MOD L.Os Flashcards
(191 cards)
1
Q
Describe the mechanisms of hypoxia (reversible)
A
Low O2 supply, e.g caused by anaemia, hypoaxaemic, ischaemia
Reversible: reduced oxidative phosphorylation- reduced ATP
-reduced Na atp ase activity = low Na = oncosis
- reduced pH –> chromatin clumping
- ribosome detachment –> ¥ PROTEIN SYNTH –> fat and denatured proteins accumulate
- high Ca levels –> damage
2
Q
Describe irreversible ischaemia
A
So permeable (ER and SER) Leads to very high calcium levels –> damage
Activates enzymes
Phospholipases–> membrane
Proteases–> membrane and cytoskeleton proteins
ATPases–> ¥ATP further
Endonucleases–> damage DNA
3
Q
Describe ischaemia reperfusion injury
A
Blood returned suddenly to ischaemia tissue. (But not necrotic)
Causes rapid increase in O2 production,
More neutrophils –> inflammation
4
Q
Describe how cyanide is toxic
A
Binds to cytochrome oxidase in the ETC.
Blocks oxidative phosphorylation
5
Q
How can free radicals contribute to cell injury
A
Cause mutations and can damage tissue--> oxi stress OH* most dangerous O2* superoxide H2O2 H2O2 + O2* --> OH* can need iron Body defends against them using: - spontaneous decay - antioxidants : SOD/ catalases/ hydroxylases Scavengers: glutathione, ACE vitamins Storage proteins
6
Q
What are heat shock proteins
A
E.g ubiquitin
Triggered in cell injury and aim to fix misfolded proteins by unfolding them again
7
Q
Described the appearence of injured cells under light microscope
A
Cytoplasmic: blebbing, pale (swelling=reversible) darker pink (increased protein)
Nuclear: chromatin clumping (reversible) and pyknosis, karryohexis, karryolyis (irreversible)
Abnormal cellular accumulations
8
Q
Describe the appearence of injured cells under electron
A
Reversible: swelling and blebs, chromatin,ribosome separation
Irreversible: more swelling, nuclear changes, rupture of lysosomes/ ER, membrane defects,
9
Q
How would you look at cell injury? Is it alive or dead?
A
Asses death on functionality: it’s permeability
Soak up dye if dead
10
Q
Define oncosis
A
Cell death with swelling Karryolyis Spectrum of changes BEFORE DEATH Can lead to adjacent inflammation Enzymes digest causing leakage
11
Q
Define apoptosis
A
Death with shrinking,
Programmed
Needs ATP
Karryohexis (fragmentation)
Often occurs in single cells not big groups
Cellular contents intact so no adjacent inflammation
12
Q
Define and describe necrosis
A
Changes that occur after cell death in a living organism
Can lead to adjacent inflammation
Enzymes digest causing leakage
Coagulative: denaturation of proteins dominates over release of proteases = solid consistance and white appearance - ghost architecture –. acute inflammation
Liquefactive: more enzyme degradation –> digestion of tissuues. Seen where there is loads of neutrophils (e.g. absecesses as theey release proteases). Infections, soft tissues.
Caseous: amorphous debris. infections e.g. TB –> granulomatus
Fat: e.g. acute pancritis –> lipases. cause chalky deposits.
Gangrene (visible)
13
Q
Describe gangrene
A
Wet- liquefactive caused by fungi or bacteria
Dry- coagulative
Gas gangrene - wet anaerobic bacteria
14
Q
Describe infarcts
A
Area of tissue cut off from blood supply
Red: still some blood supply (dual blood supply) but not enough to prevent necrosis if the tissue, often in more loose organs e,g, lungs
White: all blood supply cut off, supplied by end arteries. Often more solid organs e.g. Heart, spleen, kidneys
Leads to
15
Q
What molecule are released by injured cells
A
Potassium–> can stop heart
Enzymes–> used as markers
Myoglobin–> from dead myocardium, released after severe trauma or strenuous excercise
16
Q
Briefly list abnormal cellular accumulations
A
Water and electrolytes
Lipids- tags can lead to alcoholic liver disease, cholesterol (xanthalasma) phospholipids (myelin figures)
Proteins- Mallorys hyaline in liver disease
Pigments: exogenous. Endogenous.e.g. Haemosideran, bilirubin
17
Q
Describe pathological calcification
A
Caused by abnormal Ca deposits (increased injured cells)
Dystrophic: in dying tissue
Metastatic: caused by metabolically increased ca - PTH, destruction of bone
18
Q
Describe cellular ageing
A
Telomere shortens with each replication,
19
Q
Describe effects of excessive alcohol on liver
A
Fatty: steatosis from ¥Fat metabolism–> reversible
Acute alcoholic hepatitis–> acute hepatocyte necrosis, jaundice
Chronic–> hard shrunken liver–> irreversible, fatal. Micronodules
20
Q
List the main causes of cell injury and death
A
Hypoxia: reversible, irreversible Physical agents e.g trauma, cold, radiation Chemical and drugs Micro organisms Immune mechanisms Dietary insufficiency/excess Genetic abnormalities- e,g in metabolism
21
Q
What are the major causes of acute inflammation?
A
Microbial infection Physical agents: Trauma Chemicals Tissue necrosis Acute phase hypersensitivity reaction (immune)
22
Q
Describe the appearance of acute inflammation
A
Rubor- redness Tumour- swelling Calor- heat Dolor- pain Loss of function
23
Q
Key features of acute inflammation
A
Neutrophils!
Innate, immediate early and stereotyped (not affected by repeat problems)
24
Q
Describe the tissue changes in acute inflammation
A
1) vascular changes: constrict then dilate to increase blood flow to the area and increase permeability of the blood vessels –> increase viscosity
2) exudation of fluid. Normally exudate (proteins). Leaky membrane, arterioles dilated (increase capillary pressure). Reduced fluid back in as osmotic pressures more equal due to efflux of proteins.
3) infiltration of cells: neutrophils, fibrin,
25
How do the changes occurring in acute inflammation effectively respond to the inflammation?.
Fibrin localised injury and prevents leakage to other tissues
Neutrophils phagocytose organisms and debris and kill them
Increased fluid brings defensive proteins with it,
Opsonins
Complement
Antibodies
Inflammatory mediators
Dilute toxins
Stimulate immune response
Maintain temperature
Pain and loss of function --> rest
26
what do neutrophils do and how?
Phagocytose and kill organisms and debris
Chemo taxis to place of injury
Activate
Infiltration: margination in stasis, then roll, adhere and emigrate through the endothelium.
Recognisation and attach to bacteria
Engulf
27
Hoe do neutrophils kill bacteria
O2 dependant bacteria by oxidative burst
| O2 independent using enzymes: pro teases, lysozymes, phospholipases
28
What do chemical mediators do in acute inflammation, list 4 types
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Modulate inflammatory response, all have inhibitors to prevent continuous response
Histamines
Bradykinin
Prostaglandin
Complement system:
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29
What local complications can occur in acute inflammation
Swelling, can press on other tubes and obstruct
Damage normal tissue - from released substances
Leakage of fluid from other cells because increased pressure- burns
Pain and loss of function
30
What systemic consequences of acute inflammation
Fever
Leucytosis: increase neutrophils (bacteria) lymphocytes (viral)
Acute phase response: reduced appetite, increased pulse,
Increased acute phase proteins 0: opsonin, antitrypsin, fibrinogen
Shock
31
What are the outcomes of acute inflammation
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Resolution
Progression:
Abscess
Chronic
Death
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32
Describe lobar pneumonia
Acute appendicitis
Bacterial meningitis
Ascending cholangitis and liver abscess
D
33
Give three examples of inherited disorders of acute inflammatory process
Hereditary angio-oedema
Alpha 1 antitrypsin deficiency
Chronic granulomatous disease
34
What cells are involved in chronic inflammation
MACROPHAGES- from monocytes. Phagocytosis, presenting to immune system, synthesis of proteins e.g. Cytokines, complement. Induce fibrosis:
Eosinophils: allergy, parasites, tumours
T and B (prod antibodies) lymphocytes
Fibroblasts / myofibroblasts-
35
What are giant cells and when are they seen
Giant multinucleated cells made from a fusion of macrophages seen in granulomatous inflammation (with chronic). Occur after frustrated phagocytosis. Surround the particles forming granuloma. Take up space int he tissue.
Foreign body type:
Langhans: TB
Touton giant cell: high lipid lesions
36
Describe the characteristics of chronic inflammation? How different from acute!
Chronic is not stereotyped, non specific and can lead to fibrosis. More varied microscopically.
Acute: lasts less long, stereotyped, neutrophils, normally reversible
37
When does chronic inflammation occur?
After acute: too much damage,
Alongside acute e,g, chronic colonitis, or ongoing bacterial infection
Chronic from start - TB, auto immune conditions, toxic agents
38
Describe the possible complications of chronic inflammation
Excess fibrosis-->Impaired function e.g. Chronic colecytis
Damage to tissues
Atrophy
Immune response can be inappropriately activated
39
Describe rheumatoid arthritis
Autoimmune disease causing localised chronic inflammation in synovial joints
Can lead to systemic immune responses causing amyloidosis in other tissues.
40
Describe ulcerative colitis
Inflammation in colon and rectum Mucosal ulceration and dilated lumen
No granulomas
No fissures/ fistulae
Significantly raised cancer risk Causes diahorrea, abdominal pain, and lots of b/o
41
Describe hereditary angio- oedema
Disorder of acute inflammation
Very rare autosomal dominant condition
Deficient in C1 esterase- part of the complement system
Attacks of cutaneous oedema in the dermis, sub cutaneous and mucosa and sub mucosa,
Also abdominal oedema
42
Describe alpha 1 antitrypsin deficiency
Interferes with acute inflammation
Autosomal recessive
Interferes with A1 antitrypsin which inactivated enzymes released from neutrophils --> unchecked --> damage to normal parenchymal tissue
43
Chronic granulomatous disease
Interferes with acute inflammation
Phagocytes can't produce superoxide radicals O2*
So can't destroy oxygen dependant bacteria using oxidative burst
--> chronic inflammation and ulcers and granulomatous
44
Describe regeneration
Replacement of dead or damaged cells (collage framework intact) by functional differentiated cells from stem cells
45
Describe how the ability to regenerate varies with cell, type. Give examples of each
Labile cells: constantly dividing e.g. Epithelial/haemopoeitic
Stable cells: can divide and enter the cell cycle when needed, normally in G0 e.g, hepatocytes, osteocytes, fibroblasts
Permanent: non dividing tissues, can't regenerate leg, neurones cardiac myocytes. --> scar tissue with space filled by other cells
46
What is the role of stem cells
They have the ability to differentiate into different tissues to replace lost or damaged cells if there is an intact connective tissue scaffold
They can be unipotent: can only form one type of cell e.g epithelia
Pluripotent: can differentiate into several types leg, haemopoeitic
(Or totipotent: can differentiate into any type of cell. E.g. Embryonic stem cells )
47
Describe the components involved in fibrous repair and when it occurs
Fibrous repair occurs if the cell can't regenerate, e.g. In permenant cells If collagen frame work is destroyed, there is persistent chronic inflammation or if there is necrosis of parenchymal tissue
It repairs by forming granulation tissue
1) cells: inflammatory, endothelial (angiogenesis) fibroblasts (collagen)
2) angiogenesis--> access for cells and oxygen and nutrients. Which tumours can exploit
3) extra cellular matrix: support and communication, collagen
48
Describe granulation tissue
A loose mesh work formed of capillary loops and myofibroblasts
49
Give an overview of fibrous repair
1) haematostasis: blood clot
2) inflammation: acute and chronic (Cells recruited by chemotaxis)
3) clot replaced by granulation tissue, and angiogenesis (cytokines) and ECM Production occurs (pro fibrotic cytokines from macrophages stimulate fibroblast proliferation)
3) maturation: more collagen and less vasculature, remodelling occurs, fibrous scar forms,
50
Describe collagen. The types of collagen,
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Fibulae collagen: Ty1-3
Ty1: hard and soft tissue, in bone, fibrosis, not cartilage
Ty2: articular & hyaline cartilage
Ty3: Walls or arteries and hard organs
Ty4: bases of cell basement membranes
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51
Give an overview of how collagen is synthesised
1) synthesis as pre pro collagen then to lumen of RER
2) to ER and signal Peptide cleaved
3) hydroxylation needing vitamin C
4) N linked glycosylation in ER
5) disulphide bonds --> pro collagen
6) o linked in Golgi (glucose)
7) released by exocytosi
8) N & C peptide removed in vesicles - tropoocollagen
9) polymerises forming fibrils to fibres
52
Describe some defects of collagen synthesis
Scurvy: low vitamin C,
Ehlers danlos syndrome
Osteogenesis imperfecta
Alport syndrome
53
How do growth factors control regeneration and repair
Local hormones
Promote proliferation of the stem cells
Can be autocrine (produced by the cell) paracrine (neighbour) endocrine (blood) hormones
54
Give some examples of growth factors
Epidermal growth factor: from keratinocytes, macrophages and inflammatory cells- stimulates proliferation of endothelial cells, hepatocytes and other stable cells
Vascular endothelial GF- stems angiogenesis
Platelet derived GF: from macrophages, tumours , smooth muscle, stored in platelet a granules, and causes migration and proliferation of fibroblasts, smooth muscle, and monocytes.
Tumour necrosis factor: causes fibriblast migration and proliferation- collagen synthesis.
55
Describe contact inhibition and its affect on regeneration
Loss of contact between the cell and basement membrane can cause regeneration.
Negative feedback: when cells in contact this inhibits proliferation of the tissue. If damaged and not continuous proliferation occurs,
Exploited in cancer
56
Describe the differences between primary and secondary intention healing
Primary: clean inscision, limited foreign material, minimal clot or granulation tissue, leads to small fibrous scar tissue. Can lead to abscesses if trapped infection.
Secondary: larger wounds, sides don't meet (unopposed), large clot requiring granulation tissue --> scab. Epidermis regenerates from the base up.
Takes much longer, produces more contraction, more necrotic tissue so larger inflammation
57
Describe the healing of bone
1) haematoma formation and granulation tissue forms
2) chondrocytes invade and soft fibrocartilage calus forms
3) bony calus formation: of cancellous bone
4) remodelling to compact bone over months or years
58
Describe factors that can influence healing and repair
Local
- foreign material
- support (bandage)
- Infection
- size, location and type of wound- movement and apposition
- radiation --> angiogenesis affected and reduced fibriblast activation
Systemic
- immunosuppressed
- general health- chronic diseases? CVS status?
- age,
- drugs, e,g, steroids
- dietary deficiencies e.g protein, vit c, essential amino acids,
59
Describe possible complications of fibrous repair
Insufficient fibrosis: hernia, ulceration, due to obesity, malnutrition, elderly steroids
Excessive fibrosis: e.g. Keloid, (overproduction of collage that invades healthy surrounding tissue) , cirrhosis, lung fibrosis, and hypertrophic scarring (raised but doesn't exceed borders)
Excessive contracture: obstruction of tubes and channels e.g. Oesophageal
60
Describe repair in cardiac muscle
Cardiac myocytes can't regenerate so fibrosis occurs
| Can compromise cardiac function as leads to reduced contractility.
61
Describe and discuss healing and repair in liver, peripheral nerves, cartilages and CNS
Liver: can regenerate a bit as stable cells, but chronic damage --> cirrhosis as the architecture cant regenerate --> nodules
Peripheral nerves: undergo wallerian regeneration: degeneration of a nerve fibre that occurs after separation from the cell body. Distal fragment degenerates and proximal stump swells, and sprouts, (1-3 mm day)
CNS: No regenerative capacity, glial cells fill in
Cartilage: doesn't heal well, no blood, nerve or Lymph supply
Skeletal muscle: limited, has satellite cells
Smooth: scar tissue (vascular- limited)
62
Define haemostasis and the four key things it depends on
The body's response to stop bleeding and loss of blood
- blood vessels
- platelets
- coagulation system
- fibrinolytic
63
Describe the process of haemostasis
1) vasoconstriction (vasoconstrictors e.g. Endothelin)
2) platelet activation- primary haemostasis: plug, and aggregate- use VWF and adp
3) coagulation (secondary) more stable permenant plug, - clotting cascade stimulated by tissue factors released from activated endothelium. Thrombin coverts fibrinogen to fibrin (need to regulate)
64
Describe the regulation of the coagulation system
Intact endothelium near injury activated releasing anticoagulant factors restricting growth of clot
Positive feedback of thrombin on factors V VIII and XI
Thrombin inhibitors: anti thrombin 3, alpha 1 antitrypsin (balances enzymes released from neutrophils) protein C / S: vitamin K dependant, slow cascade,
Hereditary deficiencies of these lead to thrombophillia and thrombosis.
65
Describe fibrinolysis
Break down of fibrin by plasmin,
Catalysed by plasminogen activator t-Pa.
E,g, streptokinase, activates plasminogen - clot busters
Drastic treatment
66
Define thrombosis
The production of a solid mass from the constituents of blood within the circulation- not the same as normal clotting
67
Describe the mechanisms for thrombosis occurring
Change in blood flow, stagnation, turbulence
Change in blood components: smokers, pregnancy, post op
Change in vessel walls: atherosclerosis, injury, inflammation
68
Describe the differences in appearance of venous and arterial thrombi
Arterial: pale,granular, lines of Zahn (separate areas of high rbc and read with more fibrin) lower cell content
Venous: deep red, soft, gelatinous, higher cell content
69
Describe the outcomes of thrombi
Arterial: ischaemia, infarction --> mi, blockage if vessels, stroke
Venous: congestion, oedema, ischaemia if tissue pressure increases higher than arterial and impedes arterial supply
70
What are the possible outcomes of thrombosis
Dissolution/lysis by fibrinolytic system, blood flow re established.
Recanalisation: incomplete restoration of blood flow
Embolism: breaks off and travels elsewhere
Organisation: no recovery if flow, fibroblasts and capillaries try to remair but remains blocked.
Propagation: enlarges and spreads progressively (dis tally in arteries pros in veins)
71
Describe embolism
Blockage of a blood vessel caused by a solid, liquid or gas at a site distant from its origin.
Most are thrombi emboli
72
Describe thrombi emboli, their formation and the effect on Blood supply
From breaking off a thrombosis
The emboli travel along the blood supply until they reach a vessel that's narrower than its diameter and this caused a blockage. Can occur in different types of vessel
E.g. Systemic veins --> pulmonary embolism
From the heart --> other organs e.g, kidneys, spleen, or to left side of heart
Carotid arteries --> brain and stroke :L
Atheromas abdominal arteries --> legs and feet
73
Describe the effects of pulmonary emboli
Massive PE - from over 60% reduction in blood flow--> fatal
Major: major vessels blocked --> shortness of breath, pulmonary infarct (blood stained sputum)
Minor: small peripheral arteries blocked --> minor shortness of breath,
Recurrent PE --> pulmonary hypertension
74
Describe how DVT occurs, and it's risk factors
Occurs when there is a reduction in flow of the blood- stasis, or increased coagulability leading to increased clotting.- hyper coagulability
Risk factors: bed rest, surgery, pregnancy, oral contraceptives, severe burns, cardiac failure, dehydration, infection
75
How would you treat thromboembolic diseases
Risk reduction- offer prophylaxis to most at risk, leg compression boots
Drugs: IV heparin (anticoagulant, cofactor for anti thrombin 3, withdrawn as warfarin kicks in, use initially)
Oral warfarin: interferes with vitamin k dependant clotting factors - slows cascade
76
List the other types of emboli
Fat - fracture, oily drugs into arteries not veins
Air- injection, open wound large veins
Medical (Iatrogenic embolism)
Cerebral embolism- atrial fibrillation --> stasis --> thrombus
Nitrogen - bends.
Tumour cells
Amniotic fluid
77
Describe haemophilia and its effect on coagulation
A or B
X linked recessive, (boys) due to nonsense point mutation
deficiency in clotting factors: A (VIII) or B (IX)
Varies in severity, can cause haemorrhage in joints
muscle bleeding can lead to pressure on nerves
Haemorrhage into urinary tract, soft tissue bleeding,
Treat: factor replacement therapy (home treatment)
78
Disseminated intravascular coagulation (DIC)
Pathological activation of coagulation mechanisms leading to small clots
This uses up clotting factors so that when an injury occurs there is increased clotting time. Normally presents with increased bruising, spontaneous bleeding, e,g, from IV access, trauma,
Triggered by infection, trauma, liver disease, obstetric complications. Not genetic
79
Describe thrombocytopenia
Platelet count well below reference range (150-400x109/L)
Due to:
- failure of platelet production
-Increased destruction (e.g. immune thrombocytopenia)
-Sequestering of platelets e.g, DIC
- often occurs with anaemia, or bone marrow problem e.g. Leukaemia. Can be inherited or acquired
80
Describe thrombophillia
Acquired or inherited
Deficiency in Factor V, prothrombin and antithrombin --> increased risk of venous thromboemboli (VTE).
Acquired causes include: antithrombin deficiencies, cancer, inflammatory conditions, haemolytic anaemias
81
How would you test for coagulation
Full blood count
Plasma: enzyme assays, antibodies, glucose, fat, chemical,
Blood cells: RBC (size number) Hb, WBC, platelets
Coagulation tests: prothrombin time, activated partial thromboplastin time, platelet aggregation test, bone marrow test, FDPs(fibrin degradation products)
82
Treatments for coagulation
Warfarin- vit k factors inhibited
Dabigatron: used in Atrial fibrillation (non valvular) prevents thrombin working, acts in 2-4 hours
Has more risks associated
83
What substances would you measure in the blood to test for an MI
Troponin C
| Creatine kinase
84
What is Trosseau syndrome? Why does it occur?
Repeated episodes of vessel inflammation due to a clot, recurrent and occur in different locations over time- due to early cancer
85
How does chronic excessive alcohol lead to fatty change/steatosis?
Accumulation of triglycerides --> yellow liver
caused by alcohol affecting fat metabolism
Mild steatosis is reversible if stop drinking,
Advanced- increased size, greasy, and first stage of alcoholic liver disease.
86
How does acute alcoholic hepatitis develop?
binge of alcohol can result in acute hepatitis leading to focal hepatocyte necrosis.
Mallory bodies (damaged proteins in hepatocytes, accumulated keratin), neutrophils infiltrate
fever jaundice and liver tenderness - reversible (usually)
87
How does cirrhosis of the liver develop?
in 10-15% alcoholics
hard shrunken liver, with micronodules of regenerating hepatocytes surrounded y bands of collages.
irreversible, serious and can be fatal
88
Describe intrinsic and extrinsic apoptosis and the molecules triggering the response
various triggers for intrinsic apoptosis: increased mitochondrial permeability --> cytochrome c released --> apoptosome --> activates caspases.
extrinsic apoptosis: activated by external ligands e.g TRAIL binding to death receptors -->caspase activation
Important apoptotic molecules:
p53: mediates apoptosis in response to DNA damage
Cytochrome c, APAF 1, caspase 1: form an apoptosome
Bcl2: prevent Cyto c = inhibits apoptosis
Death ligands e.g. TRAIL and their receptors
Caspases- effector molecules
89
Describe what happens in paracetamol overdose
Saturates phase 2 conjugatin pathway ( with glucorinide or sulphate)
Goes through phase 1 pathway --> NAPQI --> 2dary pathway where conjugated with glutathione (ROS)
90
Describe Hepatitis
Causes: viral (A,B,E), drug induced liver injury, autoimmune
Efect: injury to hepatocytes with cell death. Can lead to chronic inflammation, liver disease or resolution
91
Describe acute pancreatitis
This is acute inflammation of the pancreas, releasing exocrine enzymes that cause autodigestion of the organ. There may be involvement of local tissues and distant organs. Often caused by gall stones or alcohol abuse leading to periductal necrosis
92
describe acute appendicitis
Acute inflammation of the appendix
Cause: usually obstruction (parasites, hard faeces, crohns disease???) leading to blockage. Then invasion of glut flora leading to infection and acute inflammation. If this then ruptures it can lead to invasion and spread of infected and faetal matter peritoneal cavity: life threatening septicaemia
Mucosal ulceration also occur, blood vessels blocked by inflammatory infiltrate --> ischaemia.
93
Describe bacterial menigitis
Infection of the cerebral spinal fluid. By bacterial or viral infections e.g. streptococci oneumoniae, neisseria medingditidis.. loads. and different in different age groups.
Complications; pressure on brain and brain stem. --> balance, cerebral palsy, seizure, hearing, vison, coma, absecc
94
Describe ascending cholangitis and liver absecess
Ascending cholangitis is an acute inflammation of the gall bladder, often occuring if the bile duct is partially obstructed by gall stones. Leads to infection, inflammation and necrosis. Can also be caused by parasitic infections, tumours, chemicals...
Present with jaundice, fever, tender liver,
Complications arise if sepsis occurs, or rupture into cavities
Liver abscesses can occur due to parasitic infection, they can reach the liver due to ascending cholangitis, directly, or from portal vein....
95
Describe lobar pneumonia. What type of inflammation?
Acute inflammation of the lobe of the lung.
Congestion: serous exudate
Red hepatisation:capilalries congested with oedema, so alveoli thicken --> red and hardened
Alveoli filled with exuadate: neutrophils and macrophages
Resolution: drains
can lead to pneunomia, abscesses (any acute), pleuritis, f
96
Describe Crohns diesease.
Chronic inflammation of the lining of the digestive system – unknown aetiology.
Most common in small bowel, but can be anywhere in digestive.
Features: Skip lesions, Transmural inflammation with granulomas, Thickened and fissured bowl leads to intestinal obstruction (narrowed lumen)
and fistulation (hole between 2 epithelium lined organs)
97
Briefly describe the differences between Crohns and ulcerative colitis
Crohns, can occur anywhere in the digestive system, has granulomas, skip lesions, patchy discontinuous distribution,
Ulcerative colitis: Inflmmation mostly in colon and recutum, limited to mucosa and submucosa, distorted architecture, ulcers, no fistulae, no granulomas,
Inflammatory diseases of bowel can lead to: bone disorders (recuced vit D) eye inflammation, rashes hepatitis...
98
Describe chronic cholecytis
Chronic inflammation of the cystic duct, Normally due to gall stones
99
What is an ulcer
A full thickness lockk of mucosa, an erosion would only remove the superficial layer --> heals more quickly
100
Describe chronic gastritis
Helicobacter pylori infection. Or autoimmune gastritis Gram negative bacteria binds to the gastric surface epithelium Ulceration occurs due to imbalance of acid production and mucosal defence
101
TB
TB is a chronic inflammation caused by Mycobacteroum Tuberculosis. – affects lungs.
Tuberculous granuloma
Most cases: immune systems kills or inactivates the TB bacteria.
102
Describe cirrhosis due to chronic inflammation
A number of chronic liver diseases can lead to cirrhosis,
| e.g. alcohol, Hep B&C, Non alcoholic fatty liver disease, non-alcoholic steatohepatitis (NASH)
103
Describe scurvy
Vitamin C required for hydroxylation of procollagen.
Causes reduced healing capabilities and a tendancy to bleed.
Bleeding into joints and gums
104
Descrube Ehlers- Danlos syndrome
Heritable disorder of connective tissue
Collagen fibres lack adequate tensile strength.
Skin is hypertensive, fragile, susceptible to injury.
Joints hypermobile --> dislocate
Wound healing poor.
Collagen in internal organs: rupture of colon and large arteries.
Corneal rupture and retinal detachment
105
Osteogenesis imperfecta
Autosomal dominant disease resulting in T1 collagen deformity/deficiency. Bowed ling bones, repeated fractures, blue sclera
106
Alport syndrome
Type 4 collagen abnormal, leads to dysfuction of glomerular basement membrane, cochlea of the ear and lens of the eye.
107
Define atherioscleosis
The disease caused by the thickening and hardening of vessel walls, due to atheroma
108
Define atheroma
The accumulation of lipids in the intima and media of large and medium sized arteries. Due to intracellular or extracellular lipids
109
Define arteriosclerosis
The thickening of the walls in arteries and arterioles usually as a result of hypertension or diabetes mellitus
110
Describe the cellular events leading to the formation of atheriosclerotic leisons
1) Chronic Endothelial injury: increased permeability
2) cytokines and growth factors released causes: Accumulation of Lipoproteins (oxidised LDL and cholesterol) in vessel wall. Leucyte adhesion, thrombosis, and platelet adhesion
3) Monocyte adhesion --> intima --> macrophages
4) Macrophages and smooth muscles engulf lipids --> foam cells
5) Smooth muscle cell proliferation and ECM production
111
Describe the macroscopic appearance of artheriosclerosis
Fatty streak: lipid deposits in intima, yellow
Simple plaque: raised yellow white, irregular outline, widely distributed
Complicated plaque: thrombosis in the plaque, calcification, aneurysm formation
112
Microscopic appearence of plaque and how it changes in later stages
Early: smooth muscle cell proliferation, foam cells, EC Lipid
Late: fibrosis, necrosis, cholesterol clefts, deposits in the tissue not just plaque.
Disrupts elastic lamina leading to ingrowth of blood vessels --> plaque fissuring
113
List the common sites for atherosclerosis
abdominal aorta
coronary arteries
carotid arteries
cerebral and leg arteries
114
Describe the effects of severe atherioscerosis in coronary arteries
Coronary arteries --> Ischaemic heart diesease --> mI, death, angina, arrythmias
115
Describe the effects of severe atherioscerosis in abdominal arteries
Abdominal aorta --> abdominal aortic aneurysm, aherola builds up causing the walls of the aorta to stretch and balloon --> rupture. Emboli --> other arteries
116
Describe the effects of severe atherioscerosis in cerebral arteries
Partial infarction --> transient ischaemic attack
| Ischaemia of brain tissue --> stroke,
117
Describe the effects of severe atherioscerosis in peripheral arteries
e.g. femoral
Can lead to peripheral vascular disease = intermittant claudication to Ischaemic rest pain. Often felt in glutes
Cna lead to Leriche syndrome (LL ischamia), Gangrene, skin ulceration, or critical limb ischamia
118
Describe the effects of severe atherioscerosis in mesenteric arteries
Ischamic colitis
malabsorbtion
aneurism
119
Describe recommended hypotheisi for mechanisms of angiogenesis
Response to injury hypotheisis: recommended
| Endothelial injury - Permeability - Platelets (PDGF released), macrophages , lipoproteins, t lymphocytes etc invade
120
Describe other mechanisms of angiogeneisis.
Encrustation: platelets and thrombi first
Monoclonat: smooth muscle proliferation
Lipid oxidation hypothesis: lipoproteins accumulate in intima in hyperlipiaemia --> LDL cholesterol crystals -->foam cells--> GF released
121
What are the main cells involved in angiogenesis
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Macrophages (monocytes)
platelets
lymphocytes -TNF --> lipoprotein metabolism
Endothlial cells
Smooth muscle cells
Neutrophils
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122
Risk factors of coronary heart disease
non mod: Age, gender ( women ok pre meno) Genetics-Famillial hyperlipidaemia (and corneal arcus and xanthalasma), apolipoprotein E metabolism/receptors
Modifyable:
Lifestyle: High LDL cholesterol diet, smoking, low exercise, alcohol,
Conditions: Diabetes (doubles risk), hypertension (damage), infection e.g. H. pylori
Other: geographical, ethinicity (asians), oral contraceptives, stress, obesity
123
How do you prevent atherioscelosis and treat it when it has developed
Lifestyle mods: smoking, fat intake, alcohol, excercise: diet low in saturated fat, high in fiber, and low in refined carbohydrates.
Drugs: Antihypertensives, aspirin, lipid lowering drugs ( statin, bile acid sequestrants, )
manage diabetes
124
Describe how cells can communicate with each other
throgh chemical signals to inhibit or stimulate cell proliferatin
Autocrine: produedd by cell
Intracrine: intracellular receptor produced
Paracrine: Signal to adjacent cell
Endocrine: Travels in blood stream to target cell
chemical signals include GF, hormones, cell to stroma contact
125
Give 4 examples of growth factors
EGF: Epidermal growth factor produced by a number of cells incl inflammatory cells to stimulate epithelial cells, hepatocytes and fibroblasts. specific receptor.
Vascular Endothelial Growth factor (VEGF) released from platelets in blood clotting to stimulate angiogenesis and vasculogenesis
PDGF: released from platelets, stimulates proliferation of fibroblasts, smooth muscle and monocytes
Granulocute colony stimulaing factor (G-CSF) from bone marrow to produce neutrophils (granulocytes) - in chemotherapy.
126
Descrube the cell cycle
there is 4 stages of the cell cycle: G1 (growth) S1(DNA replication ) G2 (Cell prepares to divide) M (cell division)
the cell cycle is mediated at every step: number of check points. espec: G1-S, R point
R point: Cyclins need to be activaated by cyclin dependant kinases to phosphorylate RB protein --> progression. (inhibitors of CDKs)
Increase growth by shortening cell cycle and inducing stable cells --> cell cycle
127
List the different types of stem cells
Labile, stable, permenant
128
Define regen, Which tissues can regenerate?
Replacement of cell losses by identical cells to maintain size of tissue or organ
Usually as good as original cells but takes time to reach maturity- can be beneficieal e.g in influenza virus.
Constant: epithelia, haemopoietic stem cells
Some regen: PNS cells, vascular smooth muscle, Hepatocytes, kidney, osteoblasts. Have to acivate proto-oncogenes to enter G1
No regen: cartilage, cardiac myocytes, CNS cells, skeleal muscle
129
Define hyperplasia, which tissues can undergo hyperplasia?
Increase in tissue or organ size due to increased cell numbers.
liable/stable cell pops
caused by increased functional demand/hormonal stimulation.
or pathological: secondary hyperplasia e.g.goitre, psoriasis
Can lead to neoplasia (increased cell divisions --> mutations)
Can occur with hypertrophy
130
define hypertrophy and give examples of tissues
Increase in tissue or organ size due to increased cell sizw
Permenant cells
Cause: increased deman/hormonal stimulation e.g. bodybuilding, pregnancy, atheletes heart
Increase in cellular componants aswell (can manage workload)
Pathological cause: ventricular cardiac (hypertension, valvular diease) --> capilalries dont increase though so cant meet demand --> apoxia --> fibrosis --> failure
Smooth muscle hypertrophy ( above an intestinal stenosis)
Compensatory hypertrophy
Obesity
131
Describe when cell adaptation occurs
When the cell can adapt to problems that are not severe enough to cause injury. Adaptation is the phase between normal unstressed cell to overstressed injured cell.
132
define Reconstitution and give an example
Replacement of a lost part of the body- not the same as regeneration. Requires the coordinated regeneration of several types of cell. E.g. In animals - lizards can regrow tails
In humans: limited- new blood vessels? v young children regrowing tips of fingers?
133
What are the main outcomes of cell signalling
Divide (enter cell cycle)
Differentiate (take on specialised form and function)
Survive (resist apopotosis)
Die (apoptosis)
134
Define Aplasia and give an example
Aplasia: the complete failure of a specfic tissue or organ to develop - embryonic development disorder. e.g. thymic aplasia --> infections and autoimmune disorders or aplasia of a kidney
can also describe organs that have ceased to proliferate: aplasia of bone marrow (aplastic anaemia)
135
What is the difference between an Angiogram and a atreriogram, and when would you use them
Angiogram: used to asses coronary arteries
Arteriogram: peripheral arteries
Used to view the vessels, e.g. can spot peripheral vascular disease, atheromas, emoboli etc
136
Define Involution and give an example
Normal PROGRAMMED shirnkage of organ e.g uterus after childbirth
137
Define Hypoplasia and give an example
The congenital UNDERDEVELOPMENT t of an organ or tissue. Not enough CELLs- compare with atrophy not hyperplasia as congenital
e.g. breast hypoplasia, testicular (Klinefelters syndrome)
138
Define Atresia and give an example
Congenital, Failure of perforating an opening, e.g. anus or vagina
139
Define Dysplasia and give an example
Abnormal maturation of cells within a tissue, cells have disordered tissue organisation - reversibe but can lead to neoplasia
140
Define neoplasia
abnormal growth of cells which persists after initiating stimullus has been removed
Neolasms are monoclonal- from a common nacestral cell
141
What is the difference between benign and malignant neoplasms
Benign: rounded mass that remains at site of origin
Malignant: Invades and spreads to distant sites via metastasis. Irregular mass due to infiltrative growth edges
142
Define tumour
Any clinically detectable lump or swelling - a neoplasm is a type of tumour
143
Define cancer
Any malignant neoplasm
144
Define Metastasis
Malignant neoplasm that has spread from its primary site to a new non contagious site
145
Define anaplasia
Cells with no resemblence to any tissue. So poorly differentiated.
Have increased nuclear:cytoplasm ration, mitotic figues and more variation in size and shape (pleomorphism)
146
Define Pleomorphism
Variation in size and shape of cell, cytoplasm ratio,mitotic figures?
147
Define progression
the process a neoplasm emerges from a monoclonal population: Initiation, promotors (proliferation) build up series of mutations --> neoplasm
148
Compare macroscopic features of benign and malignant neoplasms
Benign: Confined to side of orign, dont metastasise, smooher pushing rounded edges, can ulcerate
malignant: can spread from primary site, irregular outer margin. Areas of necrosis or ulceration if on a surface
149
Compare microscopic features of neoplasms
Benign: Cells well differentiated (low grade)- specialised
Minimal pleomorphism. Low mitotic count
Malignant: Well to poorly differentiated, mitotic figures, more pleomorphism variation - high cytoplasm:nucleus ratio, nucleius to one side
150
Compare the biological behaviour of neoplasms
Benign: local, retain specialisation so tissuu function may not be as affected
Malignant: spread
151
Distinguish between in-situ and invasive malignancy
In situ: neoplasm doesnt invade throgh the basement embrane
152
What type of genes are involved in Neoplasia?
Accumulation of mutations in somatic cells leading to a change in DNA - can't be lethal as passed on to daughter cells
Proto oncogenes can be activated permenantly --> Oncogene --> Neoplasm
Tumour supressor genes permenantly inactivated --> Neoplasm
153
List the key differences in neoplastic cells from normal cells (6) the 6 hallmarks of cancer
Self sufficient growth signals: HER 2 gene amplification
Resistance to antigrowth signals
Grow indefinatly: Telemores don't shorten (activate Telomerase) - immortal
Induce angiogeneisis
Resistance to apoptosis
Invade and produce metastases (malignant)
others...
154
How do you name a neoplasm?
1) benign -oma. Malignant -carcinoma (epithelial - 90%). - sarcoma if stromal (connective tissue)
2) tissue or origin: epithelial, connective, lyphois/haemopoietic, germ cell
- cyst (fluid filled spaces surrounded by epithelium) or papilloma (finger like projections)?
155
Describe the process that leads to successful metasisatis
1) Grow and develop at the primary site
2) Enter a transport system and lodge at secondary site
3) Invade and grow at secondary site to form a new tumour.
Evade destruction by immune cells at all stages- very inefficient process
156
Describe how metastasis invade surrounding tissue
3 alterations needed:
- altered adhesion: reduced E cadherin expression to cells arent as well attached to each other
- Altered stromal attachement: change in Integrin expression (G proteins)
- Altered proteolysis: Degrade stroma using proteases - matrix metalloproteinases (MMPs)
- Altered motility: form a cancer niche with nearby non neoplastic cells= GF and proteases
157
How are malignant cells transported to the secondary ste
- Blood - via capillaries and venules
- Lymph
- Transcoelomic spread - via fluid in body cavities (pleura, peritoneal, pericardial and brain)
158
What type of cells form the cancer niche?
Inflammatory cells, smooth muscle cells, fibroblasts, endothelial cells
159
How do malignant cells form a metasasis at a secondary site?
Colonisation. - greatest barrier to sucessful formation because the cells often fail to grow into tumours
160
how do relapses of cancer occur
Surviving microscopic deposits that have failed to grow can remain- micrometasases.
Can lead to tumour dormancy --> relapse years after if they start to grow again.
161
What determines the site of a metasatsis
Depends on:
Regional drainage, e.g. lympph nodes, next capilalry bed, adjacent organ
But can be unpredictable --> seed and soil, due to interactions between the malignant cells and niche at 2 site
162
How do carcinomas typically spread?
Via lymphatics first then blood stream to more distant sites
163
How to sarcomas spread?
Via blood stream
164
What are the common sites for blood bourne metasatsis?
Lung, liver, bone, brain,
165
Where do neoplasms from bone normally come from?
Breast, prostate, kidney, thyroid, bronchus,
166
Describe the local effects of neoplasms, compare benigna and malignant
- direct invasion and destruction of normal tissue
- ulceration at surface --> bleeding
-compression of adjacent structures
- blocking tubes and orifices
Benign and malignant
167
Describe the systemic effects of neoplasms (paraneoplastic syndromes)
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Parasitic effect with increased tumour burden: cachexia (appetite and weight loss), malaise, immunosupression, thrombosis
Haemotological:
Endocrine
Derm
Neuro
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168
Describe the haematological effects of neoplasms
anaemia, reduced WBC and platelets (invasion into bone marrow and/or treatments)
thrombosis
169
Describe the endocrine effects of neoplasms
Excessive secretion of hormones
Ectopic secretion e.g. Bronchial small cell carcinoma (ACTH of ADH)
Bronchial squamous --> PTHrp
Benign (and malignant tumours)
170
Describe the neurological effects of neoplasms
Neoplasms can affect the brain leading to neuropathies inc. balance, sensory problems, and myopathies -affects PNS
171
Describe the dermatological effects of neoplasms
Can cause skin problems such as pruritus (jaundice ...), clubbing, pigmentation, myositis,
172
How are neoplasms caused (generally)
Multifactorial:
intrinsic host factors e.g. genes, age, hormones
and extrinsic environmental e.g. chemicals, radiation and infections
173
Carcinogenic chemicals, give an example and explain what the risk of cancer depends on
e. g. 2-Napthylamine, an Industrial carcinogen used in the dye manufacturing industry, led to bladder carcinoma. Showed that there can be a long delay between exposure and cancer, that risk increases with exposure (total carcinogen dosage) and that they can be organ specific.
e. g. Aflatoxin (mouldy peanuts), Asbestos - mesothelioma
174
Describe the mechanism of action of carcinogenesis from chemicals
They normally require initiators: mutagenic agent
Promotor: prolonged proliferation
Leads to monoclonal expansion of the mutant cells.
Progression --> fully malignant
Ames test discovered this
175
What types of chemical carcinogens are there
Pro-carcinogens: need to be converted to carcingoens by Cytochrome P450 enzymes in the liver
Complete carcinogens: have an initatior and promotor e.g. ciggarette smoke
176
Descrube the mechanism of mutagenic radiation- examples
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UV: doesnt penetrate the skin,
Ionising radiation: alpha, beta, gamma
Radon, background radiation
Damage directly (break DNA bases, or cause single or double stranded DNA breaks)
or via free radicals
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177
Describe some infections that are mutagenic
Directly: affect genes controlling cell growth e.g. HPV expresses a gene which inhibits p53&pRb proteins which are cell proliferation inhibitors.
Indirectly: Cause chronic tissue injury- regeneration acts as a promotor e.g. Hep B&C,
bacteria and parasites (helicobacter pylori)--> inflammation --> increased risk of carcinomas.
HIV- increase risk
or causes new mutations from DNA replication errors,
178
Describe the inheritance of neoplasia
Occurs though 2 hit hypotheisis. e.g. Retinoblastoma
Inherited - first hit through the germ line and affects all the cells in the body
Second hit; somatic mutation
Sporadic retinoblastoma: needs two somatic mutations in the same cell.
179
Describe the role of tumour supressor genes and give two examples
Inhibit neoplastic growth. Both alleles need to be inactivates (2 hit hypothesis)
180
Describe the role of oncogenes
Genes that enhance neoplastic growth - normally activated versions on proto-oncogenes. Only one allele needs to be acivated
181
Describe the role of caretaker genes
Maintain genetic instability. Type of tumour supressor gene
| Without effective caretaker genes there can be an accellerated mutation rate
182
Describe the roles of
RAS
c-myc
c-erbB-2 (HER 2)
Oncogenes
RAS: G protein involves in the restriction point in the cell cycle. Mutant = always active so lets everything through
(RB gene- restrains cell proliferation by preventing passage through)
proto oncogenes can encode growth factor e.g.
MYC: transcription factor
HER2: growth factor receptor
BCL2: apoptosis
THey permenantly activate these
183
Describe the roles of TS genes
TS alleles code for proteins in the same pathways as oncogenes but they inhibit them
e.g. TP53 - important in cell proliferation . inhbited by HPV
184
Descrube the inheritance of Xeroderma Pigmentosum (XP)
Due to mutations in DNA repair genes - genes affecting DNA nucleotide excision repair (NER)
Autosomal recessive
Very sensitive to UV damage --> skin cancer
185
Describe how Hereditry Non-polyposis colon cancer develops (HNPCC)
Autosomal dominant, associated with colon carcinoma
| Affects DNA mismatch repair gene
186
What genes are affected in famillial breast carcinoma.
| What other tumours associate with it?
BRCA 1&2, repair double stranded DNA breaks
187
Describe the developement of carcinomas using colon carcinoma as an example.
Undergoes a transition: ademoma-carcinoma sequence
Adenoma to late adenoma to primary carcinoma to metastatic carcinoma
Mutations build up (7ish) over decades
PROGRESSION
INITIATION PROMOTION PROGRESSION
188
Describe progression
The monoclonal population of mutant cells picks up more proto oncogenes and TS genes including ones that cause genetic instability
Eventually produces a set of mutations --> 6 hallmarks
189
List the most common types of cancer
| Which have the most deaths?
Most common: Lung, Breast, prostate, bowel. In children leukaemia
Worst survival: pancreatic, lung, oesophageal
Best survival: testicular, melanoma, breast
190
How do we predict outcomes of neoplasms
age, general health, tumour: site, size, origin, GRADE (differentiation) STAGE and effective treatment availability
191
Describe staging of tumours
measure of tumours overall burden: TNM = worldwide
T1-4 (size)
N (0-3) regional node metasasis
M 0,1: distant metastatic spread?
