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1
Q
Asthma
A
-Chronic inflammatory disease of the airways leading to an increase in airway hyperresponsiveness and subsequent recurrent episodes of wheezing, breathlessness, chest tightness and coughing
-Episodes usually associated with airflow obstruction that is reversible
-Incidence: 15-20%
-Mortality reduced by 50% in Canada
2
Q
Asthma - Triggers
A
-Non-compliance
-Respiratory tract infections
-Irritants
-Allergens
-GERD
-Anxiety
-Drugs (NSAIDs, beta-blockers)
-Preservatives
-Cold air/exercise
3
Q
Profile of High Risk Asthmatics
A
-History of loss of consciousness during attack, intubation, ICU, and frequent ER visits
-Use of beta-agonists in excess
-Night time symptoms
-Limited daytime activities due to asthma
-Poor or very limited respiratory reserve (FEV1<60%)
4
Q
Canadian Criteria for Asthma Control
A
Parameters --> Acceptable Control --> Poor Control
1. Daytime Symptoms --> less than 3 a week --> 4 or more than a week
2. Nighttime Symptoms --> less than 1 a week --> 1 or more a week
3. Physical Activity --> normal --> restricted for 3 mos
4. Exacerbations --> mild, infrequent --> any in the past year
5. Absenteeism --> none --> missed things in the last 3 mos
6. PRN rescue inhaler use --> less than 4 a week --> 4 or more a week
5
Q
Goals of Asthma Control
A
Reduce Future Risk
-Exacerbations
-Need for acute care
-Need for oral steroids
-Permanent loss of lung function
-Mortality

Reduce/Control Symptoms
-Nighttime symptoms
-Daytime symptoms
-Need for rescue meds
-Improve lung function
-Restore ability to perform daily activities
-Return to normal quality of life
6
Q
Pharmacologic Asthma Therapy
A
Control
-Inflammation --> anti-inflammation --> ICS, LTRA, etc.
-Bronchoconstriction --> daily symptom prevention --> LABA, theophylline

Relief
-Bronchoconstriction --> acute symptom relief --> PRN SABA, fast LABA, ICS/LABA
7
Q
Management Continuum
A
1. Low dose ICS
2. Add LABA
3. Add LTRA if they do not want ICS
4. Prednisone if severe
8
Q
ICS Side Effects
A
Common - Reasons for Poor Compliance
-Hoarseness
-Thrush
-Temporary growth delay in kids
-Fluid retention
Common - Indications of Long Term Problems
-Bruising
-Fragile skin
Common - Clinically Insignificant
-Reduced bone density
-Suppression of adrenals (>1000 mcg for long periods of time)
Uncommon - Serious
-Glaucoma
-Cataracts
9
Q
Asthma Treatment
A
Ciclesonide
-Pro drug that has to land on airway mucosa to activate via esterase

LTRA
-Good or exercise induced or allergies
10
Q
Blood Glucose Levels
A
-Normal 3.5-8 mmol/L
-CNS dysfunction occurs at confusion, coma, seizure, death
11
Q
Maintenance of Glucose Levels
A
-Post-absorptive state
-Fasting state
-Prolonged starvation
-Substrate availability
+Carbs in food
+Glycogen, glycerol, lactate and amino acids
12
Q
Insulin
A
-Master signaling hormone that regulates absorption and usage of fuels
-Produced in the islets of Langerhans in the pancreas
-Secreted in response to glucose
-Actions on Target Cells (adipose, liver, muscle)
1. Induce GLUT4 migration to cell surface in order to transport glucose into the cell
2. Promotes anabolism
13
Q
Insulin in Fed vs. Non-Fed State
A
FED (Increased insulin)
-Use glucose everywhere as fuel to generate ATP (enhance uptake)
-Suppress liver production and release of glucose and fat cell lipolysis and release of fatty aids
-Promote synthesis and storage of glycogen, triglycerides, and proteins

NON FED (Decreased insulin)
-Liver makes and releases glucose to feed brain (glycogenolysis, gluconeogenesis)
-Free fatty acids used elsewhere for feul
-Prolonged fast causes ketoacids to be made
14
Q
Diabetes Mellitus
A
-Defined as absolute or relative deficiency of circulating insulin leading to impaired use of glucose
-Hyperglycemia occurs due to excess conversion of metabolites to glucose and less utilization of glucose in the body
-Leads to disordered carb, fat and protein metabolism
-Leading cause of blindness, end stage renal disease, lower limb amputation, and CV disease
15
Q
Diabetes Mellitus - Diagnosis
A
ONE of the following at least twice
-Fasting blood glucose > 7 mmol/L (N < 6)
-Casual blood glucose > 11.1 mmol/L + symptoms of polyuria, polydipsia, and weight loss
-2h blood glucose in a 75 g OGTT > 11.1 mmol/L (N < 7.8)
16
Q
Diabetes Mellitus: Type 1
A
-Insulin dependent
-Autoimmune destruction of pancreatic beta cells
-Once symptoms arise, there is already 60-80% destruction
-Insulitis: mononuclear and cytotoxic T cells clustering around and within individual islets (inflammation)
-Prone to diabetic ketoacidosis
+Insulin drops causing adipocytes to breaks on mobilization of fatty acids to fail --> fatty acids pour out and go to liver where they are converted into ketoacids
17
Q
Diabetes Mellitus: Type 1 - Pathogenesis
A
Three interlocking mechanisms responsible for islet cell destruction
1. Genetic susceptibility - 90% risk linked to MHC polymorphism
2. Autoimmunity
-Chronic, multistage process required to overcome self tolerance
-Specific destruction of beta cells
-T cell mediated injury
3. Environmental trigger
18
Q
Diabetes Mellitus: Type 1 - Treatment
A
-Exogenous insulin administered several times/day with monitoring
-Emerging Therapies
+Cadaveric islet transplants
+Cultured islet (stem cells)
+Immunemodulation
+Vaccine
19
Q
Diabetes Mellitus: Type 2
A
-Non-insulin dependent
-Prevalence increases with age and half are undiagnosed
20
Q
Diabetes Mellitus: Type 2 - Major Metabolic Defects
A
-Peripheral insulin resistance in muscle and fat
-Decreased pancreatic insulin secretion
-Increased hepatic glucose output
+Liver less able to sense insulin and thinks the body is fasting so it pours out glucose
21
Q
Diabetes Mellitus: Type 2 - Insulin Resistance
A
-Present 10-20 years before onset
-Best predictor of future diabetes
-Means too much fasting response and too little fed response
+Decreased glucose uptake after eating, protein synthesis, and triglyceride uptake by fat cells
+Increased hepatic production and release of glucose, lipolysis, and circulating FFAs
+Maldistribution of fat - there is an inverse relationship between fasting plasma fatty acids and insulin sensitivity (especially viscera fat)
22
Q
Diabetes Mellitus: Type 2 - Natural History
A
-Islet cells try to help and start secreting more insulin, but it is contending with resistance and eventually cells poop out --> hyperglycemia
23
Q
Diabetes Mellitus: Type 2 - Treatment
A
LIVER - Glucose Production by making liver more sensitive to insulin
-Biguanides (Metformin)
-Thiazolidinediones

INTESTINE - Glucose Absorption by blocking breakdown of carbs in gut so glucose not made as quickly and therefore not absorbed as fast
-Alpha-glucosidase inhibitors

PANCREAS - Insulin Secretion
-Sulfonylureas and meglitinides (augment insulin secretion)
-Dipeptidyl peptidase 4 inhibitors
-GLP-1 analogue (interacts with different receptors on beta islet cells to modulate insulin output)
-Insulin

ADIPOSE/MUSCLE - Peripheral glucose uptake, altered fat cells, less insulin resistance --> try to change bad adipocytes to more benign, subcutaneous fat cells
-Thiazolidinediones
24
Q
Diabetes Mellitus - Acute Complications
A
1. Hyperglycemia Symptoms
-Threshold for kidney to resorb glucose is 10 mmol/L and anything more appears in urine --> osmotic diuresis
-Polyuria and polydipsia
2. Diabetic Ketoacidosis (T1DM)
-Triggered by absolute absence of insulin
-Hyperglycemia --> dehydration --> loss of sodium, potassium, etc. --> very elevated levels of ketoacids --> metabolic acidosis
3. Hyper-osmolar Non-Ketotic Coma (T2DM)
->50 years, especially debilitated on diuretics
4. Hypoglycemia
-Due to too much insulin or hypoglycemic agent
-Diagnosed as glucose levels <2.5 mmol in men and 2.0 in women
-Symptoms: Activation of SyNS to secrete catecholamines leading to anxiety, palpitations, sweating, hunger, pallor, etc.; CNS dysfunction
-Reversal of symptoms by correction of glucose concentration
25
Q
Treatment of Diabetic Ketoacidosis and Non-Ketotic Coma
A
-Treat underlying cause
-Fluid resuscitation
-Insulin infusion
+DKA: Stops ketoacidosis
+Non-Ketotic Coma: Lowers glucose but patients are very sensitive --> dose and monitor
26
Q
Diabetes Mellitus - Chronic Complications
A
1. Accelerated Atherosclerosis
-Coronary artery disease (MI/angina)
-Cerebral vascular disease (stroke)
-Peripheral vascular disease (claudication, gangrene)
2. Diabetic Nephropathy
-Characteristic deposit in glomeruli
-Initial hyperfunctioning followed by gradual decline
-Increase in protein loss in urine
3. Diabetic Retinopathy
4. Diabetic Neuropathy
5. Diabetic Foot
-Vascular disease leads to poor circulation
-Loss of limb due to gangrene arising from infection
27
Q
Diabetes Mellitus - Monitoring
A
Glycemic Control
-Venous blood glucose
-Capillary glucose monitoring
+Small portable meters; finger prick
-Glycated hemoglobin (HbA1C)
+Product of non-enzymatic and irreversible binding of glucose to circulating hemoglobin
+Increase average glucose concentration and proportion of HbA1C
+3 month overview of glucose control

Kidney (urinary protein excretion)
-24 h urine protein excretion
-Microalbuminuria
+Proteinuria begins with small amounts (<300 mg/dL)
28
Q
Diabetes Mellitus - Treatment
A
-Glycemic control
-Foot care
-Modification of other risk factors or coronary artery disease
-Prevention of neuropathy
-Prevention of retinopathy - laser to prevent retinal detachment
-Prevention of nephropathy
+Tight control of BP
+Tight control of glucose
+Angiotensin converting enzyme inhibitor or ARB in presence of microalbuminuria
29
Q
Ocular Anatomy - Sclera
A
GLOBE - ANTERIOR SEGMENT
-Outer coat of the eye
-White appearing collagenous structure (0.1-0.3 mm thick)
-Site of insertion of extraoccular muscles
-Posterior perforation allows for entry of optic nerve
-Blocks extraneous light from entering globe

PATHOLOGY
-Scleritis (autoimmune and infections)
-Scleral lacerations
-Can be ruptured by direct trauma
30
Q
Ocular Anatomy - Conjunctiva
A
GLOBE - ANTERIOR SEGMENT
-Modified mucous membrane that covers the inside surface of the lids (tarsals) and the globe to the edge of the cornea (bulbar)
-Protects the globe

PATHOLOGY
-Infections
+Viral conjunctivitis (pink eye)
+Bacterial conjunctivitis
-Allergic conjunctivitis
-Steven-Johnson Syndrome
+Hypersensitivity reaction of skin and mucous membranes, often secondary to medications
+Inflammation of conjunctiva results in adhesions between bulbar and tarsal conjunctiva
+Complications
(a) Limbal stem cell deficiency with resultant corneal scarring
(b) Severe dry eye (keratoconjunctivitis sicca)
31
Q
Ocular Anatomy - Cornea
A
GLOBE - ANTERIOR SEGMENT
-Optically clear "watch-glass" over visual axis
-Continuous with sclera
-5 Specialized Layers
1. Epithelium - stratified squamous
2. Bowman's Membrane - specialized collagen
3. Stroma - regular array of collagen and mucopolysaccarides
4. Descemet's Membrane - basement membrane
5. Endothelium - metabolically active monolayer (controls hydration)

PATHOLOGY
-Acute
+Corneal abrasion - traumatic loss of epithelium
+Corneal ulcer - microbial infection of cornea characterized by a white infiltrate +/- hypopyon (WBC)
-Chronic
+Viral infections - herpes simplex keratitis produces dendritic staining pattern and may lead to loss of corneal sensation
+Trauma - can lead to iris coming off and migrating to plug hole
32
Q
Ocular Anatomy - Iris
A
GLOBE - ANTERIOR SEGMENT
-Anterior extension of ciliary body/uveal tract
-Forms the pupil
-Contains sphincter muscle to constrict pupil and dilator muscle to dilate pupil
-Pupil size varies with light intensity

PATHOLOGY
-Iritis (Anterior Uveitis)
+Inflammation of uveal tract
+Often idiopathic, but maybe related to systemic autoimmune/inflammatory conditions
+Symptoms: Photophobia, pain, redness
+Treatment: Topic steroid eye drops
33
Q
Ocular Anatomy - Ciliary Body
A
GLOBE - ANTERIOR SEGMENT
-Located behind iris, part of uveal tract
-6-7 mm wide
-3 Main functions
1. Ciliary muscle produces accommodation for near vision via action on lens (through zonules)
2. Vascular supply involved in production of aqueous humour, which provides metabolic support for the lens and cornea
3. Facilitates drainage of aqueous through actions on trabecular network

PATHOLOGY: Glaucoma
-Progressive optic neuropathy characterized by typical optic nerve head and visual field changes
-Treatment: Involves lowering IOP by decreasing aqueous production by ciliary body or increasing aqueous outflow via trabecular meshwork and ureoscleral outflow paths
34
Q
Ocular Anatomy - Lens
A
GLOBE - ANTERIOR SEGMENT
-Focuses light onto retina
-Optically clear structure that grows throughout life contained within basement membrane
-Attached to ciliary body by 60-80 zonules
-Accommodates to allow near vision as controlled by ciliary muscle

PATHOLOGY: Cataracts
-Opacity of the lens that may be
+Posterior subcapsular (trauma, steroids, diabetes)
+Nuclear sclerosis (age)
+Cortical (age, trauma)
-Treatment: Surgically remove and replace lens with intraocular lens implant to help focus light on retina
35
Q
Ocular Anatomy - Choroid
A
GLOBE - POSTERIOR SEGMENT
-Posterior extension or urea between sclera and retina
-Supplies oxygen to retinal pigment epithelium and outer 1/3 of retina
-Most vascular layer with highest rate of blood flow per gram in body
-Carries 70% of blood flow in eye

PATHOLOGY
-Malignant melanoma
-Age-related macular degeneration (AMD)
36
Q
Ocular Anatomy - Retina
A
GLOBE - POSTERIOR SEGMENT
-10 layer structure that transforms light to an electrochemical signal (phototransduction)
-0.1-0.2 cm thick
-Light penetrates outer 8 layers to reach rods and cones
-Retinal pigment epithelium supports metabolic activities of rods and cones
37
Q
Ocular Anatomy - Macula
A
GLOBE - POSTERIOR SEGMENT
-Centre of retina that produces detailed vision
-Centre of macula is fovea
-Location of cones
38
Q
Ocular Anatomy - Retinal Pigment Epithelium
A
-Monolayer of cells between retina and choroid
-Provides special metabolic and ionic conditions necessary for rods and cones, and is essential for normal vision
-Aging changes RPE-choroid interface and may result in changes of AMD

PATHOLOGY: Age-Related Macular Degeneration
-Dry (Atrophic) Form
+Non-neovascular
+Characterized by drusen and RPE atrophy
+Usually results in modest visual changes only
-Wet (Exudative) Form
+Neovascular
+Characterized by pathological choroidal neovascularlization
+Fibrosis and subsequent damage to overlying retina results in significant central visual loss
39
Q
Ocular Anatomy - Vitreous
A
GLOBE - POSTERIOR SEGMENT
-Semi-solid mixture of water, collagen and hyaluronic acid
-Optically clear, fills centre of globe
-Functions
+Maintains optically clear media
+Thermoregulation
+Shock absorption
+Maintenance of relative hypoxia
-Age-related reduction in hyaluronate results in opacities (floaters)
-Firm adhesions to optic nerve, macula, retinal blood vessels, and peripheral retina at ora serrata can produce retinal tears with age-related condensation and liquefaction
40
Q
Ocular Anatomy - Optic Nerve
A
GLOBE - POSTERIOR SEGMENT
-Axons of retinal ganglion cells converge to form optic nerve
-Ends at optic chiasm and its axons synapse at lateral geniculate body
-Pathology may be due to
+Glaucoma
+Optic neuritis/inflammation
+Ischemia
+Compression
+Toxic
41
Q
Ocular Anatomy - Eyelids
A
ADNEXAL STRUCTURES
-Protects corneal surface
-Lid contains muscle, the tarsal plate, and is the site of attachment of the orbital septum
-Lid opening is via levator palpebrae (CN III) and Muller's muscle (SyNS)
-Lid closing is via orbicularis oculi (CN VII)
42
Q
Ocular Anatomy - Bony Orbital Walls
A
ADNEXAL STRUCTURES
-Provides protection for the globe
-Pyramid in shape with apex at back
-7 bones
-Volume 30 mL
-Nerves and blood vessel supply globe pass through foramina in bones
43
Q
Ocular Anatomy - Lacrimal System
A
ADNEXAL STRUCTURES
-Tear Production
+Lacrimal Gland: Located in the upper outer orbit and produces reflex secretion in response to irritation or emotion
+Accessory Glands: Located in conjunctival fornix and provide basal secretion
-Tear Drainage: Punctum --> canaliculi --> lacrimal sac --> nasolacrimal duct --> nose
-Tear Film: 3 layer film over cornea and conjunctiva that maintains an optically smooth refractive surface and nourishes/oxygenates outer layers of cornea
1. Mucin Layer (from conjunctival goblet cells) aids tear adherence to cornea
2. Aqueous Layer forms bulk of tear layer
3. Lipid Layer (from tarsal meibomian glands) reduces evaporation on surface
44
Q
Ocular Anatomy - Extraocular Muscles
A
ADNEXAL STRUCTURES
-6 muscles that control eye movement
-Double vision can result if one muscle is weak or damaged resulting in unequal movement between eyes
45
Q
Cranial Nerves
A
Action --> Pathology

CNII Optic Nerve
Vision --> loss of vision, colour vision abnormal

CNIII Ocularmotor Nerve
4 EO muscles, levator palpebrae, and PSyNS pupil constriction --> double vision, ptosis, dilate pupil

CNIV Trochlear Nerve
1 EO muscle --> double vision

CNV Trigeminal Nerve
Ocular sensation --> anesthetic cornea, corneal ulcers

CNVI Abdunus Nerve
1 EO muscle --> double vision

CNVII Facial Nerve
Obicularis oculi, parasympathetic for lacrimal gland --> failure of eyelid closure, corneal ulcers
46
Q
Ocular Medications - Topical Anesthetics
A
DIAGNOSTIC AGENTS
-Indications
+IOP testing
+Diagnosis of corneal abrasion and ulcer with fluorsecein dye
+Anestesia for procedures and surgery
-Side Effects
+Corneal epithelial damage
+Delayed wound/epithelial healing
47
Q
Ocular Medications - Fluorescein
A
DIAGNOSTIC AGENTS - DISCLOSING AGENTS
-Water soluble non-toxic dye
-Yellow at neutral pH
-Fluoresces green with cobalt blue exposure
-Stains areas with no epithelium
-Indications
+Diagnosis of corneal abrasion
+Applanation tonometry (IOP measure) for glaucoma
+Tear layer evaluation in dry eye or contact lens fitting
48
Q
Ocular Medications - Rose Bengal
A
DIAGNOSTIC AGENTS - DISCLOSING AGENTS
-Stains devitalized/injured corneal epithelial cells rather than locations of no cells
-Indications: Subtle dry eye diagnosis and herpes simplex keratitis diagnosis
-Adverse Effects: Stings noticeably when anesthetic wears off
49
Q
Ocular Medications - Antibiotics
A
THERAPEUTIC AGENTS
-Moxifloxacin/gatifloxacin (4th gen fluoroquinolines)
-Tobramycin
-Erythromycin
-Doxycycline
50
Q
Ocular Medications - Anti-Inflammatories
A
THERAPEUTIC AGENTS
-Steroids are used to treat ocular inflammation from uveitis, surgery, etc.
+Can increase IOP
+Prednisolone 1%, dexamethasone 0.1%, lotoprednol 0.5%
-NSAIDs are used to prevent macular edema following intraocular surgery
+Can cause corneal melts
+Ketorolac 0.5%
51
Q
Ocular Medications - Glaucoma Drops
A
THERAPEUTIC AGENTS
-Decrease Aqueous Production
+Beta blockers - Timolol
+Alpha agonists - Brimonidine
+Carbonic anhydrase inhibitors - Brinzolamide
-Increase Outflow
+Trabecular Meshwork - Pilocarpine
=> AE is browache, RD, etc.
+Increase uveoscleral outflow - Bimatroprost (prostaglandin analog)
=> AE is colour changes, lash growth, inflammation, HSV
52
Q
Ocular Medications - AMD Drops
A
THERAPEUTIC AGENTS
-Dry
+Observe
+Oral antioxidants in selected cases
-Wet
+Laser photocoagulation destroys vessel and surrounding tissue
+Photodynamic therapy
+Anti-VEGF therapy - Bevacizumab + Ranibizumab
53
Q
COPD
A
-Chronic disease with SOB, cough, and sputum that presents as chronic bronchitis and emphysema
-Diagnosed using spirometry and x-ray for differential
-Cycle of Air Trapping
+Airway narrowed due to inflammation and air is trapped due to damaged pocket
+Damaged pockets do not have have force to push out the air and so breaths are trapped
+Airflow is limited because small airways are narrowed, alveoli lose elasticity, and supportive structures are lost
54
Q
COPD - Smoking Cessation
A
-Nicotine Replacement Therapy - patch, gum, inhaler
-Bupropion SR (Wellbutrin) - anxiolytic/antidepressant
-Varenicline (Champix) - nicotine receptor partial agonist

Nicotine binds to the nAChR in the VTA and releases dopamine in NAcc --> reward
55
Q
AECOPD
A
-More cough, SOB +/- purulent sputum
-Sustained worsening over 48 hours
-Lead to spiral toward mortality
-Takes almost 1 month to recover
-Management
+Maintain long acting bronchodilator and add prn SABA
+Oral steroids in mod-severe - prednisone 40 mg/day for 10 days
+Antibiotics can be used to clear airway bacteria
56
Q
AECOPD - Simple Chronic Bronchitis
A
-Any age
- 50%
-Treatment
+New macrolide
+2nd or 3rd gen cephalosporin
+Amoxicilin
57
Q
AECOPD - Complicated Chronic Bronchitis
A
->64 years
-> 4 exacerbations/yr
-Cardiac disease
-FEV < 50%
-Home oxygen
-Chronic oral steroids
-Antibiotics < 3 mos
-Treatment
+Respiratory fluoroquinolines
+Beta lactam/lactamase inhibitor
58
Q
AECOPD - Chronic Suppurative
A
-Chronic suppurative bronchitis
-Need chronic corticosteroids and frequent antibiotic treatment (>4/yr)
-FEV < 35%
-Treatment
+Target to cultures
+Empiric for P. aeruginosa (ciprofloxacin, parenteral)
59
Q
Neoplasia - Natural History
A
4 Stages
1. Transformation
2. Growth
3. Local Invasion
4. Distant Metastases

Local invasion and distant metastases are defining features of malignant tumours
60
Q
Neoplasia - Transformation
A
NATURAL HISTORY STAGE 1
-Normal cell transforms into neoplastic cell
-Transformed cell can be distinguished from normal cell based on morphological features (differentiation and anaplasia)
-Well differentiated cells still resemble the cell of origin and occur with benign tumours
-Poorly differentiated and anaplastic tumours, which lack differentiation, exist in malignant tumours
61
Q
Neoplasia - Dysplasia
A
-Disordered growth that may be a precursor to carcinoma and that may regress back to normal
-Microscopically, dysplastic epithelium has abnormal architecture, epithelial cells with abnormal morphology and increased cell proliferation without invasion
-Detection of dysplasia can prevent cancer
62
Q
Neoplasia - Growth
A
NATURAL HISTORY STAGE 2
-Neoplastic cells multiply and the tumour grows by cellular division
-Growth rate varies according to cancer type
+Colon or breast cancer --> 2-3 months
+Childhood cancers --> less than 1 month
+Salivary gland tumours --> more than 1 year
-Growth rate is inversely correlated with level of differentiation
-Fast growing tumours are more susceptible to chemotherapy
63
Q
Neoplasia - Metastases
A
NATURAL HISTORY STAGE 4
-All invasive tumour cells can spread to distant locations via
1. Direct seeding of body cavities and surfaces
2. Lymphatic channels
3. Blood vessels
64
Q
Causes of Cancer
A
-Series of genetic mutations required for transformation of cells and generation of cancer cells
-Mutations can be inherited from parents or occur later in lie after exposure to carcinogenic agents

1. Hereditary Predisposition (<10%)
a) Autosomal Dominant Inherited Cancer Syndrome
b) Defective DNA Repair Syndrome
c) Familial Cancers
2. Environmental Carcinogens
a) Chemical Carcinogens
b) Radiation
c) Microbial
d) Inflammation
65
Q
Causes of Cancer - Hereditary Predisposition
A
Divided into 3 Categories
a) Autosomal Dominant Inherited Cancer Syndrome - Inheritance of a single mutant gene, usually a tumour suppressor gene
-Ex. Mutant RB gene --> 10000 fold risk of retinoblastoma
b) Defective DNA Repair Syndrome - Inheritance of a mutant DNA repair gene
-Ex. Mutant MSH2/MLH1/MSH6 genes --> hereditary non-polyposis colon cancer (HNPCC) syndrome
c) Familial Cancers - Certain cancers are more frequent and occur at earlier ages in certain families
-Ex. Breast, colon, and ovarian cancer
66
Q
Causes of Cancel - Chemical Carcinogens
A
ENVIRONMENTAL CARCINOGEN
1. Medical Drugs
-Immunosuppressants
2. Natural Carcinogenic Chemicals
-Mycotoxin from Aspergillus flavus (mold) --> Liver cancer
-Asbestos --> Lung cancer
-Arsenic --> Skin cancer
3. PAHs - produced by combustion of tobacco and broiling meat
4. Alcohol
5. Tobacco
67
Q
Causes of Cancer - Environmental Carcinogens
A
a) Chemical Carcinogens
b) Radiation
-UV and sunlight
-Ionizing radiation (medical/occupational exposure or nuclear plant)
c) Microbial
-Oncogenic virus
+HPV --> cervical cancer
+Hep B/C --> liver cancer
+Epstein-Barr --> lymphoma
-Bacterias
+H. pylori --> stomach cancer
d) Inflammation
68
Q
Molecular Basis of Cancer
A
-Genetic mutations/damage generate a cancer cell, which divides and transmits mutation to next generation of cancer cells --> tumour cells are clonal
-Not all genetic damage leads to cancer
-Carcinogenic mutations are
+Non-lethal mutations
+Harmful mutations that alter cellular functions and allow excessive and unregulated proliferation
69
Q
Principle Targets of Genetic Damage
A
-Oncogenes - growth promoting
-Tumour suppressor genes - growth inhibiting
-Apoptosis regulating genes - cell death
-DNA repair genes
70
Q
Normal Cell Division
A
1. GF binds on cell surface
2. Receptor activated --> signal transducing proteins activated
3. Signal transmission to cell nucleus
4. Activation of DNA transcription factors leading to cell division
-The cell cycle is regulated by cylcins, cyclin dependent kinases and their inhibitors
-Cyclin binds to CDK and activates it to phosphorylate RB, which inhibits cell cylce
71
Q
Fundamental Changes in Cancer
A
1. Self-sufficiency in Growth
2. Insensitivity to Growth Inhibiting Signals
3. Evasion of Apoptosis
4. Defects in DNA Repair
5. Limitless Replicative Potential
6. Angiogenesis
7. Ability to Invade + Metastasize
8. Escape Immune Attacks
72
Q
Fundamental Changes in Cancer - Self-Sufficiency in Growth
A
-Normally, proto-oncogenes regulate cell prolieration in orderly fashion
-Oncogenes promote continuous cell proliferation in the absence of exogenous growth factor and lack important regulatory elements
-Oncogenes promote autonomous proliferation by
+Production of GF
+Increased number of GF receptors
+Production of mutant receptors
+Production of mutated signal-transducing proteins
+Dysregulation of activity of cyclins, CDKs and inhibitors
73
Q
Fundamental Changes in Cancer - Insensitivity to Growth Inhibiting Signals
A
-Tumour suppressor cells are key at checkpoints of cell cycle
-Retinoblastoma protein (RB) enforces G1-S checkpoint
+Its inactivation leads to cell proliferation, inactivation can occur by mutation or inactivation by oncogenic virus binding to RB
-P53 causes G1 and G2 arrest and induces DNA repair
+It prevents propagation of genetically damaged cells and i DNA repair fails, P53 triggers apoptosis
+Loss of function leads to DNA damage accumulates leading to malignant neoplasms
74
Q
Fundamental Changes in Cancer - Limitless Replicative Potential
A
-Telomeres progressively shorten each time a cell replicates and so normal cells can double about 60-70 times
-Telomerases regenerate that telomeres and allow for indefinite replication
75
Q
Fundamental Changes in Cancer - Angiogenesis
A
-Cancer cells secrete angiogenic factors that stimulate growth of new vessels
-Also increases access of tumours cells to blood stream and facilitates metastasis
76
Q
Fundamental Changes in Cancer - Ability to Invade and Metastasize
A
-Cancer cells lose their intercellular junctions and detach from one another
-Cancer cells acquire ability to bind to surrounding tissue, which gives them mobility
-Cancer cells and surrounding inflammatory cells secrete proteinases that digest surrounding tissue and make invasion easier
77
Q
Effects of Tumours
A
Local Effects
-Impingement on adjacent structures
-Ulceration, bleeding and infection
Systemic Effects
-Cancer cachexia - loss of body fat and muscle with fatigue, anorexia, and anemia due to cytokine production by tumour and host cells
-Hormone production - by functioning endocrine tumours
-Paraneoplastic syndrome - symptoms that occur at sites distant from tumour or its metastasis
78
Q
Grading and Staging of Tumours
A
-Grading is based on degree of differentiation
-Staging is based on size of primary tumour, its extent of spread to regional lymph nodes and presence or absence of distant metastases
79
Q
Lab Diagnosis
A
-Histological Evaluation - Examine tumour samples under light microscopy to determine tumour subtype, grade and other prognostic features
-Immunochemistry - Use specific colour-tagged antibodies to categorize poorly differentiated tumours, determine site of origin, and detect molecules that have prognostic or therapeutic significance
-Molecular Techniques
+Fluorescent in-situ hybridization (FISH) - Tag gene sequence and examine under fluorescence to see translocation in sarcomas
+Prognostication of malignant neoplasm
+Guiding therapy with drugs targeting specific oncoproteins
+Diagnosis of hereditary predisposition to cancer
-Tumour Markers
80
Q
GERD, PUD, IBD - Clinical Localization of Bleeding
A
-Hematemesis - throwing up blood --> proximal to ligament of Treitz
-Melena - tarry black stool, transit time in GI tract > 14 hours, 50-100 cc blood into UGI tract --> proximal to ileocecal valve
-Hematochezia - bright red or maroon --> colon or small bowel/massive UGI bleed
81
Q
PUD - Natural History
A
-Bleeding risk is higher for duodenal vs. gastric
-75% spontaneously stop bleeding
-25% rebleed within 8 hours
-Mortality constant for 3 decades
82
Q
PUD - Etiology
A
-Aggressive Factors - acid and pepsia
-Epithelial Defense Mechanisms - mucous/bicarb layer, PG mucosal blood flow
83
Q
PUD - Role of Gastric Acid
A
-Impairs clot formation by inhibiting platelet aggregation
-Accelerates clot lysis (pepsin)
-Impairs defense mechanism (mucosal/bicarb layer)
84
Q
PUD - UGI Bleed: Clinical Prognosis
A
-Age > 60 + comorbidities
-Severity of initial hemorrhage
+Number of units transferred blood, Hb < 80 g/L
+Hemodynamic instability
+RED blood in hematemesis +/- stool
-Endoscopic criteria
-Onset of bleeding during hospitalization for another reason
85
Q
PUD - General History
A
-Abdominal pain (eg. ulcer, mesenteric ischemia, malignancy)
-Retching (Mallory-Weiss tear)
-Meds: NSAID, ASA, COXIB
-Family or personal history of coagulopathy
-Comorbid illness
-Prior surgery or PUD, arterial bypass graft
86
Q
PUD - Management
A
-General
+Rescucitation with fluids and transfusion
+Correct coagulation status
-Specific
+PPIs
+Endoscopy to localize bleed and implement treatment
+Failure of above --> interventional radiology, surgery
87
Q
PUD - PPIs
A
-Treatment for common etiologies of UGI bleeding
-Gastric acid neutralization may promote mucosal homeostasis
-Safe, effective, reduce re-bleeding rate and need for surgery
-IV
+Continuous infusion efficacy
+Intermittent dosing is of minimal benefit
+Only used if patient cannot take by mouth or small bowel issue
88
Q
PUD - Endoscopy
A
-ID source of bleed --> risk stratification of lesion --> therapeutic hemostasis
-Medication - injection (epinephrine can offer time for vasoconstriction)
-Thermal - contact or non-contact
-Mechanical - hemoclips
89
Q
GERD
A
-Failure of anti-reflux barrier, allowing reflux of gastric contents into esophagus
-Can be endoscopic lesions (GERD) or non-erosive (NERD)
-Esophagitis is more common in men
90
Q
GERD - Causes
A
-Increase number of transient LES relaxations
-Hypotensive LES
-Disruption diaphragmatic sphincter and crural fibres
-Esophageal clearance
-Gastric emptying
-Obesity
-Hiatus hernia
91
Q
GERD - Clinical Presentation
A
Typical
-Heartburn
-Regurgitation
-Belching
-Dysphagia
-Odynophagia

Atypical
-Cough
-Hoarseness
-Wheezing
-Chest pain
92
Q
GERD - Complications
A
-Erosive esophagitis
-Ulceration
-Peptic stricture (scarring and narrowing of aperture of esophagus)
-Barrett's Esophagitis
+Acquired
+Injury to squamous epithelium in lower esophagus that is replaced with metaplastic columnar epithelium
+Tissue at risk for dysplasia and adenocarcinoma
93
Q
GERD - Treatment
A
-Lifestyle changes
-Pharmacology
+H2RAs
+PPI
+Prokinetic agents
+Surgery
94
Q
IBS
A
Inflammatory Bowel Disease
-Chronic inflammatory disorders of the intestinal tract, variable systemic involvement
-Crohn's affects any portion of the GI tract
-Ulcerative Colitis is limited to the colon and rectum
-Indeterminate Colitis has features of both
95
Q
IBS - Pathogenesis
A
-Immune response against self-antigen
-Development of autoimmunity reflects a combination of susceptibility genes and environmental triggers
+Genetic Susceptibility CD > UC
+Smoking - Positive for UC, Negative for CD
+Fish Oil CD > UC
+Stress UC > CD
96
Q
Crohn's vs. Ulcerative Colitis
A
ENDOSCOPY
CD
-Mouth to anus, segmental inflammation, skin lesions, cobblestone, psuedopolyps
-Ileocolonic (50%); Small bowel (30%), Colon (20%)
UC
-Continuous inflammation extends from anus

GROSS PATHOLOGY
CD
-Transmural (deep ulcers, fissures), serosal erythema, creeping fat
UC
-Superficial (mucosa and submucosa)
-Red and bleeds upon touch

MICROSCOPIC PATHOLOGY
CD
-Patchy, architectural distortion, granulomas (non-caseating)
UC
-Architectural distortion, gland destruction, crypt abcess
97
Q
Crohn's - Clinical Manifestation
A
-Abdominal pain
-Diarrhea
-Inflammatory mass RLQ
-Obstruction
-Weight loss due to nutrient malabsorption
-Fever
-Perianal disease
98
Q
Crohn's - Complications
A
-Stricture
-Fistula - connection from one epithelial layer to another that should not be there
99
Q
Ulcerative Colitis - Clinical Manifestation
A
-Abdominal pain
-Diarrhea (frequent, small volume - more characteristic of colonic diarrhea)
-Rectal bleeding
-Mucous
100
Q
Ulcerative Colitis - Complications
A
-Toxic Megacolon
+Colon dilated and large --> bursting
-Malignancy risk increases if
+Duration > 10 years
+Extensive disease
+Co-morbid liver disease
101
Q
Ulcerative Colitis - Extra-intestinal Manifestations
A
-Eye - episcleritis
-Skin - erythema nodesum
-Mouth ulcers
-Muscoskeletal - peripheral arthritis
102
Q
IBS - Evaluation
A
-History - travel, antibiotic use, diet, sexual history, family history, extraintestinal symptoms
-Physical Exam - abdominal and perianal
-Lab Data - CBC, iron, folate, etc.
-Radiology
+Acute - plain supine film for UC
+Small bowel studies - follow through, enema, CT enterodysis
+Ultrasound, CT for extraluminal features/complications
+MRI for perianal disease
-Endoscopy
103
Q
IBS - Goals of Therapy
A
-Remission induction and maintenance
-Prevent/treat complications
-Mucosal healing
-Improve QoL
104
Q
IBS - Principles of Therapy
A
CD
-Location: Ileocolonic > Small bowel > colon
-Severity: Multi-site
-Complications: Stricture, fistula, perianal

UC
-Location: Looking for the extent - Pancolitis > Proctitis > left sided
-Severity: # of bowel movements, rectal bleeding, fever, tachycardia, anemia
-Complications: Toxic megacolon, malignancy
105
Q
Crohn's - Medications
A
Drug: Induction and Maintenance
-5-ASA: Good for both
-Glucocorticoids: Induction
-Immunosuppressants
+Azathioprine/6MP: Good for both
+Methotrexate: Good for both
+Cyclosporin: Bad for both
-Immunobiologic (Anti-TNF): Good for both
106
Q
Ulcerative Colitis - Medications
A
Drug: Induction and Maintenance
-5-ASA: Good for both
-Glucocorticoids: Bad for both
-Immunosuppressants
+Azathioprine/6MP: Good for both
+Methotrexate: Induction
+Cyclosporin: Induction
-Immunobiologic (Anti-TNF): Good for both
-Anti-integrins (Vedolizumab): Induction

Treatment Method
-Distal Colon --> Topical 5-ASA
-Moving Proximally up --> Oral 5-ASA + consider immunosuppressant
-All over the place --> Immunosuppressant