Principles Of Medicine Flashcards

1
Q

Evidence for endosymbiotic theory

A

Mitochondria contain separate DNA with No associated histones

Mitochondria can only be formed from other mitochondria

Mitochondria contain their own protein synthesising complexes with many similarities to prokaryotic machinery

First amino acid of mitochondrial transcript fMET as is the case in bacteria and not MET as in eukaryotes

A number of antibiotics such as streptomycin will also block protein synthesis is mitochondria, but not in cytoplasm of eukaryotes.

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2
Q

Describe the steps of glycolysis including the types of each reaction

A

Glucose phosphorylated by hexokinase enzyme at carbon 6

  • requires ATP investment
  • Group transfer

Phosphoglucose Isomerise enzyme converts 5C ring to 4C, creating an extra side branch and molecular symmetry

  • isomerization
  • glucose 6 phosphate —> fructose 6 phosphate

Fructose-6-phosphate phosphorylated to fructose 1,6 bisphosphate by phosphofructokinase

  • Requires ATP investment
  • group transfer

Fructose 1,6 bisphosphate hydrolysed by aldolase to 2 3 carbon molecules including glyceraldehyde 3 phosphate
-hydrolysis

Other 3C molecule converted to glyceraldehyde 3 phosphate by TPI
-Isomerization

Inorganic phosphate added to each G3P to form 2x 1,3 bisphophoglycerate

  • NAD+ reduced by dehydrogenase enzyme
  • Group transfer

1 phosphate group removed by phosphoglycerate kinase enzyme
-ATP generated

Phosphate group moved from position 3->2 by isomerise enzyme (phosphoglycerate mutase)
-isomerization

Water eliminated to form double bond by enolase enzyme
-group removal

ATP generated by removal of final phosphate group by Pyruvate kinase
-group transfers

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3
Q

Describe formation of Lactate from pyruvate under anaerobic conditions

A

Catalysed by pyruvate dehydrogenase

NADH oxidised

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4
Q

What is the importance of lactate production in anaerobic conditions

A

Allow NAD+ to be regenerated so that glycolysis can continue as NAD+ is required for dehydration of gkyceraldehyde-3-phosphate

When rate of NADH formation in glycolysis greater than its rate of oxidation in NADH dehydrogenase complex

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5
Q

Describe the role of Creatine phosphate as a buffer

A

Acts as buffer for storage of ATP

Creatine phosphate + ADP + H+ creatinine + ATP

Catalysed by creatine kinase

Sustain supply first 4s intense exercise

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6
Q

Describe the platelet plug formation

A

Platelet binds to Von Willebrand factor or to Glpla receptor

ADP and thromboxane released

Thromboxane causes vasoconstriction

Positive feedback mechanism present

Conformational change In GP11b/111a

Opens fibrinogen binding sites

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7
Q

Mechanism of action of aspirin

A

Inihibits production of thromboxane A2.

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8
Q

Describe formation of a stable haemostatic plug (secondary haemostats)

A

FVII bind to TF in extravascular environment

Causes activation of fx->Xa and IX->IXa

Cleaves some prothrombin to thrombin

Causes activation of other cofactors which cleave more fX and IXa

Rapid, sustained generation of thrombin

Thrombin catalyses cleavage of fibrinogen to fibrin

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9
Q

Describe the action of protein C

A

Thrombin binds to thrombomodulin

Causes conformational change of protein C to APc (activates protein C)

Protein C binds and inhibits fVa and VIIIa in presence of protein S

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10
Q

Describe action of antithrombin

A

Inhibit thrombin and fxa

Potentiated by heparin

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11
Q

Describe the mechanism of action of heparin

A

Potentiates antithrombin inhibition of thrombin and fXa

IV drip

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12
Q

Mechanism of action of clopidogrel on platelets

A

Inhibits ADP binding site (P2Y12) on platelet cell membrane.

Lasts 7 days till new platelets produced

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13
Q

What Is the role of calcium ions in the thrombotic cascade

A

Help bind activated clotting factors to phospholipid surface of platelets

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14
Q

Mechanism of action of Warfarin

A

Vitamin K antagonist

Reduces synthesis of clotting cofactors
F(2,3,9,10)

Need to monitor

Several days to take effect

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15
Q

Mechanism of action of direct oral amticoagulants (DOACs)

A

Inhibit thrombin or fXa

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16
Q

Describe fibrinolysis

A

Plasminogen activated to plasmin by tPA when bound to lysine residues of fibrin

Plasmin catalyse degradation of fibrin clot

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17
Q

Mechanism of action of transexamic acid

A

Prevents plasminogen binding to lysine residues of fibrin

Prevents fibrinolysis

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18
Q

Describe how prothrombin time (PT) is measured

A

Blood collected

Sodium citrate added (prevents Ca2+ activating blood clotting)

Sample centrifuged, plasma taken

TF and phospholipid added

Calcium added and timer started

(Can use thromboplastin recombinant instead of phsopholipid and TF)

INR generated- normalised ratio

Pt patient/ Pt average

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19
Q

Describe how activated thromboplastin test is carried out (APTT)

A

Contact activator such as glass added to phospholipid after addition of sodium citrate and centrifugation

Ca2+ added and time to clot measured

(fXII activated by surface contact)

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20
Q

Describe three causes of bleeding

A

Reduction in platelet number

Reduction in platelet function

Reduction in coagulation factors

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21
Q

Describe 3 causes of thrombosis

A

Reduced anticoagulant proteins

Increased levels clotting factors

Increased platelet levels

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22
Q

What is mitochondrial uncoupling?

A

Any process which disrupts the proton concentration gradient between the intermembrane space and the mitochondrial matrix. Rate of NADH And FADH2 oxidation not linked to rate of ATP synthesis

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23
Q

Action of cyanide on mitochondria

A

Block cytochrome oxidase complex

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24
Q

Action of Malonate on mitochondria

A

Competitive inhibitor of succinate dehydrogenase

Slows flow of electrons to Co enzyme Q

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25
Q

Action of Rotenone on mitochondria

A

Inhibits transfer of electrons from complex 1 to ubiquinone

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26
Q

Action of oligomycin on mitochondria

A

Block flow of protons in F0F1 ATP synthase complex

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27
Q

Action of dinitrophenol on mitochondria

A

Introduce micropores in inner membrane
Causes mitochondrial uncoupling
Decreases proton gradient

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28
Q

Describe formation of a granulocyte from a HSC

A

Multipotent Hemopoeitc stem cell divides and differentiates to form a common myeloid progenitor.
In presence of G-CSF myeloblast formed
Further differentiate to Basophils, neutrophils and eosinophils

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29
Q

Function of neutrophils

A

Defence against infection
Phagocytosis
Neutrophil migration associated with infection

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30
Q

Function of eosinophils

A

Defence against parasitic infection

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31
Q

Function of basophils

A

Involved in regulation of immune responses

Stores of histamine and heparin and proteolytic enzymes

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32
Q

Function of monocytes

A

Present antigens to lympohoid cells

Migrate to tissues where they develop into tissue macrophages

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33
Q

Function of tissue macrophages

A

Phagocytic and scavenging function

Storage and release of iron

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34
Q

Describe formation of a natural killer (NK) cell

A

HSC differentiates to common lymphoid progenitor via mitosis

CLP further differentiates to NK cell

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35
Q

Function of natural killer (NK) cell

A

Kill tumour cells
Kill virus infected cells

secrete cytotoxic granules

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36
Q

What is leucocytosis?

A

An increase in the number of lymphocytes in the blood above the reference range

Different names depending on cell type affected
e.g. monocytosis
eoisinophilia
basophilia 
lymphocytosis
neutrophilia
37
Q

What is leucopenia?

A

An decrease in the number of lymphocytes in the blood below the reference range
e.g.
neutropenia

38
Q

Causes of neutrophilia

A

Infection,
inflammation
infarction
chronic myeloid leukaemia

Pregnancy
Exercise
Corticosteroids

39
Q

What is left shift in regards to neutrophilia?

A

Increase in non-segmented neutrophils or neutrophil precursors in the blood

40
Q

Causes of neutropenia

A
Chemotherapy/radiotherapy
Autoimmune disorders (Produce antibodies against own neutrophils)
Severe bacterial infections
Viral infections
drugs-e.g. anti-pscycotics

Benign ethnic neutropenia
-African or Afro-Caribbean ancestry

41
Q

Causes of neutrophil hypersegmentation

A

Lack of vitamin B12
Folic acid deficiency
(Megaloblastic anaemia)

42
Q

Causes of lymphocytosis

A
Viral infection (transient) e.g. whooping cough
Leukaemia (persistent)
43
Q

Histological presentation of lymphocytosis

A

Atypical lymphocytes
Basophilic cytoplasm
‘Hugging’ of red blood cells

44
Q

Causes of lymphopenia

A

HIV
Chemotherapy
Radiotherapy
Corticosteroids

45
Q

Causes of monocytosis

A

Infection (chronic)

Chronic inflammation

46
Q

Histological features of eoisinophils

A

Granular cytoplasm

lobed nuclei

47
Q

Histological features of basophils

A

Purple/blue cytoplasm

granular

48
Q

Histological features of monocyte

A

Lobular nucleus

Clear cytoplasm

49
Q

Histological features of neutrophil

A
lobed nucleus (5-7)
Clear cytoplasm
50
Q

Histological features of lymphocyte

A

Blob of cytoplasm with inner blob (purple)

51
Q

Causes of Eosinophilia

A

Allergy
Parasitic infection
leukaemia

52
Q

Causes of Basophilia

A

leukaemia (uncommon finding)

53
Q

Describe normal inflammatory pathway after vascular tear.

A
  1. Inflammatory signals:
    Non apoptotic cell death releases molecular signals
    (DAMPS)
  2. Vasodilators released:
    Histamine
    Nitric oxide
  3. Vascular changes
    Increased permeability
    reduced flow
    Plasma leakage
  4. Immune cell recruitment
    Chemokines released causes leukocyte migration to chemokine source
  5. Cytokines causes up regulation of adhesion molecules such as selectins.
    Chemokines promote low to high affinity switch in integrins.
    Neutrophils bind to selectins
    Cytoskeletal rearrangement and extension of pseudopodia causes neutrophil ‘rolling’
54
Q

Neutrophil function at site of inflammation

A

Pathogen recognition and clearance (TLR4)
Cytokine secretion promoting recruitment and activation of other immune cells
Phagocytosis
-Destruction by reactive oxygen species (ROS)

55
Q

Resolution of acute inflammation

A

Pathogen recognition
Neutrophils have short half life
Macrophages clear apoptotic cells
Repair/wound healing

56
Q

Pros vs cons of macrophage residency in chronic inflammation

A

Good:
Phagocytic
Cytotoxic
Anti-inlfmmatory

Bad:
Cytotoxic
Inflammatory
Pro-fibrotic

57
Q

Consequences of chronic inflammation

A

Fibrosis- collagen deposition
loss of function
scarring
excessive tissue damage

58
Q

Describe the structure of collagen I, II and III

A

3 alpha chains:
type I- heterotrimer (2 genes)
Type II/III- homotrimer (1 gene)

Triple helix

59
Q

Describe the primary sequence of collagen.

A

Characteristic glycine X-Y repeat
Glycine only amino acid small enough to fit in helix
X-Y normally hydroxyproline/proline

60
Q

What does post translational modification of proline lead to?

A

Hydroxylation of proline allows formation of hydrogen bonds

61
Q

How does vitamin C deficiency lead to scurvy?

A

Vitamin C required co factor in enzyme required for collagen cross linking
Unhydroxylated collagens cause tissue weekness

62
Q

Describe collagen biosynthesis from a secreted protein

Fibril associated collagen

A

Procollagen converted to tropocollagen after cleavage of end terminals
tropocollagens form collagen fibrils with hydrogen bonds between each

63
Q

What are non fibril associated collagens

A

Arrange head to tail or laterally
Form ‘web/grid’
Collagen IV in basement membrane

64
Q

What is Ehlers-Danlos syndromes (EDS)

A

Inherited connective tissue disorder resulting in stretchy skin and loose joints
Mutation in collagen gene

65
Q

Components of a basement membrane:

A

Collagens
Glycoproteins
Proteoglycans

66
Q

Consequence of diabetic nephropathy

A

Accumulation of extracellular matrix- highly thickened basement membrane
-restricts renal function

67
Q

Cause and effects of Alport syndrome

A
Mutation in collagen IV
Abnormally split and laminated GBM
-progressive loss kidney function 
-proteinuria (proteins in urine)
-hearing loss
68
Q

Describe the structure of elastic fibres

A

Elastin core

Microfibrils surround which are rich in fibrillin protein

69
Q

Consequences of Marfan’s syndrome

A

Predisposition to aortic ruptures

Spider like fingers

70
Q

Describe the structure and function of laminins

A

heterotrimic proteins
alpha, beta, gamma chain in cross shape

Multi adhesive proteins
-interact cell surface receptors (integrins, dystroglycan)
Interact with basement matrix components (collagen, proteoglycans)

71
Q

What disease is caused by an absence of the alpha 2 chain in laminin 2?

A

Congenital muscular dystrophy

72
Q

Describe the structure and function of fibronectin

A

glycoprotein
derived from single gene- alternate splicing mRNA gives rise to different types
Multi adhesive protein

73
Q

Describe formation of a collagen fibril

A

Pro alpha chains undergo covalent modifications and 3 form triple helixed procollagen molecule
Procollagen cleaved to collagen
Forms fibrils in parallel direction

74
Q

What is paracrine signalling?

A

Hormone acts on an adjacent cell

I.E. Nitric Oxide

75
Q

What is signalling between membrane proteins?

A

Plasma proteins on adjacent cells interacting

- Bacterial cell wall components with toll like receptors on haemopoetic cells

76
Q

What is autocrine signalling?

A

signalling molecule acts on same cell

- acetylcholine-presynaptic receptors

77
Q

List and describe the four types of cell signalling receptors

A

Ionotrophic receptor-
Ligand binding opens ion channel which traverses membrane

G-Protein coupled receptors
ligand binding activates intracellular G-protein complex
and GDP is converted to GTP

Enzyme-linked receptor
Ligand binding to receptor activates internal enzymes

Intracellular receptor
Membrane permeable ligand binds to a receptor inside a cell

78
Q

Describe action of an ionotrophic receptor

A

Ligand binds to receptor
Conformational change
opens pore
Ions can move in or out of cells depending on conc gradient

79
Q

Describe mechanism of a G-protein coupled receptor activating target protein.

A

Heterotrimic G-protein and receptor are inactive
extracellular ligand binding changes conformation of receptor
Unassociated G-protein can now bind with receptor (receptor increased affinity)
GDP-GTP
G protein dissociates into alpha and a beta-gamma subunit
binds to target protein

80
Q

Describe the mechanism of a G-protein coupled receptor disassociating from a target protein

A

Internal GTP-ase dephosphorylates GTP-GDP
alpha subunit dissociates from target protein and rebinds to beta/gamma subunit
Receptor remains active as long as ligand bound and can activate further G-proteins

81
Q

3 categories of G-protein alpha subunits

A

G-alpha S (Stimulate)
G-alpha I (inhibitory)
G-alpha q (activates system e.g. muscle contraction)

82
Q

Describe mechanism of an enzyme-linked receptor

A

Ligand binding causes receptors to cluster
Receptor clustering activates enzyme activity within cytoplasm
Enzymes phosphorylate receptor
phosphorylation causes binding of signalling proteins to cytoplasmic domain
signalling proteins recruit other signalling proteins
autocrine signalling

83
Q

Describe mechanism of a type 1 intracellular receptor

A

Ligand/hormone binds to receptor
Causes Heat Shock Protein (HSP) to dissociate
2 receptors bind together forming homodimer and travel to nucleus
Bind to DNA and cause DNA changes or affect transcription

84
Q

Describe mechanism of a type 2 intracellular receptor

A

Hormone/ligand binds to receptor which is bound to DNA within the nucleus
causes changes to DNA/ transcription

85
Q

Describe the structure of collagen

A

3 alpha chains, can be homo or heterotrimer
Triple helix

Glycine- X-Y repeat
(x-proline)
(Y-hydroxyproline)
Hydrogen bond cross links (hydroxylated Proline-proline)
((-PTM))
86
Q

How many chain types does type I collagen have?

How many chain types does type II/III collagen have?

A

2 chain types, 2 genes, heterotrimer

1 chain type, 1 gene, homotrimer

87
Q

Consequences of vitamin C deficiency on collagen structure

A

Results in unhydroxylated collagens, vitamin C required co-factor for enzymes involved

88
Q

Describe formation of a collagen fibril

A

Pro alpha chains undergo covalent modifications and 3 form triple helixed procollagen molecule
Procollagen cleaved to collagen
Forms fibrils in parallel direction (troop