Movement

and
Musculoskeletal Biology
Module
Reflexes – MMB 002
Cartilage – MMB 003
Organizational Pattern of Limbs (Evolutionary Biology) – MMB 004
Connective Tissue Fibrous Proteins – MMB 008
Muscle Proteins and Contractile Mechanisms – MMB 011
Neuromuscular Junction – MMB 012
Muscle Embryology/Development – MMB 016
Muscle Function in Health and Disease – MMB 019
Mediators of Acute Inflammation – MMB 022
Degenerative Joint Diseases – MMB 024
Infection of Bone, Joint, and Muscle – MMB 025
Cell and Moleculary Biology of Bone – MMB 033
Fuel Selection in Muscles – MMB 034
Bone Diseases – MMB 038
Joint Replacement and Osteointegration – MMB 046d
The Walking Cycle – MMB 057
Autoimmune Diseases – MMB 059
The Professional Duty of Self-Care – MMB VM2013
Muscle Pathologies – MMB ?
Joint Pathologies – MMB ?
Acute Inflammation – MMB ?
Musculoskeletal Systematics – MMB ?
Abnormal Bone Growth – MMB ?
Cohort Studies – MMB ?
Relevant Clinical Examinations – MMB ?

Reflexes – MMB 002

Key Concepts
-Reflex: simple response to a sensory input
-Types: Skeletal Muscle
•Voluntary Contraction:
-Definition: purposeful contraction
-Example: e.g. Fine Contraction (as is performed by Distal Limb Muscles) or Gross Contraction (as is performed by
Axial and Proximal Limb Muscles)
•Reflex Contraction:
-Definition: automatic contraction
-Example: e.g. Muscle Tone (for various purposes such as to maintain upright posture)
-Effectors: Motor Neurons

•Upper Motor Neuron:

-Site: Cerebral Cortex and Brainstem
-Function: direct effector signal to Lower Motor Neurons
-Pathway: Higher Cortical Centers à Brainstem (Cranial Nuclei) à Spinal Cord
-Corticonuclear Fibers: as the UMN descends it can give off small projections in the Brain Stem to Cranial
Nuclei (of Cranial Nerves)
•Lower Motor Neuron:
-Site: Spinal Cord (Ventral Horn) and PNS
-Function: induce contraction of target muscle
-Pathway: Spinal Cord à Effector Muscle
-Subdivisions: based on type of muscle fiber innervated
•Alpha Motor Neurons (α-MN):
-Function: innervate extrafusal muscle fibers
-Significance:
1) Extrafusal fibers are the most abundant type of muscle fiber
2) Significance: highest LMN conductance velocity
Beta Motor Neurons (β-MN):
-Function: innervate both intrafusal and extrafusal muscle fibers and therefore involved in both
muscle contraction and responsiveseness of the sensory feedback from Muscle Spindles
-Subdivisions: depending on type of intrafusal fibers they innervate
•Static: innervate Nuclear Chain Fibers
•Dynamic: innervate Nuclear Bag Fibers
•Gamma Motor Neurons (γ-MN): innervate intrafusal fibers thereby keeping Muscle Spindles taut
(thereby allowing continued firing of Alpha Motor Neurons and subsequent muscle contraction)
-Requirements:
→ Voluntary Contraction:
1) Intact Muscle
2) Intact Upper Motor Neuron
2) Intact Lower Motor Neuron
→ Reflex Contraction:
1) Intact Muscle
2) Intact Lower Motor Neuron
3) Intact Pathway of a Reflex Arc
-Pathway: Stimulus → Sensory Receptor → Afferent Limb → Integrating Center → Efferent Limb → Effector Organ → Response
-Examples:
→ Protective: Eye Blink, Gag Reflex, Limb Withdrawal Reflex
→ Regulatory: Vestibulo-Ocular Reflex (maintains gaze), Muscle-Stretch Reflex (helps maintain limb position)

Effectors of Reflexes
•Motoneurons:

-Definition: effector Neurons which stimulate muscular response

-Site:
•Cell Body: Ventral Horn of the Spinal Cord

•Axon: projects outwardly (to Effector Muscle)

-Distribution:
-Distal Muscles Motoneurons: located in the Lateral aspect of the Ventral Horn
-Proximal Muscles Motoneurons: located in the Proximal aspect of Ventral Horn
•Anterior Horn Cells (AHCs):
-AKA: Ventral Horn Cells
-Definition: cell bodies of Alpha Motor Nerves which innervate skeletal muscles fibers (and spindles)
-Site: Anterior Gray Matter of Spinal Cord
-Types: two types of cells located in the Ventral Horn of Spinal Cord
1) Interneurons: axons carry impulses within the Spinal Cord (e.g. Renshaw Cells)
2) Motor Neurons: axons carry impulses to the outside of the Spinal Cord
•α-Motor Neurons: supply ordinary contractile Skeletal Muscle Fibers (i.e. contracton of extrafusal muscle
fiber)
•γ-Motor Neurons: supply modified contractile Skeletal Muscle Fibers (i.e. contraction of intrafusal
muscle spindle)
-Specifically: to make central region more taut (thereby inducing increased sensory discharge of
muscle spindle central region)
•α-Motor Neurons:
-Impulses: controlled by →
1) Sensory Neurons: in Dorsal Root Ganglion
2) Interneurons: inside the Spinal Cord Gray Matter
3) Descending Fibers: from higher brain centers
-Site:
à Cervical and Lumbosacral Segments:
-Function: control proximal and distal muscles
-Specific:
→ Medial vs Lateral Spinal Cord:
-Medial α-Motor Neurons: supply Proximal Limb muscles (i.e. gross movements)
-Lateral α-Motor Neurons: supply Distal Limb muscles (i.e. fine movements)
→ Ventral vs Dorsal Spinal Cord:
-Ventral α-Motor Neurons: supply Flexors
-Dorsal α-Motor Neurons: supply Extensors
 à Thoracic Segments (below T1): control of axial muscles
•Motor Unit:

-Definition: single Motor Neuron and its associated/innervated muscle fibers

-Significance: basic unit of motor organization
-Types:
•Small Motor Units: may innervate 10-20 Muscle Fibers, high input resistance
•Large Motor Units: may innervate >1000 Muscle Fibers, low input resistance
-Entity: Motor Neuron Pool – total motor neuron projection to a single Muscle (can span several Spinal Cord segments)
•Muscle Spindle:

-Definition: specialized encapsulated mechanoreceptor that monitors muscle length

-Function: detect changes in muscle length (especially stretch)
-Site: ends of capsule attached to tendon of the Muscle
-Composition: consists of 3-10 Intrafusal Fibers parallel to ordinary contractile Extrafusal Fibers

•Central Part: responds to stretch by sending afferent fibers to Spinal Cord (i.e. non-contractile)
 •Peripheral Part: receives γ-efferents from Spinal Cord à causes contraction of central part of Muscle Spindle
-Types: of fibers
Nuclear Bag Fibers Nuclear Chain Fibers

-Definition: dilated area containing collection of nuclei -Definition: non-dilated area containing chain of nuclei
-Amount: 1-3 Fibers in each spindle -Amount: 3-9 Fibers in each spindle
-Function: detects onset of stretch -Function: detects sustained stretch
-Rate: rapidly-adapting (i.e. phasic) -Rate: slowly-adapting (i.e. tonic)
-Mode: acts dynamically -Mode: acts statically
-Effect: stop discharge in maintained stretch -Effect: does not stop discharge in maintained stretch
-Size: longer and thicker than Nuclear Chain Fibers -Size: shorter and thinner than Nuclear Bag Fibers
-Attachment: attached to ends of Nuclear Chain Fibers -Attachment: attached to ends of Nuclear Bag Fibers
-Afferent: both Primary Afferent (Annulospiral) and -Afferent: only Secondary Afferent (Flower Spray)
Secondary Afferent (Flower Spray)

-Innervation:

Afferent Efferent
(from the Central Receptor/ Sensory part…) (... to the Peripheral Contractile part)

1st Afferent 2nd Afferent γ-Static γ-Dynamic

-Term: Type-Ia (Primary -Term: Type-II (Secondary -Innervates: peripheral -Innervates: peripheral
Afferent) Afferent) part of Nuclear Chain part of Nuclear Bag Fibers
-Type: Annulospiral -Type: Flower Spray Fibers -Mode: acts dynamically
-Innervates: Nuclear Bag -Innervates: Nuclear Chain -Mode: acts statically
Fibers and Nuclear Chain Fibers (only)
fibers -Rate: slow conduction
-Rate: rapid conduction -Mode: acts statically
-Mode: acts dynamically
and statically
•Golgi Tendon Organ:
-Definition: proprioceptive seonsory receptor organ that sense changes in muscle tension
-Site: tendons of Skeletal Muscle (specifically at the myotendinous junctions)
-Stimulus: activated when tendon attached to an active muscle is stretched

Stretch Reflex
-Definition: reflex contraction of a muscle in response to its stretch
-Purpose:
1) Negative feedback reflex that helps maintain limb position as loads vary (i.e. returns muscle back to its normal length
when stretched)
2) To prevent muscular injury (i.e. hyperextension)
-Nomenclature/Classification: there are multiple names for the same phenomenon depending on the entity being described
•Stretch Reflex: according to stimulus
•Myotatic Reflex: according to receptor and effector
•Muscle Spindle Reflex: according to receptor
•Muscle-to-Muscle Reflex: according to sites of stimulation and response
-Components:
-Stimulus: stretch of the muscle
-Receptor: Muscle Spindle (intrafusal fibers)
-Afferent: Type Ia (rapid conductance) and Type II (slow conductance)
-Center: Spinal Cord (and AHCs specifically)
-Efferent: Aα (LMN = α-Motor Neurons)
-Response: contraction of stretched muscle
-Significance: the only monosynaptic reflex in the body (i.e. direct contact between afferent and efferent fibers)
-Cause:
1) Rapidly-Conducting Afferents
2) Least Central Delay (i.e. no Interneuron; monosynaptic)
3) Rapidly-Conducting Efferents
-Effect: fast and relatively-invariant contraction of stretched muscle
-Characteristics:
1) Spinal Deep Reflex (i.e. Spinal Cord is the center, deep receptors in muscle)
2) Short Reflex Time: due to no interneuron involvement (i.e. monosynaptic)
3) Reciprocal Innervation: contraction of a muscle accompanied by relaxation of its antagonist
4) Higher Centers: activity is controlled by higher centers changing the activity of the γ-Neurons
-Stimulation:
1) Lengthening of the whole muscle
2) γ-Efferent discharge
-Inhibition:
1) Active Muscle Contraction
2) Stimulation of the Stretch Reflex of the Antagonist Muscle
3) Stimulation of Golgi Tendon Organ Reflex (i.e. inverse stretch reflex)
-Types:
Dynamic Static

Stimulus Sudden Stretch Maintained Stretch

Receptor Nuclear Bag Fibers Nuclear Chain Fibers

Afferent Type Ia Type Ia and Type II

Center AHCs AHCs

 Efferent Aα and γ (i.e. Alpha-Gamma Aα and γ (i.e. Alpha-Gamma
Coactivation) Coactivation)
Effector Extrafusal Extrafusal

Response Sudden Contraction Maintained Contraction

Time Within a second Prolonged

Example Tendon Jerk Muscle Tone

-Functions:
1) Constitutes the basis of Muscle Tone:
-Definition: continuous partial submaximal contraction of Skeletal Muscle during rest (but increases in resistance
to passive stretch)
-Type: Static Stretch Reflex
-Causes:
-length of muscle is shorter than the distance from origin to insertion
-effect of gravity
-continuous γ-Static Discharge
-Effects:
-maintains body temperature
-maintains viscera position
-maintains venous and lymphatic return
2) Assists Voluntary Movements
-Mechanism: α-γ Coactivation (Load Reflex)
-Pathway:
a- Supraspinal facilitatory impulses activate both α-Motoneurons and γ-Motoneurons → contraction of
both Extrafusal Fibers and Peripheral Contractile Part of Nuclear Bag Fibers → receptor becomes sensitive
to stretch even during muscle contraction
b– Unexpected increase in load → stretch of the muscle → stimulation of the central receptor part →
increase in impulses in afferent → more excitation of the α-Motor Neurons → reflex potentiation of
muscle contraction
-Benefits:
1) Allows muscle contraction with minimal nervous energy
2) Ability of muscle to maintain a constant position despite application of different weights (i.e. Load
Reflex)
3) Compensates for muscle weakness or fatigue
-Specific:
•Passive Stretch:

-Definition: both intrafusal and extrafusal fibers stretch

-Status: Spindles activated
-Pathway: Type-Ia Fiber à CNS à Alpha Motor Neurons à Secondary Contraction
-Tension: stretch is too weak to activate Golgi Tendon Organs
•Active Contraction:
 -Definition: contraction of extrafusal fibers only
-Status: Spindle not activated
-Pathway: central excitation of Alpha Motor Neurons à contraction of extrafusal muscle fibers à relaxation of
intrafusal fibers (i.e. Spindle not activated)
-Pattern: tension is low and does not adjust to increased resistance (Tendon Organ activated à causes relaxation)
•Alpha-Gamma Coactivation:

-Definition: contraction of both intrafusal and extrafusal muscle fibers

-Status: Spindle activated
-Pathway: contraction of intrafusal and extrafusal muscle fibers à Spindles activates à reinforce contraction
stimulus via Type-Ia Fibers in accordance with resistance à if load too great Tendon Organ activated thereby
causing relaxation

Other Reflexes
•Reciprocal Stretch Reflex: the Type 1a inhibitory Interneuron provides the pathway for the reciprocal stretch reflex that allows
relaxation of the Antagonist muscle during stretch of the Agonist

•Golgi Tendon Reflex:

 -AKA: Inverse Stretch Reflex
-Definition: reflex relaxation of a muscle in response to its severe stretch/contraction
-Components:
-Stimulus: high tension due to severe stretch or contraction of the muscle
-Receptor: Golgi Tendon Organ
-Afferent: Type-Ib
-Center: Spinal Cord (AHCs with inhibitory Interneuron)
-Efferent: inhibition of Aα
-Effector: contractile extrafusal fibers
-Response: relaxation
-Benefits:
1) Prevents rupture and avulsion of tendon in case of severe increase in tension
2) Equalizes the contraction force between muscle fibers during voluntary contraction
•Polysynaptic Reflex:

-Definition: reflex involving more than 1 synapse

-Example: Limb Withdrawal Reflex
 -Definition: painful stimulation to a limb produces flexion withdrawal of the stimulated limb (as well as extension
of opposing Limb)
-Association: withdrawal reflex always occurs in tandem with Cross-Extension Reflex (i.e. reflex of opposing Limb)
-Purpose (of extension of other limb): to provide body support

Clinical Reflexes
•Ankle Reflex:

-AKA: Achilles Reflex

-Procedure: have patient sit on the edge of the examination bench with leg hanging freely à place relaxed foot in
dorsiflexed position à strike the Achilles Tendon with the hammer
-Purpose: tests the functionality/integrity of the Calf Muscles and the nerves that supply them
-Roots: S1 and S2
-Finding:
→ Normal: jerking of foot towards its plantar surface (i.e. plantarflexion)
→ Pathological: excessive or absent jerking of foot

•Patellar Reflex:

-Procedure: have patient sit on the edge of the examination bench with leg hanging freely à gently tap Quadriceps Tendon
(below the Kneecap)
-Purpose: tests the functionality/integrity of the Quadiceps Femoris and the nerves that supply them
 -Roots: L2, L3, L4
-Findings:
→ Normal: contraction of Quadriceps Femoris (coordinated with relaxation of the antagonistic flexor hamstring
muscle) thereby causing the leg to kick
→ Pathological: excessive or absent jerking of leg
•Brachioradialis Reflex:
-Procedure: have patient sit on the edge of the examination bench à place forearm at 90- angle to arm à strike the distal
end of the Radius either directly or above thumb à observe forearm movement
-Purpose: tests the functionality/integrity of the Quadiceps Femoris and the nerves that supply them
-Roots: C6
•Biceps Reflex:

-Procedure: have patient sit on the edge of the examination bench with the hand being examined at a 120- angle (and legs
relaxed) à place thumb on Biceps Brachii tendon à strike thumb with Reflex Hammer and observe arm movement
-Purpose: tests the functionality/intergrity of the Biceps Brachii and the nerve that supply them
-Roots: C5 and C6
-Findings:
→ Normal: reflex contraction of the Biceps Brachii (jerk of the Forearm)
→ Pathological: excessive or absent jerking of arm
•Triceps Reflex:

-Procedure: have patient sit on the edge of the examination bench and raise arm so that forearm is hanging loose at a 90-
angle to the arm à strike the Triceps Tendon with the sharp end of a Reflex Hammer
-Purpose: tests the functionality/intergrity of the Biceps Brachii and the nerve that supply them
-Roots: C6, C7
-Findings:
→ Normal: contraction of the Triceps Brachii
→ Pathological: excessive or absent jerking of arm

Cartilage – MMB 003

Composition
-Overview: combination of Cells and Matrix
-Cells:
•Chondrocytes
-Type: differentiated cells
-Site: located in Lacunae spaces
-Levels:
a– Young Chondrocytes: small oval and present singly in their lacunae
b– Mature Chondrocytes: large and present singly or in groups/clusters (‘cell nest’)
-Separation of Individuals Cells (in Cell Nest): by a thin layer of Matrix
-Separation of Clusters: by large amounts of Extracellular Matrix
-Volume: cells occupy 1%—10% of total Cartilage volume
-Special Features: cells are not interconnected (as opposed to Osteocytes in Bone)
•Chondroblasts:
-Definition: differentiated Chondrocyte progenitor of mesenchymal origin
-Function: produce Extracellular Matrix
-Matrix: composed of Ground Substance and Fibers

→ Ground Substance:
-Composition: mixture of long unbranched polysaccharide chains each composed of repeating disaccharide units
-Units: the Disaccharides are either Uronic Acid or an Amino Sugar (either N-Acetyl Glucosamine or N-Acetyl
Galactosamine; collectively referred to as Glycosaminoglycans or GAGs)
-Components:
•Glycosaminoglycans (GAGs):
-pH Level: acidic (i.e. negatively-charged) due to presence of Hydroxyl, Carboxyl, and Sulphate
side groups
-Examples:
→ Main: Hyaluronic Acid (only one with without Sulphate side groups)
→ Other: Chondroitin-4-Sulphate, Chondroitin-6-Sulphate, Dermatan Sulphate, Heparan
Sulphate, and Keratan Sulphate (differ from Hyaluronic Acid in that they are covalently-
linked to a variety of protein molecules to form Proteoglycans)
-Attachment: attach to non-collagenous protein core to form Proteoglycans
-Proteoglycans:
-Definition: huge molecules consisting of 90%—95% Carbohydrate
 -Purpose: form noncovalent links with Hyaluronic Acid Chains to form even larger molecular complexes
(polyanionic macromolecules) which bind large quantities of water (via Osmotic Pressure) within the
tensile web of Collagen Fibers (= the stiff gel-like consistency of Cartilage)
-Examples:
•Aggrecan: high molecular weight Proteoglycan characterized by a ‘bottlebrush appearance’ due
to the attachment of Chondroitin Sulfate—Keratan Sulfate GAGs to an extended protein core
Decorin: composed of a protein core containing Leucine repeats and a Glycosaminoglycan chain
containing either Chondroitin Sulfate or Dermatan Sulfate
→ Fibers:
-General Composition: the fibrous component consists of Collagen Type-I, Collagen Type-II, and Elastin
-Collagen Type-II: main type of Collagen in Cartilage and is the main component of the meshwork structure
-Notice: there are no nerves, blood vessels, or lymphatic vessels in Cartilage

Functions

1) Dissipation of Force:
-Cause: composite matrix (i.e. mixture of Collagen and Proteoglycans) and general fluid flow
-Purpose: lightens the burden of loading force (e.g. body weight, effect of gravity, change in momentum) and prevent
damage of the other supporting structures
2) Flexibility:
-Cause: presence of Connective Tissue
-Purpose: maintain shape/structure and resists deformation
3) Protection:
-Cause: relative strength of composite matrix
-Purpose: protects the joints by absorbing shocks and prevents friction
4) Development:
-Cause: endochondral ossification
-Purpose: assists in the development and growth of Long Bones
5) Structuring:
-Cause: presence of Connective Tissue and relative strength of composite matrix (relative interplay between multiple
opposing forces)
•Aggrecan: huge osmotic pressure inflates Cartilage with water (gel-swelling pressure)
•Collagen Type-II Fibers: hold Cartilage together by resisting gel-swelling tendency
•Hyaluronon: tethers/stabilizes the Aggrecan
-Purpose: acts as molding for intricate body structures (e.g. Ear Pinna, Nose Cartilage)

Types
•Hyaline Cartilage:
-Significance: basic adult Cartilage type
-Composition:
→ Water: 60%—80%
→ Collagen (predominantly Type-II):
a– Dry Weight: 40%—50%
b- Wet Weight: 10%—20%
→ Proteoglycans: 1.5%—10% (stiffness content)
-Sites: Articular Cartilages, Growth Plates, Nasal Septum, and Respiratory Tract (except for Epiglottis, Costal Cartilages, and
Fetal Skeleton)
-Repair/Healing: does not repair and slow turnover
•Elastic Cartilage:
 -Composition: similar to Hyaline Cartilage (i.e. Collagen Type-II) matrix except with more Elastic Fibers (for more
elasticity/flexibility)
-Sites: Ear Pinna, External Auditory Canal, Eustachian Tube, Epiglottis
•Fibrocartilage:
-Definition: alternating layers of Hyaline Cartilage matrix (predominantly Collagen Type-II) and Dense Collagen Type-I Fibers
with rows of Chondrocytes located within their Lacunae
-Nomenclature: named Fibrocartilage because Chondrocytes packed so close together that they are almost completely flat
(i.e. resembling Fibroblasts)
-Composition: Collagen Type-II (main) and Collagen Type-I (80% dry weight)
-Sites: Meniscus of Knee Joint, Intervertebral Discs, Symphysis Pubis

Perichondrium
-Description: dense irregular Connective Tissue that surrounds various cartilage types
-Sites: Perichondrium envelopes Hyaline Cartilage and Elastic Cartilage (but does not envelop Articular Cartilage or Fibrocartilage)
-Composition: composed of an Outer Fibrous Layer and an Inner Chondrogenic Layer
→ Outer Fibrous Layer:
-Definition: dense fibrous Connective Tissue containing Blood Vessels, Nerves, and Lymphatics (Fibroblasts and
Collagen Type-I)
-Function: muscle attachment and source of nutrition for Cartilage
→ Inner Chondrogenic Layer:
-Definition: highly-active layer containing Chondroblasts (i.e. less differentiated cells; resemble Fibroblasts) and
lacking in Lacunae
-Function: differentiate into Chondrocytes and secrete Cartilage components (Matrix and Collagen Type-II)

Cartilage/Bone Growth and Turnover

-Growth:
-Types:
•Appositional Growth:
-Site: periphery of Cartilage/Bone
-Process: Chondrocytes of the Perichondrium differentiate into Chondroblasts (as well as Matrix
synthesis) on surface of pre-existing Cartilage → formation of new cells and Matrix (at the Cartilage
boundary)
-Effect: increase in width
2) Interstitial Growth:
-Site: within the Cartilage/Bone (generally the Epiphyeal Plates)
-Process: isolated Chondrocytes divide to form characteristic nests or columns of Chondrocytes à secrete
new matrix from already-formed Cartilage (i.e. requires Hyaline)
-Effect: increase in length
-Longevity: some Cartilage are temporary while others are permanent
→ Temporary: e.g. Growth Plate, Meckel’s Cartilage, Base of Skull
→ Permanent: e.g. Nasal Septum, Trachea, Bronchioles, Articular Cartilage, Intervertebral Discs
-Process: based on sequence of zone changes
1) Zone of Resting/Reserve Cartilage
2) Zone of Proliferation: cells divide → form columns → matrix formation
3) Zone of Hypertrophy: Chondrocytes enlarge → Matrix formation
4) Zone of Calcification: Matrix mineralizing → death of most Chondrocytes (most probably by Apoptosis)
5) Erosion: blood vessels and osteogenic cells invade up lacunar rows
6) Ossification: bone formation on calcified Cartilage scaffolding
-Turnover:
-Definition: the process and rate at which Cartilage matter is replaced
-Characteristics:
1) Vascularity: avascular
2) Nourishment: by diffusion of nutrients and oxygen from à
a- capillaries in Perichondrium
b- Synovial Fluid in joint cavities
3) Cellularity: low
4) Metabolic Rate: low metabolic rate in Adult Cartilage (i.e. slow turnover of extracellular matrix)
5) Repairability: does not repair
 6) Turnover Rate: Proteoglycans > Collagen

Mineralization of Cartilage

-Definition: the scaffold upon which endochondral bone is formed

-Sites/Instances:
1) Junction of Articular Cartilage and Subchondral Bone: ‘tidemark’ zone of calcified Cartilage
2) during Endochondral Ossification
3) Hyaline Cartilage (as part of aging process)

Bone Ossification
-Overview: there are two main ways of forming bone (Intramembranous Ossification and Endochondral Ossification)
•Intramembranous Ossification:
-Definition: direct laying down of bone into the primitive Connective Tissue (Mesenchyme) without a pre-existing Cartilage
template
-Process: proliferation of Mesenchymal Cells into Osteoblasts à Osteoblasts form Ossification Center à synthesize bone

-Order: Spongy Bone formed first followed by Compact Bone

-Examples:
a- Prenatal/Intrauterine: formation of Flat Bones of Skull (i.e. Maxilla, Frontal Bone, Parietal Bones)
b- Postnatal: healing process of Bone fracture
•Endochondral Ossification:
-Description: ossification of Cartilage on ready-made template
-Process: two main processes distinguished by prenatal and postnatal onset
 èPrenatal: embryonic Mesenchyme condenses into hyaline cartilaginous model à formation of Primary
Ossification Center (occurs in middle of Diaphysis/Shaft) à Perichondrium becomes Periosteum (and
Osteoprogenitor Cells in Periosteum become Osteoblasts) à formation of Bone Collar (appositional growth) to
support new bone à Chondrocytes in Primary Ossification Center begin to grow/hypertrophy à secrete Alkaline
Phosphatase à calcification of the Cartilaginous Matrix and Chondrocytes degenerate thereby leaving spaces à
periosteal buds carry Osteoblasts and blood vessels to enter the spaces à Osteoblasts use calcified matrix as a
scaffold and begin to secrete Osteoid à Osteoid secretion forms the Bone Trabeculae à Osteoclasts break down
spongy bone to form the Medullary Cavity (AKA: Bone Marrow)
è Postnatal: Secondary Ossification Center appears in each Epiphysis of Long Bones à similar process of
ossification as in Primary Ossification à unossified Cartilage left between the Primary Ossification Center and the
Secondary Ossification Center (called Epiphyseal Plate) à Epiphyseal Plate continues to form new Cartilage which
is subsequently replaced by Bone (bone-elongation process) à growth continues until the Epiphyseal Plate is
replaced by Bone à point of union of the Primary Ossification Center and Secondary Ossification Center eventually
forms thin line (called Epiphyseal Line)
-Zones: Sequences of Zones well defined and characterized
•Zone of Resting/Reserve Cartilage
•Zone of Proliferation: cells divide forming columns à matrix formation
•Zone of Hypertrophy: Chondrocytes enlarge à matrix formation
•Zone of Calcification: matrix mineralizing (death of Chondrocytes; most often by apoptosis)
•Zone of Erosion: blood vessels and osteogenic cells invade up lacunar rows
•Zone of Ossification: bone formation on calcified cartilage scaffolding (i.e. site at which Bone grows longer)
-Example:
a- Prenatal/Intrauterine:
-development of most of the Fetal Skeleton (most Long Bones)
-formation of Skull Base (i.e. Occipital Bone, petrous part of Temporal Bone)
b- Postnatal: growing Growth Plates (continues until adulthood)
-Significance: appearance of Bone can be used to determine age of babies and children radiographically (due to defined
ossification centers and predictable sequence of ossification)

Cartilage/Bone Pathologies
•Vitamin D Deficiency:
-Premise: Vitamin D responsible for mineralization
-Pathology: degree of severity relative to age
è in Adults: causes Osteomalacia
-Onset: after Epiphyseal closure
-Site of Affection: affects bone only (not the growth plate)
-Pathophysiology: newly-formed bone Matrix fails to mineralize → proportion of mineralized bone matrix
reduced → softening of the bones
è in Children:
-Effect: causes Rickets
-Pathophysiology: defective mineralization/calcification of bones in children → widening of the Growth
•Osteoarthritis:
-Significance: most common joint disease (60% of over-35s have Osteoarthritis changes in at least one joint)
-Pathophysiology: progressive loss of Hyaline Cartilage on the articular surface of bones → abrasion of Collagen meshwork
and loss of PG aggregates → Cartilage erosion and bon outgrowths (Osteophytes) → deformity
-Cause: localized condition resulting from trauma/wear & tear/fatigue
•Rheumatoid Arthritis:
-Definition: systemic inflammatory disorder
-Pathophysiology: immune system attacks the joint (including the Cartilage, Bone, and the Synovial Membrane) → if left
untreated Cartilage and Bone erosion → fibrosis and joint deformities

Organizational Pattern of Limbs (Evolutionary Biology) – MMB 004

Tetrapod Limb Radiation
-Definition (Tetrapod): vertebrates with four limbs
-Premise: human limbs are the product of evolutionary transformations that reshaped the fin-shaped appendages of fish-like
ancestors
-Characteristics: all Tetrapods (including humans) have upper and lower limbs with a central bony axis composed of →
a- A single arm or thigh bone (e.g. Humerus, Femur)
b- Two forearms or leg bones (e.g. Radius + Ulna, Tibia + Fibula)
c- Numerous wrist and ankle bones (e.g. Carpals, Tarsals)
d- Numerous limb tips (e.g. Phalanges)

Limb Development
-Overview: out-pocketing of Ectoderm (striated muscles and their innervation) filled with Mesoderm (i.e. bones, tendons,
vasculature, fascia, dermis)
-Embryological Development: limbs can be regarded as specialized protuberances of segments of the body wall →
→ Upper Limb: C5—C7/C8 and T1
→ Lower Limb: L2—S3
-Body Cavities: not involved in limb formation

Comparative Organizational Patterns

-Characteristics: applies to all Tetrapods
•Central Axis: axis along which the central bone elements of the limbs form
•Borders:
→ Pre-Axial: faces anteriorly
→ Post-Axial: faces posteriorly
•Muscle Attachments:
-Pattern: future Skeletal Muscle cells migrate either ventrally or dorsally in relation to the Central Axis
-Origin: Dermomyotome
-Comparison:
•Fish (Fins):
→ Upper Limbs:
→ Ventral Muscles: attach to Coracoid Ossification Element to lower fins
→ Dorsal Muscles: attach to Scapular Ossification Element to lift fins
→ Lower Limbs:
→ Ventral Muscles: attach to Ischium and Pubis to lower fins
→ Dorsal Muscles: attach to Ilium and Vertebrae to lift fins
•Land Animals:
-Pattern: reorganization of the Central Axis bones reorganized to lift the body off the ground (by bending them) as
compared to fins
-Similarity:
a- Original division into dorsal and ventral muscle cells remain the same
b- Positions of the Pre-Axial and Post-Axial Borders remain the same
c- Joint and limb orientation similar to that of fish ancestor (i.e. laterally-protruding)
•Mammals:
-Pattern: simultaneous rotations of limbs by 90- around Central Axis and 90- medio-laterally results in limb position
under body rather than sticking out sideways
 → Upper Limbs:
→ Pre-Axial Border: faces dorsally
→ Post-Axial Border: faces ventrally
→ Ventral Muscles: faces forwards/cranially
→ Dorsal Muscles: faces backwards/caudally
→ Lower Limbs:
→ Pre-Axial Border: faces ventrally
→ Post-Axial Border: faces dorsally
→ Ventral Muscles: faces backwards/caudally
→ Dorsal Muscles: face forwards/cranially
-Similarity: border position and cell origin
•Humans:
→ Upper Limb (Muscle Groups):
→ Dorsal Muscles: e.g. Shoulder Extensors, Elbow Extensors, Wrist and Finger Extensors
→ Ventral Muscles: e.g. Shoulder Flexors, Elbow Flexors, Wrist and Finger Flexors
→ Lower Limb (Muscle Groups):
→ Dorsal Muscles: e.g. Knee Extensors, Ankle Extensors (for Dorsiflexion), Spinal Extensors Spinal
Erectors, Hip Extensors, Hip Abductors
→ Ventral Muscles: e.g. Spinal Flexors, Hip Flexors, Hip Adductors, Knee Flexors, Ankle Flexors (for Plantar
Flexion)

Connective Tissue Fibrous Proteins – MMB 008

Introduction
-Role: CT fills the spaces between organs/tissues and provides structural and metabolic support for other tissues/organs
-Composition: of CT
1) Cells
2) Extracellular Matrix (i.e. water, minerals, proteoglycans, fibrous proteins)
-Types: variations in the compositions of Extracellular Matrix determines the properties and function of the Connective Tissue
-Example: calcified matrix can form Bone or Teeth
-Properties:
1) Extended protein structure
2) Insoluble in water or lipid bilayers
3) Secondary Structure is simple (i.e. based on 1 type)
4) Quaternary Structure is held together by covalent bridges

α-Keratin
-Hallmarks: external protection, toughness
-Sites: Hair, Nails, Outer Layer of Skin
-Origin: made by Epidermal cells
-Composition:
-Definition: the entire Secondary Structure is an α-Helix and the α-Keratin is constructed from two supercoiled α-Helices
-Properties:
a– Rich in specific amino acids that favor α-Helix formation (i.e. Phenylalanine, Isoleucine, Valine, Methionine,
Alanine)
b– Hydrophobic sidechains on the α-Helix surface result in its insolubility
c– Rich in Cysteine residues which form Disulfide Bridges between Cysteines in separate α-Helix in order to
connect them
-Effect: the more Disulfide Bridges the stronger the α-Helix
-Order:
→ Dimer: two parallel α-Helices supercoil around each other
→ Tetramer: two dimers coiled together
→ Protofibril: arrangement of every dimer antiparallel with another dimer
→ Four-Stranded Rope: association of four Protofibrils
→ Supersecondary Structure: refers to all the secondary structures collectively

Elastin
-Definition: insoluble rubber-like protein
-Hallmarks: elasticity, stretchability
-Sites: Ligaments, Lung Walls, Elastic Blood Vessels (e.g. Aorta)
-Origin: synthesized by Fibroblasts and Chondrocytes
-States:

-Fibrous: when extended

-Globular: when relaxed
-Significance: implicated in Cardiovascular Disease and Lung Emphysema
-Composition:
-Precursor: Tropoelastin
-Process: synthesis of Proelastin → conversion to Tropoelastin → secretion into the extracellular space
-Properties:
a– Soluble Tropoelastin rich in Glycine, Valine, Alanine, Proline, and Lysine but contains little Hydroxyproline and
no Hydroxylysine
b– Crosslinking of Tropoelastin (via Lysine residues) gives Elastin extensive interconnection (ergo, rubber
consistency)
c– Some of the Lysyl residues of Trophoelastin are oxidatively-deaminated (via Lysyl Oxidase) into Allysin
-Levels:
•Amino Acid Composition:
-Overiew: 33% Glycine — 23% Alanine —13% Valine —10% Proline (i.e. ~80% of the residues come from
only 4 amino acids)
-Effect: this configuration allows Elastin network to deform (due to the fact tat the sidechains do not
interact with each other by H-bonds)
•Crosslinks:
•Desmosine:
-Definition: four Lysine residues linking 2, 3, or 4 Tropoelastin molecules
-Composition: formed of four Lysines (3 of which are oxidized)
-Cross-Link: three Allysine and one Lysine form the Desmosine crosslink
-Effect: specific configuration allows Elastin an extensively-interconnected and rubbery network
that can bend and stretch in any direction
•Lysinonorleucine: two Lysine residues linking 2 Tropoelastin molecules
•Aldol: two Lysine residues linking 2 Tropoelastin molecules
-Others: most notably the β-spiral
-Hallmark: able to stretch and relax like a coiled spring
-Composition: constructed from helices of β-turns based on the sequence of Valine, Proline, and Glycine

Collagen
-Significance: most abundant protein in the body
-Sites: Tendons, Inner Skin, Cartilage, Bones, Cornea
-Origin: synthesized by Fibroblasts and Chondrocytes
-Configuration:
-Precursor: Tropocollagen
-Description: long and thin protein
-Levels:
→ General: three coiled α-chain peptides
-Orientation: each chain is a left-handed helix
 -Safeguard: presence of Proline prevents right-handed helix formation
-Outcome: the three left-handed peptide chains are tightly twisted to form a right-handed superhelix
(Tropocollagen molecule)
→ Amino Acid Composition: α-chain always contains the repeating triplet sequence (Gly—X—Y)
•X: Proline (but can sometimes be occupied by Lysine)
•Y: Hydroxyproline (but can sometimes be occupied by Hydroxylysine)
Attachments: Glucose and Galactose attach to Hydroxylysine residues and so Collagen is considered a Glycoprotein
-Properties:
1) Residues per Turn: 3.3
2) Glycine Contribution: Glycine residues points towards the center of the triple-helix and makes polypeptide chains very
close to each other
3) Proline and Hydroxyproline Contributions: sidechains point outwardly and form covalent link with the mainchain
Nitrogen atom thereby consolidating the structure of the triple-helix
-Added Benefit: high Hydroxyproline content forms Hydrogen-bonds between chains
4) Tensile Strength: due to formation of covalent cross linkages between adjacent polypeptide chains
-Types:
-Overview: 16 main Collagen types (from various combinations of 30 different polypeptide chains)
-Main:
•Type I:
-Composition: contains two α1 chains and one α2 chain (α12α2)
-Sites: Bone, Skin, Tendon, Ligaments
•Type II:
-Composition: contains three α1 chains (α13)
-Sites: Cartilage, Intervertebral Discs, Vitreous Humour
•Type III:
-Composition: contains three α1 chains (α13)
-Sites: Skin, Blood Vessels, Internal Organs
•Type IV:
-Composition: contains three α1 chains (α13)
-Sites: Basement Membrane
-Synthesis: comprised of four main stages
Step 1) Formation of Procollagen: three separate pro-α-chains are synthesized inside the cell → selected Proline and Lysine
residues are hydroxylated to Hydroxyproline and Hydroxylysine → selected Hydroxylysine residues are glycosylated → three
pro-α-chains assemble at the C-terminus end starting with the disulfide bridge formation between the three chains → the
three chains ‘zip-up’ to form Procollagen
Step 2) Cleavage of Procollagen to Tropocollagen: N-terminal and C-terminal peptides of Procollagen are cleaved by
Prollagen Peptidase
Step 3) Assembly of Tropocollagen: spontaneous formation of one-quarter staggered array of Tropocollagen molecules by
means of noncovalent hydrogen bond interactions involving the Hydroxyl Group of Hydroxyproline
-Pattern: Collagen fibers show periodic cross-striations every ~67nm
-Gaps: there are 40nm gaps between the Tropocollagen molecules (where Calcium Phosphate is deposited during
bone formation)
Step 4) Crosslinking of Collagen Fiber: Collagen fiber is stabilized by covalent crosslinks that are formed between Lysine
residues
→ Aldol Link: joining two CHO groups leads to Aldol

→ Lysinonorleucine Link: joining one CHO and one NH2 group on two Lysine residues leads to Lysinonorleucine

-Related Pathologies:
•Osteogenesis Imperfecta:
-AKA: Brittle Bone Syndrome
 -Pathogenesis: mutant Collagen gene (buried Glycine residue is mutated to Cysteine) → partially-unfolded triple-
helix at the N-terminal end → Tropocollagen subunits cannot associate in regular packing and Collagen fiber
formation becomes weaker
-Manifestations: easily-fractured bones, slight spinal curvature, loose joints, long-tapering extremities, poor muscle
tone, hearing loss, blue sclerae
•Ehlers-Danlos Syndrome:
-Pathogenesis: reduced levels of Procollagen Peptidase results in Procollagen not being fully converted to
Tropocollagen
-Process: the 40nm gaps between Tropocollagen molecules become blocked by uncleaved peptides which
prevent Lysyl Oxidase from acting on Tropocollagen to create the crosslinks
-Manifestations: stretchable skin, hypermobile joints, short stature
•Scurvy:
-Pathogenesis: lack of Ascorbate (Vitamin C) impairs the reaction of Proline with Prolyl Hydroxylase (as it is
required as a cofactor)
-Manifestations: poor Collagen fibril formation, skin lesions, fragile blood vessels walls
•Lathyrism:
-AKA: another form of Ehlers-Danlos Syndrome
-Pathogenesis: inhibition or lack of Lysyl Oxidase → affects crosslinking of Collagen
-Process: β-aminopropionitrile prevents conversion of Lysine to the Aldehyde form (via irreversibly
inhibiting Lysyl Oxidase)
-Causes:
a– ingestion of sweet pea seeds with β-aminopropionitrile
b– Copper deficiency (Copper required for full activity of Lysyl Oxidase)
-Manifestations: deformation of spine, dislocations of joints, demineralization of bones, joint hemorrhage, aortic
aneurism

Muscle Proteins and Contractile Mechanisms – MMB 011

Key Concepts
-Muscle: grouping of muscle fiber cells bound together by Connective Tissue
-Myofibrils: cylindrical bundles in muscle fibers
-Sarcomere: unit of repeating pattern
-Filaments:
→ Thick Filament: Myosin
→ Thin Filament: Actin (and other proteins)
-Tendon: links bones to skeletal muscle

Muscle Contraction Structural Organization

-Regions
•A-band: wide band of Myosin
•H-zone: narrow region in center of A-band which constitutes the space between two sets of Thin Filaments
•M-Line: region in center of H-zone with proteins that link central regions of adjacent Thick Filaments
•Z-line/disc: two sets of Thin Filaments anchored to network of proteins at this point
-Contribution to Defining the Sarcomere: two successive Z-lines makes a Sarcomere
•I-band: contains portions of Thin Filaments that do not overlap Thick Filaments
•M-line: center of Sarcomere
-Proteins:
•Actin:
-Defintion: globular multi-functional protein which forms the backbone of the Thin Filament
-Structure: two intertwined helical chains with binding sites for Myosin
-Sub-structures: chains closely associated with Tropomyosin and Troponin which contribute to the regulatory
mechanisms of contraction
•Myosin:
-Definition: molecular motor protein that contributes structural and enzymatic roles in muscle contraction and
intracellular motility
-Significance: most abundant class of the molecular motor proteins (i.e. Myosin, Dynein, Kinesin)
-Structure: six protein subunits combine to form a protein with two heads and a long tail
-Sub-structures:
 a- Tail: lies along axis of Thick Filament
b- Heads: two heads form Cross-Bridges (each head contains bonding site for Actin and ATP)
-Contribution: Myosin proteins at ends of Thick Filaments oriented in opposite directions so that Thin Filaments
are brought towards the center of Sarcomere
•Troponin:
-Definition: group of smaller regulatory proteins bound to both Tropomyosin and Actin
-Effect: binds Calcium ions and drags Tropomyosin off of Myosin-binding site thereby initiating contraction
(removal of Ca2+ reverses the processes and contraction stops)
•Tropomyosin:
-Definition: group of integral proteins involved in regulating the function of Actin filaments
-Structure: rod-shaped molecule composed of two intertwined proteins arranged along the length of the Thin
Filament
-Effect: covers the Myosin-binding sites in absence of Calcium
-Cross-Bridges: extend from surface of Myosin towards Thin Filaments

Sliding Filament Mechanism

-Process: Myosin Cross-Bridges attach to Thin Filaments and force Thin Filaments to slide towards M-line (past stationary Thick
Filaments) thereby shortening the Sarcomere → Cross-Bridges repeat motion as long as stimulation to contract continues
-Cycle: of cross-bridges
-Overview: events from the initial biding of the Cross-Bridge to the Thin Filaments to the process of repeating the sequence
-Steps:
1) Cross-Bridge Binding:
-Pattern: energized Cross-Bridge bind to Actin when Ca2+ levels are high
-Sub-Structures: ADP and Pi are already bound to the Cross-Bridge
2) Cross-Bridge Movement (‘Power Stroke’): release of Pi causes Cross-Bridge to move towards the H-zone of the
Sarcomere → Actin Filament moves towards H-zone → ADP is released
3) Cross-Bridge Detachment: ATP binds to Myosin thereby causing the Cross-Bridge to detach from the Actin
Filament
4) Cross-Bridge Resetting: hydrolysis of ATP to ‘ADP + Pi’ provides energy → causes Cross-Bridge to move away
from the H-zone → ADP and Pi remain bound to the Cross-Bridge → cycle may begin again

Excitation-Contraction Coupling
-Definition: the Ca2+-mediated link between the membrane excitation and the mechanical contraction
-Premise: Skeletal Muscle Cells are capable of generating and propagating Action Potentials
-Processes:
-Initiation: rise in cytosolic Ca2+ released from Sarcoplasmic Reticulum → Transverse Tubules (T-tubules; invaginations of
plasma membrane) conduct the Action Potential from outer surface to inner surface→ triggers contraction
-Termination: on pumps return Ca2+ to the Sarcoplasmic Reticulum → Troponin and Tropomyosin slide back into place →
contraction stops
-Specific: Neuromuscular Junction
-Definition: junction of Motor Neuron Axon and the Muscle Fiber
-Organization:
→ Axon: divides into terminals containing vesicles of Acetylcholine
→ Junctional Folds: region of muscle fiber under Axon terminal that is folded in order to increase surface area
-Process: Na+ flows into muscle cell → depolarization wave and Action Potential

Skeletal Muscle Function

-Premise: different muscle fibers contain forms of Myosin that differ in the maximal rates at which they can hydrolyze ATP
-Types: can be categorized based on different criteria
a- by ATPase Activity
→ Fast Fibers: contain Myosin with high ATPase activity
→ Slow Fibers: contain Myosin with low ATPase activity
b- by Mitochondrial Content
→ Oxidative Fibers: contains numerous Mitochondria and have a high capacity for Oxidative Phosphorylation
-Dependent on: blood flow in order to deliver Oxygen and nutrients for ATP production
-Contains: large amount of Myoglobin as an intracellular reservoir for Oxygen
→ Glycolytic Fibers: contains few Mitochondria but a high concentration of Glycolytic Enzymes and large stores of
Glycogen
 -Contains: very few Myoglobin (responsible for the characteristic pale/white appearance)
c- by interplay of ATPase Activity and Mitochondrial Content (i.e. main categorizations of Muscle Fibers)
→ Slow-Oxidative Fibers: low rates of Myosin ATP hydrolysis but produces large amounts of ATP (i.e. used for
prolonged regular activity)
→ Fast-Oxidative Fibers: high Myosin activity and produces large amounts of ATP (i.e. suited for rapid actions)
→ Fast-Glycolytic Fibers: high Myosin activity but produces small amounts of ATP (i.e. suited for rapid intense
actions but fatigues quickly)
-Changes:
•Hypertrophy:
-Definition: increased amounts of exercise can produce an increase in the size of Muscle Fibers and their capacity
for ATP production
-Causes: exercise
-Outcome: increase in muscle size due to increase in size of individual fibers
•Atrophy:
-Definition: reduction in size of Muscle Fibers and their capacity for ATP production
-Causes: physical inactivity or impairment of Neuromuscular Junction
-Outcome: decrease in muscle size due to decrease in size of individual fibers

Role of Genetics
è Myosin Genetics:
-Molecular History: among the most ancient and conserved Eukaryotic proteins
-Specific Gene: MYH16
→ History: mutation occurred 2.4 million years ago (around the time the genus Homo appeared)
→ Expression: expressed in jaw muscles of many nonhuman primates but is a nonfunctional mutant in all humans
→ Scientific Implication: smaller/less muscular jaws may have allowed the Skull and Brain to grow larger
è Muscle Fibers Genetics:
-Specific Gene: PPAR-delta
→ Expression: activation results in expression of genes that enable cells to burn fat more efficiently
-Experimental Trials: breeding of transgenic mice expression the PPAR-delta gene in Skeletal Muscle lead to mice that
gained less weigh and had a dramatic shift to Slow-Oxidative Muscle Fibers
→ Scientific Implication: ratios of Oxidative Fibers and Glycolytic Fibers can change in Skeletal Muscle

Smooth Muscle Excitation and Contraction

-Characteristics:
-Tissue: fusiform, non-striated
-Nucleus: single centrally-placed nucleus
-Contraction: non-voluntary and modulated in a neuroendocrine manner
-Sites: Blood Vessels, GI Tract Walls, Urogenital Organ Walls, and Dermis of Skin
-Contraction:
-Triggers: voltage-gates Ca2+ channels (via depolarization), mechanical stimuli, neural stimulation
-Process: Ca2+ ions released from Caveolae/SER → complex with Calmodulin → Ca2+—Calmodulin Complex activates Myosin
Light-Chain Kinase → MLCK phosphorylates Myosin Light Chain → Myosin unfolds and binds Actin → ATP-dependent
contraction cycle ensues → contraction continues as long as Myosin is phosphorylated
-Coupling: via Gap Junctions
-Latch State: Myosin heads attached to Action dephosphorylated causing decrease in ATPase activity thereby rendering
Myosin head unable to detach from Actin (i.e. similar to Rigor Mortis in Skeletal Muscle)
-Organization:
-Components:
•Dense Bodies: plaques into which Actin filaments insert (analogous to Z-lines in Skeletal Muscle)
•Myosin Heads: oriented in ‘side polar’ arrangement
-Effect: contraction, pulls dense bodies together in a slow and sustained manner

Relevant Pathologies
•Rickets:
-Definition: improper mineral deposition causing bone deformities
-Causes: inadequate dietary Calcium intake, inadequate absorption of Calcium from the Small Intestine
-Presentation:
a- Widening of Wrists
 b- Bowing of Legs (bow-legs)

-Treatment/Prevention: Vitamin D supplementation

•Osteoporosis:
-Definition: reduction of both mineral and organic portions of Bone
-Causes: disruption of normal balance between bone formation and bone breakdown
-Treatment/Prevention: adequate Calcium intake, weight-bearing exercises, adequate dietary Vitamin D
•Myasthenia Gravis (MG):
-Definition: Skeletal Muscle fatigue and weakness
-Causes: autoantibodies that inactivate Nicotinic Acetylcholine Receptors (nAChRs) on Skeletal Muscles
-Treatments/Preventions: enzyme inhibitors (to allow Acetylcholine to persist), immune system suppression,
plasmapheresis (to remove antibodies from blood)
•Muscular Dystrophy:
-Definition: progressive degeneration of Skeletal Muscles and Cardiac Muscles
-Type: most common form is Duchenne Muscular Dystrophy (sex-linked recessive disorder)

Neuromuscular Junction – MMB 012

Key Concepts
-Action: Neuromuscular Transmission – transmission of impulse from α-Motor Neuron to Skeletal Muscle Fibers
-Innervation: Skeletal Muscle fibers innervated by large myelinated nerve fibers that originate from large motoneurons in the
Anterior Horns of the Spinal Cord
-Branches: each nerve fiber branches and stimulates 3–100+ Skeletal Muscle fibers
-Input: each Skeletal Muscle Fiber receives only one Axon terminal (i.e. only one junction per fiber)
-Ending: nerve fiber forms a complex of branching nerve terminals that invaginate into the surface of the muscle fiber (but
lie outside of the muscle fiber plasma membrane) à terminal branch communicates with the muscle fiber via the
Neuromuscular Junction
-Collective: the complex of branching nerve terminals as well as their Neuromuscular Junctions are collectively
referred to as the Motor End Plate
-Envelopment: Schwann Cells insulate the fibers from the surrounding fluids
-Pathway: Nerve Fiber/Axon à Motor End Plate (terminal nerve branches + Neuromuscular Junctions)

Neurotransmitter System
-Effector: Acetylcholine
-Source: ATP is the main energy source for synthesis of neurotransmitter (i.e. Acetylcholine)
-Origin: Mitochondria in the axon terminal
-Actions:
•Vesicle Cycle:
 -Defintion: mechanisms by which vesicles inside the Neuron collect, compartmentalize, and transport relevant
effector molecules
-Process: Acetylcholine synthesized in cytoplasm of axon à Acetylcholine absorbed rapidly into small Synaptic
Vesicles à secretory vesicles move to and fuse with nerve ending cell membrane (i.e. Active Zone) à area of
fusion between the vesicle and the cell membrane breaks down à release of Acetylcholine (without vesicles) into
Synaptic Cleft via exocytosis
-Control: Acetylcholine released from vesicles into Synaptic Cleft as a result of entry of Calcium ions (i.e. the
effective stimulus)
-Process: neurotransmitter Action Potential spreads over axon terminal à Calcium Channels open and
allow Calcium ions to diffuse from synaptic space to the interior of the axon terminal à Calcium ions
activate Ca2+-Calmodulin Dependent Protein Kinase à Kinase phosphorylates Synapsin proteins that
anchor the Acetylcholine Vesicles to the cytoskeleton and aids in their movement to the Active Zone
(where they are released)
-Requirements:
a– Calcium
b– Docking Proteins
•Neuromuscular Transmission:
-Definition: overall system of conducting and propagating an Action Potential throughout Skeletal Muscle
-Process: Action Potential carried by Voltage-Gated Sodium Channels → reaches Nerve Ending → causes
depolarization and opening of Voltage-Gated Calcium Channels (in Active Zone regions) → Calcium ions enter
Nerve Ending → triggers docking and membrane fusion of Acetylcholine vesicles → exocytosis of Acetylcholine into
Synaptic Cleft (~20—100 vesicles of Acetylcholine released) → Acetylcholine concentration rises rapidly (to around
1mM) in the Synaptic Cleft → binds to Nicotinic receptors on the Motor Endplate → binding triggers the opening of
Sodium and Potassium Ligand-Gated Channels in muscle fiber → muscle fiber membrane depolarizes (End-Plate
Potential/EPP; due to inward Sodium conductance being greater than outward Potassium conductance) →
Acetylcholine channels close as Acetylcholine is rapidly dissociated from the receptors (within 1-2 milliseconds)
and degraded by Acetylcholinesterase (present in high concentration in the Synaptic Cleft) into Acetate and
Choline
-Safeguard: there are certain mechanisms that prevent muscular excitation/contraction issues
a- dissociation and degradation of the Acetylcholine in the Synaptic Cleft prevents multiple muscle
contractions
b- some released Acetylcholine is hydrolyzed before even reaching receptors
-Recycling: new Acetylcholine vesicles can be formed later from invagination of the presynaptic membrane and/or
the uptake of Choline
•End-Plate Potential:
-AKA: Local Potential
-Definition: sudden insurgence of Sodium ions into muscle fiber – when Acetylcholine-Gated Channels open – that
causes the electrical potential inside the fiber (at the local area of end-plate) to increase in the positive direction
(as much as +50mV—+75mV)
-Trajectory: Action Potentials are generated on either side of the End Plate and are conducted away from the End
Plate in both directions along the Muscle Fiber
-Phenomenon: Quantal Release
-Premise: neurotransmitters are released from presynaptic terminals in discrete ‘quanta’
-Pattern: spontaneous events similar to Motor End-Plate Potentials evoked by presynaptic stimulation in relation to
waveform, spatial localization, and drug sensitivity
-Example (Miniature End-Plate Potentials/MEPPS): due to spontaneous release of Acetylcholine from the
presynaptic motor neuron
-Research:
 -Finding: evoked EPPs show superimposed responses to stimulation of the Presynaptic Motor Neuron
-Implication: EPP consists of multiple, mini-like quanta of Acetylcholine
-Clinical Relevance: Induced Muscle Stimulation
→ Direct Muscle Stimulation: direct stimulation of voltage-gated T-tubules initiating muscle contraction (without going into
the steps of Acetylcholine release)
→ Indirect Stimulation: stimulation of the nerve releases Acetylcholine which binds to the receptors over the muscle
opening ligand-gated Na+ channels thereby initiating End-Plate Potential

Skeletal Muscle Contraction

-Standard: normal Resting Membrane Potential is between -90mV and -80mV
-Initiation:
-AKA: Excitation-Contraction Coupling
-Process: Action Potential in muscle cell membrane causes depolarization of voltage-sensitive T-tubule Dihydropyridine
Receptor (penetrates all the way through the Muscle Fiber from one side of fiber to the other) → activated Dihydropyridine
Receptors trigger opening of the Sarcoplasmic Reticulum’s Ryanodine Receptors → Calcium Channels of the Terminal
Cisternae open and release Calcium into the muscle cytoplasm
-Units: the amount of Calcium released in each muscle fiber during each contraction is the same
-Factors: several factors determine force generation
1) Types of Muscle Fibers: the interplay of ratios of Slow-Twitch Fibers to Fast-Twitch Fibers
-Types:
•Slow-Twitch Fibers (Type I):
-Color: Red
-Purpose: muscular endurance
•Fast-Twitch Fibers (Type II):
-Color: White
-Purpose: muscular power
-Distribution: most muscles are a mixture of Slow-Twitch Fibers and Fast-Twitch Fibers
-Factors: determined by the following
a– Contractile Proteins
b– Troponin I
c– Motor Nerve Activity
-Examples:
→ Soleus (Slow Muscle):
-Express: α-Actinin-2 and Troponin-I Slow (Tnls)
-Effect: aerobic muscle optimized for long-endurance feats (e.g. distance running)
→ Tibialis Anterior (Fast Muscle):
-Express: α-Actinin-2, α-Actinin-3, and Troponin-I Fast (Tnlf)
-Effect: muscle optimized for powerful bursts of motion (e.g. sprinting)
-Principles: muscles rely on the physiological principles of ‘Recruitment’ and ‘Summation’ to bring about
productive motion
→ Recruitment: increasing the number of motor units responding to a single stimulus when the
stimulation amplitude (i.e. strength) is increased thereby resulting in the increase in tension in the whole
muscle
→ Summation: increase in tension that results when a Muscle Fiber is unable to relax between twitches
due to increased stimulation frequency
-Order: during aerobic exercise Slow-Twitch Fibers contract first until they fatigue at which point Fast-Twitch Fibers
are recruited to take over
 -Overall Strength:
-Control: CNS
-Factors: dependent on number of activated motor units and the synchrony of their activation
-Spectrum: asynchrony of motor unit activation allows generation of Smooth Muscle contraction of
varying strength depending on the frequency of Motor Neuron Action Potentials (~5-25Hz)
-Example (of high frequency Action Potential): Laryngeal Nerves
2) Frequency of Muscle Electrical Stimulation:
-Factors:
a- Muscle Twitch:
-Definition: stimulation of the muscle by a single stimulus causes contraction (ascending part)
followed by relaxation (descending part)
-Effects: muscles can respond to repeated stimulation (i.e. the contractile mechanism does not
have a refractory period) during the Contraction Phase and/or Relaxation Phase which therefore
means that multiple muscle twitches can coexist simultaneously (Phenomenon: Summation of
Contractions)
b- Degrees of Frequency Changes:
# of Twitches Effect

Muscle Twitch Single Stimulus

Pair of Twitches Two Stimuli
-Interval: 100ms apart
-Stimulation Frequency: 10Hz
Partially-Fused Tetanus Five Stimuli
-Interval: 40ms apart
-Stimulation frequency: 25Hz
Tetanus Multiple Stimuli
-Interval: 10ms apart
-Stimulation Frequency: 100Hz
c- Effect of Summation of Contractions: the tension developed during summation is greater than that
developed during single muscle twitch due to cytosolic Calcium remaining highly elevated with continuous
repeated activation of the contractile mechanism during rapid repeated stimulation
-Phenomenon: Tetanus
-Definition: an infection caused by bacteria called Clostridium tetani
-Types:
•Partially-Fused/Incomplete Tetanus: periods of incomplete relaxation between the summated
stimuli
•Complete Tetanus: no relaxation between stimuli
3) Strength of the Stimulation of the Muscle:
-Premise: each Muscle Fiber obeys the All-or-None Law according to its threshold stimulus
-Relationship: Excitation-Contraction Relationship
-Definition: the rapid communication between electrical events occurring in the plasma membrane of
skeletal muscle fibres and Ca2+ release from the SR, which leads to contraction
-Process: increasing the stimulus strength (amplitude) will increase the number of activated Muscle Fibers
in the muscle
-Levels:
→ Maximal Stimulus: results in all muscle fibers being activated
→ Supramaximal Stimulus: does not result in any change in muscle response above that of the
Maximal Stimulus
4) Length—Tension Relationship:
-Premise: both the Total Tension (tension that a muscle develops when stimulated to contract isometrically) and
the Passive Tension exerted by the unstimulated muscle vary with the length of the muscle
 -Equation: Active Tension = Total Tension — Passive Tension
-Effects:
→ Effect of Tension: Maximal Tension dependent on optimal interaction between Thick Filaments and
Thin Filaments
→ Effect of Length:
-Premise: the greater the initial length of the muscle (before contraction) the greater the Active
Tension developed during contraction
-Nomenclature: Resting Length – length of muscle at which the Active Tension is maximal
-Changes:
→ Normal Stretching: optimizes the overlap between Actin and Myosin Cross-Bridges
→ Excessive Stretching (> Resting Length): decreases overlap between Actin and Myosin
→ Decreased Stretching (< Resting Length): decreases developed Active Tension
5) Force—Velocity Relationship:
-Calculation:
-Equations: Power = Work / Time = Force x Distance / Time = Force x Velocity
-Variables:
•Power: proportional to velocity of contraction
→ Isotonic Contraction: produces Power
→ Isometric Contraction: 0 Work = 0 Power
•Maximal Velocity of Contraction (Vmax): determined by maximal ATPase activity of the Myosin
-Peak: maximum power is developed when the muscle shortens at about 1/3 of Maximum Velocity
-Influencers: Velocity
-Premise: the greatest force developed in a muscle is when there is no velocity and at maximal velocity
the muscle develops little force
-Relationship: if the speed of the contraction is increased while the force remains constant the power will
increase but increased velocity and high forces cannot be developed by Muscle Fibers at the same time
-Phenomenon: Iceberg Effect
-Definition: margin of safety mechanism implanted by muscle physiology in order to guarantee proper and full Action
Potential excitation and contraction
-Examples:
1) Neurotransmitter Release: ~5x as much Acetylcholine is released from the Nerve terminal as is needed to evoke
a Muscle Fiber Action Potential
2) End-Plate Potential Level: the EPP is much bigger than needed to reach the threshold for Action Potential
generation in the Muscle Fiber
3) Neurotransmitter Receptors: ~75% of all Acetylcholine Receptors need to be blocked to reduce the EPP below
threshold
4) Twitch Block: occurs at about 96% receptor block
-Influencers:
1) Neuromuscular Blockers:
-Examples:
a- Atracurium: competitive inhibitor to Acetylcholine on the Acetylcholine Receptor
b- Curare: competitive inhibitor to Acetylcholine on the Nicotinic Acetylcholine Receptor
c- Insecticides: block Acetylcholine Receptors on the Motor End Plate
-Effect: competitive antagonist to Acetylcholine that binds to post-synaptic Nicotinic receptors thereby preventing
propagation of stimulus
2) Neuromuscular Blocker Competitors: Anticholinesterase
-Example: e.g. Neostigmine, Edrophonium
 -Functionk: reduce degradation of Acetylcholine thereby increasing its availability to compete with these blockers
over Acetylcholine Receptors

Clinical Examples of Muscle Weakness

•Myasthenia: autoimmune disorder that results in the loss of Acetylcholine Receptor by autoantibodies
-Effect: Skeletal Muscles tire easily and may lead to paralysis (especially of Respiratory System)
-Treatment: Anticholinesterase
•Neuromuscular Block:
-Defintion: block Acetylcholine function on relevant receptors
-Example: Alpha-Bungarotoxin Venom (from Elapid snakes): Neurotoxin that binds competitively and in a relatively
irreversible manner to the Nicotinic Acetylcholine Receptors
-Effect: paralysis, respiratory failure, death
•Insecticide Poisoning: desensitization of Acetylcholine Receptors and depolarizing Neuromuscular Block

Muscle Embryology/Development – MMB 016

Limb Development
-Components:
è Limb Buds:

-Definition: a proliferation of embryonic tissue shaped like a mound from which a limb develops
-Site: Limb Buds develop from the ventro-lateral aspect of the body wall
-Onset:
à Forelimbs: begins at around the 24th day
à Hindlimbs: begins at around the 28th day
-Completion: by the 4th Week of gestation
-Sequence:

-Composition: epidermal jacket enclosing Lateral Plate Mesoderm

-Initiator: Apical Ectodermal Ridge (AER)

-Definition: ridge of columnar cells that form at the distal end of the Limb Buds
-Function: induces limb growth
 è Limb Muscle:

-Origin: Limb Muscle is formed by the Myotome region of Somites

-Course: Myotome Cells migrate into the Limb Bud during the 5th week of human development → forms large
Dorsal and ventral Condensations →
è Dorsal Muscle:
→ Forelimb: forms the Extensors and Supinators of the forelimb
→ Hindlimb: forms the Extensors and Abductors of the hindlimb
è Ventral Muscle:
→ Forelimb: forms the Flexors and Pronators of the forelimb
→ Hindlimb: forms the Flexors and Adductors of the hindlimb
-Navigation: Myotome Cells are attracted to the Limb Bud in response to Hepatocyte Growth Factor (HGF;
signaling molecule secreted by Limb Bud Cells)
-Innervation: the Limb Muscle are innervated by branches of Spinal Nerves C5—T2 on the Forelimb and L4—S3 on
the Hindlimb
-Types: both Motor Neurons and Sensory Neurons invade the Limb Bud
-Signaling: Limb Muscles not responsible for attracting Axons to the Limb Bud but they do regulate the
final branching pattern in the Limb
-Patterning:
-Axes: there are three main axes on which the patterning of the limbs occurs →
1) Proximal-Distal Axis
2) Anterior-Posterior Axis
3) Dorsal-ventral Axis
è Proximal-Distal Patterning:
-Order:
→ General Rule of Thumb: Proximal elements always differentiate first
-e.g. Humerus >> Radius and Ulna >> Carpals >> Metacarpals >> Phalanges
-e.g. Femur >> Tibia and Fibula >> Tarsals >> Metatarsals >> Phalanges
→ Special Ordering: Digits differentiate as ‘4 >> 3 >> 2 >> 1 and 5’ (i.e. digit numbers; Thumb = 1 – Little
Finger = 5)
-Process: Limb Bud Mesenchyme proliferates rapidly driving growth along the Proximal-Distal Axis
-Effector:
→ Main: Apical Ectodermal Ridge (AER)
-Significance: the source of a mitogen responsible for promoting cell division in Limb Bud
Mesenchyme
-Effects: removing the AER too early or too late results in morphological pathologies (e.g. distally-
truncated limbs)
→ Alternative: AER can be replaced by implanting Fibroblast Growth Factor (FGF)
-Process: FGFs diffuse into Limb Bud Mesenchyme and stimulates cell proliferation thereby
promoting Limb outgrowth
-Additional: FGF can stimulate the formation of an extra limb provided that the bead is implanted
in the Lateral Plate Mesoderm between the Forelimb and the Hindlimb
 -Organization: secretion of FGF by the AER maintains a high rate of cell division in the directly underlying
Mesenchyme but less so in the lower areas thereby creating layered strata of variable growth rates and FGF
concentrations (i.e. Progress Zone and Differentiation Zone)
→ Progress Zone: high FGF and high mitosis rates
→ Differentiation Zone: low FGF and low mitosis rates
-Model: the Two-Signal Model
-Definition: current most highly-supported model that explains the Proximal-Distal Patterning by
describing its Proximal Fates and Distal Fates
-Outcomes:
→ Proximal Fate: specified by Retinoic Acid from the flank
→ Distal Fate: specified by FGF from the AER (FGF acts as a morphogen; specifying Radius/Ulna,
Carpals, Metacarpals, and Phalanges at increasing concentrations)
-Rate: cells acquire their fate depending on how long they spend in the Progress Zone (with Proximal
Fates requiring less than Distal Fates)
è Anterior-Posterior Patterning:
-Organization: the Zone of Polarizing Activity (ZPA) is the organizing center for the patterning of the Anterior-
Posterior Axis of the Limb Bud

-Site: ZPA located on the Posterior Margin

-Developmental Relevance: ZPA may be the source of a Morphogen that specifies different digits at
different concentrations
-Structuring: the highest concentration specifying the most posterior digit and the lowest concentration
specifying the most anterior digit

-Effector: Sonic Hedgehog (Shh) codes for the Shh protein which is a morphogen that is involved in specifying digits
in a concentration-dependent manner

-Developmental Relevance: Shh is only expressed in the ZPA and mimics ZPA grafts when expressed in
Anterior Mesenchyme
-Relevant Pathologies:
→ General Mutation: Shh mutations cause distally-truncated limbs with few digits
→ Specific Mutation: GLI3 mutations cause Grieg Syndrome (i.e. Polydactyly and Syndactyly)
→ Rare Mutation: LMBR1 Gene mutations (on Intron 5)
 -Effect: cause Preaxial Polydactyly (PPD)
-Prevalence: 1 in 2000 humans
-Pathophysiology: defect in LMBR1 Gene à absence/impairment of ZRS (conserved
enhancer/regulator of Shh expression) à defective ZPA expression in the Limb Bud
→ Rare Deletion: LMBR1 Gene Deletion (including Exon 4)
-Effect: causes Acheiropodia (rare birth defect characterized by absence of distal
elements of limbs)

è Dorsal-Ventral Patterning:
-Organization: WNT7A is the signaling molecule expressed in the Dorsal Ectoderm of the developing Limb Bud

-Developmental Relevance: WNT7A has an important role in Dorsal-Ventral polarity (possible responsible
for establishing dorsal identity in the developing limb)
-Pathologies: mutations in the engrailed gene causes WNT7A to be expressed ventrally thereby forming a
double-dorsal Limb
-Morphology: Limb Size and Shape Regulation
 è Limb Bud Stages: the rate and process of Limb Bud cell proliferation differs during different stages
a- Early Limb Bud: positive feedback loop between Shh and FGF → FGF activates Shh in ZPA → activates Gremlin in
Progress Zone → Gremlin inhibits BMP (an inhibitor of FGF expression in AER) → FGF signaling and limb outgrowth
is maintained
b- Late Limb Bud: ZPA descendent cells (red dots) cannot express Gremlin and as limb size increases they form a
barrier between Shh and Gremlin domains → Gremlin is turned off and BMP activity increases → FGF expression in
the AER inactivated → limb outgrowth ceases
è Limb Interdigital Region Apoptosis: digits are initially separated by flaps of skin that must be removed by extensive
programmed cell death in the interdigital region

-Regulator: BMP signaling molecules that are only active in the interdigital region
-Differentiation: Forelimb/Hindlimb Differentiation
-Effectors: Tbx4 and Tbx5
-Initiation: expression of these closely-related genes during limb development
-Function: transcription factors that have similar functions in the developing limbs but that create slightly different
morphologies

•Tbx4: Hindlimb development

•Tbx5: Forelimb development
-Relevant Pathologies:
è Autosomal-Dominant Syndromes:
•Grieg Syndrome:
 -Cause: mutations in GLI3
-Effect: Polydactyly and Syndactyly
•Apert Syndrome:

-Casue: mutations in FGFR2

-Effect: Syndactyly
•Holt-Oram Syndrome:

-Cause: mutations in TBX5

-Effect: Phocomelia
è Non-Autosomal-Dominant Syndromes
•Amelia: complete failure of development of one Limb
•Phocomelia:

-Definition: rare congenital disorder in which the Limb bones are unusually short and the hands/feet are
malformed
-Cause: environmental factors (especially exposure to Thalidomide; drug prescribed in the 1950’s to
pregnant women to control morning sickness)
•Syndactyly: condition in which 2 or more digits are fused together
-Clinical Significance: most common congenital abnormality of the hand (1 in 2000 births)
-Cause: lack of apoptosis in the interdigital region during embryogenesis
•Polydactyly: presence of an extra finger

Muscle Tissue Differentiation

•Satellite Cells
-Definition: muscle resident myogenic Stem Cells
-Site: on the surface of the Muscle Fiber beneath the Basal Lamina
-Functions:
a-differentiate into Skeletal Muscle Cells
b-provide additional Myonuclei to their parent Muscle Fiber
c-return to quiescent state when necessary
-Process: Muscle Fibers sustain damage → signals trigger dormant Satellite Cells → Satellite Cells replicate → proliferating
Satellite Cells either form a new Muscle Fiber or patch the original one
-Additional: other Stem Cells aid in this process (e.g. Bone Marrow cells)

Muscle Function in Health and Disease – MMB 019

Muscle Types
(main types of Muscle in general: Cardiac, Skeletal, and Smooth)
-Premise: all muscles contain a mixture of both types of muscle fibers
-Classification System: types of Skeletal Muscle fibers dependent on three main factors
1) Main ATP Synthesis Pathway:
à Oxidative Fibers: predominantly aerobic pathway
-Type of Pathway: oxidative phosphorylation
-Site: Mitochondria
à Glycolytic Fibers: predominantly anaerobic pathway
-Type of Pathway: Glycolysis
-Site: Sarcoplasm
2) Amount of Myoglobin:
à Red Fibers: high amounts of Myoglobin
à White Fibers: small amounts of Myoglobin
3) Efficiency of ATPase:
à Fast-Twitch Fibers: decompose ATP rapidly
à Slow-Twitch Fibers: decompose ATP slowly
-Groups: types of Skeletal Muscle fibers are categorized into two main groups based on speed of contraction and type of enzymatic
activity used by muscle for ATP formation (which coincide)
Type I Fibers Type IIx/Type IIb Fibers
-AKA: Slow-Oxidative Fibers, Red Muscle Fibers -AKA: Fast-Glycolytic (FG) Fibers, White Muscle Fibers
-Size: small diameter -Size: large diameter
-Color: dark red -Color: light/white
-Vasculature: surrounded by many capillaries -Vasculature: surrounded by few capillaries
-Glycogen Content: low -Glycogen Content: high
-Mitochondria: contains many Mitochondria -Mitochondria: contains few Mitochondria
-Metabolism: Oxidative Phosphorylation (for ATP -Metabolism: Glycolysis (for quick synthesis of ATP)
formation) -Myosin ATPase Activity: high/rapid activity
-Myosin ATPase Activity: low/slow activity -Cross-Bridge Cycling: occurs relatively rapidly
-Cross-Bridge Cycling: occurs relatively slow -Contraction Speed: rapid
-Contraction Speed: slow -Contraction Intensity: high
-Contraction Intensity: low -Endurance Capacity: low
-Endurance Capacity: high -Suited for: short burst of power/speed exercise
-Suited for: prolonged aerobic exercise -Site: Quick Muscles (e.g. Upper Limb muscles, Finger
-Site: Postural Muscles (e.g. Lower Limb muscles, muscles, Eye muscles)
Back muscles) -Myosin Heavy Chain Isoform: MHC-IIa and MHC-IIx
-Myosin Heavy Chain Isoform: MHC-I -Fatiguability: fatigable fibers (due to increased Lactic
-Fatiguability: fatigue-resistant fibers Acid and depletion of Glycogen)

à Type IIa Fibers:

-AKA: Fast-Twitch Oxidative Glycolytic (FOG) Fibers
-Size: largest diameter
-Description: combined features of both Type I and Type IIb/IIx Fibers
-Prevalence: rare in humans
Muscular Adaptation
-Definition: adaptation of Skeletal Muscles (through training) changes the fibers
-Aim: to accustom muscles for prolonged and/or more intense activity with less fatigue
-Effects:
è General:
1) Changes in Vascular Supply and ATP synthesis capacity
2) Changes in Diameter (i.e. Cross-Sectional Area)
è Effect of Exercise: major factor of muscle adaptability based on type of exercise conducted
→ Types of Exercise:
•Regular Endurance Aerobic Exercise: submaximal effort of moderate intensity of long duration à
adaptation of Slow-Oxidative Fibers takes place in the form of changes that enable muscle to use O2 more
effectively as à
a- increased # of Mitochondria
b- increased # of Capillaries
c- increased Myoglobin content
d- increased aerobic ATP production
-Effect: increased endurance capacity
-Examples: Long Distance Running/Swimming
•Short Duration High-Intensity Exercise: adaptation of Fast-Glycolytic Fibers takes place in the form of à
a- increased Glycolytic enzymes
b- increased Muscle Fiber diameter
c- increased amount of Contractile Proteins
d- increased # of Cross-Bridges
-Effect: increased contractile strength
-Examples: 100-m Sprint, Heavy Weight-Lifting
→ Types of Exercisers:
-Premise: most of the body Skeletal Muscles contain a mixture of fiber types but the same muscle in
different individuals can vary in its proportions of fiber types
-Examples:
à Sprinter: will have more White/Fast-Glycolytic Muscle Fibers
à Long Distance Runner: will have more Red/Slow-Oxidative Muscle Fibers
-Innervation: in some ways the CNS affects the adaptability of different Muscle Fibers
à Evidence #1: this concept was shown in experimental models by Buller (1960)
-Paper: “Interaction between Motoneurons and Muscles in respect of the Characteristic Speeds of their
Responses”
-Control: normal innervation of Fast Motoneurons with Fast Muscle and Slow Motoneurons with Slow Muscle
-Experimental Models:
1- Cross-Innervation: the muscles were cross-innervated so that Fast Muscles got Slow Motoneuron
innervation and Slow Muscles got Fast Motoneuron innervation
-Effects:
a- Increase: contraction time of Slow Muscle accelerated when subjected to high
frequency discharge from Fast Motoneurons (~20-30 impulses per second)
b- Decrease: contraction time of Fast Muscle decelerated when subjected to low
frequency discharge from Slow Motoneurons (~10-20 impulses per second)
2- Isolation of Spinal Cord: spinal cord innervation was isolated
-Effects: Fast Muscle became appreciably slower following stimulation
-Conclusions: experiments suggest that Motoneurons do have an effect on muscle contractility
à Evidence #2: this concept was shown in experimental models by Pette & Staron (1997)
-Paper: “Transitions of Muscle Fibers Phenotypic Profiles”
-Control: normal neuromuscular activity/normal loading of muscular fibers
-Experimental Models:

1- Increasing Neuromuscular Activity/Overloading: e.g. Electrostimulation, Exercise, Myotonia (i.e.

delayed relaxation), Mechanical Overloading
2- Decreasing Neuromuscular Activity/Unloading: e.g. Denervation, Immobilization, Spinal Cord
Transection, Detraining, Hindlimb Suspension Microgravity
 -Conclusions: muscle fiber type transformations possible by different inputs/interventions
à Evidence #3: these concepts were shown in experimental models by Kidgell & Pearce (2011)
-Paper: multiple papers
-Conclusions: activation of Motor Units (i.e. frequency and number), involvement of Afferent & Efferent Pathways,
and Synchronization all effect adaptability of muscle fibers (in terms of Muscle Strength)
-Influencers:
à Strength Training:
•Overload:
-Defintiion: muscular changes when worked against a load which is greater than the normal
-Requirement: must be at least 65% of maximum (i.r. 1RM) but probably more than 80% to be considered
overload
•Specificity:
-Definition: adaptations that occur according to types of strength training as well as Length-tension
Relationships and Velocities used
-Examples: Isometrics, Isokinetics, Plyometrics, Functional Strength Training
•Individuality:
-Premise: individuals have different types and levels of adaptation to strength training
-Factors: e.g. genetic variability, metabolism, endocrine regulation, relative fitness level
•Reversibility: reveresibilty may occur in training programs not maintained
à Architectural Relationships:
•Cross-Sectional Area: increased CSA has a strong relationship with muscle strength
-Relationship: not 1:1 relationship as increased Isometric Force (through strength training) results in a
lesser percentage increase in CSA relative to the increased force production
-Rationale:
a- improved activation via Neural System
b- decreased drive to Antagonist via the Neural System
c- changes in Pennation angle
d- loss of Intramuscular Fat
e- Hypertrophy of individual fibers
•Muscle Length
•Rate of Change of Muscle Length
•Alignment of the Muscle (with respect to the axis of joint rotation)
-Organization:

→ Anatomical Cross-Sectional Area: area of cross-section of a muscle perpendicular to its longitudinal axis
→ Physiological Cross-Sectional Area:
-Definition: area of cross-section perpendicular to its fibers (i.e. perpendicular to direction of contractile force)
-Purpose: typically used to describe the contraction properties of Pennate Muscles

Muscle Ageing
-Premise: Ageing results in a number of changes that collectively diminish from the overall functionality and mobility fo muscle
-Changes:
1) Neural Activation:
-Characteristics:
a- Loss of Spinal Motor Neurons: due to apoptosis, reduced Insulin-like Growth Factor I signaling, elevated
 amounts of circulating Cytokines, and increased cell oxidative stress
b- Reduced Motor Neuron Excitability: in resting condition
c- Reduced Number and Diameter: of myelinated Axons and Motor End Plates
d- Elevated Presynaptic inhibition of 1a Afferents
e- Elevated levels of Antagonist Muscle Coactivation: during maximum voluntary contraction
-Regeneration: there is the capacity for re-innervation of abandoned Muscle Fibers
-Physiological Mechanism: Axonal Sprouting
-Requirement: critical threshold of 50% loss in Motor Unit number should be reached before stimulating
re-innervation process
-Enhancement: such re-innervation can be accelerated by exercise/training
-Effect of Ageing: axonal sprouting becomes inadequate or absent at old age à gradual loss of Motor
Units à substantial loss of Muscle Fibers that produce marked decreases in muscle mass and strength à
eventually leads to functional disability
-Influencers:
a- Loss of Motor Units:
-Significance: major mechanism responsible for loss of Muscle Fibers in ageing
-Effect: denervation atrophy of single Muscle Fiber could cause loss of Motor Units (but to a
lesser extent)
b- Effect of Strength Training: studies show that increased Skeletal Muscle mass (from heavy-resistance
strength training) may have important functional and metabolic benefits for elderly people
2) Changes in Muscle Mass:
-Premise: after maturity only Hypertrophy or Atrophy can occur (i.e. no Hyperplasia)
-Rates:
a- Mass: ~30%-50% decrease in Skeletal Muscle mass in both men and women between the ages of 40-80
years old
b- Strength/Power: approx. equivalent or greater associated decreased in strength/power (as rate of mass
change) with increased muscle weakness and fatiguability
-Calculation: Muscle Mass = Mean Volume (Fiber Length x Fiber Cross Sectional Area) x Number of Muscle Fibers in
a muscle
-Phenomenon: Sarcopenia:
-Definition: loss of Skeletal Muscle mass and strength as a result of ageing
-Process: can only occur as a result of either a change in CSA of individual fibers or a loss in the number of
fibers
-Extent: proportion of change depends on hereditary factors and physical activity (regularity and intensity)
-Effects:
a- decreased anatomical CSA
b- reduced amouts of Myogenic Satellite Cells
c- infiltration of non-contractile tissue (e.g. Collagen, Fat)
3) Changes in Muscle Fiber Type:
-Changes:
a- tendency of mean CSA of Fast Type II Muscle Fibers to decrease
b- tendency of mean CSA of Slow Type I Muscle Fibers to be maintained (even in elderly age)
-Mechanisms: compromised high-power muscular output due to à
a- loss of muscle mass (i.e. Sarcopenia)
b- relatively greater loss of MHC-II Isoforms (resulting from the preferential atrophy of Type-II Fibers)
-Findings:
a- significant decrease in percentage of both slow and fast MHC Muscle Fiber types in senile individuals as
compared to young adults
b- significant decrease in fiber size (CSA) of MHC Fast Muscle Fibers in senile individuals as compared to
that of young asults
c- no statistical significance between fiber size of MHC Slow Muscle Fibers between opposing age groups
d- co-expression of two types of MHC were no statistically significant between the two age groups in
relation to percentage proportion of MHC and fiber size
4) Muscle Architecture:
-Definition: organization of muscle fibers within muscle relative to line of force generation
-Factors:
a- Normalized Fiber Length
b- Pennation Angle (PA)
 c- Physiological Cross-Sectional Area
-Purpose: determines key muscular characteristics
a- Muscle Function
b- Force Production Capacity
c- Contraction Velocity
-Structure (Pennate):
-Form: pennate muscle has its fascicles attached obliquely to a central tendon at an angle to the force-
generating axis (i.e. Pennation Angle)
-Pennation Angle: angle between the longitudinal axis (i.e. force-generating axis) of the entire muscle and
its fibers
-Benefits:
a- Pennate Arangement: allows for greater number of fascicles to be packed (in parallel) in a
given volume of muscle à increases the physiological Cross-Sectional Area of the muscle
b- Fascicle Rotation: higher fascicle allows for greater fascile rotations (and thus a greater
decrease in fascicle lengths as compared to fascicles with relatively lesser fascile pennation)
-Notice: adaptive changes in muscle architecture is observed in elderly subjects in response to heavy-resistance
strength training
5) Length-Tension Relationship:
-Premise: amount of isometric tension that can be produced during a muscle contraction is dependent on the
length at which a muscle is held
-Changes: decreased elasticity of Skeletal Muscle
-Consequence: affects optimal length at which peak tension is developed
-Enhancement: stretching exercises (without forcing) may held improve muscle elasticity and optimal
muscle length
6) Possible Agonist/Antagonist Co-activation:
-Trend: antagonist coactivation may be elevated above normal levels (i.e. > 20%-25% maximum agonist activity)
during daily movement tasks
-Important Note: not a constant finding
-Enhancement: co-activation can be decreased in response to strength training
7) Hormonal Changes Affecting Muscle:
-Effector: Insulin-Like Growth Factor
-Changes:
a- elevated levels of inflammatory cytokines TNF-α and TNF-β (typically observed in the elderly) blunts the
IGF-I-mediated effects in the muscle tissue
b- markedly attenuated/reduced levels of Growth Hormone release with increasing age (in both trained
and untrained individuals)
-Physiological Relevance: local IGF-I synthesis is thought to be partially Growth Hormone/GH-
dependent in some IGF-responsive tissues
-Clinical Interventions: different effects on elderly individual muscle tissues
à administration of Growth Hormone alone upregulates the IGF-IEa mRNA isoform only
à prolonged resistance training upregulates both IGF-IEa and MGF (mechanosensistive
isoform) isoforms of mRNA (a single bout of high resistance exercise has no effect on
either of the isoforms)
-Specific:
•Lifespan Changes in Trained Individuals/Athletes:
-Performance Peak: usually mid-twenties to mid-thirties
-Common Trend: performance declines after approx. 40 years of age
-Activity Types: power/strength activity performance typically begins to decline earlier than endurance activity
performance
•Delaying Effect of Ageing:
-Premise: it is possible to delay effect of ageing in many physiological aspects
-Methods: Plyometric Training has been shown to improve performance of three main muscle contractions
1) Shortening
2) Isometric
3) Lengthening
-Effect: exercise/training in previously sedentary elderly individuals has been shown to improve multiple
physiological functions
1) Motor Neuron firing frequency
 2) Mucle Mass
3) Strength
4) Power
5) Endurance
-Methods:
-Focus: resistance rather than endurance training are preferred in sarcopenic elderly individuals for
improving neuromuscular function through inducing collateral re-innervation and increase in muscle mass
-Example: Plyometric Training (has been shown to improve performance of three main muscle
contractions: Shortening, Isometric, and Lengthening)
-Effects:
→ Positive:
a- maintenance (or even hypertrophy) of Muscle Fibers
b- improvement of Pennation Angle and muscle elasticity à subsequent improvement
of force of muscle contraction
c- magnitude of loss in muscle mass ( as loss of fiber quantity in Type IIb Fibres is
immutable/inevitable) can be ameliorated by degree of Muscle Fiber hypertrophy
d- possible decrease in antagonist muscle co-activation
→ Negative: both chronic inactivity and neuromuscular hyperactivity (e.g. excesive endurance
training) may decrease muscle fiber re-innervation in elderly

Muscle Innervation
-Components:
•Motor Unit:
-Definition: a single α-cell (or Motoneuron) along with its axons and the muscular fibers/cells it innervates
-Focus: each Motor Neuron innervates only one kind of Muscle Fiber and therefore all the Muscle Fibers
in a Motor Unit are of the same type
-Types:
1) Slow/Oxidative Muscle Fibers (Red)
2) Fast/Glycolytic Muscle Fibers (White)
-Range: there is a large range of number of fibers associated with a Motor Unit (dependent on muscle function)
→ Motor Unit of Fine Movement Muscles: 3-6 Fibers
→ Motor Unit of Gross Movement Muscles: 200-300 Fibers
-Recruitment: Motor Units are recruited according to the ‘Size Principle’ to generate increasing amounts of tension
→ Small Motor Units: low levels of activation to a Motoneuron Pool will activate the small, high-resistance
Motor Neurons of Small Motor Units
→ Large Motor Units: high levels of activation to a Motoneuron Pool will activate the large, lower-
resistance Motor Neurons of Large Motor Units
-Pathway: Lower Motor Neuron/LMN is the final common path for muscle contraction (i.e. both afferents of
Reflexes and Upper Motor Neuron (UMN) terminate on the α-cells of LMN)
•Motor Neuron Pool: the number of Motor Neurons that innervate the whole skeletal muscle
-Models:
•Hierarchical Model of Motor Control: the motor system produces three types of movement
1) Reflexive (primarily by Spinal Cord and Brainstem)
2) Rhythmic (primarily by Spinal Cord and Brainstem)
3) Voluntary (primarily by Motor Cortex)
•Motor Hierarchy: the levels involved in producing a motor function
1) Motor Idea: related to the Association Cortex and the Basal Ganglia
2) Motor Plan: related to the Motor Cortex and the Cerebellum
3) Execution: relation to the Brainstem and the Spinal Cord

Muscle Action Mechanics

-Premises:
a– whether muscles shorten when they are activated depends on the level of activation and the load upon them
b– when activated muscles always generate force at the joint (but they may be isotonic or isometric contractions)
-Components:
-Types: of Muscular Action
•Isotonic Contraction

-Definitionk: the force/tension generated by the muscle exceeds that of the load
-Effect: the muscle shortens and the load is raised against gravity
-Types:
•Concentric
•Eccentric
-Phases:
1) Concentric Isotonic: muscle shortens (e.g. lifting a load from the ground)
2) Eccentric Isotonic: muscle lengthens while contracting (e.g. lowering a load to the ground)
-Pathological/Clinical Significance: most likely action to cause muscular injury
-Speed: dependent on Myosin-Adenosine Triphosphatase activity and load
•Isometric Contraction

-Definition: the force/tension generated by the muscle is lower than that of the load
-Effect: the muscle shortens and the load is not raised against gravity
-Comparison:
Isometric Isotonic
Muscle Length Unchanged (constant) Shortened
Muscle Tension Markedly increased Unchanged (constant)
External Work 0 Present
(done by Muscle)
Heat Production More Less
Duration of Short Long
Contraction
Energy Required Less More
 Examples 1) trial to carry a heavy load 1) lifting light load
2) Contraction that occurs during standing 2) Contraction that occurs when legs are
to maintain posture against gravity moved in walking
-Factors: influencing Muscular Contraction
à Neural Factors: e.g. Descending Drive, Motoneuron Recruitment/Coding
à Biomechanical Factors: e.g. Cross-Sectional Area (CSA), Muscle Fiber type, Visco-Elastic Properties, Muscular
architecture, Length-Tension ratio, Load Velocity, Contraction Time
à Other Factors: e.g. Temperature, Fatigue, Pre-stretch
-Relationships:
1) Length-Tension Relationship
2) Force-Velocity Relationship
-Performance:
-Concept: the general relation between muscle ‘strength’ and ‘endurance’
-Strength: maximal force exerted by a muscle
-Endurance: total number of contractions or minutes to fatigue
-Relations:
a- there is no correlation between Isokinetic Strength and Relative Endurance (e.g. # of repetitions performed at at
given percentage of maximal strength)
b- significant and positive correlation between Isokinetic Strength and Absolute Endurance (i.e. Work Output)
-Factors: performance depends on many factors such as à
-general strength
-inherent muscle fiber type
-Myoglobin stores
-enzymatic profiles
-psychological state
-hormonal/endocrinal state
-nutritional state
-Energetics:
à Submaximal Exercise: primary reliance on Slow-Twitch Fibers
à Endurance Exercise: recruitment of Fast-Twtich Fibers (i.e. when the energy expenditure > maximal aerobic
power)
-State: Muscle Fatigue
-Definition: temporary decrease in muscle force of contraction due to previous contractile activity
-Onset: depends on three main factors à
1) Duration of Contractile Activity
2) Intensity of Contractile Activity
3) Type of Muscle Fiber
-Types:
•General Muscular Fatigue:
-Definition: depletion of energy stores inside the muscle
-Process: Lactic Acid accumulation with increased intracellular activity leads to inhibition of key enzymes
in energy pathways
•Neuromuscular Fatigue:
-Definition: depletion of Acetylcholine stores at the Motor End Plate (as the rate of ACh release is more
than the rate of ACh synthesis)
-Onset: occurs during fast-powerful activities
•Central Psychological Fatigue: occurs when CNS no longer adequately activates the Motor Neurons supplying the
working muscles

Therapeutic Exercise
-Definition: exercise primarily conducted with the aim of healing or regeneration of muscular function (but can also be used to train
athletes for competition)
-Types: can vary from selected activities targeting certain muscles to vigorous activities
à to maintain Mobility:
-Background: there are various causes of immobilization (e.g. trauma, edema, impaired circulation)
-Targets: geriatrics, hemiplegics, quadriplegics, arthritics, individuals with CNS insult, post-trauma individulas, post-
cast removal
-Type: Passive Range of Motion/PROM exercise conducted for the patient by a therapist as the patient is unable to
 do it on their own
-Aim: to prevent deposition and shrinkage of the connective tissue which is normally laid in any an immobilized
limb
à to develop Strength & Endurance:
-Muscle Strength: depends on the cross-sectional area of a muscle and the Motor Unit recruitment
-Physiological Issue: it is hard to determine exact relationship between muscle strength and associated
morphological changes
-Concept Example: Cerebral Palsy
-Definition: neurological disorder affecting motor coordination and movement
-Cause: insult to the CNS of the Fetus (i.e. during pregnancy, during delivery, or early months post-delivery)
-Effect: muscles become spastic and tight (can also be accompanied by other CNS impairments)
-Treatments: CP patients require stretching of the spastic tight muscles

Muscular Adaptations/Changes
-Hyperplasia: the enlargement of an organ or tissue caused by an increase in the reproduction rate of its cells
-Dysplasia: the abnormal development of cells within tissues or organs
-Atrophy: decrease in size or wasting away of a body part or tissue
-Hypertrophy:
-Definition: muscle adaptation involving enlargement and strengthening of the muscle fibers in response to overloading
-Process: overloaded muscle adapts by increasing its size and strength through Satellite-Cell-mediated mechanisms such as
increased protein synthesis, addition of new nuclei, and differentiation into Myoblasts
-Regulation: regulated by an array of mechanical, hormonal, and nutritional signals to increase protein synthesis
-Effectors:
à Anabolic Agents: Growth Factors (e.g. Insulin-Like Growth Factor, Testosterone)
à Negative Regulator: Myostatin (can be downregulated by strength exercise; inhibits myogenesis)

Hormonal Influence on Muscle

•Insulin-Like Growth Factor:
-Purpose: serves as a local repair and adaptive mechanism
-Physiological Significance: unique in being able to stimulate both the proliferation and differentiation of Satellite Cells
-Effects: potent effects on Motor Axon myelination, Motor Neuron apoptosis, stimulation of axonal sprouting (to re-
innervate denervated fibers), and repair of damaged axons

Muscle Pathologies
•Sarcopenia:
-Definition: loss of skeletal muscle and strength as a result of ageing
-Causes: often linked to an impairment in Satellite Cell activation
•Muscular Dystrophy: genetic degenerative disease causing progressive loss of force-generating capacity of Skeletal Muscls
•Myotonia: genetic disease characterized by delayed muscle relaxation after voluntary contraction
•Muscle Atrophy:
-Definition: decreased muscle size
-Cause: due to damage of the Motor Nerve supplying the muscle
-Effects: decreased muscle size eventually leads to paralysis and decreased Actin-Myosin content
•Myasthenia Gravis:
-Definition: extreme muscle weakness due to inability of Neuromuscular Junction to transmit signals from Nerve Fiber to
the Muscle Fiber
-Etiology: Autoimmune Disease
-Cause: body produces antibodies against its own Motor End Plate’s Nicotinic Acetylcholine Receptors à antibodies destroy
some ACh receptors à End Plate potential becomes too weak to adequately stimulate muscle fiber
-Presentation:
a- Ptosis (i.e. drooping eyelids)
b- Diplopia (i.e. double vision)
c- general weakness of extraocular muscles
d- dramatic response to Cholinesterase Inhibitors
-Treatment: short-term Anticholinesterase drug
-Example: Neostigmine
-Effect: temporarily inhibits Acetyl Cholinesterase à accumulation of Acetyl Choline in synaptic cleft à
prolongation of the action of Acetylcholine at the Neuromuscular Junction à End-Plate Potential of sufficient
 magnitude to initiate action potential contraction in muscle fiber
•Rigor Mortis:
-Defintion: condition that occurs after death due to ATP depletion
-Cause: without ATP the Calcium Pumps cannot function à exposed active sites on Actin attract Myosin cross-bridges à
Myosin attaches to Actin and is unable to detach à body becomes stiff due to bound Myosin Cross-Bridges
-Effect: muscle remain in rigor until the cellular proteins begin to breakdown ~24-48 hours after death
•Lower Motor Neuron Lesion:
-Cause: damage of α-Motor Neurons (e.g. from Diabetes, Alcoholism, Poliomyelitis)
-Effects:
1) Paralysis: Ipsilateral and localized to a muscle group (or group of muscles)
-Examples: Hypotonia, Atonia (Flaccidity)
2) Loss of all Reflexes: due to interruption of Reflex Arc
-Examples: Hyporeflexia or Areflexia
3) Marked Atrophy: of paralyzed muscles due to à
a- loss of voluntary and reflex activity of the Muscle
b- loss of trophic factors released from damaged nerve
-Hallmarks:
•Fasciculations:
-Definition: jerky contraction of a group of muscle fibers due to pathological discharge of injured Motor
Neuron
-Clinical Relevance: condition can be felt and seen
•Fibrillations:
-Definition: contraction of individual muscle fiber due to denervation hypersensitivity (i.e. sensitivity to
circulating Acetylcholine)
-Clinical Relevance: condition can be felt but not seen
•Upper Motor Neuron Lesion:

-Cause: lesions from the cortex to the AHCs or Cranial Nerve Nuclei (except Cranial Nerve I, II, VIII) may be vascular lesions
-Effects:
1) Paralysis: widespread and possible presence of Hemiplegia on the opposite side of the body
2) Muscle Tone/Reflex: hypertonia, hyperreflexia
-Cause: due to lesion affecting inhibitory response in the Upper Motor Neuron)
-Example: exaggerated Plantar Reflex (positive Babinski sign)
3) Muscle State: no wasting due to presence of Hypertonia

Mediators of Acute Inflammation – MMB 022

Vasoactive Amines
-Definition: substances containing amino acids that act on blood vessels to alter their permeability
-Effectors:
•Histamine:
-Origin: produced by Mast Cells, Basophils, and Platelets
-Trigger: Histamine released in response to specific stimuli
1) Physical Injury (e.g. trauma, heat)
2) Immune Reactions
3) Substance P (neuropeptide serving as a neurotransmitter and neuromodulator)
-Actions:
1) Vasodilation
2) Increased Vascular Permeability (by inducing endothelial contraction and formation of interendothelial
gaps)
•Serotonin:
 -Origin: found in Platelets, Granules, and Neurons
-Trigger: released in resonse to Platelet aggregation
-Actions:
1) Vasodilation
2) Regulation of intestinal motility

Complement System
-Purpose: production of pores thereby causing cell lysis
-Effectors: other split products are generated as the sequence proceeds
•C3a: anaphylatoxin causing Mast Cell degranulation
•C5a: anaphylatoxin causing Mast Cell degranulation, Phospholipase activation, and serving as a chemotaxic agent for
Neutrophils and Macrophages

Eicosanoids
-Definition: signaling molecules that play a major role in inflammation
-Origin: produced by enzymatic or non-enzymatic oxidation of Arachidonic Acid (or other Polyunsatureated Fatty Acids similar to
Arachidonic Acid)
-Types:

•Prostaglandins
•Thromboxanes
•Leukotrines
-Stimulus: Eicosanoid synthesis usually initiated by the activation of Phospholipase A2 and the release of Arachidonic Acid from
membrane Phospholipids
-Process: released Arachidonic Acid in blood vessels à AA subsequently transformed by Cyclooxygenase (COX) and Lipooxygenase
(LO) pathways to Prostaglandins, Thromboxane, and Leukotrienes (collectively referred to as Eicosanoids) à different Eicosanoids
signal for different physiological reactions
-Effects:
Prostaglandins Prostacyclin Leukotrienes Thromboxanes
-Vasodilation -Vasodilation -Vasoconstriction -Vasoconstriction
-Potentiate Edema -Inhibits Platelet Aggregation -Bronchospasm -Promotes Platelet
-Increased Permability Aggregation
-Pharmacological Relevance:
-Effect of Steroids: inhibits Phospholipases à inhibiting entire Eicosanoid cascade pathway
-Effect of Aspirin/Indomethacin: inhibits Cyclooxygenases à inhibiting Prostaglandin, Prostacyclin, and Thromboxane
production

Kinin Cascade
-AKA: Kinin-Kallikrein System
-Definition: blood proteins that play a role in inflammation, blood pressure control, coagulation, and pain
-Effectors:
•Bradykinin
•Kallidin
-Functions: Vasodilation (act on many cell types)
-Effect:

Degenerative Joint Diseases – MMB 024

Osteoarthritis

-Definition: slowly-progressive monoarticular (or less commonly polyarticular) degenerative joint disease
-Simplification: progressive loss of Hyaline Cartilage on the articular surface of bones
-Causes: inflammation, breakdown, and eventual loss of joint cartilage
-Significance: most common joint disease or Arthropathy (60% of over-35s have Osteoarthritis changes in at least one joint)
-Targets: hand joints and weight-bearing joints
-Types:
•Primary Osteoarthritis:
-Definition: deacreased resilience of Cartilage due to cross-linking with ageing
-Occurance: ~95% of cases
-Cause: most often genetic factors (i.e. intrinsic defect of the joint or its Cartilage)
-Risk Factors:
a- Gender: more common in females
b- Load-Bearing: overload exercise and obesity both worsen degenerative joint diseases as they increase
load-bearing
-Presentation:
a- Distribution: affects multiple joints bilaterally
b- Heberden’s Nodes: osteophytes of the Distal Interphalangeal Joints
c- Bouchard’s Nodes: osteophytes of the Proximal/Middle Interphalangeal Joints
d- Crepitations on movement
e- histological signs
 •Secondary Osteoarthritis:
-Description: degenerative changes in joints previously damaged by some other disease process
-Causes: diseases which may lead to secondary degenerative changes include à
a- Septic Arthritis
b- Tuberculous Arthritis
c- Rhematoid Arthritis
d- Gout
e- Congenital Dislocation of Hip
f- Ehler-Danlos Syndrome
g- general malalignment condition (e.g. bow-legs, knock-knees)
-Pathophysiology:
è General: flaking à fibrillation à erosion à eburnation
•Flaking: loss of Proteoglycans (histological effect: loss of metachromasia in the Matrix)
•Fibrillation: fraying of Cartilage surface
•Erosion: erosion of Cartilage leaving very little to none remaining
•Effects on Bone:

a- Eburantion: apposing Bones rub together (in the absence of articular cartilage) resulting in grooved
shininess and smoothness of Bones and thickening of Subchondral Trabeculae
b- Cracking of Bone: allows entry of Synovial Fluid which form Subchondral Cystic Spaces
c- Osteophyte Formation
è Specific:
•Wear and Tear Pathway: excessive long-term use of joints à release and upregulation of specific enzymes
(mainly Matrix Metalloproteinases/MMPs) by Chondrocytes à Proteoglycan and Collagen damage as well as
Chondocyte death à proliferation of residual dead Chondrocytes forming Osteophytes
-MMP Activity: increased in Osteoarthritis by
1) increased synthesis
2) increased activation of Proenzymes
3) decreased inhibitor enzyme activity (TIMP) which agonize the effects of MMPs
•Physiological Deficiency Pathway: mechanical stress and inflammation à release of pro-inflammatory cytokines
(e.g. IL-1β and TNF-α) à release of degradative enzyme (specifically Collegenases and Aggrecanases) which cause
Proteoglycan and Collagen damage à matrix breakdown and fibrillation of cartilage (loss of smooth articulating
cartilage surface) à bone remodelling (due to Cartilage damage) leads to formation of Osteophytes at the
Cartilage-Bone Interface as well as Subchondral Bone Sclerosis
à Initial: increased synthesis of low-quality proteoglycans does not suffice biomechanical demans
thereby causing Cartilage swelling
à Subsequent: proteoglycan synthesis significantly diminished thereby impairing surface lubricant film
•General Fluctuations of the Osteoarthritis Pathways:

-Hallmark: Osteophyte formation

 -Site: formed at the joint margins
-Causes:
1) penetration of vessels in Basal Layers
2) abnormal healing of stress fractures
3) venous congestion
4) stimulation of pluripotent cells by cartilage debris
-Clinical Relevance: may be responsible for restriction of joint movement as well as joint pain
-Compensation:
-Definition: Chondrocytes may attempt to repair damage and heal mild lesions
-Regulator: upregulated by anti-inflammatory Cytokines and Growth Factors
-Outcome: based on how the balance is shifted
è if the equation tips in favor of Catabolism: wear & tear progresses à net loss of Extracellular Matrix

è if the equation tips in favor of Anabolism: wear & tear does not continue à Extracellular Matrix maintained
(only generally occurs with mild lesions)
-Cycle: the imbalance between synthesis of inflammatory Cytokines and degradation of the Cartilage matrix is the major
driving force in Cartilage wear (as well as the ‘Vicious Cycle of Osteoarthritis’)
-Additional: avascularity of Cartilage – damaged Cartilage takes much longer to heal due to lack of direct blood supply (i.e.
lack of incoming circulatory cells such as Macrophages and Stem Cells)
-Reversability: it has been shown that if the initial insult on the Cartilage is removed prior to Collagen fibrillation then the Cartilage
restores its Proteoglycan content and no further damage occurs (thereby indicating that Osteoarthritis can be reversed, at least in
the easly stages)
-Presentation:
-General:
a- pain relieved by rest (although pain occurs at rest or at night in severe cases) and exacerbated by exercise
b- stiffness
c- crepitus on movement
d- limitation on movement
e- compression of spinal nerve roots
f- joint effusion
g- muscle wasting
h- tenderness of joint palpation (+/- palpated Osteophytes)
i- Locked Joint (in severe cases)
-Pathological:
à General Effects:
a- Damaged Cartilage
b- Bony Growths/Osteophytes
c- Synovitis
à Specific Effects:
a- Herberden’s Node:
-Definition: tender bony swellings (Osteophytes) that develop in the Distal Interphalangeal Joint
-Clinical Significance: characteristic sign of Osteoarthritis
b- Bouchard’s Node:
-Definition: tender bony swellings (Osteophytes) that develop in the Proximal/Middle
Interphalangeal Joint
-Clinical Significance: characteristic sign of Osteoarthritis and Rhematoid Arthritis
c- Hip Dysplasia: disease of the hip in which the Ball-and-Socket Joint in malformed (do not properly meet)
therefore resulting in a joint that rubs and grinds instead of sliding smoothly (manifests as
Trendenlenburg’s Gait)
 d- Stiff Knee Gait
e- Slow Shuffling Gait (with Spinal Stenosis)
f- asymmetric joint-space narrowing
g- subchondral sclerosis
h- subchondral cysts
-Markers:
-Function: serve as non-invasive reliable and valid markers to aid in early diagnosis of Osteoarthritis
-Types:
1) Products of Bone/Cartilage Degradation:

a- Procollagen C-terminal Telopeptide

b- Procollagen N-terminal Telopeptide
c- Collage-Type-II-specific Neoepitope
d- Cartilage Matrix Protein
e- Matrix Metalloproteinases
2) Pro-inflammatory and Anti-inflammatory Agents (Cytokines):
-Examples:
a- Pro-inflammatory Cytokines: Interleukin-1β, Tumor Necrosis Factor-α
b- Anti-inflammatory Cytokines: IGF, IL-4, IL-10, IL-13
-Effects: Cytokines contribute to Osteoarthritis by
a- Angiogenesis
b- Chemotaxis
-Chemotactic Cytokines/Chemokines:
--mobilize and activate WBCs (thus influencing inflammation)
--stimulate IL-1 production
--stimulate Proteoglycan depletion
-Angiogenic Growth Factors (FGF & TGF):
--play a role in vessel formation
--contribute to: synovitis and pain
-Management:
-Premise: there is no current cure that reverses chronic Osteoarthritis or restores Cartilage thickness/function
-Treatment: therapies aimed at managing pain and improving joint function
a- Weight Loss/Exercise Programs
b- Physiotherapy
c- Analgesics: helpful for pain and inhibiting COX-mediated inflammation
d- Viscosupplementation: by intra-articular injection of Hyaluronon
e- Complementary Medicine: e.g. Glucosamine (suggested to suppress IL-1 action; still in testing), Chondroitin
Sulfate
f- Molecular Targets:
 1) Neutralizing IL-1 Action: by using its natural antagonist IRAP (still in testing phase)
2) Growth Factor Supplementation: e.g. FGF-18
3) MMP Activity Inhibition: still in testing phase
4) Monoclonals Against Growth Factors: e.g. Tanzumab (autoantibody against Nerve Growth Factor/NGF)
g- Autologous Chondrocyte Implantation: using patient’s own Chondrocytes (prepared from biopsy of distal non-
weightbearing site) to fill small sized defect
-MACI Method: evolved/developed technique in which an entire section of ECM with its Chondrocytes fill
in the defect
h- Stem Cell Therapies: Bone Marrow (derived from mesenchymal stem cells) placed into Cartilage lesion - either
by naturally bleeding into it via microfractures or by in vitro implanation in artificial scaffolds - and its Stem Cells
produce Fibrocartilage that fill the defect
i- Surgical Intervention: (for severe cases) e.g. Osteotomy, Debridement, Partial or Total Prosthetic Joint
Replacement

Rheumatoid Arthritis
-Definition: an autoimmune systemic chronic inflammatory disease of the joint
-Origin: most probably a heterogenous group of disorders
-Onset: can occur at any age (however prevalence increases with age)
-Risk Factors:
-Gender: females 3x more likely
-Smoking: smokers 2x-3x more likely
-Genetic: HLA DW4
-Pathogenesis:
-Autoimmunity: Rheumatoid Factor (i.e. antibodies directed against the Fc fragment of IgG)
-Cell-Mediated Immunity: presence of T-lymphocyte in synovium
-Abnormal B-Cell-to-T-Cell Interaction: stimulates release of TNF, IL-1, and other cytokines
-Infectious Agents: e.g. EBV and other viruses
-Manifestations:
-Articular Lesions:
-Precursor Cellular Changes:
a- increased vascularity
b- numerous inflammatory cells
c- synovial cell hyperplasia
-Pathophysiology: synovial inflammation (i.e. precursor cellular changes) most often due to autoimmune attack à
osteclastic activity of underlying bone à bone erosion à creeping granulation tissue over and under the Articular
Cartilage withtin the eroded bone (i.e. Pannus) à destruction of articular cartilage by Collagenase (and other
proteases) release in the Pannus à fibrous or bony ankylosis (stiffening/immobility of the Joint)

-Extra-Articular Lesions:
a- Rhematoid Nodules
b- Vasculitis
-Clinical Relevance: increased risk of cardiovascular disease linked to inflammatory reaction

Vasculitis
-Features:
-Order: RA generally affects joints in a specific order
-Sequence: small joints of hands and feet (metacapophalangeal and proximal interphalangeal joints) à wrist joints
à elbow joints à knee joints
 -Exception: RA generally spares the distal interphalangeal joints of the fingers
-Systemic Symptoms: low-grade fever, weakness, malaise, weight loss
-Local Symptoms (Joint):
a- joint pain
b- joint warmth
c- joint swelling
d- morning stiffness
e- joint deformity

-Treatments:
1) Antibodies against TNF-α or B-Lymphocytes (effective in some patients)
2) Glucocorticoids
3) NSAIDs

Perthe’s Disease
-Definition: rare childhood condition in which blood supply to the femoral head is temporarly disrupted thereby causing avascular
necrosis of the bone region
-Causes: CAT IN BED acronym
à Congenital:
-Congenital dislocation of the Hip
à Acquired:
-Traumatic-Fracture
-Infective
-Neoplastic
-Blood/biochemical (e.g. Gout, Haemochromatosis)
-Endorcine (e.g. Diabetes Mellitus)
-Denegenerative (i.e. overuse)

Infection of Bone, Joint, and Muscle – MMB 025

Osteomyelitis
-Definition: inflammation of the medullary and cortical portions of bone (including the Periosteum)
-Causes:
-Main: Staphylococcus species
-Classification: according to coagulase production
a- Coagulase Positive à Staphylococcus aureaus
-Significance: ~75% of cases
b- Coagulase Negative à Staphylococcus epidermidis
-Significance: skin commensals cause most cases of Osteomyelitis associated with Prosthesis due to
biofilm formation
-Transmission:
à Hematogenous: via the circulation
-Significance: most common in children
-Risk Factors: infants/young children, elderly, IV Drug abuserse, central venous catheters, joint disease,
immunosuppression
à Direct Spread:
-Method: from adjacent infected tissue
-Examples: adjacent Septic Arthritis, Soft Tissue Abscess
à Traumatic Implantation:
-Method: from external sources/pathways
 -Examples: wounds, fractures, orthopedic surgery
-Risk Factors: predominantly immunosuppression (e.g. Cancer, Diabetes, Post-Splenectomy, Children, Elderly, HIV, Hemodialysis)
-Features:
-Categorization: lesion may be Acute, Subacute, or Chronic (depending on duration)
-Pathological Changes:
a- suppuration
b- ischemic necrosis
c- healing by fibrosis
d- bony repair
-Pathophysiology:
-Site: infection most often initiated in the metaphyseal marrow of Long Bones (i.e. Metaphysis)
-Rationale:
a- sluggish blood flow due to terminal branches of Metaphyseal Artery that forms loop-ended vessels at the
Growth Plate as well as irregular sinusoidal venous system
b- poor collateral circulation
c- susceptibility of the region to trauma à trauma leads to haematoma
d- deficiency of phagocytic cells in the lining region
-Processes:

•Bacterial Seeding: bacteria proliferate in focal region (most often initially in Metaphysis) à induce acute
inflammatory reaction à excessive Neutrophils liberate enzymes and oxygen free radicals à increased marrow
cavity pressure à compression of vessels à bone necrosis
•Abscess Formation: suppurative focus in Metaphysis passes through Medullary Canal à Pus passes through
Haversian Canals à passes into Cortical Bone à passes into Periosteum thereby forming a Subperiosteal Abscess
-Significance: subperiosteal abscess more common in children because children’s periosteum loosely
attached
•Abscess Effect: abscess increases in size à abscess ruptures à muscle and fascia infected à skin infected
(evidenced by ‘Sinus Tract’; i.e. abnormal channel that originates or ends in one opening)
•Effects on Bone: suppuration and impaired blood supply to Cortical Bone à erosion, thinning, and infarction
necrosis of Cortex (i.e. ‘Sequestrum’)
•Healing/Repair: with time new bone formed beneath the Periosteum to encase dead bone (i.e. ‘Involucrum’)
-Types:

•Pyogenic Osteomyelitis:
-Cause: most commonly bacteria
-Effectors:
→ Most Common: Staphylococcus aureus
→ Neonates: E. coli and Group B Streptococci
→ Bone Trauma: mixed bacterial infection
-Chronicity: may lead to Brodie’s Abscess
•Vertebral Osteomyelitis:
 -Pathogenesis: bacteria circulating through blood may enter a Vertebra or a disc space via arterial blood supply or
venous system
-Trend: most commonly via Metaphyseal Arteries
-Manifestations:
è General:
1) Manifestations of primary infection
2) Non-specific backache +/- edema, hotness, redness
3) Late/masked onset of S&S (takes up to 2 months to diagnose)
è in Children: the Intervertebral Disc comes first
-Definition: bacterial colonization of Intervertebral Disc
-Anatomical Relevance: intraosseous arteries have extensive anastomosis with some vessles
penetrating the Intervertebral Disc
-Rationale: septic embolus (via hematogeneous spread) does not cause bone infarction due to
extensive anastomosis and therefore infection located essentially within the disc
è in Adults: the Vertebral Bodies comes first
-Definition: bacterial colonization of the metaphyseal region
-Anatomical Relevance: Intervertebral Disc is avascular (unlike Children IVDs which are partially
vascular as they are growing)
-Rationale: septic emboli pass through from one Metaphysis to the other in a single vertebral
body via inter-metaphyseal arteries without involvement of midportion of vertebra (leads to
classic Spondylodiscitis presentation)
-Complications:
a- Spread:
-Direct: to joints (leading to Arthritis) and to muscles (leading to Myositis)
-Hematogeneous: causing toxemia, septicemia, and pyemia
b- with Chronicity:
-pathological fracture
-amyloidosis
-malignancy within Sinus Tract (e.g. Squamous Cell Carcinoma)
-Diagnosis:
a- Bone Biopsy (Gold Standard)
b- positive blood culture
c- high ESR and CRP
d- X-ray/MRI/PET
•Tuberculous Osteomyelitis:
-Significance: rare (~5% of TB cases)
-Effector: Mycobacterium tuberculosis
-Cause: complication of Pulmonary Tuberculosis due to blood spread
-Pathophysiology: tuberculous tissue à spreads via Haversian Canals (and marrow spaces) à decalcification and
resorption of bony framework à bony structures become replaced by caseous material à extensive endarteritis
leads to necrosis à Sequestrum formation à involved bone eventually infiltrated by tuberculous granulation
tissue and becomes porous/friable
-Presentation:
1) Long Bone: development of circumscribed tuberculous focus in the Metaphysis and extension along the
Epiphyseal Line thereby giving rise to Subperiosteal Cold Abscess

2) Short Bone: whole diaphysis of Short Bone invaded and converted into mass of tuberculous granulation
tissue and caseous material while a layer of new bone laid down under Periosteum
 -AKA: Tuberculous Dactylitis
3) Flat Bone: initial sub-periosteal lesion in Flat Bone (i.e. Ribs, Sternum, Pelvis, Skull) that ends by
formation of superficial cold abscess

4) Vertebrae:
-AKA: Pott’s Disease
-Etiology: hematogeneous spread
-Sites: commonly in lower dorsal and upper Lumbar Vertebrae
-Features:
a- Deformity: bodies of Vertebrae become caseous while spine remains intact thereby
causing an acute convex curvature (Kyphosis)
b- Cold Abscess: tuberculous vertebrae collapse under body weight and caseous
material collects anteriorly under the prevertebral fascia thereby forming the cold
abscess
c- Paraplegia: pressure of Cold Abscess leads to paralysis (~10% of cases)
-Treatment:
1) Chemotherapy:
-Course: treatment for at least 6 monthts (and possibly up to 9-12 months) for extensive bone
infections
-Medications:
a- Two Months or More: Rifampicin + Izoniazid + Pyrazinamide + Ethambutol
b- Up to Ten Months: Rifampicin + Izoniazid
2) Surgery: prefereably combination of anti-tuberculosis chemotherapy and surgical debridement
3) Physical Care: bed rest and bracing
•Chronic Osteomyelitis:
-Causes:
à following Acute Osteomyelitis: due to lack of treatment, inadequate treatment, or incomplete surgical
debridement of dead bone
à de Novo: due to localized bone infection with few organisms or with bacteria of low-grade
pathogenicity
-Manifestations:
1) Brodie’s Abscess:

-Definition: small intraosseous cortical absecess walled off by reactive bone with no periosteal
reaction
-Association: related to focus of Subacute Pyogenic Osteomyelitis
-Presentation: abscess cavity may or may not contain infectious organisms
2) Garre’s Sclerosing Osteomyelitis:
 -Defintiion: continuous extensive new bone formation
-Site: most often occurs in the jaws, specifically the Mandible (it can also be referred to as
Periostitis Ossificans)
-At-Risk: mainly children and young adults
-Association: typically associated with odontogenic infection
•Syphilitic Osteomyelitis
-Presentation:
→ Systemic: fever, malaise
→ Local: inability to move affected limb/joint, pain, hotness, redness, swelling, stiffness
→ Chronic: Chronic Osteomyelitis symptoms are not always apparent but theire could be pain and drainage of the infected
area
-Diagnosis: clinically suspected based on symptoms
→ Laboratory Tests: e.g. increased WBCs, TLC (Total Leukocyte Count)
→ Radiological Tests: e.g. X-ray, CT
•X-ray: early osteolytic metaphyseal lesion not definitive enough (only definitive when Ostemyelitis becomes
chronic)
→ Pathological Tests: e.g. Bone biopsy
•Aspiration Biopsy: at the point of maximal tenderness à Pus aspirated and cultured
•Intra-Operative Biopsy: heavy leukocytic infiltrate with necrotic bony remnants and a subperiosteal abscess (most
definitive diagnosis)
-Treatment:
1) Hospitalization/Surgery:
-Procedure: immediate surgical release of pus
-Purpose:
a- eradication of infection by achieving viable environment
b- debridement of dead tissue
c- prevent recurrences
2) Antibiotic Therapy: immediate I.V. of Flucoxacillin +/- Fucidin or Teicoplanin
3) Symptomatic Treatment: Analgesics and Anti-pyretics
4) Blood Sugar Control: for Diabetic patients
5) Follow-Up:
-Review: for modification of I.V. if needed after blood and aspirate culture
-Continuation: continued treatment for 6-8 weeks

Septic Arthritis
-AKA: Infectious Arthritis
-Definition: invasion of a joint by an infectious agent resulting in joint inflammation
-Causes:
-Main: bacteria are the most significant pathogens due to rapidly-destructive nature
à Hemophilus influenza
à Streptocococcus
à Staphylococcus epidermidis (i.e. infection from artificial joint)
-Notice: bacteria, viruses, mycobacterisa, and fungi have all been implicated
-Pattern: typically affects one large joint (e.g. Knee, Hip) and less frequently affects multiple joints
-Transmission:
à Joint Modification: e.g. Prosthetic Joint, recent Joint Surgery, Inoculation
à Direct Spread: e.g. skin infection, bone infection
à Hematogeneous Spread:
a- Diabetes Mellitus
b- HIV infection
-Presentation:
 → Systemic Symptoms: fever, fatigue, malaise
→ Local Symptoms: inability to move limb with infected joint, severe pain in affected joint (especially with movement),
swelling, warmth, redness
-Management:
-Diagnosis: complete medical history, physical exam, and laboratory tests
-Treatment:
a- Hospitalization
b- Arthrocentesis: draining the infected synovial fluid from the joint
c- Initial Intravenous (IV) Antibiotics
d- Continuation of Antibiotics (~4-6 weeks to ensure complete eradication of infectious agents)

Soft Tissue Infections

(main Clinical Presentations are Cellulitis, Necrotizing Fasciitis, and Gangrene)
-Causative Agents:
à Streptococcus pyogenes:
-Classification: Group A Streptoccoci (facultative anaerobes)
-Significance: most common cause of Cellulitis and Necrotizing Fasciitis
-Factors:
a- M-Protein (adhesin, nti-complement)
b- Streptokinase-Fibrinolytic Enzyme (spreading factor)
c- DNase (spreading factor)
d- Hyaluronidase (spreading factor)
e- Proteases
-Pathophysiology: adherence à avoidance of host defences à produce enzymes/toxins to spready and destroy
tissue à cause thrombosis (of perforating arteries) and ischemia
à Clostridium perfringens (strict anaerobe)
à Mixed Infection (i.e. with facultative and strict anaerboes)
-Types:
•Cellulitis:
-Definition: non-necrotizing infection of skin and subcutaneous fat which may result from cut, bite, or associated
subcutaneous abscess
-Diagnosis: usually based on medical history and physical exam (blood and skin samples may also be taken to
confirm)
-Treatment:
a- Analgesic Antibiotics: Clindamycin and Benzyl Penicillin
b- Bed Rest: with elevation of affected limb
•Necrotizing Fasciitis:
-Definition: infection of the subcutaneous tissue characterized by skin sloughing and tissue necrosis
-Diagnosis: usually based on medical history and physical exam (blood and skin samples may also be taken to
confirm)
-Treatment:
a- Surgical Procedure: radical excision of necrotic tissue
b- IV Antiobiotics: Clindamycin and Benzyl Penicillin
•Gangrene:
-Definition: death of body tissue due to either lack of blood flow or serious bacterial infection
-Targets: typically affects the extremities but can also occur in msucles and internal organs
-Risk Factors:
a- Trauma
b- Surgical Wound
c- Blood Vessel Disease (most at risk; e.g. Atherosclerosis)
d- Diabetes
-Type: Gas Gangrene
-Causative Agent: most often caused by Clostridium perfringes
-Virulence Factors: Exotoxins, Phosphoplipase C
-Pathophysiology: pathogen reaches tissue through cut wound à low oxygen tension in tissues à
production of hydrolytic enzymes à tissue destruction and spread of pathogen (with further necrosis) à
gas bubbles in tissue (can be felt and visualized)
-Effects:
 a- Spore production
b- Cell lysis
c- Production of hydrolytic enzymes (ferment tissue carbohydrates thereby producing acid and
gas; i.e. bad odor, bullae formation)
d- break down tissue proteins by groups of Proteases
-Presentaiton:
a- Skin Discoloration: ranging from pale to blue/purple/black
b- Swelling: +/- formation of blisters filled with fluid on the skin
c- Demarcation Line: between healthy and damaged skin
d- Severe Pain: followed by feeling of numbness
e- Foul-Smelling Discharge
f- Unusual Skin Features: thi shiny skin, skin without hair, skin that feels cold to the touch
g- Weak or Absent Peripheral Pulse
-Treatment:
a- Surgery: immediate debridgement excision of all affected tissue (may need amputation)
b- Benzyl Peniccilin therapy

Cell and Moleculary Biology of Bone – MMB 033

Key Concepts/Background Information
-Bone Classification:

-Bone Components:

-Forms:
Immature/Woven Bone Mature/Lamellar Bone
-Definition: randomly arranged Collagen fibers in the Osteoid -Definition: regular parallel bands of Collagen (confers
-Characteristic: rapid production of Osteoid tissue by strength)
Osteoblasts -Characteristic: Osteoid tissue formed slowly
-Occurance: found in -Occurance: found in virtually all bone in a healthy adult
a- Fetal Bone development -Cell Configuration: small flattened regularly-spaced Osteocytes
b- Adult Bone pathologies: -Fiber Diameter: regular Collagen fiber diameter
1) Healing Fracture -Turnover: slow
2) Paget’s Disease
-Cell Configuration: large rounded irregularly-spaced
Osteocytes
-Fiber Diameter: variable Collagen fiber diameter
 -Turnover: rapid

Bone Matrix
-Structural Overview:

-Components:
•Organic Component:
•Collagen Type-I – structural protein providing strength and flexibility
•Mixture of Proteins: including Growth Factors, Osteocalcin, Osteonectin, Osteopontin, Glycoproteins,
Phosphoproteins, Sialoprotein, and more (all produced by Osteoblasts and Type-I Collagen)
-Notice: Osteocalcin blood level is a marker for bone turnover
•Mineral Component: mainly Calcium Hydroxyapatite
-AKA: Ca4(PO4)3(OH) or Ca10(PO4)6(OH)2 (i.e. denotation of the cystal form which comprises two entities)
-Purpose: provides bone rigidity and strength
-Process: Mineralization
-Defintion: the process in which inorganic material precipitates in the organic Matrix
-Factors: dependent on active form of Vitamin D (1,25-dihydroxyvitamin D)
-Effector: Alkaline Phosphatase Enzyme/ALP
-Function: releases inorganic Phosphate ions (PO43-) from diverse molecules via Hydrolysis
-Expression: expressed at high levels by differentiated Osteoblasts
-Significance: useful circulating marker for bone cell activity
-Process: ALP promotes mineralization in two main ways
1) directly increases local concentration of inorganic Phosphate ions
2) hydrolyzes Pyrophosphate (key inhibitor of mineralization in tissues)
-Subsidiary Outcome: hydrolyzation indirectly generates more inorganic Phosphate ions
-Effect: crystals of Calcium Hydroxyapatite impregnate and surround Collagen fibers thereby providing rigidity and
resistance to compression
-Relavant Pathology: Vitamin D deficiency results in failure of mineralization of Osteoid tissue à leads to
•Rickets: in children
•Osteomalacia: in adults
-Clinical Relevance: clinically-important factors regulating bone remodelling include PTH, RANKL/OPG/RANK, 1,25(OH)2-Vitamin D,
Calcitonin, Estrogens, Andorgens, Glucocorticoids, Acid-Base Balance, Oxygen Tension, and Mechanical Forces/Exercise

Bone Remodelling
-Definition: perpetual process of repair and renewal of Bone
-Site: generally a surface phenomenon
-Process: mineralized bone matrix is resorbed by Osteoclasts and replaced in lamellae by Osteoblasts
-Stimulus: process takes places in response to altered mechanical loading
-Purpose:
a- provide local strengthening of Bone
b- remove structurally redundant areas
-Influencers: bone remodelling influenced mainly by hormones and cell signals
-Hormones:
à Calcium-Regulating Hormones:
-Background: Calcium
-Premise: solubility of Ca2+ low, therefore increase in Ca2+ levels leads to inappropriate precipitation
(tissue mineralization)
-Usage:
a- Serves as vital second messenger within cells
b- Necessary for normal blood coagulation, muscle contraction, and nerve function
c- Main ion in mineral deposits (>99% of Ca2+ in body exists as mineral deposits)
-Defect: Hypocalcemia results in excitation of nerve and muscle cells leading to spasms, tetany, and
asphyxia
-Types:
•Parathyroid Hormone (PTH):
-Functions:
a- increases bone turnover
b- increases plasma Ca2+ levels (critical regulator)
c- increases Osteoclast formation and activity
d- increases Osteoblast formation and activity
-Effects:
à Intermittent PTH: bone formation in vivo
à Continuous High-Dose PTH: bone loss (due to increased bone resorption)
•Calcitriol (1,25{OH}2D; active form of Vitamin D):
a- increases plasma Ca2+ levels
b- increases gut Ca2+ uptake
c- increases Osteoblast differentiation (required for normal matrix mineralization; deficiency
leads to osteomalacia, rickets)
d- decreases Osteoblast proliferation
e- increase Osteoclast formation and activity
-Calcitonin:
-AKA: ‘Emergency Hormone’
-Premise: does not have much affect in normal adults
-Effects:
a- decreases plasma Ca2+ (by depositing Ca2+ in Bone)
b- decreases Osteoclast formation and activity
à Phosphate-Regulating Hormones:
-Effector: Fibroblast Growth Factor 23/FGF-23 (lowers PO43- levels)
-Regulation: less tightly regulated than Calcium
-Relevant Pathology: Phosphate ion retention is toxic (generally implicated in accelerated ageing)
à Other Hormones:
•Glucocorticoids:
-Examples: e.g. Cortisol, Cortisone
-Purpose: necessary for normal bone development/function
-Defect: excess Glucocorticoids results in bone loss/osteoporosis
•Growth Hormone: required for normal bone growth
•Sex Steroids
-Examples: Estrogens & Androgens
-Purpose: exert critical long-term/slow-acting beneficial effects
-Effects:
a- decreases Osteoclast recruitement/activity
b- increase Osteoblast activity
c- may inhibit production of some Interleukins (minor effect)
-Defect: deficiency leads to increased bone turnover rate (e.g. osteoporosis)
-Signaling:
à Systemic Growth Regulators:
 -Purpose: molecules used in commincation between bone cells, control of cell dividison, differentiation, and
survival of cells
-Examples:
a- Growth Factors: formed by bone cells
b- Cytokines: formed by Immune Cells and Bone Cells
à Local Growth Regulators:
-Types: generally paracrine and autocrine factors
-Examples:
•Growth Factors: normal Osteoblast products depositied in matrix that mediate some hormone actions ( a
to f ar Mitogens)
-Main:
•Transforming Growth Factor β/TGF- β
•Bone Morphogenetic Proteins/BMP
•Insulin-like Growth Factors I&II (IGF)
•Platelet-derived Growth Factors (PDGF)
•Fibroblast Growth Factors (FGF)
-Functions:
1) increase Osteoclast recruitment/activity
2) increase Osteoblast proliferation (as well as other cells)
3) decrease Plasma PO43+ (specific to FGF23)
•Glycoproteins:
•Wnt Proteins: signaling molecules
-Function: increase Osteoblast differentiation and bone formation
-Inhibition: blocked by Scleostin
•Sclerostin: Osteocyte-produced bone-specific protein which acts as a natural brake on bone
formation
-Function: inhibit Wnt Proteins, decrease Osteoblast differentiation, and decrease bone
formation
-Mechanism: mechanical unloading and/or Estrogen deficiency à release/secretion of
Sclerostin à Sclerostin inhibits Osteoblast formation à inhibition of bone formation à
stimulates RANKL expression à Osteoclast formation and Bone resorption
•Dickkopf Proteins:
-Definitionk: antagonist of the Wnt signaling pathway
-Function: deactivates/suppresses Wnt signaling pathway
•Cytokines: products of immune and bone cells
a- increased Osteoclast Formation/Activity: causes general Bone loss
•Interleukins: IL-1, IL-6
•Tumor Necrosis Factor: TNF-α
•RANK Ligand (major factor required for OC formation)
•Macrophage Colony-Stimulating Factor (M-CSF)
b- decreased Osteoclast Formation/Activity:
•Interleukins: IL-4, IL-10, IL-12, IL-13, IL-18
-Actions: may mediate some actions of PTH, Calcitriol, and Sex Steroids
•Interferon: IFN-γ
•Granulocyte Macrophage Colony-Stimulating Factor (G-CSF)
•Inorganic Agents: both local and systemic
•Protons/H+ (low pH; acidity):
-Increases Osteoclast activity
-Decreases Osteoblast activity (mineralization)
•Phosphates/PO43+: decreases Osteoclast recruitment/activity
•Pyrophosphates: decreases mineralization (key inhibitor)
•Calcium/Ca2+: decreases Osteoclast recruitment/activity (minor effect)
•Strontium/Sr2+: increases bone formation
•Fluorides/F-: increases bone formation (but low quality)
•Hypoxia (low oxygen tension; PO2 <5%): increases Osteoclast recruitment and decreases
Osteoblast activity
•Nitric Oxide/NO: decreases Osteoclast activity and increased Osteoblast differentiation
•Intracellular Factors:
 a- increase Osteoblast differentiation (and Bone formation):
•β-cantenin (Wnt mediator)
•Osterix
•Runx-2
b- increases Osteoclast function:
•Nuclear Factor of Activated T-Cells 1 (NFATc1)
•TRAF-6
•Other Molecules:
•Prostaglandins: involved in both resorption and formation
-increases Osteoclast recruitment
-decreases Osteoclast activity
-mediate some actions of Growth Factors and Cytokines
-responds to mechanical stimuli and hypoxia
•Extracellular ATP
-increases Osteoclast formation/activity
-possible mediator of inflammatory Bone loss
•Calcitonin Gene-Related Peptide (CGRP):
-decreases Osteclast formation/activity
•Mechanical Effects:
a- Mechanical Unloading: stimulates bone resorption (e.g. bed-rest, micro-gravity)
b- Mechanical Loading: downregulates Sclerostin à increases bone formation
c- Large Changes in Hydrostatic Pressure: increased Osteocyte death
-Outcomes:
à Formation > Resorption
-Net Bone Density: gain
-Age Group: newborn to ~20 years old
à Formation = Resorption (Balanced)
-Age Group: ~20 years old to 45 years old
-Notice: bone may be removed from one site and deposited at another in order to achieve shape changes whilse
keeping overall bone mass constant
à Formation < Resorption:
-Net Bone Density: loss
-Age Group: 45 years old onwards
-Examples: Osteoporosis, Osteopenia, elderly
-Trend: Trabecular Bone (e.g. in Vertebral Bodies) are particulary susceptible to remodelling imbalances as a result
of relatively-high Tunover Rate (~25%/year)

Fuel Selection in Muscles – MMB 034

Key Concepts/Background Information
-Types of Skeletal Muscle Fibers:
à Type I Fibers:
-Color: Red
-Twitch: Slow-Twitch
-Citric Acid Cycle Activity: high rate
-Intracellular Components: rich in Mitochondria, Myoglobin, and intramuscular Triacylglycerol
à Type II Fibers:
-Subtypes:
a- Type IIA Fibers (‘Fast Oxidative Fibers’): high rate of Citric Acid Cycle activity
b- Type IIB Fibers (‘Fast Glycolytic Fibers’): low rate of Citric Acid Cycle activity
-Color: White
-Twitch: Fast-Twitch
-Intracelullar Components:
a- poor in Mitochondria, Myoglobin
b- rich in muscle Glycogen
-Rationale for Different Types: the body produces a variety of functions and therefore requires different types of muscles to fulfill
different biomechanical objectives
-Examples of Functions: these functions are opposite
a- generate rapid movements
 b- maintain high levels of tension (without fatigue)
-Examples of Muscle & Differences: opposite sides of the spectrum
a- Soleus:
-Function: aids in maintaining upwards posture of Lower Limbs as well as normal movement
-Usage: ‘endurance muscle’ that can be in constant use for hours at a time
-Tension: reaches peak tension in 80mins-200mins (i.e. slow)
-Muscle Fibers: predominantly contains slow-contracting muscle fibers
-Biomechanical Interpretation: Soleus requires slow-contracting muscle fibers as the muscle is
predominantly used for postural purposes which implies that it will be in action for long periods of time
( it cannot afford to fatigue quickly)
b- Ocular Muscles:
-Function: produce intermittent rapid movements
-Usage: transient usage (i.e. do not need to maintain tension for long)
-Tension: reaches peak in 7mins-8mins (i.e. fast)
-Muscle Fibers: contains predominantly fast-contracting muscle fibers
-Biomechanical Interpretation: Ocular Muscles require fast-contracting muscle fibers as the muscle is
predominantly used for rapid/transient movements which implies that it will be in action for short periods
of time
(∴ it does not need to be capable of endurance)

Muscle Fuels
-Adaptability: muscles can use a variety of fuels and therefore the fuel used is dependent on à
1) Intensity: i.e. the degree and rate of work being performed
2) Metabolic State: i.e. whether the individual is in the Fed State or the Fasting State
-Sources:
Sources Onset of Usage
Carbohydrates Plasma Glucose Fed State, Exercise, and Post-
Exercise
Muscle & Liver Glycogen (i.e. Fasting State (<18 hrs) and High-
Glycogenolysis) Intensity Exercise
Fats Muscle and Adipose Tissue (i.e. Fasting State and Low-Intensity
Triglycerides) Exercise
Plasma NEFA (Non-Esterified Fatty Fasting and After Exercise
Acids) and Lipoproteins
Ketone Bodies Circulating Ketone Bodies Very Prolonged Fasting State and
Prolonged Exercise
Proteins Amino Acids (i.e. degraded muscle Starvation
tissue)

-Trends:
-Overview: in the Fed State (and/or high-intensity Exercise) Carbohydrates are utilized most à in Fasting State Glucose
used until depleted, at which point TAGs and KBs are utilized most à after long-term Starvation the muscles break down its
own Proteins and Amino Acids becomes utilized most
-Representation:
-States:
à Fed State:
-Effector: secretion of Insulin
-Stimulation: triggered by increase in blood Glucose
-Process:
•Pancreatic Action: β-cells sense high Glucose levels à Glucose uptake increases à Insulin release
stimulated à Insulin stimulates increase in Glucose entry into cells à Glycogenesis & Glycolysis increase
 and Fatty Acid oxidation inhibited
•Hepatic Action: Liver senses high Glucose levels à Glucose uptake increases à Glucose used for
Glycogenesis and glycolysis occurs for Lipogenesis à Insulin favors Lipogenesis and ∴ inhibits Lipolysis
-Effects: Insulin stimulates storage of fuels and synthesis of proteins by à
a- Glycogenesis: increased
b- Gluconeogenesis: decreased
c- Glycolysis: increased
d- Lipogenesis: increased (as a result of Glycolysis)
e- Lipolysis: decreased (and ultimately inhibited)
à Fasting State:
-Onset: blood Glucose levels drop several hours after a meal
-Effector: Glucagon
-Stimulation: decreased blood Glucose levels
-Process: β-cells sense low Glucose levels à decrease in Insulin secretion and rise in Glucagon secretion (Glucagon
secreted in response to a low blood-sugar level) à decreased Glucose entry into cells and increased Fatty Acid
oxidation (Amino Acids may also be released) à Liver releases Glucose from Glycogen stores (via Glycogenolysis)
à after prolonged fasting (i.e. ~ >12 hours; depletion of Glycogen stores) Liver starts forming new Glucose to
release into the blood (i.e. Gluconeogenesis) à low Insulin favors release of Fatty Acids
-Effects: Glucagon leads to increase of Blood Glucose levels by à
a- Glycogenolysis: increased
b- Glycogenesis: decreased (and ultimately inhibited)
c- Lipogenesis: decreased
d- Gluconeogenesis: increased
e- Glycolysis: decreased
-Concentrations:
a- Muscle & Liver Glycogen: decreases due to depletion (i.e. Glycogenolysis)
b- Muscle & Adipose Tissue Triacylglycerols/TAGs: usage increases due to more demand
c- Plasma Lipoproteins & Plasma NEFA: secreted from muscle during fasting
d- Ketone Bodies: usage increases during very prolonged fasting
à Starved State:
-Onset: >16 hours after last meal
-Process: degradation of muscle Amino Acids as last resort for muscular and cellular fuel
-Cycle: Fed-Starve Cycle includes four main stages

è Well-Fed Stage/Absorptive Stage:

-Definition: stage 0-4hrs after ingestion of average meal
-Processes:
1) Absorption: Glucose and Amino Acids transported from Intestine to the blood
2) Storage: Dietary Lipids packaged into Chylomicrons and transported to the blood
3) Metabolism: increased Blood Glucose leads to Insulin secretion à Insulin stimulates Glycogen synthesis
(i.e. Glycogenesis) in both Muscle and Liver à Gluconeogenesis suppressed in Liver à Glycolysis
accelerated in Liver à leads to increase in synthesis of Fatty Acids
è Early Fasting Stage/Post-Absorptive Stage:
-Definition: stage 4hrs-12hrs after ingestion of average meal
-Processes:
1) Transition: decrease in Insulin secretion to rise in Glucagon secretion
 2) Metabolism: Glucagon secreted in response to low blood-sugar level (signals official Starved State) à
multiple parallel paths follow
a- Glycogen Breakdown: Glucagon stimulates Glycogen dissociation à causes inhibition of
further Glycogen synthesis à triggers cyclic AMP cascade à phosphorylation/activation of
Phosphorylase à inhibition of Glycogen Synthase
b- Fatty Acid Synthesis: Glucagon inhibits Fatty Acid synthesis by diminishing the production of
Pyruvate and lowering the activity of Acetyl CoA Carboxylase (by maintaining it in an
unphosphorylated state)
c- Gluconeogensis: Glucagon stimulates Gluconeogenesis in the Liver and blocks Glycolysis by
lowering the level of Fructose 2,6-Bisphosphate (i.e. F-2,6-BP)
è Prolonged Fasting Stage/Starved Stage:
-Definition: stage >12 hours fasting
-Process: Ketone Bodies à Amino Acids
è Early Refed Stage
-Influencers: Exercise/Physical Activity States
-Factors: fuel choice determined by intensity and duration of activity
-Mechanism: Exercise à Adrenaline secretion increases à stimulates release of FAs from TAG stored in Adipose Tissue
depots in the body à FAs entry allowed by relieving inhibition of Carnitine Palmitoyltransferase-1/CPT-1 à use of FAs as
fuel source leads to an increase in Acetyl CoA production à Acetyl CoA accumulation causes inhibition and redirection of
metabolism of Glucose and Glycogen by multiple mechanisms à
1) Inhibition of Glycolysis: Acetyl CoA directly inhibits Pyruvate Kinase/PK
2) Inhibition of Glycogenolysis: accumulation of Acetyl CoA causes Citrate to enter the Cytosol à Citrate inhibits
both Pyruvate Kinase/PK and Phosphofructokinase-1/PFK-1 à inhibition of PFK-1 leads to accumulation of G-6-P
à G-6-P inhibits Glycogen Phosphorylase
-Effect: use of FAs slows the rate at which Glycogen is used up thereby delaying the onset of exhaustion
-Sub-states:
à At Rest State:
-Energy: uses external sources of fuel
-Example: Blood Glucose, TAGs, KBs
à Low-to-Moderate Exercise State:
-Energy: uses internal sources of fuel
-Examples: Muscle Glycogen, TAGs
-Rationale: Oxidative Metabolism can produce ATP at necessary rates and ∴ Fatty Acids are the more
suitable fuel
-Regulation: Fatty Acid oxidation is regulated in terms of supply only and not within the pathway itself
(unlike Glycolysis which can be regulated by both mechanisms)
-Measurement:
a- Low: ~25% VO2 Max
b- Moderate: ~65% VO2 Max
-Interpretation: total Fatty Acid oxidation increases when intensity increases from 25% VO2 Max to 65%
VO2 Max due to oxidation of intramuscular Triglycerides (which provide ~1/2 of Fat for oxidation)
-Impact:
→ Trained Endurance Individuals: (typically endurance as this is their average VO2 Max used)
have accelerated oxidation of Intramuscular Triglycerides and NOT necessarily greater rate of
oxidation of the FFAs removed from blood
→ Untrained Individuals: greater abilities to mobilize FFAs from blood than they do oxidation of
them
à High-Intensity Exercise State:
-Energy:
-Type: mainly uses blood Glucose
-Requirement: requires high rate of ATP replenishment
-Source: Glycolysis is the most suited pathway for this state due to lack of reliance on Oxygen
diffusion to tissues
-Effectors: Type II Fibers recruited for high-intensity contractions
-Processes:
a- Creatine Phosphate stores replenish ATP via Creatine Kinase/CK
b- ADP replenishes ATP via Adenylate Kinase
c- AMP produced acts as allosteric effector for several enzymes
 -Issue: Fat from body stores and/or dietary supplementation cannot adequately replace muscle Glycogen
and blood Glucose as fuels for intense exercise because even the smallest amount of Glycogen/Glucose
inputs reduces fat oxidation (largely through the action of Insulin)
-Concentrations/Usage: general usage of fuel sources during exercise
a- Muscle & Liver Glycogen: decreases due to depletion (i.e. Glycogenolysis)
b- Muscle & Adipose Tissue Triacylglycerols/TAGs: usage increases due to more demand (especially for low-
intensity exercise)
c- Plasma Lipoproteins & Plasma NEFA: secreted from muscle post-exercise
d- Ketone Bodies: usage increases during prolonged exercise

Fuel Source Availability

-Methods: of Glucose Availability
1) Muscle Glycogenolysis: breakdown of muscle Glycogen (stimulated by activation of Glycogen Phosphorylase)
2) Liver Glycogenolysis: breakdown of liver Glycogen (stimulated by similar processes)
3) Translocation of GLUT4: muscle contraction translocates Glucose Transporters to the membrane thereby allowing it to
take up Glucose from the blood
4) Other Factors:
a- Nutritional State (i.e. Fed State vs Fasting State)
b- Duration of Physical Activity/Exercise
-Significance: Upregulation of Glycolysis – the main method of utilizing Glucose energy is upregulated by two specific mechanisms
-Mechanism #1: by increasing supply of Glucose
-Mechanism #2: by increasing activity of the regulatory enzymes of Glycolysis
-Effectors:
•Phosphorylase Kinase (PKA):
-Action: activates Glycogen Phosphorylase enzyme → Glycogen Phosphorylase can be partially activated by
phosphorylation (via PKA), by Ca2+, or maximally activated by both
-Sites:
1) Muscle:
a- Adrenaline stimulates PKA
b- Muscle contractions lead to release of Ca2+ in the cytosol
2) Liver:
a- Glucagon stimulates PKA
b- Adrenaline stimulates PKA and Ca2+ release
-Contribution: provides supply of Glucose (i.e. Mechanism #1)
-Outcome: all PKA (and Ca2+) actions ultimately stimulates Glycogen Phosphorylase to stimulate Glycogenolysis in
order to supply Glucose for muscle usage
•Hexokinase:
-Action: phosphorylates Glucose thereby forming Glucose-6-Phosphate

-Inhibition: inhibited by Glucose-6-Phosphate (G-6-P)

-Cessation: Inhibition is relieved as the rate of Glycolysis is increased
-Contribution: increased activity of regulatory enzymes of Glycolysis (i.e. Mechanism #2)
•Pyruvate Kinase:
-Action: catalyzes the conversion of Phosphoenolpyruvate (and ADP) to Pyruvate (and ATP)
-Mechanisms: activated by two main mechanisms
a- increased [AMP]
b- accumulation of Fructose 1,6-Bisphosphate (Feed-Forward Activation)
-Contribution: directly involved in Glycolysis pathway
•Phosphofructokinase-1 (PFK-1):
-Action: catalyzes the conversion reaction of Fructose-6-Phosphate/F-6-P to Fructose 1,6-Bisphosphate
-Mechanism: activated by increased [AMP]
 -Substrate: ATP
-Inhibition:
a- when [ATP] and [CP] are high à leads to shutting down of all Glycolysis
b- if Fatty Acids are being oxidized Citrate inhibits PFK-1
-Significance: considered the central regulatory enzyme in Glycolysis because it determines the activity of
Hexokinase and Pyruvate Kinase
-Contribution: increased activity of regulatory enzymes of Glycolysis (i.e. Mechanism #2)

Energy Utilization
-Premise: intensity and duration of muscular exercise is limited by how quickly ATP can be renewed and for how long
-Standards: the initial concentrations of intracellular fuels in resting muscles
→ [ATP]: 4mM
→ [ADP]: 0.013mM
→ [Creatine Phosphate]: 25mM-30mM
→ [Creatine]: 13mM
-Methods: three main biochemical systems for production of ATP (in order of usage)
1) Using ATP/CP:
-Premise: all Muscle cells have enough ATP initially to last ~3 seconds
-Alternative: Creatine Phosphate (high-energy compound in all muscle cells)
-AKA: Phospho-Creatine (PCr)
-Mechanisms: decrease in pH and rise in ADP drives à triggers transfer of CP’s high-potential Phosphoryl
group to ADP à regeneration of ATP
-Significance: main source of Phosphoryl group for ATP regeneration in the initial phase of exercise
-Analysis:
à ATP:
-Pros: readily available in muscles without notice
-Cons: only lasts ~3 seconds
àCP:
-Pros: CP can supply energy needed for muscle work at a very high rate
-Cons: CP only lasts ~8-10 seconds
-Optimization: optimal system for short-intense exercise (e.g. weightlifters, short-distance sprinters)
2) Using Glycogen & Glucose (anaerobic respiration):
-Premise: Muscles have large stores of Glycogen
-Process: Glycogen broken down to Glucose molecules to feed into ATP production system
-Analysis:
-Pros:
a- Duration: produces enough energy to last about 90 seconds
b- Anaerobic: does not require Oxygen and ∴ relieves Heart/Lungs from the burden of supplying
oxygenated blood constantly
-Cons: Glycolysis takes ~12 chemical reaction steps to completion which means it supplies energy slowly
(relative to Creatine Phosphate)
-Issue: Lactate Formation (i.e. Glycolysis; Glycogen into Lactate) à Acidosis
-Optimization: optimal for intermediate-intensity/intermediate-duration exercise (e.g. 100-Meter Swim, 200-
Meter or 400-Meter Run)
3) Using Glycogen & TAGs (aerobic respiration):
-Onset: after ~2 mins of exercise
-Sources:
a- Glucose: e.g. food in Intestine
b- Glycogen: e.g. in Liver
c- Fat Reserves: in Adipose Tissue and/or Muscle Fibers
d- Proteins (i.e. extreme cases): from Muscles
-Transitions:
1) Type of ATP Production: body transitions from anaerobic ATP production to aerobic ATP production
2) Type of Fuel Used: aerobic respiration can use all types of fuel sources but TAGs are the most suitable
and ∴ the most used ( as Glucose and its origins/derivatives are less prevalent/available)
-Process: TAGs in Adipose Tissues (and Muscle Fibers) release Free Fatty Acids/FFAs à FFAs transported by plasma
flow (carried by Albumin) à FFAs enter Mitochondria in Muscle Cells à accumulation of FAs leads to increase in
Acetyl CoA production à accumulation of Acetyl CoA inhibits and redirects the metabolism of Glucose and
 Glycogen à leads to inhibition of Glycogenolysis and Glycolysis (i.e. Fatty Acid oxidation occurs instead)
-Effect: use of FAs slows the rate at which Glycogen is used up thereby delaying the onset of exhaustion
-Analysis:
-Pros: capacity to supply ATP production for several hours (or as long as supply of fuels last)
-Cons:
a- slowest system of all as it undergoes more chemical reactions
b- release of protons (H+) from intensely-active muscle concomitantly lowers the blood pH
(acidosis)
-Optimization: optimal for endurance exercises
-Examples: marathon runners, triathletes, distance skaters
-Biochemical Mechanisms: low blood-sugar level leads to high ‘Glucagon : Insulin ratio’ à mobilizes Fatty
Acids from Adipose Tissue à Fatty Acids enter muscles à Fatty Acids degraded by β-oxidation to Acetyl
CoA and then to CO2 à elevated Acetyl CoA level decreases activity of Pyruvate Dehydrogenase complex
à subdued Pyruvate Dehydrogenase in turn hinders the conversion of Pyruvate into Acetyl CoA à Fatty
Acid oxidation decreases the funneling of sugars into Citric Acid Cycle & Oxidative Phosphorylation à
Glucose spared so that just enough remains available at the end of endurance event
-Influencers:
1) Effect of Training/Conditioning:
à Anaerobic Exercise:
-Change: size of Type II fibers increases
-Effects:
a- increase in bulk of Muscle
b- increase in Glycogen storage
à Aerobic Exercise:
-Changes:
a- increase in Glycogen Synthase activity
b- increase in density of capillaries supplying muscle
c- increase in the expression of FA transport proteins
d- activation of enzymes for FA oxidation (i.e. AMP-activated Protein Kinase)
e- increase in size and number of Mitochondria (up to 5x)
f- increase in activity of TCA and FA oxidation enzymes
-Effects:
a- increased Glycogen stores which ultimately increases endurance (result of increased Glycogen
Synthase activity)
b- increased capacity to oxidize fats (result of activation and increase of enzymes for FA
oxidation)
--Overall Effect: all changes increase the capacity to oxidize FAs and spare Glycogen (however these changes are
temporary and reversible)
2) Effect of Disuse:
-Examples: incapacitation (due to severe injury), sedentary lifestyle
-Effects:
a- number of Mitochondria may fall to ~10%
b- maximal power generated can fall to ~120W (relative to 10W of resting muscle or 3600W of a sprint)
-Overview: with respect to energy systems utilized and the duration of exercise

Energy Metrics
-Overview: there are methods for measuring the energetics of a system as well as what fuel sources are most utilized
-Measurement: Respiratory Quotient/RQ
-AKA: Respiratory Coefficient
-Purpose: used in calculations of Basal Metabolic Rate/BMR
-Calculation: the ratio of Carbon Dioxide produced to Oxygen consumed (i.e. CO2 : O2)
-Analysis: the specific RQ value indicates which macronutrients are the main metabolites at that specific moment
-Levels:

à RQ (= 0.7): indicates Lipids mainly metabolized

à RQ (=0.8): indicates Proteins mainly metabolized (or indicates RQ of a mixed diet)
à RQ (=1.0): indicates Carbohydrates mainly metabolized
-Rationale: increase in the proportion of Fats in the diet à decreased RQ value (due to the decrease in amount of
CO2 produced) à reduction of amount of energy spent on respiration (due to reduced respiratory burden of
eliminating CO2)

Bone Diseases – MMB 038

Osteoporosis
-Definition: loss of bone density with deterioration of microarchitecture leading to increased risk of fracture with minimal trauma
-Cause: abrupt decline in circuling estrogens at menopause ( androgens decline more gradually with age)
-Pathophysiology: trabecular bone plates become eroded by the action of Osteoclasts (often into rod-like elements) which may then
be perforated and perhaps irreversibly lost
-Biophysical Interpretation: lateral elements are particularly vulnerable to Osteoporosis pathological effects due to the fact
that Cortical Bone loss (which is generally slower than Trabecular Bone loss) results from endosteal resorption proceeding
faster than periosteal formation thereby leading to thinner bone shafts of increased diameter as individual ages
-Risk Factors:
1) Gender:
a- Females: 10x more likely in females than in males (due to Estrogen deficiency; e.g. Menopause, Oophorectomy)
b- Males: Hypogonadism
2) Age: more likely in individuals over age of 60
3) Ethnicity: Caucasians more likely than Afro-Carribeans (due to generally lower bone mass/density)
4) BMI: small build-low body weight
5) Lifestyle: sedentary lifestyle
6) Drug Miuse: e.g. smoking, alcohol abuse, excessive caffeine
7) Nutrition: excessive protein intake
8) Physiological States: chronic low-level acidosis
9) Pre-exisiting Conditions: AIDS, Diabetes, Respiratory Disease, Kidney Disease, Transplants
-Clinical Relevance: ~25% of Caucasian women over the age of 60 will suffer from vertebral crush fractures leading loss of height
(associated with typical ‘Dowager’s Hump’/Hunchback appearance)
-Specific: Post-Menopausal Osteoporosis
-Defintion: a generalized skeletal disorder in which because of decreased bone density or deteriorating bone quality there is
increased risk of fracture
-Background: Estrogen
-Function: involved in growth and maturation of bone as well as regulation of bone turnover (mainly inhibition of
bone resorption)
-Defect: Estrogen deficiency leads to large increase in bone resorption caused by
a- increased Osteoclast numbers (due to enhanced OC formation and reduced OC apoptosis)
b- increased Osteoclast activity
-Diagnosis:
1) DEXA Scan: bone mass less than 2.5 Standard Deviations of the average (WHO definition)
2) Dowager’s Hump: hunchback appearance charactertisc of vertebral crush fractures due to osteoporosis
3) Femoral Neck Fractures:
-Significance: associated with 20% moretality rates
-Age: typically over age 70
-Gender: 2-to-1 prevalence in females as opposed to males
-Management:
-Strategies:
1) Hormone-Replacement Therapy:
-Method: low-level Estrogens in post-menopausal women effectively prevents osteoporosis
-Risk: associated slight increased risk of Breast Cancer and Endometrial Cancer
2) Intermittent PTH Injections:
-Purpose: helps restore lost bone by stimulating Osteoblasts
-Issue: remains an expensive option
3) Non-Hormonal Therapies:
-Mechanism: generally treat bone loss disorders by blocking Osteoclast activity
-Examples:
a- Bisphosphates: cheap and orally-active
b- Synthetic Antibody that binds RANK Ligand: monoclonal antibodies against Scleorostin
-Treatment:
•Hormone Replacement Therapy:
-Mechanism: direct action by enhancing apoptosis of Osteoclasts and inhibiting Osteoclast activity
-Significance: first line of management of Osteoporosis
-Risks:
a- Breast Cancer and Endometrial Cancer: inconclusive for ‘Estrogen + Progesterone’ and no
increase in Estrogen alone
b- Stroke: dependent on dosage but no increase in risk if initiated below 60 years of age
c- Venous Thrombo-Embolism: dependent on dosage/route with trainsient increase of risk in oral
HRT and no increase in risk with transdermal HRT
•Bisphosphates:
-Mechanism: inhibit the resorption of Bone by Osteoclasts (and may have an effect on Osteoblasts)
-Significance: structurally similar to Pyrophosphate (normal product of human metabolism) and therefore
gives the drug a high affinity for Bone (can remain in bone for many years)
-Risks:
a- Gastro-intestinal Side Effects
b- Atrial Fibrillation (more severe with IV Bisphosphates)
c- Osteonecrosis of the jaw (more common with IV Bisphosphates; following dental extraction)
d- Inflammatory Eye Disease (only with IV Bisphosphates)
e- Esophageal Cancer (only with Oral Bisphophates taken for > 3 years)
f- Femoral Stress Fracture (due to long term Bisphosphates)
•Tibolone:
-Definition: synthetic hormone drug that possesses estrogenic, progestogenic, and weak androgenic
properties
-Mechanism: Tibolone itself has no biological activity but its metabolites effects various tissues (tissue-
selective effects result of metabolism, enzyme regulation, and receptor activation that vary in different
tissues)
-Effect: prevents bone loss without stimulating Endometrium
-Risks:
a- Hip fracture protection not demonstrated
b- Breast Cancer (reduced risk in normal women but increased risk in previous Breast Cancer
survivors)
c-Stroke (apparent increased risk)
•Selective Estrogen Receptor Modulators (SERMs):
-Example: Raloxifene
-Mechanism: bindings to Estrogen Receptors results in activation of estrogenic pathways in some tissues
(agonism) and blockade of estrogenic pathways in others (antagonism)
-Effects (examples):
a- estrogenic action on Bone
b- anti-estrogenic actions on Uterus and Breast
•Strontium Ranelate:
-AKA: Strontium (II) salt of Ranelic Acid
-Definition: Dual-Action Bone Agent/DABA
-Mechanism: increases in vitro Osteoblast differentiation from progenitors (as well as Osteoblast activity
and survival) and decreases Osteoclast differentiation and activity (while increasing their apoptosis)
 -Others: may slow the course of Osteoarthritis of the Knee
•Teriparatide:
-Definition: recombinant form of Parathyroid Hormone (PTH key regulator of Calcium and Phosphate
metabolism in the Bone and Kidney)
-Mechanism: binds to the same receptors as natural PTH and mimics the favorable effects of PTH on bone
health
-Effects: intermittent use activates Osteoblasts more than Osteoclasts thereby causing new bone
formation
-Risks:
a- hypersensitivity reactions
b- hypercalcemia
c- hypercortisolism
d- increased Osteosarcoma risk
•Phytoestrogens:
-Definition: plant-derived Xenoestrogen not generated within the endocrine system (but consumed by
eating plants or via medication)
-Mechanism: may act like weak Estrogens on Bone
-Risks: side-effects and safety unknown
•Calcium/Vitamin D (and other Vitamins):
-Risks:
a- fracture protection only in elderly
b- increased renal calculi
c- increased cardiovascular disease
•Denosumab:
-Definition: soluble human IgG2 monoclonal antibody with affinity and specificity for human Receptor
Activater of Nucelar Factor Kappa -B Ligand/RANKL (ligand essential for formation, function, and survival
of Osteoclasts)
-Purpose: treatment of Osteoporosis, metastases to Bone, or Giant Cell Tumor of Bone
-Mechanism: prevents RANKL from activating its receptor RANK on the surface of Osteoclasts and their
precursors
•Cathepsin K Inhibitors:
-Definition (Cathepsin K): Cysteine Protease Cathepsin K/CatK (abundantly expressed in Osteoclasts)
responsible for degradation of bone matrix proteins
-Mechanism:
a- similar reduction in bone resorption markers to Bisphosphates
b- lesser reduction in bone formation markers than with Bisphosphates
-Types:
•Odanacatib: Phase 3 (50mg weekly)
•ONO-5334: Phase 2 (300mg weekly)
•MIV-711: pre-clinical
-Risks:
a- rapid offset of action after stopping therapy
b- skins adverse events with Balicatib
c- no serious adverse events with Odanacatib
•Sclerostin Monoconcal Antibody (AMG 785):
-Definition (Sclerostin): Osteocyte-secreted protein that negatively regulates Osteblasts thereby inhibiting
bone formation
-Mechanism: inhibits Sclerostin osteolytic effect
•Other Therapies: Anabolic Steroids, Fluoride, Boron, Nylestriol, Hachimijiyougan, Guinness

Osteopenia
-Definition: low bone mass pathlology that is less severe than Osteoporosis (i.e. lesser degree of Osteoporosis)
-Diagnosis: DEXA Scan – bone mass less than 1 Standard Deviation of the average (WHO definition)

Osteomalacia
-Definition: impaired mineralization of bone leads to deformities of adult bone
-Cause: Vitamin D deficiency
-Clinical Relevance (comparison to Rickets): proportion of mineralized bone matrix reduced and Osteoid tissue increased
Rickets
-Definition: impaired Growth Plate cartilage in growing children leads to deformities of growing bone
-Pathophysiology: Vitamin D deficiency leads to failure of cartilage mineralization in Growth Plate (Growth Plate widens)

Osteogenesis Imperfecta
-Definition: group of hereditary disorders of Type-I Collagen synthesis
-Cause: mutations in the genes encoding α1 and α2 chains
-Inheritance:
à Autosomal Dominant (more common)
à Autosomal Recessive (severe lethal forms)
-Effects: the severity of effects varie greatly
-Prenatal Death
-Impaired Stature
-Impaired Tooth Development and Deformity
-Minimal Deformity
-Hearing Loss
-Blue Sclera

Paget’s Disease
-Definition: deficiency of bone remodelling leading to abnormally shaped bone structure/organization
-Hallmark: focal areas of increased bone turnover leading to disorganized new bone
a- greatly-accelerated bone resorption at certain focal sites
b- compensatory increased bone formation at certain focal sites
-Etiology:
-Genetic Factors
-Environmental Factors:
à Potential Triggers:
a- Paramyxovirus Infection
b- deficiency of dietary Calcium
c- repetitive mechanical loading of the Skeleton
-Symptoms: often asymptomatic but can be associated with
1) Bone pain
2) Bone deformity
3) Osteoarthritis
4) Pathological fracture
5) Deafness
6) Nerve compression syndromes
7) Very large multinucleate overeactive Osteoclasts (histological sign)
-Treatment: inhibitors of osteoclastic bone resorption most common treatment (e.g. Bisphosphate; especially for those with bone
pain)

Sclerostosis
-Definition: autosomal recessive disorder characterized by bone overgrowth
-Manifestations:
1) Excessive Bone Formation: in Skull, Mandible, and Tubular Bones
2) Facial Deformity
3) Increased Intracranial Pressure (can cause sudden death)

Osteopetrosis
-AKA: Stone Bone, Marble Bone Disease
-Definition: rare inherited disorder in which the bones harden and become too thick/heavy to bear
-Cause: malfunctioning Osteoclasts leading to impaired modelling and remodelling of Bone

Bone Cancers
-Vicious Cycle Hypothesis: Tumor Cells produce Osteoclast stimulating factors (e.g. TNF, ILs, RANKL) à stimulation of Osteoclasts by
low O2 tension and low pH in the tumor à increased formation and activity of Osteoclasts à increased Bone resorption à
increased release of Growth Factors from bone matrix à stimulation of Bone growth (cycle begins once more) à increased bone
resorption and fractures à hypercalcemia
-Characteritics:
a- loss of appetite
b- hemorrhage & necrosis
c- infiltration
d- destruction of structure
-Examples:
•Osteosarcoma
-Description: Osteoblast tumor
-Severity: frequently aggressive
-Age Group: most common in younger individuals
•Osteoclastoma
-AKA: Giant Cell Tumor
-Description: Osteoclast tumor
-Main Characteristics:
a- Metastasis: does not metastasize
b- Severity: not directly life-threatening (due to no metastasis)
c- Effect: rapid local destruction of Bone
•Secondary Cancers to Bone:
-Description: cancers that metastasize to bone
-Types:
à Breast Cancer
à Lung Cancer
à Kidney Cancer
à Prostate Cancer

Metabolic Acidosis
-Definition: results from net addition of H+ to blood which leads to decreased HCO3- and decreased pH
-Cause: Chronic Metabolic Acidosis usually the result of Kidney disease
-Effect: causes bone loss by activating resorption processes in two main ways
1) Diseased Kidneys:
-Premise: lose the ability to form 1,25(OH)2D (Calcitriol; active form of Vitamin D)
-Process: decreased Ca2+ uptake from gut (due to Calcitriol deficiency) à decreased plasma Ca2+ à increased PTH
secretion à increased Osteoclast formation and activity
2) Osteoclasts:
-Premise: directly responsive to extracellular H+
-Process: low pH à increased resorption pit formation à release of Alkaline bone mineral (i.e. Hydroxyl Apatite)
-Treatment: emergency mechanism to correct systemic acidosis

Joint Replacement and Osteointegration – MMB 046d

(directly added radiology and histology onto this lecture 3ashan angez)
-Definition: replacement of damaged/pathological joint structures with artificial scaffolds
-Clinical Relevance: Joint Replacement and Osteointegration together are one of the main facets of Arthroplasty (defined as surgical
reconstruction or replacement of a joint)
-Purpose:
a- to relieve pain
b- to restore range of motion
c- to improve muscular ability
-Types: there are different levels of joint replacement à (Hip Joint as concept example)
•Hemiarthroplasty: for only a part of overall joint structure (e.g. if head of Femur only)
•Total Arthroplasty: for the entire joint structure (e.g. both femoral and acetabular surfaces; Total Hip Replacement/THR)
-Indications:
1) Osteoarthritis
2) Fractured Acetabulum (in which joint cannot be restored)
3) Avascular Necrosis of Femoral Head (e.g. Perthe’s Disease)
 4) Fractured Femoral Neck in Elderly
5) Reconstruction after Tumor Excision
-Fixation: joint replacement implant can be fixed into bone via à

•Cemented Fixation:
-AKA: Press Fit
-Method: using acrylic bone cement
-Purpose: functions as a grout thereby producing an interlocking fit between cancellous bone and prosthesis
•Uncemented Fixation:
-AKA: Osteointergration
-Method: biological/natural fixation of Bone to a surface coating on the Prosthesis
-Theory: Wolfe’s Law
-Definition: maintenance and transformation of skeletal form is influenced by the mechanical factors acting on bone during
use
-Interpretations:
→ Bone Formation: if load on Bone increases the Bone attempts to remodel itself to become stronger (thickening
of the Cortical Bone and architectural changes of the Cancellous Bones)
→ Bone Resorption: if load on Bone decreases (shielded) its response to normal Bone turnover becomes weaker
with no compensatory building
-Simplification:
→ Bone Formed: in regions of high stress
→ Bone Resorbed: in regions of low stress
-Issue: Stress Shielding
-Definitionk: reduction in bone density (osteopenia) as a result of removal of typical stress from the bone by an implant
-Effects (Hip Prosthesis as Concept Example): prosthesis results in forces being transmitted to associated bones in a non-
physiological way thereby leading to certain characteristic effects (due to Wolfe’s Law)

a- Bone Resorption: area of bone under less stress/relieved of stress/’shielded’ due to prosthesis will begin to be
resorbed over time (top part of Femur)
b- Bone Formation: area of bone under more stress/induced stress due to prosthesis will being formation
processes over time (Shaft and bottom part of Femur)
-Differences: between prostheses
-Rationale: the larger/longer the prosthesis à the more shielded area will increase (i.e. take up more space) à the
weaker the Bone will be
-Effects of Different Types:
•Cemented Prosthesis: allows for very little contribution from bone in force dispersal and therefore
deficient bone turnover/more bne resorption (only good for ~10 years)
 •Uncemented Prosthesis: with Osteointegration allows for Bone to contribute to force dispersal and
therefore proper bone turnover/less bone resorption (preferable; good for decades)
-Changes: many prosthesis changes happen over time
1) Loosening:
-Pattern: over time the prosthesis begins to loosen (Prosthesis Loosening) leading to general unzipping of the
fixation
-Findings: radioluscent lines progresses along the stem of the prosthesis

2) Implants Wear: over time the prosthesis material (most often Polyethylene) weas out as a result of usage

3) Osteointegration: bine growth intergrated into grooves of Prosthesis

-Response: from immune system

-Overview:
 -Findings:
a- General Wear: numerous wear particles within Macrophages

b- Metal Wear (release of Metal Particles):

-Pathophysiology: Cobalt ions and Chromium ions released due to corrosion from the bulky alloy (of Metal
Prosthesis) à debris released due to wear particles of bulk metal + loss of passive film à Macrophages
ingest ion debris and eventually die à activated T-lymphocytes react by releasing Cytokines (Chemokines)
à Osteolysis + pain sensation + recruitment of other cells
-Effects: discomfort, pain, nerve palsy (from bone wear), noticeable rash/mass, necrosis, lymphocytic
infiltration
-Management:
-Rationale: the optimal apparatus is one that uniformally disperses the forces to all surrounding areas
-Selection: differences in Prosthesis Choice (based on Age)
à Children: ceramic joint prosthesis (most optimal)
à Adults:
a- Head: metal alloy
b- Body: plastic (e.g. Polyethylene)
à Specific Prosthesis: Charnley Hip Replacement
-Components: involves Stem + Head + Liner + Shell
-Outdated: Metal-on-Metal-Articulation Prosthesis have
-Current: have become outdated as the shortcomings of this type outweight its benefits
-Pros:
a- less friction
b- more durability
-Cons:
a- release of toxic metallic ion concentrations (causing harmful pathological effects)
b- uneven dispersal of force (more evident in metal prosthesis than others)
-Follow Up: all arthroplasts require subsequent revision (as nothing lasts forever)

The Walking Cycle – MMB 057

Transmission of Body Weight
-Distribution:
è General: weight of the whole body is carried from the Vertebral Column all the way to the Sacrum à from the Sacrum
onwards ~50% of body weight is transmitted to each Sacroiliac Joint

è Sitting Position: weight of the whole body is carried from the two Sacroiliac Joints to the two Ischial Tuberosities of the
Hip Bones
 è Standing Position Distribution: ~50% of the body weight transmitted from each Sacroiliac Joint to the corresponding Hip
Joint à line of gravity descends form center of Femoral Head à the anterior convexity of the Femoral Shaft - as well as the
Femoral Condyles being on the same horizontal plane - brings the line of body weight in front of Knee Joint (thereby
producing passive hyperextension) à weight transmitted to the two Femoral Condyles (although the Lateral Condyle
receives most of the weight as the Femur lies oblique à transmitted to the Tibia à transmitted to the Talus (distributes
the body weight along the Arches of the foot) à transmitted to the Foot (line of gravity ultimately lies in front of the Ankle
thereby producing its passive hyperextension) à half the transmitted weight (i.e. ~25%) carried posteriorly through to the
heel of the Calcaneus while the other half (~25%) carried anteriorly to the Metatarsal Bones (especially 4th and 5th) via the
Lateral/Static Longitudinal Arch of Foot

è Walking Weight Distribution: same as Standing Position Distribution up until it reaches the Talus à weight transmitted
along the Medial/Kinetic Longitudinal Arch of Foot à

–Anteriorly: transmitted to Navicular à Cuneiforms à medial 1-3 Metatarsals

–Posteriorly: transmitted to heel of Calcaneus

Gait Cycle

-Definition: walking is performed through many successive steps with each step being composed of two main phases (Stance Phase
and Swing Phase)
-Cycle: cycle is considered in one limb separately
→ Beginning: when reference foot makes contact with the ground
→ End: subsequent ground contact of the same foot
-Measurements:
à Step Length:
-Defintion: distance between corresponding successive points of heel contact of the opposite foot
-Standard: Right Foot Step Length = Left Foot Step Length
 à Stride Length:
-Definition: distance between successive point of heel contact of the same foot
-Standard: double the step length
à Walking Base:
-Definition: side-to-side distance between the line of the two feet
-Standard: variable amongst individuals
à Cadence:
-Defintion: number of steps per unit time
-Standard: 100-115 steps/min (with cultural/social variations)
-Process:
à Stance/Support Phase: limb in contact with ground
•Heel Contact:
-AKA: Initial Contact
-Definition: initial contact with ground
-Action: extension of both Hip Joint and Knee Joint by Hamstrings and Quadriceps Femoris (respectively)
•Foot Flat:
-AKA: Loading Response (beginning of single-support phase)
-Definition: initial contact of forefoot with ground
•Midstance:
-Definition: most contact with ground (i.e. centered line of gravity)
-Action: weight of body transmitted forwards from the heel to the outer border of the Foot and then to
heads of Metatarsal Bones
•Heel-Off:
-AKA: Terminal Stance (end of single-support phase)
-Definition: anterior-most contact with ground
-Action: Soleus and Gastrocnemius contract to elevate the heel and toes from the ground
•Toe-Off:
-AKA: pre-swing
-Definition: loss of contact with ground
à Swing Phase: limb not in contact with ground
•Toe-Off:
-AKA: Initial Swing
-Definition: foot raised off of ground
-Action: Hip Joint and Knee Joint flexed and Ankle Joint dorsiflexed (thereby aiding in raising foot from the
ground)
•Mid-Swing:
-AKA: Acceleration
-Definition: build-up of forward momentum
-Action: extension of the Knee and swinging of the Pelvis thereby propelling the leg forwards
•Terminal Swing:
-AKA: Deceleration, Heel Strike
-Definition: returned contact with ground
-Action: Quadriceps Femoris extend the Knee and Hamstrings prevent hyperflexion of the Thigh at the Hip
-Overview:
Swing Phase
Action Muscle Root
Knee Flexion Sartorius L2, L3
Hip Flexion Iliopsoas L2, L3, L4
Knee Extension Quadriceps L3, L4
Foot Dorsiflexion Tibialis Anterior and Extensor L4, L5
Digitorum
Thigh/Leg Lateral Rotation small posterior Hip Muscles L4, L5, S1
Swing End (Hyperflexion Hamstrings L5, S1
Prevention)
Stance Phase
Action Muscle Root
Trunk Pulled over Leg Thigh Adductors L3, L4, L5
Hip Stabilization Gluteus Medius and Gluteus L4, L5, S1
 Minimus
Medial Rotation of Thigh/Leg Gluteus Medius L4, L5, S1
Trunk Stabilization Gluteus Maximus L5, S1, S2
Eversion of Foot Peroneal Muscles S1
Plantarflexion Calf Muscles S1, S2
Further Pronation of Foot Intrinsic Foot Muscles S2, S3
-Stabilization:
-Effectors:
a- Gluteus Maximus: for Trunk stabilization
b- Gluteus Medius and Gluteus Minimus: for Pelvis stabilization
c- Adductors: for stabilization of Trunk over the weight-bearing limg (during Stance Phase)
-Action: contraction of these muscles supports lower limb thereby preventing tilting of the Pelvis towards the raised limb
-Relevant Pathologies:
•Waddling Gait: from bilatereal Superior Gluteal Nerve injury
•Lurching Gait: from unilateral Superior Gluteal Nerve injury
•Wide-Base Gait:
a- Deformities: e.g. Abudcted Hip, Valgus Knee
b- Instability: e.g. Cerebellar Ataxia, Proprioception deficits
•Tabetic Gait (Tabes Dorsalis):
-Definition: ‘stomping’ gait due to use of impact sensation of hitting ground as a guide for walking instead
of touch or proprioception
-Trend: soles of their shoes said to be uniformly worn-out as the entire plantar surface of the foot strike
the ground at one time
-Specific:
•Running
-Action: most change in muscle length is not change in muscle belly length but rather an effect of stretch/recoil of
tendons
-Examples:
a- 35% stored in Achilles Tendon as elastic strain energy
b- 17% stored in foot Arch Ligaments as elastic strain energy
-Effect: the tendinous ‘springs’ approximately halve the work required by muscles for running
•Child Gait:
-Definition: early gait is jerky, unsteady, and wide-based with a flexed knee at heel strike and no coordinated arm
swing
-Speed: children run at slower speeds due to short length of Leg
-Development: children develop and mature their gait form in multiple ways
a- extension of Knee at heel strike
b- coordinated upper arm swing
c- increase in stride length
d- reduction in base width

Clinical Gait Assessment

•Tredelenburg Test:

-Purpose: used to assess Hip stability

-Procedure: patient asked to stand unassisted on each leg in turn while examiner’s fingers are placed on the Anterior
Superior Iliac Spines à foot on contralateral side is elevated from the floor by bending at the Knee
 -Results:
à Normal: Hip held stable by Gluteus Medius (and to lesser extent Gluteus Minimius) acting as an adductor in the
supporting Leg
à Pathological:
-Finding: Pelvis drops on the unsupported side (Positive Trendelenburg Sign)
-Rationale: Hip on which the patient is standing is painful or has a weak/mechanically-disadvantaged
Gluteus Medius
-Examples:
1) Superior Gluteal Nerve weakness (e.g. after Poliomyelitis)
2) Non-union or fractured neck of Femur (or joint pathology)
3) Avulsion of Gluteus Medius/Minimus insertion
4) Nerve Root Neuropathy (L5)
•Romberg’s Test:

-Purpose: used to assess balance stability

-Background Information: vision, vestibular apparatus, and proprioception are all involved in maintain balance
-Procedure: patient asked to close their eyes and stand for six seconds
-Rationale: patient eyes are closed in order to uncover disordered proprioception that may have been masked by
vision
-Results:
à Normal: patient stands normally throughout test
à Pathological: patient fidgets, jerks, or even falls

Autoimmune Diseases – MMB 059

Rhematoid Arthritis

-Definition: systemic chronic progressive inflammatory autoimmune disease affecting many tissues (mainly the joints)
-Risk Factors:
a- Sex: woman more likel than men to develop Rhematoid Arthritis
b- Age: most commonly begins between ages of 40 and 60
 c- Family History
d- Smoking
e- Obesity
-Pathogenesis:

a- Genetic Factors (e.g. HLA genes)

b- Environmental Factors (e.g. smoking, bacterial infection)
-Pathophysiology:
-Overview: immune system attacks joint synovium thereby leading to synovial inflammation & hyperplasia (swelling),
weakening of joint tendons & ligaments, and cartilage & bone destruction (deformity)
-Pathway: Genetic Factors and Environmental Factors lead to modification of body autoantigens à changes in Antigen-
Presenting Cells à activation of CD4+ Cells and T-Lymphocytes à multiple subsequent pathways that ultimately lead to
inflammation
-Effectors: Autoantigens
-Definition: normal proteins or complexes of proteins recognized by the immune system of autoimmune patients
-Types:
1) Citrullinated Peptides/Proteins (post-translational modification of Arginine to Citrulline)
2) IgG (acts as autoantigen itself)
-Production:
a- Anti-Citrullinated Protein Antibody (ACPA): autoantibodies that are directed against peptides and
proteins that are citrullinated
b- Anti-IgG (Rhematoid Factor): antibodies directed against the Fc region of Immunoglobulin-G (found in
autoimmune conditions, non-autoimmune conditions, and even healthy subjects)
-Effects:
a- T-Lymphocytes activate/release IL-17 à IL-17 activates Macrophages à Macrophages release cytokines
(especially TNFα, IL-1, IL-6) à inflammation
b- T-Lymphocytes activate/release IL-17 à IL-17 activates RANK Ligand (member of Tumor Necrosis Factor family)
à RANKL initiates Osteoclast differentiation and activation à activated Osteoclasts ultimately cause bone erosion
c- Plasma Cells (+PNLs) form Immune Complex à causes inflammation
-Outcome: results in non-suppurative Synovitis frequently progressing to destruction of Articular Cartilage and Bone à
disabling Arthritis
-Manifestations:
a- Signs of Acute inflammation (i.e. swelling, redness, heat, pain)
b- Site-Specific:
→ Initially: usually affects hands and feet
→ Subsequently: spread to wrists, knees, ankles, elbow, hips, and shoulders
→ Generally: advanced cases usually present with damage of same joints on both sides
→ Other: Rheumatoid Arthritis can affect many non-articular organs (e.g. Skin, Eyes, Lungs, Heart, Kidneys, Salivary
Gland {Sjogran Synndrome}, Nerve Tissue, Bone Marrow, Blood Vessels)
c- Gross Features:
-Pannus Formation: fibrovascular tissue or granulation tissue
-Irregular Surface: due to synovial hyperplasia
-Subchondral Cysts: involve entire head of bone (late stage RA)
-Widespread Joint Space Loss
 -Periarticular Erosion
-Osteopenia
-General Ulnar Deviation
-Joint Stiffness (usually worse in the mornings and after inactivity)
d- Hallmark/Named Features:
-Swan-Neck: flexion of Distal Interpharyngeal Joint and hyperextension of Proximal Interpharyngeal Joint
-Boutonniere: hyperextension of Distal Interpharyngeal Joint and flexion of Proximal Interpharyngeal Joint
-Z-deformity: Z-shaped deformity of thumb
e- Microscopic Features:
-Synovial Cell Hyperplasia
-Dense Inflammatory Infiltrate (i.e. CD4+ Cells, B-Cells, Plasma Cells, Dendritic Cells, Macrophages; +/- Lymphoid
Follicles)
-Angiogenesis: causing increased vascularity
-Fibrinopurulent Exudate: on synovial and joint surfaces
-Osteoclastic Activity: in underlying bone à Synovium penetrates bone à periarticular erosions and subchondral
cysts
-Pannus Formation: layer of edematous synovium, inflammatory cells, granulation tissue, fibroblasts, etc (i.e.
Pannus) à erosion of Articular Cartilage à Pannus bridges the apposing bones à Fibrous Ankylosis ossifies à
bony Ankylosis (i.e. fusion of bone)
-Diagnostics:
à Clinical Presentation
à Blood tests:
a- Cyclic Citrullinated Peptides (CCP): frequently used to detect Anti-Citrullinated Protein Antibodies (ACPAs) in
patient serum or plasma
-Significance: ACPAs are powerful biomarkers that allow diagnosis of RA at very early stages
-Relevance: recommended to measure ACPAs and Rheumatoid Factors together to improve diagnostic
accuracy (especially in cases of early Rheumatoid Arthritis)
b- Rheumatoid Factor
c- C-reactive Protein (CRP)
d- Elevated Erythrocyte Sedimentation Rate (ESR)
à Radiological Tests:
a- X-rays (help track progression of Rheumatoid Arthritis in joints)
b- MRI and Ultrasound (to test severity of disease)
-Management:
-Aim: to minimize joint pain, swelling, & visible deformity and to aid in continuation of normal work & personal activities
-Presmie: there is no cure for Rheumatoid Arthritis
-Recommendation: combination of medications to control the disease
-Treatments:
a- Surgical Intervention: Joint Replacement indicated for patients with severe joint damage
b- Medications:
1) Nonsteroidal Anti-Inflammatory Drugs (NSAIDs): relieve pain and reduce inflammation
-Side Effects: stomach irritation, cardiovascular issues, liver damage, kidney damage)
2) Steroids: reduce pain, inflammation, and slow joint damage
-Example: Prednisone
-Specific: Corticosteroids used to relieve acute symptoms (with the goal of gradually tapering off
the medication)
-Side Effects: thinning of bones, weight gain, diabetes
3) Disease-Modifying Antirheumatic Drugs (DMARDs): slows the progression of Rheumatoid Arthritis and
saves joints (and other tissues) from permanent damage
-Examples: Methotrexate, Hydroxychloroquine, Sulfasalazine
-Side Effects: liver damage, bone marrow suppression, severe lung infections
4) Rheumatoid-Arthritis-targeted Immunosuppresive Therapy
-TNF-α Inhibitors: Infliximab, Etanercept, Adalimumab
-IL-1 Inhibitors: Anakinra
-IL-6 Inhibitors: Tocilizumab
-B-cell Depletion: Rituximab (anti-CD20)
-Inhibition of T-cell Stimulation: Abatacept
Polymyositis
-Definition: muscle disease associated with inflammation and autoantibodies to Histidyl-tRNA Synthetase
-Prevalence: fairly rare (~1/20000)
-Associations: associated skin involvement (dermatomysitis) occurs in 50%-60% of cases

-Presentation:
-Patterns:
a- muscles involved usually those which are closest to the Trunk
b- both sides are affected
-Manifestations:
→ Main: muscle weakness
→ Other:
a- difficulty walking, climbing stairs, and getting up froms chairs
b- difficulty swallowing
c- difficulty lifting head from resting position
d- weakeness of muscles that produce voice (producing weak voice; Dysphonia)
e- reddish rash on face, neck, and upper chest can occur with or prior to development of muscle weakness
(Dermatomysitis)
-Treatment:
1) Anti-Inflammatory Drugs: e.g. Corticosteroids
2) Immuno-Suppressive Drugs: e.g. Azathioprine, Methorexate
3) Immunoglobulin Therapy: e.g. Rituximab (anti-CD20)

Myasthenia Gravis
-Definition: disorder of neuromuscular transmission characterized by abnormal fatigability of skeletal muscle ranging from transient
double vision to life-threatening respiratory paralysis
-Prevalence: fairly rare (1/10000)
-At-risk: all ages can be affected
-Pathophysiology: autoantibodies against Acetylcholine Receptors leading to blockage and subsequent loss of AChRs from post-
synaptic membranes
-Subtypes: Transient Neonatal Myasthenia
-Prevalence: in ~10% of babies born to myasthenic mothers
-Cause: due to transfer of maternal IgG autoantibodies
-Presentation:
→ Early: weakess in muscles controlling the eye and eyelids
→ General:
a- Ptosis (i.e. drooping eyelids)
b- Diplopia (i.e. double vision)
c- general weakness of extraocular muscles
d- dramatic response to Cholinesterase Inhibitors
-Treatment:
a- Acetylcholinesterase Inhibitors
b- Anti-inflammatory Drugs: e.g. corticosteroids
c- Immunosuppressive Drugs: e.g. Azathioprine, Cyclosporine, Cyclophosphamide, Tacrolimus
d- Plasma Exchange (Plasmapheresis): most effective in treating severe symptoms of MG crisis (e.g. difficulty breathing,
swallowing)

The Professional Duty of Self-Care – MMB VM2013

•Drug Abuse Issues:
-Main Issue: substance misuse has a huge impact on society on individuals and on health services
-Subsidiary Issues: patients with acute or chronic effects of substance misuse are treated by students/doctors with very
 judgemental attitudes towards substance miuse
-Cause: most damage to inividuals and society comes from less visible and/or extreme patterns of drinking and drug use
-Personal Factors: there are many personal factors that might influence our attitudes to patients with substance misuse
problems such as à
a- personal background/life experiences
b- religion or cultural norms
c- personal drug use
d- ability to tolerate ambiguity/uncertainty
e- misinformation and lack of knowledge
•Wellness Issue:
-Focus: one of the biggest causes of lack of self-care is due to the Drug Abuse issue
-Danger: healthcare workers may cause harm à
1) to themselves by à
a- misusing legal or illegal substances
b- using professional privileges to prescribe medication to themselves
c- taking medication from MOHP supplies for personal use
2) to others by à
a- putting patients, staff, and others at risk due to personal substance miuse problems
b- by prescribing medications that can cause Iatrogenic Addiction (e.g. Opiate Analgesics,
Benzodiazepenes)
•Fitness-to-Practice Procedures:
-Action: substance miuse case can be dealth with in a Health Pathway or a Disciplinary Pathway (or sometimes both)
-Purpose: the main concern is to protect the patients
-Support: there is always support for students/doctors to regain their fitness to practice
•Potential Restrictions: there is the possibility of restriction to speciality choice for aspiring doctors due to certain specialities’ access
to drugs

Muscle Pathologies – MMB ?

Duchenne and Becker Muscle Dystrophy
•Duchenne Muscular Dystrophy:
-Pathogenesis: mutation in Dystrophin gene
-Genetics:
-Site: on Chromosome X
-Function: codes for Dystrophin protein
-Associations: Dystrophinopathies
-Protein:
-Function: connects the cytoskeleton of Muscle Fiber to the Basal Lamina thereby providing mechanical stability to
the Muscle Fibers during contraction
-Malfunction/Impairment: makes muscle susceptible to tear during contraction
-Configuration: Dystrophin is a connecting bridge with attachments both inside the cell and in the cell membrane
→ inside Cell: N-terminus of protein attached to Actin
→ in Membrane: C-terminus of protein attached to the cell membrane Glycoprotein structures
-Pathophysiology: mutation in Dystrophin gene → Dystrophin-Glycoprotein Complex defect/impairment → makes Muscle
Cells suspectable to transient membrane tear (during contraction) → large-scale Calcium influx → disruption of intracellular
signaling → myofiber degeneration → ultimately exceeding capacity for repair
-Presentation:
 -Diagnostic/Pathological Features:
-Initial Findings:
a– chronic muscle damage exceeding the capacity for repair
b– segmental myofiber degeneration and regeneration with areas of atrophic myofibers
-Subsequent Findings:
→ Microscopic Examination:
a– muscle tissue replaced by Collagen and Adipocytes
b– rest of muscle tissue shows marked variation in size (from small atrophic fibers to large
hypertrophied fibers)
→ Immunohistochemical Examination:
a– absence of the normal sarcolemmal staining in Duchenne Muscle Dystrophy
b– reduced staining in Becker Muscular Dystrophy
-Outcome: myofiber degeneration that exceeds capacity for repair
•Becker Muscular Dystrophy:
-Onset: begins during childhood but may not be apparent for years
-Presentation:
1) Delays in walking and running for young children
2) Cramps during exercise
3) Enlarged calf muscles
4) Difficulty lifting loads or climbing stairs
5) Falling (and not being able to get up)
6) Cardiac issues
-Comparison: BMD vs DMD
1) Abnormal but functional Dystrophin production (in contrast to DMD in which there is no Dystrophin production)
2) Dystrophin levels generally 30%-80% of normal (in contrast to DMD in which it it < 5%)
3) BMD generally milder and onset of symptoms usually occurs later

Joint Pathologies – MMB ?

Key Concepts and Background Information
-Concept: Cardinal Signs of Inflammation
1) Heat
-Latin Name: calor
-Physiology: increased blood flow and chemical mediators
2) Redness
-Latin Name: rubor
-Physiology: arteriolar dilatation and engorged capillaries
3) Swelling
-Latin Name: tumor
-Physiology: edema fluid in extracellular space
4) Pain
-Latin Name: dolor
 -Physiology: stretching of tissues due to edema
5) Loss of Function
-Latin Name: functio laesa
-Physiology: pain and swelling
-Changes: reactions to Acute Inflammation
→ Vascular Changes:
-Causes:
a– Immediate:
-Transient: chemical mediators (e.g. histamine, bradykinin, NO, C5a, LTB4, PAF)
-Sustained: severe direct vessel injury
b– Delayed:
-Prolonged: endothelial cell injury (e.g. bacterial endotoxins)
-Effects:
a– Vasoconstriction (transient and insignificant)
b– Arteriolar Vasodilatation (increased blood flow with engorged capillaries)
c– Increased Vascular Permeability (dilated BVs, increased RBCs, peripheral leukocytes)
→ Cellular Changes: predominantly Leukocyte Recruitment
-Functions:
a– Inflammatory Response:
-deliver Leukocytes to the site of injury
-activate Leukocytes
b– Leukocytes:
-ingest the microbe
-neutralize microbe
-eliminate necrotic tissues and foreign substances
-Process: stimulated by chemical mediators and chemo-attractants
a– Sequence of Events: Margination and Rolling → Firm Adhesion to Endothelium → Transmigration
between Endothelial Cells → Migration within Interstitial Tissues
b– Types (of Leukocytes recruited): dependent on duration of inflammation and type of stimulus
1– Duration:
-6-24 Hours: PNLs (short-lived, apoptotic)
-24-48 Hours: Monocytes (long-lived)
2– Type of Stimulus:
-Most Infections: continuous PNLs recruitment
-Viral Infections: Lymphocytes
-Hypersensitivity Reactions: Eosinophils
c– Activation:
1– Onset: upon reaching site of infection
2– Initiators: microbes, necrotic products, and mediators
3– Mediators: vasoactive amines, complement components, eicosanoids, clotting cascade, kinin
cascade
-Effects: of Acute Inflammation
→ Beneficial:
1) dilution of toxins
2) entry of antibodies and drugs
3) Cell nutrition and oxygenation
4) initiation of immune response
→ Harmful:
1) damage to normal tissues (e.g. enzymatic digestion, abscess cavities, vascular damage)
2) swelling in critical sites (e.g. Epiglottis, Brain)
3) immune hypersensitivity reactions (e.g. tissue damage, asthma)
-Outcomes: of Inflammation
Red Hot Joint
-Definition: joint that is exhibiting two cardinal signs of acute inflammation due to one of three main pathologies
-Etiologies:
1) Infection
2) Crystal deposition
3) Flare in activity of Chronic Arthritis
4) Trauma
-Types: there are three main pathologies that cause Red Hot Joint
•Septic Arthritis:
-Transmission:
à Hematogenous (i.e. blood-bourne infection)
à Direct Extension (i.e. from a soft-tissue abscess or Osteomyelitis)
-Risk Factors:
a- existing joint issues (e.g. Osteoarthritis, Gout, Rhematoid Arthritis, artificial joint, previous joint surgery)
b- joint trauma
c- weak/compromised immune system (e.g. Diabetes, Kidney/Liver Diseases, immunity-suppressing drugs)
d- increased skin fragility and/or poor wound-healing
-Diagnostic Methods:
à Synovial Fluid Examination: observing for signs of
a- White Cell Count (usually very high)
b- Culture (i.e. bacteria or other organisms)
à X-rays: conducted only to look for damage or to rule out other causes
à Blood Tests: to monitor inflammation
-Treatment:
a- Antibiotics
b- drainage of fluid to stop injury
•Rhematoid Arthritis:

-Definition: systemic chronic progressive inflammatory autoimmune disease affecting many tissues (mainly the
joints)
-Risk Factors:
a- Sex: woman more likely than men to develop Rhematoid Arthritis
b- Age: most commonly begins between ages of 40 and 60
c- Family History
d- Smoking
e- Obesity
-Pathogenesis:
a- Genetic Factors (e.g. HLA genes)
b- Environmental Factors (e.g. smoking, bacterial infection)

-Pathophysiology: Genetic Factors and Environmental Factors lead to modification of body autoantigens à
changes in Antigen-Presenting Cells à activation of CD4+ Cells and T-Lymphocytes à multiple subsequent
pathways that ultimately lead to inflammation
a- T-Lymphocytes activate/release IL-17 à IL-17 activates Macrophages à Macrophages release
cytokines (especially TNFα, IL-1, IL-6) à inflammation
b- T-Lymphocytes activate/release IL-17 à IL-17 activates RANK Ligand (member of Tumor Necrosis
Factor family) à RANKL initiates Osteoclast differentiation and activation à activated Osteoclasts
ultimately cause bone erosion
c- Plasma Cells (+PNLs) form Immune Complex (antibodies against Fc portion of IgG) à causes
inflammation
d- Collagenase (and other Proteases) released in Pannus à destruction of Articular Cartilage à fibrous
ankylosis or bony ankylosis
-Effect: results in non-suppurative Synovitis frequently progressing to destruction of Articular Cartilage and Bone
à disabling Arthritis
-Manifestations:
a- Signs of Acute inflammation (i.e. swelling, redness, heat, pain)
b- Site-Specific: usually affects hands and feet first
c- Gross Features:

-Pannus Formation: fibrovascular tissue or granulation tissue

-Irregular Surface: due to synovial hyperplasia
-Subchondral Cysts: involve entire head of bone (late stage RA)
-Widespread Joint Space Loss
-Periarticular Erosion
-Osteopenia
-General Ulnar Deviation
d- Hallmark/Named Features:
 •Swan-Neck: flexion of Distal Interpharyngeal Joint and hyperextension of Proximal
Interpharyngeal Joint
•Boutonniere: hyperextension of Distal Interpharyngeal Joint and flexion of Proximal
Interpharyngeal Joint
•Z-deformity: Z-shaped deformity of thumb
e- Microscopic Features:
-Synovial Cell Hyperplasia
-Dense Inflammatory Infiltrate (i.e. CD4+ Cells, B-Cells, Plasma Cells, Dendritic Cells,
Macrophages; +/- Lymphoid Follicles)
-Angiogenesis: causing increased vascularity
-Fibrinopurulent Exudate: on synovial and joint surfaces
-Osteoclastic Activity: in underlying bone à Synovium penetrates bone à periarticular erosions
and subchondral cysts
-Pannus Formation: layer of edematous synovium, inflammatory cells, granulation tissue,
fibroblasts, etc (i.e. Pannus) à erosion of Articular Cartilage à Pannus bridges the apposing
bones à Fibrous Ankylosis ossifies à bony Ankylosis (i.e. fusion of bone)
-Diagnostics: Blood Sample – would reveal polyclonal antibodies directed against Fc portion of IgG
•Gout:
-Definition: abnormal crystal deposition and subsequent immune-mediated inflammatory reaction
-Historical Medicine: often referred to as the ‘Disease of Kings’ as it was associated with a lifestyle full og rich foods
and plenty of alcohol (the kind of diets only kings/wealthy could afford)
-Cause: impaired Purine metabolism and subsequent failure of waste product elimination
-Risk Factors:
a- Genetic: 20%-80% hereditary
b- Gender: more common in men than in women
c- Overweight: increased risk of developing Hyperuricemia due to more tissue being available for turnover
or breakdown à leads to excess Uric Acid production
d- Alcohol Consumption: beer contains Purines
e- Diet: consumption of Purine-rich foods (e.g. Organ Meats, Seafood {Anchovies, Sardines, Oysters,
Lobsters})
f- Lead: heavy metal directly inhibits Purine excretion
g- Drugs: e.g. Niacin, Diuretics
-Protective Factors:
a- Diet: low-fat dairy products, coffee, cereals, fruits
b- Hydration: proper/plentiful water and liquid consumption
-Pathogenesis:
a- Primary: idiopathic
b- Secondary: to some other cause
-Pathophysiology: Purine metabolism impairment leads to production of Uric Acid (final metabolite) à Uric Acid
crystallizes in the form of Monosodium Urate (if failure to eliminate by Kidneys) à precipitates in Joints, Tendons,
and Tissues à crystal deposition triggers a local immune-mediated inflammatory reaction
-Sites: deposition of Urate crystals leads Tophi (white masses) most prevalent in →
a- Joints: most often in the Articular Cartilage of Joints, Synovium, Periarticular Tendons, Ligaments, and
Soft Tissues
 b- Cartilage of Nose and Ear (causing ulceration of the overlying skin)

c- Subcutanesouly (particularly in Eye Lids; causing ulceration of overlying skin)

d- Interstitial Tissue of Kidney (causing Gouty Nephropathy)

e- Cardiac Valves
-Significance: higher primates lack Uricase
→ Pros: Uric Acid produces many beneficial physiological functions
a- antioxidant
b- maintenance of BP
c- aids in intelligence
d- neuron protective factor
→ Cons: predisposes higher primates to Gout
-Mechanisms:
-Marker: serum Urate (i.e. circulating Uric Acid) concentrations represent the balance of Urate production
and excretion
-Significance: Renal under-excretion of Uric Acid accounts for the major cause of Hyperuricaemia an Gout
in adults
-Presentation:
→ Acute Gouty Arthritis:
-AKA: Early Phase
-Site: typically monoarticular with the first MTP joint being the most common site of involvement
-Manifestations: pain, swelling, and erythema around involved joint
→ Repeated Attacks: crystals remain within the joint thereby predisposing the subsequent attacks due to
chronic low-grade inflammation
→ Chronic Gouty Arthritis: progressive disease characterized by deposition of Monosodium Urate crystals
(AKA: Tophi)
-Phases:
à Asymptomatic Disease: includes Stages A and B
•Stage A: high risk for Gout but without MUC deposition (subsequent presence of
Hyperuricemia)
•Stage B: MUC deposition without signs and symptoms of Gout (i.e. only MUC crystals)
à Symptomatic Disease: includes Stages C and D
•Stage C: MUC deposition with prior or current episodes of Gout flares (subsequent presence of
acute inflammatory response: Synovitis)
•Stage D: advanced Gout requiring specialized intervention (subsequent presence of Tophi and
joint damage)
 -Diagnostics:
1) Blood Test: high Uric Acid level in blood sample not definitive (as even people without Gout can have
high Uric Acid)
2) Aspiration: in order to examine multiple diagnostic factors (definitive/diagnostic test)
a- Cell Count
b- Serum Urate Levels (crystals begin to precipitate at approximately 6.8mg/dL concentration)
-Treatment: there are multiple stages of Gout management
à Treating Acute Attack: anti-inflammatory agents (e.g. NSAIDs, Colchicine, Corticosteroids, Intra-
articular Injections of Steroids, and possible combinations of these different medications)
à Prophylaxis: to prevent acute mobilization flares
à Lowering Urate Levels: to prevent flares of Gouty Arthritis and to prevent tissue deposition of Urate
crystals
-Indications:
a- frequent and/or disabling acute Gout flares
b- tophaceous Gout (soft tissue or bony)
c- Gout with Chronic Kidney Disease
d- Gout with Urolithiasis
e- Uric Acid overproduction and overecretion
f- radiation or chemotherapy for Lymphoma/Leukemia
à Treatment of Chronic Gout: therapy to reduce serum Uric Acid level to at least 6mg/dL
-Effects:
→ Local:
-resolution
-suppuration and severe damage to joint
-extension to nearby bone (often causing Osteomyelitis)
→ Systemic:
-Pyrexia (high body temperature)
-Malaise
-Anorexia
-Nausea
-Lymphoreticular Hyperplasia
-Elevated Erythrocyte Sedimantation Rate (ESR)
-Elevated White Blood Count (WBC)

Acute Inflammation – MMB ?

Key Concepts
-Purpose: protective response aimed at removal of the initial cause of injury/irritant (e.g. microbes) as well as disposal of the
consequences of said injury/irritant (e.g. necrotic cells)

Process
(in full order; Vascular Phase à Cellular Phase)
è Vascular Phase:

1) Transient Vasoconstriction
2) Vasodilation à increased blood flow à redness and hotness
 3) Increased Vessel Permability à swelling
è Cellular Phase:

1) Margination and Rolling

2) Firm Adhesion
3) Transmigration between Endothelial Cells
4) Migration within Interstitial Tissue
5) Phagocytosis

Leukocytes
-Activation:
-Timing: upon reaching site of infection
-Stimulus: microbes, necrotic products, and/or mediators
-Effectors:
à by Duration:
•6hrs–24hrs: Polymorphonuclear Lymphocytes
-Examples: Neutrophils
-Lifespan: short-lived (die by apoptosis)
•24hrs–48hrs: Monocytes
-Lifespan: survive longer
à by Stimulus:
→ Most Infections: continuous PNLs recruitment
→ Viral Infections: Lymphocyte recruitment
→ Hypersenstivity Reactions: Eosinophil recruitment

Pressure
-Changes:

→ Hydrostatic Pressure: increases with inflammation

→ Capillary Pressure: increases with inflammation
→ Venous Pressure: increases with inflammation
→ Colloid Osmotic Pressure: decreases with inflammation
Outcomes

Musculoskeletal Systematics – MMB ?

Key Concepts
-Systems:
•Skeletal System:
-Definition: encompasses all the anatomical and physiological aspects including the Bones, Cartilages, and Joints
-Functions: provides protection and support, allows body movements, produces blood cells
•Muscular System:
-Definition: involves the muscles attached to the Skeletal System
-Functions: maintains posture/balance, produces body movements, generates body heat
-Action: Muscle Contraction
-Definition: the particular movement of the muscles in relation to associated joints and body part moved
-Types: muscles always generate force at the joint but the action may be Isotonic or Isometric
•Isotonic Contraction: the force/tension generated by the muscle is greater than the load and therefore the
muscle shortens
•Isometric Contraction: the force/tension generated by the muscle is less than the load so the muscle cannot
shorten

Movements of Muscle
è Angular Movements:
→ Flexion/Extension: have different definitions/interpretations depending on joint involved
→ e.g. Elbow, Knee:
-Flexion: closing/reducing the joint angle
-Extension: opening/increasing joint angle
→ e.g. Shoulder, Neck, Trunk:
-Flexion: movement anterior to the Coronal Plane
-Extension: movement posterior to the Coronal Plane
→ e.g. Ankle: both directions classified as Flexion
-Plantar Flexion: towards plantar surface
-Dorsiflexion: towards shin surface
→ Abduction/Adduction: Abduction is movement of a body part away from the midline and Adduction is movement of
body part towards the midline
→ e.g. Limbs:
-Abduction: movement of arm away from midline
-Adduction: movement of arm towards midline
→ e.g. Fingers:
-Abduction: movement of fingers away from each other (i.e. separation)
-Adduction: movement of fingers towards each other (i.e. coming together)
è Circular Movements:
•Rotation: turning of structure around its long axis
 -Lateral Rotation: rotation that moves the body part towards the lateral side
-Medial Rotation: rotation that moves the body part towards the medial side
•Pronation/Supination: specific terms for rotations of the Forearm
-Pronation: rotation of the palm until it faces posteriorly (i.e. Radius and Ulna are crossed)
-Supination: rotation of the palm until it faces anteriorly (i.e. Radius and Ulna are not crossed)
•Circumduction: combination of flexion, extension, abduction, and adduction in freely-moveable joints (e.g. Shoulder)

Basic Structure and Physiology of Muscle

-Overview: Muscle → Fascicle → Muscle Fibers → Myofibrils → Thin/Actin and Thick/Myosin Filaments
-Innervation: muscles are excitable tissues that receive inputs from motoneurons of the Spinal Cord
-Motoneuron: controls contraction of several muscle fibers
-Motor Unit: the Motoneuron and its associated Muscle Fibers
-Tension: the maximum tension a muscle can generate depends on the optimal interaction between Thick and Thin Filaments and
therefore the results from a given motoneuron commands depends on the existing length of the muscle

Proprioception
-Definition: perception or awareness of the position and movement of the body
-AKA: Kinanesthesia
-Effectors:
•Muscle Spindle: responsible for detecting changes in muscle length (specifically stretch)
•Golgi Tendon Organ: responsible for detecting changes in muscle tension
-Pathway: information from the muscle proprioceptors enters patterns of neural connections within the spinal cord that organize
simple/reflex movements and may also be transmitted to the brain (via Ascending Pathways) to be used in higher levels aspects of
movement control
-Concept Example (Muscle-Stretch Reflex): simple monosynaptic reflex that is driven by input from the Muscle Spindle

Model of Motor Control

•General Hierarchical Model: motor system produces three types of muscle movements
1) Reflexive: associated with Spinal Cord and Brainstem
2) Rhythmic (central pattern generators): associated with Spinal Cord and Brainstem
3) Voluntary: associated with Motor Cortex
•Voluntary Movement Hierarchical Movement:
1) Motor Idea: associated with Association Cortex and Basal Ganglia
2) Motor Plan: associated with Motor Cortex and Cerebellum
3) Motor Execution: associated with Spinal Cord and Brainstem

Abnormal Bone Growth – MMB ?

Key Concepts
-Definition: Bone formation that does not allow for proper growth or maturing of the Bone and which therefore causes
pathologies/abnormalities
-Types:
à Deficienct Growth (Dwarfism)
à Excessive Growth (Gigantism)
à Unsatisfactory Quality/Growth

Dwarfism
-Etiology:
1) Premature Fusion: of Epiphyseal Growth Plate of Long Bones which truncates growth (e.g. Achondroplasia)
2) Poor Bone Quality (e.g. Osteogenesis Imperfecta)
-Types:
•Achondroplasia:
-Significance:
a- most common disease of Growth Plate
b- major cause of Dwarfism
-Cause: predominantly autosomal dominant inheritance
-Premise: normally FGFR3 has a negative regulatory effect on bone growth
-Mutation: FGFR3 gene (~80% of cases)
-Inheritance: Autosomal Dominant (i.e. 50% of passing onto progeny)
 -Effect: mutated form of FGFR3-gene-coded receptor makes it constitutively active
-Pathogenesis: failure of Endochondral Ossification and undisrupted Intramembraneous/Peripheral Ossification
leads to interruption of longitudinal growth of bone but normal diameter
-Mortality: homozygous infants normally die at birth or soon after from respiratory insufficiency (due to small
chest cavity)
-Presentation: general signs of heterozygous individuals
a- shortened proximal extremities
b- trunk of relatively normal length
c- large Head (with prominent Forehead)
d- depressed Nasal Root
e- longevity, intelligence, and reproductive status all normal
•Seckel Syndrome:
-AKA: Bird-Headed Dwarfism, Primordial Dwarfism
-Cause: autosomal-recessive mutation in gene encoding Ataxia-Telangiectasia Related/ATR Protein
-Background (ATR): senses DNA damage and activates DNA damage checkpoint thereby leading to cell
cycle arrest (especially important in Chromosome 3q22.1–3q22.4 areas)
-Inheritance: Autosomal Recessive
-Presentation:
a- Dwarfism with a small head
b- moderate-to-severe mental deficiency
-Prognosis: can survive to old age

Gigantism
-Etiology: Adenoma of the Pituitary Gland’s Somatotropes (Growth-Hormone-producing cells) causing excess Growth Hormone
production/distribution before epiphyseal fusion (i.e. before puberty)
-Treatment:
a- Surgery
b- Growth Hormone inhibitors

Acromegaly
-Cause: excessive production of Growth Hormone by Anterior Pituitary Gland after puberty (i.e after epiphyseal fusion)
-Etiology: >90% cases by adenoma
-Presentation:
a- Enlarged Hands and Mandible
b- Brow and forehead protrusion
c- Prognathism and malocclusion
d- Visceral enlargement (especially Heart and Kidneys)
e- Vocal Cord thickening
f- Macroglossia
g- Carpal Tunnel Syndrome

Unsatisfactory Quality/Growth
-Types:
•Osteogenesis Imperfecta:
-AKA: Brittle-Bone Disease
-Definition: group of phenotypically-related disorders of the Bone
-Cause: mutations in genes that code for Type-I Collagen synthesis (α1 and α2 chains) leading to brittle/weak
bones
-Type: most commonly point substitutions
-Inheritance:
a- Autosomal Dominant (more common)
b- Autosomal Recessive (less common; more lethal)
-Subtypes: spectrum of severity between the types
•Type I (Autosomal Dominant): normal lifespan but with blue sclerae, hearing defects, small misshapen
teeth, and frequent fractures in childhood
 •Type II (Autosomal Recessive): uniformally fatal in utero or perinatally with multiple fractures
•Cretinism:
-AKA: Congenital Iodine Deficiency Syndrome
-Cause: maternal iodine deficiency
-Presentation:
a- disproportionally short limbs
b- large head (due to delayed closure of fontanelles)
c- mental impairment

Cohort Studies – MMB ?

Key Concepts/Background Information
-Types: of Medical Studies
à Observational Studies:
-Process: investigator inquires, observes and measures different factors then proceeds to record the outcome of
the study
-Aim: to assess the presence or absence of a link between an ‘exposure’ (i.e. risk factor or protective factor) and a
disease ‘outcome’
-Exposures:
a- Host:
-Demographic (e.g. age, gender)
-Biological (e.g. blood pressure, Cholesterol)
-Behavioral (e.g. smoking, physical activity)
-Psychosocial (e.g. depression)
-Genetic/Family History
b- Environment:
-Physical (e.g. season, pollution)
-Region of Residence (e.g. specific areas of a country)
-Healthcare (e.g. procedure underuse)
c- Agent/Disease:
-Infectious Agent
-Secondary Diseases (i.e. one disease being a cause of another)
à Interventional/Experimental Studies: investigator intervenes in a pre-planned systematic way and then proceeds to
measure/record the outcome of the study
-Differentiation: in Observational Studies the investigator does not intervene in participants lives or usual medical care while in
Interventional Studies the investigator does intervene directly
-Research Design Overview:
Cohort Study Overview
-Definition: study of a group of people (i.e. ‘cohort’) in an observational capacity that is followed up prospectively
-Type: Prospective/Longitudinal Study
-Process: subjects selected on presence or absence of an exposure at one point of time à disease/condition is then assessed for all
subjects at another point in time
-Study Design: studies conducted on healthy individuals and then assessed later on for presence of disease/condition

-Process: initially using healthy participants of different experiences/lifestyles with no pre-disposing factors (to the
disease/condition being studied) à allowing specified amount of time to pass à prospectively returning to the participants
later on and measuring the rate of disease incidence (i.e. difference between amount of people who stayed healthy vs. the
amount of people who developed disease/condition)
-Features:
1) Number of Participants: usually requires a large population study (even if disease outcome is common)
2) Common Themes:
a- study of etiology (i.e. cause of disease)
b- examine multiple hypotheses
c- examine several different disease outcomes
-Key Words:
•Incidence: assessment of disease etiology starts with a group of individuals who do not have the disease and then
eventually some of them acquire the disease
•Temporality: exposure is measured before onset of disease
•Causality: provide direct evidence for the causes of disease/condition
-Significance: arguably the most important type of research study for understanding disease causation and prevention
-Empirical Supremacy: cohort studies provide stronger evidence than other observational studies (e.g. Cross-Sectional
Study, Case-Control Study) - in terms of causes of disease - due to the facts that à
a- initial participants are healthy (typically)
b- exposure is measured prior to onset of disease
c- outcomes are not pre-defined but rather observed and extrapolated from direct evidence
-Comparison (to Cross-Sectional Design): associations (or lack of them) in a cross-sectional study be due to ‘revere-causality’
while in Cohort Studies this issue is minimized as the Correlation-Causation Relationship is much clearer
-Extra Detail: in that sense Cross-Sectional Studies tend more towards assessing ‘prevalence’ of disease rather than
‘incidence’
Advantages and Disadvantages of Cohort Study
Advantages Disadvantages
-direct measurement of disease Incidence (unlike C-S or C-C -often requires large number of participants and long follow-up
studies) period
-ascertainment of new disease cases; optimal for assessing -time consuming and expensive
cause and effect relationship (better than other observational -loss of follow-up may cause result bias
studies) -not suited for study of very rare disease outcomes (i.e. would
-capcaity for examining multiple disease outcomes require too many participants)
-obtaining more complete information on Exposure (including -Cohorts based on occupational groups may lack
changes over follow-up) generalizability
-possibility of investigating rare Exposures -hard to eliminate Confounding (as with all observational
studies)

Clinical Cohort Studies

-Definition: sub-type of Cohort Study in which the intent is on investigating the disease prognosis
-Design:
-Participants: Cohort members all already have a particular disease (may be prevalent disease or new diagnosis)
-Exposure: e.g. patient characteristics, disease markers, test results, treatments
-Follow-Up: in order to investigate occurance of specific outcomes (e.g. morbidity, mortality)
-Example: Swiss HIV Cohort Study

General Epidemiology/Study Design Info (for Master Doc later on)

-Issues:
-Validity: how valid is the measurement of exposure?
-Considerations: precision, bias, repeatability/reproducibility, falsifiability
-Representation: how representative is the population used in the study?
-Considerations: generalizability, commonality vs. differentiability
-Degree of Completion: how complete is the ascertainment of the outcome?
-Considerations: efficiency of follow-up method, accountability (of human error)
-Error:
-Types of Error:
a- Precision: Definitionof random error (i.e. measure of statistical variability)
b- Bias: systematic error that contributes to the difference between the mean of a large number of test results and
an accepted reference/‘true’ value
-Optimal Levels of Error: a set of values is considered significant when the results are à
-Precise (i.e. values are close to each other)
-Unbiased (i.e. the average of the values is close to the True Value)
-Distribution of Error: the two error types are independent of each other and therefore a particular set of data can have one
of many versions of error distribution

-Confounding:
-Premises:
a- Observational Studies (e.g. Cohort Study): a simple analysis is not usually adequate
b- Randomized Control Trials/RCTs: confounding not an issue because the two Exposure (‘Treatment’) Groups have
similar characteristics at baseline (due to randomization)
-Confounding Factor: relevant factor linked to both the Exposure and Outcome
-Issue: association between Exposure and Outcome may be distorted by confounding factors as confounding may make the
association appear either stronger or weaker than it actually is
-Solution: reducing the effect of confounding on results
à Method #1 (Stratification):
-Process: stratifying confounding factors so as to avoid grouping all results by the same parameters
-Example: accounting for age as a confounder by examining the Exposure-Outcome association separately
 by age group
à Method #2 (Statistical Adjustment):
-Process: adjusting for condounders in a mutlicariable statistical model to obtain an adjusted rate/risk
ratio
-Examples: commonly used for Binary and Time-to-Event outcomes
a- Poisson Regression (if given adjusted Risk/ R ate R atios)
b- Logistic Regression (if given adjusted odds ratios)
c- Cox Proportional Hazards Regression (if given adjusted ‘Hazard R atios’)
-Measures:
•Cumulative Incidence:
-Equation: CI = # of new cases of disease in defined time period / # of cases in study population at start of time
period
-Type: simple binary variable (i.e. event occurred or did not)
•Person-Time Incidence Rate
-AKA: Incidence Rate
-Equation: IR = # of new cases of disease in defined period of time / total Person-Time at risk
-Total Person-Years at Risk: sum total number of years each individual in the study remained at risk while
still participating
-Type: Time-to-Event (in order to calculate rate)
•Relative Risk:
-Definition: describes either of Risk Ratio or Rate Ratio
-Types:
•Risk Ratio: RR = Risk in the Exposed / Risk in the Unexposed
•Rate Ratio: RR = Incidence Rate in Exposed / Incidence Rate in Unexposed
-Findings:
a- RR = 1: disease risk/rate same in Exposed and Unexposed
b- RR >1: increased risk/rate among Exposed
c- RR <1: decreased risk/rate among Exposed (factor may be protective)
☼Epidemiological Relevance: Incidence and Risk cannot be measured in observational studies (e.g. Case-Control) because
the outcome has already occurred
-Exposure:
-Premise: exposure is initially measured at a baseline and may also be measured repeatedly during follow-up (depending on
type of Study Design)
-Measurement: questionnaire, clinical/biomedical measurement, medical record review, routinely-available information,
other means
-Validity:
à Easily-Verified Measures: e.g. gender, age, body-mass index, current region of residence
à Hard-to-Verify Measures: e.g. diet-related factors, alcohol intake, sexual behavior
à Verification-of-Validity Measures: some studies attempt to validate the exposure measure itself (e.g. self-
reported smoking status & Serum Continene, Alcohol Intake & Gamme-GT)
-Optimization: ideal measurements of exposure are ‘precise, unbiased, and repeatable’
-Ascertainment of Disease Outcome:
-Methods: of Obtaining Information
a- national central registers for death
b- contacting GPs or reviewing GP/Hospital Medical records
c- repeated questionnaires to participants asking about new diagnoses, treatments, and symptoms
d- repeated assessment and examinations of participants to identify new disease
-Characteristics:
a- maintenance of high rates of Follow-Up
b- standardized definition of disease outcomes that apply throughout the study

Relevant Clinical Examinations – MMB ?

Electromyography (EMG)
-AKA: Nerve Conduction Test
-Definition: diagnostic tool/technique for evaluating and recording the electrical activity associated with Skeletal Muscles
-Purpose: to test the integrity of Peripheral Nerves (i.e. cannot be used to test integrity of CNS)
-Basis: contraction of a Skeletal Muscle broughout about by APs in an Efferent Nerve passing across the Neuromuscular Junction to
cause a Muscle Action Potential (MAP)
-Usage: for determining efficiency of Nerve Fiber in conducting a signal (Action Potential) that it receives
-Types: used to test Motor, Sensory, and Mixed Nerve Fibers
-Parameters: tests for two main parameters
1) Quality
2) Myelination
-Instances: used to test intergrity of the nerves in instances of suspicion of pathology or in order to confirm previous clincal
findings (e.g. Neuropathy)
-Limitations:
1) does not test intergrity of Spinal Cord and Brain
2) only tests integrity of large Nerve Fibers (of Peripheral Nervous System)
3) inconclusive diagnostic capacity during first two weeks of disease
-Mechanism: using the muscular reflex induced by an electric impulse (Action Potential) stimulus to gauge the nerve conductance
-Clinical/Physiological Basis:
•for the Detection: activation of a whole muscle causes currents – associated with each muscle fiber AP – to be
easily detectable by placing electrodes on the muscular surface (usually on the skin)
•for the Result: recorded signal (called an Electromyogram/EMG) is usually of irregularly shape because the
individual muscle fiber APs (which sum up to make the EMG) fire asynchronously
-Rationale: if the velocity at which Action Potentials travel along a nerve is reduced then the reflex responses occur at a
longer latency
-Pathological Relevance: reflex latency observed in multiple muscular pathologies (e.g. Multiple Sclerosis)
-Main Test: Ankle Jerk Reflex Response

-Purpose: to determine time it takes for APs to travels from the Soleus to the Recording Electrodes
-Rationale: Tendon Jerk Reflex used because there is only one synapse in the circuit and therefore the response is
fast and without confounding factors involved (and especially Ankle Jerk Reflex as it is often the most
prominent/dependable response)
-Process: tapping of Achilles Tendon with hammer à brief delay between tap and contraction of Soleus (i.e.
latency) à contraction detected by EMG machine
-Extra Option: subject could be asked to perform the Jendrassik Maneuver (clenching of teeth, flexing of
both sets of fingers, and interlocking the finger sets in hook-like foin order to get a more accurate reflex
response and EMG reading)

-Result: EMG detects competency of Peripheral Nerves and synapses in the Spinal Cord
-Other Tests: EMGs can be recorded irrespective of how a muscle is activated and therefore can be a result of à
a- Voluntary actions
 b- Initiating a reflex contraction of the muscle
c- In response to electical stimulation of the nerve to the muscle
-Clinical Relevance:
•Tap Intensity: latency not affected by level of the tap
•Distraction: latency not affected by Jendrassik Maneuver
-Measurement: EMG measures nerve conductance of a peripheral Nerve Fiber
-Factors: combined Conduction Velocities (sizes) of the Afferent Muscle Fiber (Ia Sensory Nerve Fiber) and the Alpha Motor
Nerve Fiber
-Significance: distance from muscle spindle to central synapse (in the Spinal Cord) usually equal to distance central synapse
and end of motor efferent fiber
-Equation: Conduction Velocity = Distance / Latency
-Key Point: only possible if distance travelled by APs in the reflex arc can be determined
-Findings: on EMG
-Overview:

-Waveforms:

•M-Wave:
•H-Wave:
-AKA: H-Reflex, H-Response
-Definition: Action Potential that travels along Ia Afferent Fibers, transmitted across Central Synapse to
AHCs, and fires down along the Alpha Motor Neurons
-Usage:
1) Good indicator of the strength and distribution of the stimulus input from Muscle Spindle to
the Motor Neuron Pool (which lies at the site of the Anterior Horn of Spinal Cord)
2) Used in diagnosis of Peripheral Neuropathy
3) Used to examine the state of muscle tone and spasticity
-Relevant Pathology:
•Hoffman’s Reflex:
-AKA: H-Reflex, Hoffman’s Sign
-Definition: pathological monosynaptic reflex brought about by electrical stimulation of Ia Afferent Fibers (that
project signals directly onto the Alpha Motor Neurons) and characterized by presence of H-wave on EMG reading
-Purpose: predominantly used to assess Upper Motor Neuron Lesion/UMNL (i.e. damage to upper Spinal Cord
 and/or Brain)
-Process: stimulation of Ia Afferent Fibers à signal projected onto Alpha Motor Neurons à contraction of Muscle
à contraction raises Motor Neuron excitability while decreasing Ib limitation on the reflex
-Implications:
1) Cervical Myelopathy: indicative of early signs of Cervical Myelopathy (compressed Spinal Cord)
-Finding: presence of Hoffman Sign on both sides strongly suggests the presence of Cervical
Myelopathy
2) Amyotrophic Lateral Sclerosis (ALS): H-reflexes recorded at rest from muscle – for which no reflex can
normally be demonstrated – is evidence of Hyperreflexia à raises suspicion of ALS if there is denervation
in that muscle
3) Other Diseases:
à diseases causing Myelopathy: e.g. Tumors, Degenerative Arthritis
à diseases causing Generalized Hyperreflexia: e.g. Anxiety (especially sleep-deprived),
Hyperthyroidism/Thyrotoxicosis
-Significance:
1) Positive Hoffman’s Sign can be present in entirely normal patient (more often found in those who are
naturally hyper-reflexive)
2) Positive Hoffman’s Sign considered a possibly-pathological findgins if its presence is asymmetrical or
has an acute onset
•Babinski Reflex:
-AKA: Babinski Sign
-Process: Terminal Phalanx of the middle finger flicked quickly downwards between the examiner’s thumb and
index finger à observation of response

-Effects:
à Positive Babinski Sign:
a- tip of Fingers flex
b- Thumb flexes and abducts
à Negative Babinski Sign: i.e. absent Babinski Sign
-Implication: Positive Babinski Sign considered a pathological sign of Upper Motor Neuron disease
-Signifcance: Positive Babinski Sign not indicative of a pathological sign in Infants as this is a normal reflex for the
age