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Esa 2 > MOD L.Os > Flashcards

MOD L.Os Flashcards

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
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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

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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

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4
Q

Describe how cyanide is toxic

A

Binds to cytochrome oxidase in the ETC.

Blocks oxidative phosphorylation

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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
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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

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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

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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,

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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

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10
Q

Define oncosis

A 
Cell death with swelling
Karryolyis 
Spectrum of changes BEFORE DEATH
Can lead to adjacent inflammation
Enzymes digest causing leakage
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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

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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)

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13
Q

Describe gangrene

A

Wet- liquefactive caused by fungi or bacteria
Dry- coagulative
Gas gangrene - wet anaerobic bacteria

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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

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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

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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

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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

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18
Q

Describe cellular ageing

A

Telomere shortens with each replication,

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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

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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
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21
Q

What are the major causes of acute inflammation?

A 
Microbial infection
Physical agents: Trauma
Chemicals
Tissue necrosis 
Acute phase hypersensitivity reaction (immune)
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22
Q

Describe the appearance of acute inflammation

A 
Rubor- redness
Tumour- swelling
Calor- heat
Dolor- pain
Loss of function
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23
Q

Key features of acute inflammation

A

Neutrophils!

Innate, immediate early and stereotyped (not affected by repeat problems)

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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,

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25
Q

How do the changes occurring in acute inflammation effectively respond to the inflammation?.

A

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

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26
Q

what do neutrophils do and how?

A

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

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27
Q

Hoe do neutrophils kill bacteria

A

O2 dependant bacteria by oxidative burst

O2 independent using enzymes: pro teases, lysozymes, phospholipases

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28
Q

What do chemical mediators do in acute inflammation, list 4 types

A 
Modulate inflammatory response, all have inhibitors to prevent continuous response 
Histamines
Bradykinin
Prostaglandin
Complement system:
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29
Q

What local complications can occur in acute inflammation

A

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

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30
Q

What systemic consequences of acute inflammation

A

Fever
Leucytosis: increase neutrophils (bacteria) lymphocytes (viral)
Acute phase response: reduced appetite, increased pulse,
Increased acute phase proteins 0: opsonin, antitrypsin, fibrinogen
Shock

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31
Q

What are the outcomes of acute inflammation

A 
Resolution
Progression: 
Abscess
Chronic
Death
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32
Q

Describe lobar pneumonia
Acute appendicitis
Bacterial meningitis
Ascending cholangitis and liver abscess

A

D

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33
Q

Give three examples of inherited disorders of acute inflammatory process

A

Hereditary angio-oedema
Alpha 1 antitrypsin deficiency
Chronic granulomatous disease

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34
Q

What cells are involved in chronic inflammation

A

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-

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35
Q

What are giant cells and when are they seen

A

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

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36
Q

Describe the characteristics of chronic inflammation? How different from acute!

A

Chronic is not stereotyped, non specific and can lead to fibrosis. More varied microscopically.
Acute: lasts less long, stereotyped, neutrophils, normally reversible

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37
Q

When does chronic inflammation occur?

A

After acute: too much damage,
Alongside acute e,g, chronic colonitis, or ongoing bacterial infection
Chronic from start - TB, auto immune conditions, toxic agents

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38
Q

Describe the possible complications of chronic inflammation

A

Excess fibrosis–>Impaired function e.g. Chronic colecytis
Damage to tissues
Atrophy
Immune response can be inappropriately activated

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39
Q

Describe rheumatoid arthritis

A

Autoimmune disease causing localised chronic inflammation in synovial joints
Can lead to systemic immune responses causing amyloidosis in other tissues.

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40
Q

Describe ulcerative colitis

A

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

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41
Q

Describe hereditary angio- oedema

A

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

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42
Q

Describe alpha 1 antitrypsin deficiency

A

Interferes with acute inflammation
Autosomal recessive
Interferes with A1 antitrypsin which inactivated enzymes released from neutrophils –> unchecked –> damage to normal parenchymal tissue

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43
Q

Chronic granulomatous disease

A

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

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44
Q

Describe regeneration

A

Replacement of dead or damaged cells (collage framework intact) by functional differentiated cells from stem cells

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45
Q

Describe how the ability to regenerate varies with cell, type. Give examples of each

A

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

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46
Q

What is the role of stem cells

A

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 )

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47
Q

Describe the components involved in fibrous repair and when it occurs

A

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

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48
Q

Describe granulation tissue

A

A loose mesh work formed of capillary loops and myofibroblasts

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49
Q

Give an overview of fibrous repair

A

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,

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50
Q

Describe collagen. The types of collagen,

A 
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
Q

Give an overview of how collagen is synthesised

A

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

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52
Q

Describe some defects of collagen synthesis

A

Scurvy: low vitamin C,
Ehlers danlos syndrome
Osteogenesis imperfecta
Alport syndrome

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53
Q

How do growth factors control regeneration and repair

A

Local hormones
Promote proliferation of the stem cells
Can be autocrine (produced by the cell) paracrine (neighbour) endocrine (blood) hormones

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54
Q

Give some examples of growth factors

A

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.

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55
Q

Describe contact inhibition and its affect on regeneration

A

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

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56
Q

Describe the differences between primary and secondary intention healing

A

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

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57
Q

Describe the healing of bone

A

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

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58
Q

Describe factors that can influence healing and repair

A

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,
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59
Q

Describe possible complications of fibrous repair

A

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

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60
Q

Describe repair in cardiac muscle

A

Cardiac myocytes can’t regenerate so fibrosis occurs

Can compromise cardiac function as leads to reduced contractility.

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61
Q

Describe and discuss healing and repair in liver, peripheral nerves, cartilages and CNS

A

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)

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62
Q

Define haemostasis and the four key things it depends on

A

The body’s response to stop bleeding and loss of blood

  • blood vessels
  • platelets
  • coagulation system
  • fibrinolytic
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63
Q

Describe the process of haemostasis

A

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)

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64
Q

Describe the regulation of the coagulation system

A

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.

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65
Q

Describe fibrinolysis

A

Break down of fibrin by plasmin,
Catalysed by plasminogen activator t-Pa.
E,g, streptokinase, activates plasminogen - clot busters
Drastic treatment

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66
Q

Define thrombosis

A

The production of a solid mass from the constituents of blood within the circulation- not the same as normal clotting

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67
Q

Describe the mechanisms for thrombosis occurring

A

Change in blood flow, stagnation, turbulence
Change in blood components: smokers, pregnancy, post op
Change in vessel walls: atherosclerosis, injury, inflammation

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68
Q

Describe the differences in appearance of venous and arterial thrombi

A

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

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69
Q

Describe the outcomes of thrombi

A

Arterial: ischaemia, infarction –> mi, blockage if vessels, stroke
Venous: congestion, oedema, ischaemia if tissue pressure increases higher than arterial and impedes arterial supply

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70
Q

What are the possible outcomes of thrombosis

A

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)

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71
Q

Describe embolism

A

Blockage of a blood vessel caused by a solid, liquid or gas at a site distant from its origin.
Most are thrombi emboli

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72
Q

Describe thrombi emboli, their formation and the effect on Blood supply

A

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

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73
Q

Describe the effects of pulmonary emboli

A

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

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74
Q

Describe how DVT occurs, and it’s risk factors

A

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

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75
Q

How would you treat thromboembolic diseases

A

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

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76
Q

List the other types of emboli

A

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

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77
Q

Describe haemophilia and its effect on coagulation

A

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
Q

Disseminated intravascular coagulation (DIC)

A

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
Q

Describe thrombocytopenia

A

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
Q

Describe thrombophillia

A

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
Q

How would you test for coagulation

A

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
Q

Treatments for coagulation

A

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
Q

What substances would you measure in the blood to test for an MI

A

Troponin C

Creatine kinase

84
Q

What is Trosseau syndrome? Why does it occur?

A

Repeated episodes of vessel inflammation due to a clot, recurrent and occur in different locations over time- due to early cancer

85
Q

How does chronic excessive alcohol lead to fatty change/steatosis?

A

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
Q

How does acute alcoholic hepatitis develop?

A

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
Q

How does cirrhosis of the liver develop?

A

in 10-15% alcoholics
hard shrunken liver, with micronodules of regenerating hepatocytes surrounded y bands of collages.
irreversible, serious and can be fatal

88
Q

Describe intrinsic and extrinsic apoptosis and the molecules triggering the response

A

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
Q

Describe what happens in paracetamol overdose

A

Saturates phase 2 conjugatin pathway ( with glucorinide or sulphate)
Goes through phase 1 pathway –> NAPQI –> 2dary pathway where conjugated with glutathione (ROS)

90
Q

Describe Hepatitis

A

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
Q

Describe acute pancreatitis

A

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
Q

describe acute appendicitis

A

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
Q

Describe bacterial menigitis

A

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
Q

Describe ascending cholangitis and liver absecess

A

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
Q

Describe lobar pneumonia. What type of inflammation?

A

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
Q

Describe Crohns diesease.

A

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
Q

Briefly describe the differences between Crohns and ulcerative colitis

A

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
Q

Describe chronic cholecytis

A

Chronic inflammation of the cystic duct, Normally due to gall stones

99
Q

What is an ulcer

A

A full thickness lockk of mucosa, an erosion would only remove the superficial layer –> heals more quickly

100
Q

Describe chronic gastritis

A

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
Q

TB

A

TB is a chronic inflammation caused by Mycobacteroum Tuberculosis. – affects lungs.

Tuberculous granuloma

Most cases: immune systems kills or inactivates the TB bacteria.

102
Q

Describe cirrhosis due to chronic inflammation

A

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
Q

Describe scurvy

A

Vitamin C required for hydroxylation of procollagen.
Causes reduced healing capabilities and a tendancy to bleed.
Bleeding into joints and gums

104
Q

Descrube Ehlers- Danlos syndrome

A

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
Q

Osteogenesis imperfecta

A

Autosomal dominant disease resulting in T1 collagen deformity/deficiency. Bowed ling bones, repeated fractures, blue sclera

106
Q

Alport syndrome

A

Type 4 collagen abnormal, leads to dysfuction of glomerular basement membrane, cochlea of the ear and lens of the eye.

107
Q

Define atherioscleosis

A

The disease caused by the thickening and hardening of vessel walls, due to atheroma

108
Q

Define atheroma

A

The accumulation of lipids in the intima and media of large and medium sized arteries. Due to intracellular or extracellular lipids

109
Q

Define arteriosclerosis

A

The thickening of the walls in arteries and arterioles usually as a result of hypertension or diabetes mellitus

110
Q

Describe the cellular events leading to the formation of atheriosclerotic leisons

A

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
Q

Describe the macroscopic appearance of artheriosclerosis

A

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
Q

Microscopic appearence of plaque and how it changes in later stages

A

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
Q

List the common sites for atherosclerosis

A

abdominal aorta
coronary arteries
carotid arteries
cerebral and leg arteries

114
Q

Describe the effects of severe atherioscerosis in coronary arteries

A

Coronary arteries –> Ischaemic heart diesease –> mI, death, angina, arrythmias

115
Q

Describe the effects of severe atherioscerosis in abdominal arteries

A

Abdominal aorta –> abdominal aortic aneurysm, aherola builds up causing the walls of the aorta to stretch and balloon –> rupture. Emboli –> other arteries

116
Q

Describe the effects of severe atherioscerosis in cerebral arteries

A

Partial infarction –> transient ischaemic attack

Ischaemia of brain tissue –> stroke,

117
Q

Describe the effects of severe atherioscerosis in peripheral arteries

A

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
Q

Describe the effects of severe atherioscerosis in mesenteric arteries

A

Ischamic colitis
malabsorbtion
aneurism

119
Q

Describe recommended hypotheisi for mechanisms of angiogenesis

A

Response to injury hypotheisis: recommended

Endothelial injury - Permeability - Platelets (PDGF released), macrophages , lipoproteins, t lymphocytes etc invade

120
Q

Describe other mechanisms of angiogeneisis.

A

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
Q

What are the main cells involved in angiogenesis

A 
Macrophages (monocytes) 
platelets
lymphocytes -TNF --> lipoprotein metabolism
Endothlial cells
Smooth muscle cells
Neutrophils
122
Q

Risk factors of coronary heart disease

A

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
Q

How do you prevent atherioscelosis and treat it when it has developed

A

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
Q

Describe how cells can communicate with each other

A

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
Q

Give 4 examples of growth factors

A

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
Q

Descrube the cell cycle

A

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
Q

List the different types of stem cells

A

Labile, stable, permenant

128
Q

Define regen, Which tissues can regenerate?

A

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
Q

Define hyperplasia, which tissues can undergo hyperplasia?

A

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
Q

define hypertrophy and give examples of tissues

A

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
Q

Describe when cell adaptation occurs

A

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
Q

define Reconstitution and give an example

A

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
Q

What are the main outcomes of cell signalling

A

Divide (enter cell cycle)
Differentiate (take on specialised form and function)
Survive (resist apopotosis)
Die (apoptosis)

134
Q

Define Aplasia and give an example

A

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
Q

What is the difference between an Angiogram and a atreriogram, and when would you use them

A

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
Q

Define Involution and give an example

A

Normal PROGRAMMED shirnkage of organ e.g uterus after childbirth

137
Q

Define Hypoplasia and give an example

A

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
Q

Define Atresia and give an example

A

Congenital, Failure of perforating an opening, e.g. anus or vagina

139
Q

Define Dysplasia and give an example

A

Abnormal maturation of cells within a tissue, cells have disordered tissue organisation - reversibe but can lead to neoplasia

140
Q

Define neoplasia

A

abnormal growth of cells which persists after initiating stimullus has been removed
Neolasms are monoclonal- from a common nacestral cell

141
Q

What is the difference between benign and malignant neoplasms

A

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
Q

Define tumour

A

Any clinically detectable lump or swelling - a neoplasm is a type of tumour

143
Q

Define cancer

A

Any malignant neoplasm

144
Q

Define Metastasis

A

Malignant neoplasm that has spread from its primary site to a new non contagious site

145
Q

Define anaplasia

A

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
Q

Define Pleomorphism

A

Variation in size and shape of cell, cytoplasm ratio,mitotic figures?

147
Q

Define progression

A

the process a neoplasm emerges from a monoclonal population: Initiation, promotors (proliferation) build up series of mutations –> neoplasm

148
Q

Compare macroscopic features of benign and malignant neoplasms

A

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
Q

Compare microscopic features of neoplasms

A

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
Q

Compare the biological behaviour of neoplasms

A

Benign: local, retain specialisation so tissuu function may not be as affected
Malignant: spread

151
Q

Distinguish between in-situ and invasive malignancy

A

In situ: neoplasm doesnt invade throgh the basement embrane

152
Q

What type of genes are involved in Neoplasia?

A

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
Q

List the key differences in neoplastic cells from normal cells (6) the 6 hallmarks of cancer

A

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
Q

How do you name a neoplasm?

A

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
Q

Describe the process that leads to successful metasisatis

A

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
Q

Describe how metastasis invade surrounding tissue

A

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
Q

How are malignant cells transported to the secondary ste

A
  • Blood - via capillaries and venules
  • Lymph
  • Transcoelomic spread - via fluid in body cavities (pleura, peritoneal, pericardial and brain)
158
Q

What type of cells form the cancer niche?

A

Inflammatory cells, smooth muscle cells, fibroblasts, endothelial cells

159
Q

How do malignant cells form a metasasis at a secondary site?

A

Colonisation. - greatest barrier to sucessful formation because the cells often fail to grow into tumours

160
Q

how do relapses of cancer occur

A

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
Q

What determines the site of a metasatsis

A

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
Q

How do carcinomas typically spread?

A

Via lymphatics first then blood stream to more distant sites

163
Q

How to sarcomas spread?

A

Via blood stream

164
Q

What are the common sites for blood bourne metasatsis?

A

Lung, liver, bone, brain,

165
Q

Where do neoplasms from bone normally come from?

A

Breast, prostate, kidney, thyroid, bronchus,

166
Q

Describe the local effects of neoplasms, compare benigna and malignant

A
  • direct invasion and destruction of normal tissue
  • ulceration at surface –> bleeding
    -compression of adjacent structures
  • blocking tubes and orifices
    Benign and malignant
167
Q

Describe the systemic effects of neoplasms (paraneoplastic syndromes)

A 
Parasitic effect with increased tumour burden: cachexia (appetite and weight loss), malaise, immunosupression, thrombosis
Haemotological: 
Endocrine
Derm
Neuro
168
Q

Describe the haematological effects of neoplasms

A

anaemia, reduced WBC and platelets (invasion into bone marrow and/or treatments)
thrombosis

169
Q

Describe the endocrine effects of neoplasms

A

Excessive secretion of hormones
Ectopic secretion e.g. Bronchial small cell carcinoma (ACTH of ADH)
Bronchial squamous –> PTHrp
Benign (and malignant tumours)

170
Q

Describe the neurological effects of neoplasms

A

Neoplasms can affect the brain leading to neuropathies inc. balance, sensory problems, and myopathies -affects PNS

171
Q

Describe the dermatological effects of neoplasms

A

Can cause skin problems such as pruritus (jaundice …), clubbing, pigmentation, myositis,

172
Q

How are neoplasms caused (generally)

A

Multifactorial:
intrinsic host factors e.g. genes, age, hormones
and extrinsic environmental e.g. chemicals, radiation and infections

173
Q

Carcinogenic chemicals, give an example and explain what the risk of cancer depends on

A

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
Q

Describe the mechanism of action of carcinogenesis from chemicals

A

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
Q

What types of chemical carcinogens are there

A

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
Q

Descrube the mechanism of mutagenic radiation- examples

A 
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
177
Q

Describe some infections that are mutagenic

A

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
Q

Describe the inheritance of neoplasia

A

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
Q

Describe the role of tumour supressor genes and give two examples

A

Inhibit neoplastic growth. Both alleles need to be inactivates (2 hit hypothesis)

180
Q

Describe the role of oncogenes

A

Genes that enhance neoplastic growth - normally activated versions on proto-oncogenes. Only one allele needs to be acivated

181
Q

Describe the role of caretaker genes

A

Maintain genetic instability. Type of tumour supressor gene

Without effective caretaker genes there can be an accellerated mutation rate

182
Q

Describe the roles of
RAS
c-myc
c-erbB-2 (HER 2)

A

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
Q

Describe the roles of TS genes

A

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
Q

Descrube the inheritance of Xeroderma Pigmentosum (XP)

A

Due to mutations in DNA repair genes - genes affecting DNA nucleotide excision repair (NER)
Autosomal recessive
Very sensitive to UV damage –> skin cancer

185
Q

Describe how Hereditry Non-polyposis colon cancer develops (HNPCC)

A

Autosomal dominant, associated with colon carcinoma

Affects DNA mismatch repair gene

186
Q

What genes are affected in famillial breast carcinoma.

What other tumours associate with it?

A

BRCA 1&2, repair double stranded DNA breaks

187
Q

Describe the developement of carcinomas using colon carcinoma as an example.

A

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
Q

Describe progression

A

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
Q

List the most common types of cancer

Which have the most deaths?

A

Most common: Lung, Breast, prostate, bowel. In children leukaemia
Worst survival: pancreatic, lung, oesophageal
Best survival: testicular, melanoma, breast

190
Q

How do we predict outcomes of neoplasms

A

age, general health, tumour: site, size, origin, GRADE (differentiation) STAGE and effective treatment availability

191
Q

Describe staging of tumours

A

measure of tumours overall burden: TNM = worldwide
T1-4 (size)
N (0-3) regional node metasasis
M 0,1: distant metastatic spread?

Esa 2 (4 decks)

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