1
Q
What are the main components of innate immunity?
A
Soluble Factors: - antibacterial factors - complement system Cellular Factors: - scavenger phagocytes - neutrophils - macrophages
2
Q
What are the main antibody isotypes?
A
IgM: main antibody of primary response
IgG: main antibody of secondary response
IgA: present in secretions and lines epithelial surfaces
IgE: high affinity binding to mast cells (role in allergy)
3
Q
What is the general structure of antibodies?
A
- Fab region: antigen binding region
- Light chains
- Heavy chain (longer)
- Fc region: binds to Fc receptors on phagocytes, activates complement
4
Q
What is the function of antibodies?
A
- Opsonise for phagocytosis
- Activate complement for lysis
- Neutralise toxins and pathogen binding sites
5
Q
What are the main differences between class I and II MHC?
A
- Class I presents to CD8 T cells, class II to CD4
- Class I presents intra-cellular antigen, class II extracellular
- Class II found on APCs, class I on all nucleated cells
6
Q
What is type 1 hypersensitivity?
A
Immediate, atopic reaction mediated by IgE binding to mast cells
Mast cell degranulation of;
- histamine (smooth muscle contraction)
- proteinase
- cytokines, chemokines, PGs (smooth muscle contraction) and leukotrienes (pro-inflammatory)
7
Q
What is anaphylaxis?
A
- Severe, systemic type 1 hypersensitivity
- Widespread mast cell degranulation caused by systemic exposure to antigen (e.g. penicillin)
- Vascular permeability is principal immediate danger
- Can be rapidly fatal
8
Q
What are type 2 and 5 hypersensitivity?
A
- Caused by binding of ABs directed against human cells (IgG usual cause)
- Common cause of autoimmune disease
- Steps:
- sensitisation
- opsonisation of cells (as cells are different, no longer recognised as self)
- cytotoxicity (complement, inflammation-> tissue destruction)
- Type V is direct activation with receptor/antigen
9
Q
What is type 3 hypersensitivity?
A
- Mediated by immune complexes bound to soluble antigen
- AB complexes aggregate in small blood vessels
10
Q
What is type 4 hypersensitivity?
A
Lymphocytes infiltrate area and cause injury several days after (contact dermatitis- contact alters cells so no longer recognised as self-antigen)
11
Q
What causes rheumatoid arthritis?
A
- Inflammation leads to release of PAD from inflammatory cells
- Alters variety of proteins by converting alanine to citrulline
- Hence inflammation as proteins no longer recognised as self
- Inflammatory pannus aggregates in joints
12
Q
What are the systemic effects of RA?
A
- Pulmonary nodules and fibrosis
- Pericarditis and valvular inflammation
- Small vessel vasculitis
- Soft tissue nodules
- Skin inflammation
- Weight loss, anaemia
13
Q
What is disease?
A
Loss of (normal) homeostasis, and a combination of the causative agent and the body’s response to it
14
Q
What are broad categories of disease?
A
MEDIC HAT PINE
- Metabolic
- Endocrine
- Degenerative
- Inflammatory
- Congenital
- Haematological
- Autoimmune
- Trauma
- Psychological
- Idiopathic/Iatrogenic
- Neoplastic
- Environmental
15
Q
What are the broad causes of cell injury?
A
- Physical agents
- Chemicals/drugs
- Infections
- Hypoxia/ischaemia
- Immunological reactions
- Nutritional imbalance
- Genetic disease
16
Q
What is reversible cell injury?
A
- Changes due to stress in environment
- Return to normal once stimulus removed
17
Q
What is irreversible cell injury?
A
- Permanent
- Cell death, usually necrosis, follows
- Threshold between reversible and irreversible
18
Q
Give examples of reversible cell injury:
A
- “Cloudy swelling” is osmotic disturbance, loss of energy-dependent Na pump leads to Na influx and build up of intracellular metabolites
- Cytoplasmic blebs, disrupted microvilli and swollen mitochondria
- “Fatty change”: accumulation of lipid vacuoles in cytoplasm caused by disruption of fatty acid metabolism, especially in liver
19
Q
What are the broad mechanisms of cell injury?
A
Damage to:
- mitochondria: disrupted aerobic respiration/ATP synthesis
- cell membrane: disrupted ion concentrations, esp. increases Ca2+ ions
- cytoplasm including ribosomes: disrupted enzyme and structural protein synthesis and architecture
- nucleus: disrupted DNA maintenance and DNA damage
- oxidative stress: caused by reactive oxygen species, formed pathologically by absorption of radiation, toxic chemicals, hypoxia and damage made more likely by lack of antioxidants
20
Q
What is necrosis?
A
Unprogrammed cell death following injury due to external stimuli. Always pathological
21
Q
What are the histological changes upon cell necrosis
A
- Cell swelling, vacuolation, and disruption of membranes of cell and its organelles including mitochondria, lysosomes and ER
- Release of cell contents (cell lysis) including enzymes causes adjacent damage and acute inflammation
- DNA disruption and hydrolysis
22
Q
What are the types and main features of necrosis?
A
Coagulative:
- firm, tissue outline retained
- haemorrhagic: due to blockage of venous drainage
- gangrenous
Colliquitive:
- tissue becomes liquid and its structure is lost (e.g. infective abscess, cerebral infarct)
Caseous:
- combination of coagulative and colliquitive, appearing “cheese-like”: classical for granulomatous inflammation, especially TB
Fat:
- due to action of lipase on fatty tissue
23
Q
What are depositions?
A
Abnormal accumulations of substances, located either intra or extracellularly, or in CT
24
Q
Describe amyloid:
A
- Organisation of soluble protein fibrils into specific abnormal, insoluble aggregates
- Can be systemic or localised
- Occurs due to excessive production/accumulation of a normal protein, production/accumulation of an abnormal protein or tendency of protein to misfold
- Clinical effects depend on site of deposition (brain = dementia)
25
What are the two main types of normal protein that forms amyloid?
- AL amyloid
- immuonglobin light chain
- produced in B-cell neoplasms
- AA amyloid
- serum amyloid associated protein, produced in liver
- produced in prolonged chronic inflammation (RA)
26
Describe pathological calcification:
- Deposition of calcium salts
- May be:
- dystrophic (in abnormal tissue with normal serum Ca) or metastatic (deposition on normal tissue with raised serum Ca)
27
What causes pathological calcification?
- Increased levels of parathyroid hormone (PTH)
- primary: PT gland tumour
- secondary: kidney disease
- May be systemic effect with cancer (most common)
28
How does vascular dilatation occur?
- Histamine from mast cells, prostaglandins and NO released
- Arterioles dilate increasing blood flow in response
- Stasis of blood flow
- Fluid passes into tissue causing swelling
29
How does neutrophil activation occur?
- C5a, leukotriene B4, bacterial products accumulate
- Activation of neutrophils
- Rolling, adhesion, pass between endothelial cells
- Chemotaxis
- Phagocytosis and bactericidal
30
How does endothelial activation occur?
- 5-HT, histamine, C3a, C5a, bradykinin leukotriene involved
- Activates vascular endothelium
- Increased cell adhesion molecules
- Increased leakiness of endothelium
- Plasma proteins travel into tissues including immunoglobulins, complement and fibrinogen
31
Explain the signs of inflammation:
- Redness, caused by increased blood flow (hyperaemia)
- Swelling, caused by fluid exudate and hyperaemia
- Heat, caused by hyperaemia
- Pain, caused by release of bradykinin and PGE2
- Loss of function, caused by all of above
32
Describe various exudates:
- Neutrophilic exudate
- supportive/purulent
- Fibrinous exudate
- pink strands histologically, contains much fibrin
- Serous inflammation
- peritoneal or pleural
33
How may infection spread?
- Breach of natural barriers (through wound in skin)
- Air borne
- Blood borne
- Immune factors (IgA deficiency, loss of defence in airway, diabetes and chronic steroids can also predispose to infection)
34
What are the sequelae of acute inflammation?
- Abscess
- Resolution
- Healing by repair
- Chronic inflammation
35
When does chronic inflammation occur?
Results from persisting tissue damage and ongoing acute inflammation (or de novo in viral infection)
36
Describe chronic inflammation:
- Associated with chronic inflammatory cell infiltrate
| - Often leads to fibrosis or scarring
37
What is granulomatous inflammation?
- Presence of granulomas- collection of epitheloid macrophages and multinucleate giant cells
- Subtypes include necrotising, non-necrotising, foreign body granulomas
38
What are the stages of healing?
Types of wound/healing:
- primary intention (simple incision)
- secondary intention (dirty/infected wound)
Stages
- granulation tissue
- fibrous scar
(- bone heals by regeneration rather than repair, callus formation)
39
What does a post-mortem involve and demonstrate?
- Can reveal real cause of death when unclear or in criminal cases
- Involves external examination, internal examination (evisceration, organ dissection (macro and microscopic assessment), return of organs to body, death certificate writing and report prepared by pathologist
40
What disease are usually seen on post-mortem in Scotland?
From most to least common,
- Malignant neoplasm of bronchus and lung
- Acute MI
- Chronic ischaemic heart disease
- COPD
- Unspecified dementia
- Pneumonia
- Stroke
- Vascular dementia
- Alzheimer's disease
- Sequelae of CVS disease
41
What are the risk factors for DVT?
- Vessel wall
- increasing age, varicose veins, surgery
- Blood flow
- obesity, pregnancy, immobilisation, IV catheters, external vein compression
- Composition of blood
- thrombophilias (including family history), inflammatory conditions, oestrogen hormones
42
How is DVT treated?
- Prevent thrombus extending or embolising
- anticoagulation for 3-6 months
- Remove risk factors
- Pain relief
- Graduated elastic compression stockings
43
How is VTE (DVT) prevented?
- Avoid risk factors if possible
- Risk assess at hospital admission or surgery
- Provide thrombo-prophylaxis when appropriate
- anti-embolism stockings
- heparin (LMWH daily sub cut)
- education patients on risks and avoidance measures
44
What is virchow's triad?
3 categories of factors that contribute to thrombosis: hypercoaguable state, vascular wall injury and circulatory stasis
45
What is the difference between arterial and venous thrombosis?
Arterial: many platelets, with small amounts of fibrin (reflects high flow)
Venous: many fibrin with trapped red cells (reflects slow flow)
46
How is DVT investigated?
- Clinical score (Wells) indicates likelihood
- D-dimer test
- Wells <2 and d-dimer negative suggests very unlikely DVT
- Other results treated as DVT until confirmed with ultrasound or venography
47
How is MI or acute coronary syndrome diagnosed?
- Suggestive history
- Clinical evidence of cardiac dysfunction
- ECG findings
- Biochemical evidence of myocardial damage (ischaemia)
- elevated troponin
- Visualisation of coronary arteries
- cardiac catheterisation
48
How is acute coronary syndrome treated?
- Prevent thrombus extension
- anti-platelet agent (aspirin, clopidogrel)
- anticoagulant (heparin)
- Remove thrombus
- thrombolysis (alteplase, tenecteplase)
- remove clot via catheter (PCI)
- Widen stenotic plaque
- balloon angioplasty, insert coronary artery stent
- Prevent further thrombus
- anti-platelet agent, statin
49
What are the normal visible structures seen on CXR?
- Trachea
- Hilum
- Lungs
- Diaphragm
- Heart
- Aortic knuckle
- Ribs
- Scapulae
- Breasts
- Stomach
50
What are important invisible or obscured structures on CXR?
- Sternum
- Oesophagus
- Spine
- Fissures
- Pleura
- Aorta
51
What is PA projection?
Direction of beam is posterior to anterior, standard projection but not always possible
52
Describe AP projection:
- XR penetrate through the front of the patient onto the film
- Heart appears magnified as it is closer to film
- All CXR from ICU are AP as patients cannot stand
53
How can you gauge rotation on a CXR?
From the angle of the spinous processes
54
What is the silhouette sign?
Normal adjacent anatomical; structures of differing densities form a crisp silhouette or contour, loss of this at a specific location can help show position of disease
55
Where are important locations to look for silhouette sign?
- Trachea
- Hilum
- Lungs
- Diaphragm
- Heart
- Aortic knuckle
- Ribs
- Scapulae
- Breasts
- Stomach
- Apices and costophrenic angles
56
How are specimens handled in pathology labs?
- Removal of tissue, into formalin in surgery
- Transport to pathology
- Pathologist examine and trim tissue
- Tissue fixed in formalin
- Tissue processing
- Tissue embedded into wax
- Tissue blocks sectioned
- Tissue stained with H&E
- Tissue examined by pathologist and reported or additional testing requested
57
What steps are involved in tissue processing?
- Dehydration
- Clearing
- Wax impregnation
58
What additional tests might be requested after tissue is examined?
- Special stains
- Immunohistochemical testing
- Molecular prenanalytical techniques
- Molecular testing (NGS/FISH)
59
What is the timetable for tissue in pathology labs?
- Urgent < 1 week
| - Others < 4 weeks
60
What are special stains used to demonstrate?
- Mucin in epithelial cells for adenocarcinoma classification
- Normal elastic tissue in vessels
- Depositions e.g. fibrous tissue, amyloid, iron in hepatocytes
- Infections
61
What is immunohistochemistry (IHC)?
- Staining technique which yields brown staining of specific proteins
- Used in tumour diagnosis and classification
62
What is a developmental anomaly?
Structural congenital anomaly
63
What is a hamartoma?
- Malformation that may resemble a neoplasm that results from faulty growth in an organ
- Composed of a mixture of mature tissue elements which would normally be found at the site
64
Describe ventricular septal defect:
- Hole in ventricular septum causes left-to-right shunt of blood
- Aycanotic initially, but can develop pulmonary resistance leading to the reversal of the shunt and causing cyanosis (deoxygenated blood circulated around the body)
65
What is diverticular disease?
- Circumscribed pouch/sac caused by herniation of lining mucosa of an organ through defect in muscular coat
- Effects include inflammation, bleeding, perforation and fistulation
- Chronic inflammation causes fibrosis causing hypertrophy of smooth muscle and can lead to stenosis and colonic obstruction
66
What is intussusception?
Part of the intestine folds onto the next section
67
What is Meckel's diverticulum?
- Congenital
- Diverticulum at terminal ileum
- 2 inches long
- Contains all layers of the intestine and often has ectopic tissue within it (pancreatic/gastric)
- Complications include inflammation, bleeding (from ulcerated gastric tissue), perforation and obstruction/intussusception
68
Compare hypertrophy and hyperplasia:
Hypertrophy is increases in size of cells
- enlargement is due to an increased synthesis of structural proteins and organelles
- occurs when cells are incapable of dividing
- caused by increased functional demand or hormonal stimulation
Hyperplasia is increase in the number of cells
- adaptive response in cells capable of replication
- critical response of connective tissue cells in wound healing
- can be physiological (hormonal or compensatory when part of tissue is removed or diseased) or pathological (excessive signalling)
69
What is atrophy?
- Shrinkage in the size/numbers of the cell by the loss of cell substance
- Results from decreased protein synthesis and increased protein degradation
- Causes
- loss of innervation
- diminished blood supply
- inadequate nutrition
- decreased workload
- loss of endocrine stimulation
- ageing (senile atrophy)
70
What is metaplasia?
- Reversible change from one fully differentiated cell type into another
- Adaption so cells sensitive to a particular stress are replaced by other cells better able to withstand the adverse environment
71
What is a neoplasm?
- An abnormal tissue mass with excessive growth (not physiological) and uncoordinated compared to adjacent normal tissue
- Persists even after cessation of the stimuli that caused
72
What is the difference between neoplastic and non-neoplastic growths?
Neoplastic growths are uncontrolled and irreversible and non-neoplastic growths are controlled and reversible
73
Compare tumours and neoplasms:
- Tumour and neoplasm are not synonymous
- Tumour is a swelling or lump, but not all swelling are tumours (hamartomas) and not all neoplasms cause swelling (myelofibrosis, leukaemia, some lymphomas
74
What are the differences between benign and malignant neoplasms?
Benign
- a neoplasm that grows without invading adjacent tissue or spreading to distant sites
- usually well-circumscribed due to the lack of invasions of surrounding tissues
Malignant
- a neoplasm that invaded the surrounding normal tissue
- can spread to distant sites (metastasis)
- usually is not well circumscribed
- malignant tumour is cancer
75
How are specific tumours defined and classified?
- Benign tumours usually end with suffix -oma (with a few exceptions)
- Malignant tumours have to be one of the following:
- carcinoma; epithelial origin
- sacroma; mesenchymal origin
- melanoma; melanocytic origin
- lymphoma; haemopoietic origin
- germ cell tumours
- glial tumours
76
How are tumours graded and staged?
- Tumour grade refers to the differentiation of a malignancy: a high grade malignancy is a poorly differentiated cancer
- Tumour stage refers to how far a tumour has spread/how advanced it is
- each speciality has its own dataset to stage tumours
77
What is carcinoma in-situ (CIS)?
- Full-thickness epithelial dysplasia extending from the basement membrane to the surface of the epithelium
- Only epithelial neoplasms can be CIS
- If entire lesion is no more advanced than CIS then risk of metastasis is low as there are no blood vessels or lymphatics within the epithelium above the basement membrane
Phase 3
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