All of medicine in 12 hours… Dr. Alan McLeod (F2).
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Transcript of All of medicine in 12 hours… Dr. Alan McLeod (F2).
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All of medicine in 12 hours…
Dr. Alan McLeod (F2)
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The Plan
Day One
• A systematic approach• Chest Pain• Acute sob• Chronic sob• Haemoptysis• TATT• Painful Limb• Breast Pain• Emergency management
Day Two
• Maximising your marks• Swallowing• Change in bowel habits• Hepatomegaly• Abdo pain • Pregnancy / Birth • Recurrent Infections• Headache• Stroke• Pharmacology basics
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2 Minutes
10 Causes of Chest Pain
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Puzzled?
You Need A SYSTEM…
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Puzzled?
What do I do?
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I GET VINO…
I Infectious / inflammatory
G Genetic / Idiopathic
E Endocrine
T Trauma
V Vascular
I Iatrogenic / ingested
N Neoplastic
O Organs
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2 Minutes
10 Causes of Chest Pain
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Chest Pain? Where’s that wine…
I Infectious / inflammatory Pneumonia, pleurisy, Costochonditis
G Genetic / ideopathic
E Endocrine
T Trauma Fractured rib, pulled muscle, pneumothorax
V VascularMyocardial infarction, angina, aortic dissection, PE
I Iatrogenic / ingested Surgical scar
N Neoplastic Bony mets
O Organs / other
Oesophagus (spasm, reflux), heart (pericarditis)Lung, Aorta, bones, muscle, cartilege, anxiety
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Ischaemic Heart Disease
• Approx 1/3rd of all male deaths
• Approx ¼ of all female deaths
• Atheroma of coronary vessels
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Right: Right Ventricle, most of Right Atrium, Part of Left Atrium
Left: Left Ventricle, part of Right atrium, most of Left atrium
Left circumflex: Left margin of heart and its entire posterior wall, Left atrium, posterior IV septum
LAD: Anterior 2/3 of IV septum, anterior portion of LV, whole apex
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SA Node: Right 51-65%, Left 35-45%, Bilateral <10%
AV Node: Right 80-90%, Left 10-20%
ALL HIGHLY VARIABLE!!!
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Coronary Arteries: Fill During DIASTOLE
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Arterial Disease
Arteriosclerosis• Thickening and
hardening of wall– Reduced lumen
– Reduced flow
– Reduced elasticity– Reduced contrractility
• Diabetes• Hypertension
Atherosclerosis• Commonest cause of
arteriosclerosis• Specific disease• Tunica intima• Mostly large and
medium vessels• Small in prolonged
systemic hypertension
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Atherosclerosis
• Changes in intima thrombus formation
• Reduced lumenal size– Poor
perfusion/hypoxia– Tissue death
• Loss of elasticity– Aneurysm formation
Smaller vessel atherosclerosis
• Ischaemic heart disease
• Most strokes• Peripheral heart
disease
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Plaque Formation
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Plaque Formation
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Plaque Formation
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Plaque Formation
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Plaque Anatomy
Plaque Anatomy (early)• Free Lipid• Foam cells• Increased myointimal
cells• Collagen• Disruption of internal
elastic lamina
Plaque Anatomy (later)• Collagen cap• Extracellular lipid mass• Foam cells• Myointimal cells• Disrupted internal elastic
lamina• Pressure atrophy of
muscle collagenous replacement
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Atheroma – Risk factors
Non-preventable• Increasing age• Male sex• Family history
Preventable• Hyperlipidaemia
– LDL and Cholesterol
• Hypertension– Diastolic most
important
• Diabetes• Smoking
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Fibrous Pericardium
Fibrous Pericardium
Parietal Layer of Serous PericardiumParietal Layer of
Serous Pericardium
MyocardiumMyocardium
Pericardial Space
Pericardial Space
EndocardiumEndocardium
FoldFold
Visceral Layer of Serous PericardiumVisceral Layer of
Serous Pericardium
Layers of the Heart
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Compare Skeletal and Cardiac Muscle
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Muscle Comparison
Skeletal Cardiac Smooth
Voluntary Involuntary Involuntary
Striated Striated Non-striated
Multinucleated Mononucleated Mononucleated
Unbranched Branched Unbranched
No gap junctions Gap junctions No gap junctions
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Myocyte Action Potential
Phase Ion Voltage
0 Na+ IN +ve (rapid)
1 K+ OUT -ve
2Ca++ INK+ OUT
Steady
3 K+ OUT -ve
4 K+ OUT -ve (slow)
NAK-CAKKK
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In Detail
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Pacemaker Action Potential
0
-40
-80
Ca++ In K+ Out
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Comparison of action potentials
Pacemaker cell Myocyte
Slow diastolic repolarisation in phase 4
Constant phase 4 (resting) potential
Pot. Approx -65 to -40mV Resting Pot. approx -90 mV
Phase 0 less steep Phase 0 more steep
Phase 0 via slow channels Phase 0 via fast Na channels
Plateau not sustained Plateau sustained
Repolarisation more gradual Repolarisation less gradual
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Excitation-contraction coupling
• Electrical signal• Stimulates contraction
Generally• Signal causes
depolarisation• CA++ entry results• Causing contraction
• In The Heart• Calcium induced
calcium release• Act Pot from SA Node
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Excitation-contraction coupling
L Type Calcium Channel
Ca++
Ca++
Ca++Ca++
SR
SAN
Ca++
Ca++
Ca++
Ca++
Ca++
Ca++
Excitation
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L Type Calcium Channel
Ca++
Ca++
Ca++Ca++
SR
Ca++
Ca++
Ca++
Ca++
Ca++
Ca++
Ryanodine Receptor
Excitation-contraction coupling
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L Type Calcium Channel
Ca++
Ca++
Ca++Ca++
SR
Ca++
Ca++
Ca++
Ca++
Ca++
Ca++
Ryanodine Receptor
Excitation-contraction coupling
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Ca++
Ca++
Ca++
Ca++
SR
Ca++
Ca++
Ca++
Ca++
Ca++Tropomysin
Excitation-contraction coupling
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Ca++
Ca++
Ca++
Ca++
SR
Ca++
Ca++
Ca++
Ca++Tropomysin
Excitation-contraction coupling
Ca++
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Ca++
Ca++
Ca++ Ca++
SR
Ca++
CA++
Ca++
Ca++
Ca++
Tropomysin
Excitation-contraction coupling
Contraction
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Describe Sliding Filament Theory
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Sliding Filament Theory
http://uk.youtube.com/watch?v=gJ309LfHQ3M&feature=related
• Calcium enters• Binding sites on actin
uncovered by movement of Tropomyosin / troponin complex
• Myosin binds to site powerstroke
• ATP binds to myosin release from binding
• ATP ADP + Pi – cocks myosin for another Powerstroke
• Continues as long as ATP and Ca present
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Sliding Filament Theory
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Normal Lead 2
A Segment is Shorter than an interval
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The Normal ECG
PR interval: first deflection of P first deflection of QRS– 120-200 ms (3-5 small sq)
QRS interval: first deflection of QRS end of last deflection– <100 ms (<3 small sq)
QT interval (QTc is QT corrected for heart rate). Start of QRS end of T wave– 360-440 ms (<11 small sq)
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Additional Abnormalities
• Pathological Q wave– Duration > 1 small sq
• ST Depression– 1mm or more over
isoelectric line
• ST Elevation– 0.5mm or more below
isoelectric line
• T wave abnormality– Normally upright in I, II
& V1 – V3– Normally inverted in
aVr– Variable in others
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STEMI and NSTEMI
STEMI• ST Elevation MI
• ST elevation on ECG• Positive enzyme tests
NSTEMI• Non ST Elevation MI
• No ST elevation• Positive enzyme tests
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STEMI and NSTEMIA: Normal ECG
B: ST Elevation
C: ST Depression
ST elevation in response to Isoelectric line (I)
I
B
C
A
P TQRS
ST Segment
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Evolution of ECG Changes in STEMI
• Minutes to hours– Peaked T waves
• Hours– ST elevation
• Hours to days– T wave inversion– Loss of R wave
• Days– Pathological Q wave
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Cardiac Enzymes
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Fibrinolysis
• tPa
• Streptokinase
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ACS? GO CARDIO ABCDG GTN
O Oxygen
C Clot prevention - enoxaparin
A Aspirin ± clopidogrel
R Raised position
D Diamorphine + antiemetic
I Investigate: ECG, enzymes, Troponin, CXR
O Observe: Repeat ECG + Basic obs,
AACE inhibitor within 24 hours
B Beta blocker
C Cholesterol - statin
D Diabetic control – tight control for at least 24 hours
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2 Minutes
5 Causes of acute Dyspnoea
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Acute Dyspnoea? Need alcohol!
I Infectious / inflammatoryAsthma, Pneumonia, COPD exacerbation (e.g. upper resp tract infection)
G Genetic / ideopathic
E Endocrine
T Trauma Pneumothorax
V Vascular Myocardial infarction, PE
I Iatrogenic / ingested Foreign body (mostly children)
N Neoplastic
O Organs / other Lungs
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Lung Anatomy
3 Lobes2 Lobes
Diaphragmatic
MediastinalCupular
Costal
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The Alveolus
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Muscles of Breathing
Diaphragm• Phrenic nerve C3,4 & 5
Intercostal muscles• External• Internal
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Compare the bronchial and pulmonary arteries
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Vessels in the Lung
• Pulmonary Artery– Deoxygenated blood– From Right Ventricle– Oxygenated in lungs– Affected in PE
• Bronchial Artery– Oxygenated blood– From systemic supply– Supplies tissues of lung
• Pulmonary vein– Oxygenated blood– From lungs– To Left atrium
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Velocity and Flow
Velocity• Displacement of single
particle per unit time • Inversely proportional to
cross sectional area– Faster in thinner tubes
• Aorta is thinner than total mass of capillaries– V slow capillary flow– Time for gaseous exch
Flow• Volume of fluid passing
point A at time B• Proportional to pressure
difference• Inversely proportional to
tube length• Proportional to r4
• Inversely proportional to viscosity
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Resistance (R)
In Parallel:1/RTOT = 1/R1 + 1/R2 + 1/R3
In Series: RTOT = R1 + R2 + R3
Resistance may be varied in arteries and arterioles by control of lumen cross sectional area via smooth muscle
contraction / relaxation
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Laminar and Turbulant Flow
Laminar:• Concentric thin
adjacent layers of fluid
• ‘Rings within rings’• Speed max at centre• Elements stay in one
lamina
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Laminar and Turbulant Flow
Turbulant:• Fluid elements not
contained in one lamina
• Radial and circumferential mixing
• Vortex generation• Pressure needed to
maintain flow is increased
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Venous Thromboembolism
Virchow’s Triad• Or FECing blood…
– Flow disturbances• Stasis• Slow• turbulant
– Endothelial damage• E.g. atheroma• Stasis / turbulance
– Coagulability changes• Genetic• Oral contraceptive pill
Genetic Disorders• Factor V Leiden
– Factor V not inactivated
• Anticoagulant lack– Protein C deficiency
– Protein S deficiency
– Antithrombin III defic.
• You may not need to know these…
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Consequences of VTE
PORT• Propagation
– Grows along vessel
• Organisation– Granulation tissue
• Recanalisation– New passages through
granulation tissue
• Thromboembolism– E.g PE
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Embolism
A Variety of materials
• Thrombus
• Tumour mass
• Fat/ bone marrow
• Amniotic fluid
• Air
A variety of consequences
• Unstable angina
• Stroke / TIA
• Pulmonary embolism
• Other infarct
• Lower limb muscle
‘Occlusion of a vessel by a mass of material transported through the bloodstream’
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DVT and PE
From Vein to Artery…• DVT in leg• Loss of embolus
– Travels in systemic circ
• Lodges in pulmonary artery– 85% Minor PE
– 10% Major
– 5% Massive
– Rarely recurrent
Major• Dyspnoea• Haemoptysis• Pleuritic chest pain
Minor• Possibly assymptomatic• Dyspnoea• Pleuritic chest pain
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Predisposing Factors
To PE• Previous PE• DVT
To DVT• Immobility• Post-operative• Pregnancy / post
partum• OCP• Nephrotic syndrome• Trauma esp severe
burns• Cardiac failure
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Asthma
Airway
COS of Three Pathologies
Constriction Oedema Secretions
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ABGs - pH
Henderson-Hasselbalch (H-H) equation
pH = 6.1 + log [HCO3-] / pCO2 x 0.23
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What are the main factors measured on an ABG?
What are the Reference Ranges?
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Reference Ranges
pH: 7.35 – 7.45
pCO2: 4.7 – 6.0 kPa (about 35-45 mmHg)
pO2: >10.6 kPa (>80 mmHg)
[HCO3-]: 22-25 mmol/L*
Base excess:
+/- 2 mmol/L*
* standardised, as if pCO2 were 5.3
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2 Minutes
5 Causes of Chronic Dyspnoea
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Chronic Dyspnoea? Gimme Wine!
I Infectious / inflammatory COPD
G Genetic / ideopathic
E Endocrine
T Trauma
V Vascular Anaemia
I Iatrogenic / ingested
N Neoplastic Lung Cancer
O Organs / otherLungs: fibrosis, pleural effusionHeart: failure, pericardial effusion
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Heart Failure
'failure of heart to pump blood forwards at a sufficient rate to meet metabolic demand'
(forward failure)
'ability to pump sufficient blood to meet metabolic demand only if cardiac filling pressures are abnormally high’
(backward demand)
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Heart Failure
• Left sided (varied causes – see right)
• Right sided – caused by LEFT heart failure or cor pulmonale
• Congestive failure – failure of both left and right sides
Pathological causes• Myocardial disease
– Myocardial infarction
• Volume overload– Regurgitation– Arteriovenous shunts
• Pressure overload– Hypertension (including
pulmonary in RHF)– Stenosis
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Define Preload and Afterload
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Useful Terms
Preload• Stretch on myocardial
fibre before contraction
Afterload• Ventricular wall tension
during contraction– The resistance that
must be overcome
Ejection fraction• Fraction of end
diastolic volume ejected from ventricle during systole– 55-70% normal
Remember• CO = SV x HR
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List Clinical Features of Right Heart failure
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Heart Failure - Features
L e f t s i d e d
UNG
RELATED
•Dyspnoea•Orthopnoea•PND•Fatigue
•Tachypnoea•Haemoptysis•Tachycardia•Sweating
R i g h t s i d e d
EST
OF
BODY
•Swollen legs•RUQ discomfort•Nausea•Anorexia
•Pitting periph. oedema•Elevated JVP•Hepatomegaly
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Central Venous Pressure
• Pressure measured in central veins.• Indicates mean right atrial pressure • Frequently used as an estimate of right ventr. preload.• CVP rises with poor right ventr. Function or obstructed
pulmonary circulation.
Measuring CVP• Central Line• Catheter placed thorugh subclavian vein• Invasive• Alternative is CVP
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Measuring CVP
Jugular venous pressure• Use right internal jugular
vein • Patient at a 45° angle,
head to the left • Light source that shines
obliquely from the left • Locate the anatomical
landmarks • Locate the JVP• Measure the level of the
JVP
Anatomical landmarks• Medial end of clavicle• To ear lobe• Under medial aspect of
sternocleidomastoid
• Level is measured from the sternal angle of Louis to top of column
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JVP
JVP vs Carotid pulse• The JVP pulse is • Not palpable • Obliterated by pressure • Characterised by a
double waveform • Varies with respiration -
decreases with inspiration • Enhanced by the
hepatojugular reflux
The Hepatojugular Reflux• Firm pressure is applied
to the right upper quadrant using the palm of the hand
• A transient increase in the JVP will be seen in normal patients
• There may be a delayed recovery back to baseline which is more marked in right ventricular failure
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Jugular venous waveform
a wave: rise in right atrial pressure during atrial contraction
x descent: atrial relaxation + RV contraction (pulls atrium downward)
c wave: bowing of tricuspid valve into RA during systole
v wave: right atrial filling, tricuspid valve closed
y descent: emptying of right atrium after tricuspid valve opens
a
c
v
x
x’
y
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Starling Curve
• RAP=Right Atrial Pressure
• CO=Cardiac Output
• Remember: too much stretch reduces ability to contract… (blue dashed line)
Normal physiological range, high sensitivity to RAP changes
Heart has reached limit of response, insensitive to further changes in RAP
RAP (mmHg)
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Flow / Volume Loops
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Flow / Volume Loops
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List the common diastolic and systolic murmurs
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A Piratical Crew…Dire Stolic Ms ARrrrrr
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A Piratical Crew…
DIASTOLIC murmurs are:
MS: Mitral stenosis
AR: Atrial regurg.
MS ARrrrrr…
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Systolic? Meet MR ASs
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Sympathetic stimulation
Location Receptor Type Action if stimulated
Heart Beta Increased HR and contractility
Blood vessels in skeletal muscle
Beta Vasodilatation
Blood vessels elsewhere
Alpha Vasoconstriction
Bronchioles Beta Relaxes smooth musc.
Pupil of eye Beta Dilates (darkness)Salivary glands Beta Little, thicker secrSweat glands Alpha Promotes sweatLiver Alpha, Beta Glycogenolysis
GluconeogenesisGut Secretion None -Gut motility Alpha, Beta Inhibits peristalsis
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GPCRs
http://uk.youtube.com/watch?v=tOcGbnBCdMM
http://uk.youtube.com/watch?v=bU4955rLv_8&feature=related
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GPCR Summary
• Receptor complex + G protein
• G Protein has 3 subunits (alpha, beta & gamma)
• Receptor binds ligand
• Conformational change
• Loss of GDP from G protein alpha subunit
• Binding of GTP
• Separation of alpha subunit from beta-gamma dimer
• Alpha and beta-gamma freed to interact with effectors.
• Cascade effect.
• Cycle starts again
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GPCRs in the heart
Beta receptors
• GPCRs
• Gs activates adenylate cyclase– Increased cAMP
– ATP cAMP
• cAMP activates PKA
• PKA phosphorylates alpha-1 subunit on voltage-gated Ca++ channels
• Increased Ca++ influx
• Increased inotropy
• Increased rate
Ca++ In
Ca++ In
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Beta-adrenergic antagonists
‘Beta blockers’• Combat the harmful
activation of the sympathetic nervous system
• Decrease HR• Decrease contractility
Examples• Propranalol• Sotalol
Side effects• Bronchoconstriction• Bradycardia
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GPCRs in the lung
Beta receptors• GPCRs• Gs actvates
adenylate cyclase– Increased cAMP– ATP cAMP
• cAMP causes relaxation of the smooth muscle
• Decreases sensitivity of the IP3 receptor, decreasing release of calcium from intracellular stores in response to IP31
• Some proponents argue for a cAMP independent PKA mechanism as well2
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Parasympathetic stimulation
Location Action if stimulated
Heart Decreased HR
Blood vessels in skeletal muscle -
Blood vessels elsewhere -
Bronchioles -
Pupil of eye Constricts (light)
Salivary glands Abundant watery secr
Sweat glands -
Liver Glycogen formation
Gut Secretion Stimulates
Gut motility Stim peristalsis
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Parasympathetic vs Sympathetic
ACh
ACh
ACh
NA
Synapse Near Target Organ
Synapse Near CNS Origin
Target Organ
Long Postsynaptic N
Long Presynaptic N
ParasympatheticCN 3, 7, 9, 10S2,3,4
SympatheticT1 – L2
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ACE Inhibitors
• In HF the renin-angiotensin-aldosterone pathway is activated inappropriately– Poor renal perfusion– Sympathetic activation
(beta receptors)– Diuretics
Effects• Reduce vasc.
resitance– Reduce afterload– Improve perfusion
• Inhibit aldosterone & reduce Na+ reabsorp– Cause naturiuresis
• Proven to prolong life
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Heart Failure – ACE Inhibitors
• Reduce ATII formation
• So reducing Na+ reabsorption
• So reducing water retention
• So reducing central venous pressure
• So reducing load upon heart
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TB (or not TB…)
Re-emerging organism• HIV• Drug resistance
• Mycobacterium– Mycolic acid wax coat– Resistant to drying– Acid fast– Slow growing
Spread:• Coughed into air• Remain for hours as
micronuclei• Bypass cilliary cells• Enter alveoli• Enter resident
macrophages
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Two disease forms
Primary• 91% no disease• 3% progressive
systemic leading to death
• Remainder pulmonary or extrapulmonary TB
Secondary• Reactivation• Damage is from host
immune response
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Tuberculosis
Features• Shortness of breath • Fever and sweating,
especially at night • Haemoptysis • Loss of appetite • Weight loss • Fatigue and tiredness • Lymphadenopathy
Demographics• Black African (211 per
100,000)• Pakistani (145 per
100,000) • Indian (104 per
100,000)
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Diagnosis and Management
Diagnosis
• PPD / Mantoux • Sputum culture
– Acid Fast Stain (ZN)
• Chest X-ray• Bronchoscopy ±
biopsy
Management
BCG Vaccine
RIPE
• Rifampicin 6 months
• Isoniazid 6 months
• Pyrazinamide 2 months
• Ethambutol 2 months
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What is meant by ‘concordance’
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Social Science: Taking the pills…
• Compliance– Extent to which
patient’s behaviour matches recommendations from the prescriber
• Adherence– Extent to which the
patient’s behaviour matches agreed recommendations from the prescriber.
• Concordance– Extent to which the
patient’s behaviour matches agreed recommendations from the prescriber after exploring and discussing the patients beliefs, views and opinions.
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Social Science: Taking the pills…
Poor concordance• The homeless• Minority groups• Learning difficulties• Dementia • Psychological illness• Those with a history
of non-concordance
Increasing concordance• Directly observed
therapy• Key workers• Home visits• Health education• Reminder letters• Foreign lang
materials
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2 Minutes
5 Causes of Haemoptysis
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Haemoptysis? Where’s that wine…
I Infectious / inflammatory Pulmonary tuberculosis
G Genetic / idiopathic
E Endocrine
T Trauma Chest trauma
V Vascular Pulmonary embolism
I Iatrogenic / ingested
N Neoplastic Bronchial carcinoma
O Organs / otherNose: epistaxis; oesophagus: maller weiss tearLung: bronchiectasis; Heart: mitral stenosis
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Lung cancer
• Male: Female 7:1• Decreasing
• Male peak in 60s• Female peak in 70s• Rare under 25 years
Presenting complaints• 90% symptomatic
– 40% Haemoptysis– 75% Anorexia– 75% Dyspnoea– 75% Cough– 75% Pain
• Remember Weight Loss
• 10% Incidental imaging
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Lung Cancer - Diagnosis
• Imaging– Plain film– CT– MRI
• Cytology– Sputum– Bronchoscopic
washings
Biopsy• Peripheral lesions
– Percutaneous biopsy
• Proximal lesions– Bronchoscopic biopsy
• Pleural Effusions– Fine needle aspiration
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Lung Cancer
Types
• Small Cell (20-30%)
• Non-small Cell– Large Cell (10-15%)
– Adenocarcinoma (~20%)• Commonest non-smoking
– Squamous cell carcinoma (40-60%)
• Commonest smoking related
Treatment
• Small cell– Early metastasis
– Chemotherapy and radiotherapy first line
• Non-small cell– Surgery first line
• Lobectomy
• Pneumonectomy
– Radio / chemo as req
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Haemostasis
Stops your blood falling on the floor…
• Vasoconstriction
• Platelet aggregation
• Clotting cascade
Platelets
• Made from Megakaryocytes
• Last ~10 days
• Do nothing until activated
• Collagen
• Thromboxane A2 (TXA2)
• Thrombin (from clotting)
• ADP
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Platelet Aggregation
Activated Platelets• Release TXA2• Change form• Form plug by adhering to
– Other platelets– Collagen under epithelium– Via Von Willibrand’s Factor
• Promote Coagulation
• Prostacyclin and CD39 prevent activation
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Clotting
Damage to tissue outside vessel
Damage to tissue outside vessel
Tissue Thromboplastin
Tissue Thromboplastin Clotting cascadeClotting cascade
Damage to the blood vessel
Damage to the blood vessel
Factor X (inactive)Factor X (inactive)
Factor Xa (active)
Factor Xa (active)
Factor II - Prothrombin (inactive)
Factor II - Prothrombin (inactive)
Factor IIa - Thrombin (active)
Factor IIa - Thrombin (active)
FibrinogenFibrinogen FibrinogenFibrinogen ClotClot
Extrinsic Intrinsic
Common
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Clotting
Damage to tissue outside vessel
Damage to tissue outside vessel
Tissue Thromboplastin
Tissue Thromboplastin Clotting cascadeClotting cascade
Damage to the blood vessel
Damage to the blood vessel
Factor X (inactive)Factor X (inactive)
Factor Xa (active)
Factor Xa (active)
Factor II - Prothrombin (inactive)
Factor II - Prothrombin (inactive)
Factor IIa - Thrombin (active)
Factor IIa - Thrombin (active)
FibrinogenFibrinogen FibrinogenFibrinogen ClotClot
Factor 9Factor 9Factor 8Factor 8
Extrinsic Intrinsic
Common
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Clotting
Damage to tissue outside vessel
Damage to tissue outside vessel
Tissue Thromboplastin
Tissue Thromboplastin Clotting cascadeClotting cascade
Damage to the blood vessel
Damage to the blood vessel
Factor X (inactive)Factor X (inactive)
Factor Xa (active)
Factor Xa (active)
Factor II - Prothrombin (inactive)
Factor II - Prothrombin (inactive)
Factor IIa - Thrombin (active)
Factor IIa - Thrombin (active)
FibrinogenFibrinogen FibrinogenFibrinogen ClotClot
Factor 9Factor 9Factor 8Factor 8
Extrinsic Intrinsic
Common
Haemophilia A
Haemophilia B
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Clotting
Damage to tissue outside vessel
Damage to tissue outside vessel
Tissue Thromboplastin
Tissue Thromboplastin Clotting cascadeClotting cascade
Damage to the blood vessel
Damage to the blood vessel
Factor X (inactive)Factor X (inactive)
Factor Xa (active)
Factor Xa (active)
Factor II - Prothrombin (inactive)
Factor II - Prothrombin (inactive)
Factor IIa - Thrombin (active)
Factor IIa - Thrombin (active)
FibrinogenFibrinogen FibrinogenFibrinogen ClotClot
Factor 9Factor 9Factor 8Factor 8
Extrinsic Intrinsic
Common
A
B
INR / PT aPTT (PTT)
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Haemophilia
X-Linked Recessive
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What is the role of vitamin K in blood clotting?
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Vitamin KReductase
Vitamin K and Warfarin
• Factors 2,7,9 & 10 must be gamma carboxylated
• Vitamin K is a vital cofactor
• Warfarin inhibits enzyme– Prevents Vitamin K
recycling
Vitamin KReductase
Oxidised Vitamin K
ReducedVitamin K
Factors 2,7,9 & 10
Gamma carboxylated
Vitamin K
Warfarin
--
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Vitamin K Dependent Factors
Intrinsic Pathway Extrinsic Pathway
Common Pathway
K
KK
K
aPTT (PTT)
INR / PT
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ATIII and Unfractionated Heparin
IIaIIaIIa
ATIII
Heparin
Factor IIa(Thrombin)
XaFactor
Xa
XaXa
*
*
* Note the change in ATII conformation
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ATIII and LMW Heparin
IIaIIaIIaLMW
Heparin
XaFactor
Xa
XaXa
*
*
* Note the change in ATII conformation
No substrate binding
No substrate binding needed
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ATIII and Heparin - Summary
• Antithrombin III deactivates clotting factors IIa (thrombin) & Xa
• It does NOT need heparin to do this
• BUT heparin makes it go FASTER
• LMWH only works on Xa
• Longer molecules in unfractionated heparin work on IIa (thrombin) as well
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The Clot
• Platelet activation• Fibrinogen fibrin• Fibrin assembles into
long fibrils• Platelets + Fibils =
Clot• RBCs join later
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2 Minutes
10 Causes of a Painful Limb
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Painful Limb? Time for some Wine!
I Infectious / inflammatory Cellulitis, septic arthritis
G Genetic / ideopathic Osteogenesis imperfecta related fracture
E Endocrine Osteoporosis related fracture
T TraumaFracture, dislocation, pulled muscle, ligamentous injury
V Vascular Claudication
I Iatrogenic / ingested Corticosteroid osteoporis fracture
N Neoplastic Bony mets, Primary bone cancer (rare)
O Organs / otherJoints: osteoarthritis, rheumatoid arthritis Nerves: sciatica
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Fracture
• Pain• Swelling• Deformity• Loss of function
• High impact• Repetitive impact
(stress)• Pathologic
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Fractured Neck of Femur
Blood supply to head
- In order of importance• Capsular supply
– From Med + Lat circumflex
– From Deep femoral
• Nutrient artery– From deep femoral
• Ligamentum teres– From Medial epiphyseal
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Fractured Neck of Femur
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Fractured Neck of Femur
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Colles & Smiths Fractures
Colles• Distal radius• Dorsal angulation• FOOSH• Elderly• Osteoporosis
Smiths - as above but• Volar angulation
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Scaphoid fracture
• FOOSH• Tenderness in
anatomical snuffbox– Structures of
snuffbox
• Three X-ray views• Blood supply enters
distally– Potential avascular
necrosis
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Humeral fracture
• Most Commonly at Surgical neck– Axillary nerve damage
• Also mid shaft• If involves radial groove
– Radial nerve damage
• Distal radius uncommon
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Humeral fracture
Distal radius uncommon
• Supracondylar– Median nerve
• Medial epicondyle– Ulnar Nerve
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What is this fracture?
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Monteggia and Galleazzi
Medics Monteggia (a)
Under Ulnar shaft
Pressure Proximal Radio-ulnar Joint
Get Galleazzi (b)
Really Radial Shaft
Drunk Distal RUJ
Fracture-dislocations
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Fracture Management
The “Three R’s”• Reduce• Retain
– Cast– Internal fixation– External fixation
• Rehabilitate
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Pulled elbow
• Mostly Children 1-4 yrs
• Dislocation of radial head from annular ligament
• 50% have no Hx
• Not using limb
• Extension + pronation No deformity
In adults Monteggia fracture dislocation is likely differential
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Bone Healing
Mins – 3 days
• Haematoma and Necrotic tissue
2 days – 2 weeks
• Phagocytosis
• Provisional callus
3 weeks on
• Firm callus
• Mineralisation
Weeks - months
• Remodeling
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Factors influencing Healing
Local• Tissue damage• Tissue loss• Infection• Foreign body
Systemic• Patient age• Nutritional status• Smoking / alcohol• Steroids• Systemic illnesses such as
diabetes, renal, lung, cardiac.
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CollagenSynthesis
http://depts.washington.edu/bonebio/ASBMRed/collagen/collagen.swf
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Compare and contrast rheumatoid arthritis with
osteoarthritis
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Osteo and Rheumatoid
Osteoarthritis• Disease of cartilage• No immune
component– M=F– Rheumatoid factor -ve
• Assymetric• Large > small joints• DIP Joints
Rheumatoid arthritis• Disease of synovium• Autoimmune
– M<F (approx 1 : 3-4)– Rheumatoid factor
80%
• Symmetrical• Small > large joints• MCP + PIP Joints
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Septic Arthritis
‘joint inflammation caused by the presence of live intra-articular micro-organisms’
•Acute•Painful•Swollen•Effectively immobile
Risk of rapid joint loss
Management• Aspirate pus
– Send for analysis
• Surgical washout• IV antibiotics
• Differential: Gout
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Septic Arthritis
Routes of infection
1.Haematogenous
2.Direct Trauma
3.Iatrogenic
4.Osteomyelitis
5.Inflamed extraarticular structures
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2 Minutes
5 Causes of Breast pain
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Breast Pain? Back to the Drinking…
I Infectious / inflammatory Costochonditis
G Genetic / ideopathic
E Endocrine
T Trauma
V Vascular Cardiac Pain
I Iatrogenic / ingested
N Neoplastic Benigng or malignant breast cancer
O Organs / otherOesophagus: spasm; Heart :cardiac painLung: pleurisy
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Non-cancer conditions
Abnormalities of development
• Cyclical mastalgia• Non-cyclical mastalgia• Epithelial Hyperplasia• Sclerosis• Cysts• Fibroadenoma• Duct ectasia
Benign tumours• Ductal papilloma• Lipoma• Oil cysts• Sebaceous cysts• Lymph nodes
• TB
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Cancers
Non-invasive• Lobular carcinoma in
situ• Ductal carcinoma in
situ
Invasive• 80% carcinomas are
ductal– 5% lobular – poorer
outcome
Management• Social / psych support• Surgery
– Local / mastectomy– reconstruction
• Radiotherapy– Breast / axilla
• Chemotherapy
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Modifying Oestrogen
• Oestrogen• Progesterone
• Normal breast tissue• AND 60% of tumours
• Pre-menopause prod.– Ovaries
• Post Menopause– Peripheral fats
• Therapy aims to reduce oestrogen production
• Ovarian ablation– GNRH agonists– Surigal or radiation
• Aromatase Inhibitors– Post menopausal
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Risk
Risk factors• Menarche <11• Menopause >54• Western diet• OCP and HRT• Radiation
• Family history (only 5% of Br. Ca are familial)
Inherited breast cancers• BRCA1
– 51% by age 50– 85% by age 70– Also ovarian cancer
• BRCA2– Male breast cancer– Prostatic cancer– Ovarian cancer
• Present early with advanced disease
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Risk Assessment
Think Benign• Young patient• No family history• Smooth lump• Movable lump• Cyclical symptoms
Think Malignant• Patient >55• Family history br. Ca.• Fixed mass
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Testing for breast cancer
Triple Assessment• Physical examination• Imaging
– Ultrasonography (<35)– Mammography
• Sampling– USS guided core
biopsy– Or FNA + cytology– Ideally after imaging
The screening programme
• Women• Aged 50+• Every 3 years• 2 view mammography
• Will save ~1,250 lives annually by 2010
• 1 / 500 screened
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Describe some of the features that make a disease suitable
for screening
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A good screening Programme
• An important public health problem
• In which early detection is possible and advantageous
• With a reliable, acceptable test
• And available, effective treatment
• There should be agreement on who is suitable to investigate and treat.
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Neoplasia
• 'Irreversible changes in genetic material of cells, due to exposure to certain noxious stimuli, leading to abnormal cellular growth patterns.’
• Tumours develop from a single cell – they are monoclonal
• Normal tissue is polyclonal
• Learn– Breast– Bowel– Lung
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Neoplasia
• Oncogenes– Abnormal expression– Genes controlling cell
growth– Dominant
• Tumor suppressor genes– Loss of activity– Protect against
neoplasia– Recessive
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Neoplasia
• Tumor suppressor genes– Loss of activity– Protect against
neoplasia– Recessive
• p53, Chromosome 17 – initiates DNA repair– prevents division of
cells with irreparable DNA damage
• Rb, Chromosome 13.– Abnormal copies of
this gene are implicated in retinoblastoma.
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Growth Characteristics
Benign Malignant
Expands onlyGrows locally
Expands and invades local tissuesMay metastasise
Generally slower Generally faster
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Cytoplasmic Characteristics
Benign Malignant
Normal or slight increase in nucleus:cytoplasm ratio
High nucleus:cytoplasm ratio
Resembles cell of origin (well differentiated)
Failure of differentiation
Retains specialisations Loses specialisationsDiploid Range of ploidy
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Histological CharacteristicsBenign Malignant
Few Mitoses Many mitoses – some of which are abnormal
Cell uniform throughout tumour
Cells vary in shape and size (cellular pleomorphism) and/orNuclei vary in shape and size (nuclear pleomorphism)
Organised tissue Disorganised tissue
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Invasion and Metastasis
• Invasion is the spread into adjacent tissues – may occur along natural tissue planes such as along nerves
• Metastasis is the spread of cells to distant parts of the body – there are several mechanisms for this
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To Metastasise
• Changes occur in only some cells of the tumour
• By random mutation
• Binds to basement membr
• Becomes motile• Becomes able to attach
to extracellular matrix• Becomes able to degrade
extracellular matrix
• Must be able to survive and grow at site of implantation
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Routes of
Metastasis
• Vascular
• Lymphatic
• Coelomic
Fig 1
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Local and systemic effects
Local• Pressure• Invasion• Ulceration• Obstruction
Systemic• Weight loss
(cachexia)• Loss of appetite
(anorexia)• Fever• Anaemia• General Malaise• Paraneoplastic
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Who gets Cancers?
Inherited tendencies• Xeroderma
pigmentosum• Down’s syndrome• Ataxia telangectasia
Diseases predisposing to cancer
• FPC: Colon• HNPPC: Colon
Genes• Breast / ovarian
– BRCA1– BRCA2
• Colon– MLH1
• DNA mismatch repair• Dominant
– MSH2
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What is a carcinogen? Suggest one together with its
mode of action.
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Carcinogens
Cigarette smoke
Chemicals• PAH• Aromatic amines• Nitrosamines
UV Radiation
Ionising radiation• Radiotherapy• Radon gas (lung)• Industry/military
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Carcinogens
Viruses• EBV (Epstein-Barr)• HPV (Papilloma virus)• HBV (Hepatitis B
virus)
Stages in carcinogenesis
• Initiation• Promotion• Progression