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Foundation Objective and Key Points

Contents
L2 – Human Body
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9
Define the anatomical reference lines and planes
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9
Explain the clinical significance of regional and surface anatomy
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10
Explain the hierarchical organization of systems, organs, tissues, and cells
...
11
Define the skeleton, axial skeleton, and appendicular skeleton in terms of their components
(bone, cartilage, and joints) and functions (form, posture, movement)
...
12
Describe the classification of bones (long, short, flat, irregular, and sesamoid)
...
13
Describe the functional classification of joints (syn/amphi/di-arthrosis) in terms of stability
and movement
...
14
L4 Histology 1
...
15
Describe major characteristics of epithelial tissue
...
15
Describe morphological and functional differences between different types of exocrine and
endocrine glandular epithelia
...
17
Describe the major characteristics of the 3 other basic tissues
...
17
Describe morphological and functional feature of different types of muscle
...
19
L6 Developmental Biology
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20

Explain the significance of these processes in normal development, anomalies, and other
pathological conditions
...
23
L7 Body Cavities
...
24
Describe the positions of the pleural and pericardial cavities, and mediastinum within the
thoracic cavity
...
25
Explain the embryological basis for the arrangement of thoracic organs
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25
Describe the location of the major abdominal and pelvic visceral organs
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26
L8 Radiology
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27
Discuss the strengths and weaknesses of each imaging modality
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27
L9 Nervous System
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28
Describe the nervous system in terms of functional systems (motor, sensory, and associative)

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30
L10 Pathology Intro
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31
Understand the significance of pathology in modern medical practice
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33
Become away of the Dal Med pathology curriculum roadmap
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33
Describe the structural components of the CV system: heart, blood vessels (arteries, veins,
capillaries), and lymphatic vessels
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35

Explain the significance of vascular anastomoses and portal systems
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35
L12 Genomes and Gene Expression
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36
Outline the processes by which genes are transcribed and translated in eukaryotes
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37
Discuss the basic principles behind gene manipulation and analysis (cloning, sequence
hybridization, RNAi)
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38
Define pathology and basic concepts (etiology, pathophysiology, morphology, clinical
manifestation)
...
39
Describe mechanisms of cell death (necrosis and apoptosis)
...
42
Understand the types of inflammation
...
42
Understand the possible outcomes of chronic inflammation
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45
Understand the basic classification and nomenclature of neoplasia
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46
Understand the basic principles of the pathogenesis of neoplasia
...
47
Navigate the 4 levels of protein structure in a variety of pictorial formats, providing examples
of structural diversity and its role in various protein functions
...
49
Describe or predict how mutations and chemical or environmental factors can impact protein
structure and function and contribute to disease
...
49
Explain how enzymes work at the molecular level, including basic principles of catalysis,
substrate specificity, and inhibition
...
50

L18 & 19 Pharmacodynamics
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50
Describe common classes of receptors that are targeted by therapeutic drugs
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51
Distinguish classes of pharmacological agonists including partial and full agonist
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51
Distinguish common mechanisms of drug desensitization
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52
Understand basic physiochemical properties that govern the interaction of drugs with receptors

...
53
Understand the relationship of adverse effects to the intended mechanism of action for a drug

...
53
Understand the general concept of PK and how it impacts patient response to drugs
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54
Understand drug absorption and common factors that impact this process
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54
Understand drug metabolism and the importance of this process in the bioavailability,
bioactivation and elimination of drugs
...
56
Describe major routes of drug excretion from the body
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57
Describe common drug elimination concepts such as elimination rate, half-life and clearance

...
57
Understand how multiple dosing can be used to maintain steady-state drug concentrations and
therapeutic benefit
...
58
Describe the major organelles in a eukaryotic cell, including their structures, functions, and
dynamics
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58

Explain the general principle by which proteins reach their cellular destinations
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60
Demonstrate an appreciation of how cells and cell components can be manipulated and
visualized using modern approaches
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61
Identify several general types of medications available without a prescription
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63
L24 Metabolic Biochemistry
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64
List the main energy stores at the cellular and whole body levels and describe in general terms
how their breakdown (oxidation) leads to generation of ATP
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65
Describe how flux in metabolic pathways is controlled, including the role of enzymes, ratelimiting reactions, and reversible and irreversible reactions
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68
L25 Introduction to EBP
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68
Differentiate basic types of clinical questions
...
68
Identify different types of evidence based resources
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69
L26 Stats
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70
Define and interpret summary measures of association (ie: t-tests, odds ratio, relative risk,
relative risk reduction, risk difference, NNT/NNH)
...
71
Define and interpret p value
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72
L27 Diagnostic and Screening Tests
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72

List the types of error that occur when using diagnostic or screening tests
...
73
Discuss how diagnostic and screening tests are used to support clinical decision making
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75
Identify several steps and sources of information involved in the process of clinical reasoning

...
76
Briefly describe several limitations in the clinical reasoning process
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77
L29 Signal Transduction and Cellular Fate
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78
Explain the (5) fundamental themes and principles common to most signal transduction
pathways and how diversity within these are adapted to different types of cellular
communication
...
81
Appreciate that complex diseases (like cancer) often result from aberrant signal transduction81
Explain the terms oncogene and tumour suppressor and the link between mutations in those
genes and their impact on cellular fate
...
82
Name the major anatomical pathology disciplines (cytopathology, surgical pathology, autopsy
pathology, and molecular pathology)
...
82
Discuss the importance of pathologic examination of all tissue resected at surgery
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83
Explain the difference between a cytology specimen and a tissue biopsy; outline the general
reporting system for cytology specimens
...
84
Identify one example of a molecular screening test for an inherited cancer syndrome
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85

Recognize gross and macroscopic features of hypertrophy, necrosis, and tissue repair with
fibrosis
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86
Acknowledge morphologic subtypes and varied differentiation in tumors
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87
Introduce TMN surgical staging in a pathology report
...
87

L2 – Human Body
Describe and demonstrate the anatomical position of the human body
Erect, arms at side, face palms and toes forward
Comparative = on all fours

Define the anatomical reference lines and planes
Coronal plane (ear to ear)
Sagital plane (back to chest)
Horizontal/Transverse plane (up and down)

Define terms used to denote relative position
Anterior = front of coronal
Posterior = back of coronal
Lateral = Away from sagittal
Medial = towards sagittal
Superior = above horizontal
Inferior = below horizontal
Comparative = Dorsal (to back)
Cranial Rostral (head) < ^ > Caudal (to pelvis)
Ventral (to belly)
Limbs (Left):
Arm: Proximal (superior)
Ulnar (medial) < ^ > Radial (lateral)
Distal (inferior)
Leg: Proximal (superior)

Tibia (medial)<^>Fibular (lateral)
Distal (inferior)

Middle = mid of set
Median = midline of body/limb (plane or nerve)
Medial = towards the midline, opposite of lateral
Intermediate = between 2
Central/Peripheral, Superficial/Deep, Internal (deep or medial)/External (superficial/lateral)

Explain the clinical significance of regional and surface anatomy
Regional = body parts, their parts, and neighbors
Surface = surface regions of body and landmarks of internal structures
Head (face and neuro), Neck (jaw base to clavicles), Upper Limb (shoulder on), Trunk (thorax,
abs, pelvis), L
...
part)
Urinary
o Kidney
o Ureter, bladder, urethra
Genital
o Internal (Gonads, ducts and glands)
o External

Integrative
-

Integument
o Skin, subcutaneous tissue, epidermal derivatives
Cardiovascular
o Hear, BV, Lymphatic vessels
Lymphoid
o Lymphoid organs/tissues
Endocrine system
o Endocrine glands /cells
Nervous system
o CNS, PNS, Sense organs

Explain the hierarchical organization of systems, organs, tissues, and cells
...


Describe the structure and function of a bone
Calcified living connective tissue, highly vascular
Osteoblasts = build
Osteocytes = cells
Osteoclasts = chew up
Collagen fibers within matrix
Functions
-

Support structures (weight bearing)
Protect vital organs
Reservoirs of Ca and P

-

Lever for muscles
Containers for blood-producing cells

Describe the classification of bones (long, short, flat, irregular, and sesamoid)
Long (longer than wide) = humerus, radius, ulna, metacarpals, phalanges
Short = carpals and tarsals
Flat = scapula, hip (ilium, ischium, pubis), cranium
Irregular = Vertebra, face, mandible
Sesamoid (in tendons) = patella (kneecap), mini in thumb & big toe

Describe the classification of joints and the major types of fibrous and
cartilaginous joints
Bony union = bone-bone
Fibrous = bone – fibrous tissue – bone
-

Suture = bone – short FT – bone (skull)
Gomphosis = bone – short FT – tooth
Syndesmosis = bone – long FT – bone (radius and ulna)

Cartilaginous = bone – cartilage – bone
-

Synchondrosis = bone – hyaline cart – bone
o (growth centres, 1st rib & manubrium, ribs and costal cartilage
Symphsis = bone – fibro cart – bone
o (midline of body; intervertebral discs, symphysis pubis and manubriosternal)

Synovial = bone – cartilage – synovial fluid – cartilage – bone
-

Capsule: surrounds joint
Synovium: membrane in capsule, secretes fluid, rich nerve and blood
Articular surface: over bone, hyaline cartilage, poor nerve and blood
Ligaments: long regularly arranged fibrous tissues connecting bone to bone (inside
capsule but outside synovial membrane; syndesmosis joint)
Fibro-cartilaginous discs (knee, TMJ, sternoclav, radio-ulnar) = movement; poor nerve
and no blood
Sheath and bursa (later)

Describe the functional classification of joints (syn/amphi/di-arthrosis) in
terms of stability and movement
Movement
-

Diarthroses = moveable (synovial)
Amphiarthroses = somewhat moveable (symphyseal)
Synarthroses = immovable (suture, gomphodid)

Stability: type, shape of articulate surface, presence of articular cartilages, bony processes,
ligaments around joints stabilize but limit movement, contracted muscles stabilize but limit
movement, tendons stabilize
-

Plane = sliding only, flat surfaces (inter-metacarpal and carpal)
Hinge = uniaxial, flex and extend (humero-ulnar, interphalangeal)
Trochoid = uniaxial with pivot (radio-ulnar, dens – atlas and transverse ligament)
Saddle = biaxial at right angle (carp-metacarp of thumb: flex, extend, add abd)
Bicondylar = biaxial hinge (knee: flex, extend, pivot medial and lateral
...
Quick reactions; forearm burn = contract bicep

Arm = anterior (flexor) and posterior (extensor) compartments
Leg = Anterior, medial and posterior compartments
Muscle fiber -> endomysium -> bundle -> perimysium -> all bundles -> epimysium -> (deep)
fascial
-

All come together to make tendon
Muscle attaches to bone through connective tissue (e/p/e mysium)

(Synovial) Bursae = between bone and tendon/skin; movement of soft tissue against bone
(Synovial) Tendon sheath = surrounds tendon, allows movement of tendon against bone and over
joint

L4 Histology 1
Describe the 4 basic tissue types (epithelial, connective, muscle, nerve)
Epithelial (below)
CT = Cells, fibers, ground substance, cartilage, bone
Muscle = Striated, cardiac, smooth
Nervous tissue = Neurons (motor, sensory, interneurons), glia (CNS), Schwann & satellite (PNS)

Describe major characteristics of epithelial tissue
Closely aggregate; small amount of extracellular matrix; covering and lining (surface ep, skin,
gut); absorption and secretion (glandular ep, gut and glands respectively); sensation (skin,
neuroepithelium)
-

-

Shapes: squamous, cuboidal or columnar
Polarity: apical, basal, lateral
Adhesions and junctions
o Zonula occludens = tight junctions
o Zona adherens = adhesion junctions
o Gap junctions (not connecting)
o Desmosome = firm adhesions
Surface specializations: Microvilli (brush border), Stereocilia (long, non-motile), cilia
and flagella (motile)
Basement Membrane (LM) and basal lamina (TEM, more detailed); cancer metastasis
Lamina Propria and papillae

Explain the functional significance of the different types of surface epithelia
Simple
-

Squamous = blood vessel (Called Endothelium)
Cuboidal = Kidney (proximal Convoluted tubule)
Columnar = oviduct (Usually ciliated, propel egg)

Stratified

-

Squamous = mouth (Top layer is FLAT)(non-keratinized = wet); Skin (keratinized, water
tight)
Cuboidal = Transitional or Urothelium ; Bladder (liquid = bladder expands, # layers
decrease)
Columnar = Pseudo-Stratified; Respiratory (Nuclei at diff level, but every cell BM ->
apical; ciliated = moves mucus)

Describe morphological and functional differences between different types of
exocrine and endocrine glandular epithelia
Exocrine = DUCTS
-

-

Simple = 1 duct
Compound = ducts with 2+ branches
Secretory portion (Actually produces)
o Tubular (long simple or coiled, branched) – sweat gland
o Acinar (round shape, simple or branched) – mammary gland
Secretion types
o Merocrine = exocytosis
§ Sweat, saliva, mucous and serous fluid

§
o Holocrine = cell produces so much product it ruptures
§ sebaceous, (skin);

§
o Apocrine = apical portion pinches off
§ Mammary

§
Endocrine = Hormones directly into blood stream
-

Paracrine = R close by
Autocrine = R on that cell

Carcinoma = epithelial cell origin; 45yo, >90% of tumors

L5 Histology 2
Describe the major characteristics of the 3 other basic tissues
Describe morphological and functional feature of different types of CT
Note: Edema occurs when water is retained in CT (can palpate or see); Hydrostatic and osmotic
pressure are different
Cells (6)
-

-

Fibroblasts: most common (active); synthesizes extracellular matrix, healing and scar
formation
...
Fr bone marrow
Mast Cell: histamine, inflam/immune response
...


Smooth Muscle
-

Weak slow involuntary contractions
No actin-myosin overlap (non-striated)
Autonomic NS
Fusiform cells
Central nuclei
Gap junctions, endomysium
Bouton en passant (nerve terminals in endomysium)

Describe morphological and functional feature of nervous tissue
Neurons
-

Nucleus (nucleolus), cytoplasm, dendrites = short cytoplasmic extensions
Axons = Largest extension; leaves CNS > PNS

Glia (CNS): White matter = myelinated axons; grey matter = cell bodies, glia
-

Oligodendrocytes: myelin (Disease = MS)
Astrocytes: support
Microglia: phagocytes
Ependymal cells: lining of the ventricles and central canal

Supporting PNS cells
-

Schwann cells (myelinated and unmyelinated axons)

-

o Multiple Schwann cells around an axon -> Node of Ranvier allows AP to jump
very fast
Satellite cells : Only present in ganglia (unique to PNS, supporting cell around neuronal
bodies; sensory in cranial/spinal nerves or autonomic)
Wrapping: Epineurium, perineurium and endoneurium
o Each unit is a myelinated axon, similar to muscles
o CT is everywhere (vasculature)

L6 Developmental Biology
Define the 3 basic developmental processes
Proliferation: Increase number of cells; mitotic; limit ~60 cycles (10^18 cells, but we only use
10^14); 1st week; daily doubling every ~20hrs; Capsule around embryo = zona pellucida;
Embryo isn’t growing, cells are getting smaller each divide
Differentiation
-

-

Generation of cellular diversity
Covert = commitment of cells to particular fates
o Specification: early, reversible
o Determination: Irreversible, fates confirmed
Overt = changes in cell biochem, structure and fuction
Several hundred mature cell types
3rd week = 3 layer embryonic disc
Potency and proliferation decreases as differentiation increase
o Embryonic Stem cells (totipotent - any) > Stem cells (pluripotent - many) >
Progenitor cells (Multipotential - several) > Precursor cells (Committed – single
fate)

Morphogenesis
-

-

-

Creation of form and structure; many processes
Histogenesis = tissue
Organogenesis = Organs and body parts
Classical: follow a cell to see how it moves and changes
o Aggregation & dispersal of cells
o Changes in cell size and shape
o Cell migration
o Tissue movements: delamination, splitting, fusing, folding, bending
Induction: one group can influence another; regional differences in proliferation and
differentiation
o Organizer: group of cells that influence the growth of adjacent competent cells via
an evocator
o Competence: ability of a cell to respond to an inductor
o Euro plan (linear and independent) vs American plan (conditional, based on
surroundings)
PCD
o Sculpting digits
o Culling of Nervous system: 2x motor neurons made than needed
...


Congenital anomalies (“Birth defects”)
-

-

Structural defects
o Macroscopic
§ Malformations - intrinsic cause (genetic chance, internal dev mechanism)
§ Disruptions – Extrinsic cause (teratogens, infections, chemicals) ie: drugs
§ Deformations – Extrinsic cause (physical) ie: not enough amniotic fluid
o Microscopic structural defects = dysplasia (tissue not formed properly)
Functional defects (ie: errors in metabolism, cellular and molecular abnormalities,
physiological disturbance, and mental retardation)
...

Neural crest: Lateral area to neural tube
...
Epithelium of oral and nasal cavities;
other endo and exo glands (mammary), special sense organs (lens of eye, inner ear)

Mesoderm
-

Paraxial mesoderm:
o Sclerotome => Axial skeleton (except bones in face),
o Myotome => Skeletal muscle
o Dermatome => Dermis of back

-

-

Intermediate mesoderm: Sagittal stripe down either side of paraxial mesoderm; flanks
gut, Kidneys (mesonephros = 1st kidney), ureters, gonads and reproductive ducts, adrenal
cortex (Primary retroperitoneal organs if they stay there)
Lateral (plate) mesoderm:
o Mesothelium (lining of body cavities, 2 sides)
o Splanchnic (visceral) mesoderm: Muscle and CT of perimative gut; Heart
myocardium and endocardium
o Somatic (parietal) Mesoderm: CT of anterolateral body walls and limbs,
Appendicular skeleton

Endoderm – Epithelial derivatives of the primitive gut; a lot grows out of it
-

Alimentary system: Pharynx, Alimentary canal, Accessory glands (Liver and Pancreas)
Respiratory system: Larynx trachea, bronchi, lungs
Urinary and genital systems: Urinary bladder, urethra, vagina and prostate
Derivatives of pharyngeal pouches: Middle ear, tonsils, thymus, thyroid and parathyroid

L7 Body Cavities
Define the 3 main body cavities
Cranial – brain, meninges (dura, arachnoid and pia matter between skull and brain), pituitary and
pineal glands
Thoracic – heart; ribcage, sternum, thoracic vertebrae; diaphragm is the base; cupula pleurae is
the top (near neck)
Abdominopelvic – liver; diaphragm = roof, anterolateral abdomen wall, posterior abdomen wall,
pelvic diaphragm = floor
...
By Inferior Vena cava
Posterior mediastinum: esophagus, descending aorta

Explain the embryological basis for the arrangement of thoracic organs
~4 weeks
Lungs: Inferior part of pharynx -> bifurcation and enters pleural cavity -> continues to divide
(2^20)
Heart: From mesoderm
...
Liver, anterior stomach, posterior transverse colon,
(Small intestine?)
Omental Bursa: Lesser sack: posterior Stomach, anterior transverse colon
Extraperitoneal space:
Retroperitoneal space: Back; pancreas, duodenum, and aorta (not Spine)
Subperitoneal space: Bladder, uterus, vagina, rectum, pelvic floor

Describe the location of the major abdominal and pelvic visceral organs
Intra: Esophagus (abdo part), Stomach, Spleen, Liver, Gallbladder, biliary tree, Tranverse colon
Retro: Inverior vena cava, abdo aorta, Kidney, ureters, suprarenal glands; Secondary:
Duodenum, Pancreas, Caecum and Ascending (R) colon, Descending (L) colon

Explain the embryological basis for intraperitoneal and primary and
secondary retroperitoneal locations of various abdominal organs (ie: segments
of GI tract, liver, pancreas, and kidneys)
Primary retroperitoneal = Derived from intermediate mesoderm; develop and stay there (Kidney
and adrenal cortex)
-

Not all that develop stay there, ie: gonads

Liver is intraparetoneal
GI tract: Gut grows out and twists; Cranial end moves right, caudal moves left (Duodenum is on
right, end of transverse colon left); rotation and then attachment = secondary peritoneal
-

Same idea with pancreas

L8 Radiology
Describe how x-rays, ultrasound, nuclear magnetic resonance and
radioisotope decay are used to image structure and function in living human
beings
Xray: x-rays -> body -> film
-

Put organ you want to view close to film
AP = front to back
PA = back to front
Lateral = side
Black: Air > Fat > Water > Bone > white
Barium dye to show up

Computed tomography: Lots of X-rays in a circle
-

Gray-scale contrast allows to view brain
Also IV inject with Iodine -> goes with blood (especially where BBB breaks down like
with tumors)

Nuclear medicine: Swallow/inject radioactive material, let it spread, take picture
...
Functional localization,
neurons, synaptic transmission (mostly chemical), reflex action, integration (pathway
convergence and divergence)
...
Conditioning: US->UR, CS+US->UR, CS->CR
Sense memory -> working memory <-> Long term memory

CNS: Brain (Forebrain, brainstem, cerebellum), spinal chord
PNS: Special sense organs (Cranial nerves to eye and ear), Autonomic division (Cranial and
spinal nerves); swelling = ganglia
12 cranial, 31 spinal nerves
1 and 2 brain nerves = forebrain
Nerve 3-12 brain stem
Cells
Neurons

CNS
Motor neurons & internerons

Glial cells

Astrocytes
Oligodendrocytes
Microglial cells
Ependymal cells

PNS
Motor neurons & sensory
neurons
Schwann cells
Satellite cells

Neurons (Much larger than supporting cells)
-

Sensory neurons = Pseudounipolar (AP can start farther back = more rapid) or bipolar
Interneurons = Multipolar; Long-axon (projection) or short-axon (local)
Motor neurons = multipolar

Glial Cells (Neural glia comes from neural tube)
-

-

Schwann cells make myelin; each axon has many Schwann cells; space between = node
of Ranvier
Satellite cells clustered around neuronal bodies; mostly supportive
Ependymal = lining
Astrocytes = connective tissue of NS
...
BBB
...
Restricts the compounds that can access NS
Can act as fibroblasts
...
Scar tissue of brain
Oligodendrocytes make ~35 internodes (Wrap around 35 segments of axons, could be
even 35 different neurons)
Microglia invade brain ~20 weeks
...
-> macrophages

Microanatomy of NS
Areas rich in neuronal cell
bodies
Intermediate areas
Areas rich in axons
Lining of ventricles

CNS
Gray matter
- Laminae
- Nuclei
Reticular formation
White matter
Ependyma

PNS
Ganglia
- Sensory ganglia
- Autonomic ganglia
Peripheral nerve

Gray on outside and deep within brain
Gray H in spine
Dorsal horn (back, grey matter) and Reticular formation (integrates Brain and Spine)
Epinerium > Perineurium > Endonuerum
Ganglia = Large cell, prominent nucleolus, satellite cells around it

Describe the nervous system in terms of functional systems (motor, sensory,
and associative)
Motor system

-

-

Somatic
o Pyramidal = cortical spine down to motor neurons
o Extrapyrmidal = brain stem to spinal chord
o Basal ganglia = facilitates movement
o Cerebellar = coordinating movement together
Visceral (Autonomoc) systems = cardiac & resp function
Hypothalamic neurosecretory systems

Sensory Systems
-

-

General (somatovisceral) sensory systems
o Somatic sensory
§ Cutaneous (exteroceptive) sensory systems
§ Musculoskeletal (Proprioceptive) sensory systems
o Viseral (interoceptive) sensory systems
Special Sensory systems
o Chemical (taste & smell)
o Visual
o Auditory
o Vestibular

Assocative/Integrative Systems
-

Neuromodulatory: sleep and arousal
Regulatory: Homeostasis
Limbic: Emotion, motivation, memory
Cognitive: perception, though, planning

Describe the general form (roots, trunk and branches) and functional
components (somatic and visceral, sensory and motor) of spinal nerves
Roots
-

Anterior (ventral) root – efferent motor fibers
Posterior (dorsal) root – afferent sensory fibers

Spinal ganglion: dorsal root ganglion
Nerve trunk = mixed nerve
Rami = branches
-

Posterior ramus = small strip to the back
Anterior ramus = all the rest of the body(Anterolateral body wall, limbs, autonomic
division)

Functional components
Somatic (voluntary)
Visceral (involuntary)

Motor (efferent; towards)
Somatic efferent
TO voluntary skeletal muscle
Visceral efferent
TO autonomic ganglia
TO involuntary (smooth and
cardiac) muscle and glands

Sensory (afferent; away)
Somatic afferent
From cutaneous and
musculoskeletal receptors
Visceral afferent
From visceral and vascular
receptors

L10 Pathology Intro
Appreciate the various scientific disciplines encompassed by Pathology
The study of suffering; or diagnosis and monitoring of disease
Anatomical pathology

-

Autopsy
o Manner (Suicide, homicide, accidental etc), cause (underlying disease), and
mechanism (processes of organ failure) of death
o Perinatal autopsies (implications in genetic counseling)

Hematopathology
-

Diagnose and monitor diseases of blood, bone marrow, lymph nodes
o Anemia, hemophilia, blood-clotting disorders, leukemia, lymphoma
Manage blood transfusion services

Medical Microbiology
-

Expert in infectious disease
Analyze tissue and body fluids for microorganisms (bac, virus, parasite, fungi)
Test bac for antibiotic resistance
Role in infectious disease control

Medical Biochemistry
-

Diagnose and monitor disease through exam of body fluids for abnormal levels of various
substances (electrolytes, hormones, enzymes, proteins, drugs, poisons)

Understand the significance of pathology in modern medical practice
(Above)

Understand the relationship of the medical practitioner to the diagnostic
laboratory
20% of docs can’t read tests correctly, 40% of docs unaware of certain tests => unnecessary and
additional testing, waste of resources, delay in diagnosis, Choosing Wisely
Intra-operative consults/Frozen sections
-

Rapid diagnosis to assist surgeon
ID disease processes (benign vs malignant)
Assessment of surgical resection margins during tumor removal

Cancer diagnosis – Major role of anatomical pathologist
-

Complex biology, multiple somatic mutations and/or germline mutations, different
natural histories (aggressive vs indolent)
Screening programs: reduced deaths but may find insignificant cancers or legions
o Pap smears, prostate antigens, mammography screenings

Uncertainty in Pathology
-

Pathologic diagnosis = gold standard
Diagnosis = opinion (interpretation of evidence), not a direct test result
Inherent error rate; ideally <1%

Become away of the Dal Med pathology curriculum roadmap

L11 Cardiovascular System & Lymphatic System
Describe the structural components of the CV system: heart, blood vessels
(arteries, veins, capillaries), and lymphatic vessels
Heart: Superior & inferior Vena cava, R&L atrium and ventricle, sinoatrial node
Cardiac muscle; Intercalated disks; Adhesive junctions (anchorage) Desmosome (binding of
cells) gap junctions (ionic continuity)
Purkinje Fibers on top of cardiac muscle cells; lots of mitochondria and glycogen
Specialized cardiac muscle cells make cardiac conducting system (SA & AV node and Purkinje
fibers)
Arteries (Large 40+ layers, to small 8-10 layers, to arterioles 1-2 layers

-

Endothelium (simple squamous; permeability, antithrombogenic barrier, blood flow,
immune response regulator, hormone producer and lipoprotein modifier)
Tunica Intima
Tunica Media
Tunica Adventitia

Endothelium functions
-

Selective permeability
Antithrombogenic barrier
Blood flow (Ang 1->2)
Immune regulator
Hormonal producer (GF)
Lipoprotein modifier (atherosclerotic plaques)

Capillaries
-

Continuous (muscle)
Fenestrated (kidney) = windows; allow certain sized things through
Discontinuous (Liver) = lets all things through

Microcirculation
-

Usual
AV shunt (quick and direct passage; usually for ends of the body ie: fingers, nose, penis,
anastomoses)
Kidney (Glomerular)
Liver (venous blood from GI)

Veins: Large to small, Media thinner than arteries, but adventitia is thicker; has valves
-

Tunica Intima
Tunica Media
Tunica Adventitia

Blood
-

90+% other fluids
Whole blood
o Half blood plasma
o 45% RBC
o Some platelets
o 5% White blood cells
§ Neutrophils 60-70%
§ Lymphocytes 20-25%
§ Others

Describe in general terms pulmonary and systemic circulation, and lymphatic
drainage
R Atrium > R ventricle > Pulmonary artery > Lungs > Pulmonary vein > L atrium > L ventricle
> Aorta
Coronary arteries supply heart with blood

Explain the significance of vascular anastomoses and portal systems
Normal Anastomoses
-

Artery-artery: Collateral circulation (backup plan for heart and brain, but variation in the
population so different susceptibility to ischemia and infarctions)
Vein-vein: alt drainage paths
Arteriole-venule: regulation of blood flow, ie: skin and intestines

Pathological anastomoses: due to trauma or disease; congenital, acquired or enlargement of
existing anastomoses
Hepatic Portal circulation
-

Venous blood from gut > hepatic portal > liver for processing
Connection without dilution (mixing with the rest of systemic circulation)
Functional significance
Other portal vessels can be arteriolar (glomerular arterioles)

Define the primary and secondary lymphoid organs in structural and
functional terms
Primary = where lymphocytes originate: Thymus and Bone Marrow
Secondary = where you can find lymphocytes; usually in recognition to pathogens: Lymph
nodes, spleen (dense, encapsulated) or non-encapsulated (loose) = MALT, GALT, BALT
(mucosa, gut, bronchus associated lymphoid tissue)
Lymph node = organ associated
Accumulation of lymphocytes = not a node
Lymph Node
-

Afferent lymph vessels
Lymphoid nodule
Cortex (meaty stuff) Outer and inner
Trabecula (ingrowths)
Capsule (outside)

-

-

Medulla
o Medullary cords (blue stain, plasma cells and lymphocytes)
o Medullary sinus (pink stains, macrophages)
Afferent lymph vessel

Spleen = blood filtration
-

PeriArterial Lymphatic Sheath (PALS)
Red pulp (blood)
White pulp (lymphocytes)

L12 Genomes and Gene Expression
Describe the chemical composition, organization, and replication of the
human genome
DNA
Nucleotides (base, phosphodiester linkage)
-

A and G are purines (big)
C and T are pyrimidines (small)
Purine-Purine = Transition
Purine- pyrimidine = Transversion

DNA are antiparallel, 5’ to 3’
A – T (2 H-bonds), G – C (3 H-bonds)
Packaging
-

Genome = 3x10^9 bp x2 per cell
DNA > Beads on a string > 30nm fibre > Chromosome folding > Chromosome
Nucleosome = DNA around a histone
23 pairs of chromosomes (22 autosomes plus x/y)
Coding sequence (exons) and non-coding (introns)
Exome = 21000 proteins

Half repeated sequences (LINEs SINEs,) half Unique sequence (Only ~3% is protein coding)

Outline the processes by which genes are transcribed and translated in
eukaryotes
Semi-conservative process
Leading strand: Primer + dna polymerase; helicase unwinds
Lagging strand needs okazaki fragments and many primers
RNA
-

2’ hydroxyl on the sugar
U replaces T
mRNA = protein (<5%)
rRNA = protein synthesis on ribosomes
tRNA = adaptors between mRNA and AA
miRNA = regulators, block expression by blocking mRNA translation
siRNA = block gene expression at mRNA degradation and chromatin

RNA polymerase reads antisense strand and makes RNA 5’ to 3’
Eukaryotes transcription
-

5’ capping
3’ poly A tail
RNA splicing to remove introns
Differential splicing to allow for more mRNA combos

Prokaryotes it’s just DNA -> RNA
Translation
-

mRNA interacts with ribosome
tRNA with matching anticodon brings AA
AA is attached to growing peptide chain and removed from tRNA
Genetic code is degenerate but not ambiguous
UAA, UAG, UGA are stop, AUG = Met (start)
Bacterial ribosome is slightly different

Describe the various levels at which gene expression can be regulated
Initiation of transcription (Most important)
Capping, elongation, and splicing
Cleavage, poly A, and termination
Export of mRNA

mRNA degradation
Initiation of translation
Completion of protein synthesis / folding
Protein regulation
Can be housekeeping or regulated
Regulation = combination of protein factors in the transcription complex (ie: TF)
Epigenetics = inherited info not part of DNA sequence ie: histone methylation levels

Discuss the basic principles behind gene manipulation and analysis (cloning,
sequence hybridization, RNAi)
Restriction endonucleases
PCR amplification
Expression by cloning into vectors
cDNA libraries
DNA sequencing
Probe hybridization to determine genotype (SNPs or southern blot) or gene expression
(microarrays, Northern blot)
Manipulations of genes and expression (RNAi, CRISPR, transgenic)

L13 Pathology Concepts

Define pathology and basic concepts (etiology, pathophysiology, morphology,
clinical manifestation)
Pathology = study of disease; the study of structural, biochemical, molecular and functional
changes in cells, tissues, and organs that underlie disease
Etiology = the cause of a disease
-

Genetic: mutations, genetic polymorphisms, etc

-

Acquired: infection, nutritional, chemical, physical, etc
Single etiologic agent (ie: HFE gene in hemochromatosis, single mutation, less common)
Multifactorial (ie: atherosclerosis; much more common)

Pathogenesis = sequence of events that occurs in response of cells/tissues to the etiologic agent
Morphological changes
-

-

Structural changes in cells/tissues characteristic of the disease
o Tools: physical exam, gross exam, LM (tissue, including stains and
immunochem), TEM (cellular)
Molecular changes
o DNA, RNA, Chromosomal, amplifications, deletions, mutations
o Tools: Karyotypes, PCR, SNP chips, cDNA microarray, array CGH (comparative
genomic hybridization), Whole genome seq

Clinical manifestations
-

Symptoms (ie: chest pain) and signs (ie: jaundice)
Caused by underlying abnormalities in cells/tissues

Understand common adaptations and responses to cell injury: hypertrophy,
hyperplasia, atrophy, metaplasia
Response = Adaptations, or cell death
-

Other morphology = inflammation and neoplasia (next lectures)

Homeostasis = steady state, normal
Adaptations = reversible structural/functional changes in response to injury/stress
-

New SS, cell/tissue survives

Cell death = irreversible injury; necrosis or apoptosis
Adaptations
-

-

Hypertrophy
o Increased cell size, due to increased cellular protein
o Physiologic = uterus during pregnancy
o Pathologic = cardiomyopathy
Hyperplasia
o Increase in # of cells in an organ/tissue
o Typically results in increased tissue/organ mass
o Physiological: Hormonal (breast prolif at puberty) or Compensatory (partial
hepatectomy, liver regenerates)
o Pathological: warts

-

-

Atrophy
o Reduced size of organ/tissue due to decrease in cell size or #
o Physiologic: Notochord; uterus after birth
o Pathological: Skeletal muscle after SC injury
o Causes: decreased work, denervation, decreased blood, poor nutrition, loss of
endocrine stimulation, pressure
Metaplasia
o Reversible change from one differentiated cell type to another (eg: columnar to
squamous mucosa in bronchi of smoker, or squamous to columnar in Barretts
esophagus)

Describe mechanisms of cell death (necrosis and apoptosis)
Causes of cell injury
-

-

Oxygen deprivation (hypoxia)
o Ischemia, inadequate Ox of blood, Decrease Ox carrying capacity of blood, blood
loss
Physical agents: Trauma, temp, pressure, radiation, electricity
Chemical agents: Drugs, poisons, toxins, recreational, medications (direct or toxic
metabolites)
Infectious agents (virus, bacteria, fungi, parasite)
Immunological reactions: Autoimmune or reaction to external agents
Genetic derangements (SNPs up to Chromosomal abnormalities)
Nutrition imbalances

Mechanisms of cell injury
-

ATP depletion
Mitochondrial damage
Loss of Ca homeostasis
ROS
Membrane permeability defects
Damaged DNA/proteins

Cell death (irreversible injury)
-

-

Necrosis
o Messy, inflamm associated
o Always pathologic
o Blebs, breakdown of membrane and organelles, leakage
Apoptosis
o Neat, no inflamm
o Pathologic or physiologic

o Fragmentation into apoptotic bodies > eaten by phagocytes
Necrosis: lethally injured cells lose membrane integrity, contents leak out, lysosomal enz
denature and digest proteins, leukocytes release lysosomal enz; Sheets of cells dying at once
-

-

-

Coagulative necrosis (major)
o Tissue structure preserved for days
o Anucleated ghost cells stay
o Heart attack
Liquefactive necrosis (major)
o Tissue digested into amorphous liquid mass
o Pus = liquefactive + neutrophils
o Stroke
Gangrenous necrosis
o Clinical; usually limb with loss of blood supply (gangrene )
Caseous necrosis
o Cheese-like appearance; TB
Fat necrosis
o Fat destruction in pancreatitis (a form of coagulative)
Fibrinoid necrosis
o Blood vessel wall necrosis in vasculitis

Hypoxia & Ischemia
-

-

Hypoxia = lack of O2, but can still have blood flow
Ischemia = lack blood flow; hypoxia + no substrates brought or no waste removed
Ischemia-reperfusion injury: after blood flow is resorted, reperfusion paradoxically
causes cell injury/death; generation of ROS, Ca overload, inflamm, complement =>
Death
Infarct = Area of necrosis caused by ischemia
Causes of ischemia/infarct
o Bleeding
o Thrombosis: Formation of a blood clot within BV or heart chamber (common)
o Embolism: Detached intravascular (s,l,g) mass carried by bloodstream from one
point to another where it can cause injury/infarction (bone marrow after fracture,
ambionic fluid; rare but catastrophic)

Apoptosis: Programmed cell death, tightly regulated, dying cell activates pathways that degrades
DNA and proteins, cell brakes into apoptotic bodies, phagocytes come and ingest; minimal
inflamm
-

Intrinsic (mitochondrial) pathway = Injury -> antagonize anti-apoptotic proteins (Bax =
activator; Bcl-2 and Bcl-x inhibit), channels open in mito membrane, activation of
caspases

-

-

Extrinsic (death receptor) pathway = Fas-fas ligand, activation of caspases
Physiologic causes
o Embryogenesis
o Hormone withdrawal
o Elimination of self-reactive lymphocytes
o Death of inflamm cells
Pathologic causes
o DNA damage (chemo, radiation)
o Accumulation of protein misfolding (Alzheimer’s)
o Infection (Hep C)

L 14 Inflammation
Understand the types of inflammation
Inflamm = to set on fire
Protective response; trying to get rid of: microbes, toxic, chemicals, foreign materials, ischemia,
damaged/dead cells (necrosis), internal antigens (autoimmune)
Can be acute or chronic
Acute = rapid onset, short duration
Chronic = slow onset, longer duration, may or may not follow acute
Inflammation is terminated when offending agent is eliminated
Can be useful, harmful, or both
Closely tied with repair process
4 signs: Redness, swelling, heat, and pain; => Loss of function

Understand the clinical features of acute inflammation
Dilation of small BV
Accumulation of leukocytes (NEUTROPHILS; multi-nucleated)
Edema
Stimulation for Acute inflame
-

Infection

-

Necrosis (any cause)
Foreign bodies
Immune reactions

Components
-

Altered vasculature => increased blood flow
Structural changes in microvasculature => plasma proteins and leukocytes leave
circulation (edema)
Emigration of leukocytes from microcirculation -> accumulation in focus of injury ->
activation to eliminate offending agent

Leukocytes adhere and pass through endothelial wall
Exudate edema = increased permeability of BV -> high [proteins] in extravascular fluid
Transudate edema = Increase hydrostatic pressure; fluid leakage; fluid with low protein content
Leukocytes: Neutrophils and macrophages mostly; ingest and destroy bacteria, produce GF and
aid repair
...
In tissues not capable of
regen/extensive fibrin exudation
Progression to chronic inflame (persistence of agent, or interference with normal healing)

Understand the possible outcomes of chronic inflammation
Inflam, injury, and attempted repair for prolonged duration (weeks/months)
May follow acute or may not
Causes
-

Persistent infections
Hypersensitivity disease; autoimmune
Prolonged exposure to potential toxins

Morphologic features
-

Infiltration by Mononuclear cells (macrophages, lymphocytes, plasma cells)
o Other cells = eosinophils (2 nuclie, parisites or allergies) mast cells (allergies)
Tissue destruction
Attempts at healing = small vessel proliferation (angiogenesis) and CT replacement
(fibrosis)
Granulomatous inflame = collection of macrophages and often T lymphocytes (often with
multinucleated Langhans giant cell); attempt to contain agent ->often injures normal
tissue (central necrosis)
o Foreign body granuloma = from inert forein bodies ie: suture, silicone
o Immune granuloma = inciting agent is difficult to irradiate like microbe or selfantigen

Systemic effects (acute phase response)
-

Fever
Leukocytosis (^ WBC)
Elevated Acute phase proteins
Increase pulse, BP, degreased sweating, shivering, chills anorexia, somnolence and
malaise
Septic shock with severe bacterial infection

Repair
-

-

Regeneration: some tissue types can replace damaged components; triggered by
cytokines and growth factors (mucosal lining, skin, liver, bone marrow)
CT deposition (Scar formation): Cardiac and skeletal muscle and neurons cant
regenerate; replace injured cells with CT
o Angiogenesis
o Migration and proliferation of fibroblasts
o Collagen synthesis and CT remodeling -> eventual scar
o Multiple growth factors stimulate the prolif of repair cell types
Wound strength (after suture removal)

-

o At 1week: 10%
o 70-80% normal by 3 months; usually no higher (collagen cross-linking)
Factors that influence healing
o Ongoing infections
o Diabetes
o Poor nutrition
o Steroids
o Poor perfusion
o Impacted foreign bodies
o Type/extent/location of injury

L15 Neoplasia
Understand the basic classification and nomenclature of neoplasia
Neoplasia = new growth
-

Non-lethal DNA damage -> genetic alterations passed to progeny cells
Unregulated cell proliferation that becomes autonomous (independent of growth stimuli)
Clonal proliferation

Neoplasm = entity
Tumor = swelling or mass
Cancer = malignant neoplasm
Key regulatory genes
-

Oncogenes = growth promoting
Tumor suppressor genes = growth inhibiting
Apoptosis regulators
DNA repair genes

Essential malignant alterations
-

Self-sufficient growth signals
Insensitive to growth inhibition signals
Evade apoptosis
Limitless replicative potential
Sustained angiogenesis
Ability to invade and metastasize *Key
Defects in DNA repair

Causes of cancer

-

-

Carcinogenesis – non-lethal DNA damage
o Radiation (sunlight, imaging, atomic bombs)
o Chemical (procarcinogens, smoking)
o Microbial (viral, HPV)
Also: age, env, genetics, chronic inflamm

Understand the clinical, macroscopic and microscopic features of benign and
malignant neoplasms
Classification based on behavior (benign vs malignant) and tissue site of origin
Benign
-

Slow
Compress adjacent tissue
Capsule
Usually don’t lead to death (unless in sensitive area)
No metastasize
Cured by surgical removal
Smaller
Homogeneous (uniform size, shape, polarity)

Malignant
-

-

Fast
Invade and infiltrate adjacent tissue
No capsule
Invade BV and lymphatics (breaks BM)
Usually lead to death
Metastasize
o Major distinction
o Change place
o Disassociate from primary (first) tumor and lodge somewhere else and grow to
second tumor mass
o Spreads via lymphatics, via blood stream or via body cavities
Treat by radical surgical removal +/- chemo/radiation
Heterogeneous

Naming: tissue of origin = Malignant (benign)
-

Epithelial = carcinoma (oma)
CT = sarcoma (oma)
Melanocytes = melanoma

-

Lymphoid = lymphoma
Bone marrow = leukemia
Mesothelium = mesothelioma

Understand the basic principles of the pathogenesis of neoplasia
Dysplasia
-

Often with neoplastic prolif arising in lining epithelium
Cells have excess growth but haven’t got ability to invade
Precancerous
Mild -> severe
Ie: in-situ carcinoma (limited by BM) vs invasive carcinoma (invades beyond BM)

Clinical behavior
-

-

-

Tumor type: benign or malignant; where do they come from
Tumor stage: reflects Spread of malignancy (1 to 4)
o Better predictor than grade
o Based on size, extent of spread, level of invasion, lymph node involvement,
metastasis
Tumor grade: reflects Differentiation of the tumor cell
o How much do the resemble the original tissue
o Low grade = well differentiated (looks similar)
o High grade = poorly differentiated (a mess)
o Reflects behavior
Other prognostic factors

Clinical presentation
-

Symptoms due to impaired function or injury to organ
Mass effects on adjacent organs/tissues
General: weight loss, appetite loss, fever, malaise; secreted cytokine like tumor necrosis
factor
Paraneoplastic syndrome: disease or symptom that’s a consequence of the presence of a
cancer, but not due to the local presence of cancer cells
o Ie: release of cytokines/hormones by malignant cells -> systemic response; or
immune response to malignant antibodies that cross react with normal cells

L16 Proteins and Enzymes

Navigate the 4 levels of protein structure in a variety of pictorial formats,
providing examples of structural diversity and its role in various protein
functions
...


Distinguish common mechanisms of drug desensitization
Receptor mediated
-

-

Loss of receptor function
o Rapid; due to change in R conformation
o Usually due to feedback
o Ie: P of specific AA in GPCR to block coupling
Loss of receptor number
o Slower; due to change in #
o Again feedback, this time telling it to internalize R

Non-receptor mediated
-

-

Reduction of receptor-coupled signaling components
o Ie: reduction of cellular ATP stores
Reduction of drug concentration
o Increased metabolism/elimination
o Lowers plasma [D]
Physiological adaptation
o Not well characterized

Provide a general classification of adverse drug effect
Side effect
-

Dose dependant
Not directly related to desired effect
Action of drug at other sites

Toxic effect
-

Dose dependant
Directly related to desired effect
Excessive action of drug at intended target

Allergic
-

Not dose-dependant
Not related to desired effect
Immunological response (unpredictable for the 1st time)

Understand basic physiochemical properties that govern the interaction of
drugs with receptors
Not really discussed; Look at molecular qualities of a drug in next section

Understand the concepts of drug potency and efficacy
Potency = amount of drug needed to produce an effect (more potent = left shift)
Efficacy = maximum effect from a particular agonist (more efficacious = up shift)
-

Full agonist gets maximum efficacy regardless of potency
Most important therapeutically

Understand the relationship of adverse effects to the intended mechanism of
action for a drug
Above

L20 & 21 Pharmacokinetics
Understand the general concept of PK and how it impacts patient response to
drugs
What the body does to drugs; time course of [D] in the body;

Describe common routes for drug administration
Systemic
-

Enteral = digestive tract (oral); subject to 1st pass effect
o Not suitable for rapidly metabolized, acid labile, or GI irritating drugs
Parenteral = Systemic, other than digestive tract; IV, IM, subcutaneous
o 100% bioavailability, (may require professional, sterile, costly)

Topical
-

Epi-cutaneous
Inhalation
Eye/ear/nose drops
Vaginal

Understand drug absorption and common factors that impact this process
Site of admin (GI) > site of measurement (Blood)
Passage across enterocytes in intestine wall; PASSIVE DIFFUSION across membrane
Factors
-

[D] across membrane; very large and similar for most drugs
Size; larger = less efficiently absorbed, but similar for most drugs (100-500MW)
Polarity = Very polar less absorbed; variable based on drugs
Ionization = Very ionized less absorbed; variable based on drugs, and dependant on
environmental pH (1-3 in stomach vs 5-7 in duo and 7-8 SI)
Also: GI motility, metabolism in enterocytes, and pH changes in GI tract (altered by
food, disease, or drugs)

SI has very large surface area (microvilli) and high blood flow; 250m2, 1000x > stomach

Understand drug distribution and common factors that impact this process
Reversibly leaves blood and distributed throughout tissues
Dependant on:
-

Blood flow (Lungs, kidney, liver > brain, skeletal muscle > adipose, bone)
Ability of drugs to transverse cell membranes
Degree of blood protein binding
Unique drug/tissue properties

Volume of Distribution (Vd)
-

-

Apparent volume to which a drug is dispersed
Determined from measuring initial [D] in plasma after bolus injection;
Vd = Q/Co; Q = dose, Co = initial plasma []
Apparent because it assumes equal partitioning
28L intracellular, 10 Interstitial, 4L plasma
Small Vd (<42 L) => retention within plasma
o Low lipophilic, high polarity, ionization and MW
o Drugs bind to blood serum albumin => therapeutically inactive
§ Binding is reversible; can be displaced by another drug => potentially
dangerous increase in [D]
§ Big concern for drugs highly bound (>90%) with narrow TI (ie: warfarin,
Vd = 8L)
Large Vd ( >42L) => retention in volumes outside plasma (ie: tissues)
o High lipophilic, low polarity and ionization, low molecular weight (can better
traverse biological membranes)
o Bones/Teeth: tetracycline likes Ca (Vd = 100)
o Thyroid: Iodine containing drugs sent here
o Adipose: accumulates lipid-soluble drugs (ie: chloroquine, Vd = 15000)

Understand drug metabolism and the importance of this process in the
bioavailability, bioactivation and elimination of drugs
Most drugs are lipophilic; but that means they are poorly excreted by kidney and liver (binding
of plasma proteins, reabsorbtion, partitioning into adipose tissue)
Metabolism ^ polarity, ionization, and water sol
Metabolites often deactivated; but prodrugs get bioactivated
Liver (and some GI) is major site of biotransformation = first pass effect
Bioavailability = amount of drug that reaches systemic circulation unchanged
-

IV = 100%
Oral <100%
Other routes < or = 100%
Factored into dose calculations

Liver = systemic metabolism (all drugs eventually)
Phase 1 and 2 (smaller and larger polar groups); Phase 1 is usually more important, rate limiting
CYP superfamily

Provide examples and understand the mechanism of common PK drug
interactions
CYP3A4 = most relevant, metabolized 50-70% of all drugs;
-

Inhibited by some antifungals (ketoconazole) , antibiotic (erythromycin), and grapefruit
juice;
Induced by: Anticonvulsant (phenobarbital), Steroid (dexamethasone), HIV inhib
(Saquinavir), Antibiotic (Rifampicin)
Adverse reaction
o Inhibit Felodipine metabolism; active form builds up = toxic
o Inhibit Terfenadine prodrug to fexofenadine; prodrug buildup = toxicity and no
active effect
o Induce: Cyclosporine gets metabolized faster => rejection

Individual differences
-

Diet & environment
Age
Disease
Genetic factors

CYP2D6 = highly polymorphic, 15% of drug metabolism
-

PM = Caucasians
IM = East Asia and S
...
Africa and Oceania
Ie: codeine metabolism into morphine; PM may not get pain relief, UM may get resp
...
7/kel
Inherent property of a drug; constant over normal dosing range; short T1/2 = short duration of
action
After 5 t1/2s more than 95% of drug will have been cleared

Clearance (Cl) = rate of elimination/drug plasma concentration (C)
Cl = Kel * amount of drug / C
Cl = Kel * Vd
T1/2 = 0
...
7/kel

Cl = kel * Vd
T1/2 = 0
...
5
Ca 1-2 / 0
...
2g/day OTC

Based on pharmacologic principles, identify some key concerns regarding
dosage, adverse effects, and DDI for common OTC medications
Decongestants: Stimulate AAR = vasoconstriction
-

Hypertension: systemic AAR = ^ BP ^ risk CV event
Glaucoma: may ^ pressure

Diabetic Patients
-

Cough syrup = high sugar
Salicylic acid = wound healing issues

NSAIDS – GRABB criteria
-

GI

-

o Ibuprofen might cause stomach ulcers / GI bleeds
Renal : contraindicated in sever renal impaired patients
Age: Dosing is age
...
4g/day in kids; old people may have bad renal)
Bleeding disorders: increased risk of GI bleeds and stomach ulcers
Blood pressure: ^ mean arterial pressure long-term use

Multivitamins, Metal Ions and Antibiotics
-

Fluoroquinolone and tetracycline chelate metal ions in antacids/multivitamins => reduced
absorption of antibiotics so treatment fails

Sever Drug Interactions
-

St John’s wort = Induces CYP3A4
Cyclosporine = immunosuppressant, metabolized by CYP3A4

L24 Metabolic Biochemistry

Explain basic concepts related to cellular metabolism and energy
transformation, including free energy, equilibrium, anabolic and catabolic
Catabolic pathways
-

Destroys -> provides building blocks
Carbs, fat, proteins -> CO2, H2O, NH3
Oxidative process
Generates reduced cofactors (NAD+ and FAD -> NADH and FADH)
Yields energy (ATP)

Anabolic pathways
-

Builds
Uses ATP and the reduced cofactors (NADH, FADH)
Reductive process; requires energy
AA, sugars, N-bases, fatty acids -> Proteins, polysaccharides, nucleic acids, lipids

Free energy: energy intake (food) = expenditure + weight gain/loss
-

-

G measured in calories
Spontaneous if deltaG <0
o Due to release in heat (delta H – enthalpy) or increase in disorder (delta S –
entropy)
Standard free energy = Delta G* (all same [])
In Actual body, the reaction depends on DG (so DG* and the [])
Unfavorable (endergonic) rxn can proceed if its coupled with a favourable (exergonic)
rxn

List the main energy stores at the cellular and whole body levels and describe
in general terms how their breakdown (oxidation) leads to generation of ATP
Storage: glycogen (animals), starch (plants), triacylglycerols (fat*) and protein
Transport: Glucose, fatty acids, glycerol, AA
Energy Release: pyruvate, Acetyl CoA; breakdown coupled to ATP synthesis
We get our energy from the oxidation of glucose, FA, or other fuel molecules
ATP

Coenzymes get reduced from NAD+ to NADH
NADH subsequently reoxidized to NAD+ in the e-transport chain, which is coupled to
ATP synthesis by oxidative phosphorylation (in mitochondrion)

-

Generated mostly during glycolysis via oxidative phos
2 high energy phosphoanhydride bonds
ATP hydrolysis is very exergonic
Short lived – must be replenished constantly
Non-membrane permeable so it cant be exchanged among cells
Used in anabolic rxns, transport, muscle contractions etc, where ATP hydrolysis is
COUPLED to drive an otherwise endergonic process

Outline the functions, regulation, and organ interrelationships of the key
pathways of glucose metabolism

Glycogen: Branched polymer of glucose in the cytosol; short term storage from
-

Synthesis of glycogen and hydrolysis back to glucose are controlled mainly by insulin
and glucagon
Storage organs: Liver (blood glucose control), Skeletal muscle (own energy )

Glycolysis
- Central catabolic pathway for glucose; all other dietary sugars can enter
- 1 molecule of glucose -> 2 pyruvate + 2 ATP + 2 NADH
- Only ATP source outside of mitochondria
- NADH used to generate more ATP in ETC (aerobically) or used to regenerate NAD+ by
reduction of pyruvate to lactate (anaerobic, active muscle tissue)
TCA Cycle
- Catabolism of Carbs, AA, and FA converge
- Carbon enters as Acetyl CoA

-

Maximum energy from glucose (32 ATP) if sufficient Oxygen
Generates CO2
Not a closed cycle; intermediates used for AA synthesis and gluconeogenesis

Gluconeogenesis
- Liver: to replenish blood glucose during longer fasting period
- Uses pyruvate, lactate, glycerol, but not Acetyl CoA
- Not just a reversal of glycolysis
- Glycolysis and gluconeogenesis are reciprocally regulated by insulin and glucagon
- Required for erythrocytes who only use glucose
- Also Brain needs a LOT
Organ interrelationships
- Glucose = Fuel transport molecule
- Preferred energy source for all cells, especially Brain and erythrocytes
- Must be kept at strict levels in the Blood
- Liver = coordinating blood glucose
- Fed state: Anabolic period, high insulin, tissues uses glucose while liver and adipose
store glycogen and triglycerides (respectively)
- Fasting state: several hours after meal; catabolic; high glucagon/insulin;
o Glycogen for the first day (from liver)
o Gluconeogenesis after first day (from liver)
- T1D = high blood sugar (low insulin)
- Pancreas secretes insulin (stimulated by high BG) and glucagon (stimulated by low BG)
o Insulin triggers FA and glycerol to fat in fat tissue
o Insulin triggers AA to proteins in muscle tissue
o Insulin triggers glucose to glycogen in liver
o Opposite for glucagon
Tissue profiles
Tissue
Brain
Skeletal Muscle

glycogen, protein

Heart

Some glycogen

Liver

Glycogen

Kidney


Energy storage
practically none

Some glycogen

Metabolite used
glucose, ketone
bodies (starved)
Glucose (fed), FA,
ketone bodies
Glucose (fed), FA,
ketone bodies
All except ketone
bodies

Metabolites secreted
None
Lactate, AA
none
Glucose,
triacylglycerol,
ketone bodies
Some glucose

Describe how flux in metabolic pathways is controlled, including the role of
enzymes, rate-limiting reactions, and reversible and irreversible reactions
Above

Predict in general how disease or drugs affecting a particular metabolic
pathway might alter levels of pathway intermediates
Above

L25 Introduction to EBP
Explain what Evidence-Based Practice means, and how it is used
Best evidence from research + clinical experience + patient specific problems/needs
Evidence (published, cultural, operational) à Getting the evidence straight (topic selection,
formal search and appraisal) -> Getting the evidence used (protocol, operationalization, evaluate
performance

Differentiate basic types of clinical questions
How to form a question, (PICO)
How to search, (proper database; focused)
How to critically appraise,
-

Are the results valid (methods)
What are the results (results)
Will they apply specifically to my patient

How to apply clinically,
How to evaluate performance

Frame a searchable question
PICO
Patient, intervention, comparison, outcome
Other question considerations; is your question:
-

Regarding the effectiveness of intervention for a particular condition (treatment)
Concerned with the natural course (prognosis)
Asking which test/tool will help with diagnosis
Wondering why an aspect of the health system works/doesn’t

Background = textbook questions (novice)
Foreground = situational, specific to current patient (expert)
DPICO = design…

Identify different types of evidence based resources
Systems > Summaries > Synopses of Synthesis > Synthesis > Synopses of studies > Single
studies

Distinguish which resources are appropriate to answer different types of
clinical questions
Hierarchy – Are the results valid
-

Systematic review/metaanalysis: even small studies can be put in a meta-analysis
Randomized CT: remove bias
Cohort: start with exposure (one group on drug and one on placebo) and follow up to
look at outcomes
Historical cohort: start with historical exposure, then measure outcomes and follow up
Case-control (start with outcome, look back at exposure)
Uncontrolled: just give and look
Case series (only a few persons)
Case reports (one person)
Editorials > Animal research > in vitro

Observational
-

Case report
Case series
Cross-sectional survey
Case-control
Cohort

Experimental
-

Non-randomized = more like cohort
Randomized
o Preventative = give everyone X to see if you can stop something in future
o Therapeutic = had something, now give them drug X

GRADE recommendations
-

For or against
Strong or weak

L26 Stats
Define variables; specifically independent vs dependent variables
Things we measure, control, or manipulate
Predictors/exposure/Interventions/Treatments = independent variables (x axis)
Co-variables = confounding variables
Outcome variables = dependant variables (y axis)
A variable can be all 3, depending on the research question
Categorical
-

2 categories = dichotomous; alive/dead
>2 categories = blood type

Quantitative
-

Continuous; can take any number ie: Blood pressure
Discrete; can only take specific numeric values ie: number of languages spoken

Define and interpret summary measures of association (ie: t-tests, odds ratio,
relative risk, relative risk reduction, risk difference, NNT/NNH)

Independent = dichotomous; Outcome = dichotomous; Use Chi-Squared
Independent = dichotomous; Outcome = quantitative; use t-test
Chi squared good for statistical sig, but doesn’t provide any info on the MAGNITUDE
-

Can use RR and/or OR

Relative risk = Rate of outcome in treatment / Rate of outcome in comparison
-

A = 829, B = 621
...
3
If the proportions were identical, RR = 1
If CI contains 1, then it is not statistically significantly different

Number needed to treat (NNT)
-

Group A – Group B = absolute risk reduction

-

NNT = 1/ARR
Ie: group A = 86%, group B = 65%; ARR = 0
...
21 = 4
...
In this example, for every 5 (round up) people who receive A, one
additional person will be adherent

Relative risk = A/B
-

Risk in A = 14%
Risk in B = 35%
RR = 14/35 = 0
...
40
RRR = 1-0
...
60
People in group A are about 60% less likely to have a heart attack compared to group B

Odds ratio
-

-

-

(Group A adherence / Group A non-adherence) / (Group B adherence / Group B
nonadherence)
Ie: A adhere = 829, nonadhere = 132, B adhere = 621, B nonadhere = 339
Odds ratio = (829/132)/(621/339) = 6
...
83 = 3
...
4x more likely to adhere (remember from risk, they’re only 1
...
So there is a 95% chance that the CI contains the
true population mean value
...

For difference in mean between A and B, if CI contains 0 => not a statistically significant diff
-

Ie: -2
...
0 to 1
...


For relative risk between A and B, if CI contains 1 => not statistically sig
...
05) => statistical significance; reject the null

Differentiate statistical significance from clinical importance
Dependant on the trial
RR / OR will give a better idea than Chi-squared (just stats)

L27 Diagnostic and Screening Tests
Explain the difference between diagnosis vs screening
Screening = id of unrecognized disease or defect through application of tests, examinations, or
other procedures in apparently healthy people
-

Healthy non-patients
No diagnostic intent
Low disease prevalence
Pre-clinical phase is necessary to have a screening program

Diagnosis = confirmation of presence or absence of disease in someone who is suspected of
having it or is at high risk
-

Sick people
Diagnostic intent
Low to high disease prevalence

Disease onset -> impairment -> signs and symptoms -> disability (about patient) ->
(consequences) -> handicap (effecting how others view you)

List the types of error that occur when using diagnostic or screening tests
Screening may not be perfect – does a +’ve test mean disease 100% of the time?
Might not actually impact heath
Harms
-

Complications for investigation
Adverse effects of treatment
Unnecessary/overtreatment in both false and true +’ve
Adverse effects of labelling/early diagnosis
Anxiety
Cost and inconvenience

Understand the difference between test characteristic sensitivity and
specificity and their interpretation when applied to patients or populations
(ie: positive predictive value and negative predictive value)
Sensitive: +’ve in a Positive person
Specific: -‘ve in a Negative person
Validity (accuracy) = ability of the test to correctly categorize individuals as diseased or not
(combo of the 2)

Test +
Test -

Disease +
a (true positive)
c (false negative)

Sensitivity = a/(a+c)
-

True positives over all diseased
The % of people with a disease that test +’ve

Specificity = d/(b+d)
-

True negatives over all non-diseased
The % of people without a disease that test –‘ve

Validity = (a+d)/N

Disease b (false positive)
d (true negative)

-

Proportion of all people that were studied that got correctly labeled

Positive predictive value = a/(a+b)
-

True positives over all test positives
% of correct results in those with a +’ve test
Ie: if you test positive, do you have the disease

Negative predictive value = d/(c+d)
-

True negatives over all test negatives
% of correct results in those with a –‘ve test
Ie: if you test negative, are you disease-free

PPV and NPV based on PREVALANCE in the population as well as the test
-

For a given test, sens and spec is the same
But as prevalence of a disease goes up, PPV also goes up (but NPV will go down)

50

100

5

1000

Sens = 50/55 = 91%
Spec = 1000/1100 = 91%
Prevalence = 55/1155 = 3%
PPV = 50/150 = 33% (this means a +’ve test = only 1/3 chance you actually have the disease)
NPV = 1000/1005 = 99
...
5% of total encoded proteins) and regulated, but slower
than Ca signalling

Generally think P can turn things on, but sometimes it turns it off

4) GTP hydrolysis by G-proteins acts to regulate the activity and timing of many signaling
pathways
G-proteins = switches
-

GDP bound = off
GTP bound = on; bind and activate downstream proteins

More like timers, because they have intrinsic GTPase activity (so they’re enzymes)
-

Further regulated
GEFs = GDP -> GTP
GAPs = GTP -> GDP (makes a gap in the cascade, ie turns it off)

2 major classes; hetero-trimeric (A,B,G subunits) or monomeric
Largest family (>50%) of GPCR are for olfactory signalling
GPCR activation of PKA
-

Hormone binds to GPCR -> changes confirmation
Able to interact with G-protein (Gs)
Gs: GDP -> GTP
Gs can then bind adenylyl cyclase: ATP -> cAMP
When hormone is gone, GPCR reverts to its resting state, GTP->GDP on Gs and Adenyly
cyclase is deactivated
cAMP can target cAMP-dependant PKA which can then send out its catalytic subunits
and P other molecules -> cellular effects
So this one binding can be amplified to P many proteins

Receptor tyrosine Kinases (RTKs)
-

R is an enzyme
Passes through membrane once
Forms dimer when bound to ligand
Autophosporylation of Tyr OH on each other
Signalling proteins come and bind to these P docking sites
Brings proteins together in time and space

5) Assembly of signaling complexes are facilitated using a limited repertoire of modular
protein domains
Domain = 50-200 AA, independently fold & function

Proteins that dock may have different domains
PTB and SH2 and P-binding domains
SH3 can bind to proline-rich segments on other proteins
PH binds to P head group in phospholipids
Sometimes just there as scaffold (Grb2)
RTK and Ras activation
-

Ligand-binding and auto-P of RTK
Grb2 is docked to P
Grb2 pulls SOS
SOS (a GEF) catalyzes GDP -> GTP in Ras
Ras has multiple effectors so it can bind to and turn on a lot of things

Navigate a complex signal transduction pathway, explaining the type of
information transfer at each step and possible downstream consequences
Extracellular signal molecule -> cell-surface R protein -> signal to alter protein function (fast)
OR signal to alter protein synthesis (slower) -> altered cytoplasmic machinery -> altered cell
behavior

Appreciate that complex diseases (like cancer) often result from aberrant
signal transduction
Ras: Mutations near the active site (Gly-12) impair GTPase activity and therefore it is
constituently active (always on, bound to GTP)
-

Mutations on reside 12/13 alter its ability to turn itself off
Everything downstream will be continually effected

Can effect cascades, like the MAPK cascade (an example of a cascade of protein Kinases
effected by upstream kinases, not a 2nd messenger like cAMP)
-

Ras turns on Raf (Map K K K)
Raf turns on Mek (Map K K)
Mek turns on Erk (Map K)
P’s many proteins and genes

Explain the terms oncogene and tumour suppressor and the link between
mutations in those genes and their impact on cellular fate
Oncogenes

-

Promotors or proliferators
Constitutively active
Gain function
Dominant
Gas pedal stuck
Ras, cMyc, Erk

TS genes
-

Checkpoint/inhibitory genes
Knockout/dysfunctional
Loss of function
Recessive at cell level
Brakes don’t work
P53
...

Can determine: Architecture, tumor grade (differentiation), nuclear atypia, and mitotic activity
-

Can’t determine tumor stage

Proper sampling and staining = info about prognosis, if they need more surgery, what drugs will
work, and if full body chemo is necessary

Identify one example of a molecular screening test for an inherited cancer
syndrome
Immunohistochemistry Biomarker tests; see if tumor cells have these R on the outside
-

Estrogen receptor
Progesterone receptor
HER2
Can get negative, equivocal (can’t tell) or positive
Prognosis and predictive significance

Fluorescence in situ hybridization
-

Targets actual genes
Uses a control gene, see if the ratio of Her2 genes is > control

HNPCC/Lynch Syndrome

-

-

Autosomal dominant germline mutation
Mismatch repair pathway
Genes MLH1, MSH2, MSH6, PMS2
Loss of function -> microsatellite instability; can’t repair small DNA deficits
Risk of colorectal cancer, but as a woman also uterine cancer (50+%)
Complex history for LS screening; family history plays a role
Immunohistochemical staining for MMR protein loss
o 1st step; done by pathologist
o Don’t detect MMR proteins => lynch syndrome diagnosis
o Can be done before germline molecular testing
Microsatellite instability testing or germline mutation molecular testing
o More complex

Discuss the role of autopsy in determining cause of death, and the differences
between a clinical vs medicolegal autopsy
Cause = disease or injury which initiated a series of events that terminated in death
Manner = natural, accidental, homicide, suicide, unexplained; more broad
Medicolegal
-

Determine cause and manner
Required by law

Clinical
-

Provide additional information about the illness
Requested by family and patient’s physician (family must consent)
Medical examiner says he doesn’t need an autopsy => you can do/request a clinical one

Recognize gross and macroscopic features of hypertrophy, necrosis, and tissue
repair with fibrosis
Necrosis = areas where there are just dead cells (possibly sheets) and no nucleus; surrounded by
inflammation
Cell injury
-

Adaptation
o Hyperplasia (#)
o Hypertrophy (size)
o Atrophy

-

-

o Metaplasia
Injury
o Reversible
o Irreversible
§ Apoptosis
§ Necrosis
• Reduced O2
• Chemical injury
• Infection
Intracellular accumulations
Cellular aging

Granulation tissue
Dense fibrosis = a lot of collagen (pink)
Shrunken lumen
Atherosclerosis = major cause of MI; fibrosis and some calcification
Thrombosis blocking coronary artery
Hypertrophy = bigger myocytes, wide, some have 2 nuclei

Discuss the features assessed on a tumor biopsy
Tumor type (ductal, lobular), grade, size, margins, Lymphatic invasion, precursor lesions,
presence of any metastases to lymph nodes, biomarker profile (ER, PR, HER2)
Architecture, nuclear atypia, tumor grade, mitotic activity
And features of a malignant tumor (above)
Can’t determine stage
TNM

Acknowledge morphologic subtypes and varied differentiation in tumors
Variety how a tumor behaves
Different morphology and differentiation patterns
Crowding
Gland fusing (adenocarcinoma)
Rhabdoid cells = nucleus off to the side

Exemplify how the diagnosis may be altered from biopsy to excision
May find tumor in multiple places
Or may find that it is not malignant at all
Additional information may alter the diagnosis and prognosis

Introduce TMN surgical staging in a pathology report
T = tumor stage; how far it’s invaded local tissue (1-4)
N = has it invaded lymph nodes (0 or 1) [sometimes 0-3]
M = metastasised to distant organs (0 or 1)

Discuss HNPCC/Lynch syndrome as an example of an inherited syndrome
with a defined molecular screening test
(Above)



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