Respiratory Flashcards
(331 cards)
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
2
Q
What does PICOT stand for?
A
P = population I = intervention C = comparator/control O = outcome T = timing
3
Q
What is PICOT used for?
A
Frame question which will be used to search literature
4
Q
What is stratified randomisation?
A
Randomisation divided by levels of key confounders
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
6
Q
What is the p-value?
A
Probability that observe result rose from chance
Conventional cutoff = 0.05
p <0.05 - statistically significant
7
Q
What does the width of the 95% confidence interval measure?
A
Precision of result
8
Q
How is external validity assessed?
A
By determining degree of concordance between randomised control trial and clinical setting in terms of PICOT
9
Q
What is Klinefelter syndrome?
A
XXY trisomy
10
Q
What is Turner’s syndrome?
A
XO monosomy
11
Q
What is the Guthrie test?
A
Dried blood spot from heel prick
Enables mass screening of all newborns
12
Q
How is phenylketonuria (PKU) screened for with a Guthrie test?
A
Blood spot can be tested for phenylpyruvate
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
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
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
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
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
18
Q
What limits transfer of oxygen acroos the alveolar membrane?
A
Perfusion, not diffusion
19
Q
When is gas change most efficient?
A
Ventilation and perfusion matched: V/Q = 1
20
Q
What does a low V/Q mean?
A
Reduced partial pressure of oxygen > hypoxia
21
Q
Low partial pressure of oxygen due to what responds to supplemental oxygen?
A
Low V/Q
Not due to shunt
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
23
Q
How is ventilation and perfusion distributed throughout the lungs?
A
Almost all alveoli similar distance from mouth > all have similar resistance
24
Q
What is an elevated partial pressure of carbon dioxide due to?
A
Inadequate alveolar ventilation
Rarely due to inefficient gas exchange
25
What do central and peripheral chemoreceptors respond to?
```
Central chemoreceptors sensitive to H ions in CSF - prooduced by CO2
Peripheral chemoreceptors respond to
- H ions
- CO2
- O2
```
26
What does central cyanosis mean?
Arterial blood less saturated with oxygen
27
What are the characteristics of airflow obstruction?
```
Increased sensation of breathing
Increased respiratory muscle effort
Active exhalation
Longer time to inspire
Longer time to exhale
Reduced maximum ventilation
```
28
What causes increased sensation of breathing?
Increased load to breathe or an increased drive for breathing
29
What can increase the load to breathe?
Stiff lungs
Narrow airways
Chest wall
Diaphragm
30
What can increase the drive for breathing?
```
Higher centres
Mechanoreceptors
Irritant receptors
Chemoreceptors
Baroreceptors
Temperature
```
31
If airway obstruction is present, what accounts for the increase in work of breathing?
Inspiratory muscles need to generate higher [pressures to overcome obstruction to airflow
32
What are the consequences of airway obstruction?
Recruitment of accessory muscles
Increased oxygen consumption by respiratory muscles
Respiratory muscle fatigue
33
What is pulsus paradoxus?
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
34
Why do people with airflow obstruction generally take deep, slow breaths?
Minimises work of breathing for particular amount of ventilation needed
Lungs still able to expand properly, so people take advantage of this
35
Why do people with chronic airflow obstruction become breathless easily on exertion?
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
36
What happens if the airflow obstruction causes uneven ventilation?
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
37
What happens in severe airway obstruction when V/Q mismatch is minimised?
Overall decreased gas exchange > hypoxia
38
What is the function of the nasopharynx?
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
39
Describe the respiratory epithelium and its constituent cells
```
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
```
40
What is the structure of the trachea?
```
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
```
41
What makes up the mucosa of the trachea?
Respiratory epithelium
| Lamina propria
42
What makes up the submucosa of the trachea?
Glands
| Connective tissue
43
What makes up the adventitia of the trachea?
Cartilage
| Outer layer of connective tissue
44
Describe the structure of a bronchus
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
45
How do bronchioles differ from bronchi in structure?
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
46
What are Clara cells?
Columnar/cuboidal cells
Short microvilli
Secrete surfactant
May also neutralise toxins
47
Describe the structure of terminal bronchioles
```
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
```
48
What structures arise from the respiratory bronchioles?
Alveoli
| Chains of alveoli = alveolar ducts
49
What type of epithelium do respiratory bronchioles contain?
Cuboidal > squamous - needed for gas exchange
50
How are alveoli separated and connected?
Separated by interalveolar septum > contains
- Reticular fibres and elastin fibres arranged radially > keep alveoli from collapsing
- Pores > allow air to equilibrate
51
Describe the epithelial cells of the alveolus
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
52
What is the blood-gas barrier?
Basal lamina of type I penumocyte fused with basal lamina of endothelial cell of capillary
Oxygen and CO2 exchanged across barrier
53
What do intra-alveolar macrophages do?
Ingest particles of foreign debris
When full
- Migrate up airways > carried off by ciliated cells
- Deposit in interalveolar septum loaded with particles
54
What is the histology of the pleura?
```
Mesothelium = simple squamous epithelium
Underlying connective tisse
- Blood vessels
- Lymphatics
Some lymphatics drain into pleural space and contribute to lubrication of space
```
55
Where are mast cells particularly prevalent?
Body sites in contact with external environment
| Because these sites particularly prone to attack
56
How are mast cells stimulated in exercise-induced asthma?
Hyperosmolarity of airway surface fluid during exercise triggers bronchospasm and activates mast cells
57
What is red man syndrome?
Profound vasodilation produced by mast cells
58
How are mast cells activated?
Allergen cross-links IgE > adjacent IgE receptors on mast cells bound > 2nd messenger cascade > degranulation
59
How long does the initial reaction from mast cell degranulation take?
30-45 sec
60
What is released from mast cells?
```
Immediate
- Histamine
- Heparin
- Tryptase
- TNF-alpha
Rapid
- Leukotrienes
- PGD2
Slow
- IL-4
- IL-5
- GM-CSF
```
61
What do leukotrienes and PGD2 released from mast cells do?
Potent bronchoconstrictors
62
Which histamine receptors are acted on during mast cell degranulation?
H1 receptors
63
What are the immediate actions of histamine released from mast cells?
```
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
```
64
Which cells produce cysteinyl leukotrienes?
Eosinophils
Mast cells
Macrophages
65
What are the stimuli for cysteinyl leukotriene production?
Allerge
| C5a
66
What do cysteinyl leukotrienes do?
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
67
What are the endogenous inhibitors of mast cell activation?
PGE2
Adrenaline
Cortisol
Pharmacological agents
68
What are the main actions of disodium cromoglycate and nedocromil sodium?
Weak anti-inflammatory action
| Reduction in mast cell degranulation, sensory C-fibre activation and eosinophil activation
69
Why are disodium cromoglycate and nedocromil sodium well tolerated?
Don't gain access to systemic circulation
70
What is omalizumab?
Humanised mAB against IgE
71
What is the mechanism of action of omalizumab?
Reduces sensitisation of mast cells over time by sterically hindering IgE binding to receptor
72
In what ways may mediator production from mast cells be inhibited?
Glucocorticoids
| - Reduce mast cell cytokine production
73
In what way may mast cell mediator actions be inhibited?
H1 receptor antagonists = antihistamines
74
What are the indications for cysteinyl luekotriene receptor antagonists?
Aspirin-induced and exercise-induced asthma
75
What is asthma?
Chronic inflammation associated with airway hyper-responsiveness > recurrent episodes of
- Wheezing
- Breathlessness
- Chest tightness
- Coughing
76
How does the respiratory epithelium change with asthma?
Desquamation
Eosinophil infiltration in and under epithelium
- Damages epithelium
- Exposes sensory nerve > airway hyper-responsiveness
77
What is the pathophysiology of asthma?
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
78
Why is there an increased likelihood of airway collapse during expiration?
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
79
What are the mediators contributing to airway smooth muscle balance?
```
Constriction
- Acetylcholine
- Histamines
- Leukotrienes
Dilation
- PGE2
- Adrenaline
- Prostacyclin
```
80
Describe the histological changes of airway remodelling
```
Goblet cell metaplasia
Subepithelial collagen thickening
Infiltration of inflammatory cells
Increased mucosal vascularity
Increased smooth muscle volume
```
81
What are the key features of short acting beta2-adrenoceptor agonists?
Rapid onset = 2-5 min
| Selectivity for beta2-adrenoceptors
82
What is the drug class of salbutamol?
Short-acting beta2-adrenoceptor agonist (SABA)
83
What are the adverse effects of SABAs?
May be beta1-related
- Tachycardia
- Tremor
- Hypokalaemia
84
How is tolerance to SABAs dealt with?
Happens because of full agonists
| Now only partial agonists used
85
How do salmeterol and formeterol differ as long-acting beta2-adrenoceptor antagonists (LABAs)?
Salmeterol has slow onset
| Formeterol has rapid onset
86
How does indacaterol differ to other LABAs?
Longer duration of action = 24 hrs
87
What is the indication for LABA use?
Prophylaxis, combined with inhaled glucocorticoids
88
What is the eclipse period during viral replication?
When virus broken down inside cell and being replicated > no release of virus yet
89
What are the stages of viral replication?
1. Attachment/adsorption
2. Penetration
3. Uncoating
4. Amplification of viral genome and proteins
5. Assembly
6. Release
90
What are the two methods of viral penetration?
Fusion with host cell membrane and release of viral nucleocapsid directly into cytoplasm
Endocytosis > lysis of endosome
91
How does replication of negative sense RNA virus differ from that of a positive sense RNA virus?
Negative sense viruses must bring their own RNA-dependent RNA polymerase as they can't be translated automatically
92
What can be virus induced changes in cells?
Transformation to tumour cells
Lytic infection
Chronic infection
Latent infection
93
How do viruses evolve?
Mutation
Recombination
Reassortment
94
How can the infectious process of viruses be halted?
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
95
What are the sgates undertaken by a virus in order to cause infection?
Entry into body
Multiply and spread
Target appropriate organ
96
How may a virus be maintained in nature
Shed into environment
Taken up by arthropod vector/needle
Passed congenitally
97
What is the difference between local and systemic viral replication?
Local viral replication = confined to organ of entry
| Systemic viral replication = involves many organs
98
What is tropism?
Anatomical localisation of infection
| Initially determined by receptor specificity of virus
99
Why do most viruses enter via the epithelial cells of the mucosa?
Can't enter through keratinised dead skin
100
How may respiratory tract viruses be acquired?
Aerosol inhalation
| Mechanical transmission of infected nasal secretion
101
What is required in order for viruses to enter cells?
Attach to specific receptors on epithelial cells
102
Describe the pathophysiology of the measles virus
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
103
What forms Koplick spots in measles?
Accumulations of lymphocytes
104
Why do viruses that infect the intestinal tract generally not have an envelope?
Envelope easily broken down in intestinal tract by proteases
105
How do viruses such as HIV and HBV enter the body even though the do not have receptors for epithelial cells?
Breach in epithelial surface
106
How may viruses use M cells to cause infection?
M cells constantly sampling environment
Some enteric viruses use this pathway to gain entry to deeper tissues
Other viruses infect and destroy M cells
107
How do some diarrhoea causing viruses promote spread of virus by diarrhoea?
Secretion of viral protein from infected cells increases fluid secretion of remaining intestinal cells > intensifies diarrhoea
108
Desribe the viral progression of enterovirus infections
```
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
```
109
How may the skin be bypassed to cause infection?
```
Minor trauma
Injection via
- Needles
- Body piercing
- Tattooing
Insect/animal bite
Genital tract
Conjunctiva
```
110
What are the mechanisms of viral spread in the body?
Local spread on epithelial surfaces
Subepithelial invasion and lymphatic spread
Viraemia
Neural spread
111
Explain the concept of the carriage state as a result of viraemia
Mother has viraemia > baby born with viraemia > immunotolerant to HBV > can't kill HBV > carrier
112
What is the pathophysiology of congenital rubella syndrome?
```
Slows down rate of cell division
Babies
- Small
- Development of key organs in 1st trimester impaired
- Microcephaly
- Congenital heart defects
- Cataracts
- Deafness
```
113
What are the different mechanisms of viral-induced damage to tissues and organs?
Death as direct result of viral replication
| Loss of function
114
How can viruses induce disease due to consequences of the immune response?
Immunopathology
Immunosuppression
Autoimmunity
115
What do type 1 interferons do?
```
Inhibit viral replication
Activate NK cells
Enhances MHC class I expression
Prduced by virus infected
- Macrophages
- DCs
- Tissue cells
```
116
What do type 2 interferons do?
```
Inhibit viral replication
Activate macrophages
Enhance MHC class I and class II expression
Produced by
- NK cells
- T cells
```
117
How do viruses evolved to evade immune attack?
```
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
```
118
How do NK cells function?
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
119
Describe the distribution of microbiota in the upper respiratory tract
```
Upper respiratory tract has lots of microbiota up to level of larynx
Sterile sites
- Trachea
- Bronchi
- Bronchioles
- Alveoli
```
120
What are non-typable Haemophilus influenzae?
Type of H influenzae dependent on its capsule
| Non-capsulated H influenzae considered non-typable
121
What are the frequent aetiological agents of the common cold?
```
Rhinovirus
Parainfluenza virus
Respiratory syncytial virus (RSV)
Enterovirus
Coronavirus
```
122
What are the frequent aetiological agents of pharyngitis/tonsillitis with nasal involvement?
Adenovirus
Enterovirus
Parainfluenza virus
Influenza virus
123
What are the frequent aetiological agents of pharyngitis/tonsillitis without nasal involvement?
```
Adenovirus
Enterovirus
Influenza
Reovirus
Streptococcus pyogenes
Bacteria
```
124
What are the frequent aetiological agents of sinusitis?
Primary sinusitis part of viral common cold
Secondary sinusitis caused by
- H influenzae
- Streptococcus pneumoniae
125
What are the frequent aetiological agents of otitis media?
S pneumoniae
H influenzae
Moraxella catarrhalis
126
What is the primary aetiological agent causing epiglottitis?
H influenzae type b - largely eradicated by vaccine
127
What are the frequent aetiological agents of croup?
Parainfluenza virus
Influenza A
RSV
128
When is laboratory diagnosis required for upper respiratory tract infections?
Mainly for
- Pharyngitis
- Tonsillitis
- Epiglottitis
129
What laboratory tests are undertaken for a patient suspected of epiglottitis?
Blood culture
| Don't take throat swab/touch epiglottis > might cause epiglottis spasm > airway obstruction
130
How are upper respiratory tract infections generally treated?
Mostly supportive treatment
- Bed rest
- Fluids
131
When is otitis media treated?
If <2 years
| Prolonged and severe
132
When is croup treated?
Not treated specifically - supportive treatment
133
How is acute bronchitis usually caused?
Complication/acute exacerbation of viral upper respiratory tract infection
134
In what way are people with chronic bronchitis immunocompromised?
Innate immune system weakened due to chronic smoking damage > prone to infection by low-grade pathogenic bacteria from upper respiratory tract infection
135
What are the main causative agents of an acute exacerbation of chronic bronchitis?
S pneumoniae
| H influenzae
136
How does RSV cause bronchiolitis in infants?
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
How do acute bacterial pneumonia and atypical pneumonia differ in site of inflammation?
Acute bacterial pneumonia infections usually restricted to airways
Atypical pneumonia usually affects lung interstitial tissue
138
What are the common causative agents of acute bacterial pneumonia?
```
S pneumoniae
H influenzae
Staphylococcus spp
Klebsiella pneumoniae
Legionella
TB
Chlamydophila
```
139
What are the common causative agents of atypical pneumonia?
```
Mycoplasma
Chlamydia spp
M catarrhalis
Influenza virus
RSV
Adenovirus
```
140
How does Legionella cause pneumonia from air conditioning?
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
How is laboratory diagnosis of pneumonia achieved?
```
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
How is diagnosis of Legionella pneumophila type 1 achieved?
Urine Ag detection
143
Why are penicillin G and tetracycline/macrolide used as combination empirical treatment for pneumonia?
Penicillin targets pneumococci
| Doxycycline and macrolides target all atypical pneumonias
144
How do pneumococcal vaccines differ for adults and children?
Adults given 23-valent polysaccharide vaccine
| Children given 13-valent conjugate vaccine
145
What is a systematic review?
Literature review focused on single question > identifies, appraises, selects and synthesises high-quality evidence relevant to question
Highest level of evidence
146
What are the four purposes of meta-analysis?
Increase power
Resolve uncertainty
Improve estimates of effect size
Answer other questions
147
What are the key aspects of meta-analysis?
Outcome
Weighting of individual studies
Heterogeneity
148
Which studies contribute the most weight in a meta-analysis?
Larger studies
| Studies with small confidence intervals
149
How is statistical and non-statistical heterogeneity of studies assessed?
```
Statistical
- Effect sizes
- Variances
Non-statistical
- PICOT
```
150
What does the validity of a meta-analysis depend on?
Relies on whether component studies similar enough to be pooled
151
What is the most common tool used in reporting systematic reviews?
PRISMA checklist
152
What is the difference in pressure in the pulmonary circulation compared to systemic circulation?
Low pressure
153
What is the functional purpose of low pulmonary circulatory pressure?
Aims to prevent movement of fluid from pulmonary vasculature into lung
154
How does the pulmonary vasculature change with increased cardiac output?
Pulmonary artery pressure doesn't rise with increased cardiac output due to dilatation and recruitment of pulmonary vessels which aren't normally needed
155
What are the two types of abnormalities of the pulmonary circulation?
Increased leakage of fluid across the pulmonary capillaries
| Increased pressure in pulmonary arteries
156
What is the mechanism of crepitations?
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
What is perihilar alveolar opacity on a chest x-ray indicative of?
Increased size of pulmonary veins
158
What are Kerley B lines due to?
Dilated interlobular septa
159
During metabolic acidosis, what are the causes of low bicarbonate?
Loss of bicarbonate from body
| Buffering - bicarbonate consumed to combat new acid
160
What are the factors that determine fluid movement across the pulmonary capillaries?
Hydrostatic pressure inside and outside capillary
Oncotic pressure inside and outside capillary
Permeability of capillary
161
What are the mechanical changes that occur during pulmonary oedema?
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
How is gas exchange affected in pulmonary oedema?
Hypoxaemia due to shunt
Low V/Q units due to increased airway resistance and compensatory vasoconstriction
Diffusion impairment
163
What is the effect of interstitial oedema and alveolar oedema on lung function?
Interstitial oedema causes little functional effect
| Alveolar oedema has large effect on lung function
164
What is the purpose of a diagnostic test?
Confirmation of disease or otherwise
| Applied to patients in whom clinical suspicion of disease
165
How does the purpose of a screening test differ from that of a diagnostic test?
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
What is the difference between sensitivity and specificity?
```
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
What are positive predictive value (PPV) and negative predictive value (NPV), and what do they measure?
PPV and NPV dependent on sensitivity and specificity and underlying prevalence of disease
Utility of diagnostic/screening test dependent on prevalence of disease
168
What are likelihood ratios?
Likelihood that given test result would be expected in patient with disease compared to patient without disease
169
What is the receiver operator character (ROC) curve?
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
What is the rationale for screening tests?
Early detection > better outcomes
| Assessment of population to identify risk factors and early disease
171
What are the limitations of screening programs?
Inaccuracy of screening tests
May not be cost effective
Physical and psychological side effects
Biases in measurement of effectiveness
172
What are the biases involved in screening programs?
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
What is the alveolar-capillary membrane composed of?
Layer of surfactant
Type 1 alveolar cells
Basement membrane
Vascular endothelial cell
174
Which conditions can disrupt the A-C membrane?
```
Pulmonary fibrosis
Emphysema
Pneumonia
Non-infective inflammation
Cancer
```
175
What are the likely physiological effects of disrupting the A-C membrane?
Abnormal gas exchange
Abnormal lung mechanics
Pulmonary vascular complications
176
What are the causes of low oxygen concentrations?
Low levels of oxygen in air breathed in
Low ventilation
Abnormal gas exchange
177
What are the causes of high carbon dioxide concentrations?
Low ventilation
178
When does diffusion limitation of oxygen transfer occur?
During exertion in diseases state
| Higher demand for oxygen becomes limiting factor > can't adequately diffuse across diseased membrane
179
Why do the lungs not collapse in restrictive lung diseases?
Elasticity of chest wall muscles keep stiffened lungs from collapsing
180
What is the altered pattern of breathing in restrictive lung diseases?
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
Name the main types of obstructive lung diseases
Asthma
Chronic obstructive pulmonary disease (COPD)
Bronchiectasis
182
Name the main types of restrictive lung diseases
Idiopathic
Pneumoconiosis
- Asbestosis
Sarcoidosis
183
What are the two types of asthma?
Atopic/allergic asthma
| Non-allergic asthma
184
What is the pathophysiology of asthma?
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
What are the serious short term complications of asthma?
Death
Atelectasis
Spontaneous pneumothorax
186
What is atelectasis?
Ventilation present but obstruction means that gas exchange is not possible > lung collapse
187
What is spontaneous pneumothorax?
Air can get in but can't get out > pierces pleural space and air goes into pleural space
188
What are the severe complications of chronic asthma?
```
Airway remodelling
- Fibrosis
- Irreversible
- Obstruction
Chronic hypoxia > pulmonary hypertension > cor pulmonale
```
189
What is emphysema?
Abnormal, permanent enlargement of air spaces distal to terminal bronchiole from destruction of alveolar wall septa without fibrosis
190
What are the types of emphysema?
Centriacinar
Panacinar
Distal acinar
Irregular
191
Which type of emphysema is mainly caused by cigarette smoking?
Centriacinar
192
How does cigarette smoking cause emphysema?
Disrupts protease:anti-protease balance:
- Increases
- Neutrophil elastase activity
- Macrophage elastase
- MMP
- Decreases anti-protease activity
193
How does emphysema cause airway obstruction?
```
Loss of elastic recoil
- Elasticity of parenchyma keeps small airways open
- Loss > collapse
Associated conditions
- Small airways disease
- Chronic bronchitis
```
194
What are the complications of emphysema?
Hypoxia caused by airflow obstruction (mainly)
Loss of diffusion capacity - late-stage
Pulmonary hypertension and cor pulmonale
Pneumothorax
195
What is the clinical definition of chronic bronchitis?
Persistent cough productive of sputum for at least 3 months in 2 consecutive years
196
What is the pathogenesis of chronic bronchitis?
Chronic irritation by inhaled substances > increased mucus production in larger airways > airway inflammation, scarring, and narrowing in smaller airways
197
What is the morphology seen in chronic bronchitis?
```
Hypertrophy of mucus-secreting glands
Increased goblet cells
Mild increase in
- Lymphocytes
- Macrophages
- Plasma cells
- Oedema
Peribronchial fibrosis in small airways
```
198
What are the complications of chronic bronchitis?
Squamous metaplasia may > squamous cell carcinoma
Superimposed infective exacerbations
Hypoxia > pulmonary hypertension > cor pulmonale
199
How does smoking predispose to pulmonary infection?
Inhibition of muco-ciliary escalator
Increased mucus
Inhibition of leukocyte function
Direct damage to epithelial layer
200
What is bronchiectasis?
Irreversible, abnormal dilatation of bronchi/bronchioles
201
What is the pathogenesis of bronchiectasis?
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
What are the causes of bronchiectasis?
```
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
What are the two main findings used to diagnose restrictive lung disease?
Restrictive spirometry
| Inflammation and fibrosis of inter-alveolar septa
204
How does restrictive lung disease appear on chest x-ray?
Diffuse reticulo-nodular and/or ground-glass appearance
205
Why do LABAs act for longer than SABAs?
Due to lipophilicity = stay in lipid membrane and act for longer
206
What are the indications for LABA use?
Must be combined with inhaled glucocorticoids and monotherapy associated with increased morbidity/mortality
Indicated for prophylaxis only
207
What is the mechanism of action of muscarinic antagonists?
Act to block muscarinic receptors on airway smooth muscle > prevent contraction
208
What is the drug class of ipratropium bromide?
Short-acting non-specific muscarinic antagonist
209
What is the drug class of tiotropium bromide?
Long-acting non-specific muscarinic antagonist
210
What is ipatropium bromide preferred in airway disease over atropine?
Atropine has central effects as well as bronchodilatory effects
Ipatropium bromide doesn't diffuse across BBB
211
What are the effects of glucocorticoids in asthma?
Decreased inflammatory cell number and activation
| Decreased probability and severity of asthmatic episodes
212
What is the mechanism of action of glucocorticoids?
Bind to receptor > diffuse across plasma membrane > dimerisation > translocated to nucleus > initiate gene expression > anti-inflammatory and bronchodilatory gene products
213
What are the indications for glucocorticoid use to treat asthma?
Inhaled glucocorticoids indicated if beta2-adrenoceptor agonists required >3 times per weel
214
What are the adverse effects of glucocorticoid use?
```
For inhaled
- Dysphonia
- Oral candidiasis
For oral
- Adrenal atrophy > metabolic disturbances
- Osteoporosis
- Diabetes
- Muscle wasting
- Growth suppression
```
215
What is COPD?
Peristent airflow limitation
Usually progressive
Associated with enhanced chronic inflammatory response in airways and lungs to noxious particles/gases
216
What is air trapping in COPD?
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
How do CD8 T cells exacerbate COPD?
Release IFN-gamma and perforin/granzymes
| - Perforin and granzymes: destruction and apoptosis of type I pneumocytes
218
What are the therapeutic options for the management of COPD?
```
Smoking cessation
LABAs
- Symptom relief
- Reduce exacerbations
Combining bronchodilators of different pharmacological classes
Inhaled corticosteroids
```
219
How does theophylline act to relax smooth muscle?
Phosphodiesterase inhibitor: raises cAMP > activates PKA
- Inhibits TNF-alpha and leukotriene synthesis
- Reduces inflammation and innate immunity
220
What is the effectiveness and tolerability of theophylline compared to LABAs in the management of COPD?
Theophylline less effective and well tolerated
221
What are the causes of pneumonia?
Mostly due to infections
- Bacteria = 85%
- Viruses
- Fungi and protozoa - in immunocompromised host
222
What are the clinical features of pneumonia?
```
Fever and chills
Unrelenting cough
Sputum production
- Purulent
Chest pain if pleural inflammation
Impaired gas exchange
- Dyspnoea
- Tachypnoea
```
223
Why is it importnat to identify if pneumonia is community-acquired, hospital-acquired, or of an immunocompromised host?
Guides empirical treatment
224
What are the possible routes of entry of infective pneumonias?
Inhalation of pathogens in air droplets
Aspiration of infected secretions from upper respiratory tract
Aspiration of infected particles
Haematogenous spread
225
What are the three aetiological classifications of infective pneumonia?
Upper respiratory tract flora
Enteric saprophytes
Extraneous pathogens
226
What are the two patterns of infective pneumonia?
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
What are the two types of alveolar pneumonia?
Bronchopneumonia = patchy consolidation
Lobar pneumonia = whole lobe affected
easily identified in chest x-ray
228
What are the most common causes of lobar pneumonia?
S pneumoniae
| Haemophilus influenzae
229
How may organisms causing lobar pneumonia be identified?
Sputum culture
| Bacteraemia
230
What are the four stages of lobar pneumonia?
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
Which patients are especially susceptible to acute bronchopneumonia?
Extremes of life
Secondary to pre-existing chronic disease
Hospitalised patient populations
Post-operative patients
232
What are the complications of pneumonia?
```
Pleuritis
Pyothorax
Lung abscess
Bronchiectasis
Interstitial fibrosis
Cysts
```
233
What are the causes of lung abscess?
```
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
What can cause interstitial pneumonia?
```
Viral infection
Bacterial infection causing atypical pneumonia
Non-infectious causes
- Drugs
- Immunological disease
- Radiation
```
235
What is the pathology of infective pneumonia with interstitial inflammation?
Alveolar septa widened > infiltrated with lymphocytes, plasma cells, and macrophages
Often associated bronchiolitis
236
What is the typical presentation of atypical pneumonia?
```
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
What are some causes of atypical pneumonia?
Mycoplasma pneumoniae
Coxiella burnettii
Legionella spp
Chlamydia pneumoniae
238
How is TB unique when compared to other pneumonias?
Can't clear infection - must instead wall it off
May lie dormant for many years
May subsequently cause secondary infections
239
What is the Ghon complex?
Characteristic of TB infection
| Parenchymal Ghon focus and enlarged hilar lymph node caseating lesions
240
What is the pathophysiology of secondary TB?
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
What are the complications of secondary pulmonary TB?
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
What are the clinical features of TB?
```
Variable weight loss
Malaise
Fevers
Night sweats
Haemoptysis
Dyspnoea
Chronic cough
```
243
Describe the spread of TB
Lymphatic spread of TB to pleura and contralateral lung
Spread of TB to bronchial tree > caseous necrosis in bronchi, bronchioles > bronchopneumonia
Haematogenous spread
244
What is miliary TB and how does it arise?
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
What is single organ TB?
Usually secondary TB of other rgans with caseation
246
Where is the central controller of the respiratory control system?
Brainstem
- Medulla
- Pons
Cortex = voluntary hyper- and hypoventilation
247
Describe the locations and roles of the respiratory system sensors
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
How can CO2 act as a stimulant to ventilation?
In response to rising CO2 levels
| In response to lowered pH due to high CO2
249
What is the ventilatory response to exercise?
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
Define hypoventilation
Rate of alveolar ventilation not meeting metabolic requirements for oxygen consumption and carbon dioxide production
251
What are the causes of hypoventilation?
```
Reduced respiratory centre activity
Neuromuscular disease
Chest wall deformity
Obesity
Sleep disordered breathing
```
252
Why does snoring and obstruction occur in obstructive sleep apnoea?
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
What are the causes of breathlessness in young athletes?
Normal sensation at maximal effort
Performance anxiety
Disease
254
How may people with disease and people who are deconditioned be distinguished from each other?
Therapeutic trial - 3 month aerobic training program > re-measure exercise capacity
255
How may psychogenic manifestations of breathlessness and breathlessness caused by disease b distinguished?
Stress test
| Vocabulary used to describe breathlessness
256
What are the different types of influenza virus?
Seasonal
| Pandemic
257
What are the at-risk groups of influenza?
Extremes of age
| Underlying chronic disease
258
How is the influenza virus spread?
Droplet infection from coughing and sneezing
259
What is the incubation period for influenza?
1-5 days
260
What is the pathogenesis of seasonal influenza?
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
What are the two outcomes of a seasonal influenza infection?
```
Clearance
Secondary bacterial pneumonia
- H influenzae
- S aureus
- S pneumoniae
```
262
What family does influenza virus belong to?
Orthomyxoviridae
263
What is the molecular structure of influenza virus?
Enveloped
| Segmented negative sense ssRNA genome
264
Which types of influenza virus infect humans?
A infects humans and other species
| B endemic to humans
265
Describe the structure of an influenza virion
```
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
What is the target of antivirals against influenza virus?
M2 ion chhannel
267
What are the roles of haemagglutinin (HA) and neuraminidase (NA)?
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
How do the type A influenza subtypes differ from each other?
Differ in form of HA and NA they encode
269
Why is influenza strictly confined to the respiratory tract?
Tryptase Clara needed for maturation not found anywhere else
| - Snips HA after budding to make it active
270
Describe the adaptive immune response to influenza virus infection
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
If the antibody response to the influenza virus is lifelong, why do we continually get influenza throughout our lifetime?
Ag drift
| Viruses with mutations where Ab binds can no longer be bound by Ab > mutated sequences selected for
272
When do influenza epidemics arise?
When all 5 Ag sites have mutated - unlikely we'll have Abs to any of these sites
273
What are the targets of vaccine-induced immunity to influenza?
Ab to HA blocks attachment
| Ab to NA blocks efficient release
274
Describe the influenza vaccine
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
What do the antivirals amantadine and rimantadine do?
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
What do the antivirals zanamivir and oseltamivir do?
Block action of NA
- Effective against both influenza A and B
- Zanamivir inhaled by mouth
- Oseltamivir preferred because orally-administered prodrug
277
How does antigenic shift differ to antigenic drift?
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
How does reassortment create a new human subtype of influenza?
Swapping of gene segments in pig upon co-infection of single cell
279
What is the WHO's TB control strategy?
DOTS
| Stop TB strategy - MDR TB, TB and HIV, weak health systems
280
What are the issues of the WHO's TB control strategy?
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
What are the proximate risk factors for TB?
```
Exposure to infectious droplets
Host defence (HIV)
Malnutrition
Indoor air pollution
Alcohol abuse
Other disease
Depression and stress
```
282
What are some ways in which low socioeconomic status can be linked with the proximate risk factors for TB?
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
What are the recommendations for action against TB epidemics?
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
What is a thrombus?
Clotted mass of blood forming within unruptured cardiovaascular system during life
285
What is the pathophysiology of factor V Leiden mutation?
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
Describe the venous drainage of the leg
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
What are the common clinical signs of DVT?
```
Swelling
Redness
Warmth
Discomfort
Pain
Tenderness
Usually unilateral
50% lack symptoms and signs
```
288
What do the effects of a pulmonary thromboembolism depend on?
Size of embolus
Presence/absence of lung disease
Presence/absence of cardiovascular disease
289
What is the typical clinical presentation of a patient with pulmonary embolism (PE)?
Variable dyspnoea
Haemoptysis
Cough
Syncope: in severe cases with cardiac insufficiency
Pleuritic pain: commonly present if there's an infarct
290
What pathophysiological abnormalities may be present with PE?
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
Why are pulmonary infarcts uncommon?
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
What are the consequences of small pulmonary emboli?
Chronic pulmonary hypertension
| Chronic cor pulmonale
293
What are the long term outcomes of DVT?
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
Define sleep
Behavioural state characterised by
- Decreased awareness of external environment
- Decreased reactivity to stimuli
- Capability to return rapidly to wakefulness
Stereotypical postures
295
What are the functions of sleep?
Learning
Brain development
Repair and maintenance
Energy preservation
296
How is subjective impairment different to objective impairment in terms of sleep deprivation?
Performance declines objectively, but subjective sleepiness doesn't increase as much
297
Describe the control of breathing during sleep
Emotional stimuli input lost
Higher brain centre input lost
Wakefulness drive to breathe lost
Other stimuli of breathing depressed
298
Why is there increased upper airway resistance during sleep?
Reduced upper airway muscle tone
299
What happens to ventilation and carbon dioxide levels during sleep?
Minute ventilation falls at sleep onset
CO2 levels rise until new sleep set-point reached
Chemoreceptor drive = major regulator of breathing
300
How does eye and muscle movement change from non-rapid eye movement (NREM) to rapid eye movement (REM) sleep?
Eye movement greater in REM sleep
| Muscle movement greater in NREM sleep
301
How ling is a typical REM cycle?
90-120 min
302
How does sleep change with age?
In elderly
- Less deep sleep
- More waking events
303
What are the hallmarks of cancer cells?
```
Sustaining proliferative signalling
Evading growth suppressors
Activating invasion and metastasis
Enabling replicative immortality
Inducing angiogenesis
Resisting cell death
Immune evasion
Tumour inflammation
```
304
What is desmoplasia?
TGF-beta secreted by some malignant cells to recruit fibroblasts to lay down extracellular matrix inside and outside tumour
305
What are the mechanisms of tumour metastasis?
```
Local invasion
Blood-borne spread
Lymphatic spread > can then spread into venous system
Trascoelomic spread = along
- Pleural spaces
- Pericardial spaces
- Peritoneal spaces
```
306
What is lymphangitis carcinomatosis?
Pattern of spread of lung cancers, noted by thickening of vessels
307
What are the histopathological features of neoplasia?
```
Larger nuclei
Pleomorphic nuclei
Coarser nuclear chromatin
Hyperchromatic nuclei
Larger and more prominent nucleoli
More mitotic activity, abnormal mitotic figures
Architectural disorganisation
```
308
What does the grade of the tumour refer to?
Its degree of differentiation
309
What does the tumour microenvironment comprise?
```
Tumour stroma
- Fibroblasts
- Extracellular matrix
- Endothelial cells
- Immune cells
- Soluble molecules
Tissue where tumour located
```
310
What are the four classes of normal regulatory genes that are the principal targets of genetic damage in carcinogenesis?
Growth-promoting proto-oncogenes
Growth-inhibiting tumour suppressor genes
Genes that regulate apoptosis
Genes involved in DNA repair
311
How do mutations in DNA repair genes promote carcinogenesis?
Cell no longer able to correct cell division induced DNA errors
Rapid accumulation of secondary mutations affecting genes of other classes
312
How do mutations in proto-oncogenes promote carcinogenesis?
Involved in regulating growth
| Mutations turn them into oncogenes > uncontrolled growth
313
How do mutations in tumour suppressor genes promote carcinogenesis?
Control growth by suppressing cel division
| Mutation > continuous growth
314
To promote carcinogenesis, only one allele of oncogenes needs to be mutated whereas both alleles of tumour suppressor genes must be lost. Why?
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
What are the types of mutations in cancer?
Errors in DNA replication which aren't repaired
Point mutations
Amplification of oncogenes
Chromosomal rearrangements
316
What is the difference between a mutation and a polymorphism?
```
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
What are the steps of normal cell proliferation?
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
How do mutations in Ras promote carcinogenesis?
Dephosphorylation of Ras blocked in mutant Ras
Ras always in active form
Constant activation of MAP kinase pathway
Constant activation of transcription
319
What is the role of p53? What are the consequences of its deletion or mutation?
```
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
Wat is the consequence of DNA methylation?
Excessive methylation around promoter region silences expression of tumour suppressor genes
321
How do oncogenes and tumour suppressor genes affect the cell cycle?
Oncogenes inhibit regulatory controls of cell cycle
322
Describe the concept of tumour cell immortality
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
Outline the process of tumour metastasis
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
What is the pathophysiology of squamous cell carcinoma in the lung?
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
If the tumour type cannot be determined on H&E, what technique is used instead?
Immunohistochemistry used to detect tumour proteins using labelled Abs
326
What does the stage of a tumour refer to>
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
How are tumours generally managed?
Surgery
Radiotherapy
Chemotherapy
Targeted therapy
328
How does sulfonamide exert its effects on bacteria?
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
How does methotrexate act?
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
Why are kidneys subject to relative hypoxia? Why is this problematic?
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
What is the triple-whammy and why is this problematic?
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
