Week 10 Flashcards
1
Q
What is a forced vital capacity?
A
After slow maximal inspiration, exhalation as hard and long as possible, its total lung volume minus residual volume
2
Q
What is FEV1.0/FVC ratio?
A
Measure of airflow obstruction
3
Q
What does Hypoxia tend to result from?
A
V/Q mismatching
4
Q
What is a normal FEV1.0/FVC ratio?
A
> 0.7
5
Q
What is the FEV1.0/FVC ratio for obstructive lung disease?
A
< 0.7
6
Q
List 4 common obstructive lung diseases?
A
- Asthma
- COPD
- Bronchiectasis
- Cystic fibrosis
7
Q
Describe Asthma?
A
- Non-smoking related
- Allergic
- Younger patients
- Intermittent
- Non-progressive
- Eosinophil infiltration
- Diurnal variation
- Good corticosteroid & bronchodilator response
- Preserved FVC & TLCO
- Normal gas exchange
8
Q
Descrive COPD?
A
- Smokers
- Non-allergic
- Over 50s
- Chronic
- Progressive
- Neutrophils
- No diurnal variation
- Poor corticosteroid & bronchodilator response
- Reduced FVC & TLCO
- Impaired gas exchange
9
Q
What is the FEV1.0?
A
Forced expiratory volume after 1 second of maximal expiration
10
Q
What is FVC?
A
Forced vital capacity, volume exchanged from maximum inhalation to maximum exhalation
11
Q
How is FCV affected by obstructive lung disease?
A
May be reduced
12
Q
How is FEV affected in obstructive lung disease?
A
Reduced
13
Q
How is FRC affected in obstructive lung disease?
A
Increased
14
Q
How is TLC affected in obstructive lung disease?
A
Increased
15
Q
How is FCV affected in restrictive lung disease?
A
Decreased
16
Q
How is FEV1 affected in restrictive lung disease?
A
May be decreased
17
Q
How is FRC affected in restrictive lung disease?
A
Decreased
18
Q
How is RV affected in restrictive lung disease?
A
Decreased
19
Q
How is TLC affected in restrictive lung disease?
A
Decreased
20
Q
How is asthma diagnosed clinically?
A
- Wheeze
- Breathlessness
- Chest tightness
- Cough
- Esp. if diurnal variation in symptoms & history of atopy
21
Q
What are asthma symptoms in response to?
A
- Allergen
- Exercise
- Cold air
22
Q
What are the 3 pathophysiological components of asthma?
A
- Airway narrowing/obstruction (Reversible)
- Airway hyper-responsiveness
- Airways inflammation (eosinophils)
23
Q
What different pathological changes can occur in asthma?
Airway remodelling
A
- Smooth muscle hypertrophy & hyperplasia
- Thickened BM
- Oesematous submucosa
- Cellular infiltration
- Hyperplasia of mucous glands
- Desquamation of epithelium
- Mucous plug
- Neovascularisation
24
Q
What are the 3 SIGN approved non-pharmacological intervention for asthma?
A
- Achieve & maintain a normal BMI if overweight
- Breathing exercise programmed
- Stop smoking
25
What makes a condition chronic?
Symptoms last more than 3 months in 2 consecutive years
26
What does the "pulmonary" part in COPD mean?
Disease affects both the airways & the lungs
27
What is COPD?
- Common, preventable & treatable
- Persistent airflow limitation
- Usually progressive & associated with enhanced chronic inflammatory response in airways & lung to noxious particles or gases
- Exacerbations & comorbidities contribute to overall severity
28
What are the 3 main causes of COPD?
1. Mainly Tobacco smoking
2. Indoor/outdoor pollution from biomass fuels
3. a1 antitrypsin deficiency
29
What is the pathophysiology of COPD?
- Inflammation & fibrosis of the bronchial wall
- Hypertrophy of the submucosal glands & hyper secretion of mucous
- Loss of elastic, parenchymal lung fibres (emphysema)
30
What does a1-antitrypsin do?
Inhibits the release of elastase
31
What is Elastase?
An enzyme that digests elastin and can cause emphysema
32
Define and describe a "Pink Puffer" presentation of COPD?
- Person where emphysema is primary underlying pathology
- Pink, pursed lips
- Barrel chest due to air trapping
- Use of accessory muscles
- Decreased breath sounds
- Weight loss
33
Define and describe a "Blue Bloater" presentation of COPD?
- Person who suffers from recurring episodes of bronchitis
- Cyanosed
- Signs of right heart failure
- Skeletal muscle dysfunction
- CVS disease
- Depression
- Osteoporosis
34
What are the 5 grades of Breathlessness Assessment for COPD?
1. Not troubled except on strenuous exercise
2. Short of breath when hurrying on level / walking slight hill
3. Walk slower, stops after a mile or so / stops after 15mins walking at own pace
4. Stops for breath after walking ~100yds / after few mins on level
5. Too breathless to leave house/undress
35
What is the main intervention for COPD?
STOP SMOKING!
36
What do we tend to give COPD & asthma patients?
LABA= Long-acting beta-agonists which are bronchodilator
37
What is the criteria for patients with domiciliary oxygen therapy?
- PaO2 <7.3 - 8kPa
- Must have stopped smoking
- Must be breathed for >15 hours/day to improve mortality
38
When is something/unit called a capacity and not a volume?
- When its a sum of more than one volume.
| - Volume cannot be sub-divided!
39
What are the 3 Observational studies in EBM?
1. Case control
2. Cohort
3. Cross Sectional studies
40
What are the 2 Experimental studies in EBM?
1. Randomised trails
| 2. Non-randomised trails
41
What are the 3 examples of Reviews for EBM?
1. Expert opinion
2. Systematic review
3. Meta-analysis
42
What are case studies?
Report written from patient file and history taking on particularly interesting/rare patient
43
What is a case series?
Case studies of multiple patients
44
What are the advantages of a Case study, series or report?
- Quick & cheap
- Rapid publication
- Early indicators of problems
- Can help detect new drug side effects and potential uses (adverse/beneficial)
45
What are the disadvantages of a Case study, series or report?
- Statistically weak
- No control group
- Very small numbers of patients
- Cases may not be generalisable to wider population
46
What is a Cross Sectional Survey?
Observational study that analyses data collected from a population, or a representative subset, at a specific point in time
47
What are the advantages of a cross sectional survey?
- Cheap & simple
- Ethically safe
- Useful for planning purposes
48
What are the disadvantages of a cross sectional survey?
- Cause & effect?
- Volunteer bias
- Unequal distribution of confounders
49
What is a confounder?
- Uncontrolled extraneous variables
| - ie. Smokers tend to have smaller babies than non-smokers
50
What is a spurious association?
- When 2+ events/variables are not causally related to each other, yet it may be wrongly inferred that they are
- ie. is ultrasound harmful to fetus?
51
What is the aim of case control studies?
Epidemiologically working out underlying cause for health problems by looking at consistent differences between patients and controls
52
What are the advantages of a Case control study?
- Simultaneously look at multiple risk factors
- Good for studying rare conditions or diseases
- Useful as initial studies to establish an association
53
What are the disadvantages of case control study?
- Retrospective study which relies on patient recall to determine exposure (recall bias) or patient records
- Confounders
- Selection of control group is difficult
54
What is a Cohort Study?
Take a group of interest and comparison/control group, follow both over time and compare outcomes
55
What are the advantages of a Cohort Study?
- Ethically safe
- Subjects can be matched
- Can show cause precedes the effect
- Easier & cheaper than RCT
56
What are the disadvantages of a Cohort Study?
- High drop out rate
- Exposure may be linked to hidden confounder
- Blinding is difficult
- Outcome of interest may take a long time to occur
57
What is a randomized control trial?
Group of patients are randomly allocated treatment or control intervention, and are followed up and compared
58
What does "Single blind" mean?
Subjects did not know which treatment they were receiving
59
What does "Double Blind" mean?
Neither subjects or investigators aware of which treatment subjects receives
60
What does "Crossover" mean?
Each subject received both the intervention and control treatment (randomly) often separated by a washout period
61
What does "Placebo controlled" mean?
Control subjects receive placebo (inactive pill, sham operation)
62
What are the advantages of a RCT?
- Unbiased
- Clearly identified populations
- Randomised helps statistical analysis
- More likely to be "blinded"
63
What are the disadvantaged of a RCT?
- Expensive
- Volunteer bias (population may not be representative)
- Ethical issues if treatment group are seen to respond badly or better than expected
64
What does parallel group comparison involve in RCTs?
Each group receives a different treatment simultaneously and you compare the groups
65
What does paired (matched) comparison in RCTs involve?
Subjects are matched to balance out confounders such as age and sex, and differences are analysed between subject pairs
66
What is the meaning of within subject comparison in RCTs?
Subjects assessed before and after an intervention, within subject changes
67
What are the 5 problems associated with RCTs?
1. Impossible- in very rare diseases number of patients too limited
2. Unnecessary- when there are already good treatments
3. Stopping trials early- interim analyses stops trials early
4. Resources- cost of RCTs substantial money, time, energy
5. Generalisability- specific types of patients for relatively short periods of time
68
What are the 6 points in the Bradford hill criteria for establishing cause and effect?
1. Strength of association
2. Dose-response relationship
3. Temporality
4. Consistency
5. Biological plausibility
6. Reversibility
69
What is an expert (narrative) review?
Review written by an expert in the field (secondary research)if
70
What are the advantages of an expert (narrative) review?
- Comprehensive survey
| - Answer a specific question
71
What is the disadvantage of an expert (narrative) review?
Expert bias
72
What is a Systematic Review?
- Attempts to identify, appraise and synthesise all empirical evidence that meets pre-specified eligibly criteria to answer a given research question.
- Aimed to minimise bias
73
Why are systematic reviews viewed as the "gold standard"?
Avoidance and/or minimisation of bias
74
what are the advantages of systematic reviews?
- Comprehensive analysis of all the best primary evidence using explicit and reproducible methodology
- Results can be combined and statistically analyzed as if they were one study
- Considered an evidence based resource and the best guide to practice
- Less costly to review studies than to initiate a new study
75
What are disadvantages of systematic reviews?
- Results often disagree
- Publication bias
- Very time consuming
76
What is meta analysis?
Combines qualitative & quantitative study data from several selected studies to develop a single conclusion that has greater statistical power
- establish statistical significance with studies that have conflicting results
- develop a more accurate estimate of effect magnitude
- provide a more complex analysis of harms, safety data and benefits
- examine subgroups with individual numbers that are not statistically significant
77
What are the advantages of meta analyses?
- Greater statistical power
- Greater ability to extrapolate to the general population
- Considered an evidence based resource
78
What are the disadvantages of meta analyses?
- Results often disagree
- Heterogeneity of study populations
- Very time consuming
- Requires advanced statistical techniques
79
What is the definition of an Allergy?
- An altered capacity of the body to react to a foreign substance
- Disease following a response by the immune system to an otherwise innocuous antigen
80
Describe Type I Hypersensitivity reaction?
- EXAMPLE: Allergy, Asthma
- IgE
- Soluble antigen
- Effector mechanism is Mast cell activation
81
Describe Type II Hypersensitivity reaction?
- EXAMPLE: Chronic Urticaria, Drugs
- IgG
- Antigen is cell/matrix associated or a cell surface receptor
- Effector mechanism is Complement, FcR+ cells or Ab alters signalling
82
Describe Type III Hypersensitivity reaction?
- EXAMPLE: Arthus reaction
- IgG
- Soluble antigen
- Effector mechanism is Complement, phagocytes
83
Describe Type IV Hypersensitivity reaction?
- Th1 cells- soluble antigen, macrophage activation. EXAMPLE: contact dermatitis tuberculin reaction
- Th2 cells- soluble antigen, eosinophil activation. EXAMPLE: chronic asthma & allergic rhinitis
- CTL- cell-associated antigen, cytotoxicity.
EXAMPLE: contact dermatitis
84
When does an allergy occur?
- When IgE triggers Mast cell degranulation
| - Always occurs on secondary exposure to an allergen never 1st!!!
85
Where is IgE produced?
By plasma B cells in lymph nodes OR locally at site of inflammation
86
Why has IgE got a low serum concentration?
Located mostly in tissue, bound to Mast cell surface
87
What route of antigens favours IgE antibody production?
Transmucosal at low doses
88
Which T cell phenotype favors IgE responses?
CD4+ T cells of the Th2 phenotype
89
What interleukin do CD4+ Th2 cells produce?
IL4
90
What do CD8 cytotoxic cells produce?
- IFNγ, TNFα
| - Target cell lysis
91
What do CD4 Th1 cells produce?
- IFNγ, GM-CSP, TNFα
| - Macrophage activation
92
What do CD4 Th2 cells produce?
- IL4, IL5
| - B cell activation
93
What is the only type of inhaled allergen which can induce T cell responses?
Proteins
94
What are normally enzymatically active allergens?
Often proteases
95
What does low dose inhaled allergens favour?
IL4 producing CD4 T cells
96
What is a feature of small size inhaled allergens?
Can diffuse out of particle
97
What is a feature of high soluble inhaled allergens?
Elutes readily from particle
98
What is a feature of a stable inhaled allergen?
Can survive desiccation (extreme dryness)
99
What is the major allergen in faeces of house dust mites?
| What can this allergen do?
- Der p 1
| - Can cleave tight junctions between epithelial cells in airway, thus enhancing access
100
How is Der p 1 allergen taken up in the body?
Taken up by Dendritic cells, presented to T cells, which become Th2, and cause B cells to secrete IgE
101
What is the 2 most important factors in what symptoms occur due to an allergen?
1. Location of antigen
| 2. Distribution of antigen
102
What other use might IgE have?
Defence against parasites
103
Describe Allergic Asthma?
- Bronchial constriction
- Increased secretion of fluid and mucus, trapping inhaled air
- Chronic inflammation may occur due to continued presence of Th2 T cells, eosinophils, neutrophils
- Chronic asthma driven originally by specific antigen, then results in hyperreactive airway to other irritants
104
Describe a skin allergy?
- Rash
- Wheal & Flare 1st appearing in few mins, result of vasodilation after Mast Cell degranulation, localised redness
- ~6hrs more diffuse oedema at site due to influx of lymphocytes & other leukocytes, attracted by chemokines
105
What 2 main symptoms does ingested allergens lead to?
1. Activation of GI Mast cells result in transepithelial fluid loss & smooth muscle contraction (diarrhea, vomiting)
2. Enters bloodstream, generalised rash, Urticaria, (hives)
106
What can happen in severe cases of food allergy ie. nuts & shellfish?
Life threatening generalised anaphylaxis & cardiovascular collapse
107
What is the main chemical mediators of allergic responses?
Mast cell granules contain inflammatory mediators, lipids, toxic mediators, cytokines & enzymes
108
What do lipid prostaglandins do during an allergic response?
Increase vascular permeability & body temp
109
What does lipid Platelet activating Factor do during an allergic response?
Increase adhesion between endothelium & neutrophils
110
What do Leukotrienes do during an allergic response?
Attract & activate neutrophils, increase vascular permeability
111
What does Toxic mediator Histamine do during an allergic response?
Increase vascular permeability and promotes movement of fluid from the vasculature by constricting vascular smooth muscle
112
What does Toxic mediator Heparin do during an allergic response?
Inhibits coagulation
113
What do Cytokines IL-4, IL-13 do during an allergic response?
Amplify Th2 response
114
What do Cytokines IL-3, IL5, GM-CSF do during an allergic response?
Promote eosinophil activation and production
115
What do Cytokines TNF-α do during an allergic response?
- Pro-inflammatory
| - Activates endothelium
116
What to Chemokine MIP-1α do during an allergic response?
Attracts macrophages & neutrophils
117
Name 4 enzymes which have a role in the bodies allergic response?
- Tryptase
- Chymase
- Cathepsin G
- Carbopeptidase
118
What are the 2 main types of treatment currently used for allergy?
1. Desensitisation
| 2. Blockage of effector pathways
119
What is the aim of desensitisation and blockage treatment for allergy?
- Shift response from IgE to IgG dominated
| - Injected with escalating doses of allergen, Th2 shifts to Th1 T cells
120
What do you do when patient has severe anaphylaxis?
Epinephrine (adrenaline) injection in thigh
121
What is Helminth?
- Parasitic worm (tapeworm)
| - IgE used in defense
122
What is the Hygiene hypothesis?
The fact we are all living in a cleaner environment than in the past which makes us more susceptible for having allergic reactions
123
What is Antibiotic Resistance?
When a previously susceptible organism is no longer inhibited by an antibiotic at levels/concentrations that can be safety achieved clinically
124
How can intermediate resistance be treated?
With an increase from standard dose
125
What is intrinsic resistance?
When all strains of a species are resistant
126
Define the Minimum Inhibitory Concentration (MIC)?
Lowest concentration of an antibiotic that completely inhibits the growth of a bacterium
127
Define the Minimum Bactericidal Concentration (MBC)?
Lowest dose that completely kills a bacterium
128
What 3 things defines the breakpoint?
1. Distribution of MICs of target bacteria
2. Achievable therapeutic concentration in tissue
3. Maximum achievable concentration
129
What type of antibiotics is Streptococci naturally resistant to?
Aminoglycosides
130
What type of antibiotics is Pseudomonas spp. normally resistant to?
Beta Lactams
131
What type of antibiotics is Mycoplasma spp. normally resistant to?
Beta Lactam
132
What type of antibiotics is Enterobacteriaciae resistant to?
Metronidazole
133
What is Acquired Resistance?
When a previously susceptible strain or species develops an increase in the MIC that takes it beyond the therapeutic range
134
Which antibiotics are inactivated by enzymatic destruction?
1. Cephalosporins
| 2. Expanded spectrum beta lactamases
135
Which antibiotic is inactivated by enzymatic addition?
Aminoglycosides (acylated)
136
Which antibiotics are effected by Efflux?
1. Tetracyclines
2. Quinolones
3. Macrolides
137
Which antibiotics are affected by altered binding sites (of RNA polymerase)?
1. Fluoroquinolones
2. Sulphonamides
3. Rifampicin
138
What antibiotic is affected by alternative pathway?
MRSA MecA
| 1. Flucoxacillin
139
Describe the evolution of Quinolone Resistance?
- gyrA & parC genes
- Point mutations in the genes change the affinity of the proteins for DNA
- Mutation in one gene= low level resistance
- Mutation in both genes= high level resistance
140
What is the most active Fluoroquinolone against 2nd step S. pneumoniae mutants?
Gemifloxacin
| active against single & double mutants
141
Describe a bacterial plasmid?
- Accessory circular DNA
- Can encode virulence, metabolic functions and resistance determinants
- Allows characteristics to be shared rapidly by bacteria
142
Describe bacterial Transposons & Integrons?
- Small segments of DNA that encode their own transmission
- Allow genome plasticity
- May collect resistance determinants
143
What is a Superbug?
Organism that has gained resistance to a critical OR multiple antibiotic(s)
144
Name 4 examples of superbugs?
1. Meticillin Resistant Staph Aureus (MRSA)
2. Glycopeptide Resistant Staph Aureus (GISA)
3. Vancomycin Resistance Enterococcus (VRE)
4. Expanded spectrum beta-Lactamases (ESBLs)
145
Name the 3 types of Carbapenemases?
1. Klebsiella Pneumoniae Carbapenemase (KPC)
2. New Delhi Metallo-betalactamase (NDM)
3. Oxa-48 group
146
What 2 antibiotics are susceptible to the Carbapenemases?
- Cephalosporins
| - Carbapenems
147
What are the 3 main factors which make us worry in resistant superbugs?
1. Consequences of infection are severe and the organism is common (MRSA, ESBL gram negatives)
2. Organism is naturally resistant to many antibiotics (E. faecium & Ps. aeruginosa)
3. Infection is in a site where it is difficult to get high concentrations of antibiotic (pneumococcal meningitis)
148
How do we clinically address the problem of antibiotic resistance to optimise treatment?
- Better diagnosis
- Focussed treatment
- Appropriate length of courses
(make a diagnosis, give right antibiotic at the right dose and the right period of time)
149
How do you treat resistant bugs?
- Culture essential
- Susceptibility testing
- Use the most bactericidal drug available
- Consider the use of combinations
150
What are the 2 main classes of fungi that infect humans?
1. Yeasts
| 2. Filamentous fungi
151
What diseases can candida spp. (yeast) cause?
- Thrush
| - Fungaemia
152
What diseases can Cryptococcus neoformans (yeast) cause?
- Meningitis
- Pneumonia
- Fungaemia
153
What diseases can Pityriasis Versicolor (yeast) cause?
- Chronic skin infection
154
What diseases can Histoplasma capsulatum (systemic yeasts) cause?
Pulmonary / disseminated infections
155
What diseases can Aspergillus spp., Mucor, Rhizopius, Absidia (filamentous fungi) cause?
- Pulmonary / ocular infection
- "Farmers lung"
- Bronchopulmonary aspergillosis
- Fungaemia
156
What disease can Dermatophytes (Epidermophyton, Microsporum, Trichophyton) cause?
- Chronic infection of skin and nails
| - Kerion
157
What are the 4 Tri-azole Drugs?
1. Fluconazole
2. Itraconazole
3. Posaconazole
4. Voriconazole
158
What is Fluconazole used to treat?
- Very well absorbed after oral administration
- Good penetration into CSF to treat fungal meningitis
- Excreted largely unchanged in urine so used to treat candiduria
159
What is Itraconazole used to treat?
- Wide range of dermatophytes
- Capsules require acid environment in stomach for optimal absorption
- Can cause liver damage and should be avoided in liver disease patients
160
What is Posaconazole used to treat?
Invasive fungal infections unresponsive to conventional treatment
161
What is Voriconazole used to treat?
- Broad-spectrum anti-fungal
| - Used in life-threatening infections
162
What is Flucytosine used for?
- Systemic yeast and fungal infections
| - Adjunct to amphotericin in cryptococcal or systemic candidiasis
163
What are the cautions for using Flucytosine?
- Elderly
- Blood disorders
- Liver & Kidney function tests & blood counts required
- Avoid if possible: pregnancy and breast-feeding
164
What are the main Polyenes drugs?
- Amphotericin
| - Nystatin
165
What is Nystatin used for?
Oral, oropharyngeal and perioral infections by local application
166
What is Amphotericin used for?
IV infusion used for systemic fungal infections
167
What are the problems with amphotericin?
- Highly protein bound so poorly absorbed
| - Given parenterally its toxic with usual side effects
168
How do polyenes anti-fungal drugs work?
Create pores in fungal membrane allowing leakage of intracellkular cations (Ca2+, Na+, K+)
169
What are the main drugs of the Echinocandins antifungals?
- Anidulafungin
- Caspofungin
- Micafungin
170
What are Echinocandins active against?
Aspergillus spp. and Candida spp.
| not effective affairs fungal infections of CNS
171
What are Terbinafine used to treat?
- Dermatophyte infections of the nails
- Ringworm
- Oral therapy
172
What are the cautions of using Terbinafine?
- Psoriasis excacerbation
- Autoimmune disease
- Hepatic impairment
- Breast feeding & pregnancy
173
What is Griseofulvin used to treat?
- Dermatophyte infections of the skin, scalp, hair and nails
174
What are the cautions of Griseofulvin?
- May impair performance of skilled task (driving)
- Breast feeding
- Severe liver disease
- Systemic lupus erythematosus
- Acute porphyria
175
How do Triazole anti-fungal drugs work?
Block P450 and sterol 14 alpha demethylase in cell wall
176
How do Flucytosine anti-fungal drugs work?
Inhibits protein synthesis
177
How do Terbinafine anti-fungal drugs work?
Inhibits squalene epoxies that accumulates toxic sterols in the cell wall
178
How do Griseofulvin anti-fungal drugs work?
Inhibits fungal mitosis
179
How do Echinocandin anti-fungal drugs work?
Inhibit 1,3 beta glucan in cell wall polysaccharide
180
What are the 7 mechanisms by which microbial cells might develop resistance?
1 Target enzyme overproduced, so that the drug does not inhibit the biochemical reaction completely.
2. Drug target is altered so that the drug cannot bind to the target.
3. Drug is pumped out by an efflux pump.
4. Entry of drug is prevented at cell membrane/cell wall level.
5. Cell has bypass pathway that compensates for the loss-of-function inhibition due to the drug activity.
6. Some fungal “enzymes” that convert an inactive drug to its active form are inhibited.
7. The cell secretes some enzymes to the extracellular medium, which degrade the drug.
181
What is the treatment of invasive candidiasis?
- Echinocandin
- Fluconazole
- Amphotericin (initial if CNS),
- Voriconazole (fluconazole resistant infections, intolerance)
- Flucytosine (used with IV amphotericin)
182
How are superficial candidiasis infections treated?
- Treated locally (e.g. Miconazole)
| - If widespread req. systemic treatment (Fluconazole)
183
How is vaginal candidiasis treated?
Locally with anti-fungals, Fluconazole orally or Itraconazole if resistant
184
Where does aspergillosis usually affect?
Respiratory tract
| in severely immunocomprimised, can affect heart, brain, skin
185
How is Aspergillosis treated?
Voriconazole
| Liposomal Amphotericin if voriconazole can't be used
186
How is Cryptococcal Meningitis treated?
Amphotericin by IV followed by IV Flucytosine, followed by oral Flucytosine
187
What is the treatment of systemic fungal infections?
- Parenteral Itraconazole in healthy patient, non meningeal, (incl. chronic pulmonary histoplasmosis)
- Parenteral Amphotericin in patients with fulminant or severe infections
188
Describe Type II Hypersensitivity?
- IgG binding to components of cell membranes or extracellular matrix
- Can be self-components or exogenous components
189
What is Goodpasture's Syndrome?
- Can be caused by Type II Hypersensitivity
- Rare autoimmune disease when antibodies bind to basement membrane collagen type IV causing glomerulonephritis in kidney and pulmonary haemorrhage in lung
190
What is an example of Type II Hypersensitivity that involves antibodies binding to exogenous components?
Haemolytic anemia caused by Penicillin
191
What is an example of Type II Hypersensitivity that involves antibodies binding to self-components?
Goodpasture's syndrome
192
Describe how haemolytic anaemia can be caused by Penicillin?
- Penicillin has capacity to bind to rbc
- If rbc is taken up by phagocyte & digested, parts of penicillin-rbc complexes maybe preserved & presented to antibody secreting cells
- Therefore Penicillin creates a neoantigen that targets rbc's.
- Plasma cells secrete antibodies (IgG) that will bind to RBCs- fixing complement, resulting in lysis of rbc and Fc receptors encouraging phagocytosis by macrophages
193
Describe Type III Hypersensitivity?
- IgG, sometimes IgM
- Directed to soluble antigens
- Cleared by reticuloendothelial system (RES)
- Excess immune complex deposition in tissues leads to pathology
194
What is the reticuloendothelial system (RES)?
- Immune system with phagocytic cells located in reticular connective tissue
- Macrophages, neutrophils in liver spleen and bone marrow
195
Where are the 5 common sites of immune complex deposition and why?
1. Glomeruli: filtration process
2. Blood vessel walls: IC accumulates causing vasculitis
3. Synovial Membranes: rheumatoid arthritis
4. Skin: IC deposition, causes rashes
5. Systemic sites: kidney, joints, skin, vasculature, muscle etc.
196
Describe Type IV Hypersensitivity?
- Cell-mediated
- Complement does NOT play a role
- Caused by CD4+ delayed type hypersensitivity (DTH) reactions
- Macrophages not specific
197
Describe what happens in Rheumatoid Arthritis?
- IgG of immune complexes becomes the antigen itself
- IgM rheumatoid factors develop and the IgG-IgM complexes are deposited in the synovial membrane, causing complement activation and inflammation
198
What is SLE?
Systemic Erythematous Lupus
199
Give examples of DTH reactions
- Listeria
- Leishmania
- M. tuberculosis
- M. Leprae
200
What can DTH responses lead to?
Walling off infectious sites- granulomas
201
What is Contact Sensitivities?
Special category of DTH reaction in which antigen is not an infectious agent, but a chemical that binds to cell surface
202
Give examples of substances which can cause Contact Sensitivities?
- Heavy metal sensitivity
| - Poison Ivy (catechols)
203
List 5 autoimmune diseases which can be classified in the same way as Type II Hypersensitivity reactions?
1. Autoimmune hemolytic anemia
2. Autoimmune thrombocytopenic purpura
3. Goodpastures syndrome
4. Pemphigus vulgaris
5. Acute Rheumatic fever
204
List 3 autoimmune diseases which can be classified in the same way as Type III Hypersensitivity reactions?
1. Mixed essential cryoglobulinemia
2. SLE
3. Rheumatoid arthritis
205
List 3 autoimmune diseases which can be classified in the same way as Type IV Hypersensitivity reactions?
1. Insulin dependent Diabetes Mellitus
2. Rheumatoid arthritis
3. Multiple sclerosis
206
What should we be cautious of when using Fluconazole?
- Can cause QT interval prolongation (sudden death)
| - Hepatoxic
207
What are the 4 Types of Chemotherapy?
1. Alkylating agents
2. Antimetabolites
3. Cytotoxic antibiotics
4. Plant derivatives
208
How do Alkylating agents work?
- Form covalent bonds with suitable nucleophillic substances
- Intrastrand cross linking of DNA
- Makes guanine molecules more acidic changing it from a Keto tautomer to Enol
- Causing mispairing with thymine residues & DNA damage triggering apoptosis
209
What are the 3 main groups of Alkylating Agents?
1. Nitrogen mustards
2. Nitrosoureas
3. Platinum based compounds
210
What is an example of Nitrogen mustards?
Cyclophosphamide
211
How does Cyclophosphamide work?
- Activated in liver by P450 mixed function oxidases to form Aldophosphamide
- Aldophosphamide transported to other tissues where it forms phosphoramide (cytotoxic) and Acrolein (side effects)
- Mesna counteracts effects of Acrolein
212
What are examples of Nitrosoureas?
- Lomustine
| - Carmustine
213
Why are Nitrosoureas good treatment for brain & meninges tumours?
Lipid soluble and can cross blood-brain barrier
214
Describe the uses of Busulphan?
- Selective effect on bone marrow
- Depressing formation of granulocytes & platelets in low dosage & red cells in higher dosage
- Hardly any effect on lymphoid tissue/GI tract
- Used in chronic granulocytic leukaemia
215
What is an example of Platinum based compounds?
Cisplatin
216
How does Cisplatin work?
- Its a central platinum atom surrounded by 2 Cl atoms & 2 ammonia groups
- Causes Cl- dissociates and complex reacts with water and then interacts with DNA
- Intrastrand cross-linking between N7 & O6 of adjacent guanine molecules
- Local denaturation of DNA chain
217
What are the 3 main groups of Antimetabolites?
1. Antifolates
2. Antipyrimidines
3. Antipurines
218
What is an example of an Antifolate?
Methotrexate
219
What are 2 examples of an Antipyrimidine?
- 5-FU (fluorouracil)
| - Gemcitabine
220
What is are 2 examples of an Antipurine?
Mercaptopurine, Thioguanine
221
What are 4 examples of a Cytotoxic Antibiotic?
- Anthracycline ie. Doxorubicin
- Dactinomycin
- Bleomycin
- Mitomycin
222
How do Cytotoxic Antibiotics work?
Antitumour antibiotics produce their effects mainly by direct action on DNA
223
How does Plant derivatives chemotherapy work?
Spindle poisons (inhibitors) affects microtubule function & prevent mitotic spindle formation OR Topoisomerase I/II inhibitors
224
What are 4 examples of Plant Derivatives chemotherapy?
1. Vinca alkaloids
2. Taxanes
3. Camptothecins
4. Etoposide
225
What are the main Vinca Alkaloids and how do they work?
- Vincristine & vinblastine
| - Bind tubulin and prevent polymerization to microtubulins
226
What are the main Taxanes and how do they work?
- Paclitaxcel (taxol), docetaxel
| - Stabilise microtubules
227
What is the main Camptothecins and how do they work?
- Irinotecan
| - Binds & inhibits topoisomerase I
228
How do Etoposide's work?
Inhibits mitochondrial function, nucleoside transport and topoisomerase II
229
What is the main drawback of current chemotherapy of cancer?
- Targets cell proliferation not the more lethal properties of invasiveness & metastasis
- Side effects reduces patients compliance
230
Give 3 examples of monoclonal antibodies and what they are used for?
1. Rituximab- targets B cell surface protein, used in B cell lymphomas
2. Trastuzumab (Herceptin) targets epidermal growth factor receptor, used in treatment of breast cancer
3. Imatinib (gleevec) inhibits bcr-abl gene signaling pathways, used in chronic myeloid leukaemia
231
What is Personalised medicine?
- Takes into account individual genetic differences
- Genomic/genetic testing
- Proteomic profiling
- Metabolomic analysis
232
What are the 4 aims of NHS Scotland?
1. Improved prevention
2. Earlier diagnosis
3. Precise diagnosis
4. Targeted interventions
233
Describe Personalised Medicine in Lung Cancer (NSCLC)?
1. EGFR mutation analysis: Erlotinib
2. KRAS mutation analysis: not drugs
3. ALK rearrangement analysis: Crizotinib
234
Describe Personalised Medicine in Colorectal Cancer?
1. Cetuximab: anti-EGFR monoclonal antibody therapy
2. KRAS/NRAS mutation analysis: no mutation- Cetuximab + chemotherapy. Presence of RAS mutation= lack of response to therapy
235
Describe Personalised Medicine in Melanoma?
- Vermurafenib: mutated B-Raf inhibitor
- NRAS mutations: MEK inhibitors/combinations
- KIT (c-Kit) mutations: Imatinib
236
Describe Personalised Medicine in Brain Tumours (high grade glioblastomas)?
- Temozolomide: Alkylating agent (+ radiation therapy as 1st line)
- MGMT promoter gene methylation: high methylation- temozolomide efficacy
237
What is O6-Methylguanine-DNA-Methyltransferase (MGMT)?
Enzyme thought to repair DNA damage caused by chemotherapy alkylating agents such as Temozolomide
238
Describe Personalised Medicine in Gastric Tumours?
- Anti-Her2: Trastuzumab
| - c-KIT positive metastatic GIST: Imatinib
239
Describe Personalised Medicine in Soft Tissue & Bone tumours?
FISH analysis for Ewing's sarcomas, alveolar rhabdomyosarcomas, leiomyosarcomas, fibromyxoid sarcomas
240
Describe Personalised Medicine in anti-PD-1/PD-L1?
- Anti-PD-1 antibody: nivolumab (used in melanoma)
| - Anti-CTLA-4 antibody: ipilimumab (used in metastatic melanoma)
241
What are Beta-Defensins?
- Small cysteine-rich cationic proteins
| - Puncture holes in microbial cell membranes
242
Where are Beta-Defensins found?
Inflammatory cells & epithelia
243
What does expectorated mean?
- Substance being coughed/spit (mucus) from throat or lungs
| - Cilia do this to mucus
244
Give 2 examples of occupational diseases which compromise the mucociliary clearance elevator?
1. Silicosis
| 2. Pneumoniosis
245
Give 7 examples of what compromises the mucociliary clearance elevator?
1. Cystic fibrosis
2. Kartagener's syndrome (no cilia)
3. Silicosis
4. Pneumoniosis
5. Smoking
6. Previous infection (pneumonia)
7. Obstruction of bronchi
246
What do respiratory bacteria have to do to cause pneumonia?
- Colonise the nasopharynx / be inhaled into alveolus
- Adhere to respiratory cells
- Evade the immune system
- Multiply
- Express virulence factors that cause disease
247
What does the complement pathway do in acute inflammation?
- Attract PMNs (granulocytes) & macrophages
| - Attach to bacteria and opsonise them to make it easier for phagocytes to engulf
248
What is Respiratory Burst?
Rapid release of reactive oxygen species (superoxide radical and hydrogen peroxide) usually from immune cells
249
What 3 things does Acute inflammation trigger?
1. Vasodilation
2. Exudation
3. Oedema
250
What is Myeloperoxidase?
- Peroxidase enzyme in humans, encoded by MPO gene on chromosome 17
- MPO most abundantly expressed in neutrophil granulocytes
251
How does acute inflammation end?
If problem resolves, neutrophils apoptose and are neatly tidied away
252
What happens in chronic inflammation?
- Granulation tissue
- Macrophages
- Fibrosis
- Repair/remodelling
253
How do neutrophils kill bacteria?
- Use reactive O2 pathway
- O2 free radicals join with H2O to form H2O2+
- This joins with Cl- to form bleach which is produced to kill pathogens
- Also lysosymes, proteases and free radicals released if the neutrophil dies
254
Describe Bronchiolitis?
- Usually primary viral infection in infants
- May be secondary to other inhaled irritants or part of a systemic disease process
- Causes dyspnoea & tachypnoea
255
Describe Pneumonia?
- Alveolar inflammation
- Protein-rich exudate
- Polymorphs & later lymphocytes & macrophages
- Can be lobar / bronchopneumonia
256
Describe Lobar Pneumonia?
- Affects anatomically delineated segments or the entirety of a lobe
- Relatively uncommon in infancy & old age
- Affects males more than females
- 90% due to Streptococcus pneumoniae (pneumococcus)
- Cough & fever with purulent or "rusty" sputum
257
Describe Bronchopneumonia?
- Patchy consolidation often several lobes or bilateral
- Centred on bronchioles or bronchi
- Usually in infancy or old age
- Usually secondary to pre-existing disease
258
What is an Exudate?
Abnormal fluid with proteins due to loosening of links between epithelial cells
259
What are the 2 clinical circumstances of pneumonia?
| Give examples.
1. Primary- in an otherwise healthy person
| 2. Secondary- with local or systemic defects in defence
260
What are the 4 possible aetiological agents in pneumonia?
| Give examples.
1. Bacterial- Streptococcus pneumoniaem Staphylococcus aureus, Mycobacterium tuberculosis etc.
2. Viral- Influenza, measles etc.
3. Fungal- Cryptococcus, Candida, Aspergillus etc.
4. Other- pneumocystis jiroveci, Mycoplasma, aspiration etc.
261
What are the 2 host reactions to pneumonia?
1. Fibrinous
2. Suppurative
According to dominant component of exudate
262
What are the 2 anatomical patterns of pneumonia?
1. Lobar pneumonia
| 2. Bronchopneumonia
263
What lung fungus should you be sucpicious of in an acute attack of asthma?
Aspergillus
264
Give examples of conditions that lung remodelling may occur?
- Post-viral
- Chronic suppuration
- TB
- Cystic fibrosis
- Obstruction
265
What are risk factors for tuberculosis?
- immunocompromised
- young
- overcrowding
- malnourishment
- alcoholism
- civil disruption
- occupational risks
266
Describe Primary Tuberculosis?
Produces a small mid-zone lesion with involvement of hilar lymph nodes
267
Describe Secondary Tuberculosis?
Lesions are usually apical and often bilateral
268
Describe Miliary Tuberculosis?
In lungs & many other organs contain numerous small granulomas
269
What are the most frequent complications of pulmonary tuberculosis?
Intrapulmonary / pleural spread
270
What is Bronchiectasis?
Permanent dilation of bronchi
271
What is currently the initial phase of tuberculosis treatment?
(drug and length)
- Drugs: Isoniazid, Rifampicin, Pyrazinamide, Ethambutol
| - Length: 8 weeks
272
Whats is currently the continuation phase of tuberculosis treatment?
(drug and length)
- Drugs: Isoniazid, Rifampicin
| - Length: 18 weeks
273
What is the action of Isoniazid?
Inhibition of mycolic acid biosynthesis
274
Why is Isoniazid good to use?
- Easily tolerated orally
- Inexpensive
- Toxicity relatively low
275
What are the possible side effects of Isoniazid?
- Hepatitis
- Peripheral neuropathy
- Rash
- Nausea
276
What drug can be given with Isoniazid to reduce the peripheral neuropathy side effect?
Pyridoxine (vitamin B6)
277
What is the action of Rifampicin?
Inhibits bacterial DNA-dependent RNA polymerase.
| Its well tolerated!
278
What are the possible side effects of Rifampicin?
- Hepatitis
- Dermatological (rash)
- CYP 450 induction which decreases activity of many other drugs (warfarin, antiretrovirals)
279
What is the action of Pyrazinamide?
- Considered bacteriostatic although bactericidal at an acid pH (inside cells)
- Action UNKNOWN
280
What are the possible side effects of Pyrazinamide?
- Hepatitis
- Gastrointestinal intolerance is fairly common
- Hyperuricemia
- Rash
- Blood changes
- Joint pains
281
What is the action of Ethambutol?
- Bacteriostatic
| - Action not well known
282
What are the possible side effects of Ethambutol?
- Optic neuritis
- Headache, dizziness, confusion
- Gastrointestinal toxicity
283
What are the 2nd line drugs mainly used for multi-resistance?
- Fluoroquinolones
- Aminoglycosides (streptomycin, kanamycin)
- Cycloserine
- PAS
- Ethionamide, prothionamide
- Clofazamine
284
What does "DOTS" stand for?
Directly Observed Short Course Treatment
| tuberculosis control strategy
285
What are the 5 components of the DOTS approach in tuberculosis treatment?
1. Political commitment with increased and sustained financing (legislation, planning)
2. Case detection through quality assured bacteriology (strengthening labs, resistance surveillance)
3. Standardised treatment with supervision and patient support
4. Effective drug supply/management system
5. Monitoring and evaluation system and impact measurements
286
What have we learnt about TB and how to treat it?
- Required more than one drug
- Appropriate drug doses
- Regular dosing
- Sufficient total period of time on therapy
287
Describe mutations?
- Occurs at steady rate
- Failure of exactness in polymerases & proof reading functions
- Its stochastic/unpredictable
288
What increases the risk of resistance in a patient?
- Larger risk in patients with higher bacterial load & extensive cavitation
- Larger risk when patients take therapy irregularly
- Larger risk if patient takes inactive drugs
- Physician provided wrong prescription
289
What is the risk of resistance in all the tuberculosis drugs mentioned?
- Rifampicin 10-8
- Isoniazid 10-6
- Pyrazinamide ?
- Streptomycin 10-6
- Cycloserine 10-3
290
What are conditions associated with multi-drug resistant TB (MDRTB)?
- Cavitatory disease
- Empyaema
- HIV
- Previous tuberculosis
291
What are the steps to control MDRTB?
1. Identify patients at risk
2. 24 hour Z-N service
3. PCR detection of rpoB mutations
4. Isolate patient
5. Treat effectively
6. Prevent new cases
292
Why is MDRTB such a threat?
- Patients remain infectious for longer
- Susceptibility is rarely performed
- Patients exposed to successive inadequate regimens so multiple resistance grows
- 2nd & 3rd line agents very weakly bactericidal
293
How do we isolate MDRTB patients?
- Side room
- Negative pressure ventilation
- Effective masks for staff
- Careful consideration of discharge
294
How do we prevent emergence of new cases of MDRTB?
- Better shorter treatment regimens
- Open access to diagnostic services
- Specialist management of cases
- Systems to ensure high cure rates
- Contact tracing
- Molecular epidemiology
- Integrated TB diagnostic and clinical service
295
What are the factors associated with a poor outcome of TB?
- Male gender worse
- Smear positivity
- Alcohol use
- Low BMI
- Fluoroquinolone resistance
- Presence of an Extensively drug-resistant TB (XDRTB) pattern
296
What is Extensively drug-resistant TB (XDRTB)?
Resistance to Isoniazid & Rifampin, plus any Fluoroquinolone & at least 1 of 3 injectable 2nd line drugs
297
Describe Bedaquiline (new TB drug)?
- Approved for treatment of MDRTB in combination
- Diarylquinoline
- Orally active
- Limited to mycobacteria
- Inhibits ATPase in mycobacterial cell wall that pumps protons out the cell
