Respiratory Flashcards
How do internal and external validity differ?
Internal validity = how well trial deals with limitations like bias and confounding
External validity = applicability of trial results
What does PICOT stand for?
P = population I = intervention C = comparator/control O = outcome T = timing
What is PICOT used for?
Frame question which will be used to search literature
What is stratified randomisation?
Randomisation divided by levels of key confounders
What does stratified randomisation seek to achieve?
To make composition of groups more similar with respect to key confounders > further reduce potential for confounding
What is the p-value?
Probability that observe result rose from chance
Conventional cutoff = 0.05
p <0.05 - statistically significant
What does the width of the 95% confidence interval measure?
Precision of result
How is external validity assessed?
By determining degree of concordance between randomised control trial and clinical setting in terms of PICOT
What is Klinefelter syndrome?
XXY trisomy
What is Turner’s syndrome?
XO monosomy
What is the Guthrie test?
Dried blood spot from heel prick
Enables mass screening of all newborns
How is phenylketonuria (PKU) screened for with a Guthrie test?
Blood spot can be tested for phenylpyruvate
What is the pathophysiology of PKU?
Lack of phenylalanine hydroxylase: needed for conversion of Phe > Tyr
Phe converted to phenylpyruvate in alternate metabolism
Elevated PKU damages brain and inhibits tyrosinase
What is the pathophysiology of cystic fibrosis (CF)?
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
Describe the mechanism of quiet inspiration
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
What happens to the parietal pleura as the dimensions of the thorax increase?
Parietal pleura becomes more separated from visceral pleura
More volume in intrapleural space > more negative pressure generated
Pulls visceral pleura and lung outwards
What law models gass diffusion involved in respiration?
Fick’s law > dependent on
- Surface area
- Difference in partial pressures
- Thickness of membrane
- Solubility of gas
What limits transfer of oxygen acroos the alveolar membrane?
Perfusion, not diffusion
When is gas change most efficient?
Ventilation and perfusion matched: V/Q = 1
What does a low V/Q mean?
Reduced partial pressure of oxygen > hypoxia
Low partial pressure of oxygen due to what responds to supplemental oxygen?
Low V/Q
Not due to shunt
What is a shunt?
Extreme form of low V/Q unit with no ventilation
Leads to hypoxia
Hb not fully saturated with oxygen
How is ventilation and perfusion distributed throughout the lungs?
Almost all alveoli similar distance from mouth > all have similar resistance
What is an elevated partial pressure of carbon dioxide due to?
Inadequate alveolar ventilation
Rarely due to inefficient gas exchange
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
What does central cyanosis mean?
Arterial blood less saturated with oxygen
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
What causes increased sensation of breathing?
Increased load to breathe or an increased drive for breathing
What can increase the load to breathe?
Stiff lungs
Narrow airways
Chest wall
Diaphragm
What can increase the drive for breathing?
Higher centres Mechanoreceptors Irritant receptors Chemoreceptors Baroreceptors Temperature
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
What are the consequences of airway obstruction?
Recruitment of accessory muscles
Increased oxygen consumption by respiratory muscles
Respiratory muscle fatigue
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
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
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
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
What happens in severe airway obstruction when V/Q mismatch is minimised?
Overall decreased gas exchange > hypoxia
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
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
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
What makes up the mucosa of the trachea?
Respiratory epithelium
Lamina propria
What makes up the submucosa of the trachea?
Glands
Connective tissue
What makes up the adventitia of the trachea?
Cartilage
Outer layer of connective tissue
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
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
What are Clara cells?
Columnar/cuboidal cells
Short microvilli
Secrete surfactant
May also neutralise toxins
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
What structures arise from the respiratory bronchioles?
Alveoli
Chains of alveoli = alveolar ducts
What type of epithelium do respiratory bronchioles contain?
Cuboidal > squamous - needed for gas exchange
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
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
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
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
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
Where are mast cells particularly prevalent?
Body sites in contact with external environment
Because these sites particularly prone to attack
How are mast cells stimulated in exercise-induced asthma?
Hyperosmolarity of airway surface fluid during exercise triggers bronchospasm and activates mast cells
What is red man syndrome?
Profound vasodilation produced by mast cells
How are mast cells activated?
Allergen cross-links IgE > adjacent IgE receptors on mast cells bound > 2nd messenger cascade > degranulation
How long does the initial reaction from mast cell degranulation take?
30-45 sec
What is released from mast cells?
Immediate - Histamine - Heparin - Tryptase - TNF-alpha Rapid - Leukotrienes - PGD2 Slow - IL-4 - IL-5 - GM-CSF
What do leukotrienes and PGD2 released from mast cells do?
Potent bronchoconstrictors
Which histamine receptors are acted on during mast cell degranulation?
H1 receptors
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
Which cells produce cysteinyl leukotrienes?
Eosinophils
Mast cells
Macrophages
What are the stimuli for cysteinyl leukotriene production?
Allerge
C5a
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
What are the endogenous inhibitors of mast cell activation?
PGE2
Adrenaline
Cortisol
Pharmacological agents
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
Why are disodium cromoglycate and nedocromil sodium well tolerated?
Don’t gain access to systemic circulation
What is omalizumab?
Humanised mAB against IgE
What is the mechanism of action of omalizumab?
Reduces sensitisation of mast cells over time by sterically hindering IgE binding to receptor
In what ways may mediator production from mast cells be inhibited?
Glucocorticoids
- Reduce mast cell cytokine production
In what way may mast cell mediator actions be inhibited?
H1 receptor antagonists = antihistamines
What are the indications for cysteinyl luekotriene receptor antagonists?
Aspirin-induced and exercise-induced asthma
What is asthma?
Chronic inflammation associated with airway hyper-responsiveness > recurrent episodes of
- Wheezing
- Breathlessness
- Chest tightness
- Coughing
How does the respiratory epithelium change with asthma?
Desquamation
Eosinophil infiltration in and under epithelium
- Damages epithelium
- Exposes sensory nerve > airway hyper-responsiveness
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
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
What are the mediators contributing to airway smooth muscle balance?
Constriction - Acetylcholine - Histamines - Leukotrienes Dilation - PGE2 - Adrenaline - Prostacyclin
Describe the histological changes of airway remodelling
Goblet cell metaplasia Subepithelial collagen thickening Infiltration of inflammatory cells Increased mucosal vascularity Increased smooth muscle volume
What are the key features of short acting beta2-adrenoceptor agonists?
Rapid onset = 2-5 min
Selectivity for beta2-adrenoceptors
What is the drug class of salbutamol?
Short-acting beta2-adrenoceptor agonist (SABA)
What are the adverse effects of SABAs?
May be beta1-related
- Tachycardia
- Tremor
- Hypokalaemia
How is tolerance to SABAs dealt with?
Happens because of full agonists
Now only partial agonists used
How do salmeterol and formeterol differ as long-acting beta2-adrenoceptor antagonists (LABAs)?
Salmeterol has slow onset
Formeterol has rapid onset
How does indacaterol differ to other LABAs?
Longer duration of action = 24 hrs
What is the indication for LABA use?
Prophylaxis, combined with inhaled glucocorticoids
What is the eclipse period during viral replication?
When virus broken down inside cell and being replicated > no release of virus yet
What are the stages of viral replication?
- Attachment/adsorption
- Penetration
- Uncoating
- Amplification of viral genome and proteins
- Assembly
- Release
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
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
What can be virus induced changes in cells?
Transformation to tumour cells
Lytic infection
Chronic infection
Latent infection
How do viruses evolve?
Mutation
Recombination
Reassortment
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
What are the sgates undertaken by a virus in order to cause infection?
Entry into body
Multiply and spread
Target appropriate organ
How may a virus be maintained in nature
Shed into environment
Taken up by arthropod vector/needle
Passed congenitally
What is the difference between local and systemic viral replication?
Local viral replication = confined to organ of entry
Systemic viral replication = involves many organs
What is tropism?
Anatomical localisation of infection
Initially determined by receptor specificity of virus
Why do most viruses enter via the epithelial cells of the mucosa?
Can’t enter through keratinised dead skin
How may respiratory tract viruses be acquired?
Aerosol inhalation
Mechanical transmission of infected nasal secretion
What is required in order for viruses to enter cells?
Attach to specific receptors on epithelial cells
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
What forms Koplick spots in measles?
Accumulations of lymphocytes
Why do viruses that infect the intestinal tract generally not have an envelope?
Envelope easily broken down in intestinal tract by proteases
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
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
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
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
How may the skin be bypassed to cause infection?
Minor trauma Injection via - Needles - Body piercing - Tattooing Insect/animal bite Genital tract Conjunctiva
What are the mechanisms of viral spread in the body?
Local spread on epithelial surfaces
Subepithelial invasion and lymphatic spread
Viraemia
Neural spread
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
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
What are the different mechanisms of viral-induced damage to tissues and organs?
Death as direct result of viral replication
Loss of function
How can viruses induce disease due to consequences of the immune response?
Immunopathology
Immunosuppression
Autoimmunity
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
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
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
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
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
What are non-typable Haemophilus influenzae?
Type of H influenzae dependent on its capsule
Non-capsulated H influenzae considered non-typable
What are the frequent aetiological agents of the common cold?
Rhinovirus Parainfluenza virus Respiratory syncytial virus (RSV) Enterovirus Coronavirus
What are the frequent aetiological agents of pharyngitis/tonsillitis with nasal involvement?
Adenovirus
Enterovirus
Parainfluenza virus
Influenza virus
What are the frequent aetiological agents of pharyngitis/tonsillitis without nasal involvement?
Adenovirus Enterovirus Influenza Reovirus Streptococcus pyogenes Bacteria
What are the frequent aetiological agents of sinusitis?
Primary sinusitis part of viral common cold
Secondary sinusitis caused by
- H influenzae
- Streptococcus pneumoniae
What are the frequent aetiological agents of otitis media?
S pneumoniae
H influenzae
Moraxella catarrhalis
What is the primary aetiological agent causing epiglottitis?
H influenzae type b - largely eradicated by vaccine
What are the frequent aetiological agents of croup?
Parainfluenza virus
Influenza A
RSV
When is laboratory diagnosis required for upper respiratory tract infections?
Mainly for
- Pharyngitis
- Tonsillitis
- Epiglottitis
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
How are upper respiratory tract infections generally treated?
Mostly supportive treatment
- Bed rest
- Fluids
When is otitis media treated?
If <2 years
Prolonged and severe
When is croup treated?
Not treated specifically - supportive treatment
How is acute bronchitis usually caused?
Complication/acute exacerbation of viral upper respiratory tract infection
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
What are the main causative agents of an acute exacerbation of chronic bronchitis?
S pneumoniae
H influenzae
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
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
What are the common causative agents of acute bacterial pneumonia?
S pneumoniae H influenzae Staphylococcus spp Klebsiella pneumoniae Legionella TB Chlamydophila
What are the common causative agents of atypical pneumonia?
Mycoplasma Chlamydia spp M catarrhalis Influenza virus RSV Adenovirus
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
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
How is diagnosis of Legionella pneumophila type 1 achieved?
Urine Ag detection
Why are penicillin G and tetracycline/macrolide used as combination empirical treatment for pneumonia?
Penicillin targets pneumococci
Doxycycline and macrolides target all atypical pneumonias
How do pneumococcal vaccines differ for adults and children?
Adults given 23-valent polysaccharide vaccine
Children given 13-valent conjugate vaccine
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
What are the four purposes of meta-analysis?
Increase power
Resolve uncertainty
Improve estimates of effect size
Answer other questions
What are the key aspects of meta-analysis?
Outcome
Weighting of individual studies
Heterogeneity
Which studies contribute the most weight in a meta-analysis?
Larger studies
Studies with small confidence intervals
How is statistical and non-statistical heterogeneity of studies assessed?
Statistical - Effect sizes - Variances Non-statistical - PICOT
What does the validity of a meta-analysis depend on?
Relies on whether component studies similar enough to be pooled
What is the most common tool used in reporting systematic reviews?
PRISMA checklist
What is the difference in pressure in the pulmonary circulation compared to systemic circulation?
Low pressure
What is the functional purpose of low pulmonary circulatory pressure?
Aims to prevent movement of fluid from pulmonary vasculature into lung
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
What are the two types of abnormalities of the pulmonary circulation?
Increased leakage of fluid across the pulmonary capillaries
Increased pressure in pulmonary arteries
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
What is perihilar alveolar opacity on a chest x-ray indicative of?
Increased size of pulmonary veins
What are Kerley B lines due to?
Dilated interlobular septa
During metabolic acidosis, what are the causes of low bicarbonate?
Loss of bicarbonate from body
Buffering - bicarbonate consumed to combat new acid
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
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
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
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
What is the purpose of a diagnostic test?
Confirmation of disease or otherwise
Applied to patients in whom clinical suspicion of disease
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
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
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
What are likelihood ratios?
Likelihood that given test result would be expected in patient with disease compared to patient without disease
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
What is the rationale for screening tests?
Early detection > better outcomes
Assessment of population to identify risk factors and early disease
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
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
What is the alveolar-capillary membrane composed of?
Layer of surfactant
Type 1 alveolar cells
Basement membrane
Vascular endothelial cell
Which conditions can disrupt the A-C membrane?
Pulmonary fibrosis Emphysema Pneumonia Non-infective inflammation Cancer
What are the likely physiological effects of disrupting the A-C membrane?
Abnormal gas exchange
Abnormal lung mechanics
Pulmonary vascular complications
What are the causes of low oxygen concentrations?
Low levels of oxygen in air breathed in
Low ventilation
Abnormal gas exchange
What are the causes of high carbon dioxide concentrations?
Low ventilation
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
Why do the lungs not collapse in restrictive lung diseases?
Elasticity of chest wall muscles keep stiffened lungs from collapsing
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
Name the main types of obstructive lung diseases
Asthma
Chronic obstructive pulmonary disease (COPD)
Bronchiectasis
Name the main types of restrictive lung diseases
Idiopathic
Pneumoconiosis
- Asbestosis
Sarcoidosis
What are the two types of asthma?
Atopic/allergic asthma
Non-allergic asthma
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
What are the serious short term complications of asthma?
Death
Atelectasis
Spontaneous pneumothorax
What is atelectasis?
Ventilation present but obstruction means that gas exchange is not possible > lung collapse
What is spontaneous pneumothorax?
Air can get in but can’t get out > pierces pleural space and air goes into pleural space
What are the severe complications of chronic asthma?
Airway remodelling - Fibrosis - Irreversible - Obstruction Chronic hypoxia > pulmonary hypertension > cor pulmonale
What is emphysema?
Abnormal, permanent enlargement of air spaces distal to terminal bronchiole from destruction of alveolar wall septa without fibrosis
What are the types of emphysema?
Centriacinar
Panacinar
Distal acinar
Irregular
Which type of emphysema is mainly caused by cigarette smoking?
Centriacinar
How does cigarette smoking cause emphysema?
Disrupts protease:anti-protease balance:
- Increases
- Neutrophil elastase activity
- Macrophage elastase
- MMP
- Decreases anti-protease activity
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
What are the complications of emphysema?
Hypoxia caused by airflow obstruction (mainly)
Loss of diffusion capacity - late-stage
Pulmonary hypertension and cor pulmonale
Pneumothorax
What is the clinical definition of chronic bronchitis?
Persistent cough productive of sputum for at least 3 months in 2 consecutive years
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
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
What are the complications of chronic bronchitis?
Squamous metaplasia may > squamous cell carcinoma
Superimposed infective exacerbations
Hypoxia > pulmonary hypertension > cor pulmonale
How does smoking predispose to pulmonary infection?
Inhibition of muco-ciliary escalator
Increased mucus
Inhibition of leukocyte function
Direct damage to epithelial layer
What is bronchiectasis?
Irreversible, abnormal dilatation of bronchi/bronchioles
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
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
What are the two main findings used to diagnose restrictive lung disease?
Restrictive spirometry
Inflammation and fibrosis of inter-alveolar septa
How does restrictive lung disease appear on chest x-ray?
Diffuse reticulo-nodular and/or ground-glass appearance
Why do LABAs act for longer than SABAs?
Due to lipophilicity = stay in lipid membrane and act for longer
What are the indications for LABA use?
Must be combined with inhaled glucocorticoids and monotherapy associated with increased morbidity/mortality
Indicated for prophylaxis only
What is the mechanism of action of muscarinic antagonists?
Act to block muscarinic receptors on airway smooth muscle > prevent contraction
What is the drug class of ipratropium bromide?
Short-acting non-specific muscarinic antagonist
What is the drug class of tiotropium bromide?
Long-acting non-specific muscarinic antagonist
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
What are the effects of glucocorticoids in asthma?
Decreased inflammatory cell number and activation
Decreased probability and severity of asthmatic episodes
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
What are the indications for glucocorticoid use to treat asthma?
Inhaled glucocorticoids indicated if beta2-adrenoceptor agonists required >3 times per weel
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
What is COPD?
Peristent airflow limitation
Usually progressive
Associated with enhanced chronic inflammatory response in airways and lungs to noxious particles/gases
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
How do CD8 T cells exacerbate COPD?
Release IFN-gamma and perforin/granzymes
- Perforin and granzymes: destruction and apoptosis of type I pneumocytes
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
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
What is the effectiveness and tolerability of theophylline compared to LABAs in the management of COPD?
Theophylline less effective and well tolerated
What are the causes of pneumonia?
Mostly due to infections
- Bacteria = 85%
- Viruses
- Fungi and protozoa - in immunocompromised host
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
Why is it importnat to identify if pneumonia is community-acquired, hospital-acquired, or of an immunocompromised host?
Guides empirical treatment
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
What are the three aetiological classifications of infective pneumonia?
Upper respiratory tract flora
Enteric saprophytes
Extraneous pathogens
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
What are the two types of alveolar pneumonia?
Bronchopneumonia = patchy consolidation
Lobar pneumonia = whole lobe affected
easily identified in chest x-ray
What are the most common causes of lobar pneumonia?
S pneumoniae
Haemophilus influenzae
How may organisms causing lobar pneumonia be identified?
Sputum culture
Bacteraemia
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
Which patients are especially susceptible to acute bronchopneumonia?
Extremes of life
Secondary to pre-existing chronic disease
Hospitalised patient populations
Post-operative patients
What are the complications of pneumonia?
Pleuritis Pyothorax Lung abscess Bronchiectasis Interstitial fibrosis Cysts
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
What can cause interstitial pneumonia?
Viral infection Bacterial infection causing atypical pneumonia Non-infectious causes - Drugs - Immunological disease - Radiation
What is the pathology of infective pneumonia with interstitial inflammation?
Alveolar septa widened > infiltrated with lymphocytes, plasma cells, and macrophages
Often associated bronchiolitis
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
What are some causes of atypical pneumonia?
Mycoplasma pneumoniae
Coxiella burnettii
Legionella spp
Chlamydia pneumoniae
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
What is the Ghon complex?
Characteristic of TB infection
Parenchymal Ghon focus and enlarged hilar lymph node caseating lesions
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
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
What are the clinical features of TB?
Variable weight loss Malaise Fevers Night sweats Haemoptysis Dyspnoea Chronic cough
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
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
What is single organ TB?
Usually secondary TB of other rgans with caseation
Where is the central controller of the respiratory control system?
Brainstem
- Medulla
- Pons
Cortex = voluntary hyper- and hypoventilation
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
How can CO2 act as a stimulant to ventilation?
In response to rising CO2 levels
In response to lowered pH due to high CO2
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
Define hypoventilation
Rate of alveolar ventilation not meeting metabolic requirements for oxygen consumption and carbon dioxide production
What are the causes of hypoventilation?
Reduced respiratory centre activity Neuromuscular disease Chest wall deformity Obesity Sleep disordered breathing
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
What are the causes of breathlessness in young athletes?
Normal sensation at maximal effort
Performance anxiety
Disease
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
How may psychogenic manifestations of breathlessness and breathlessness caused by disease b distinguished?
Stress test
Vocabulary used to describe breathlessness
What are the different types of influenza virus?
Seasonal
Pandemic
What are the at-risk groups of influenza?
Extremes of age
Underlying chronic disease
How is the influenza virus spread?
Droplet infection from coughing and sneezing
What is the incubation period for influenza?
1-5 days
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
What are the two outcomes of a seasonal influenza infection?
Clearance Secondary bacterial pneumonia - H influenzae - S aureus - S pneumoniae
What family does influenza virus belong to?
Orthomyxoviridae
What is the molecular structure of influenza virus?
Enveloped
Segmented negative sense ssRNA genome
Which types of influenza virus infect humans?
A infects humans and other species
B endemic to humans
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
What is the target of antivirals against influenza virus?
M2 ion chhannel
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
How do the type A influenza subtypes differ from each other?
Differ in form of HA and NA they encode
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
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
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
When do influenza epidemics arise?
When all 5 Ag sites have mutated - unlikely we’ll have Abs to any of these sites
What are the targets of vaccine-induced immunity to influenza?
Ab to HA blocks attachment
Ab to NA blocks efficient release
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
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
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
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
How does reassortment create a new human subtype of influenza?
Swapping of gene segments in pig upon co-infection of single cell
What is the WHO’s TB control strategy?
DOTS
Stop TB strategy - MDR TB, TB and HIV, weak health systems
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
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
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
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
What is a thrombus?
Clotted mass of blood forming within unruptured cardiovaascular system during life
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)
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
What are the common clinical signs of DVT?
Swelling Redness Warmth Discomfort Pain Tenderness Usually unilateral 50% lack symptoms and signs
What do the effects of a pulmonary thromboembolism depend on?
Size of embolus
Presence/absence of lung disease
Presence/absence of cardiovascular disease
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
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
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
What are the consequences of small pulmonary emboli?
Chronic pulmonary hypertension
Chronic cor pulmonale
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
Define sleep
Behavioural state characterised by
- Decreased awareness of external environment
- Decreased reactivity to stimuli
- Capability to return rapidly to wakefulness
Stereotypical postures
What are the functions of sleep?
Learning
Brain development
Repair and maintenance
Energy preservation
How is subjective impairment different to objective impairment in terms of sleep deprivation?
Performance declines objectively, but subjective sleepiness doesn’t increase as much
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
Why is there increased upper airway resistance during sleep?
Reduced upper airway muscle tone
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
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
How ling is a typical REM cycle?
90-120 min
How does sleep change with age?
In elderly
- Less deep sleep
- More waking events
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
What is desmoplasia?
TGF-beta secreted by some malignant cells to recruit fibroblasts to lay down extracellular matrix inside and outside tumour
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
What is lymphangitis carcinomatosis?
Pattern of spread of lung cancers, noted by thickening of vessels
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
What does the grade of the tumour refer to?
Its degree of differentiation
What does the tumour microenvironment comprise?
Tumour stroma - Fibroblasts - Extracellular matrix - Endothelial cells - Immune cells - Soluble molecules Tissue where tumour located
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
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
How do mutations in proto-oncogenes promote carcinogenesis?
Involved in regulating growth
Mutations turn them into oncogenes > uncontrolled growth
How do mutations in tumour suppressor genes promote carcinogenesis?
Control growth by suppressing cel division
Mutation > continuous growth
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
What are the types of mutations in cancer?
Errors in DNA replication which aren’t repaired
Point mutations
Amplification of oncogenes
Chromosomal rearrangements
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
What are the steps of normal cell proliferation?
- Growth factor binds to its specific receptor
- Transient, limited activation of growth factor receptor with signal transduction
- Transmission of signal across cytosol to nucleus via 2nd messengers/signal transduction cascade
- Initiation of DNA transcription
- Entry and progression into cell cycle
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
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
Wat is the consequence of DNA methylation?
Excessive methylation around promoter region silences expression of tumour suppressor genes
How do oncogenes and tumour suppressor genes affect the cell cycle?
Oncogenes inhibit regulatory controls of cell cycle
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
Outline the process of tumour metastasis
- Detachment of tumour cells from each other
- Degradation of extracellular matrix
- Attachment to novel extracellular components
- Migration of tumour cells
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
If the tumour type cannot be determined on H&E, what technique is used instead?
Immunohistochemistry used to detect tumour proteins using labelled Abs
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
How are tumours generally managed?
Surgery
Radiotherapy
Chemotherapy
Targeted therapy
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
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
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
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
