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MD1 Revision > Respiratory > Flashcards

Respiratory Flashcards

1
Q

How do internal and external validity differ?

A

Internal validity = how well trial deals with limitations like bias and confounding
External validity = applicability of trial results

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2
Q

What does PICOT stand for?

A 
P = population
I = intervention
C = comparator/control
O = outcome
T = timing
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3
Q

What is PICOT used for?

A

Frame question which will be used to search literature

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4
Q

What is stratified randomisation?

A

Randomisation divided by levels of key confounders

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5
Q

What does stratified randomisation seek to achieve?

A

To make composition of groups more similar with respect to key confounders > further reduce potential for confounding

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6
Q

What is the p-value?

A

Probability that observe result rose from chance
Conventional cutoff = 0.05
p <0.05 - statistically significant

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7
Q

What does the width of the 95% confidence interval measure?

A

Precision of result

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8
Q

How is external validity assessed?

A

By determining degree of concordance between randomised control trial and clinical setting in terms of PICOT

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9
Q

What is Klinefelter syndrome?

A

XXY trisomy

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10
Q

What is Turner’s syndrome?

A

XO monosomy

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11
Q

What is the Guthrie test?

A

Dried blood spot from heel prick

Enables mass screening of all newborns

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12
Q

How is phenylketonuria (PKU) screened for with a Guthrie test?

A

Blood spot can be tested for phenylpyruvate

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13
Q

What is the pathophysiology of PKU?

A

Lack of phenylalanine hydroxylase: needed for conversion of Phe > Tyr
Phe converted to phenylpyruvate in alternate metabolism
Elevated PKU damages brain and inhibits tyrosinase

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14
Q

What is the pathophysiology of cystic fibrosis (CF)?

A

Autosomal recessive conditions caused by mutation in CFTR gene
Cl ions can’t flow out of cell
Buildup of mucus in lungs
May lead to repeated chest infections
Pancreatic duct may be blocked too > insufficient pancreatic enzyme release > GIT problems

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15
Q

Describe the mechanism of quiet inspiration

A

Contraction of diaphragm
- Increases longitudinal and lateral dimensions of thorax
- Generates negative intrapleural pressure
Contraction of external intercostals
- Increases AP diameter of thorax
- Generates negative intrapleural pressure
Lung expands > inhalation
Relaxation of diaphragm and external intercostals > passive exhalation

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16
Q

What happens to the parietal pleura as the dimensions of the thorax increase?

A

Parietal pleura becomes more separated from visceral pleura
More volume in intrapleural space > more negative pressure generated
Pulls visceral pleura and lung outwards

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17
Q

What law models gass diffusion involved in respiration?

A

Fick’s law > dependent on

  • Surface area
  • Difference in partial pressures
  • Thickness of membrane
  • Solubility of gas
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18
Q

What limits transfer of oxygen acroos the alveolar membrane?

A

Perfusion, not diffusion

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19
Q

When is gas change most efficient?

A

Ventilation and perfusion matched: V/Q = 1

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20
Q

What does a low V/Q mean?

A

Reduced partial pressure of oxygen > hypoxia

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21
Q

Low partial pressure of oxygen due to what responds to supplemental oxygen?

A

Low V/Q

Not due to shunt

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22
Q

What is a shunt?

A

Extreme form of low V/Q unit with no ventilation
Leads to hypoxia
Hb not fully saturated with oxygen

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23
Q

How is ventilation and perfusion distributed throughout the lungs?

A

Almost all alveoli similar distance from mouth > all have similar resistance

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24
Q

What is an elevated partial pressure of carbon dioxide due to?

A

Inadequate alveolar ventilation

Rarely due to inefficient gas exchange

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25
Q

What do central and peripheral chemoreceptors respond to?

A 
Central chemoreceptors sensitive to H ions in CSF - prooduced by CO2
Peripheral chemoreceptors respond to
- H ions
- CO2
- O2
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26
Q

What does central cyanosis mean?

A

Arterial blood less saturated with oxygen

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27
Q

What are the characteristics of airflow obstruction?

A 
Increased sensation of breathing
Increased respiratory muscle effort
Active exhalation
Longer time to inspire
Longer time to exhale
Reduced maximum ventilation
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28
Q

What causes increased sensation of breathing?

A

Increased load to breathe or an increased drive for breathing

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29
Q

What can increase the load to breathe?

A

Stiff lungs
Narrow airways
Chest wall
Diaphragm

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30
Q

What can increase the drive for breathing?

A 
Higher centres
Mechanoreceptors
Irritant receptors
Chemoreceptors
Baroreceptors
Temperature
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31
Q

If airway obstruction is present, what accounts for the increase in work of breathing?

A

Inspiratory muscles need to generate higher [pressures to overcome obstruction to airflow

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32
Q

What are the consequences of airway obstruction?

A

Recruitment of accessory muscles
Increased oxygen consumption by respiratory muscles
Respiratory muscle fatigue

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33
Q

What is pulsus paradoxus?

A

Normally, systolic blood pressure lower on inspiration
In severe airflow obstruction when inspiratory effort high > much greater difference between systolic blood pressure during inspiration and expiration
- More negative intrapleural pressure on inspiration
- Lower transpulmonary pressure

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34
Q

Why do people with airflow obstruction generally take deep, slow breaths?

A

Minimises work of breathing for particular amount of ventilation needed
Lungs still able to expand properly, so people take advantage of this

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35
Q

Why do people with chronic airflow obstruction become breathless easily on exertion?

A

Reduced maximum minute ventilation due to decreased FEV1
Minute ventilation demand increases upon exercise
In those with airflow obstruction, maximum ventilation possible achieved before maximum heart rate

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36
Q

What happens if the airflow obstruction causes uneven ventilation?

A

Patchy perfusion > decreased gas exchnage capabilities
Compensatory mechanism to limit effect of having narrowed airways as capillaries constrict and block blood flow to affected alveoli
Aim to divert blood away from areas not being ventilated so abnormal gas exchange minimised

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37
Q

What happens in severe airway obstruction when V/Q mismatch is minimised?

A

Overall decreased gas exchange > hypoxia

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38
Q

What is the function of the nasopharynx?

A

Turbinates warm and moisten air > respiratory tract not dehydrated
Cools exhaled air to maintain moisture in nasal passage
Sinuses give timbre of voice
Olfactory epithelium for smell

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39
Q

Describe the respiratory epithelium and its constituent cells

A 
Pseudostratified ciliated columnar cells = move mucus
Goblet cells = secrete mucus
Basal stem cells in base of epithelium = renew epithelium
Brush cells with microvilli = possible sensory role
Serous cells = secretory role but unknown function
Small granule cells = endocrine function
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40
Q

What is the structure of the trachea?

A 
Tube
12 cm long
2 cm in diameter
10-12 C-shaped hyaline cartilage rings reinforcing wall
Opening of cartilage faces backwards - bridged by smooth muscle
3 layers
- Mucosa
- Submucosa
- Adventitia
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41
Q

What makes up the mucosa of the trachea?

A

Respiratory epithelium

Lamina propria

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42
Q

What makes up the submucosa of the trachea?

A

Glands

Connective tissue

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43
Q

What makes up the adventitia of the trachea?

A

Cartilage

Outer layer of connective tissue

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44
Q

Describe the structure of a bronchus

A

Initially like trachea, but with thinner walls
Cartilage rings become cartilage plates in intrapulmonary bronchi
- Stiffens wall
- Prevents collapse under negative pressure
Smooth muscle at boundary between lamina propria and submucosa
- Complete ring around mucosa
Glands

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45
Q

How do bronchioles differ from bronchi in structure?

A

No cartilage
Radial connective tissue keeps airways open
Surfactant reduces surface tension
With increasing divisions, lose goblet cells, then ciliated columnar cells
Gains Clara cells

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46
Q

What are Clara cells?

A

Columnar/cuboidal cells
Short microvilli
Secrete surfactant
May also neutralise toxins

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47
Q

Describe the structure of terminal bronchioles

A 
Final level of conducting system
No goblet cells
Clara cells and few cuboidal ciliated epithelial cells
1-2 layers of smooth muscle
Give rise to respiratory bronchioles
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48
Q

What structures arise from the respiratory bronchioles?

A

Alveoli

Chains of alveoli = alveolar ducts

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49
Q

What type of epithelium do respiratory bronchioles contain?

A

Cuboidal > squamous - needed for gas exchange

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50
Q

How are alveoli separated and connected?

A

Separated by interalveolar septum > contains

  • Reticular fibres and elastin fibres arranged radially > keep alveoli from collapsing
  • Pores > allow air to equilibrate
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51
Q

Describe the epithelial cells of the alveolus

A

Type I pneumocytes
- Simple squamous epithelium > majority of alveolar surface area
- Exchange surface
- Tight junctions
- Prominent basal lamina
Type II pneumocytes
- Cuboidal cells often in angle where 2 interalveolar septa meet
- Produce surfactant
- Local stem cells - produce type I and II

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52
Q

What is the blood-gas barrier?

A

Basal lamina of type I penumocyte fused with basal lamina of endothelial cell of capillary
Oxygen and CO2 exchanged across barrier

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53
Q

What do intra-alveolar macrophages do?

A

Ingest particles of foreign debris
When full
- Migrate up airways > carried off by ciliated cells
- Deposit in interalveolar septum loaded with particles

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54
Q

What is the histology of the pleura?

A 
Mesothelium = simple squamous epithelium
Underlying connective tisse
- Blood vessels
- Lymphatics
Some lymphatics drain into pleural space and contribute to lubrication of space
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55
Q

Where are mast cells particularly prevalent?

A

Body sites in contact with external environment

Because these sites particularly prone to attack

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56
Q

How are mast cells stimulated in exercise-induced asthma?

A

Hyperosmolarity of airway surface fluid during exercise triggers bronchospasm and activates mast cells

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57
Q

What is red man syndrome?

A

Profound vasodilation produced by mast cells

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58
Q

How are mast cells activated?

A

Allergen cross-links IgE > adjacent IgE receptors on mast cells bound > 2nd messenger cascade > degranulation

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59
Q

How long does the initial reaction from mast cell degranulation take?

A

30-45 sec

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60
Q

What is released from mast cells?

A 
Immediate
- Histamine
- Heparin
- Tryptase
- TNF-alpha
Rapid
- Leukotrienes
- PGD2
Slow
- IL-4
- IL-5
- GM-CSF
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61
Q

What do leukotrienes and PGD2 released from mast cells do?

A

Potent bronchoconstrictors

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62
Q

Which histamine receptors are acted on during mast cell degranulation?

A

H1 receptors

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63
Q

What are the immediate actions of histamine released from mast cells?

A 
Sensory nerve activation > pain and itch
Bronchospasm
Mucus secretion
Vasodilation
Increased vascular leak
H1 receptors in gut > colic pain
H2 receptors in gut > gastric acid secretion
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64
Q

Which cells produce cysteinyl leukotrienes?

A

Eosinophils
Mast cells
Macrophages

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65
Q

What are the stimuli for cysteinyl leukotriene production?

A

Allerge

C5a

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66
Q

What do cysteinyl leukotrienes do?

A

Potent bronchoconstrictor
Hypotension during anaphylactic shock
Vasodilator in skin musculature
Diminished cardiac output
Hypovolaemia
Mucus oedema and airway smooth muscle shortening > airway obstruction in asthma
Mucus and oedema > nasal obstruction in hayfever

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67
Q

What are the endogenous inhibitors of mast cell activation?

A

PGE2
Adrenaline
Cortisol
Pharmacological agents

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68
Q

What are the main actions of disodium cromoglycate and nedocromil sodium?

A

Weak anti-inflammatory action

Reduction in mast cell degranulation, sensory C-fibre activation and eosinophil activation

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69
Q

Why are disodium cromoglycate and nedocromil sodium well tolerated?

A

Don’t gain access to systemic circulation

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70
Q

What is omalizumab?

A

Humanised mAB against IgE

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71
Q

What is the mechanism of action of omalizumab?

A

Reduces sensitisation of mast cells over time by sterically hindering IgE binding to receptor

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72
Q

In what ways may mediator production from mast cells be inhibited?

A

Glucocorticoids

- Reduce mast cell cytokine production

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73
Q

In what way may mast cell mediator actions be inhibited?

A

H1 receptor antagonists = antihistamines

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74
Q

What are the indications for cysteinyl luekotriene receptor antagonists?

A

Aspirin-induced and exercise-induced asthma

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75
Q

What is asthma?

A

Chronic inflammation associated with airway hyper-responsiveness > recurrent episodes of

  • Wheezing
  • Breathlessness
  • Chest tightness
  • Coughing
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76
Q

How does the respiratory epithelium change with asthma?

A

Desquamation
Eosinophil infiltration in and under epithelium
- Damages epithelium
- Exposes sensory nerve > airway hyper-responsiveness

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77
Q

What is the pathophysiology of asthma?

A

Allerge sensitises mast cells and macrophages/DCs
Produce chemotactic factors > bring eosinophils to area
Epithelial damage > sensory nerve exposure > hyper-responsiveness
Sensory nerve activation > airway smooth muscle contraction > dsypnoea and wheeze
Inflammatory mediators > vasodilation and increased vascular permeability > oedema of bronchial wall
Other inflammatory mediators > mucus hypersecretion and hyperplasia > mucus plug formation > productive cough to try and remove airway obstruction

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78
Q

Why is there an increased likelihood of airway collapse during expiration?

A

Load on airway smooth muscle determinant of how fast and how much shortening occurs
Load decreases on expiration
Increase in airway resistance
Increased likelihood of airways collapsing

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79
Q

What are the mediators contributing to airway smooth muscle balance?

A 
Constriction
- Acetylcholine
- Histamines
- Leukotrienes
Dilation
- PGE2
- Adrenaline
- Prostacyclin
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80
Q

Describe the histological changes of airway remodelling

A 
Goblet cell metaplasia
Subepithelial collagen thickening
Infiltration of inflammatory cells
Increased mucosal vascularity
Increased smooth muscle volume
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81
Q

What are the key features of short acting beta2-adrenoceptor agonists?

A

Rapid onset = 2-5 min

Selectivity for beta2-adrenoceptors

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82
Q

What is the drug class of salbutamol?

A

Short-acting beta2-adrenoceptor agonist (SABA)

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83
Q

What are the adverse effects of SABAs?

A

May be beta1-related

  • Tachycardia
  • Tremor
  • Hypokalaemia
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84
Q

How is tolerance to SABAs dealt with?

A

Happens because of full agonists

Now only partial agonists used

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85
Q

How do salmeterol and formeterol differ as long-acting beta2-adrenoceptor antagonists (LABAs)?

A

Salmeterol has slow onset

Formeterol has rapid onset

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86
Q

How does indacaterol differ to other LABAs?

A

Longer duration of action = 24 hrs

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87
Q

What is the indication for LABA use?

A

Prophylaxis, combined with inhaled glucocorticoids

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88
Q

What is the eclipse period during viral replication?

A

When virus broken down inside cell and being replicated > no release of virus yet

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89
Q

What are the stages of viral replication?

A
  1. Attachment/adsorption
  2. Penetration
  3. Uncoating
  4. Amplification of viral genome and proteins
  5. Assembly
  6. Release
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90
Q

What are the two methods of viral penetration?

A

Fusion with host cell membrane and release of viral nucleocapsid directly into cytoplasm
Endocytosis > lysis of endosome

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91
Q

How does replication of negative sense RNA virus differ from that of a positive sense RNA virus?

A

Negative sense viruses must bring their own RNA-dependent RNA polymerase as they can’t be translated automatically

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92
Q

What can be virus induced changes in cells?

A

Transformation to tumour cells
Lytic infection
Chronic infection
Latent infection

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93
Q

How do viruses evolve?

A

Mutation
Recombination
Reassortment

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94
Q

How can the infectious process of viruses be halted?

A

Ab blocks uptake and/or neutralises virus
Killing infected cell by
- Cytotoxic T cells
- NK cells
- Ab mediated mechanisms
IFN
Blocking replication cycle by antiviral drugs

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95
Q

What are the sgates undertaken by a virus in order to cause infection?

A

Entry into body
Multiply and spread
Target appropriate organ

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96
Q

How may a virus be maintained in nature

A

Shed into environment
Taken up by arthropod vector/needle
Passed congenitally

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97
Q

What is the difference between local and systemic viral replication?

A

Local viral replication = confined to organ of entry

Systemic viral replication = involves many organs

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98
Q

What is tropism?

A

Anatomical localisation of infection

Initially determined by receptor specificity of virus

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99
Q

Why do most viruses enter via the epithelial cells of the mucosa?

A

Can’t enter through keratinised dead skin

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100
Q

How may respiratory tract viruses be acquired?

A

Aerosol inhalation

Mechanical transmission of infected nasal secretion

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101
Q

What is required in order for viruses to enter cells?

A

Attach to specific receptors on epithelial cells

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102
Q

Describe the pathophysiology of the measles virus

A

Primary viral replication in epithelial cells of upper respiratory tract > binds to receptors on macrophages, lymphocytes, and DCs > amplifies in draining lymph node > moved around body by circulating infected macrophages, lymphocytes, and DCs > amplifies whenever infected cells reach lymph node > returns to epithelial cells in lung and mouth > spread via respiratory route

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103
Q

What forms Koplick spots in measles?

A

Accumulations of lymphocytes

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104
Q

Why do viruses that infect the intestinal tract generally not have an envelope?

A

Envelope easily broken down in intestinal tract by proteases

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105
Q

How do viruses such as HIV and HBV enter the body even though the do not have receptors for epithelial cells?

A

Breach in epithelial surface

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106
Q

How may viruses use M cells to cause infection?

A

M cells constantly sampling environment
Some enteric viruses use this pathway to gain entry to deeper tissues
Other viruses infect and destroy M cells

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107
Q

How do some diarrhoea causing viruses promote spread of virus by diarrhoea?

A

Secretion of viral protein from infected cells increases fluid secretion of remaining intestinal cells > intensifies diarrhoea

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108
Q

Desribe the viral progression of enterovirus infections

A 
Enters via aerosol/ingestion > replication in oropharynx and tonsils causes sore throat > enters circulation = primary viraemia > secondary viraemia at target tissue
- Aseptic meningitis
- Encephalitis
- Rashes/ulcers
- Myocarditis
- Pericarditis
Replication in Peyer's patches
Viral spread can occur as virus in faeces
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109
Q

How may the skin be bypassed to cause infection?

A 
Minor trauma
Injection via
- Needles
- Body piercing
- Tattooing
Insect/animal bite
Genital tract
Conjunctiva
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110
Q

What are the mechanisms of viral spread in the body?

A

Local spread on epithelial surfaces
Subepithelial invasion and lymphatic spread
Viraemia
Neural spread

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111
Q

Explain the concept of the carriage state as a result of viraemia

A

Mother has viraemia > baby born with viraemia > immunotolerant to HBV > can’t kill HBV > carrier

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112
Q

What is the pathophysiology of congenital rubella syndrome?

A 
Slows down rate of cell division
Babies
- Small
- Development of key organs in 1st trimester impaired
- Microcephaly
- Congenital heart defects
- Cataracts
- Deafness
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113
Q

What are the different mechanisms of viral-induced damage to tissues and organs?

A

Death as direct result of viral replication

Loss of function

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114
Q

How can viruses induce disease due to consequences of the immune response?

A

Immunopathology
Immunosuppression
Autoimmunity

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115
Q

What do type 1 interferons do?

A 
Inhibit viral replication
Activate NK cells
Enhances MHC class I expression
Prduced by virus infected
- Macrophages
- DCs
- Tissue cells
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116
Q

What do type 2 interferons do?

A 
Inhibit viral replication
Activate macrophages
Enhance MHC class I and class II expression
Produced by
- NK cells
- T cells
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117
Q

How do viruses evolved to evade immune attack?

A 
Latency
Ab evasion via Ag variation
Evasion of T cell priming by DCs
Evasion of cytotoxc T cell recognition
Evasion of NK cell recognition
Interference with IFN activity
Evasion of cytokine activation
Apoptosis inhibition
Virus-encoded homologues of complement control proteins
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118
Q

How do NK cells function?

A

Spontaneous cytotoxicity towards variety of tumour and virus-infected cells
Major source of IFN-gamma
Activation receptor recognises molecules on cell surface
Inhibitory receptor binds MHC class I on target cell

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119
Q

Describe the distribution of microbiota in the upper respiratory tract

A 
Upper respiratory tract has lots of microbiota up to level of larynx
Sterile sites
- Trachea
- Bronchi
- Bronchioles
- Alveoli
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120
Q

What are non-typable Haemophilus influenzae?

A

Type of H influenzae dependent on its capsule

Non-capsulated H influenzae considered non-typable

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121
Q

What are the frequent aetiological agents of the common cold?

A 
Rhinovirus
Parainfluenza virus
Respiratory syncytial virus (RSV)
Enterovirus
Coronavirus
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122
Q

What are the frequent aetiological agents of pharyngitis/tonsillitis with nasal involvement?

A

Adenovirus
Enterovirus
Parainfluenza virus
Influenza virus

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123
Q

What are the frequent aetiological agents of pharyngitis/tonsillitis without nasal involvement?

A 
Adenovirus
Enterovirus
Influenza
Reovirus
Streptococcus pyogenes
Bacteria
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124
Q

What are the frequent aetiological agents of sinusitis?

A

Primary sinusitis part of viral common cold
Secondary sinusitis caused by
- H influenzae
- Streptococcus pneumoniae

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125
Q

What are the frequent aetiological agents of otitis media?

A

S pneumoniae
H influenzae
Moraxella catarrhalis

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126
Q

What is the primary aetiological agent causing epiglottitis?

A

H influenzae type b - largely eradicated by vaccine

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127
Q

What are the frequent aetiological agents of croup?

A

Parainfluenza virus
Influenza A
RSV

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128
Q

When is laboratory diagnosis required for upper respiratory tract infections?

A

Mainly for

  • Pharyngitis
  • Tonsillitis
  • Epiglottitis
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129
Q

What laboratory tests are undertaken for a patient suspected of epiglottitis?

A

Blood culture

Don’t take throat swab/touch epiglottis > might cause epiglottis spasm > airway obstruction

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130
Q

How are upper respiratory tract infections generally treated?

A

Mostly supportive treatment

  • Bed rest
  • Fluids
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131
Q

When is otitis media treated?

A

If <2 years

Prolonged and severe

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132
Q

When is croup treated?

A

Not treated specifically - supportive treatment

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133
Q

How is acute bronchitis usually caused?

A

Complication/acute exacerbation of viral upper respiratory tract infection

134
Q

In what way are people with chronic bronchitis immunocompromised?

A

Innate immune system weakened due to chronic smoking damage > prone to infection by low-grade pathogenic bacteria from upper respiratory tract infection

135
Q

What are the main causative agents of an acute exacerbation of chronic bronchitis?

A

S pneumoniae

H influenzae

136
Q

How does RSV cause bronchiolitis in infants?

A

RSV Abs from mother transferred across placenta to foetus
Baby infected with RSV > Ag-Ab complexes form and deposit in bronchioles > inflamed bronchioles cause collapse of small airways upon expiration > expiratory wheeze

137
Q

How do acute bacterial pneumonia and atypical pneumonia differ in site of inflammation?

A

Acute bacterial pneumonia infections usually restricted to airways
Atypical pneumonia usually affects lung interstitial tissue

138
Q

What are the common causative agents of acute bacterial pneumonia?

A 
S pneumoniae
H influenzae
Staphylococcus spp
Klebsiella pneumoniae
Legionella
TB
Chlamydophila
139
Q

What are the common causative agents of atypical pneumonia?

A 
Mycoplasma
Chlamydia spp
M catarrhalis
Influenza virus
RSV
Adenovirus
140
Q

How does Legionella cause pneumonia from air conditioning?

A

Ameoba ingest Legionella bacteria
Legionella can survive in amoeba
Ameoba good at surviving in cooling towers
Legionella bacteria can survive in macrophages in similar manner

141
Q

How is laboratory diagnosis of pneumonia achieved?

A 
Properly collected sputum
- No buccal epithelium
Transtracheal aspirate - normally sterile
Aspiration via tracheostomy, endotracheal tube
Aspiration via bronchoscope
Pleural tap
- If effusion present
Lung biopsy
Blood for culture
142
Q

How is diagnosis of Legionella pneumophila type 1 achieved?

A

Urine Ag detection

143
Q

Why are penicillin G and tetracycline/macrolide used as combination empirical treatment for pneumonia?

A

Penicillin targets pneumococci

Doxycycline and macrolides target all atypical pneumonias

144
Q

How do pneumococcal vaccines differ for adults and children?

A

Adults given 23-valent polysaccharide vaccine

Children given 13-valent conjugate vaccine

145
Q

What is a systematic review?

A

Literature review focused on single question > identifies, appraises, selects and synthesises high-quality evidence relevant to question
Highest level of evidence

146
Q

What are the four purposes of meta-analysis?

A

Increase power
Resolve uncertainty
Improve estimates of effect size
Answer other questions

147
Q

What are the key aspects of meta-analysis?

A

Outcome
Weighting of individual studies
Heterogeneity

148
Q

Which studies contribute the most weight in a meta-analysis?

A

Larger studies

Studies with small confidence intervals

149
Q

How is statistical and non-statistical heterogeneity of studies assessed?

A 
Statistical
- Effect sizes
- Variances
Non-statistical
- PICOT
150
Q

What does the validity of a meta-analysis depend on?

A

Relies on whether component studies similar enough to be pooled

151
Q

What is the most common tool used in reporting systematic reviews?

A

PRISMA checklist

152
Q

What is the difference in pressure in the pulmonary circulation compared to systemic circulation?

A

Low pressure

153
Q

What is the functional purpose of low pulmonary circulatory pressure?

A

Aims to prevent movement of fluid from pulmonary vasculature into lung

154
Q

How does the pulmonary vasculature change with increased cardiac output?

A

Pulmonary artery pressure doesn’t rise with increased cardiac output due to dilatation and recruitment of pulmonary vessels which aren’t normally needed

155
Q

What are the two types of abnormalities of the pulmonary circulation?

A

Increased leakage of fluid across the pulmonary capillaries

Increased pressure in pulmonary arteries

156
Q

What is the mechanism of crepitations?

A

Crepitations due to fluid in alveoli/terminal bronchioles
Crackles caused by explosive opening of small airways and are
- Discontinuous
- Non-musical
- Brief
Crackles much more common during inspiration
May be heard during both phases in acute heart failure

157
Q

What is perihilar alveolar opacity on a chest x-ray indicative of?

A

Increased size of pulmonary veins

158
Q

What are Kerley B lines due to?

A

Dilated interlobular septa

159
Q

During metabolic acidosis, what are the causes of low bicarbonate?

A

Loss of bicarbonate from body

Buffering - bicarbonate consumed to combat new acid

160
Q

What are the factors that determine fluid movement across the pulmonary capillaries?

A

Hydrostatic pressure inside and outside capillary
Oncotic pressure inside and outside capillary
Permeability of capillary

161
Q

What are the mechanical changes that occur during pulmonary oedema?

A

Decreased lung compliance if lungs full of fluid > harder to inflate lung > lung volumes decrease
Small bronchioles compressed by fluid > increased airway resistance > increased resistive work of breathing

162
Q

How is gas exchange affected in pulmonary oedema?

A

Hypoxaemia due to shunt
Low V/Q units due to increased airway resistance and compensatory vasoconstriction
Diffusion impairment

163
Q

What is the effect of interstitial oedema and alveolar oedema on lung function?

A

Interstitial oedema causes little functional effect

Alveolar oedema has large effect on lung function

164
Q

What is the purpose of a diagnostic test?

A

Confirmation of disease or otherwise

Applied to patients in whom clinical suspicion of disease

165
Q

How does the purpose of a screening test differ from that of a diagnostic test?

A

Identification of patients who may have disease
Applied to patients in whom no clinical suspicion of disease
Used to identify likelihood of disease in those who’re at risk of disease > instigate early prevention
Needs confirmation with diagnostic tests

166
Q

What is the difference between sensitivity and specificity?

A 
Sensitivity = true positive/(true positive + false negative) = percentage of people with disease that test positive
Specificity = true negative/(true negative + false positive) = percentage of people without disease that test negative
167
Q

What are positive predictive value (PPV) and negative predictive value (NPV), and what do they measure?

A

PPV and NPV dependent on sensitivity and specificity and underlying prevalence of disease
Utility of diagnostic/screening test dependent on prevalence of disease

168
Q

What are likelihood ratios?

A

Likelihood that given test result would be expected in patient with disease compared to patient without disease

169
Q

What is the receiver operator character (ROC) curve?

A

Plots 1-specificity vs sensitivity
Forms graphical representation of trade-off between sensitivity and specificity in tests
Area under curve measures usefulness of test

170
Q

What is the rationale for screening tests?

A

Early detection > better outcomes

Assessment of population to identify risk factors and early disease

171
Q

What are the limitations of screening programs?

A

Inaccuracy of screening tests
May not be cost effective
Physical and psychological side effects
Biases in measurement of effectiveness

172
Q

What are the biases involved in screening programs?

A

Selection bias: healthy more likely to be screened
Lead-time bias: seems to be more effective due to earlier detection, not actual prolonged survival
Length-time bias: diseases which have slower progression will be selected for as there’s more time to detect them

173
Q

What is the alveolar-capillary membrane composed of?

A

Layer of surfactant
Type 1 alveolar cells
Basement membrane
Vascular endothelial cell

174
Q

Which conditions can disrupt the A-C membrane?

A 
Pulmonary fibrosis
Emphysema
Pneumonia
Non-infective inflammation
Cancer
175
Q

What are the likely physiological effects of disrupting the A-C membrane?

A

Abnormal gas exchange
Abnormal lung mechanics
Pulmonary vascular complications

176
Q

What are the causes of low oxygen concentrations?

A

Low levels of oxygen in air breathed in
Low ventilation
Abnormal gas exchange

177
Q

What are the causes of high carbon dioxide concentrations?

A

Low ventilation

178
Q

When does diffusion limitation of oxygen transfer occur?

A

During exertion in diseases state

Higher demand for oxygen becomes limiting factor > can’t adequately diffuse across diseased membrane

179
Q

Why do the lungs not collapse in restrictive lung diseases?

A

Elasticity of chest wall muscles keep stiffened lungs from collapsing

180
Q

What is the altered pattern of breathing in restrictive lung diseases?

A

Short and shallow breaths due to lower lung volumes
Diseases of alveolar-capillary membrane can increases work of breathing because inspiratory muscles need to generate higher pressures to overcome stiffness of lungs
To minimise muscles having to generate higher pressures, people take shorter and shallower breaths

181
Q

Name the main types of obstructive lung diseases

A

Asthma
Chronic obstructive pulmonary disease (COPD)
Bronchiectasis

182
Q

Name the main types of restrictive lung diseases

A

Idiopathic
Pneumoconiosis
- Asbestosis
Sarcoidosis

183
Q

What are the two types of asthma?

A

Atopic/allergic asthma

Non-allergic asthma

184
Q

What is the pathophysiology of asthma?

A

Trigger > release of mediators from mast cells > immediate response: increased vascular permeability > oedema, increased mucus production, bronchospasm > late phase response 4-8 hours later: chemotaxis of eosinophils, mast cells, lymphocytes, macrophages > ongoing inflammation, epithelial damage

185
Q

What are the serious short term complications of asthma?

A

Death
Atelectasis
Spontaneous pneumothorax

186
Q

What is atelectasis?

A

Ventilation present but obstruction means that gas exchange is not possible > lung collapse

187
Q

What is spontaneous pneumothorax?

A

Air can get in but can’t get out > pierces pleural space and air goes into pleural space

188
Q

What are the severe complications of chronic asthma?

A 
Airway remodelling
- Fibrosis
- Irreversible
- Obstruction
Chronic hypoxia > pulmonary hypertension > cor pulmonale
189
Q

What is emphysema?

A

Abnormal, permanent enlargement of air spaces distal to terminal bronchiole from destruction of alveolar wall septa without fibrosis

190
Q

What are the types of emphysema?

A

Centriacinar
Panacinar
Distal acinar
Irregular

191
Q

Which type of emphysema is mainly caused by cigarette smoking?

A

Centriacinar

192
Q

How does cigarette smoking cause emphysema?

A

Disrupts protease:anti-protease balance:

  • Increases
    • Neutrophil elastase activity
    • Macrophage elastase
    • MMP
  • Decreases anti-protease activity
193
Q

How does emphysema cause airway obstruction?

A 
Loss of elastic recoil
- Elasticity of parenchyma keeps small airways open
- Loss > collapse
Associated conditions
- Small airways disease
- Chronic bronchitis
194
Q

What are the complications of emphysema?

A

Hypoxia caused by airflow obstruction (mainly)
Loss of diffusion capacity - late-stage
Pulmonary hypertension and cor pulmonale
Pneumothorax

195
Q

What is the clinical definition of chronic bronchitis?

A

Persistent cough productive of sputum for at least 3 months in 2 consecutive years

196
Q

What is the pathogenesis of chronic bronchitis?

A

Chronic irritation by inhaled substances > increased mucus production in larger airways > airway inflammation, scarring, and narrowing in smaller airways

197
Q

What is the morphology seen in chronic bronchitis?

A 
Hypertrophy of mucus-secreting glands
Increased goblet cells
Mild increase in
- Lymphocytes
- Macrophages
- Plasma cells
- Oedema
Peribronchial fibrosis in small airways
198
Q

What are the complications of chronic bronchitis?

A

Squamous metaplasia may > squamous cell carcinoma
Superimposed infective exacerbations
Hypoxia > pulmonary hypertension > cor pulmonale

199
Q

How does smoking predispose to pulmonary infection?

A

Inhibition of muco-ciliary escalator
Increased mucus
Inhibition of leukocyte function
Direct damage to epithelial layer

200
Q

What is bronchiectasis?

A

Irreversible, abnormal dilatation of bronchi/bronchioles

201
Q

What is the pathogenesis of bronchiectasis?

A

Severe destructive inflammation of airways > loss of surrounding elastic tissue and muscle > exceeds contraction of fibrous tissue > airways dilate > clearance of organisms and fluid impaired (often full of pus) > predisposition to recurrent infections

202
Q

What are the causes of bronchiectasis?

A 
Necrotising infections
- S aureus
- Influenza
- Aspergillus
Obstruction and infection
Cystic fibrosis
Cilia disorders
Non-infectious inflammatory conditions
- Connective tissue disorders
- Graft vs host disease
- Allergic bronchopulmonary aspergillosis
203
Q

What are the two main findings used to diagnose restrictive lung disease?

A

Restrictive spirometry

Inflammation and fibrosis of inter-alveolar septa

204
Q

How does restrictive lung disease appear on chest x-ray?

A

Diffuse reticulo-nodular and/or ground-glass appearance

205
Q

Why do LABAs act for longer than SABAs?

A

Due to lipophilicity = stay in lipid membrane and act for longer

206
Q

What are the indications for LABA use?

A

Must be combined with inhaled glucocorticoids and monotherapy associated with increased morbidity/mortality
Indicated for prophylaxis only

207
Q

What is the mechanism of action of muscarinic antagonists?

A

Act to block muscarinic receptors on airway smooth muscle > prevent contraction

208
Q

What is the drug class of ipratropium bromide?

A

Short-acting non-specific muscarinic antagonist

209
Q

What is the drug class of tiotropium bromide?

A

Long-acting non-specific muscarinic antagonist

210
Q

What is ipatropium bromide preferred in airway disease over atropine?

A

Atropine has central effects as well as bronchodilatory effects
Ipatropium bromide doesn’t diffuse across BBB

211
Q

What are the effects of glucocorticoids in asthma?

A

Decreased inflammatory cell number and activation

Decreased probability and severity of asthmatic episodes

212
Q

What is the mechanism of action of glucocorticoids?

A

Bind to receptor > diffuse across plasma membrane > dimerisation > translocated to nucleus > initiate gene expression > anti-inflammatory and bronchodilatory gene products

213
Q

What are the indications for glucocorticoid use to treat asthma?

A

Inhaled glucocorticoids indicated if beta2-adrenoceptor agonists required >3 times per weel

214
Q

What are the adverse effects of glucocorticoid use?

A 
For inhaled
- Dysphonia
- Oral candidiasis
For oral
- Adrenal atrophy > metabolic disturbances
- Osteoporosis
- Diabetes
- Muscle wasting
- Growth suppression
215
Q

What is COPD?

A

Peristent airflow limitation
Usually progressive
Associated with enhanced chronic inflammatory response in airways and lungs to noxious particles/gases

216
Q

What is air trapping in COPD?

A

Normally alveolar attachments maintain tension so alveoli don’t collapse
In COPD, inflammation > loss of alveolar attachments > loss of elasticity > airways no longer under any tension > collapse upon expiration

217
Q

How do CD8 T cells exacerbate COPD?

A

Release IFN-gamma and perforin/granzymes

- Perforin and granzymes: destruction and apoptosis of type I pneumocytes

218
Q

What are the therapeutic options for the management of COPD?

A 
Smoking cessation
LABAs
- Symptom relief
- Reduce exacerbations
Combining bronchodilators of different pharmacological classes
Inhaled corticosteroids
219
Q

How does theophylline act to relax smooth muscle?

A

Phosphodiesterase inhibitor: raises cAMP > activates PKA

  • Inhibits TNF-alpha and leukotriene synthesis
  • Reduces inflammation and innate immunity
220
Q

What is the effectiveness and tolerability of theophylline compared to LABAs in the management of COPD?

A

Theophylline less effective and well tolerated

221
Q

What are the causes of pneumonia?

A

Mostly due to infections

  • Bacteria = 85%
  • Viruses
  • Fungi and protozoa - in immunocompromised host
222
Q

What are the clinical features of pneumonia?

A 
Fever and chills
Unrelenting cough
Sputum production
- Purulent
Chest pain if pleural inflammation
Impaired gas exchange
- Dyspnoea
- Tachypnoea
223
Q

Why is it importnat to identify if pneumonia is community-acquired, hospital-acquired, or of an immunocompromised host?

A

Guides empirical treatment

224
Q

What are the possible routes of entry of infective pneumonias?

A

Inhalation of pathogens in air droplets
Aspiration of infected secretions from upper respiratory tract
Aspiration of infected particles
Haematogenous spread

225
Q

What are the three aetiological classifications of infective pneumonia?

A

Upper respiratory tract flora
Enteric saprophytes
Extraneous pathogens

226
Q

What are the two patterns of infective pneumonia?

A

Alveolar inflammation with consolidation
- Neutrophils in alveolar space
- Generally caused by bacterial pathogens
Interstitial inflammation
- Lymphocytes and macrophages in alveolar septa
- Generally casued by viruses and bacterial causes of atypical pneumonia
- No inflammatory cells in air spaces

227
Q

What are the two types of alveolar pneumonia?

A

Bronchopneumonia = patchy consolidation
Lobar pneumonia = whole lobe affected
easily identified in chest x-ray

228
Q

What are the most common causes of lobar pneumonia?

A

S pneumoniae

Haemophilus influenzae

229
Q

How may organisms causing lobar pneumonia be identified?

A

Sputum culture

Bacteraemia

230
Q

What are the four stages of lobar pneumonia?

A

Congestion = alveoli contain proteinaceous fluid containing bacteria
Red hepatisation = alveolar spaces containing neutrophils and RBCs (haemorrhage) > squeeze through pores in capillaries
Grey hepatisation = organisation (fibrin) with neutrophils and macrophages
Resolution

231
Q

Which patients are especially susceptible to acute bronchopneumonia?

A

Extremes of life
Secondary to pre-existing chronic disease
Hospitalised patient populations
Post-operative patients

232
Q

What are the complications of pneumonia?

A 
Pleuritis
Pyothorax
Lung abscess
Bronchiectasis
Interstitial fibrosis
Cysts
233
Q

What are the causes of lung abscess?

A 
Cavity containing pus
Complications of
- S aureus
- Klebsiella
- Pseudomonas
Aspirations of infected material from upper respiratory tract/gastric contents
Distal of bronchial obstruction by tumours/foreign bodies
Septic emboli to lung
234
Q

What can cause interstitial pneumonia?

A 
Viral infection
Bacterial infection causing atypical pneumonia
Non-infectious causes
- Drugs
- Immunological disease
- Radiation
235
Q

What is the pathology of infective pneumonia with interstitial inflammation?

A

Alveolar septa widened > infiltrated with lymphocytes, plasma cells, and macrophages
Often associated bronchiolitis

236
Q

What is the typical presentation of atypical pneumonia?

A 
Systemic symptoms over respiratory symptoms
- Malaise
- Aches and pains
- Headache
- Diarrhoea
Dry and non-productive cough
Patients often have extensive radiological signs of pneumonia
- Still healthy enough to walk
237
Q

What are some causes of atypical pneumonia?

A

Mycoplasma pneumoniae
Coxiella burnettii
Legionella spp
Chlamydia pneumoniae

238
Q

How is TB unique when compared to other pneumonias?

A

Can’t clear infection - must instead wall it off
May lie dormant for many years
May subsequently cause secondary infections

239
Q

What is the Ghon complex?

A

Characteristic of TB infection

Parenchymal Ghon focus and enlarged hilar lymph node caseating lesions

240
Q

What is the pathophysiology of secondary TB?

A

Reactivation of dormant infection/reinfection
Causes lobar pneumonia involving upper lobe
Cell-mediated immune response > extensive caseation and cavitation if caseous material discharges into bronchus

241
Q

What are the complications of secondary pulmonary TB?

A

Progressive spread of caseation into surrounding lung
Erosion of blood vessels > haemoptysis
Erosion into bronchial tree > spread of infections via airways
Pleural inflammation and fibrosis > lung scarring

242
Q

What are the clinical features of TB?

A 
Variable weight loss
Malaise
Fevers
Night sweats
Haemoptysis
Dyspnoea
Chronic cough
243
Q

Describe the spread of TB

A

Lymphatic spread of TB to pleura and contralateral lung
Spread of TB to bronchial tree > caseous necrosis in bronchi, bronchioles > bronchopneumonia
Haematogenous spread

244
Q

What is miliary TB and how does it arise?

A

Form of progressive TB caused by dissemination of bacteria via bloodstream
Can involve lung and/or multiple other organs like
- Liver
- Spleen
- Bone marrow
- Brain

245
Q

What is single organ TB?

A

Usually secondary TB of other rgans with caseation

246
Q

Where is the central controller of the respiratory control system?

A

Brainstem
- Medulla
- Pons
Cortex = voluntary hyper- and hypoventilation

247
Q

Describe the locations and roles of the respiratory system sensors

A

Central chemoreceptors: on ventral surface of medulla, surrounded by CSF
- Increase in PaCO2 > increase in CSF [H] > sensory input to brainstem > increase in ventilation
Peripheral chemoreceptors: in carotid bodies at birfurcation of common carotid artery, and aortic bodies around arch of aorta
- Rapid responses to decrease in PaO2, decreased pH, increased PaCO2 > inreased ventilation
Lung and other receptors
- Pulmonary stretch, irritant and J receptors
- Upper airway receptors, joint and muscle receptors, painful stimuli

248
Q

How can CO2 act as a stimulant to ventilation?

A

In response to rising CO2 levels

In response to lowered pH due to high CO2

249
Q

What is the ventilatory response to exercise?

A

Ventilation increases with work to maintain PaO2 and PaCO2 at baseline
Beyond anaerobic threshold, relative increase in ventilation due to extra H production from lactic acid

250
Q

Define hypoventilation

A

Rate of alveolar ventilation not meeting metabolic requirements for oxygen consumption and carbon dioxide production

251
Q

What are the causes of hypoventilation?

A 
Reduced respiratory centre activity
Neuromuscular disease
Chest wall deformity
Obesity
Sleep disordered breathing
252
Q

Why does snoring and obstruction occur in obstructive sleep apnoea?

A

Airway muscles relax
Throat already narrowed due to
- Racial factors
- Obestiy
- Tonsils in children
Tongue falls backwards, especially if supin
1st, partial obstruction > vibration of pharyngeal tissue > snoring
Can progress to completely closed over upper airway > snoring stops > complete obstruction of airway

253
Q

What are the causes of breathlessness in young athletes?

A

Normal sensation at maximal effort
Performance anxiety
Disease

254
Q

How may people with disease and people who are deconditioned be distinguished from each other?

A

Therapeutic trial - 3 month aerobic training program > re-measure exercise capacity

255
Q

How may psychogenic manifestations of breathlessness and breathlessness caused by disease b distinguished?

A

Stress test

Vocabulary used to describe breathlessness

256
Q

What are the different types of influenza virus?

A

Seasonal

Pandemic

257
Q

What are the at-risk groups of influenza?

A

Extremes of age

Underlying chronic disease

258
Q

How is the influenza virus spread?

A

Droplet infection from coughing and sneezing

259
Q

What is the incubation period for influenza?

A

1-5 days

260
Q

What is the pathogenesis of seasonal influenza?

A

Droplets containing virus enter respiratory tract > virus binds to sialic acid-containing receptors on non-ciliated respiratory epithelium > virus replicates in epithelial cells of upper and lower respiratory tract but particularly large airways > tissue damage and inflammatory response = cytokine and IFN production >

  • IL-1 > fever
  • IFN > malaise, head and muscular aches
261
Q

What are the two outcomes of a seasonal influenza infection?

A 
Clearance
Secondary bacterial pneumonia
- H influenzae
- S aureus
- S pneumoniae
262
Q

What family does influenza virus belong to?

A

Orthomyxoviridae

263
Q

What is the molecular structure of influenza virus?

A

Enveloped

Segmented negative sense ssRNA genome

264
Q

Which types of influenza virus infect humans?

A

A infects humans and other species

B endemic to humans

265
Q

Describe the structure of an influenza virion

A 
Envelope
Underneath, have matrix
Inside, segmented RNA genome
- 8 segments
- Each segment wrapped in nucleoprotein
- RNA-dependent RNAse contained at end of each segment
266
Q

What is the target of antivirals against influenza virus?

A

M2 ion chhannel

267
Q

What are the roles of haemagglutinin (HA) and neuraminidase (NA)?

A

Both surface glycoproteins
Interact with sialic acid
HA = gripper - gets virus into cell
NA = snipper - cuts sialic acid receptors from cell surface > newly budded virus won’t bind to dying cell

268
Q

How do the type A influenza subtypes differ from each other?

A

Differ in form of HA and NA they encode

269
Q

Why is influenza strictly confined to the respiratory tract?

A

Tryptase Clara needed for maturation not found anywhere else

- Snips HA after budding to make it active

270
Q

Describe the adaptive immune response to influenza virus infection

A

CD8 T cells
- Recognise peptides derived from internal Ags of virus
- Broadly cross-reactive between type A subtypes
- Not long-lived but can be boosted by repeated exposure to virus
Ab
- Ab to HA predominantly speeds clearance of virus
- Binds to virus and inhibits attachment of virus to receptor
- Classical pathway of complement activated
- Lifelong Ab response

271
Q

If the antibody response to the influenza virus is lifelong, why do we continually get influenza throughout our lifetime?

A

Ag drift

Viruses with mutations where Ab binds can no longer be bound by Ab > mutated sequences selected for

272
Q

When do influenza epidemics arise?

A

When all 5 Ag sites have mutated - unlikely we’ll have Abs to any of these sites

273
Q

What are the targets of vaccine-induced immunity to influenza?

A

Ab to HA blocks attachment

Ab to NA blocks efficient release

274
Q

Describe the influenza vaccine

A

Inactivated trivalent vaccine
Contains 3 different influenza viruses representing most recent strains of
- Influenza A H1N1
- Influenza A H3N2
- Influenza B
Must predict correct strains which will be present in following season
Killed virus vaccine > can’t activate T cell cross-reactivity, but can activate Ab responses

275
Q

What do the antivirals amantadine and rimantadine do?

A

Block M2 ion channel

  • Inhibits uncoating of influenza A virus in endosome during entry
  • Not active against type B
  • Not used widely due to development of drug-resistant mutants
276
Q

What do the antivirals zanamivir and oseltamivir do?

A

Block action of NA

  • Effective against both influenza A and B
  • Zanamivir inhaled by mouth
  • Oseltamivir preferred because orally-administered prodrug
277
Q

How does antigenic shift differ to antigenic drift?

A

Ag drift = new strain of existing HA subtype
Ag shift = new HA
- Causes pandemic because complete lack of protective immunity, leading to rapid global spread

278
Q

How does reassortment create a new human subtype of influenza?

A

Swapping of gene segments in pig upon co-infection of single cell

279
Q

What is the WHO’s TB control strategy?

A

DOTS

Stop TB strategy - MDR TB, TB and HIV, weak health systems

280
Q

What are the issues of the WHO’s TB control strategy?

A

Biomedical approaches with little regard to reducing vulnerability
Vast majority of people with TB from poorest segments of society
Need to explicitly address underlying factors that make these groups more vulnerable in 1st place

281
Q

What are the proximate risk factors for TB?

A 
Exposure to infectious droplets
Host defence (HIV)
Malnutrition
Indoor air pollution
Alcohol abuse
Other disease
Depression and stress
282
Q

What are some ways in which low socioeconomic status can be linked with the proximate risk factors for TB?

A

More frequent contact with people with active TB disease
Higher likelihood of crowded and poorly ventilated living and working conditions
Limited access to safe cooking facilities
More food insecurity
Lower levels of awareness and lesser capability to address issues concerning healthy behaviour
Limited access to high quality healthcare

283
Q

What are the recommendations for action against TB epidemics?

A

High quality medical technologies with extra efforts to reach most vulnerable groups
Strengthen collaboration between national TB programs and other public health programs to address number of diseases
Promote multisectorial approaches to respond to upstream social and economic determinants of health leading to TB

284
Q

What is a thrombus?

A

Clotted mass of blood forming within unruptured cardiovaascular system during life

285
Q

What is the pathophysiology of factor V Leiden mutation?

A

Activated protein C = natural anticoagulant > neutralises activated factor V
Point mutation in factor V means activated protein C can’t bind to activated factor V and deactivate it > pro-thrombotic state
Heterozygotes have 5 fold increased risk of developing deep vein thrombosis (DVT)

286
Q

Describe the venous drainage of the leg

A

DVT typically affects
- Common iliac vein
- Femoral vein
- Popliteal vein
Saphenous veins run in subcutaneous tissues superficially
Blood flows from superficial to deep veins due to 1-way valve

287
Q

What are the common clinical signs of DVT?

A 
Swelling
Redness
Warmth
Discomfort
Pain
Tenderness
Usually unilateral
50% lack symptoms and signs
288
Q

What do the effects of a pulmonary thromboembolism depend on?

A

Size of embolus
Presence/absence of lung disease
Presence/absence of cardiovascular disease

289
Q

What is the typical clinical presentation of a patient with pulmonary embolism (PE)?

A

Variable dyspnoea
Haemoptysis
Cough
Syncope: in severe cases with cardiac insufficiency
Pleuritic pain: commonly present if there’s an infarct

290
Q

What pathophysiological abnormalities may be present with PE?

A

Acute pulmonary hypertension due to obstruction > hypoxaemia > V/Q mismatch
Platelets in thrombus produce TXA2 > more widespread vasoconstriction > excess right ventricle stress
Constriction of airways distal to bronchi
Decreased pulmonary compliance due to haemorrhage and loss of surfactant

291
Q

Why are pulmonary infarcts uncommon?

A

Lung itself usually supplied by bronchial arteries, not pulmonary arteries
When they do occur = haemorrhagic with coagulative necrosis
Associated with
- Pleuritic chest pain
- Pleural friction rub
- Pleural effusion

292
Q

What are the consequences of small pulmonary emboli?

A

Chronic pulmonary hypertension

Chronic cor pulmonale

293
Q

What are the long term outcomes of DVT?

A

Fibrinolysis, organisation, complete/partial recanalisation of thrombus
- New vessels may form in organised scar
Damaged incompetent valves
- Increased blood flow into superficial veins of lower limb > varicose veins
- Chronic venous insufficiency > venous stasis, chronic oedema, pigmentation, chronic ulceration

294
Q

Define sleep

A

Behavioural state characterised by
- Decreased awareness of external environment
- Decreased reactivity to stimuli
- Capability to return rapidly to wakefulness
Stereotypical postures

295
Q

What are the functions of sleep?

A

Learning
Brain development
Repair and maintenance
Energy preservation

296
Q

How is subjective impairment different to objective impairment in terms of sleep deprivation?

A

Performance declines objectively, but subjective sleepiness doesn’t increase as much

297
Q

Describe the control of breathing during sleep

A

Emotional stimuli input lost
Higher brain centre input lost
Wakefulness drive to breathe lost
Other stimuli of breathing depressed

298
Q

Why is there increased upper airway resistance during sleep?

A

Reduced upper airway muscle tone

299
Q

What happens to ventilation and carbon dioxide levels during sleep?

A

Minute ventilation falls at sleep onset
CO2 levels rise until new sleep set-point reached
Chemoreceptor drive = major regulator of breathing

300
Q

How does eye and muscle movement change from non-rapid eye movement (NREM) to rapid eye movement (REM) sleep?

A

Eye movement greater in REM sleep

Muscle movement greater in NREM sleep

301
Q

How ling is a typical REM cycle?

A

90-120 min

302
Q

How does sleep change with age?

A

In elderly

  • Less deep sleep
  • More waking events
303
Q

What are the hallmarks of cancer cells?

A 
Sustaining proliferative signalling
Evading growth suppressors
Activating invasion and metastasis
Enabling replicative immortality
Inducing angiogenesis
Resisting cell death
Immune evasion
Tumour inflammation
304
Q

What is desmoplasia?

A

TGF-beta secreted by some malignant cells to recruit fibroblasts to lay down extracellular matrix inside and outside tumour

305
Q

What are the mechanisms of tumour metastasis?

A 
Local invasion
Blood-borne spread
Lymphatic spread > can then spread into venous system
Trascoelomic spread = along
- Pleural spaces
- Pericardial spaces
- Peritoneal spaces
306
Q

What is lymphangitis carcinomatosis?

A

Pattern of spread of lung cancers, noted by thickening of vessels

307
Q

What are the histopathological features of neoplasia?

A 
Larger nuclei
Pleomorphic nuclei
Coarser nuclear chromatin
Hyperchromatic nuclei
Larger and more prominent nucleoli
More mitotic activity, abnormal mitotic figures
Architectural disorganisation
308
Q

What does the grade of the tumour refer to?

A

Its degree of differentiation

309
Q

What does the tumour microenvironment comprise?

A 
Tumour stroma
- Fibroblasts
- Extracellular matrix
- Endothelial cells
- Immune cells
- Soluble molecules
Tissue where tumour located
310
Q

What are the four classes of normal regulatory genes that are the principal targets of genetic damage in carcinogenesis?

A

Growth-promoting proto-oncogenes
Growth-inhibiting tumour suppressor genes
Genes that regulate apoptosis
Genes involved in DNA repair

311
Q

How do mutations in DNA repair genes promote carcinogenesis?

A

Cell no longer able to correct cell division induced DNA errors
Rapid accumulation of secondary mutations affecting genes of other classes

312
Q

How do mutations in proto-oncogenes promote carcinogenesis?

A

Involved in regulating growth

Mutations turn them into oncogenes > uncontrolled growth

313
Q

How do mutations in tumour suppressor genes promote carcinogenesis?

A

Control growth by suppressing cel division

Mutation > continuous growth

314
Q

To promote carcinogenesis, only one allele of oncogenes needs to be mutated whereas both alleles of tumour suppressor genes must be lost. Why?

A

Mutation in proto-oncogene > oncogene now active
Active oncogene has gain of function > takes over to accelerate growth
Both tumour suppressor genes functional in normal state
If 1 lost, functional allele can still suppress cell division
Both must be mutated to lose this capability

315
Q

What are the types of mutations in cancer?

A

Errors in DNA replication which aren’t repaired
Point mutations
Amplification of oncogenes
Chromosomal rearrangements

316
Q

What is the difference between a mutation and a polymorphism?

A 
Mutation = any change in DNA sequence away from normal - normal allele and abnormal variant
Polymorphism = DNA sequence variation that's common in population - no 1 allele regarded as normal
317
Q

What are the steps of normal cell proliferation?

A
  1. Growth factor binds to its specific receptor
  2. Transient, limited activation of growth factor receptor with signal transduction
  3. Transmission of signal across cytosol to nucleus via 2nd messengers/signal transduction cascade
  4. Initiation of DNA transcription
  5. Entry and progression into cell cycle
318
Q

How do mutations in Ras promote carcinogenesis?

A

Dephosphorylation of Ras blocked in mutant Ras
Ras always in active form
Constant activation of MAP kinase pathway
Constant activation of transcription

319
Q

What is the role of p53? What are the consequences of its deletion or mutation?

A 
Transcription factor > regulates expression of cell cycle factors
Usually responds to cellular stress and activates cellular responses
- Apoptosis
- Cell cycle arrest
- DNA repair
- Differentiation
- Senescence
Defective when p53 mutated/deleted
320
Q

Wat is the consequence of DNA methylation?

A

Excessive methylation around promoter region silences expression of tumour suppressor genes

321
Q

How do oncogenes and tumour suppressor genes affect the cell cycle?

A

Oncogenes inhibit regulatory controls of cell cycle

322
Q

Describe the concept of tumour cell immortality

A

In cells with disabled checkpoints, DNA repair pathways inappropriaately activated by shortened telomeres > massive chromosomal instability and mitotic crisis > tumour cells reactivate telomerase > stave off mitotic catastrophe > immortality

323
Q

Outline the process of tumour metastasis

A
  1. Detachment of tumour cells from each other
  2. Degradation of extracellular matrix
  3. Attachment to novel extracellular components
  4. Migration of tumour cells
324
Q

What is the pathophysiology of squamous cell carcinoma in the lung?

A

Smoke > irritation to airways > stem cells become stratified squamous instead of columnar > squamous metaplasia > carcinogens in smoke > mutations in proto-oncogenes and tumour suppressor genes > dysplasia > carcinoma in situ > invasion into underlying stroma

325
Q

If the tumour type cannot be determined on H&E, what technique is used instead?

A

Immunohistochemistry used to detect tumour proteins using labelled Abs

326
Q

What does the stage of a tumour refer to>

A

Progression of malignancy has made in terms of local spread and metastasis
T = size and/or local extent of primary tumoour
N = regional lymph node metastases
M = absence/presence of distal metastases
T, N, and M components combined to give stage grouping with 4 stages

327
Q

How are tumours generally managed?

A

Surgery
Radiotherapy
Chemotherapy
Targeted therapy

328
Q

How does sulfonamide exert its effects on bacteria?

A

Similar in structure to PABA = in folic acid pathway
Dihyropteroate synthase binds to sulfonamide instead of PABA > inactivated
Folic acid pathway inhibited > DNA synthesis inhibited

329
Q

How does methotrexate act?

A

Resembles folic acid
Binds to dihyrofolate reductase in folic acid pathway instead of folate > inhibition
Vaguely selective against rapidly-dividing cells which have high DNA replication/synthesis rate
Used as generic cytotoxic anticancer agent
Many side effects

330
Q

Why are kidneys subject to relative hypoxia? Why is this problematic?

A

Due to couter-current mechanism
- O2 can move from arterioles to venules, bypassing capillaries
Kidneys use a lot of ATP but O2 delivery sometimes marginal
Conditions leading to low renal perfusion can cause renal damage

331
Q

What is the triple-whammy and why is this problematic?

A

Combination of diuretic and ACE inhibitor = effective treatment for hypertension
Adding NSAID to combination can > acute renal failure
- Blocks prostaglandin-mediated vasodilation - needed to preserve renal blood flow

MD1 Revision (9 decks)

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