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Phase 2a > Intro to clinical sciences > Flashcards

Intro to clinical sciences Flashcards

1
Q

Hospital autopsies

A

Account for less than 10% UK autopsies
Requires medical certificate of cause of death
Used for teaching, research, governance

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2
Q

Medico-legal autopsies

A

Account for more than 90% UK autopsies
CORONIAL AUTOPSIES - death is not due to unlawful action
FORENSIC AUTOPSIES - death is thought unlawful

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3
Q

Role of coronial autopsy - answer what 4 questions?

A

Who was deceased?
When did they die?
Where did they die?
How did their death come about?

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4
Q

Why deaths are referred to the coroner? 3

A

Presumed natural
Presumed unnatural
Presumed iatrogenic

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5
Q

Why deaths referred to coroner - presumed natural

A

Cause of death unknown
Patient has not seen doctor within 14 days prior to death
Most common reason for referral

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6
Q

Why deaths referred to coroner - presumed iatrogenic

A

Peri/ postoperative deaths
Anaesthetic deaths
Illegal abortions
Complications of therapy (even if recognised complication)

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7
Q

Why deaths referred to coroner - presumed unnatural

A 
Accidents 
Industrial deaths 
Suicides 
Unlawful killing (eg murder)
Neglect 
Custody death
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8
Q

Who refers for autopsy?

A

Doctor
Registrar of BDM
Others

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9
Q

Who refers for autopsy - doctors

A

NOT a statutory duty to refer
Common law duty
GMC will provide guidance

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10
Q

Who refers for autopsy - registrar of BDM

A

STATUATORY DUTY to refer

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11
Q

Who refers for autopsy - others

A

Police

Relatives

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12
Q

Who performs which autopsies - histopathologists

A 
Hospital autopsies 
Coronial autopsies (NATURAL deaths, drowning, suicide, accidents, road traffic deaths, fire deaths, industrial deaths, peri/postoperative deaths
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13
Q

Who performs which autopsies - forensic pathologists

A

Coronial autopsies (homicide, death in custody, neglect, any from list above that may be due to action of 3rd party)

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14
Q

What are the 5 stages of an autopsy?

A
  1. History/ scene
  2. External examination
  3. Evisceration
  4. Internal examination
  5. Reconstruction
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15
Q

What tests and processes does an autopsy include?

A 
Microbiology 
Toxicology 
Radiology 
Digital photography 
Genetics 
HISTOLOGY
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16
Q

Autopsy - external examination

A 
IDENTIFICATION 
formal identifiers 
gender, age 
body habitus (build) 
body modification 
clothing 
jewellery 
DISEASE AND TREATMENT 
INJURIES
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17
Q

Autopsy - evisceration

A
  • Y shaped inscision - from behind ears down to clavicles then down to midline
  • Open ALL body cavities
  • Examine all organs in situ
  • Remove thoracic and abdominal organs
  • Remove brain
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18
Q

Autopsy - internal examination

A 
Heart and great vessels 
Lungs, trachea, bronchi 
Liver, gallbladder pancreas
Avoid lower GI tract if possible (infection risk) 
Spleen, thymus, lymph nodes 
GU tract (common place for cancer) 
Endocrine organs 
CNS
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19
Q

Acute inflammation definition

A

The initial and often transient series of tissue reactions to injury - may last from few hours to few days

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20
Q

An example of acute inflammation

A

Appendicitis

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21
Q

What is inflammation?

A

Local, physiological response to tissue injury

Not a disease, usually a manifestation of disease

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22
Q

Inflammation benefits

A

Destruction of invading microorganisms
Walling off of an abscess cavity
Preventing the spread of infection

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23
Q

Inflammation limitations

A

DISEASE - an abscess in brain act as space occupying lesion compressing vital surrounding structures
FIBROSIS occurring from chronic inflammation (may distort tissues and permanently alter their function)

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24
Q

5 steps of acute inflammation?

A
  1. INITIAL REACTION of tissue to injury
  2. VASCULAR COMPONENT: dilation of vessels
  3. EXUDATIVE COMPONENT: vascular leakage of protein rich fluid
  4. NEUTROPHIL POLYMORPH - is the characteristic cell recruited to tissue
  5. OUTCOME
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25
Q

4 outcomes of acute inflammation occurring?

A

Resolution
Suppuration (pus formation, abscess)
Organisation (granulation tissue)
Progression to chronic inflammation

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26
Q

‘Organisation’ outcome of acute inflammation

A
  • SUBSTANTIAL DAMAGE to connective tissue framework and/ or tissue lacks ability to REGENERATE SPECIALISED CELLS
  • healing by FIBROSIS (scar formation)
  • dead tissues, exudate removed by MACROPHAGES
  • filled ingrowth GRANULATION TISSUE (this is organisation)
  • granulation tissue produces COLLAGEN to give fibrous scar
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27
Q

What is granulation tissue?

A

A specialised vascular connective tissue

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28
Q

IMPORTANT - Give 6 causes of acute inflammation

A
  1. microbial infections (pyogenic (pus causing) bacteria, viruses)
  2. hypersensitivity (parasites, tubercule bacilli)
  3. physical agents (trauma, ionising radiation, heat, cold)
  4. chemicals (corrosives, acid, alkalis, reducing agents)
  5. bacterial toxins
  6. tissue necrosis (ischaemic infarction)
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29
Q

Causes of acute inflammation - microbial infections

A

One of most common causes

Viruses -> death of individual cells by intracellular multiplication

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30
Q

Causes of acute inflammation - microbial infections - BACTERIA

A

Release specific EXOTOXINS (chemicals synthesised by them that specifically initiate inflammation
Release specific ENDOTOXINS (associated with their cell walls)

(some organisms cause immunologically mediated inflammation through hypersensitivity reactions)
(parasitic infections + tuberculous inflammation are instances where hypersensitivity is important)

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31
Q

Causes of acute inflammation - hypersensitivity

A

ALTERED STATE of immunological responsiveness causes inappropriate or excessive immune rxn that damages tissues
All have CELLULAR or CHEMICAL mediators similar to those involved in inflammation

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32
Q

Causes of acute inflammation - physical agents

A

Physical trauma, UV/ ionising radiation, burns, excessive cooling (frostbite)
Cause tissue damage leading to inflammation

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33
Q

Causes of acute inflammation - irritant and corrosive chemicals

A

Corrosive = acids, alkalis, oxidising agents
Inflammation through GROSS TISSUE DAMAGE
Specific chemical irritants from infecting agents DIRECTLY cause inflammation

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34
Q

Causes of acute inflammation - tissue necrosis

A

Death of tissues from lack of oxygen/ nutrients from inadequate blood flow (infarction) = potent inflammatory stimulus
EDGE of recent infarction often shows acute inflammatory response due to PEPTIDES from dead tissue

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35
Q

5 essential macroscopic appearances of acute inflammation

A
  1. Redness - rubor
  2. Heat - calor
  3. Swelling - tumor
  4. Pain - dolor
  5. Loss of function
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36
Q

Acute inflammation - redness, rubor

A

dilation of small blood vessels within damaged area

eg sunburn, cellulitis due to bacterial infection, acute conjunctivitis

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37
Q

Acute inflammation - heat, calor

A

Seen only in peripheral parts of body eg skin
Due to increased blood flow (hyperaemia) so vascular dilation, delivery warm blood to area
SYSTEMIC FEVER from some chemical mediators of inflammation also contributes

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38
Q

Acute inflammation - swelling, tumor

A
  1. Oedema (accumlulation fluid in extravascular space as part of fluid exudate)
  2. Lesser extent- physical mass of inflammatory cells migrating to area
  3. Formation of new connective tissue
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39
Q

Acute inflammation - pain, dolor

A
  • Stretching and distortion of tissues from inflammatory oedema
  • Pus under pressure in abscess cavity
  • Some chemical mediators of acute inflammation (bradykinin, prostaglandins, serotonin) can induce pain
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40
Q

Acute inflammation - loss of function

A
  • Movement of inflamed area consciously and reflexly inhibited by pain
  • Severe swelling may physically immobilise
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41
Q

What 3 things accumulate in extracellular spaces of damaged tissues during early stages of acute inflammation?

A
  1. Oedema fluid
  2. Fibrin
  3. Neutrophil polymorphs
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42
Q

What is essential for HISTOLOGICAL diagnosis of acute inflammation?

A

Neutrophil polymorph (cellular component)

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43
Q

IMPORTANT - 3 stages of acute inflammatory RESPONSE PROCESS?

A
  1. Change vessel calibre (wider) so increased vessel flow
  2. Increased vascular permeability, formation of FLUID exudate
  3. Formation CELLULAR exudate, neutrophil polymorphs migrate to extravascular space
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44
Q

Vascular changes in acute inflammation: exudation

A
  • Pre-capillary sphincters (formed by smooth muscle of arteriolar walls) RELAX
  • Increased capillary hydrostatic pressure so plasma proteins escape into extravascular space
  • More fluid leaving vessel than is returned
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45
Q

Acute inflammation- 3 causes of increased vascular permeability?

A
  1. Chemical mediators eg histamine, bradykinin, NO (dilator), C5a (complement), PAF - immediate transient
  2. Severe direct vascular injury eg trauma - immediate sustained
  3. Endothelial cell injury: Xrays, bacterial toxins - delayed prolonged
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46
Q

Acute inflammation - 4 stages of neutrophil polymorph emigration?

A
  1. Margination of neutrophils
  2. Adhesion of neutrophils
  3. Neutrophil emigration
  4. Diapedesis (passage through walls)
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47
Q

Acute inflammation - neutrophil polymorph emigration - stage 1 Margination

A
  • Loss intravascular fluid
  • Increase plasma viscosity
  • At site of acute inflammation, means neutrophils flow in PLASMATIC ZONE
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48
Q

Acute inflammation - neutrophil polymorph emigration - stage 2 Adhesion

A
  • PAIRED ADHESION MOLECLUES on leucocyte and endothelium interact
  • Pavementing (adhesion to vascular endothelium)
  • Early only in venules
    (chemical inflammatory mediators can make adhesion molecules more active)
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49
Q

Acute inflammation - neutrophil polymorph emigration - stage 3 Emigration

A
  • Leucocytes migrate venules, small veins (not capillaries)

- Neutrophils, macrophages, eosinophil polymorphs INSERT PSEUDOPODIA, migrate, through basal lamina

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50
Q

Acute inflammation - neutrophil polymorph emigration - stage 4 Diapedesis

A
  • RBCs escape passively (hydrostatic pressure)

- Lots RBCs in extravascular space implies severe vascular injury

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51
Q

Chemical mediators of acute inflammation - explanation of process

A
  • Small area tissue damaged
  • Tissue releases chemical substances which spread out to uninjured areas
  • HISTAMINE and THROMBIN (released by original inflammatory stimulus) cause up-regulation of adhesion molecules on endothelial cell surface
  • Causing very firm neutrophil adhesion
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52
Q

IMPORTANT - what 5 things do endogenous chemical mediators cause?

A
  1. Vasodilation
  2. Emigration of neutrophils
  3. Chemotaxis (attraction neutrophil polymorphs to certain chemicals)
  4. Increased vascular permeability
  5. Itching and pain
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53
Q

Acute inflammation - histamine

A
  • Causes vascular dilatation, immediate transient phase increased vascular permeability
  • Stored in preformed granules - immediate effect
  • In: mast cells, basophil and eosinophil leucocytes, platelets
  • Release stimulated by C3a, C5a, lysosomal proteins from neutrophils
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54
Q

Acute inflammation - 4 other chemical mediators

A
  • Lysosomal compounds
  • Eicosanoids (prostaglandin)
  • Serotonin ( 5-hydroxytryptamine)
  • Chemokine (chemotactic cytokine)
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55
Q

Acute inflammation - 4 plasma enzymatic cascade systems?

A
  1. Complement
  2. The Kinins
  3. Coagulation factors
  4. Fibrinolytic system
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56
Q

Acute inflammation - plasma cascades - the complement system

A
  • Complex system interacting plasma proteins
  • Major effector system for antibody mediated immune reactions
  • Remove or destroy antigen - direct lysis or opsonisation
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57
Q

Acute inflammation - plasma cascades - ACTIVATION OF the complement system

A
  • Tissue necrosis, cells release enzyme that can activate complement
  • Infection - antigen antibody complexes - activate via classical pathway
  • Infection - endotoxins gram neg bacteria - alternative pathway
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58
Q

Acute inflammation - plasma cascades - the kinin system

A
  • Activated factor XII, plasmin activate conversion prekallikrein to kallikrein
  • leucocyte proteases (trypsin) can activate prekallikrein
  • Conversion of kininogens to kinins (eg bradykinin - vasodilation)
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59
Q

Acute inflammation - what 2 important chemical mediators do TISSUE MACROPHAGES secrete? and what effects do these chemical mediators have?

A
  • The cytokines INTERLEUKIN-1 and TUMOR NECROSIS FACTOR ALPHA
    (their stimulatory effects occur after histamine and thrombin’s)
  • cause endothelial cells, fibroblasts, epithelial cells to secrete MCP-1, chemotactic protein, attracts neutrophil polymorphs
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60
Q

Acute inflammation - leucocytes

A
  • Blood monocytes - arrive site of inflammation, leave vessels, transform to macrophages, more metabolically active, motile, phagocytic
  • Phagocytosis enhanced opsonisation (by antibodies, complement)
  • Most acute inflamm macrophages lesser role than neutrophil polymorphs
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61
Q

Acute inflammation - macrophages

A
  • Appear first few hours, don’t predominate
  • Later stage, neutrophils diminished, macrophage population enlarged by local proliferation
  • Neutrophils and macrophages discharge lysosomal enzymes to extracellular fluid, aids digestion inflammatory exudate
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62
Q

Acute inflammation - lymphatics

A
  • Terminal are blind ended endothelial lined
  • In most tissues, similar number to capillaries
  • Collecting lympatics drain to terminal, have valves (propel passively), neighbouring muscles contract, to nodes
  • Dilate in acute inflamm to drain OEDEMA fluid of inflamm exudate
  • Antigens to regional lymph nodes, recognition by LYMPHOCYTES
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63
Q

Acute inflammation - what colour does neutrophil polymorph stain using H&E?

A
  • Nucleus = blue

- Cytoplasm = pink / purple

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64
Q

Acute inflammation - binding of immunoglobulins to microorganisms

A
  • Bind by their Fab component
  • Leaves Fc component exposed
  • Neutrophils have surface receptor for Fc (so can bind microorganism before ingesting)
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65
Q

Acute inflammation - what are the two common cells which implement phagocytosis?

A
  • Macrophages

- Neutrophil polymorphs

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66
Q

Acute inflammation - basic steps of phagocytosis?

A
  • Opsonisation facilitates adhesion to cell surface
  • Ingestion by phagocyte surrounding particle using pseudopodia
  • Fuse = phagosome surrounded by cell membrane
  • Lysosomes fuse phagosome = phagolysosomes, intracellular killing
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67
Q

Acute inflammation - neutrophil polymorphs - intracellular killing using NOXIOUS MICROBICIDAL AGENTS

A

Similar to bleach

  • OXYGEN DEPENDENT (hydrogen peroxide + myeloperoxidase in cytoplasmic granules in presence of halide (Cl-) to produce potent microbicidal agent)
  • OXYGEN INDEPENDENT (lysozyme (muramidase) and lactoferrin)
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68
Q

Acute inflammation - neutrophil polymorphs - effects of release of lysosomal products?

A
  • damages local tissue - proteolysis - elastase, collagenases
  • activates coag factor XII
  • attracts leucocytes
  • some increase vascular permeability
  • some PYROGENS induce systemic fever act on hypothalamus
  • lifespan only 1-3 days
  • die locally, leave via lymphatics, removed by apoptosis
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69
Q

Acute inflammation - Role of mast cells?

A
  • Stimulation by C3a/C5a components
  • Release preformed inflamm mediators (histamine) stored in granules
  • Metabolise ARACHIDONIC ACID into new inflamm mediators eg leukotrienes, prostaglandins, thromboxanes
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70
Q

Acute inflammation - special macroscopic appearances

A

Cardinal signs modified according to tissue + type of agent

  • Serous inflammation
  • Suppurative inflammation
  • Membranous inflammation
  • Pseudomembranous inflammation
  • Necrotising (gangrenous) inflammation
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71
Q

Acute inflammation - beneficial effects of the fluid exudate?

A
  • dilution of toxins (carried away in lymphats)
  • entry of antibodies (lysis via complement, phagocytosis via opsonisation, neutralisation of toxins)
  • transport of drugs
  • fibrin formation (exuded fibrinogen, traps, matrix for formation granulation tissue)
  • delivery of nutrients, oxygen (neutrophils)
  • stimulation of immune response (lymph)
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72
Q

Acute inflammation - harmful effects (of lysosomal enzyme release) ?

A
  • digestion of normal tissues (collagenases, proteases, vascular damage)
  • swelling (children, enclosed spaces eg cranial cavity)
  • inappropriate inflammatory response
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73
Q

4 main outcomes of acute inflammation - outcome 1 - resolution

A
  • complete restoration to normal
  • example acute lobar pneumonia

conditions that favour:

  • minimal cell death/ damage
  • organ capable of regen eg liver not CNS
  • rapid phagocytosis
  • rapid local vascular drainage
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74
Q

4 main outcomes of acute inflammation - outcome 2 - suppuration

A
  • pus - living, dying, dead neutrophils bacteria, cell debris, lipid
  • persistant infective pyogenic stimulus
  • pyogenic membrane - sprouting capillaries, neutrophils, fibroblasts –> granulation tissue, scarring
  • bacteria in abscess relatively inaccessible antibodies, antibiotics
75
Q

Acute inflammation - abscesses

A
  • ‘point’ then burst
  • obliterated by organisation +fibrosis
  • leaves small scar
  • hollow organ = mucosal layers outflow tract may fuse together by fibrin = empyema
76
Q

4 main outcomes of acute inflammation - outcome 3 - organisation

A
  • replacement by granulation tissue (blood vessels + fibroblasts)

conditions that favour

  • large amounts fibrin (cannot be removed completely by fibrinolytic enzymes)
  • much necrosis, dead tissue thats not easily digestable
  • exudate + debris cannot be removed
77
Q

4 main outcomes of acute inflammation - outcome 3 - WHAT HAPPENS DURING organisation?

A
  • new capillaries grow (into exudate)
  • macrophages migrate
  • fibroblasts proliferate - due to TGF-BETA
  • fibrosis, possible scar

example - in pleural space post acute lobar pneumonia

78
Q

4 main outcomes of acute inflammation - outcome 4 - progression to chronic inflammation

A
  • acute inflamm agent not removed
  • cellular exudate changes: now lymphocytes, plasma cells, macrophages, MNGC, fibroblasts (lay down collagen)

often occurs as primary event (no acute before)

79
Q

Acute inflammation - systemic effects of inflammation

A
  • Pyrexia (fever)
  • Constitutional symptoms
  • Reactive hyperplasia of the reticuloendothelial system
  • Haematological changes
  • Amyloidosis
80
Q

Acute inflammation - systemic effects - Pyrexia

A
  • neutrophil polymorphs, macrophages produce ENDOGENOUS PYROGENS - act on hypothalamus - set thermoreg systems to higher temperature
  • release pyrogens stimulated by phagocytosis, endotoxins, immune complexs
  • IL-2 pyrogen has greatest effect
81
Q

Acute inflammation - systemic effects - 4 constitutional symptoms

A
  1. malaise
  2. anorexia
  3. nausea
  4. weight loss (neg nitrogen balance (energy to produce inflamm mediators) common w/ extensive chronic inflammation)
82
Q

Acute inflammation - systemic effects - reactive hyperplasia of reticuloendothelial system

A
  • local/ systemic lymph node enlargement

- splenomegaly (certain specific infections eg malaria, infectious mononucleosis)

83
Q

Acute inflammation - systemic effects - haematological changes

A

+ WBCs
- neutrophils: pyogenic infections, tissue destruction
- eosinophils: allergies, parasitic
- lymphocytes: chronic + viral infections, whooping cough
- monocytes: bacterial infections
Anaemia: blood into inflamm exudate, haemolysis due to bacterial toxins

84
Q

Acute inflammation - systemic effects - amyloidosis

A
  • long standing chronic inflamm
  • elevates serum amyloid A protein (SAA)
  • amyloid = abnormal protein, deposited various tissues
  • secondary (reactive) amyloidosis
85
Q

IMPORTANT - CHRONIC INFLAMMATION - definition

A

The subsequent and often PROLONGED tissue reactions to injury following the initial response
Can be defined as an inflamm process in which lymphocytes, plasma cells, macrophages predominate

86
Q

Chronic inflammation - example

A

Leprosy

chronic usually primary (sometimes after acute)

87
Q

Chronic inflammation - 4 causes

A
  • primary chronic inflammation
  • transplant rejection
  • progression from acute inflamm
  • recurrent episodes of acute inflamm
88
Q

Chronic inflammation - causes - primary chronic inflammation

A

no initial phase acute inflamm

  • endogenous materials (bone, uric acid crys)
  • exogenous materials (asbestos fibres)
  • some autoimmune diseases (rheumatoid)
  • specific disease of unknown aetiology (IBS)
  • resistance of infective agent to phagocytosis+intracellular killing (TB)
  • primary granulomatous diseases (crohns)
89
Q

Chronic inflammation - causes - progression from acute inflammation

A
  • most common: suppurative
  • deep seated abscess cavity, delayed/inadequate drainage
  • develops thick walls from granulation/ fibrous tissue
  • rigid walls fail come together, stagnating pus organised ingrowth granulation tissue
  • replaced fibrous scar
90
Q

Chronic inflammation - causes - progression from acute inflammation - indigestible materials

A
  • keratin
    -fragments of necrotic bone
  • foreign body materials eg wood (chronic suppuration)
    are inert, resistant to lysosomal enzymes
  • GRANULOMATOUS INFLAMM
  • cause macrophages to form multinucleate giant cells (foreign body giant cells)
91
Q

Chronic inflammation - causes - recurrent episodes of acute inflammation example?

A

Chronic cholecystitis (due to gallstones)

92
Q

Chronic inflammation - 5 macroscopic appearances

A
  • chronic ulcer (eg peptic: breach of mucosa)
  • chronic abscess cavity (osteomyelitis)
  • thickening of wall of hollow organ
  • granulomatous inflammation (walling off)
  • fibrosis (thickening/scarring connective tissue)
93
Q

Chronic inflammation - THE IMPORTANT microscopic feature

A

Cellular infiltrate consists mainly of lymphocytes, plasma cells, macrophages
(few eosinophil polymorphs may be present)
(macrophages may form multinucleate giant cells)

94
Q

Chronic inflammation - 4 microscopic features

A
  • exudation fluid not prominent
  • maybe new fibrous from granulation tissue
  • continuing destruction same time regen
  • tissue necrosis (esp granulomatous)
95
Q

Chronic inflammation - paracrine stimulation of connective tissue proliferation

A
  • regen and migration of specialised cells
    1. angiogenesis
    2. fibroblast proliferation
    3. collagen synthesis
    4. formation of granulation tissue
  • regulated by growth factors eg TGF-beta, IGF-1, TNF
96
Q

Chronic inflammation - lymphocyte cooperation

A
  • lymph tissue infiltrate
  • B cell: contact with antigen –> plasma cells
  • T cell: cell mediated immunity, encounter antigen, produce soluble factors (cytokines), recruitment/activation other cell types
97
Q

Chronic inflammation - what is a granuloma?

A

An aggregate of epithelioid histiocytes

may also contain lymphocytes

98
Q

Chronic inflammation - role of macrophages

A
  • move by amoeboid motion
  • respond to certain chemotactic stimuli
  • ingest wider range + live longer than polymorphs, harbour viable organisms (delayed type hypersensitivity response)
99
Q

Chronic inflammation - macrophages in inflamed tissue

A
  • derived from blood monocytes (migrated out vessels, transformed in tissues)
  • part of mononuclear phagocyte system/ reticular-endothelial system
  • activation as migrate to area inflamm = +size, protein syn, mobility, phagocytic activity, content lysosomal enzymes
100
Q

Chronic inflammation - give 3 examples of important cytokines macrophages produce?

A

Interferon-alpha and beta
Interleukin-1 6 and 8
Tumor necrosis factor alpha

101
Q

Chronic inflammation - granulomas

A
  • TB, leprosy, Crohns, sarcoidosis
  • usually lungs and skin
  • TB commonest cause granuloma
  • ziehl-neelsen stain bright red result: TB
102
Q

Chronic inflammation - epithelioid histiocytes

A
  • vaguely similar epithelial cells
  • large vesicular nuclei
  • plenty eosinophilic cytoplasm
  • elongated
  • clusters
  • little phagocytic activity
  • adapted to secretory function-secrete ACE
  • ACE levels marker for systemic granulomatous disease
103
Q

Chronic inflammation - granulomas

A
  • appearance altered by presence caseous necrosis or histiocytes –> multinucleate cells
  • granulomas+eosinophils = parasite
  • indigestibility particulates by macrophages
  • small traces elements eg berylium=granulom
104
Q

Chronic inflammation - 5 causes of granulomatous disease

A
  1. specific infections (fungi,parasites,TB)
  2. materials resist digestion (keratin,talc)
  3. specific chemicals (beryllium)
  4. drugs (sulphonamides)
  5. unknown (crohns, sarcoidosis)
105
Q

Chronic inflammation - histiocytic giant cells

A
  • form where particulate matter indigestible by macrophages accumulate
  • eg large foreign particles
  • multinucleate giant cells (100 nuclei) form when many macrophages digest same thing
  • MNGC little phagocytosis,unknown function
106
Q

Chronic inflammation - Langerhans giant cells

A
  • horseshoe peripheral nuclei one pole cell
  • TB
  • nothing to do with islets of langerhans
107
Q

Chronic inflammation - foreign body giant cells

A
  • large cells
  • nuclei randomly scattered cytoplasm
  • ## particulate foreign body material
108
Q

Chronic inflammation - Touton giant cells

A
  • central ring nuclei, peripheral to lipid
  • when macrophages attempt to ingest lipids
  • xanthoma, dermatofibroma
109
Q

Role of inflammation in systemic and organ-specific disease - acute inflammation is involved in which system?

A
  • Cardiovascular system

- Response to acute MI , cardiac rupture

110
Q

Role of inflammation in systemic and organ-specific disease - chronic inflammation is involved in which systems?

A
  • initiation, propagation and progression of cancer eg ulcerative colitis
  • myocardial fibrosis after MI
111
Q

Role of inflammation in systemic and organ-specific disease - atheroma

A
  • macrophages adhere to endothelium
  • migrate to arterial intima
  • (along with Tcells) express cell adhesion molecules (recruit more cells)
  • macrophages process lipids in plaques
112
Q

Role of inflammation in systemic and organ-specific disease - tissue injury and CNS

A
  • tissue injury associated with neurodegenerative disorders of CNS
  • eg multiple sclerosis = chronic demyelinating neurodeg disorder
  • chronic inflamm plays important role
113
Q

Repair and regeneration - cell renewal - labile cells

A
  • good capacity to regenerate
  • include surface epithelial cells (constantly lost, replaced by deeper)
  • injury/ normal ageing = cells lost, replaced stem cell pool in labile+stable cell population
114
Q

Repair and regeneration - cell renewal - stable cell populations

A
  • divide very slowly normally
  • retain capacity divide when necessary
  • eg hepatocytes, renal tubular cells
  • injury/ normal ageing = cells lost, replaced stem cell pool in labile+stable cell population
115
Q

Repair and regeneration - cell renewal - permanent cells

A
  • NO effective regeneration

- eg nerve cells, striated muscle cells

116
Q

Repair and regeneration - cell renewal - stem cells

A
  • mitotic division, 1 differentiates 1 stays as stem cell

- minority, discrete compartments

117
Q

Repair and regeneration - cell renewal - stem cells LOCATIONS

A
  • epidermis = basal layer, hair follicles, sebaceous glands
  • intestinal mucosa = bottom of crypts
  • Liver = between hepatocytes+bile ducts
  • Bone marrow = haematopoietic stem cells, seed into other organs+differentiate
118
Q

Repair and renewal - complete restitution

A
  • loss part of labile population can be completely restored
  • eg minor skin abrasion
  • contact inhibition of growth+movement important control mechanisms
119
Q

IMPORTANT - repair and renewal - organisation definition

A

The repair of specialised tissues by formation of fibrous scar
(common consequence of pneumonia)

120
Q

Repair and renewal - organisation process

A
  • scaffold of fibrin
  • granulation tissue formed
  • dead tissue removed by neutrophil polymorphs and macrophages
  • granulation tissue contracts, accumulates collagen, forms scar, remodelling
  • organised area firmer shrunken puckered
121
Q

Repair and renewal - granulation tissue

A
  • specialised/ complex tissue destroyed can only repair not reconstruct
  • capillary endothelial cells proliferate (loops)
  • fibroblasts divide, secrete collagen
  • myofibroblasts form
  • capillary loops+myofibroblasts = granulation tissue
122
Q

Repair and renewal - wound contraction and scarring

A
  • reducing volume tissue repair by 80%
  • myofibroblasts contract (attached to each other and matrix components)
  • collagen forms scar (replace lost specialised tissue)
  • infection+inflamm can increase scarring
123
Q

Repair and renewal - problems caused by would contraction

A
  • circumferential damage round lumen of tube eg gut = stenosis/obstruction
  • permanent shortening of muscle (contracture)
  • burns to skin = contraction = cosmetic damage and reduced mobility
124
Q

IMPORTANT - Pharmacology - definition

A

the study of the effects of drugs

125
Q

IMPORTANT - Pharmacology - pharmacokinetics definition

A

how the BODY affects the drug: absorption, distribution, metabolism, excretion (ADME)

126
Q

IMPORTANT - Pharmacology - pharmacodynamics defnition

A

how the DRUG affects the body

D in Dynamics so drug first

127
Q

Pharmacology - possible drug targets

A
  • ligand-gated ion channels
  • G protein coupled receptors
  • kinase-linked receptors
  • cytosolic/ nuclear receptors
  • enzymes
  • transporters
  • ion channels
    (most drug targets are proteins)
128
Q

Pharmacology - drug targets - receptors

A
  • main target
  • principle means for chemical commu:
  • neurotransmitters: ACh, serotonin
  • Autoacids; cytokines, histamine
  • hormones; testosterone, hydrocortisone
129
Q

Pharm - drug targets - ligand gated ion channels

A
  • nicotinic ACh receptor
  • binding ACh opens pore
  • allows cations to move into cell
130
Q

Pharm - drug targets - GPCRs

A
  • beta-adrenoceptors
  • ‘serpent like’ receptors
  • 7 transmembrane proteins
  • muscarinic receptors, beta-2-adrenoreceptor use GPCRs
  • majority react with PLC or AC
131
Q

Pharm - drug targets - kinase linked receptors

A
  • receptors for growth factors
  • show intrinsic kinase activity
  • tyrosine phosphorylation
132
Q

Pharm - drug targets - cytosolic/ nuclear receptors

A
  • steroid receptors
  • can modify gene transcription
  • zinc fingers recognise discrete regions of DNA
133
Q

Pharm - imbalance of drugs/ receptors can lead to pathology

A
  • Chemicals: allergy; increased histamine, Parkinsons; decreased dopamine
  • Receptors: Myasthenia gravis; loss of nicotinic ACh receptors, mastocytosis; increase in C-kit receptor
    (essential to identify receptor involved in pathophysiology, to develop drugs act on this receptor)
134
Q

Pharm - what is a receptor ligand?

A

Anything that acts at a receptor eg propranolol

135
Q

IMPORTANT -pharm - what is potency?

A

A measure of how well a drug works

136
Q

Pharm - what is EC50?

A

The concentration that gives half the maximal response

137
Q

IMPORTANT - pharm - what is an agonist?

A

a compound that binds to a receptor and activates it

138
Q

Pharm - normal response curve

A
  • Linear or sigmoidal

- Partial agonist does not get maximal response (compared to full agonist)

139
Q

IMPORTANT - pharm - what equation do you use to calculate intrinsic activity?

A

Intrinsic activity = Emax partial agonist / Emax full agonist

140
Q

Pharm - describing the activity of agonists

A
  • Compound is more potent if lower concs of it give a greater response
  • Compound is more efficacious if it has a higher Emax
141
Q

IMPORTANT - pharm - antagonist definition

A

A compound that reduces the effect of an agonist

142
Q

Pharm - antagonists

A
  • Do not activate receptors

- Affinity of antagonist for receptor affects it activity

143
Q

Pharm - competitive antagonism

A
  • reverse effects of agonists by competing with agonist to bind receptors
  • dose response curve shifts RIGHT (more agonist required for same response)
144
Q

Pharm - non competitive antagonism

A
  • binds near receptor (prevents activation)
  • agonist still able to bind just not activate
  • dose response curve shifts RIGHT and DOWN
  • even more agonist required for same response
145
Q

Pharm - cholinergic receptor categorisation

A

AGONIST ANTAGONIST RECEPTOR
muscarine atropine mAChR
nicotine curare nACHhR

146
Q

Pharm - histamine receptor characterisation

A 
Histamine - agonist 
contraction of ileum 
acid secretion from parietal cells 
Mepyramine - antagonist
reversed ileum contraction 
no effect on acid secretion
147
Q

IMPORTANT - Pharm - affinity definition

A
  • describes how well a ligand BINDS to the receptor

- a property shown by both agonists and antagonists

148
Q

IMPORTANT - pharm - efficacy definition

A
  • describes how well a ligand ACTIVATES the receptor

- ONLY AGONISTS SHOW EFFICACY (antagonists show zero efficacy)

149
Q

Pharm - number of receptors at a tissue

A
  • less receptors at tissue = more drug required to illicit same effect
  • in most cases only need small number receptors to get full effect
150
Q

Pharm give an example of a drug that will inactivate a receptor

A

BAAM - bromoacetyl alprenolol (irreversible B-adrenoreceptor antagonist
(Furchgott equation used to calculate how many receptors are available)

151
Q

Pharm - receptor reserves

A
  • many tissues have holds for full agonists

- no receptor reserve for partial agonists

152
Q

Pharm - signal amplification

A
  • ligand binds receptor
  • sets off signalling cascade
  • signal amplification determines how powerful response will be
  • determined by type of tissue receptor is in
153
Q

Pharm - other types of receptor ligand

A
  • allosteric modulation: binding allosteric ligand, affects agonists effect on receptor
  • affinity modulation: change in EC50 value
  • efficacy modulation: change in Emax
  • positive modulation = allosteric
  • negative modulation = orthosteric
  • benzodiazepine = allosteric ligand
    inverse agonism: rarer
154
Q

Pharm - tolerance

A
  • reduction in drug/agonist effect over time

- continuous, repeated, high conc drug

155
Q

Pharm - desensitisation of receptors

A
  • uncoupled = receptor cant interact with G protein
  • receptor internalised in vesicle of cell
  • receptor becomes degraded
156
Q

Pharm - specificity

A

No compound is ever truly specific

157
Q

Pharm - SELECTIVITY (better to describe activity than specificity)

A
  • agonists can be selective and non selective
    (isoprenaline non selective B-adrenoreceptor agonist, activates both B1 and B2 receptors)
    (salbutamol selective B2-adrenoreceptor agonist (but at very high concs looses specificity so will activate both B1 and B2)
158
Q

Pharm - enzymes as drug targets

A
  • NSAIDs
  • ACE inhibitors
  • B-lactam antibiotics
159
Q

Pharm - NSAIDs

A
  • aspirin, ibuprofen, 50 aprox
  • analgesic, anti-pyretic, anti-inflamm
  • competitively inhibit cyclooxygenase (COX) (breaks down arachidonic acid to prostaglandin H2)
160
Q

Pharm - COX enzyme

A
  • arachidonic acid -> prostaglandin H2
  • 2 isoforms
    COX-1 normally and widely around body
    COX-2 induced, found mainly in inflamm
    (aspirin in non selective and irreversibly blocks active site)
161
Q

Pharm - angiotensin-converting-enzyme inhibitors

A
  • antihypertensives eg enalapril
  • less angiontensin2 to bind receptors
  • reduced vasoconstriction
  • less aldosterone released
  • mostly competitive inhibition
162
Q

Pharm - what is a pro-drug?

A

Drug that needs to be enzymatically cleaved to be activated

163
Q

Pharm - B-lactam antibiotics

A
  • penicillins, amoxicillins, cephalosporins
  • inhibit peptidoglycan cell wall biosynthesis
  • inhibit certain enzymes
164
Q

Pharm - enzymatic inactivation of drugs

A
  • most drugs kidney excretes
  • lipophilic are passively absorbed
  • CYP450 adds OH group
  • inhibitors/activators of CYP450 affect this
165
Q

Pharm - transporters as drug targets

A
  • proton pump inhibitors
  • diuretics
  • neuronal uptake inhibitors
    (transporters transport ions, small organic molecules) (most active so use ATPase)
166
Q

Pharm - proton pump inhibitors

A
  • omeprazole, lansoprazole
  • activated in acidic environments
  • inhibit acid secretion
  • stomach reduces H+/K+ ATPase pump
167
Q

Pharm - diuretics

A
  • inhibit symporters, increase water excretion
  • thiazide inhibit Na+/Cl- co-transporter DCT
  • antihypertensives, treat heart failure
168
Q

Pharm - neuronal uptake inhibitors

A

+ conc of neurotransmitter in synapse by preventing their reuptake - increasing levels of this neurotransmitter

  • neurotransmitters subject to uptake: serotonin, dopamine, noradrenaline, GABA
  • SSRIs, imipramine, cocaine inhibits reuptake of dopamine
169
Q

Pharm - ion channels as drug targets - 2 examples of drugs

A
  • calcium channel blockers

- local anaesthetics

170
Q

Pharm - calcium channel blockers

A
  • eg verapamil, treat hypertension
  • block voltage dependant Ca channels
  • reduces vasoconstriction
171
Q

Pharm - local anaesthetics

A
  • lidocaine, procaine
  • interrupt axonal neurotransmission in sensory nerves
  • block voltage dependant Na channels
  • no depolarisation, no threshold
  • pain not transmitted to brain
  • diffuse through mucus membranes easily so can act on muscles too
172
Q

IMPORTANT - microbiology - pathogen definition

A

Organism that causes or is capable of causing disease

173
Q

IMPORTANT - microbiology - commensal definition

A

Organism which colonises the host but causes no disease in normal circumstances

174
Q

IMPORTANT - microbiology - opportunist pathogen definition

A

Microbe that only causes disease if host defences are compromised

175
Q

IMPORTANT - microbiology - virulence/ pathogenicity definition

A

The degree to which a given organism is pathogenic/ any strategy to achieve this

176
Q

IMPORTANT - microbiology - asymptomatic carriage definition

A

When a pathogen is carried harmlessly at a tissue site where it causes no disease

177
Q

Microbiology basic facts

A
  • viruses usually smaller than bacteria
  • only 2-5% bacteria are pathogenic
  • more bacteria in colon than cells in body
178
Q

Microbiology - 7 tests and stains

A
  1. gram stain
  2. ziehl-neelsen stain
  3. catalase test
  4. coagulase test
  5. haemolysis test
  6. optochin test
  7. oxidase test
179
Q

Microbiology - gram stain - test process

A
  1. heat fix bacteria, primary stain eg crystal violet
  2. add iodine, binds crystal violet, fixes it to the cell wall
  3. decolorise with ethanol or acetone
  4. counterstain with pink safranin
180
Q

IMPORTANT - Microbiology - gram stain - results gram NEGATIVE

A
  • gram negative - double membrane -
    decoloriser interacts with lipids, cells loose outer lipopolysaccharide membrane and crystal violet-iodide complexes - thus appear PINK with counterstain
181
Q

IMPORTANT - Microbiology - gram stain - results gram POSITIVE

A
  • gram positive - single membrane -
    decoloriser dehydrates cell wall, crystal violet-iodide complexs get trapped in multilayered peptidoglycan, PURPLE appearance with counterstain
182
Q

IMPORTANT - Microbiology - Ziehl-Neelsen stain

A
  • gram differentiates most bacteria
  • MYCOBACTERIUM are ACID FAST BACILLI
    and do not take up gram stain
  • ACID FAST BACILLI = RED
  • NON ACID FAST BACILLI = BLUE
183
Q

IMPORTANT - Microbiology - catalase test

A
  • add H2O2 look for bubbling
  • STAPHLOCOCCI = catalase POSITIVE
  • STREPTOCOCCI = catalase NEGATIVE
    (many gram negative bacteria = catalase+)

Phase 2a (3 decks)

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