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Lecture overview/possible questions
TB
Transmission, pathophysiology, latent vs active
Brief history of early treatments and current treatments
Cystic Fibrosis (CF)
Incidence, mutations, organs affected
CF airway pathophysiology
Therapeutic approaches to CF

Bacteria that causes TB = Mycobacterium Tuberculosis (infectious lung disease)

Transmission:
Most cases TB is spread from person to person through the air via droplet nuclei
M
...

Not all Mycobacteria cause TB
You can't stain TB with a gram stain as it has an outer membrane (gram -ve)

In 2012, an estimated 8
...
3 million died from
the disease
The UK reported 8,751 cases of TB in 2012 with most cases occurring in its cities
Most cases of TB are curable if treated effectively and promptly and early treatment also
prevents the spread of infection
TB transmission
Most of the larger droplet nuclei become lodged in the upper
respiratory tract, where infection is unlikely to develop
However, droplet nuclei may reach the small air sacs of the lung
(the alveoli), where infection begins

Immune Response
Macrophages engulf bacteria but are not destroyed by phagocytosis and bacteria multiply
within macrophages

Latent TB infection
Within 2 to 8 weeks tubercle forms (infected macrophages
surrounded by layers of macrophages, neutrophils and
lymphocytes)
Shell --> trying to encapsulate the bacteria
Granuloma
These cells form a barrier shell that keeps the bacilli
contained and under control (LTBI) (Latent TB Infection)
People with LTBI are not infectious
TB lung damage
The bacteria are contained and form granulomatous caseating lesions (thick puss), some
superinfected by fungal mycetoma

TB Granuloma containing mycetoma
(Aspergilloma) (fungus ball)

Active TB infection
If the immune system CANNOT keep
tubercle bacilli under control, bacilli
begin to multiply rapidly and cause TB
disease
About 10% of all people with normal
immune systems who have LTBI will
develop TB disease at some point in
their lives (highest the first 2 years
after infection)

Multiple Caseating Granulomas

Progression to TB disease
Some conditions increase probability of LTBI progressing to TB disease:
Weakening of the immune system

Sites of TB disease
A small number of tubercle bacilli enter
bloodstream and spread throughout body
Bacilli may reach any part of the body, but
common sites include:

Spine - specifically the intervertebral discs

Observations: Multiple Miliary nodules in both lungs
Interpretation: Miliary TB
TB treatment history
Before TB antibiotics,many patients were sent to sanatoriums and followed a regimen of
bed rest, open air, and sunshine
TO try and avoid secondary infections
TB Vaccine
An avirulent bacillus was produced - result was inability to cause tuberculosis disease in
research animals from a strain of the attenuated (weakened) live bovine tuberculosis
bacillus, Mycobacterium bovis
...

Second line antibiotics:
Used to treat multi-resistant TB
Resistant to INH and RIF
Fluoroquinolones
Moxifloxacin (inhibits bacterial chromosomal replication)
Injectable drugs
Amikacin
Kanamycin
Capreomycin
Inhibit mRNA translation to protein via ribosomal binding
XDR-TB = Extensively Resistant TB

Current problems
Multiple drug resistance (MDR-TB)
Extensive drug resistance (XDR-TB)
TB and HIV/AIDS co-morbidity
HIV leads to TB reactivation (10% risk per year) and TB accelerates HIV replication
Antibiotics (eg Rifampicin) and HIV drugs interact -reduce efficacy of HIV drugs
Solutions?
Increase concentrations?
Leads to liver and optic toxicity
Best bet is to increase Rifampicin to increase therapeutic effects
Better use of current drugs?
Shorten chemotherapy? (less time to develop resistance)
Use fewer antibiotics?
New antibiotics?
New Drugs?
Cystic Fibrosis
Cystic fibrosis (CF) is an incurable, ultimately fatal inherited
disorder that causes thick, sticky mucus which can damage
lung tissue and block airways, making it difficult for patients to
breathe and promoting lung infections
CF has many other manifestations, including pancreatic
insufficiency, gastrointestinal problems, endocrine disorders
and infertility
Autosomal recessive disease caused by mutations in the
Cystic Fibrosis Transmembrane Conductance Regulator
(CFTR) an ion channel gene located on long limb of
chromosome 7
...


CFTR model

Consists of: 2 Membrane Spanning Domains (MSD), 2 Nucleotide Binding Domains
(NBD) and a Regulatory (R) domain

Model of ATP-dependant gating of CFTR
In absence of R domain phosphorylation – channel is closed
Cyclic AMP stimulates PKA to phosphorylate serines on R domain
CFTR binds ATP at NBDs and conformational change occurs – channel opens

CFTR mutations
Approx 1900 mutations in CFTR gene have been identified – highest density in two
nucleotide binding regions
Some in transmembrane regions
Majority (~40%) are missense mutations
Mutations cause varying degrees of CF
Some have no effect

CFTR mutations (classes I-V)
Learn:

cAMP
activated
Cl‾
channel

No mRNA
or protein
(premature
stop codon
or splicing
defects)

Protein not
trafficked
to
membrane

Cl‾ channel
not regulated
by cAMP

Cl‾ channel
function
altered

Defective
synthesis
of normal
Cl‾ channel

Most common is mutation class II - missense - protein produced but not transported to
membrane
ΔF508 - is the most common mutation (~70%) and the best studied
Deletion of the phenylalanine amino acid at position 508 resulting in mis-folding of
CFTR protein - prevents maturation in the ER and impairs trafficking to the membrane
G55ID - mutation that disrupts the binding site through which ATP-dependent gating
normally occurs
...
e
...

Alternatives - Airway rehydration
Hypertonic saline (HS)
Inhaled HS acts as an osmotic agent to draw water onto airway surfaces
Mannitol
Inhaled mannitol acts as an osmotic agent
...
Phase II study showed substantial improvement of
FEV
Mucolytics
Human recombinant DNAse - break down of sticky mucus Pulmozyme; Cysteamine
Physiotherapy for abnormal mucus

Therapeutic Approaches to CF for Abnormal CFTR Protein
Targeting nonsense premature stop codon
PTC124 (Ataluren)
Termination suppressor; allows translation of full-length CFTR in airway epithelial
cells of patients with premature CFTR stop codon by ‘tricking’ ribosomes to ignore
them
Altered regulation
VX-770 (Ivacaftor);
Binds directly to PKA phosphorylated CFTR (ΔF508 and G551D mutations) and
opens channel, independently of ATP binding and hydrolysis
Genistein
Channel modulation, potentiating its opening at low concentrations, but inhibits at
high doses
...

Targeting abnormal processing/trafficking
VX-809 (Lumacaftor)
Improves trafficking of misfolded ΔF508-CFTR to cell surface
Targeting abnormal processing/degradation
4-phenylbutyrate (4-PBA)
Prevents degradation of ΔF508-CFTR by altering chaperone protein expression
through transcription factors
...
g

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