MoD Flashcards
(369 cards)
1
Q
What are the 4 types of hypoxia?
A
- Hypoxaemic (arterial content of O2 is low)
- Anaemic (decreased ability of haemoglobin to carry O2)
- Ischaemic (intrusion to blood supply)
- Histiocytic (inability to utilise O2, disabled phosphorylation enzymes)
2
Q
What are the 4 principle targets for cell injury?
A
- Cell membranes
- Nucleus
- Proteins
- Mitochondria
3
Q
Summarise hypoxic cell injury
A
Cell deprived of O2; mitochondrial ATP production stops.
ATP- driven membrane ionic pumps run down, Na+ and H2O seep into cell, causing it to swell, plasma membrane is stretched.
Glycolysis enables cell to limp on for a while, cell initiates heat-shock (stress) response, won’t be able to cope if hypoxia continues.
pH of cell drops due to lactic acid accumulation
Ca2+ enters cell…
ER and other organelles swell
Enzymes leak out of lysosomes, enzymes attack cytoplasmic components
All cell membranes damaged and start to show blebbing
Cell dies (possibly killed by burst of bleb)
4
Q
Once Ca2+ enters a cell damaged by hypoxia, what 4 things does it activate?
A
- Phospholipases - causing cell membranes to lose phospholipid
- Proteases - damaging cytoskeletal structures and attacking membrane proteins
- ATPase - causing more loss of ATP
- Endonucleases - causing the nuclear chromatin to clump
5
Q
What are the 7 causes of cell injury?
A
- Hypoxia
- Physical agents
- Chemical agents
- Micro-organisms
- Immune mechanisms
- Dietary insufficiency
- Genetic abnormalities
6
Q
What 3 things may ischemia reperfusion injury be due to?
A
- Increased production of O2 free radicals
- Increased number of neutrophils following reinstatement of blood supply resulting in more inflammation and increased tissue injury
- Delivery of complement proteins and activation of the complement pathway
7
Q
When free radicals attack lipids in cell membranes, what do they cause?
A
Lipid peroxidation
8
Q
Name the 3 free radicals of particular biological significance
A
Hydroxyl (OH*)
Superoxide (O2-)
Hydrogen Peroxide (H2O2)
9
Q
What’s the name of the reactions that produce hydroxyl (OH*) radicals?
A
Fenton and Haber-Weiss
10
Q
What are the vitamins which help reduce biological free radical levels?
A
ACE
11
Q
What reaction does superoxide dismutase (SOD) catalyse?
A
O2- —-> H2O2
Catalyses complete the process of free radical removal
12
Q
Give an example of a heat shock protein
A
Ubiquitin
13
Q
What do heat shock proteins do?
A
Their synthesis is increased when cell is under stress. Concerned with protein repair - important when the folding step goes astray. Recognise incorrectly folded proteins and repair or destroy them.
14
Q
What are the 3 main alterations that can be seen under the microscope with cell injury?
A
- Cytoplasmic changes - reduced pink staining of cytoplasm due to accumulation of water. Followed by increased pink staining due to detachment of ribosomes and accumulation of denatured proteins
- Nuclear changes - chromatin is subtly clumped. Followed by various levels of pyknosis, karryohexis, and karryolysis of nucleus.
- Abnormal intracellular accumulations
15
Q
List irreversible electron microscopy changes
A
Nuclear changes (pyknosis, karyolysis, karyorrhexis),swelling and rupture of lysosomes, membrane defects, appearance of myelin figures (damaged membranes), lysis of ER due to membrane defects, amorphous densities in swollen mitochondria
16
Q
Define oncosis
A
Oncosis: cell death with swellings the spectrum of changes that occur in injured cells prior to death
17
Q
Define necrosis
A
Necrosis: in a living organism the morphological changes that occur after a cell had been dead for some time (e.g. 4-24hrs).
An appearance, not a process, describes morphological changes.
18
Q
Define apoptosis
A
Apoptosis: cell death with shrinkage, induced by a regulated intracellular programme where a cell activates enzymes that degrade its own nuclear DNA and proteins
19
Q
What are the 4 types of necrosis?
A
Coagulative
Liquifactive
Caseous
Fat necrosis
20
Q
Describe coagulative necrosis
A
Denaturation of proteins dominates, dead tissue has solid consistency and appears white to the naked eye. Histologically cellular architecture is somewhat preserved, creating ‘ghost outline’ of cells (first few days only).
21
Q
Describe Liquifactive necrosis
A
Enzyme degradation dominates, leading to enzymatic digestion of tissues. Seen in massive neutrophil infiltration (neutrophils release proteases), so often bacterial infections and brain as is fragile tissue
22
Q
Describe caseous necrosis
A
Caseous = cheese (latin), to naked eye has cheesy appearance. Structuresless debris (no ghost outlines). Associated with infections e.g. TB and form of inflammation 'granulomatous'
23
Q
Describe fat necrosis
A
Occurs when there is destruction of adipose tissue, typically as a consequence of acute pancreatitis as release of lipases. Causes release of free fatty acids, which can react with Ca to form chalky deposits in fatty tissue, these can be seen on X-ray, and to naked eye in surgery/autopsy. Can also occur as a result of direct trauma especially to breast tissue.
24
Q
Describe gangrene
A
Not a type of necrosis! Clinical term for necrosis visible to the naked eye. Classified into dry (exposed to air, coagulative necrosis) or wet (infected with bacteria, liquifactive). Gas gangrene is wet gangrene where tissue is infected with anaerobic bacteria which produce visible bubbles of gas in the tissue.
25
Describe infarction
Refers to the cause of necrosis, namely ischaemia. An area of tissue death caused by obstruction of the tissues blood supply is an infarct. Can lead to gangrene. Mostly due to thrombosis or embolism. Necrosis resulting can be coagulative or liquifactive.
26
Describe the 2 types of infarct
White (anaemic) - occurs in solid organs, after occlusion of an 'end' artery. White due to lack of blood in tissue.
Red (haemorrhagic) - occurs where there is extensive haemorrhage into dead tissue, e.g. In tissues with duel blood supply, if numerous anastomoses are present, loose tissue, previous congestion, raised Venus pressure. Secondary arterial supply insufficient to rescue tissue but does allow blood to enter dead tissue
27
What do the consequences of an infarct depend on?
Whether tissue effected has an alternative blood supply
How quickly ischaemia occurred (if slowly time for development of additional perfusion pathways?)
How vulnerable tissue is to hypoxia
O2 content of blood (more serious if anaemic patient)
28
List the principal molecules released by injured, dying and dead cells
Potassium - Ecell high conc. High concs reaching heart can cause MI. Can cause massive necrosis elsewhere
Enzymes - can indicate organ involved and extent
Myoglobin - released from myocardium/striated muscle, in large conc causes rhadbomyolysis. Can block renal tubules causing renal failure
29
Does apoptosis involve lysosomal enzymes
No
30
Does apoptosis require energy?
Yes
31
Describe the microscopic features of apoptosis
Chromatin condenses, pyknosis, karyorrhexis. Cytoplasmic budding (not blebbing as in oncosis!), progresses to fragmentation into membrane bound apoptotic bodies (containing cytoplasm, organelles and nuclear fragments), eventually removed by macrophage phagocytosis. No leakage of cell contents, so inflammation not induced
32
Name the key stages of apoptosis
Initiation
Execution
Degradation/phagocytosis
33
What are caspases?
Proteases that mediate the cellular effects of apoptosis. Act by cleaving proteins breaking up the cytoskeleton and initiating the degradation of DNA
34
Name the 2 key mechanisms for triggering apoptosis
Intrinsic and extrinsic
35
What is p53?
The 'guardian of the genome' - mediates apoptosis in response to DNA damage
36
What are cytochrome c, APAF1 and caspase 9 together?
Together they are the apotosome
37
Give an example of a death ligand
TRAIL
38
Give an example of a death receptor
TRAIL-R
39
Name the 5 main groups of intracellular accumulations
1. Water and electrolytes
2. Lipids
3. Proteins
4. 'Pigments'
5. Carbohydrates
40
What is lipofuscin
'Age pigment'. Brown pigment seen in aging cells, sign of previous free radical injury. Yellow-brown grains in cytoplasm
41
What is haemosiderin?
Iron storage molecule. Forms when systemic (deposited everywhere, haemosiderosis, seen in conditions such as haemolytic anaemia of hereditary haemochromatosis)or local excess of iron.
42
Name the two types of pathological calcification
Dystrophic and metastatic
43
Describe dystrophic calcification
Occurs in dying tissue. No abnormality of Ca2+ metabolism, local changes to tissue favours nucleation of hydroxyapatite crystals. Can cause organ disfunction.
44
Describe metastatic calcification
Disturbance is body-wide. Hydroxyapatite crystals deposited in normal tissue throughout body. Hypercalcaemia secondary to disturbances in Ca2+ metabolism (e.g. Increased secretion of PTH, destruction of bone tissue)
45
Why can germ/stem cells replicate indefinitely?
Contain an enzyme called telomerase which maintains the original length of telomeres
46
Name 3 major effects of excessive alcohol on the liver
Fatty change
Acute alcoholic hepatitis
Cirrhosis
47
What is the main reparative mechanism in the CNS?
Gliosos
48
List some causes of acute inflammation
```
Microbial infections
Hypersensitivity reactions
Physical agents
Chemicals
Tissue necrosis
```
49
List the 4 main clinical signs of acute inflammation
1. Rubor - redness
2. Tumor - swelling
3. Calor - heat
4. Dolor - pain
Resulting loss of function
50
What are the 3 steps of acute inflammation?
1. Changes in blood flow
2. Exudate on of fluid into tissues
3. Infiltration of inflammatory cells
51
What are the changes in blood flow which occur during acute inflammation?
1. Initial brief vasoconstriction of arterioles
2. Vasodilation of arterioles then capillaries (increased blood flow, heat and redness)
3. Increased permeability of blood vessels (exudate on of protein rich fluid to tissues, slowing of circulation. Swelling)
4. Increased viscosity of blood (increased conc. of RBC. = stasis)
52
Which cells release histamine? In response to what stimuli?
Mast cells, basophils and platelets
| In response to physical damage, immunologic reactions, factors from neutrophils and platelets
53
What does histamine cause?
Vascular dilation
Transient increase in vascular permeability
Pain
54
Define oedema
Increased fluid in tissue spaces. Leads to increased lymphatic drainage
55
Describe the 2 forms of oedema
Transudate (same amount of protein as blood, present due to hydrostatic pressure imbalance)
Exudate (more protein than blood, type present in inflammation).
56
Describe the 5 mechanisms of vascular leakage
1. Endothelial contraction (>gaps) - histamine, leukotrienes
2. Cytoskeletal reorganisation (>gaps) - cytokines IL-1 and TNF
3. Direct injury - toxic burns, chemicals
4. Leukocyte (WBC) Dependent Injury - toxic O2 species and enzymes from leukocytes
5. Increased transcytosis - channels across endothelial cytoplasm - VEGF
57
Give a synonym of 'neutrophil'
Polymorph
58
Describe the 4 stages of neutrophil infiltration
1. Marination - stasis causes neutrophils to line up at the edge of blood vessels, along the endothelium
2. Rolling - neutrophils roll along endothelium, sticking intermittently
3. Adhesion - neutrophils stick more avidly
4. Emigration - neutrophils emigrate through blood vessel wall, infiltrate tissues
59
What is 'diapedesis'
The digestion of the basement membrane by an infiltrating neutrophil
60
Define chemotaxis
Movement along concentration gradients of chemoattractants
61
Name some opsonins that aide phagocytosis by neutrophils
Fc (fixed component present in all antibodies)
| C3b (form of complement)
62
What are the 2 major killing mechanisms of neutrophils?
O2 dependent - produces superoxide a and H2O2.
O2 independent - lysozyme and hydrolases, bacterial permeability increasing protein (BPI), cationic proteins
63
Name 2 chemical mediators that increase blood flow
Histamine
| Prostaglandins
64
Name 2 chemical mediators that increase vascular permeability
Histamine
| Leukotrienes
65
Name 3 chemical mediators which aide neutrophil chemotaxis
C5a
LTB4
Bacterial Peptides
66
Name a chemical mediator which aides phagocytosis by neutrophils
C3b
67
How does exudation of fluid help combat injury?
Delivers plasma proteins to site of injury (e.t. immunoglobulins, inflammatory mediators, fibrinogen)
Dilutes toxins
Increases lymphatic drainage
68
How does infiltration of cells help combat injury?
Removes pathogenic organisms and necrotic debris
69
Give 4 local complications of acute inflammation
1. Swelling - could block tubes
2. Exudate - serositis, compression
3. Loss of fluid e.g. Burn
4. Pain and loss of function
70
Name 3 systemic effects of acute inflammation
Fever
Leukocytosis
Acute phase response
71
Give 4 possible things which could occur after acute inflammation
1. Complete resolution
2. Continued acute inflammation with chronic inflammation - abscess
3. Chronic inflammation with fibrous repair, tissue regeneration
4. Death
72
What is chronic inflammation?
Chronic (>12wk) response to injury with associated fibrosis
73
List 3 ways chronic inflammation may arise
1. Takes over from acute inflammation
2. Arises de novo e.g. Chronic infection (TB), autoimmune (RA), chronic low level irritation (eg silica)
3. Develop alongside acute inflammation e.g. On going bacterial infection.
74
List 5 cell types present in chronic inflammation
1. Macrophages
2. Lymphocytes (T&B)
3. Eosinophils
4. Plasma cells
5. Fibroblasts/myofibroblasts
75
Name and describe 3 types of giant cell (formed by fusion of macrophages)
1. Langhans (TB) - peripheral nuclei
2. Foreign body type - random nuclei. Engulf foreign body if it's small enough, otherwise sticks to edge of body.
3. Touton (fat necrosis) - nuclei in ring towards centre. Form leisions where there is a high lipid content e.g. Fat necrosis, xanthomas.
76
List 4 consequences of chronic inflammation
1. Fibrosis
2. Impaired function
3. Atrophy
4. Stimulation of immune response
77
What is a granuloma?
A cohesive group of macrophages and other inflammatory cells
78
Under what circumstances do granulomas arise?
Persistent, low-grade antigenic stimulation or Hypersensitivity.
E.g.
Mildly irritant foreign material
Infections (some fungi, mycobacteria e.g. TB, leprosy)
Unknown causes, sarcoid, Crohn's disease
79
Name 2 types of TB
```
Miliary TB (many bugs)
Single organ TB (few bugs)
```
80
Which type of giant cell has peripheral nuclei?
Langhans
81
Which type of giant cell has randomly arranged nuclei?
Foreign body giant cells
82
Which type of giant cell has nuclei arranged in a ring towards the centre of the cell?
Touton
83
Define regeneration
The replacement of dead or damaged cells by functional, differentiated cells. Normal structure is restored.
84
Define repair
Response to injury involving both regeneration and fibrosis (scar formation). Normal structure is permanently altered.
85
Name and describe the 3 groups tissues of the body are divided into on the basis of their proliferative activity.
1. Liable tissues (continuously dividing) - proliferate throughout life replacing cells that are destroyed e.g. Surface epithelia
2. Stable tissues (quiescent tissues) - normally have a low level of replication but can undergo rapid division in response to stimuli and can reconstruct tissue of origin. E.g. Parenchymal cells of liver/kidney.
3. Permanent tissues (non-dividing tissue) - contain cells that have left the cell cycle and can't undergo mitotic division in postnatal life. E.g. Neurones, cardiac muscle cells.
86
Define unipotent
Can only produce one type of differentiated cell e.g. Epithelia
87
Define multipotent
Can produce several types of differentiated cell e.g. Haematopoietic
88
Define totipotent
Can produce any type of cell i.e. embryonic stem cells
89
Describe what an autocrine signal is
Cell responds to signal made by itself
90
Describe what a paracrine signal is
Cell produces signal which acts on nearby cells
91
Describe what an endocrine signal is
Endocrine organ produces signal which acts on cells far away
92
List the main components of fibrous repair
Cell migration
Blood vessels - angiogenesis
Extracellular matrix production & remodelling
93
What does VEGF stand for and what does it do?
Vascular Endothelial Growth Factor
| Proangiogenic factor, initiates angiogenesis
94
Describe the 5 major stages of angiogenesis
1. Endothelial proteolysis of basement membrane
2. Migration of endothelial cell via chemotaxis
3. Endothelial proliferation
4. Endothelial maturation and tubular remodelling
5. Recruitment of periendothelial cells.
95
Describe the 5 main stages of fibrous repair
1. Phagocytosis of necrotic tissue debris
2. Proliferation of endothelial cells which results in small capillaries that grow into the area (angiogenesis)
3. Proliferation of fibroblasts and myofibroblasts that synthesise collagen and cause wound contraction (repair tissue at this stage is granulation tissue)
4. Granulation tissue becomes less vascular and matures into a fibrous scar
5. Scar matures and shrinks due to contraction of fibrils within myofibroblasts
96
List 5 functions of the extracellular matrix in wound repair
1. Supports and anchors cells
2. Separates tissue compartments
3. Sequesters growth factors
4. Allows communication between cells
5. Facilitates cell migration
97
What types of collagen are fibrillar?
1-3
| E.g. Dermis, bone
98
What types of collagen are amorphous?
4-6
| E.g. Basement membrane
99
Describe the mechanism of fibrous repair
1. Inflammatory cells infiltrate (blood clot forms, acute/chronic infection)
2. Clot replaced by granulation tissue (angiogenesis, myo/fibroblasts migrate and differentiate, producing extracellular matrix)
3. Maturation (relatively long lasting, collagen increases, cell pop. falls, myofibroblasts contract, vessels differentiate and are reduced, left with fibrous scar)
100
How are inflammatory cells recruited?
Chemotaxis
101
When are angiogenic cytokines produced?
In response to hypoxia
102
Describe healing by primary intention
Occurs in clean wounds with opposed edges. BM minimally obscured/minimal damage to BM. Minimal contraction &a scarring.
Risk of trapping infection (abscess) by epidermis regenerating over wound
103
Describe healing by secondary intention
Large wound, ulcer, infarct, abscess. Unapposed wound edges. Considerable contraction required to close wound edges (initially by blood clot, then myofibroblasts. Epidermis regenerates from the base up.
Much more granulation tissue produced than in primary intention, so takes much longer to heal.
104
List 6 local factors that might influence wound healing
1. Type/size/location of wound
2. Apposition (lack of movement)
3. Blood supply (arterial/venous)
4. Infection (suppuration, gangrene, systemic)
5. Foreign material
6. Radiation damage
105
List 6 general factors which might influence wound healing
1. Age
2. Drugs (e.g. Steroids) and hormones
3. General dietary deficiencies (e.g. Protein)
4. Specific dietary deficiencies (Vit. C, essential amino acids)
5. General state of health (chronic diseases?)
6. General cardiovascular status
106
What is wound dehiscence?
Separation of wound edges e.g. Abdominal insicion
107
List 5 possible complications of fibrous repair
1. Formation of fibrous adhesions
2. Loss of function due to replacement of specialised functional parenchymal cells by non-functional collagenous scar tissue
3. Disruption of complex tissue relationships within an organ i.e. Distortion of architecture interfering with normal function
4. Overproduction of fibrous scar tissue e.g. Keloid scar.
5. Excessive scar contraction causing obstruction of tubes, disfiguring scars following burns or joint contracture a (fixed flextures)
108
What 4 factors does successful haemostasis depend upon?
1. Vessel wall (constricts to limit blood loss)
2. Platelets (adhere to damaged wall/each other)
3. Coagulation system
4. Fibrinolytic system (prevents too much haemostasis occurring)
109
Name the 'important' stages of the coagulation cascade
Prothrombin ---> Thrombin
|
|
Fibrinogen ---> Fibrin
110
Give 3 fundamental predisposing factors to thrombosis. What are these known as?
1. Abnormalities of blood flow (stagnation, turbulence)
2. Abnormalities of blood vessel wall (atheroma, direct injury, inflammation)
3. Abnormalities of the constituents of the blood (smokers, post-partum, post-op)
Known as Virchow's triad.
111
Tight regulation of thrombin is required (1ml of blood can generate enough thrombin to convert all the fibrinogen in the body to fibrin!). How is this achieved?
Balance of procoagulant and anticoagulant forces.
E.g. Thrombin inhibitors:
Anti-thrombin III
Protein C and S
112
What is fibrinolysis?
The breakdown of fibrin
113
What do plasminogen activators do?
Convert plasminogen into its active form, plasmin, which is then used in fibrinolysis.
114
Define thrombosis
The formation of a solid mass of blood within the circulatory system DURING LIFE
115
Describe the appearance of an arterial thrombi
Pale
Granular
Lines of Zahn
Lower cell content
116
Describe the appearance of venous thrombi
Soft
Gelatinous
Deep red
Higher cell content
117
What are the 5 possible outcomes of thrombosis?
Lysis (complete dissolution of thrombus, fibrinolytic systems activate, bloodflow re-established. Most likely when thrombi are small)
Propagation (progressive spread of thrombosis, in direction of blood flow)
Organisation (reparative process, ingrowth of fibroblasts and capillaries, lumen remains obstructed)
Recanalisation (bloodflow re-established but usually incompletely, one or more channels formed through organising thrombus)
Embolism (part of thrombus breaks off, travels through bloodstream, lodges at distant site)
118
What are the effects of arterial thrombosis?
Ischaemia
Infarction
Depends on site and collateral circulation
119
What are the effects of venous thrombosis?
Congestion
Oedema
Ischaemia
Infarction (rare, consequence of built up tissue pressure)
120
Define embolism
The blockage of a blood vessel by solid, liquid or gas, at a site distant from its origin.
121
What % of emboli are thrombo-emboli?
>90%
122
Name 6 possible types of embolism
```
Thrombo
Air
Amniotic fluid
Nitrogen ('benz')
Medical equipment
Tumour cells
```
123
List predisposing factors for deep vein thrombosis
```
Immobility
Post-operative
Pregnancy and post-partum
Oral contraceptives
Severe burns
Cardiac failure
Disseminated cancer
```
124
How can deep vein thrombosis be treated?
Intravenous heparin
| Oral warfarin
125
Define atheroma
The accumulation of intracellular and extracellular lipid in the intima and media of large and medium sized arteries
126
Define atherosclerosis
The thickening and hardening of arterial walls as a consequence of atheroma
127
Define arteriosclerosis
The thickening of the walls of arteries and arterioles usually as a result of hypertension or diabetes mellitus
128
Describe the macroscopic features of atheroma
Fatty streak - yellow, slightly raised, lipid deposits in intima
Simple plaque - raised yellow/white, irregular outline, widely distributed, enlarge and coalesce
Complicated plaque - thrombosis, haemorrhage into plaque, calcification, aneurysm formation
129
List common sites for atheroma
```
Aorta (especially abdominal)
Coronary arteries
Carotid arteries
Cerebral arteries
Leg arteries
```
130
Describe the microscopic early changes of atheroma
Proliferation of smooth muscle cells
Accumulation of foam cells
Extracellular lipid
131
Describe the later microscopic changes of atheroma
```
Fibrosis
Necrosis
Cholesterol clefts
Inflammatory cells
Disruption of internal elastic lamina
Damage extends into media
Ingrowth of blood vessels
Plaque fissuring
```
132
What is intermittent claudication? (With reference to peripheral vascular disease)
Pain in legs due to reduced blood supply. Pain goes away on resting.
133
List risk factors for atheroma
```
Age
Gender (women protected before menopause)
Hyperlipidaemia
Hypertension (endothelial damage)
Infection
Obesity
Lack of exercise
Oral contraceptives
Genetics/family history
Alcohol
Diabetes mellitus
Smoking
```
134
What (6) cells are involved in atheroma formation?
```
Endothelial cells
Platelets
Smooth muscle cells
Macrophages
Lymphocytes
Neutrophils
```
135
What role do endothelial cells have in atheroma formation?
Key role in haemostasis
Altered permeability to lipoproteins
Production of collagen
Stimulation of proliferation and migration of smooth muscle cells
136
What role do platelets have in the formation of atheroma?
Key role in haemostasis
| Stimulate proliferation and migration of smooth muscle cells
137
What role do smooth muscle cells have in the formation of atheroma?
Take up LDL and other lipid to become foam cells
| Synthesise collagen and proteoglycans
138
What role do macrophages have in the formation of atheroma?
Oxidise LDL
Take up lipid to become foam cells
Secrete proteases which modify matrix
Stimulate proliferation and migration of smooth muscle cells
139
What role do lymphocytes have in the formation of atheroma?
TNF may affect lipoprotein metabolism
| Stimulate proliferation and migration of smooth muscle cells
140
What role do neutrophils have in the formation of atheroma?
Secrete proteases leading to continued local damage and inflammation
141
Describe the unifying theory of atheroma formation
Endothelial damage occurs
Endothelial damage causes platelet adhesion, smooth muscle cell (SMC) proliferation and migration. Insudation of lipid, LDL oxidation, so uptake of lipid by SMC and macrophages
Stimulated SMC produce matrix material
Foam cells secrete cytokines causing further SMC stimulation and recruitment of other inflammatory cells
142
What may cause endothelial damage?
Raised LDL
Toxins, e.g. Cigarette smoke
Hypertension
Haemodynamic stress
143
What do the size of cell populations depend upon?
Rate or cell proliferation, cell differentiation and cell death by apoptosis
144
What regulates normal cell proliferation?
Proto-oncogenes
145
Give the possible outcomes of signalling biochemistry (4 points)
Divide (enter the cell cycle)
Differentiate (take on a specialised form and function)
Survive (resist apoptosis)
Die (undergo apoptosis)
146
List the 3 ways cell to cell signalling can be via
1. Hormones
2. Local mediators
3. Direct cell-cell or cell-stroma contact
147
Signalling molecules binding to receptors results in what?
Modulation of gene expression
148
List functions of a cell that growth factors can affect
```
Cell proliferation and inhibition
Locomotion
Contractility
Differentiation
Viability
Angiogenesis
Activation
```
149
How does an increase in cell growth occur once cells are instructed to divide?
Shortening cell cycle
| Conversion of quiescent cells to proliferating cells, making them enter the cell cycle too
150
What is the most critical 'checkpoint' in the cell cycle?
The restriction point, towards the end of G1
151
What are labile cell populations?
Stem cells that divide persistently to replenish losses
152
What are stable cell populations?
Stem cells, normally quiescent or proliferate very slowly, but proliferate persistently when required
153
What are permanent cell populations?
Stem cells present, but cannot mount an effective proliferative response to significant cell loss.
154
Name the 5 important types of cell adaptation
1. Regeneration - cells multiply to replace loses
2. Hyperplasia - cells increase in number above normal
3. Hypertrophy - cells increase in size
4. Atrophy - cells become smaller
5. Metaplasia - cells are replaced by cells of a different type
155
Are regenerated cells as good as the original cells?
Usually, but not always, and not immediately
156
What is aplasia?
Complete failure of a specific tissue or organ to develop, embryological developmental disorder. Term also used to describe an organ whose cells have ceased to proliferate.
157
What is hypoplasia?
Congenital underdevelopment/incomplete development of a tissue or organ at the embryological stage. Inadequate number of cells within tissue present.
158
What is involution?
Normal programmed shrinkage of an organ (overlaps with atrophy) e.g. Uterus after childbirth
159
What is atresia?
'No orifice', congenital inperforation of an opening
160
What is dysplasia?
Abnormal maturation of cells within a tissue. Potentially reversible, although often pre-cancerous
161
Define neoplasm
An abnormal growth of cells that persists after the initial stimulus is removed
162
Define malignant neoplasms
'An abnormal growth of cells that persists after the initial stimulus is removed' AND invades surrounding tissue with potential to spread to distant sites.
163
What is a tumour?
Any clinically detectable lump or swelling
| A neoplasm is just one type of tumour
164
What is cancer?
Any malignant neoplasm
165
What is a metastasis?
A malignant neoplasm that has spread from its original site to a new non-contiguous site.
Original location = Primary site
New location = Secondary site
166
What is dysplasia?
A pre-neoplastic alteration in which cells show disordered tissue organisation. Not a neoplastic change as is reversible
167
What is a benign neoplasm?
Remains confined to its site of origin, does not produce metastases
168
What is a malignant neoplasm?
Has the potential to metastasise
169
Describe the appearance of a benign neoplasm, to naked eye and microscopically
Eye: Confined to local area, so have pushing outer margin.
Microscopically: Cells closely resemble the parent tissue (still well differentiated)
170
Describe the appearance of a malignant tumour, to the naked eye and microscopically
Eye: Have an irregular outer margin and shape. May show areas of necrosis and ulceration (if on a surface).
Microscopically: range from well to poorly differentiated.
171
What are cells that show no resemblance to any tissue called?
Anaplastic
172
Describe what one would see in worsening cell differentiation
Increasing nuclear size
Increasing nuclear to cytoplasmic ratio
Increased nucleus staining (hyperchromasia)
More mitotic figures
Increased variation in size and shape of cells and nuclei (pleomorphism)
173
Define neoplasm
An abnormal growth of cells that persists after the initial stimulus is removed
174
Define malignant neoplasms
'An abnormal growth of cells that persists after the initial stimulus is removed' AND invades surrounding tissue with potential to spread to distant sites.
175
What is a tumour?
Any clinically detectable lump or swelling
| A neoplasm is just one type of tumour
176
What is cancer?
Any malignant neoplasm
177
What is a metastasis?
A malignant neoplasm that has spread from its original site to a new non-contiguous site.
Original location = Primary site
New location = Secondary site
178
What is dysplasia?
A pre-neoplastic alteration in which cells show disordered tissue organisation. Not a neoplastic change as is reversible
179
What is a benign neoplasm?
Remains confined to its site of origin, does not produce metastases
180
What is a malignant neoplasm?
Has the potential to metastasise
181
Describe the appearance of a benign neoplasm, to naked eye and microscopically
Eye: Confined to local area, so have pushing outer margin.
Microscopically: Cells closely resemble the parent tissue (still well differentiated)
182
Describe the appearance of a malignant tumour, to the naked eye and microscopically
Eye: Have an irregular outer margin and shape. May show areas of necrosis and ulceration (if on a surface).
Microscopically: range from well to poorly differentiated.
183
What are cells that show no resemblance to any tissue called?
Anaplastic
184
Describe what one would see in worsening cell differentiation
Increasing nuclear size
Increasing nuclear to cytoplasmic ratio
Increased nucleus staining (hyperchromasia)
More mitotic figures
Increased variation in size and shape of cells and nuclei (pleomorphism)
185
How does neoplasia arise?
Caused by accumulated mutations in somatic cells. Mutations are caused by initiators (mutagenic agents), and promoters (which cause cell proliferation).
186
What is progression?
The process through which a neoplasm emerges via a monoclonal population. Characterised by the accumulation of yet more mutations
187
What does monoclonal mean?
Body of cells all originates from a single cell
188
What is the bronchial circulation and what does it do?
Part of the systemic circulation, meets the metabolic requirements of the lungs
189
What is the average pressure in the pulmonary artery? In mmHg
15-30
___________
4-12
190
What is the average pressure in the right ventricle? In mmHg
15-30
__________
0-8
191
What is the average pressure in the aorta? In mmHg
100-140
______________
60-90
192
What is the average pressure in the left ventricle? In mmHg
100-140
_____________
1-10
193
What is the average pressure in the left atrium? In mmHg
1-10
194
What is the average pressure in the right atrium? In mmHg
0-8
195
What are the features and function of the pulmonary circulation?
Supplies blood to alveoli for gas exchange. Works with low pressure (prevents rupture of thin alveolar linings) and low resistance (many parallel capillaries, relatively little smooth muscle in arterioles, short wide vessels)
196
What is the V/Q ratio?
Ventilation/perfusion ratio
197
What is the optimum value for the V/Q ratio? Maintaining this means what?
0.8
| Maintaining this means diverting blood from alveoli which are not well ventilated
198
Describe hypoxic pulmonary vasoconstriction
Alveolar hypoxia results in vasoconstriction of pulmonary vessels. Ensures perfusion matches ventilation, poorly ventilated alveoli are less well perfused. Most important mechanism regulating pulmonary vascular tone, helps to optimise gas exchange
199
When might chronic hypoxic vasoconstriction occur, and what can it cause?
Can occur at altitude or as a consequence of lung disease. Can cause right ventricular failure (chronic increase in vascular resistance leads to chronic pulmonary hypertension, leads to high after load on right ventricle..)
200
Describe the effects of exercises on pulmonary circulation
Increases cardiac output
Small increase in pulmonary arterial pressure
Opens apical capillaries
Increased O2 uptake by lungs
As bloodflow increases, capillary transit time is reduced (from ~1s at rest to ~0.3s without compromising gas exchange)
201
What minimises the formation of lumping lymph (pulmonary oedema) normally?
Low capillary pressure (9-12mmHg normally)
202
What is mitral valve stenosis, and what might it cause?
Abnormal narrowing of the mitral valve
| Can lead to pulmonary oedema
203
What can you do to relieve symptoms of pulmonary oedema?
Use diuretics to relieve symptoms. Treat underlying cause if possible
204
What % of cardiac output does the brain demand?
15%
205
How is the cerebral circulation demand for O2 met?
High capillary density
High basal flow rate (x10 for rest of body)
High O2 extraction (35% above average)
206
How long before hypoxia leads to irreversible damage to neurones?
~4mins
207
How is s secure cerebral blood supply ensured?
Structurally - anastomoses between basilar and internal carotid arteries
Functionally - myogenic auto regulation maintains perfusion during hypotension
208
Below what blood pressure will cerebral autoregulation of bloodflow fail?
Below 50mmHg
209
What is hypercapnia?
Increase in concentration of CO2 in the blood
210
What is hypocapnia?
Decrease in the concentration of CO2 in the blood
211
What is the response of the cerebral vessels to hypercapnia?
Vasodilatation
212
What is the response of the cerebral vessels to hypocapnia?
Vasoconstriction
213
What is adenosine?
A powerful vasodilator of cerebral arterioles
214
Describe cushings reflex
Increases in intracranial pressure impairs cerebral blood flow. Impaired bloodflow to vasomotor control regions of the brainstem increases sympathetic vasomotor activity (increasing arterial blood pressure, helping to maintain cerebral blood flow)
215
What is the bronchial circulation and what does it do?
Part of the systemic circulation, meets the metabolic requirements of the lungs
216
What is the average pressure in the pulmonary artery? In mmHg
15-30
___________
4-12
217
What is the average pressure in the right ventricle? In mmHg
15-30
__________
0-8
218
What is the average pressure in the aorta? In mmHg
100-140
______________
60-90
219
What is the average pressure in the left ventricle? In mmHg
100-140
_____________
1-10
220
What is the average pressure in the left atrium? In mmHg
1-10
221
What is the average pressure in the right atrium? In mmHg
0-8
222
What are the features and function of the pulmonary circulation?
Supplies blood to alveoli for gas exchange. Works with low pressure (prevents rupture of thin alveolar linings) and low resistance (many parallel capillaries, relatively little smooth muscle in arterioles, short wide vessels)
223
What is the V/Q ratio?
Ventilation/perfusion ratio
224
What is the optimum value for the V/Q ratio? Maintaining this means what?
0.8
| Maintaining this means diverting blood from alveoli which are not well ventilated
225
Describe hypoxic pulmonary vasoconstriction
Alveolar hypoxia results in vasoconstriction of pulmonary vessels. Ensures perfusion matches ventilation, poorly ventilated alveoli are less well perfused. Most important mechanism regulating pulmonary vascular tone, helps to optimise gas exchange
226
When might chronic hypoxic vasoconstriction occur, and what can it cause?
Can occur at altitude or as a consequence of lung disease. Can cause right ventricular failure (chronic increase in vascular resistance leads to chronic pulmonary hypertension, leads to high after load on right ventricle..)
227
Describe the effects of exercises on pulmonary circulation
Increases cardiac output
Small increase in pulmonary arterial pressure
Opens apical capillaries
Increased O2 uptake by lungs
As bloodflow increases, capillary transit time is reduced (from ~1s at rest to ~0.3s without compromising gas exchange)
228
What minimises the formation of lumping lymph (pulmonary oedema) normally?
Low capillary pressure (9-12mmHg normally)
229
What is mitral valve stenosis, and what might it cause?
Abnormal narrowing of the mitral valve
| Can lead to pulmonary oedema
230
What can you do to relieve symptoms of pulmonary oedema?
Use diuretics to relieve symptoms. Treat underlying cause if possible
231
What % of cardiac output does the brain demand?
15%
232
How is the cerebral circulation demand for O2 met?
High capillary density
High basal flow rate (x10 for rest of body)
High O2 extraction (35% above average)
233
How long before hypoxia leads to irreversible damage to neurones?
~4mins
234
How is s secure cerebral blood supply ensured?
Structurally - anastomoses between basilar and internal carotid arteries
Functionally - myogenic auto regulation maintains perfusion during hypotension
235
Below what blood pressure will cerebral autoregulation of bloodflow fail?
Below 50mmHg
236
What is hypercapnia?
Increase in concentration of CO2 in the blood
237
What is hypocapnia?
Decrease in the concentration of CO2 in the blood
238
What is the response of the cerebral vessels to hypercapnia?
Vasodilatation
239
What is the response of the cerebral vessels to hypocapnia?
Vasoconstriction
240
What is adenosine?
A powerful vasodilator of cerebral arterioles
241
Describe cushings reflex
Increases in intracranial pressure impairs cerebral blood flow. Impaired bloodflow to vasomotor control regions of the brainstem increases sympathetic vasomotor activity (increasing arterial blood pressure, helping to maintain cerebral blood flow)
242
When does bloodflow through the left coronary arterie occur mainly?
Diastole
243
How is the demand for O2/nutrients met by the coronary circulation?
High capillary density facilitates efficient O2 delivery
| Diffusion distance
244
Coronary arteries dilate due to hyperaemia. List some vasodilators of coronary arteries...
Adenosine
High [K+]
Low pH
245
What type of arteries are coronary arteries?
Functional end arteries
246
How is the large range or bloodflow to skeletal muscle achieved?
High vascular tone (permits lots of dilation)
| At rest, only 1/2 of capillaries are perfused at any one time, allows for increased recruitment
247
List vasodilators for skeletal muscle
```
High [K+]
Increased osmolarity
Inorganic phosphates
Adenosine
Adrenaline (skeletal muscle specific via beta2 receptors)
High [H+]
```
248
What are artereovenous anastomoses and what do they do?
Blood vessels under skin involved in temperature regulation. Under (sympathetic) neural control (decrease in core temperature increases sympathetic tone in AVAs, decreasing blood flow to apical skin)
249
What are the major contents of the extracellular matrix, and what do they do?
Matrix glycoproteins - organise and orientate cells, e.g. Figronectin, laminin
Proteoglycans - matrix organisation, cell support, regulation of growth factors e.g. Heparin
Elastin - provides tissue elasticity
250
What is most likely to kill you with a malignant neoplasm?
Tumour burden - vast numbers of 'parasitic' malignant cells (number of which greatly increased by ability to spread to distant sites)
251
What 3 main stages are there in the process of malignant cells getting from a primary site to a secondary site?
1. Grow and invade at the primary site
2. Enter a transport system and lodge at a secondary site
3. Grow at the secondary site to form a new tumour (colonisation)
252
Why is the process of malignant cells getting from a primary site to a secondary site inefficient?
Cells must evade destruction by immune cells at all points
253
Reduction in expression of what enables altered adhesion between malignant cells?
E-cadherin
254
Altered adhesion between malignant cells and stromal proteins involves changes in what expression?
Integrin
255
What proteins are involved in the degradation of basement membrane and stroma in the invasion of malignant neoplasms?
Altered expression of proteases, notably matrix metalloproteinases (MMPs)
256
What is a cancer niche and what does it do?
Nearby cells taken advantage of by malignant cells (together form cancer niche). Provide some growth factors and proteases.
257
How does signalling through integrins occur?
Via small G-proteins e.g. Members of the Rho family
258
What does altered motality in malignant neoplasms involve?
Changes in the actin cytoskeleton
259
Transport to distant sites can occur via malignant cells entering:
Blood vessels via capillaries and venules
Lymphatic vessels
Fluid in body cavities (pleura, peritoneal, pericardial, brain ventricles), known as transcoelomic spread
260
What is extravasation?
The process by which a malignant neoplastic cell gets out of a vessel at secondary site
261
What are micrometastases?
Surviving microscopic deposits that fail to grow
262
What is tumour dormancy?
An apparently disease free person may harbour many micrometastases
263
What does the secondary site of a neoplasm depend on?
Regional drainage of blood (often next capillary bed), lymph (lymph nodes), or coelomic fluid (other areas in coelomic space)
'Seed and soil' - due to interactions between malignant cells and the local tumour environment (is niche) at secondary site.
264
How do carcinomas typically spread via first?
Lymphatics first
265
How do sarcomas generally spread via?
Blood stream
266
What are common sites for blood borne metastasis?
Lung, bone, liver, brain
267
Name some neoplasms that commonly spread to bone
Breast, bronchus, kidney, thyroid, prostate
268
What is likelihood of metastasis dependent on?
Type of malignant tumour
| Size of primary neoplasm (basis of cancer scaling)
269
What are direct local effects of a neoplasm caused by?
Due to primary &/or secondary neoplasm
270
What are indirect systemic effects of a neoplasm caused by?
Increasing tumour burden
Secreted hormones
Miscellaneous
271
What are indirect systemic effects of a neoplasm sometimes referred to?
Paraneoplastic syndromes
272
Give examples of local effects caused by neoplasms
Direct invasion and destruction of normal tissue
Ulceration at a surface, leading to bleeding
Compression of adjacent structures
Blocking tubes & orifices
273
What is most likely to kill you with a malignant neoplasm?
Tumour burden - vast numbers of 'parasitic' malignant cells (number of which greatly increased by ability to spread to distant sites)
274
What 3 main stages are there in the process of malignant cells getting from a primary site to a secondary site?
1. Grow and invade at the primary site
2. Enter a transport system and lodge at a secondary site
3. Grow at the secondary site to form a new tumour (colonisation)
275
Why is the process of malignant cells getting from a primary site to a secondary site inefficient?
Cells must evade destruction by immune cells at all points
276
Reduction in expression of what enables altered adhesion between malignant cells?
E-cadherin
277
Altered adhesion between malignant cells and stromal proteins involves changes in what expression?
Integrin
278
What proteins are involved in the degradation of basement membrane and stroma in the invasion of malignant neoplasms?
Altered expression of proteases, notably matrix metalloproteinases (MMPs)
279
What is a cancer niche and what does it do?
Nearby cells taken advantage of by malignant cells (together form cancer niche). Provide some growth factors and proteases.
280
How does signalling through integrins occur?
Via small G-proteins e.g. Members of the Rho family
281
What does altered motality in malignant neoplasms involve?
Changes in the actin cytoskeleton
282
Transport to distant sites can occur via malignant cells entering:
Blood vessels via capillaries and venules
Lymphatic vessels
Fluid in body cavities (pleura, peritoneal, pericardial, brain ventricles), known as transcoelomic spread
283
What is extravasation?
The process by which a malignant neoplastic cell gets out of a vessel at secondary site
284
What are micrometastases?
Surviving microscopic deposits that fail to grow
285
What is tumour dormancy?
An apparently disease free person may harbour many micrometastases
286
Give examples of local effects caused by neoplasms
Direct invasion and destruction of normal tissue
Ulceration at a surface, leading to bleeding
Compression of adjacent structures
Blocking tubes & orifices
287
What are indirect systemic effects of a neoplasm sometimes referred to?
Paraneoplastic syndromes
288
What are indirect systemic effects of a neoplasm caused by?
Increasing tumour burden
Secreted hormones
Miscellaneous
289
What are direct local effects of a neoplasm caused by?
Due to primary &/or secondary neoplasm
290
What is likelihood of metastasis dependent on?
Type of malignant tumour
| Size of primary neoplasm (basis of cancer scaling)
291
Name some neoplasms that commonly spread to bone
Breast, bronchus, kidney, thyroid, prostate
292
What are common sites for blood borne metastasis?
Lung, bone, liver, brain
293
How do sarcomas generally spread via?
Blood stream
294
How do carcinomas typically spread via first?
Lymphatics first
295
What does the secondary site of a neoplasm depend on?
Regional drainage of blood (often next capillary bed), lymph (lymph nodes), or coelomic fluid (other areas in coelomic space)
'Seed and soil' - due to interactions between malignant cells and the local tumour environment (is niche) at secondary site.
296
What are the 5 leading behavioural & dietary risks which lead to 30% of cancer deaths?
```
High BMI
Low fruit and veg
Lack of physical activity
Tabacco use
Alcohol use
```
297
What are the 3 main categories for extrinsic cancer risk factors?
Chemicals
Radiation
Infections
298
What characteristics are shown for exposure to some extrinsic factors causing cancer?
Risk of cancer depends on total carcinogen dosage
Long delay between carcinogen exposure used and malignant neoplasm onset
Sometimes organ specificity for particular carcinogens is seen
299
What organ specificity does the cancer induced by 2-napthylamine (industrial carcinogen used in dyes)
Bladder cancer
300
What are initiators?
Mutagens
301
What do promotors cause?
Prolonged proliferation in target tissues
302
What are the 5 ways to classify mutagenic chemical carcinogens
```
Polycyclic aromatic hydrocarbons
Aromatic amines
N-nitroso compounds
Alkylating agents
Natural products
```
303
What in the liver converts pro-carcinogens to carcinogens?
Cytochrome P450 enzymes
304
What are compete carcinogens?
Carcinogens which act as both initiators and promotors
305
What is radiation?
Any form of energy travelling through space
306
How may radiation damage DNA?
Can damage DNA bases
Cause single, and double strand DNA breaks
Indirect DNA damage via free radicals
307
Give an example of a virus that acts as a direct carcinogen
HPV (Human Papilloma Virus)
| Expresses E6 & E7 proteins that inhibit p53 & pRB protein function (important for cell proliferation)
308
Give 2 examples of 2 infections that can indirectly cause cancer?
Hep B & C - cause chronic liver cell injury & regeneration
HIV - lowers immunity, enabling other potentially carcinogenic infections to occur
309
How many alleles must be inactivated in order for tumour suppressor genes to permit cancer growth?
Both alleles
310
How many alleles must be inactivated in order for proto-oncogenes to permit cancer growth?
Only one allele
311
What is RAS?
An oncogene that encodes a small G protein that relays signal into the cell, eventually pushing cell past cell cycle restriction point
312
What does the RB gene do?
Restricts cell proliferation by inhibiting passage through restriction point
313
What is xeroderma pigmentosum (XP)?
Autosomal recessive. Mutation in DNA repair genes (nucleotide excision repair). Patients are very sensitive to UV light
314
Describe hereditary non-polyposis colon cancer (HNPCC) syndrome
Autosomal dominant
| Associated with colon carcinoma and the germline mutation affects 1 of several DNA mismatch repair genes
315
Familial breast carcinoma is associated with which genes? What do they do?
BRCA1 or BRCA 2
| Important for repairing double stranded DNA breaks
316
What is progression?
Mutations occur during sequence (time frame often decades); step wise accumulation of mutations in malignant neoplasms
317
What are the 6 hallmarks of cancer? Plus one enabling factor
- Self-sufficiency in growth signals
- Resistance to growth stop signals
- No limit on the number of times a cell can divide (cell immortalisation)
- Sustained ability to induce new blood vessels (angiogenesis)
- Resistance to apoptosis
- Ability to invade and produce metastasis
+ Genetic instability
318
Name 7 factors protooncogenes/tumour suppressor genes may effect
- Growth factors
- Growth factor receptors
- Plasma membrane signal transducers
- Intracellular kinases
- Transcription factors
- Cell cycle regulators
- Apotosis regulators
319
What are the 4 types of cancer that make up 54% of all cancer incidence in the UK?
Lung
Breast
Prostate
Bowel
320
What are the most common types of cancer in children under 14?
Leukaemias
CVS tumours
Lymphomas
321
What is 'Ann Arbor' staging used for?
Lymphoma
322
What is 'Dukes staging' used for?
Colorectal carcinoma
323
Describe the Ann Arbor staging system
Stage 1: lymphoma in a single node region
Stage 2: lymphoma in separate regions, on one side of the diaphragm
Stage 3: lymphoma spread to both sides of the diaphragm
Stage 4: diffuse or disseminated involvement of one or more extra-lymphatic organs e.g. bone marrow, lungs
324
Describe the Dukes staging system
Dukes A: invasion of lamina propria (not through bowel)
Dukes B: invasion of muscularis propria (through bowel wall)
Dukes C: involvement of lymph nodes
Dukes D: distant metastasis
325
What is grading used to determine?
How differentiated a carcinoma is
326
Describe the general grading system
G1: well differentiated
G2: moderately differentiated
G3: poorly differentiated
G4: anaplastic (undifferentiated)
327
What is the Bloom-Richardson system used for?
Grading of breast carcinoma
328
Describe the Bloom-Richardson grading system
Grade 1: tubules
Grade 2: mitoses
Grade 3: nuclear pleomorphism
329
What is adjuvant treatment?
Treatment given after surgical removal of a primary tumour to eliminate subclinical disease
330
What is neoadjuvant treatment?
Treatment given to reduce the size of a primary tumour prior to surgical excision
331
Why is radiotherapy given in fractionated doses?
Minimise normal tissue damage
332
What form of radiation is used in radiotherapy?
Ionising radiation (e.g. X-rays)
333
How does radiotherapy kill cells?
High doses causes direct, or feed radical induced DNA damage, that is detected by the cell cycle check points, triggering apoptosis (especially in G2 of cell cycle).
Double stranded DNA breakages cause damaged chromosomes that prevents M phase from completing correctly
334
How do antimetabolite chemotherapy drugs work?
Mimic normal substrates involved in DNA replication
335
How do alkylation and platinum based chemotherapy drugs work?
Cross lint the 2 strands of DNA helix
336
How do plant-based chemotherapy drugs work?
Blocks microtubule assembly, interfering with mitotic spindle formation
337
How might antibiotic chemotherapy drugs work?
Inhibit DNA topoisomerase (doxorubicin)
| Cause double stranded DNA breaks (bleomycin)
338
How might hormone therapy be used to treat breast carcinoma?
Hormone receptor-positive breast cancer.
Selective oestrogen receptor modulators (SERMs) bind to oestrogen receptors, preventing oestrogen from binding (e.g. Tamoxifen)
339
What is oncogene targeting?
Identifying cancer-specific alterations e.g. Oncogene mutations, provides an opportunity to target drugs specifically at cancer cells
340
What can tumour markers be used for?
Diagnosis
| Monitoring tumour burden during treatment and follow up
341
What might tumour markers be?
Hormones
'Oncofetal' antigens
Specific proteins
Mucins/glycoproteins
342
What are possible problems caused by cancer screening?
Lead time bias
Length bias
Over diagnosis (might never effect patient at all anyways)
343
What cancers are screened for in the UK?
Cervical
Breast (50-70yrs, every 3 yrs)
Bowel (60-74yrs, every 2 yrs)
344
What is karryohexis?
The destructive fragmentation of the nucleus of a dying cell, whereby the chromatin is distributed irregularly throughout the cytoplasm
345
What is karyolysis?
Dissolution of a cell nucleus
346
What is pyknosis (karyopyknosis)?
The irreversible condensation of chromatin in the nucleus of a cell undergoing necrosis or apoptosis. Followed by karyorrhexis (fragmentation of nucleus)
347
What is a sarcoma?
Cancer of soft tissue, connective tissue or bone
348
What is the normal capillary pressure in the lungs?
9-12mmHg
349
What is human chorionic gonadotropin a tumour marker for?
Trophoblastic tumours
| Non-seminomatous germ cell tumours of the testes
350
What is calcitonin a tumour marker for?
Medullary carcinoma of the thyroid
351
What are catecholamines and metabolites tumour markers for?
Phaeochromocytoma and related
Liver cell carcinoma
Non-seminomatous germ cell tumour of the testes
352
What is carcinoembryonic antigen a tumour marker for?
Colon cancer
353
What is prostate specific antigen a tumour marker for?
Prostate cancer
354
What is CA-125 a tumour marker for?
Ovarian cancer
355
What is CA19.9 a tumour marker for?
Pancreatic cancer
356
What must first happen to neutrophils before infiltration?
They must be activated (switched to a higher metabolic state)
357
What are the signs and symptoms of the acute phase response?
Decreased appetite, raised pulse rate, altered sleep patterns, changes in plasma concentrations of acute phase proteins
358
When is complete resolution impossible?
When tissue architecture has been damaged/destroyed
359
What are the 4 types of exudate?
Pus/abscess - creamy white, rich in neutrophils. Typical of infection by chemotactic bacteria
Haemorrhagic - contains many RBCs, indicates vascular damage, seen in destructive infections or when exudate is a result of infiltration by a malignant tumour.
Serous - clear, contains plasma proteins but few lymphocytes indicating no infection, e.g. Blister
Fibrinous - significant deposition of fibrin e.g. In pericardial/pleural spaces. Heard as a rubbing sound
360
How is the endothelium naturally anti-thrombotic?
Contains plasminogen activators (NO, thrombomodulin, prostacyclin)
361
What causes Alpert syndrome?
Type 4 collagen is abnormal, basement membrane is dysfunctional
362
How does gliosis work?
Neural tissue is replaced by proliferation of CNS supportive elements (glial cells)
363
Describe how peripheral neurons repair
Axons degenerate, proximal stumps sprout/elongate and are guided back to tissue by Schwann cells
364
What factors control regeneration?
Growth factors - promote proliferation in stem cell population. Extracellular signals transduced into cell, promote expression of genes controlling cell cycle. Protein/hormone
Contact between basement membrane and adjacent cells - signalling through adhesion molecules. Inhibits proliferation in intact tissue (contact inhibition), less contact promotes proliferation (deranged in cancer)
365
When does initiation and promotion lead to neoplasm formation?
When they effect protooncogenes and tumour supressor genes
366
What are 'caretaker genes'?
Genes that maintain genetic stability
367
Describe the sequence of progression leading to colon carcinoma
Adenoma --> primary carcinoma --> metastatic carcinoma
| Stepwise Sequence of acquisition of mutations
368
What is androgen blockade used as a treatment for?
Treatment of prostate cancer (example of hormone therapy)
369
What could tumour markers be?
Hormones, 'oncofetal' antigens, specific proteins or mucins/glycoproteins
