin deposition, formation of papillary structures, nodules of lymphocytes, plasma
cells, increased vascularity
 Le important Pannus
o Late event of Rheumatoid arthritis: Formation of granulation tissue (known as Pannus,
literally means wet bread)
o What does Pannus do?
 Grows over to cover the cartilage: Since cartilage are avascular and depends on
the synovial fluid to supply nutrition, growing over it hinders diffusion of
nutrients, hence the cartilage dies
 Erode into subchondral bone and form cyst, followed by attempted remodeling
(Osteophyte formation) and breakdown (Osteoclast)
o End event:
 Ankylosis: Pannus and joint replaced by fibrous tissue (Fibrosis, no articular
cartilage, periarticular bone loss)

56
ANKYLOSING SPONDYLITIS

 Details see other lectures. Highlight of features / Important characteristics:

o HLA-B27
o Calcification and ossification --> Rigidity and increased curvature (Patient
cannot see the sun)
o Intervertebral disk replaced by bone formation (Know the very typical X-ray)
o

GOUT

 Cause: Hyperuricemia (due to increased production e.g. hematic malignancies; or decreased

excretion e.g. renal)
 Important features:
o Inflammation (mediated by inflammasome) + Cardinal features of inflammation is
*important*
o Gouty toufus (Chokey white): Deposition of urate crystals (Needle shape)>
Inflammation (Giant cell reaction) / Erosion of bones (Arthritis; joint deformities,
soft tissue deposition)
 Don’t mix up with Pannus in RA. (Easy to remember: Goat milk cheese = Gouty tofu)
o Giant cell reaction: (Recall IASM) Histiocytes, giant cells
 Location: 1st metatarsophalangeal joint
 Diagnosis: Arthrocentesis + Polarized light = Needle shaped Urate crystals (vs. Rhomboid in
Pseudogout)

PSEUDOGOUT

 Important features: Rhomboid Calcium pyrophosphate, (X-ray) Calcification of menisci

 So important:

57
LEARNING OBJECTIVES

 List 4 histological changes of cartilage with damage

 Provide a salient clinical description of the 5-common arthritis in the general population
 Define osteoarthritis (OA) and correlate the radiological with the pathological changes
 Define rheumatoid arthritis and contrast 3 features between OA and RA
 Describe 5 histological features seen in RA
 List 3 differences between gout with pseudogout and explain the basis for these differences

TEACHER'S QUESTIONS (FROM PROF. NICHOLLS)

Question
1 What cells are present in synovium?
2 What are the components of
cartilage?
3 What makes cartilage unique?
4 What are the 4 problems of OA?
5 What are the radiological features of
OA?
6 What is the difference between OA
and RA?
7 What cells are involved in RA?
8 What is pannus?
9 How does gout present in acute
stage? Why?
10 What radiological features may be
seen in the intermediate form of
gout?
11 How may CPPD present?
12 What is the difference between gout
and pseudogout?
13 Why is CPPD associated with OA?
Answer
Type A and B
Chondrocytes and matrix
Avascular
Abnormal load, upset matrix regulation, inadequate
repair process and remodeling
Loss of joint surface, cyst, osteophyte and subchondral
sclerosis
Age, causality, symmetrical, inflammation, systemic
Macrophage derived, plasma cells, pannus
Vascularized granulation tissue
Sim to acute inflammation
Bone erosion
Acute attack in existing arthropathy. Elderly, Atypical
joints
Crystals, joint location, other conditions.
OA damaged cells release ATP converted to
pyrophosphate.

58
MSS19 BONE STRUCTURE, REMODELING AND REPAIR

OUTLINE

 Background information
 Components of bones and classifications: Bone cells, Membranes, Types
 Osteogenesis, bone remodeling and repair

BACKGROUND INFORMATION

 Divisions of skeletal system: Axial, Appendicular

 Types of bones (By shape): Long (e.g. humerus, phalanges), Short (e.g. trapezoid), Flat (e.g.
Sternum), Irregular (e.g. Vertebra), Sesamoid (e.g. Patella)
 Functions of bone:
o Support (e.g. withstand stress) and protection (e.g. blood vessels, nerve, organs)
o Muscle attachment for movement
o Reservoir of Ca & P
o Harbors bone marrow
 Basic biochemistry.
o Bone: Inorganic (Calcified hydroxyapatite crystal) + Organic (Type I collagen +
Proteoglycans + Glycoproteins), Highly vascular, Appositional growth (Layer by layer)
only
o Cartilage: Collagen Type II (No calcification), Avascular, Appositional & interstitial (from
center) growth

COMPONENTS OF BONES AND CLASSIFICATIONS

TYPES OF BONE CELLS

 Cell types of bones: Osteoblast, Osteocytes, Osteoclast

o Osteoblast: Bone forming (forms organic matrix osteoid & CaP for calcification)
 From osteoprogenitor cells, both surfaces
 Status: Active (Cuboidal / Chubby, High ALP) vs. Inactive (Lining cells, flat, low
ALP).
 When they get trapped in the house they build ('surrounded by newly
synthesized matrix'): Becomes osteocytes
o Osteocytes: Bone maintenance (+Allows fast transit with surroundings for renewal of
matrix)
 Surrounded by lacunae (the bone matrix they make)
 Canaliculi for communication with other cells
o Osteoclast: Bone resorption
 Large, multinucleated cells; derived from monocytes; Acidophilic cytoplasm
(Also fluffy: contains acids and collagenase)
 Lies within Howships lacunae (Bony depression)
 Important features: Ruffled border (Increase SA) + Clear zones

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PERIOSTEUM & ENDOSTEUM

 Periosteum (outer surface), Endosteum (inner surface i.e. marrow). Important features:
o Periosteum: Outer fibrous layer, Inner cellular layer (osteoprogenitor cells); +Sharpey's
fiber for anchoring
 Function: Prevent osteoclast resorption, supply osteoblast, blood vessels in periosteum

TYPES OF BONES

 By arrangement of fibers: Primary vs. Secondary

o Primary: Immature / Woven bones (Random deposition of collagen, temporary)
o Secondary: Mature / Lamellar bones (Organized by osteoclast & osteoblast)
 By gross structure: Compact vs. Cancellous
o Compact: Cortical bone, without cavities.
 Unit: Osteon (Haversian system: Haversian canal; Canaliculi, Volkmann’s;
Lacunae)
o Cancellous: Spongy bone with cavities; forms core.
 Unit: Trabecula (Increase SA for metabolic, red bone marrow and highly
vascular)

OSTEOGENESIS, BONE REMODELING AND REPAIR

OSTEOGENESIS

 Types by origins: Intramembranous, Endochondral

o Intramembranous: Start from membrane, for flat bones. Process: Mesenchymal cells
differentiate to osteogenic cells. In detail:
1. Bone matrix synthesized and mineralized by osteoblast
2. Osteoblast trapped to become osteocytes
3. Surrounding connective tissue becomes periosteum of newly formed bone,
Infiltration of blood vessels
4. Continuous remodeling: Primary becomes secondary, Thickening by
appositional growth
o Endochondral: Start from cartilage, for most other bones (important in elongation of
long bone). Process:
1. Chondrocyte proliferation and hypertrophy, Death of chondrocytes and
calcification of cartilage
2. Remodeling: Calcified cartilage reabsorbed by periosteum, invasion of
osteoprogenitor cells and blood vessels (osteogenic buds). Osteoprogenitor
cells become osteoblast to synthesize bone matrix (the same way discussed
above)
o 5 zones of epiphyseal plate (from epiphyseal side of cartilage): Resting zone
(resting hyaline cartilage); Proliferative zone (Stacked chondrocytes),
Hypertrophic cartilage zone, Calcified cartilage zone, Ossification zone

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BONE REMODELING

 Function: Repair fractures and microdamage’s, Ca homeostasis

 Activity of osteoblast should be balanced with osteoclast

BONE REPAIR FOLLOWING TRAUMA

 Mostly endochondral ossification. Stages:

1. Inflammatory (0-4D): Inflammatory cells, fibroblast infiltration, granulation tissue
(vascular)
2. Reparative (4D-12W): Soft callous (Fibrous), Hard callous (Woven bones
3. Remodeling (3-6M): TO original shape and thickness

(Forget about this, there’s a much better version of Bone Remodeling in another lecture MSS20
Musculoskeletal Trauma.)

LEARNING OBJECTIVES

 Part 1:
o List the functions of bone
o Know the classification of bones by shapes
o Identify the major components of bone
 Part 2:
o Explain the histology characteristics and functions of different types of bone tissue
 Part 3:
o Explain the difference between primary and secondary bones
o Compare the histological structures of the spongy and compact bones
 Part 4:
o Explain the processes of osteogenesis
o Compare the differences between the two types of osteogenesis
o Describe the processes of bone remodeling and repairing

(利申: Not my meme!)

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IMPORTANT POINTS
Question Answer
Types of bones (by Long (Humerus, Phalanges), Short (Trapezoid), Flat (Sternum), Irregular
shape) (Vertebrae), Sesamoid (Patella)
Functions of bones Support, muscle attachment for locomotion, Protection, CaP Reserve &
homeostasis, Harbors bone marrow
Simple biochemistry Bone (Inorganic + Organic components. Inorganic: Calcium hydroxyapatite.
of Bones and Organic: Type 1 Collagen, Proteoglycan + Glycoprotein). Cartilage (Type 2
Cartilage collagen)
Types of bone cells Osteoclast (Breakdown, Fat, not a stem cell but will become osteocyte
when enclosed in matrix.) Osteocyte (Maintenance, Surrounded by lacune &
with canaliculi for communication). Osteoclast (Resorption. Large &
acidophilic, in Howships lacunae, Ruffled border & clear zones)
Types of osteogenesis Intramembranous, Endochondral. Intramembranous (Mesenchymal cells
become osteoprogenitor cells. Progenitor cells becomes osteoblast.
Osteoblast lay down matrix and becomes osteocyte. Osteocytes calcify and
die. Additionally, increase vasculature & Bone remodeling; Appositional
growth.). Endochondral (From cartilage, Chondrocytes proliferate, then
hypertrophy, then calcify and die. Calcified cartilage reabsorbed by
periosteum and invaded by osteoprogenitor cells, which becomes
osteoblast. Increase in vasculature & continuous remodeling.
Primary vs. Secondary Woven (Random arrangement fibers) vs. Lamellar (Organized)
bones
Compact vs. (Cortical bone) Osteon, Haversian system (Canal, Canaliculi, Volkmann's
Cancellous bones lacunae) vs. Trabecula
For more please see Exam Focus.

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MSS20 INTRODUCTION TO MUSCULOSKELETAL TRAUMA

OVERVIEW

1. Injuries
2. Bone healing
a. Process
b. Other important concepts
c. Fracture treatment

INJURIES

 Common injuries. Classified by

o Wound: Closed, Open
 Closed: Severe contusion / Internal deglove, Sprain injury, Closed fracture
 Open: Abrasion, Laceration (need suture), Avulsion, Deglove, Puncture (e.g.
bullets), Bite wounds (Canine, Homo Sapiens)
o Mechanism: Fall, Impact, Crush, Torsion, Blast, Burn, others (Not good since this alone
doesn't imply prognosis & management. This should combine with energy: High, Low.
 High energy: Common in teenagers, highly preventable, Polytrauma.
 Low energy: Normal daily activity in old people, less preventable. Try telling
grandma (e.g. slippery floors)
 More on Bones
o Properties of bone: Anisotropic (Strong in compression, Weak in torsion)
o Fraction patterns (e.g. direction) depends on (1) Force; (2) Direction
o Note: Fracture involves bones AND soft tissues (e.g. muscles, nerves, skin, tendon,
ligament, vessels. Those need to heal too!)
 Fracture: Public Health
1. Injury is a leading cause of death among young, even in HK
2. Young males (High energy) and old females (Low energy; Osteoporosis) have high
fracture risk
3. Low energy injury less preventable than high

BONE HEALING

PROCESS (IMPORTANT)

 Defn.: Body's replacement of destroyed tissue by living tissue. Either by regeneration OR repair
 Processes & Phases: Bleeding, Inflammation, Proliferative, remodeling
1. Bleeding (Hrs): Hematoma, Hemostasis
2. Inflammation (D): VD (Vasodilation) VP(Increase vascular permeability) Exudates,
Growth factors, Cytokines
3. Proliferative (W): Fibroblast, Collagen, non-functional patch. Re-epithelialization. Soft
(fibrous) & Hard (calcified) callus: Widen healing zone for more mechanical stability.
4. Remodeling (M): Rearrange fibers

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  Note: Important growth factors: Insulin-like, Platelet-derived, Transforming, Vascular
endothelial

OTHER CONCEPTS

 Bone healing: Primary vs. Secondary

o Primary isn't bone healing at all. It is just usual remodeling (Cutting cone i.e. Osteoclast
remove, Osteoblast laydown). For microfractures from stress.
o Secondary those above. It happens when there's a gap.
 Requirements of bone healing: [1] Biology (blood supply of O2 and nutrition, Growth factors),
[2] Mechanical stability (micromotion required), [3] Bone contact
 Healing at different tissue is similar. Exceptions: [1] Cartilage heals too, but not hyaline
cartilage. [2] Nerve healing is unpredictable (Depends on injury: Neurapraxia [Days to heal],
Axonotmesis [Months], Neurotmesis [Y/Never: Wallerian degeneration: Axonal sprout may not
be able to penetrate bands of Bungner > Neuroma]
 Adverse factors of healing: Refer to IASM
o Local: Types of wound e.g. Crushing, Inflammation, Foreign body; Blood supply,
Excessive movement; Appositioning (Hematoma), Contraction (Tissue Tethering).
o General: Nutrition, excessive Glucocorticosteroid, Systemic diseases (e.g. DM)
 Complications: Infection; Excessive tissue (Granulation, Keloid), Weak scar (Hernia),
Cicatrization (Stenosis); Painful scars (Neurotoma), Pigmentary change, Wound dehiscence
o Specifically for bones: Malunion / Nonunion

FRACTURE TREATMENT

 Retraction & Stabilization when necessary, Rehabilitation always

o Retraction: Avoid wounds too tight, excessive retraction or dissection; Wound
debridement. Angiogram. Bone shortening for easy healing. Muscle / Skin flap; Bone
graft.
o Stabilization: Casting, External / Internal fixation, External traction
o Rehabilitation (most important): Physical (Prosthesis, physiotherapy), Mental (patient
support groups)

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MSS21 DRUGS FOR THE MANAGEMENT OF GOUT AND OSTEOPOROSIS

LEARNING OBJECTIVES

 Identify the different types of drugs used in the management of gout and osteoporosis
 Identify the mechanism of actions of the three classes of urate-lowering agents
 Recognize the risk of gout flare and identify how to avoid its occurrence
 Compare different categories of drugs used in the management of osteoporosis in terms of
their pharmacodynamics and adverse effect profiles

OUTLINE

 Gout
o Acute
o Long term
 Osteoporosis

Continue on next page…

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GOUT

ACUTE MANAGEMENT: REDUCE INFLAMMATION (ALL ANTI-INFLAMMATORY)

Class Examples Mechanism Side effects & Contraindications; Other notes
Colchicine Inhibit microtubule formation > Application: During attack, prophylaxis
Leukocyte less urate phagocytosis Severe GI, Adjust when comorbid e.g. renal, hepatic. High
& less ILB4 IV dose no longer approved, now oral only at 0.6mg
Typical anti-infl. NSAID Reduce prostanoids Always NOT Salicylates in gout (/with gout history) ∵
(indomethacin) inhibit urate secretion)
Glucocorticoids The usual ones If NSAID not okay (e.g. hepatic renal comorbidities)
Dose tapering needed
Interleukin-1 inhibitors Anakinra, canakinumab, rilonacept

LONG TERM: LOWERING URATE LEVEL (URATE LOWERING AGENTS)

Class Examples Mechanism Side effects & Contraindications; Other notes
Reduce Allopurinol, Inhibits Xanthine oxidase: (Prodrug) [1] Renal stone formation (Patient needs to increase urine
urate febuxostat (non- metabolized by Xanthine oxidase to volume and keep urine pH high);
formatio purine) Alloxanthine (oxypurinol) > Inhibits Xanthine [2] Gout flare (Less plasma urate > Urate leave tissue). Initially
n oxidase, Hypoxanthine and Xanthine less only, avoid by anti-inflammatory drugs
converted to Urate Allopurinol: Hypersensitivity (+Steven Johnson), GIT, Not for
moms and children, Comorbidity adjustment (Renal)
Febuxostat: Comorbidity adjustment (liver)
Uricosuric Probenecid, Increase excretion (by reducing reabsorption Renal stones, Gout flare
agents benzbromarone, of urate at PCT / Proximal convoluted Drug interactions (anions secretion inhibited e.g. penicillin),
lesinurad tubule): Inhibit organic anion transporter not for urate overproduction, comorbidities (Renal), GI, fetal if
(OAT) & urate transporter-1 (URAT-1) in PCT overdose (BBB)
to reduce reabsorption > more excreted Note: effect reduced by salicylates
Uricolytic Pegloticase, Convert urate to soluble allantoin: Gout flare
agents Rasburicase Recombinant urate oxidase > convert urate Side effects: Hemolytic anemia (in G6PD), Allergy, infusion
(Enzymes) to allantoin reaction
Application: Refractory in other therapy (Pegloticase), or High
urate due to anti-cancer therapy (Rasburicase)
Prophylactic regimen: Allopurinol + Anti-inflammatory drugs
OSTEOPORSIS
Class Examples Mechanism Side effects & Contraindications; Other notes
Bisphosphonate (-dronate) [1] Block osteoclast bone - Pyrophosphate analogs, most common treatment esp. risk high
s alendronate, resorption (antiresorptive) - Pharmacokinetics: Poor absorption, take with full glass of water +
risedronate, [2] Increase osteoclast overnight fast
ibandronate apoptosis - Adverse effects: GI, MSS pain, (over-suppression of bone turnover;
drug holiday required)
- Precautions: Children, mom, comorbidities (GI, esophageal, renal)
Denosubmab Mimic osteoprotegerin (OPG): Adverse: HypoCa, allergy, Jaw-bone osteonecrosis & atypical femoral
RANKL can't bind to RANK (on fractures
precursor and osteoclasts' Contraindication: Low Ca, Pregnant
surface) > No osteoclast
formation, no resorption
Parathyroid Teriparatide, [Subcutaneous] Agonize Injection site pain, nausea, HyperCa, Osteosarcoma (<2Y treatment,
hormone (PTH) abaloparatide parathyroid hormone receptors only used in refractories in other treatments), Contraindications in
and Parathyroid on bones >Increase bone comorbid (bone metastasis / radiation, high ALP)
hormone related formation > BMD increase
protein (PTHrP
analogs)
Romosozumba [Subcutaneous] Inhibits Used when intolerant to others
sclerostin > More formation, Arthralgia, headache, insomnia, paresthesia, Hypersensitivity;
less resorption Osteonecrosis of jaw, atypical femur fractures); CVD contraindicated
[AMI, Stroke]
Non-pharmacological management to reduce fracture risk: Weight bearing exercise (increase muscle strength), Ca and VitD intake, no
smoking / alcohol)
HORMONES, MINERALS, AND VITAMINS
Name Mechanism Side effects & Contraindications; Other notes
Estrogen (+Progestin) Receptor >Increase bone Breast cancer and CVD risk (hence only used if patient has vasomotor
mineral density (BMD) symptoms and without CVD risk i.e. risk-benefit assessment + reassessment)
Selective estradiol receptor Estrogen receptor agonist Estrogen therapy alternative (increase venous thromboembolism)
modulators (SERMs) > increase BMD
e.g. Raloxifene
Calcium Mechanism: suppress bone remodeling > Increase BMD
Vitamin & its analogs: Improve Ca absorption, HyperCa, hyperCaU / hypercalciuria

67
Cholecalciferol (Vitamin D3), Suppress parathyroid
Calcitriol function for bone
remodeling > Increase
BMD
Calcitonin Bind osteoclast to reduce Parenteral / Nasal: Nausea, injection site reactions, nasal discomfort &
bone resorption > Increase epistaxis
BMD

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MSS22 ANATOMY OF THE SPINE

OUTLINE

1. Background
2. The vertebrae
3. Muscles of spine
4. X-ray

BACKGROUND

 Vertebral column
o 33 Vertebrae, in 5 regions: C7, 12T, 5L, 5S, 4Co
o CT movable, LS immobile (S fused: Sacrum)
o Function: Support body and head, house and protect spinal cord, maintain upright body
 Vertebrae:
o Composition: Body, Arch (Pedicles and laminae), 7 process (1 spinous, 2 transverse, 2
superior articular, 2 inferior articular)
o Articular process forms Foramen. Foramen:
 Vertebrae foramen: forms vertebral canal (for housing spinal cord)
 Intervertebral foramen: for Spinal nerve roots & ganglion

THE VERTEBRAE

 Cervical: Transverse foramen (for vertebral artery), Bifid spinous process (but vertebra
prominens at C7), Wide degree of movement (Vertebral disk ratio big). Atypical:
o C1 (Atlas): No body, no spinous process; instead ring shaped (2 Lateral + A&P arches).
Superior articular forms atlantooccipital joint; Vertebral artery behind
o C2: Dens (odontoid process) for pivot (lateral rotation), 3 atlantoaxial joint (Pivot,
articular facets).
o C7: Has transverse foramina (like C) but long &non-bifid spinous process (like T)
 Thoracic: Heart shaped body, costal facets & all transverse processes articulate with rib.
Spinous long and slender.
o T1: Transverse process articulates with rib alone (not with C7)
o T11, T12: Does not articulate with transverse process
 Lumbar: Kidney shaped (big), Pars interarticularis, No rotation (sagittal articular process).
Spinous short and sturdy.
  Sacrum: Wedge shaped. 4 pairs of Sacral foramina (Anterior, Posterior). Sacrum bone sitting.
 Coccyx: Wedge shaped and fused.

OTHER THINGS

 Curves of vertebral column. 4 natural curvatures

o Kyphosis (Primary): Thoracic, Sacral
o Lordosis (Secondary): Cervical, Lumbar
o vs. Clinical conditions: Scoliosis (Lateral deviation), Kyphosis (Humpback), Lordosis
(Swayback)
 Intervertebral disk. Components: Anulus fibrosus, Nucleus pulposus
o Anulus fibrosus: (Fibrocartilage) Concentric lamellae
o Inner nucleus pulposus: Collagen proteoglycan hydrated gel, absorb shock & permits
movements
o Disk herniation: Degenerated annulus fibrosus  Nucleus pulposus herniates into
spinal cord  Pain
 Ligaments of Vertebral column
o Function: Withstand mechanical loads & shearing stress, limits range of movement
o Including: Anterior & Posterior longitudinal ligament, Ligamentum flavum,
Intertransverse ligament, Interspinous ligament, Supraspinous ligament
 Intervertebral joints: Cartilaginous (Disk / Symphysis), Synovial (Other facets)
 Movements: Flexion, extension, Lateral, Rotation only at upper body (Sagittal arrangement of
lumbar process)

MUSCLES OF SPINE

 Function: Posture, Movements

 Innervation: Posterior rami of spinal nerves
 Extension. Intrinsic back muscles: Superficial, Intermediate, Deep layer
o Superficial: Splenius capitis (head), Splenius cervicis (neck) [Head & Neck movement]
o Intermediate: Erector spinae / Sacrospinalis (Iliocostalis, Longissimus, Spinalis)
o Deep: Transversospinalis, Interspinales, Intertransversarii, Levatores costarum
 Flexion:
o H&N: longus coli, scalene, sternocleidomastoid

70
 o Trunk: Rectus abdominis, Psoas major

X-RAY ASSESSMENT

 Inspection: Anterior, Posterior vertebral line, Posterior edge of vertebral arch, Spinous process
line
 Scottie dog (See image)

Superficial Intermediate Deep

Flexors of Head and Neck Flexors of trunk X-ray lines

71
 1. Transverse process
2.Pedicle
3.Superior articular process
4.Pars interarticularis
5.Lamina
6.Inferior articular process
7.Spinous process
8.Interlaminar space
9.Intervertebral disc

LEARNING OBJECTIVES

 Describe the main anatomical features of vertebrae column, individual vertebrae and
intervertebral disc.
 Compare functions of vertebrae in relation to their structures.
 Identify the principal muscles and ligaments of the vertebral column.
 Explain their roles in stability and movement of the vertebral column.
 Interpret basic radiographs of the spine.

FEW POINTS TO NOTE

 Most frequent level involved in lumber degenerative disc disease: L4-L5

[M17 2nd Summative] A 60-year-old man has neck pain due to a herniated disc between 5th and 6th
cervical vertebrae. Which cervical nerve root(s) is/are compressed?
A. 4th cervical neve root
B. 5th cervical neve root
C. 6th cervical neve root
D. 7th cervical neve root
E. 7th and 8th cervical neve roots
Ans: C

[M21 2nd Summative] For a patient with far lateral prolapse at intervertebral disc between 4th and
5th lumbar vertebrae, compressing on intervertebral foramen of L4/L5, which spinal level will be
compressed?
A. L2
B. L3
C. L4
D. L5
Cervical: Nerve goes above
E. S1
The rest: Nerve goes below
Ans: C

72
MSS23 INTRODUCTION TO SPINAL CORD/ NERVE COMPRESSION DISORDERS

OUTLINE

1. Terminology
2. Anatomical note
3. Pathologies

TERMINOLOGY

 Spinal cord: Part of CNS, lesion causes spasticity below affected area ∵upper motor neuron (See
HNS)
 Nerve root: Part of PNS, Lesion causes hypotonicity ∵lower motor neuron (See HNS)
 Cauda equina: Lumbar spine, lower motor neuron. Lumbar sacral nerve roots, anatomical
 Claudication: Numbness, severe pain (e.g. burning), lower neurological deficit, sphincter
problem. Neurogenic vs. vascular (both leads to numbness, but different onset & area e.g.
dermatome vs. muscles). [A PBL LO]
 Sciatica: Along sciatic nerves. Nerve root irritation. Regardless of cause e.g. disc herniation
 Radiculopathy vs. Myelopathy: Nerve root dysfunction vs. spinal cord. Lower vs. Upper motor
neuron. Pain, numbness vs. Proprioception, weakness generalized in peripheries

ANATOMICAL NOTE

 Lumbar
o The spinal level of the central canal is a bit higher than the peripheral ones (e.g. at the
same cross section if L4 is leaving the foramina, the central canal contains S1)
o The nerve leaving the foraminal follows the one above (i.e. pedicle)
 Cervical spine:
o 5 articulations (Disk, 2 uncovertebral, 2 facet); Dorsal & ventral ramus
o 7 vertebrae but 8 nerve roots
 Neuroanatomy: descending tracts are motor, ascending tracts are sensory

 Blood supply to spinal column: Anterior + Posterior (x2) + Radicular (varied)

o Anterior spinal artery: Formed by 2 vertebral artery; midline lies on anterior median
fissure.
o Posterior spinal artery (uncommon): Formed by posterior inferior cerebellar artery /
vertebral artery.
o Radicular: (Largest) Artery of Adamkiewicz.

73
PATHOLOGIES

 History taking: Pain, Numbness (know dermatomes), Weakness (know myotomes), Balance (may
be due to poor proprioception, severe weakness), Sphincter control (Bowel, bladder)
 Compression related:
o Causes: Disc herniation, Osteophyte, Joint hypertrophy (e.g. facet), Ligament ossification /
Hypertrophy (e.g. Ligamentum flavum, Posterior longitudinal ligament)
o Diseases
 Lumbar spinal stenosis: Dural sac and nerve root compression. Lateral (Compress
exiting & Transversing root), Central (Transversing), Foraminal (Exiting)
 Cervical Myelopathy (Spinal cord)
 Facet dislocation ( Injury Spinal cord)
 Central cord syndrome: Due to trauma existing stenosis e.g. arthritis. Elderly.
Weakness arms more than legs
 Brown-Sequard syndrome: ipsilateral weakness and position sense loss,
contralateral pain and temperature loss. Good prognosis. (See HNS)
 Ischemia-related (See HNS)
o Anterior cord syndrome: Motor and sensory loss, poor recovery
o Posterior cord syndrome: position sense loss, better prognosis than anterior cord syndrome
o Thoracic cord: Susceptible, limited anastomosis, largest radicular artery: artery of
Adamkiewicz
 Spondylodiscitis
o Hematological spread to the endplate most common
o TB (vs. pyogenic): Multiple levels & skip lesion, more bony involvement (vs. displaced),
subligamentous spread
o Pathology: Start infecting vertebral end plate  Inflammation & Necrosis  Collapse 
Spread to adjacent disc & vertebra (Paravertebral & Epidural abscess)  Infect meninges &
Spinal cord
 Spinal metastasis
o Venous plexus spread (Batson: Tumor e.g. prostate cancer goes pelvis to spinal cord /
'metastatic embolization': Valveless veins with many anastomoses)
o Winking owl sign (though only when 30-50% destroyed); Compressed
vertebral column compresses spine
o Pathways: Breast (via Azygous), Lung (via Pulmonary vein), Prostate (via
Pelvic plexus)
o Surgery is an adjunct to oncological treatment

LEARNING OBJECTIVES

1. List common presentations of spinal cord/nerve compression disorders

2. Recognize the pathological changes in the disc anatomy in degenerative disc disease
3. Understand the basic anatomy in treatment of spinal cord/nerve compression disorders
4. Explain the etiology of spinal infections and metastatic disease using pathoanatomy

74
MSS24 NON-OPIOID ANALGESICS

OVERVIEW

1. Acetaminophen
2. Traditional NSAID
3. Selective COX-2 inhibitors NSAID

SUPPLEMENTARY KNOWLEDGE THAT DOESN’T FIT IN TABLE

 Immune defense:
o Pathogen > Receptors (Dendritic, Macrophage) > Cytokines (TNFa, IL1) > VD
(Vasodilation) VP (Vascular permeability) increase (Provide WBC and materials to war),
Express more adhesion molecules (for WBC diapedesis); Other cascades e.g.
Complement (Histamine, Phagocytosis); Coagulation, Fibrinolytic , Kinin (Bradykinin:
VP, Pain, Eicosanoids & NO for VD)
o Immune: positive feedback for more inflammation
 Types of Traditional NSAIDS & Special characteristics summary
1. Salicylates (Aspirin, diflunisal)
 Aspirin: Cheap, Safe, good for CVD comorbid, but GI disturbances
 Diflunisal: Strong AntiInflam, less toxic, but can't help fever
2. Propionic Acids (ibuprofen, naproxen): COX2 selective, Less toxic.
3. Acetic Acids (indomethacin, sulindac)
 Indomethacin: Super AntiInflam, More toxic (other mechanisms)
 Sulindac: Long T.5
4. Oxicams (piroxicam): Long T.5
5. Fenamates (meclofenamic acid)
 Other information
o COX 1 for GIT physiology, COX 2 induced by inflammatory stimulus. Higher COX2
binding= Larger effect + Less GID
o IC50: Concentration of drug required to inhibit 50% of receptors. Lower = more
selective.
 Choice of NSAID: considers Efficacy (Ibuprofen>Aspirin), Safety (e.g. GI comorbid), Cost-
effectiveness (Celecoxib>Aspirin), Individual differences (e.g. hypersensitivity, therapeutic
trial). Don't combine NSAID!
 Algorithm: Evaluate GI and CV risk. Low: traditional. High CV risk: Naproxen with PPI (Proton
pump inhibitor). High GI risk: COX2 Inhibitor with PPI. Avoid NSAID if possible.

LEARNING OBJECTIVES

 Describe the three main classes of non-opioid analgesics and their clinical usages
 Identify how NSAIDs produce their therapeutic effects
 Explain the adverse effect profile of traditional NSAIDs and their limitations
 Compare different categories of NSAIDs in terms of their pharmacodynamics,
pharmacokinetics and adverse effect profile

75
TABLE
Class Examples Effects Mechanism Adverse/ ContraInd.
Acetaminophen Analgesic, Inhibits prostaglandin Adverse: Safe (Minor allergies). Overdose: Hepatorenal toxicity
Antipyretic, synthetase > less CNS [Mechanism: Metabolized to toxic intermediate NAPQI > Usually
but no use prostaglandin (Raise conjugative by GSH to non-toxic, but if high dose uses up GSH then
if inflam. Pain threshold, hepatoxicity & renal toxicity. +Frequent use will deplete GSH  Asthma).
thermo set point) Toxicity prone: Alcohol (less COX), Fasting (GSH depletion)
N-acetylcysteine can conjugate with toxic intermediate to prevent toxicity
Traditional See above AntiInflam, Inhibit COX1&2 > less 1. GI Damage (Increase acid; Decrease mucus secretion > Hemorrhage).
NSAIDS Analgesic, prostanoids: 2. Bleeding (Inhibit Thromboxane A2 production, less aggregation; esp. for
Antipyretic 1. AntiInflam: Less VD aspirin i.e. irreversible COX inhibition & platelet cannot make new COX [8-
& VP; 10 days till platelet turnover]);
2. Analgesic: Less 3. Hypersensitivity: Skin reactions, Asthma (more Leukotrienes)
pain sensitization
(Bradykinin, but not Contraindication:
visceral pain), (1) Bleeding: PU (/glucocorticoid), Late pregnancy / Surgery (discontinue
3. Antipyretic: Lower 2W prior), Elderly, Drugs (blood thinner, Protein binding drugs);
set-point at (2) ACEI (HyperK);
hypothalamic (3) Other NSAIDs (patient may not know these are NSAIDs)
thermoregulatory
center
Salicylates Note: Higher concentration needed for anti-inflammation. Even higher concentration in intoxication (e.g. Tinnitus,
respiratory failure).
Contraindications: (1) Children (Reye's syndrome), (2) Gout! (3) Clotting problems (e.g. Hypoprothrombinemia /
VitK), (4) CVD & Renal except aspirin (VD). (5) Drugs (Uricosuric agents, Penicillin)
Selective (-coxib) Same as Traditional NSAIDS Adverse: Good: No GID, no Platelet. But renal insufficiency, CVD blackbox
COX2 Celecoxib, (AntiInflam, Analgesic, Antipyretic) for non-selective COX2Inhibitor i.e. Naproxen, Diclofenac. [Note
inhibitors Etoricoxib mechanism: Platelet reaction. COX1 produce TXA2 (for platelet
, aggregation), but prostacyclin PGI2 (by endothelium) inhibits adhesion.
Rofecovib [i.e. when wound, endothelium break, TXA2 more than PGI2, hence clot].
In some patients, COX2 also produce PGI2, inhibit COX2 leads to clotting >
CVD.]

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MSS25 MOLECULAR AND GENETIC ASPECTS OF SKELETAL DISORDERS

OUTLINE

1. Introduction
2. Osteogenesis imperfecta
3. Marfan
4. Summary

INTRODUCTION

 Development of bone: Proliferation (at Reserve zone)  Hypertrophy  Endochondral

ossification: Type X collagen to mineralize  Degenerated by osteoclast and replaced with
bone (Collagen I)
 Osteochondysplasias:
o Disorders that affect the epiphysis, metaphysis or diaphysis of bones
o Collagen disorders: Mutations in collagen production. Affects different tissues (e.g.
Type I Bone, Type 2 Cartilage, Type 3 Skin & arteries, etc.)

OSTEOGENESIS IMPERFECTA

BACKGROUND

 Clinical: Fragile & Brittle bone, Deafness ,Hypermobility of joints, Tendon rupture. Special
feature: Blue sclera (from their densely vascular choroid); Tubulation of fibula & tibia.
 Classification: Clinical & Inheritance (I: Mildest; II: Most severe & Perinatal lethal; III & IV:
Wheelchair bound, depend on whether blue sclera) [V (Special): Hyperplastic callous in repair]
 Mostly autosomal dominant (Recessive rare) [Newer classification includes recessive forms &
enzymes involved in collagen modification]

OSTEOGENESIS IMPERFECTA: GENETICS

 Original: Sanger COL1A1 and COL1A2 (Skin sample) [Now no use Sanger, NGS allows
screening of more (i.e. 22) genes implicated]
 Caveats:
o Gene panel testing: Can miss larger indels, Structural variants and non-coding variants;
new disease genes not in panel may not be detected.
o Whole genome sequencing solves these but is less cost-effective

 Types of Point mutation: Missense, Nonsense (Stops too early; destroyed by nonsense
mediated mRNA decay; T1OI), Promotor or Enhance (Changes expression)

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OSTEOGENESIS IMPERFECTA: COLLAGEN BIOSYNTHESIS

 Normal:
o Prototype of collagen: 2AlphaI, 1Alpha II; Both C- and N- propeptides would be cleaved.
Each 3rd AA is glycine (Gly-X-Y) for helical turn; some Proline (for intramolecular) &
Lysin (intermolecular) undergo glycosylation for stability (H bonds > Cross links).
o Translated by Ribosome and Assembled in ER, single peptides cleaved and zipped at C
terminal, post-translational modification (e.g. hydroxylation which requires ascorbic
acid) > Golgi
o Outside cell: (Assemble fibrils) intramolecular cross linking by lysine oxidase
 In Osteogenesis imperfecta. Glycine mutations:
o Since glycine is responsible for turns, glycine mutations are generally more severe than
X Y mutations (Gly-X-Y)
o Mutations at C-terminal more severe than N. Since assembly starts at C, mutations
close to C > More time in formation till triple helix, overmodification

Dominant negative
 Mutant chain has a negative impact on normal chain, giving an abnormal molecule > (Matrix
assembly) Cross links compromised, weak structure and bones
 Impaired secretion adds another negative effect in OI (Loss of function mutations i.e. only one
copy)

TREATMENTS OF OI

 Surgical
 Bisphosphates (Having inferior bone better than not having enough; Reduce osteoclast activity)
 See more in pharmacology lecture later

MARFAN

 Cause: Overactivation of TGFβ due to Fibrillin 1 mutation. (+ECM interaction)

o TGFβ is a latent protein. TGFβ + Latency associated peptides (LAP); trapped in Large
latent complex (LLC) in ECM.
o TGFβ is activated by Furin. e.g. when Mechanical strain. Fibrillin 1 also part of the
activation pathway.
 (Other examples ECM importance: Asporin, CLIP also regulates TGFβ signaling, these are genetic
risk factors for some degenerative MSS diseases (e.g. OA, Disc degeneration))

GENERAL PARADIGM / SUMMARY

 ECM affects structural & developmental roles

 Loss of function mutation leads to reduced expression (i.e. 1 functional allele) but less severe
 Dominant negative (Normal + Structurally mutated collagens) more severe

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LEARNING OBJECTIVES

 Lessons learnt from mutations causing skeletal malformations

o Loss-of-function and dominant-negative mutations in ECM components
o Consequence in relation to biosynthesis and structural function
 Molecular defects in osteochondrodysplasias
o Osteogenesis imperfecta (OI)
 Interplay between ECM and signaling molecules
o Marfan syndrome
o Common degenerative disorders

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MSS26 MOLECULAR MECHANISM OF BONE DEVELOPMENT

OUTLINE (PROVIDED BY PROFESSOR)

 Processes in bone development: Morphogenesis, Organogenesis, Growth
 What genes are involved?
 What happens when these genes are defective?
 Molecular and clinical outcomes
 Gain-of-function mutations as a disease mechanism

OVERVIEW

 Process of bone development:

o Development of tissues: Lateral plate mesoderm makes skeletal tissue, somite gives
nerves, blood vessels, muscles
o Alignment: Stylopod (Scapula), Zeugopod (Radius and ulnar), Autopod (Carpels,
Metacarpals, Phalanges)
o Outgrowth and patterning:
 FGF signal for Proximal Distal patterning.
 Hedgehog signaling for anterior-posterior patterning.
 WNT for Dorsal Ventral patterning.
 General framework of development. Steps:
1. Migration (of mesenchymal cells to site);
2. Cell interaction (between mesenchymal cells and epithelial basement membrane);
3. Condensation (of mesenchymal cells);
4. Differentiation (Chondrocytes/ Osteoblasts).
 2 types of ossification:
1. Intramembranous ossification (Mesenchymal > Osteoblast): For most craniofacial
bones
2. Endochondral ossification (Mesenchymal > Chondrocytes > Cartilage > Bone): Axial &
Appendicular bones

MORPHOGENESIS: GENES INVOLVED & MECHANISM

Gene Function Mechanism Pathological (+Notable symptoms)
RUNX2 - Master regulator for osteoblast differentiation Cleidocranial dysplasia (LOP
(controls differentiation of mesenchymal > mutations in RUNX2 leads to bone
osteoblast). abnormalities e.g. aplastic clavicles,
- Expression of bone required specific ECM. delayed closure of cranial suture).
SOX9 - Regulations chondrogenesis (controls Campomelic dysplasia (Bowing of
differentiation of mesenchymal > Chondrocytes). bones, sex reversal).
- Required for expression of cartilage specific
ECM (e.g. Collagen 2).
(Early activation of SOX9 is required for
osteochondroprogenitor generation; i.e. both
bone and cartilage need)

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ORGANOGENESIS: GENES INVOLVED & MECHANISM

 Limb patterning: Cartilages are formed as continuous rods > Bifurcations + Segmentation +
Cavitation forms joints, ligaments, synovial membranes, meniscus etc.
 Anterior & Posterior patterning to determine skeletal elements (e.g. number of digits):
Determined by Hedgehog (morphogens, meaning function based on concentration)

Gene Function Mechanism Pathological

(+Notable
symptoms)
Hedgehog Different 2 components: Sending & Receiving cells Greig cephalon-
s concentrations  Sending: Hh produced as precursor, polysyndactyly
give different signaling group cleaved and cholesterol syndrome:
results (e.g. group added as end terminal (Impaired
different cell  Receiving: Ptc (receptor), Smo number &
fate). Far away (Transducer). identity of
= lower Ptc constantly suppresses Smo, hence Gli acts as digits) e.g.
concentration = repressor of gene expression. When Hh is many digits,
different cells synthesized and secreted, it binds to Ptc to fused digits
release inhibition on Smo, unknown mechanisms
and Gli becomes transcription activator

GROWTH: GENES INVOLVED & MECHANISM

Endochondral bone formation: Center chondrocytes hypertrophy (forms primary ossification center) >
Cartilage mineralization, vascular invasion; + Osteoclast/blast activity (becomes bones) > Formation of
growth plate (End cartilage retained).  Main point: Chondrocyte proliferation is an important event!

Gene Function Mechanism Pathological (+Notable

symptoms)
FGFs (In normal 1. FGF binds to FGFR3 receptor Achondroplasia (more common,
(Receptor places: > Dimerization > G380R mutation),
tyrosine mitogenic, Phosphorylates STAT1 to Hypochondroplasia,
kinase, here:) Suppress STAT1P Thanatophoric dysplasia.
requires chondrocytes 2. STAT1P activates p21(CIP1) Commonly presented as
heparan proliferation > Binds to CDK2&4 to inhibit dwarfism. Cause: FGFR3 (Gain of
sulphate (i.e. opposite to Cyclin D- and E- dependent function mutation):
proteoglycan FGF) kinase activity > Inhibit G1 to Phosphorylates STAT1 etc. (See
as co-factor.) S, no chondrocyte above)1
proliferation, no growth
PTH, PTHrP, Stimulates - Ihh: Expressed by - Mutation in PTH1R: Loss
PTH1R; chondrocyte prehypertrophic chondrocytes. inhibition on hypertrophy, cells
Indian proliferations, - Short range: Stimulates enter hypertrophy earlier than
hedgehog prevents chondrocytes proliferation they should > Number of cells for
(Ihh) chondrocytes - Long range: Stimulates proliferation decreased >
1
Gain of Function mutations, aka. ligand independent activation: Usually, ligand Binding & receptor
Dimerization  Stable and function longer time. Mutations occur so that dimerization forms even
without ligand (disulphide bonds) / active even without dimerization.

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 hypertrophy. PTHrP activation at
periarticular region > Diffuse
back to prehypertrophic
chondrocytes where PTH-1R is
located > Activate signals
suppressing hypertrophy
(negative feedback, controlled
about of Ihh produced)
Retarded bone growth. Similar
for mutation in ligand.
- Excessive PTHrP signaling (e.g.
too much ligand, receptor
regulation): More time in
proliferation, less in
differentiation > More cells but
less conversion to bone >
Insufficient mineralized cartilage
for bone formation > Dwarfism

SUMMARY (PROVIDED BY PROFESSOR)

 Key molecular signals regulating limb patterning in development

o Concept of morphogen gradient regulating cell fate (Indian Hedgehog)
 Key transcription factors initiating chondrogenesis (Sox9) and osteogenesis (Runx2)
 FGFR3 in bone growth (negative regulator) and pathology
o Concept of gain-of-function mutations and disease outcomes
 IHH/PTHrP negative feedback loop regulating bone growth

LEARNING OBJECTIVES

1. Processes in skeletal development

2. Role of key transcription factors in skeletal morphogenesis and growth
a. Runx2 for osteogenesis
b. Sox9 for chondrogenesis
3. Key signaling pathways skeletal patterning and bone growth
a. Morphogen gradient: Hedgehog signaling
b. Fibroblast growth factors (FGFs)
c. A negative-feedback loop between Indian Hedgehog and PTHrP signaling

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SUMMARY TABLE
Gene Function Mechanism Pathological (+Notable symptoms)
Morphogenesis
RUNX2 - Master regulator for osteoblast differentiation (controls differentiation of Cleidocranial dysplasia (LOP mutations in RUNX2 leads to
mesenchymal > osteoblast). bone abnormalities e.g. aplastic clavicles, delayed closure of
- Expression of bone required specific ECM. cranial suture).
SOX9 - Regulations chondrogenesis (controls differentiation of mesenchymal > Campomelic dysplasia (Bowing of bones, sex reversal).
Chondrocytes).
- Required for expression of cartilage specific ECM (e.g. Collagen 2).
(Early activation of SOX9 is required for osteochondroprogenitor generation; i.e.
both bone and cartilage need)
Organogenesis
Hedgehogs Morphogens: 2 components: Sending & Receiving cells Greig cephalon-polysyndactyly syndrome: (Impaired number
Different conc.  Sending: Hh produced as precursor, signaling group & identity of digits) e.g. many digits, fused digits
gives different cleaved and cholesterol group added as end terminal
results (e.g.  Receiving: Ptc (receptor), Smo (Transducer).
different cell fate). Ptc constantly suppresses Smo, hence Gli acts as repressor of
Far away = lower gene expression. When Hh is synthesized and secreted, it
conc. = different binds to Ptc to release inhibition on Smo, unknown
cells mechanisms and Gli becomes transcription activator
Growth
FGFs (Receptor (In normal places: 1. FGF binds to FGFR3 receptor > Dimerization > Achondroplasia (more common, G380R mutation),
tyrosine kinase, mitogenic, here:) Phosphorylates STAT1 to STAT1P Hypochondroplasia, Thanatophoric dysplasia. Commonly
requires heparan Suppress 2. STAT1P activates p21(CIP1) > Binds to CDK2&4 to inhibit presented as dwarfism. Cause: FGFR3 (Gain of function
sulphate chondrocytes Cyclin D- and E- dependent kinase activity > Inhibit G1 to S, mutation): Phosphorylates STAT1 etc.
proteoglycan as proliferation (i.e. no chondrocyte proliferation, no growth
co-factor.) opposite to FGF)
PTH, PTHrP, Stimulates - Ihh: Expressed by prehypertrophic chondrocytes. - Mutation in PTH1R: Loss inhibition on hypertrophy, cells
PTH1R; Indian chondrocyte - Short range: Stimulates chondrocytes proliferation enter hypertrophy earlier than they should > Number of cells
hedgehog (Ihh) proliferations, - Long range: Stimulates PTHrP activation at periarticular for proliferation decreased > Retarded bone growth. Similar
prevents region > Diffuse back to prehypertrophic chondrocytes where for mutation in ligand.
chondrocytes PTH-1R is located > Activate signals suppressing hypertrophy - Excessive PTHrP signaling (e.g. too much ligand, receptor
hypertrophy. (negative feedback, controlled about of Ihh produced) regulation): More time in proliferation, less in differentiation
> More cells but less conversion to bone > Insufficient
mineralized cartilage for bone formation > Dwarfism

83
SUMMARY

Yuen Yuen

[M18 2nd Summative]

Q88: FGFR3 mutation in cartilage lead to reduced proliferation. What type of mutation is
FGFR3 mutation?
A.
B. Loss of function
C. Dominant-negative
D. Gain-of-function
E. Haploinsufficiency

Ans: D
[M19 2nd Summative]
Q99: Mutations in FGFR3 can cause achondroplasia, a dwarfism condition in humans. In which
of following zones of cartilage in a growing long bone would mutations have an impact on?
A. Articular
B. Hypertrophic
C. Prehypertrophic
D. Proliferative
E. Reserve
Ans: D
[Repeated] In growth plate, Indian Hedgehog (IHH) and parathyroid hormone-related protein
(PTHrP) signalling pathways form a negative feedback loop in control of chondrocyte
proliferation and hypertrophy, regulating linear growth of long bones.
(a) Which cell type in growth plate normally expresses IHH? (1 mark)
(b) In the growth plate, IHH signals to immediate or nearby chondrocytes. What would be the
response of these chondrocytes? (1 mark)
(c) IHH signalling also activates the expression of PTHrP at a distant site. Which region of the
cartilage tissue expresses PTHrP? (1 mark)
(d) PTHrP signals through its receptor (PTHrP-R). Which cell type in the growth plate expresses
this receptor? (1 mark)
(e) How does this feedback by PTHrP control the level of IHH? (2 marks)
(f) For loss-of-function mutations in either the PTHrP-R or PTHrP gene, what would be two
compounding cellular effects that lead to reduced bone growth and dwarfism? (4 marks)
Ans:
(a) Pre-hypertrophic cells
(b) Increase proliferation via PTC
(c) Peri-articular region
(d) Pre-hypertrophic cells
(e) Pre-hypertrophic cells release Ihh. Ihh diffuse far away to bind stimulate PTHrP
expression. PTHrP diffuse to pre-hypertrophic cells to bind to PTH1R, which suppresses
differentiation and hypertrophy. Less hypertrophy, more proliferating cells, less Ihh
(negative feedback). Also, meaning more cells but less calcified to form bones. Less bone
formation, dwarfism.
(d) Loss-of-function of PTHrP or PTH1R, less suppression by pre-hypertrophic cells on
hypertrophy, meaning more hypertrophy & differentiation, less proliferation. Leading to
premature hypertrophy & differentiation but less cells (thin growth plate), hence reduced
bone growth & dwarfism.

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MSS27 LIVING WITH CHRONIC ILLNESS

OUTLINE

1. Chronic illness
2. Disability
3. Impact on individuals & society

CHRONIC ILLNESS

 Definition: Long term (3-6M), usually non-reversible, onset sudden (e.g. SOB) or gradual,
mostly non-communicable (except for some e.g. HIV, Hepatitis)
 5 major types: CVD (incl. stroke), Cancer, Chronic respiratory, Diabetes, Others (e.g. visual
impairment, arthritis, etc.)
 Treatment: often palliative (Non-cure)
 Patient characteristics:
o High uncertainty (since unknown flair / recurrent).
o Need to take more active role in managing disease (e.g. adherence, lifestyle
modification)
 Prevalence: Hong Kong situation: Over 2 million (31%), increasing trend, commonly
hypertension, diabetes, heart disease. Mostly aged 65+ (more multi-morbidity), More
female > male. Mostly economically inactive (e.g. retired, homemakers).
 Factors to increase in chronic illness: Better medical care (survive through acute stage,
health screening improves prognosis), Aging population, change in lifestyle (e.g. diet,
sedentary TV / Internet), change in living environment (e.g. air pollution)

DISABILITY

 3 components of Definition: Impairment, activities, restrictions

 Impairment is based on medical model; Activity & Restriction is based on psychosocial
 E.g. short sightedness is an impairment, but activity limitation is totally compensated by
eyeglasses. Participation restriction is limited, but we may be denied some fields of work).
 I.e. Impairment doesn't need to be a restriction if society helps overcome the impairment.
Hence disability isn't just an individual's problem, Disadvantages + Deprived =
Opportunities that a person missed because of barriers in the environment (?)
 Prevalence: 500,000 with disability (e.g. restricted body movement, seeing, hearing,
speech, diagnosed with mental disorders e.g. autism); increasing trend. Restricted body
movement most common. Mostly 70+, more female.

IMPACT OF ON INDIVIDUALS AND SOCIETY

 Difficulties:
1. Medical regimens: Cope medical technologies (e.g. insulin pen), Adherence
(overwhelmed to life-long commitment, may interfere with job)
2. Preventing medical crisis: Signs & symptoms (e.g. DM hyperglycemia)
3. Biographical disruption: Loss of personal independence (+Guilt as burden), change
of body image (e.g. abnormal gait), low sense of self

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 4. Disruption of family & Social life: Strain on family members, family roles, withdraw
from social roles / social isolation
5. Uncertainty: 3 phases: Pre-diagnostic, Trajectory (e.g. prognosis), Symptomatic
(e.g. side effects, when will symptoms flair / recur).
6. Cost: Healthcare services, time from family
 Impact varies depends on various factors: e.g. severity, onset (children=greater), stability,
visibility (e.g. loss of hair)
 How can clinicians help:
1. Give information: Reduces uncertainty. If you talk about diagnosis, please talk
about treatment plan too. Information given should suit patient's information
preference, e.g. maximal vs. minimal (may change over time, may depend on
diagnosis / treatment).
2. Empower self-care & emphasize shared responsibility e.g. adherence, lifestyle
chance
3. Patient centered approach and personalized plan to address patient's needs
4. Continuity care, Multidiscipline approach

SUMMARY

 Many people have chronic illness which might involve some impairment
 Impairment does not necessarily lead to disability (Depending on whether supportive
environment)
 Social and political factors are involved in both the definition and management of chronic
illness and disability

LEARNING OBJECTIVE

 Section 1: Describe the prevalence and characteristics of chronic illness

 Section 2: Compare and contrast the concepts of impairment, and disability
 Section 3:
o Analyze the meaning of being chronically ill
o Synthesize effects of chronic illness and disability on individuals, groups, and
society
o Discuss implications for patient care

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MSS30 MUSCLE DISORDERS

OUTLINE

1. Introduction
2. Duchenne muscular dystrophy

INTRODUCTION

Muscle disorders:
 Types: Progressive muscle weakness (e.g. Dystrophies), defective substrate utilization (e.g.
exercise intolerance), defective contractile mechanism (e.g. sudden paralysis)
 Muscular dystrophies. Group of disease. Characteristics: Hereditary, Progressive, distinctive
patterns of muscle hypotrophy (i.e. muscles affected) for each disease.

DUCHENNE MUSCULAR DYSTROPHY

 Prevalence: 1:3500 in live male births

 Course:
o Age: Start between 1-4, 8-9 rapid progression, 12 cannot walk, 20 deaths.
o Manifestation: Shoulder & Pelvis  Upper trunk & limbs.
 Other types
o Becker Type of Muscular Dystrophy: Less severe, later onset, slow progression.
Characteristic hypertrophic calves, Failure to walk.
o Outliers: Between Duchenne & Becker.
 Pathogenesis:
o Cause: mutation in dystrophin gene (multiple promotors that can start transcription
in multiple sections, exons/slicing led to different combinations)
o Possible mutation: Point, deletion, slicing, promotor (affects expression)
o Function
 Dystrophin stabilizes muscle cells by linking ECM, via Membrane
glycoprotein complex, to F-actin
 DMD: Muscle cell membrane not stable in exercise  Damage  Dead
muscle cell, muscle degeneration
 Genetics:
o Short arm of X chromosome, X-linked recessive (Nearly always male affected,
mom and sister are carrier)
o Check family history (e.g. relatives) to determine whether due to mom, or new
mutations
 Diagnosis:
o Genetic tests (e.g. Sequencing, Southern blot)
o Blood test: CK 10-100x increase. Cannot test dystrophin level in blood!
o EMG
o Muscle biopsy:
 Fiber size decrease, big gaps between fibers (Yet: not specific of DMD)
 Laboratory tests:
 Immunostaining (Detects dystrophin): Level of protein reduced.

88
 o Dystrophin totally absent / reduced in baker type.
o Mechanism: 1st antibody binds dystrophin; 2nd antibody
binds 1st antibody with color developing enzyme
(commonly Horseradish peroxidase): Color intensity
indicates dystrophin concentration
 Western blot: Abnormal size (In some Becker)
o Better than Immunostaining since can see size. Worse
because cannot see muscle location / morphology
 Treatment
o Drug: Some can prolong walking time of 2-3Y
o Therapeutic possibilities:
 Gene therapy: Gene repair, introduce new copy (Difficulty: too big, hard to
clone and hard to introduce)
 Cell transfer: Myoblast transfer, Human stem cell (Induced pluripotent stem
cell)

LEARNING OBJECTIVES

 Distinguish between Duchene Muscular Dystrophy, Becker Type Muscular Dystrophy, and
outlier.
 Define the molecular function of dystrophin protein.
 Describe the diagnosis method for Duchene Muscular Dystrophy, Becker Type Muscular
Dystrophy, and outlier.

SELECTED QUESTIONS

[Self-assessment] Individuals affected with Duchenne muscular dystrophy (DMD), an X-linked

recessive trait, become progressively weaker starting early in life. Margaret comes to see you
with her 3-year-old son because of her family history of Duchenne muscular dystrophy. Her
brother and maternal uncle have DMD. What is probability that her son will develop disease?

A. 1/2
B. 1/4
C. 1/8
D. 1/16
E. 1/32
Ans: B (Highly recommend drawing own genetic diagram / pedigree to reduce chance of careless
mistakes)

[M17 2nd Summative] Mutations in dystrophin gene lead to Duchene muscular dystrophy
(DMD). Dystrophin is a linker protein. Which one of following interactions is directly affected in
DMD?

A. Actin filaments and microtubules

B. Actin and actin
C. Membrane glycoprotein complex and actin
D. Microtubules and microtubules
E. Myosin and kinesis

89
Ans: C (See together with next question. Affected: ECM, Membrane glycoprotein complex, F-actin.
Dystrophin linkage repeatedly asked. )

[M20 2nd Summative] DMD, which is affected

A. Interaction between actin and kinesin

B. Interaction between myosin and actin
C. Interaction between actin and microtubules
D. Interaction between extracellular matrix and cytoskeleton
Ans: D (ECM, Membrane glycoprotein complex, F-actin. Dystrophin linkage repeatedly asked. )

[M11 2nd Summative] Duchenne Muscular Dystrophy, Becker Type Muscular Dystrophy, and
Duchenne outlier are diseases caused by mutations in the same gene.
(a) Rank the order of these three diseases in decreasing severity. (2 marks)
(b) What is correlation between disease severity and dystrophin protein level? (2 marks)
(c) Give three types of genetic mutations that can lead to Duchenne Muscular
Dystrophy (3 marks) and describe possible effects of these mutations on protein for
each type of mutation. (3 marks)
Ans:
(a) Duchenne muscular dystrophy > Outlier > Becker’s type MD
(b) Inverse (More severe, less dystrophin)
(c) Deletion, Frameshift, Point.
a. Deletion (e.g. Chromosome abnormality): No dystrophin (DMD).
b. Frameshift: Likely non-functional dystrophin, e.g. structurally altered / nonsense
(e.g. Outlier).
c. Point: Either missense (Potentially non-functional) or Promotor (less transcription)
(e.g. Becker’s).

[M14 2nd Summative] Duchenne Muscular Dystrophy can be diagnosed by immunostaining of

muscle biopsy for dystrophin protein.

(a) Compared to normal individual, what can be concluded on dystrophin protein levels
in these patients? (2 marks)
(b) What is likely clinical diagnosis for patient 1? (1 mark)
(c) What is likely clinical diagnosis for patient 2? (1 mark)
(d) Justify your diagnosis for these two patients. (4 marks)
(e) Give one possible mutation in dystrophin gene that may cause the disease in patient
1 (1 mark); and give one possible mutation that may cause the disease in patient 2. (1
mark)

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Ans:
(a) Patient 1 reduced; Patient 2 none.
(b) Becker’s type muscular dystrophy
(c) Duchenne muscular dystrophy (Try making an effort to spell ‘Duchenne’)
(d) Severity in inverse proportion with amount of dystrophin. Becker’s type less severe than
Duchenne. Patient 1 reduced but preserved dystrophin = less severe. Patient 2 absent
dystrophin = more severe. [Dis 4 mark?! Idk what else already…]
(e) Patient 1 (DMD): Point mutation. Patient 2 (BMD): Deletion.

91
MSS31 BASIC PHYSIOLOGY OF SKIN AND MECHANISMS OF SKIN DISEASES

OVERVIEW

1. Functions of skin & Pathological examples

2. Common dermatological conditions

FUNCTIONS OF SKIN & PATHOLOGICAL EXAMPLES

Descriptor Pathological examples
(1) Physical barrier
Prevent loss of Signs of dehydration: Pathological:
water & Hypotension, Hypernatremia, - Toxic epidermal necrolysis: Full-thickness
electrolytes pre-renal failure epidermal cell death
- Erythroderma: 90%+ covered by
erythema. Causes: e.g. Psoriasis, eczema,
drug eruption
Minimize harm e.g. due to lack of Stratum Darier's disease, epidermolysis
of toxic corneum (dead keratin hyperkeratosis
materials envelope)
Prevent Common skin flora:
infiltration by  Bacteria: Staphylococcus, Streptococcus, Pseudomonas
micro-organisms  Viral: Herpes simplex, Varicella-zoster
 Fungus: Dermatophytes, candida
 Parasites: Scabies
See below for list of common skin infections
Avoid allergen Pathological example: Atopic dermatitis (eczema)
entrance Predisposition: filaggrin gene mutation, lack of sphingolipids.
Allergen examples: House dust mites
Protect against - Stratum corneum reflects/ - Avoids skin malignancy (SCC, BasalCC,
UV scatter photons Melanoma)
- Melanosome of melanocyte - Avoids photo-aging (wrinkles, solar
also absorbs photons elastosis)
(Additional use: skin color)
(2) Thermo- Eccrine sweating (evaporative cooling; esp. palm, soles, axilla; hypotonic
regulation sweat), Vessel tone
(3) Repair of Types of injury: Physical, Chemical, Thermal, UV
injury Types of Healing:
 Epidermal: by complete regeneration
 Dermis (e.g. 2-3 degree burn): Granulation  Scarring
(4) Innate & Acquired immunity (Immune cells, Complements, etc.) Please see
Immunological IASM Immunology block.
defense Anti-microbial peptides:
 Anti-bacterial, viral, mycotic properties; Secreted from epidermis
 Examples: HBD, Dermocidine
 Psoriasis: Increased HBD-2 expression (they usually have less
bacterial infection)
APC of skin: Langerhans (Epidermis), Dendritic cell (Dermis), Macrophage
(5) Endocrine  Vitamin D
function  Glucocorticoids: Loosen intercellular connections, weaken epidermis
 Sex hormones: Increase epidermal thickness, wound healing,
92
 increase dendritic cells against cancer
(6) Psychosocial  Sense of beauty, youth, healthiness; Attraction (not us, don’t ff)
function  Organ for communication (e.g. smile, frown)

COMMON DERMATOLOGICAL CONDITIONS

1. Atopic dermatitis (Eczema)
o Clinical features: Ill-defined erythematous scaling patches.
o Types
 Acute (Swelling, vesicles),
 Subacute (discoid, weeping),
 Chronic (Lichenification / skin lines).
o Related to Atopic tendency (Asthma, allergic rhinitis, allergic conjunctivitis)
o Pathophysiology: Genetic (Filaggrin gene mutation), Immunological (IgE high, Th),
Environmental (Allergens), Microbiological (S. aureus colonization)

2. Psoriasis:
o Clinical: Well-demarcated erythematous scaling plaques (usually at extensor
surfaces e.g. elbow), Nail & Scalp. Psoriatic arthropathy.
o Pathophysiology: Genetic (family history, HLA), Immunology (T helper,
Interleukins), Environmental (Alcohol, some drugs), Microbiological (Streptococcus
in children's guttae psoriasis)

3. Contact dermatitis
o Irritant vs. Allergic types
 Irritant: More common. E.g. Washing hands & Rubbing alcohol a lot
 Allergic: Type 4 hypersensitivity (in terms of pathogenesis), Driven by
allergens (e.g. herbal medications, cosmetics, masks, skin products, eye
drops, nickel, cobalt). Patch testing for confirmation.
o Clinical: very well-defined (e.g. a square patch of Chinese medicine), itchiness,
erythema, scaling, weeping, vesicles (if acute)

4. Cutaneous infections
o Bacterial: Impetigo, Erysipelas
o Viral: Herpes simplex, Varicella-zoster
o Fungal: Dermatophytes, Candida ('annular scaly plaque with advancing border')
o Parasitic: Scabies (Burrows, Pustules)

LEARNING OBJECTIVE
 Recognize various important functions of skin
 Describe the role of skin in homeostasis
 Describe the innate and adaptive immunological function of the skin
 Describe the psychosocial importance of the skin
 Describe the pathophysiology in common skin diseases

93
MSS32 PERIPHERAL NERVOUS SYSTEM

OUTLINE

1. Autonomic Nervous System

2. Clinical Relevance: Disorders and Injury of PNS

AUTONOMIC NERVOUS SYSTEM

Sympathetic, Parasympathetic, (Enteric)

SYMPATHETIC AND PARASYMPATHETIC

Sympathetic Parasympathetic
Center Lateral horn of T1-L2/3 Brainstem, S2-4
Higher center Hypothalamus
Effect Fight, Flight, Fear Rest, Digest
Effect (Specific)

🧠 Paravertebral: 3C, 12T, 4L, 4-5S, 1 🧠 Head and Neck: Ciliary (CN3),
Ganglia

impar (L&R fuse) Pterygopalatine (CN7),

🧠 Prevertebral: Celiac, Aorticorenal,

Submandibular (CN9), Otic (CN 10)

Superior mesenteric, Inferior 🧠 Terminal ganglion: Pelvic

mesenteric Splanchnic nerves
Synapse See below At supplied region

Important Understanding box: Pathway of SYMPATHETIC nervous system

Come out of Lateral horn (Pre-synaptic fiber) White
communicating ramus (Only T1-L2/3)  Sympathetic chain (go
up & down)  Gray communicating ramus (Post-synaptic
fibers)  Sympathetic chain. 3 fates:
1. Synapse at same level  Leave at gray ramus
2. Go up & Down  Synapse at other levels  Leave at
gray ramus
3. (Be splanchnic nerves [T5 below]) Enter plexus as pre-
synaptic fibers  Synapse  Exit to organs

Note:
 White ramus only at T1 to L2, but grey ramus at every level
 All splanchnic nerves presynaptic except cardiopulmonary (arise from stellate ganglia)
SPLANCHNIC NERVE
94
 Total of 6:
S/P Origin To ganglia
Greater Symp. T5-9/10 Celiac
Lesser Symp. T10-11 Abdominal/Renal
Least Symp. T11-12 Abdominal/Renal
Lumbar Symp. L1-2 Abdominal/Hypogastric
Sacral Symp. Sacral part of Inferior hypogastric
symp. trunk
Pelvic Para. S2-4 Terminal ganglia

Information for reference: Enteric nervous system

 Lots (100-500 million) of neurons; Communicates with sympathetic & parasympathetic,
can operate independent from brain, can reflex independently
 Plexus: Myenteric (Auerbach); Submucosal (Meissner's)
 Function: Regulates motility, Secretion, Local reflex

LEARNING OBJECTIVES

1. Describe the components of the PNS and their anatomical locations

2. Explain the organization of the PNS
3. Describe the microscopic structures of the PNS
4. Explain the common disorders and injuries of the PNS
5. Relate the functions and structures of the PNS

MSS32 Peripheral nervous system –Supplementary material (Continue on next page)

95
 This is a Page Break

96
ADDITIONAL SECTION: PAST MATERIALS (REVISION)

OUTLINE

1. Quick Recap
a. General outline of nervous system
b. Structures of Nerve Fibers
c. Glial cells in PNS
d. Nerve Endings
2. Cranial Nerves
3. Spinal Nerves
4. Somatic Nervous System

GENERAL OUTLINE OF NERVOUS SYSTEM

Divisions of the nervous system (as usual):

 CNS
 PNS (outside brain & spinal cord + Special
nerve endings)
o Cranial nerves + ganglia
o Spinal nerves + ganglia
o Autonomic nerves + ganglia
 Functionally
o Somatic
o Autonomic

STRUCTURES OF NERVE FIBERS

The old things 🧠

GLIAL CELLS IN PNS

97
 Schwann cells, (Perineuronal) satellite cells:
 Schwann cells: Myelin
 Satellite cells: Control microenvironment,
Exchange of metabolic materials,
Electrical insulation (cell body at
Ganglion)

NERVE ENDINGS

 Neuromuscular junction
o Acetylcholine
o Synaptic cleft: Between axon terminal and muscle cell membrane
 Sensory nerve ending: E.g. Free nerve ending (Pain, temperature), Tactile discs, Hair
receptors (touch), tactile corpuscles (touch),Muscle spindles (proprioceptors)

(2) CRANIAL NERVES

 12 pairs
 Arises mainly within the brain
 BUT CN II (Optic nerve) is part of CNS

o 🧠 : Optic = See = C = CNS

 Sensory ganglia. Total 8 of them (My opinion: My table below is NOT important. In HNS
block a lot more will be learnt, and cranial ganglia will be classified in much better ways):

CN Ganglia
5 Trigeminal
7 Geniculate
8 Spiral
8 Vestibular
9 Glossopharyngeal superior (jugular)
9 Glossopharyngeal inferior (petrosal)
10 Vagus superior (rostral)
10 Vagus inferior (nodose)

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(3) SPINAL NERVE

BASIC INFORMATION
31 pairs Plexus
 Cervical: 8  Cervical: C1-4
 Thoracic: 12  Brachial: C5-T1
 Lumbar: 4  Lumbar: T12/L1-4
 Sacral: 5  Sacral: L4-S4
 Coccygeal: 1
Sensory ganglia: Dorsal root ganglion

ANATOMY OF SPINAL NERVE

(4) SOMATIC NERVOUS SYSTEM

2 divisions: Motor, Sensory

Motor Sensory
Direction Efferent Afferent
Cell body location CNS PNS
Neuron type Multipolar Pseudounipolar
((Except Olfactory & Retinal: Bipolar)

99
 Motor. Sensory (Quick recall: dorsal root ganglion for
SENSORY!)

100
MSS PATHOLOGY PRACTICAL - DISEASES OF BONE, CARTILAGE AND JOINTS

GALLERY: MICROSCOPIC

Tidemark dividing calcified vs. Chondrocytes. Note the shape of the

non-calcified layers. chondrocytes along the cartilage.

Acellular purple deposits. No Rhomboid crystals may be Vs. Pink deposits in Gout.
giant cells, little inflammation. seen at high magnifications.
(CPPD case, i.e. pseudogout) (Pseudogout)

(Gout) Macrophages & Needle shape architecture in (Gout) Giant cell

lymphocytes. Giant cells. gout. (Independent crystals
unlikely seen because fixing)

101
 (RA) Proliferation
(Hyperplastic) of synovium.
Papillary structure, high
vasculature, inflammatory
cells.
Lymphocytes, Plasma cells (∵
autoimmune).
Inflammatory cells destroy
endothelium  Fibrin
deposition, Exudate formation ±
Destroy cartilage; Granulation
tissue (Pannus)

GALLERY: MACROSCOPIC

Condyle of femur, Patellar, Tibia. White granular deposits Head of femur. 3 abnormalities:
(Crystals, Inflammatory cells). Patient complains of renal stones Joint irregular with osteophyte
(urate renal colic), nodules in soft tissue (gouty toufus) [Right: formation. Cartilage erosion.
Enlarged] Subchondral cyst. Osteoarthritis.

Head of femur. Necrosis of tissue Area of necrosis again, leading to collapse and impinge of spinal
that is replaced by new bone. No cord. Causes: Granuloma (Bone TB) [See right: Sepsis most likely
subchondral cyst, no fibrosis. from case history since this boy is 3/Y which is likely too young

102
 Cartilage in even thickness (no for cancer and vascular. Staphylococcus not at joints usually,
erosion), hence nothing to do septic arthritis usually not at spine, TB can be at spine.] One shall
with cartilage. Diagnosis: see caseous necrosis & acid-fast bacilli on microscope.
Avascular necrosis (Regional
death of bone due to ischemic;
esp. in immunocompromised /
trauma). Associated with SARS
(Steroid treatment).

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MSS PUBLIC HEALTH PRACTICAL

OUTLINE

 Diagnosis
 Prognosis
 Survival
 Regression

DIAGNOSIS

 Screening vs. Diagnostic tests

o Targets: Asymptomatic vs. Symptomatic
o Aim: Prevention vs. Diagnosis (Definitive diagnosis, or rule out DD)
 Validity of a diagnostic test is estimated by their:
1. Predictive values (Influenced by both pre-test probability/prevalence, and
Sensitivity & Specificity)
2. Likelihood ratio LR: p (test result if disease present) / p (test result if disease absent).
Pre-test probability x LR= Post-test probability
 Positive and Negative likelihoods ratio (-LR, +LR, see below)
 Reflects the change in probability of having the diagnosis (See reference
image)

 LR> 10 good to rule-in disease (I.e. patient has disease); LR<0.1 good to rule
out disease (I.e. healthy), LR=1 useless (Your test is like throwing a coin)
 Most diagnostic tests have intermediate LR (neither too high nor too low),
so multiple tests are required
 Not all diagnostic tests improve patient-oriented outcomes (Morbidity, Mortality, QoL)

PROGNOSIS

 Prognosis: Likely course & outcome of a disease.

 2 types: Clinical course (received treatment) vs. Natural history (no treatment)
 Types of prognosis questions: Overall prognosis, Prognostic factors, Risk prediction (who
has worse outcomes)

104
  Level of evidence: Cohort > Case control (for prognostic factors, but no outcome rates) >
Randomized control trials (participants do not represent population of interest)
 Bias in Prognostic measurement:
o Patient selection: Recruitment, Low response rate, excluded patients, (Attrition)
loss in follow-up
o Measurement: Heterogenous diagnosis (e.g. different definitions of OSA), lack of
blinding

INCEPTION COHORT
 Inception cohort: A designated group of persons assembled at a common time early in the
development of a specific clinical disorder (e.g., at first exposure to the putative cause or at
initial diagnosis)
 Avoid selection bias caused by early death or early recovery of some patients

MORTALITY
 All-cause mortality
o Includes all causes of mortality, even those seemingly unrelated to study exposure
 Bad: Difficult to avoid confounding
 Good: Includes potential causations that may be seemingly unrelated
o Less prone to misclassification; Easier to measure
 Disease specific mortality:
o Heavily relies on accuracy and completeness of death certification
o More prone to misclassification (It is easy to tell is one is alive vs. dead, but harder to
determine the cause of death)
 Standardized mortality ratio: Ratio of number of deaths observed in study population to
that of standard population
 Case fatality rate:
o The proportion of cases of a specified condition that are fatal within a specified time
(Deaths / Diagnosed cases)
o Limitations:
 Sensitive to period (too short=underestimate because many disease does
not cause instant death)
 Patients undiagnosed won't contribute to CFR (may overestimate
deadliness of disease)

SURVIVAL

1. Survival curve: 100% and decrease over time (Survival%/Years after diagnosis)
o Attrition not accounted for
2. Kaplan Meier curve: Similar to survival curve, but accounts for attrition (losing follow-up)
3. Hazard & Hazard ratio:
o Hazard: Instantaneous incidence rate
o Hazard ratio: Hazards between 2 groups (e.g. exposed vs. control). HR>1 higher
hazard than control, HR<1 lower hazard than control, HR=1 no difference in hazard

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REGRESSION

 Statistical technique to adjust for confounding; allows estimation of many exposures

 Cox regression: time sensitive (analyzing time to occurrence of event)
o Assumptions: Ratio of hazards comparing different exposure groups remain
constant over time (If this assumption isn't true, it doesn't make sense to use HR to
describe difference between the exposure group)

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MSS Exam Focus
EXAM FOCUS DESCRIPTION

 Revision notes in Question-and-Answer format

 What it includes:
o Highlights of important points from most lecture contents
o Highlights of important points from past paper
 However, there are some limitations:
 Areas where notes may be incomplete:
o Anatomy, Histology, Embryology: Study resources using images seems better for
these subjects.
o Pharmacology
 MoA: All MoAs are assumed to be in Importance Class A (See explanatory
table below) and they could easily be found in lecture notes. So it is not
documented below.
 Side effects: Key side effects might be missing from the table.
o It doesn’t include all lectures. Some lectures are still missing (If you can’t find the
lecture code below, then that lecture is missing)
 Suggested use: Find paper to cover up right hand side  Recite  Then check the answer
 Note:
o Some lectures have been combined during documentation, because they teach very
similar things. E.g. MSS030415 means it already included key points from both
MSS03, MSS04, and MSS15.
o Some questions require very long answers, so it is not documented in the table
below. In that case, you will be referred to lecture notes, where the answer could be
found (usually under a certain bullet-point / subheading)
 Special feature. Importance rating:

Meaning
A Very important, will help
greatly in exam
B Quite important
C Important
D Good to know
E Not important, Quick read-
through is good enough
Comments
Often because they frequently appear in Past Paper while
carrying a lot of marks, or lecturer placed special emphasis
on this, or it is crucial to the overall understanding the
lecture.
Likely appeared in past paper, or lecturer placed some
emphasis. These should be memorized.
Although less important, it may still appear in exam. I
suggest memorizing these too.
These are unlikely to appear in exam because they are
relatively trivial knowledge.
It is still good to know them, after all ‘no knowledge is
useless.’ But maybe after A, B, and C.

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MSS EXAM FOCUS
Importance
No. Lecture No. ↑ Question Answer
1 MSS030415 1 B Important signs of Rheumatoid arthritis (A) Periarticular erosions, Juxta-articular osteoporosis, narrowing joint spaces,
subluxation Proliferative / Hyperplasia in nature. What it is not: Widening joint
spaces, subchondral cyst (B) Sometimes also: Lymphoid nodules & pannus, vascular
involvement; Fibrinoid necrosis
2 MSS030415 2 B Characteristics of Gout: Cell types & Arthrocentesis: Needle-shaped crystals (Urate), Eosinophil infiltrate, *giant cells*
microscopic findings
3 MSS030415 3 B Characteristics of Pseudogout Calcification of meniscus, calcium pyrophosphate crystals
4 MSS030415 4 D Precursor of uric acid Guanosine
5 MSS030415 5 C Osteoarthritis injection viscosupplement Hyaluronic acid (NOT aggrecan!)
6 MSS030415 6 C Crystals: Gout vs. Pseudogout Gout (Urate, needle-shape); Pseudogout (Calcium pyrophosphate, rhomboid)
7 MSS030415 7 B Gout pathogenesis Urate accumulation (Increase production or Intake / Decrease excretion) >
Crystallization & deposition at cold areas > Histamine from mast cells triggers
inflammation (Redness, Swelling, Heat, Pain)
8 MSS030415 8 A Osteoarthritis 4 big pathological signs + [1] Loss of joint space (Cartilage mechanical erosion); [2] Osteophyte formation
Short explanation (Eburnation exposes subchondral bone, osteophyte formation as attempt to increase
SA to reduce pressure); [3] Subchondral sclerosis (Osteocyte attempts to repair /
Fibrous scar); [4] Subchondral cyst (Cartilage erosion > Large intra-articular pressure
> Synovial fluid forced into subchondral bone)
9 MSS030415 9 C Why is CPPD associated with OA? OA damaged cells release ATP converted to pyrophosphate.
10 MSS030415 10 C What cells are involved in RA? Macrophage derived, plasma cells
11 MSS05 1 D Pick imaging modality: Superficial soft Ultrasonography (USG)
tissue mass
12 MSS05 2 D Imaging modality: Septic arthritis Ultrasound more useful for diagnosis (Aspirate)
13 MSS05 3 B Application of MRI (1) Neural involvement e.g. sciatica, (2) Soft tissue / Disc, (3) Spondylodiscitis (Note:
For spinal pathology you can use CT too, but certainly wouldn’t be most sensitive.)
14 MSS06 1 C Molecules that hold water Hyaluronic acid / Aggrecan, Proteoglycans (due to negative charge)
15 MSS06 2 C Cartilage composition. Collagen: 1:1: small amounts
Proteoglycan: Elastin?
 16 MSS06 3 C Main enzyme responsible for Aggrecan MMP
cleavage
17 MSS06 4 C Collagen type found in bone vs. 1 vs. 1 vs. 2
fibrocartilage vs. hyaline cartilage.
18 MSS06 5 B Biochemical composition of Bone Collagen I, Osteopontin, Osteocalcin
19 MSS06 6 B Biochemical composition of Cartilage Collagen II, Aggrecan, Fibronectin
20 MSS06 7 C Post-translational modifications for At RER: Signal peptide cleavage, prolyl hydroxylation; Extracellular: Proteolytic
collagen synthesis processing, fibril assembly and cross-linking
21 MSS06 8 D MMP classes example Collagenase, Stromelysin (membrane bound)
22 MSS06 9 C 3 levels of MMP activity regulation Production, activation of proenzyme, TIMPs
23 MSS06 10 B Using cartilage as an example, state the (1) Collagen: Type 1 in fibrous cartilage (the bones), Type 2 in Hyaline cartilage; For
functions of: Collagen, Proteoglycan, tensile strength. (2) Proteoglycan (Aggrecan): Absorb water to swell to withstand
Glycoprotein compressive force. (3) Glycoprotein (Fibronectin): Cellular attachment and
communication with ECM
24 MSS06 11 D Cell-matrix interaction examples (1) Integrins: Binds with transmembrane protein with focal adhesions; (2) Syndecan:
Binds to collagen and fibronectin
25 MSS06 12 C Organization of collagen Triple helical structure, Glycine at every 3rd residue (Gly-X-Y), Stabilized by
interchain H bonds
26 MSS06 13 C Properties of GAG (1) Highly negative charge: attract cations; (2) Hydrophilic: Supports swelling
pressure
27 MSS06 14 D How does ECM regulate IHH level (ECM (1) Aggrecan act as selective sieves to regulate traffic of molecules; (2) Binds to
& Cell interaction) signalling molecules
28 MSS07 1 B Summary of disease and causative *Epidermis: Dermatophytosis (Trichophyton, Epidermophyton, Microsporum;
agents (Epidermis, Dermis, Multiple Including onychomycosis from trichophyton; Scalp from Microsporum), Paronychia
layers (S. aureus). *Dermis: Folliculitis, impetigo (S. aureus). Abscess incl. furuncle &
carbuncle, Cellulitis, Erysipelas (S. pyogenes). *Multiple layers. Necrotizing: Gas
gangrene (Clostridium perfrenges), Necrotizing fasciitis (S. pyogenes, Vibrio).
Others: Osteomyelitis, Infective arthritis (S. aureus)
29 MSS07 2 C Causative agent of: onychomycosis Trichophyton
30 MSS07 3 C Causative agent of: scalp infection Microsporum
31 MSS07 4 C Causative agent of: Paronychia S. aureus
109
 32 MSS07 5 C Causative agent of: Folliculitis S. aureus
33 MSS07 6 C Causative agent of: Impetigo S. aureus
34 MSS07 7 C Causative agent of: Furuncle S. pyogenes
35 MSS07 8 C Causative agent of: Carbuncle S. pyogenes
36 MSS07 9 C Causative agent of: Cellulitis S. pyogenes
37 MSS07 10 C Causative agent of: Erysipelas S. pyogenes
38 MSS07 11 C Causative agent of: Gas gangrene Clostridium perfrenges
39 MSS07 12 C Causative agent of: Necrotizing fasciitis S. pyogenes
40 MSS07 13 C Causative agent of: Osteomyelitis S. aureus
41 MSS07 14 C Causative agent of: Infective arthritis S. aureus
42 MSS07 15 B Standard antibiotic for S. aureus Cloxacillin (In MCQ)
43 MSS07 16 B Specimens to collect in Joint Swelling Blood, Synovial fluid aspirate
44 MSS07 17 C Bone infection sample collection Bone biopsy (NOT blood; definitely not synovial fluid aspirate)
45 MSS07 18 C Polyarthritis with papules Neisseria gonorrhoea
46 MSS07 19 C Kindergarten outbreak, superficial Impetigo (but usually for this one: S. pyogenes)
pustules
47 MSS07 20 B Note: the differentiation between S. Ok.
aureus & S. pyogenes based on (e.g. Impetigo can be caused by S. pyogenes, can also be caused by S. aureus. MCQ
pathology is not definite. past paper seems disputed as to which is most likely.)
48 MSS07 21 C Vertebral infection first infects Vertebral endplate (NOT disk! Those are avascular.)
49 MSS1112 1 B Common drug for myasthenia gravis & Tensilon (Edrophonium), acetylcholinesterase inhibitor (increase ACh level at motor
effect end plate)
50 MSS1112 2 B ACh receptors in muscles: Nicotinic or Nicotinic (that's why they always stress on Conformational change. Muscarinic relies
Muscarinic? on secondary ion transport)
51 MSS1112 3 B Which ion change permeability when Sodium (Not K and don't mix up with Ca)
ACh binds to AChR in muscle fibres?
52 MSS1112 4 B 3 phases of muscle twitch + brief Latent period (for 1. AP propagation; 2. Ca release from SR); Contraction phase,
description Relaxation phase
53 MSS1112 5 B Incomplete vs. Complete tetanus Reduced vs. Eliminated relaxation phase

110
 54 MSS1112 6 A Explain the pathogenetic mechanisms of (initially) Binding of autoantibodies to nicotinic cholinergic receptors that alters
myasthenia gravis function; (progressively) stimulates AChR endocytosis hence reduced AChR density.
(Late events) Lower end plate potential > only motor units with less power activated
+ fewer motor units recruited > muscle weakness with less force
55 MSS1112 7 B What happens when muscle constantly Prolonged depolarization > Zone of electrical inexcitability around endplates >
depolarized (e.g. neuromuscular poisons Flaccid, muscle paralysis wf. decreased motor response
SARIN)?
56 MSS1112 8 B 3 pathogenic mechanisms of NMJ (1) Attract MAC > NMJ structure destroyed (e.g. junctional folds gone); (2) AChR
diseases generally dimerized and cross linked > AChR Endocytosed > AChR density decrease
[Myasthenia gravis]; (3) Inhibited AChR channel property (> cannot signal for muscle
activation)
57 MSS1112 9 C 3 serological tests of NMJ diseases ELISA (Colour), RIPA (Radioactive), Cell-based (Fluorescence)
58 MSS1112 10 C Presynaptic & postsynaptic adaptation of Clustering of vesicles, clustering of AChR (Agrin-LRP4-MuSK)
NMJ
59 MSS1112 11 B Spatial vs. Temporal recruitment More motor units vs. increased firing frequency
60 MSS1112 12 A ACh: Production, Release, Recycling, Refer to notes
Activation
61 MSS1112 13 A How is ACh produced (Substrate, AcetylCoA(- CoA)+Choline=Acetylcholine; Choline acetyltransferase
Enzyme)
62 MSS1112 14 A How is ACh degraded (Enzyme, Acetylcholinesterase; Acetate, Choline (recycled)
Products)
63 MSS1112 15 B Sarcomere bands A (Thick), H (Thick only), I (Thin only)
64 MSS1112 16 B Contraction cycle proteins Actin (thin), Myosin (Thick); Troponin (Ca binding), Tropomyosin (unblocks actin).
Titin (Elasticity), Nebulin (aligns actin). Recall IASM.
65 MSS1112 17 C Ca release and uptake Release (DHP+Ryanodine + small external influx), Uptake (SERCA + small external
outflow)
66 MSS13 1 A Prerequisites of normal gait (5) Stance stability, foot clearance, swing phase prepositioning e.g. ankle landing, Step
length, Energy conservation
67 MSS13 2 B What is stride length, step length, and See notes
step width?

111
 68 MSS13 3 B Explain abnormal gait patterns esp. Antalgic (Shortened stance phase to avoid pain), Trendelenburg (Weakened hip
compensations (Antalgic, abductors lead to dropping pelvis on CONTRAlateral side), Short limb (Knee bending
Trendelenburg, Short limb, Cerebral & circumduction at long limb; Tiptoeing at short limb), Cerebral palsy (Muscle
palsy spasticity leads to tiptoing; soft tissue contracture leads to crouching)
69 MSS13 4 A What are the 2 phases of gait cycle Swing, Stance
70 MSS13 5 B 6 Determinants of gait Horizontal pelvic rotation, Frontal pelvic tilt, Lateral displacement of pelvis, Stance
knee flexion, Knee & ankle motion, foot motion
71 MSS13 6 A Changes in CG during gait cycle (Highest, Highest when single support, Lowest when double support; Changes: Sine wave
lowest, curve) vertically & horizontally
72 MSS13 7 B Increase in energy expenditure in None (i.e. same)
wheelchair
73 MSS19 1 C Types of bones (by shape) Long (Humerus, Phalanges), Short (Trapezoid), Flat (Sternum), Irregular (Vertebrae),
Sesamoid (Patella)
74 MSS19 2 C Functions of bones (5) Support, muscle attachment for locomotion, Protection, CaP Reserve & homeostasis,
Harbours bone marrow
75 MSS19 3 C Simple biochemistry of Bones and Bone (Inorganic + Organic components. Inorganic: Calcium hydroxyapatite. Organic:
Cartilage Type 1 Collagen, Proteoglycan + Glycoprotein). Cartilage (Type 2 collagen)
76 MSS19 4 B Types of bone cells Osteoblast (Deposition, round, not a stem cell but will become osteocyte when
enclosed in matrix.) Osteocyte (Maintenance, Surrounded by Howship's lacune &
with canniculi for communication). Osteoclast (Resorption. Large & acidophilic, in
Howships lacunae, Ruffled border & clear zones)
77 MSS19 5 A Types of osteogenesis Intramembranous, Endochondral. Intramembranous (Mesenchymal cells become
osteogenitor cells. Progenitor cells becomes osteoblast. Osteoblast lay down matrix
and becomes osteocyte. Osteocyte calcify and die. Additionally, increase vasculature
& Bone remodelling; Appositional growth.). Endochondral (From cartilage,
Chondrocytes proliferate, then hypertrophy, then calcify and die. Calcified cartilage
reabsorbed by periosteum and invaded by osteogenitor cells, which becomes
osteoblast. Increase in vasculature & continuous remodelling.
78 MSS19 6 C Primary vs. Secondary bones Woven (Random arrangement fibres) vs. Lamellar (Organized)

112
 79 MSS19 7 C Compact vs. Cancellous bones (Cortical bone) Osteon, Haversian system (Canaliculi, Volkmann's canal, Howships
lacunae) vs. Trabecula
80 MSS20 1 B Bone healing: Types, Phases, Important Processes & Phases: Bleeding, Inflammation, Proliferative, Remodelling. [1] Bleeding
growth factors (Hrs): Hematoma, Haemostasis. [2] Inflammation (D): VD VP Exudates, Growth
factors, Cytokines. [3] Proliferative (W): Fibroblast, Collagen, non-functional patch.
Re-epithelialization. Soft (fibrous) & Hard (calcified) callus: Widen healing zone for
more mechanical stability. [4] Remodelling (M): Rearrange fibres. Note: Important
growth factors: Insulin-like, Platelet-derived, Transforming, Vascular endothelial.
81 MSS20 2 C Adverse factors of healing Local: Types of wound e.g. Crushing, Inflammation, Foreign body; Blood supply,
Excessive movement; Appositioning (Haematoma), Contraction (Tissue Tethering).
General: Nutrition, excessive Glucocorticosteroid, Systemic diseases (e.g. DM)
82 MSS20 3 C Complications of healing Specific to bone: Malunion / Non-union. Infection; Excessive tissue (Granulation,
Keloid), Weak scar (Hernia), Cicatrization (Stenosis); Painful scars (Neurotoma),
Pigmentary change, Wound dehiscence.
83 MSS20 4 C Fracture treatment directions (Slogan + Retraction & Stabilization when necessary, Rehabilitation always. Retraction: Wound
Details) debridement, Angiogram, Bone shortening, Muscle/skin flap, bone graft.
Stabilization: Casting, External & Internal fixation, External traction. Rehabilitation:
Physical e.g. Prosthesis, Physiotherapy. Mental e.g. Patient support group.
84 MSS20 5 D Is injury a leading cause of death in HK? Depends on age, yes for young people
85 MSS20 6 D Which demographic group has highest Old females (Osteoporosis), Young males (High energy polytrauma)
fracture risk?
86 MSS20 7 B EMQ: Femur fractured which is Callus
immobilized by a cast
87 MSS2223 1 A Draw a diagram showing the ligaments See supplementary diagram at the end of notes
of vertebrae
88 MSS2223 2 B Joint type of intervertebral joint Symphysis (i.e. Cartilagenous joint)
89 MSS2223 3 B Joint type of facet joint Synovial
90 MSS2223 4 B Name the characteristics of each section See notes (MSS22)
of vertebrae, their number, and
exceptions *
91 MSS2223 5 B Which spinal level does dural sac S2
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 terminates
92 MSS2223 6 B Which spinal level does the spinal cord L2
end
93 MSS2223 7 B Lumbar puncture pierces through which Skin, subcutaneous tissue, supraspinous ligament, interspinous ligament,
7 structures (in order) ligamentum flavum, epidural space, dural mater, arachnoid mater, subarachnoid
space
94 MSS2223 8 C Muscles of the back associated with Extensors. Superficial (Splenius capitis, Splenius cervicitis). Intermediate (Erector
spine spinae), Deep (Transversospinalis, Interspinales, Intertransversarii, Levatores
costarum), Flexion (Longus coli, Scalene, Sternocleidomastoid). Trunk (Rectus
abdominis, Psoas major)
95 MSS2223 9 C Blood supply of vertebrae Anterior spinal (From vertebral), Posterior spinal (uncommon), Radicular (Largest
artery of Adamkiewicz).
96 MSS2223 10 C Outline the nerve outlet at spinal cord C1-8, then the rest goes *below* the corresponding vertebrae
wrt. Vertebral number
97 MSS2223 11 C Name the components of 'scotty dog' 1. Transverse process. 2.Pedicle. 3.Superior articular process. 4.Pars interarticularis.
lumbar spine X-ray: 5.Lamina. 6.Inferior articular process. 7.Spinous process. 8.Interlaminar space.
https://ibb.co/Gv3RKLy 9.Intervertebral disc
98 MSS2223 12 C Sign of sciatica Lasegue's (Straight leg raise)
99 MSS25 1 B Mutations of OI and Severity (Quantity, Haploinsufficiency (e.g. by loss-of-function mutation, or by nonsense mutation via
Quality; Type 1 vs. 2) nonsense mediated mRNA decay) leads to reduced collagen production (Quantity).
This alone leads to Less severe forms of OI (e.g. Type 1). Missense Glycine
substitution (e.g. by insertion, deletion, point mutation) leads to reduced quality (i.e.
via Dominant negative). This leads to More severe forms of OI (e.g. Type 2)
100 MSS25 2 C What is dominant negative? State the Dominant negative: Mutant chain has negative impact on normal chain. Ratio=1:3
ratio of normal: abnormal collagen.
101 MSS25 3 C General structure of collagen. Post- General structure: 1 alpha 2, 2 alpha 1. Turn at Glycine, Gly-X-Y. Post translational
translational modification. modification: (1) Proline & Lysine undergo glycosylation, form H bonds for stability.
(2) Zipping from C to N, hence mutation at C more severe. (3) Hydroxylation of
proline with ascorbic acid as cofactor. (4) Assembly of fibrils via Lysine oxidase

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 102 MSS25 4 C Marfan pathogenesis (Normal vs. TGFbeta is a latent protein; they are associated with Latency associated peptides
Pathogenic) (LAP) trapped in Large latent complex (LLC) in the ECM. During mechanical stress,
Furin actives LLC via Fibrillin 1 to activate TGFbeta (a class of signalling molecule).
Marfan is caused by Fibrillin 1 mutation that causes TGFbeta overactivation.
103 MSS25 5 D Examples of genetic risk factors of Asporin, CLIP (also regulates TGFbeta signalling)
degenerative MSS diseases
104 MSS26 1 A Dictate the genes that control bone See notes (Summary section of the lecture)
growth as seen in Danny's chapter
105 MSS2728 1 C Meaning of efficiency Maximizing benefit from fixed resources
106 MSS30 3 B DMD gene, chromosome, and arm Xp21, X-chromosome, short arm
107 MSS30 4 C Function of dystrophin & pathogenesis in Dystrophin forms complex (see below) to fix & stabilize muscle cell. Muscle
DMD membrane not stable leads to damage and death (degeneration) of muscle cells.
108 MSS30 5 B Which 3 things does dystrophin bind to ECM, Membrane glycoprotein complex, actin
specifically
109 MSS30 6 A Important 3 types of mutations in DMD Deletion, Frameshift, Point. Deletion: No dystrophin (DMD). Frameshift: Likely non-
and fates functional dystrophin (e.g. Outlier). Point: Either missense (Potentially non-
functional) or Promotor (less transcription). Becker’s.
110 MSS30 7 D Abnormal patterns in dystrophin Abnormal dystrophin size (western blot) and amount (immunostaining)
production in muscles in DMD
111 MSS30 8 D Histological changes in muscles in DMD Fibre size decrease, gaps between fibres increase
112 MSS30 9 D DMD blood test findings CK x 100-1000
113 MSS30 10 D What does each of these detect: Mnemonic SNOW DROP: South for DNA, North for RNA, West for Protein. East for
Northern, Eastern, Southern, Western post-translational modifications.
blot
114 MSS30 11 D Note: DMD genetics question: Please Ok.
draw genetic diagram out! Low accuracy
if not.
115 MSS30 1 B Rank the severity of DMD related DMD > Outliers > Becker's type MD
conditions
116 MSS30 2 A Inheritance pattern of DMD? X-linked recessive

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 117 MSS31 1 D 6 functions of skin Physical barrier (Prevent loss of: Electrolytes, water, UV, toxic chemicals, micro-
organisms, allergens), Thermoregulation (Eccrine sweating & vasodilation), Repair of
injury, Immunity (Innate, Acquired; Anti-microbial peptides, APC e.g. Langerhans,
Dendritic), Endocrine (Vitamin D, Glucocorticoids, Sex hormones), Psychosocial
118 MSS31 2 B Cause of atopic dermatitis Decrease epidermal level of ceramides, Filaggrin mutation
119 MSS31 3 D 4 common dermatological conditions Atopic dermatitis (Ill defined lesion), Psoriasis (Well-defined, Munro's microabscess,
arthropathy), contact (Irritant vs. Allergic: Very well defined), Cutaneous infection
120 MSS32 1 B Where is the sympathetic center located? Lateral horn of T1-L2
121 MSS32 2 B Where is the parasympathetic center Brainstem, S2-4
located?
122 MSS32 3 C Sympathetic paravertebral ganglia 3C, 12T, 4L, 4S, 1Impar
123 MSS32 4 C Sympathetic prevertebral ganglia Celiac, Aorticorenal ,Superior mesenteric, Inferior mesenteric
124 MSS32 5 D 6 splanchnic nerves Sympathetic: Greater (T1-9; Celiac). Lesser (T10-11; Renal), Least (T11-12;
Abdominal), Lumbar (L1-2, Hypogastric), Sacral (Sacral sympathetic trunk, Inferior
hypogastric). Parasympathetic: Pelvic (S2-4, Terminal ganglia)
125 MSS32 6 C Pathway of sympathetic nervous system Lateral horn > White communicating ramus (at T1-L2) > Sympathetic chain (go up
and down) > leave at gray ramus / be splanchnic nerve (T5 below), go to prevertebral
ganglia and leave.
126 MSS33 1 C 3 types of reflex Spinal somatic, Spinal autonomic, Cranial autonomic, Short reflex
127 MSS33 2 A Stretch reflex Examples & Explained (& e.g. Tonic vibration at tendon, Knee jerk, Ankle jerk, Biceps & triceps reflex.
Tonic vibration reflex) Stretch>Muscle spindle>Sensory neuron Ia>monosynaptic>alpha motor
neuron>contraction. Supplementary actions: [1] Reciprocal inhibition, [2] Alpha-
gamma co-activation (for intrafusal muscle fibres)
128 MSS33 3 A Golgi tendon reflex Increase in tension (due to muscle contraction) >Golgi tendon organ>Sensory neuron
Ib>polysynaptic>alpha motor neuron less firing>Relax
129 MSS33 4 B Flexor withdrawal reflex Pain>Pain receptor>afferent>Polysynaptic>alpha motor neuron more>Flexor
contraction
130 MSS33 5 B Crossed extensor reflex If ipsilateral flexed, then contralateral extended
131 MSS33 6 B Superficial cord reflex Examples & Plantar(Babinski), Abdominal. Test higher motor neuron (corticospinal tract)
Function.

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 132 MSS33 7 B Defecation reflex Faeces & Stretch > Stretch receptor > Sensory nerve > Spinal cord >Parasympathetic
nerve > Rector & Sigmoid colon contraction, internal anal sphincter relaxation
133 MSS33 8 B Micturition Reflex Faeces & Stretch > Stretch receptor > Sensory nerve > Spinal cord >Parasympathetic
nerve > Bladder contraction & internal urethral sphincter relaxation
134 MSS33 9 B Pupillary reflex (Please CHECK your Light>Photoreceptor>Optic nerve>Midbrain>Oculomotor nerve (parasympathetic)>
answer) Pupillary constrictor muscle contraction (Direct & Consensual response)>Smol pupil
135 MSS33 10 C Chemoreceptor Blood CO2 up/O2 down/pH down>Chemoreceptor>Vagus & glossopharyngeal nerve
(Vasovagal)>More parasympathetic (less sympathetic)> VC (HR increase)
136 MSS33 11 C Baroreflex BP increase>Baroreceptor>Vagus & glossopharyngeal nerve>more sympathetic; less
parasympathetic>HR decrease & VD
137 MSS33 12 D Function of reflex Posture, Protection, Excretory, Automatic (e.g. pupillary), Homeostasis [HAPPE]
138 MSS33 13 B Reflex center of: Biceps C5-6
139 MSS33 14 B Reflex center of: Triceps C7
140 MSS33 15 C Reflex center of: Supinator C6-7
141 MSS33 16 B Reflex center of: Knee L2-4
142 MSS33 17 C Reflex center of: Ankle S1
143 MSS33 18 C Reflex center of: Plantar L4-S2
144 MSS33 19 B Characteristics of Spinal reflex in [1] Stereotyped (a) Motor response, e.g. flexion. (b) Coordination, e.g. reciprocal. (c)
movement Locomotor pattern, e.g. walking. [2] Controlled sensitivity, e.g. alpha-gamma co-
activation. [3] Other characteristics: Fast, involuntary, innate. [4] Function:
Protection.
145 MSS33 20 A Important: Vibration of tendon is what Stretch reflex (NOT golgi tendon!), activating muscle spindle
reflex?

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SUPPLEMENTARY DIAGRAM

MSS2223 Q1 Draw a diagram showing the ligaments of vertebrae

~The End~