CSIM2- mechanisms and investigations of disease Flashcards
2 types of imaging that use NON-ionising radiation
US
MRI
3 pros of US
no radiation
patient centred
can be focussed
3 cons of US
hard to interpret
needs specialist operator
may give false reassurance
4 cons of MRI
slow
needs IV contrast to be effective (anaphalaxis, NSF)
needs a specific question
accessibility
contraindications for MRI
any metal: pacemaker insulin pumps hearing aids metal clips
4 uses of interventional radiology
biopsies
drainage
angioplasty
tumour ablation
two groups particularly at risk from radiation
pregnant
children
however clinical need outweighs risk
1 CT scan is equal to what life time risk of cancer
1/1000
what are 2 potential risks of using IV contrast?
anaphylaxis contrast nephropathy (tell the radiologist about any renal impairment)
what are the RED FLAGS in sepsis according to the sepsis trust?
Pulse > 130 resp. >25 lactate >2 purpuric rash less than A on AVPU
define secondary brain injury
damage due to hypoxic insult some time after the initial injury
how to calculate the cerebral perfusion pressure?
CPP = MAP - ICP
mean arterial pressure - intracranial pressure
when ICP increases how does the body compensate?
squeeze out some of the CSF and venous blood
what happens in the skull when the brain can no longer compensate for an increase in pressure?
uncal herniation (transtentorial herniation) blood vessels kink
4 signs of increased ICP
decreased level of consciousness
pressor response
projectile vomiting
CN 6 palsy
what is another name for the pressor response and what are the characteristic triad?
cushing’s response:
irregular breathing
increased BP
reduction in HR
4 signs of brainstem herniation
CN 3 palsy
motor posturing
lower extremity rigidity
hyperventilation
what is the normal range of ICP? when to treat?
5-15mmHg , treat above 20
how can the ICP be lowered artificially?
remove mass/ lesion
drain CSF
reduce parenchymal volume
reduce cerebral blood flow
how can we reduce the parenchymal vol. in raised ICP?
osmotic therapy
sometimes resection
how can the arterial blood flow to the brain be reduced in raised ICP?
sedation
mechanical ventilation
avoid fever
treat seizures
how can cerebral blood in the veins be reduced in raised ICP?
head up
avoid jugular pressure
how does sedation and controlled ventilation reduce ICP?
if o2 decreases then there will be vasodilation in the brain -> increased blood flow
same with high co2
what is the main imaging tool in major trauma and why?
CT because it shows where the bleeding is coming from
5 reasons for a trauma call and an example for each?
physiological- ABC approach
anatomical- 2 or more proximal long bone fractures/ head penetration etc.
high risk mechanism of injury- car crash
multiple trauma victims
discretionary-consider age, co-morbidities
what is the bodies response to reduced MAP due to haemorrhage? (3)
baroreceptor response : increase SNS and decrease PNS
endocrine response : catecholamine and steroid release
reduced renal perfusion ->RAA axis activation -> Na and hence water retention
where does blood go in major trauma?
blood on the floor and 4 more:
- long bones
- pelvis
- abdomine
- thorax
what would you expect an ABG to look like in major trauma?
pH: decreased pCO2: decreased pO2: variable lactate: increased bicarb: decreased base excess: decreased
i.e. metabolic (lactic) acidosis with resp. compensation where possible
what is likely to happen to Hb immediately after major trauma?
stay the same: it is a conc. so blood loss will not reduce the conc. of Hb immediately. in the following hours fluid will be sucked in from surrounding tissue (or given IV) so the Hb will DECREASE
how should the circulating blood volume be restored?
give blood ideally , or FFP (fresh frozen plasma)/ platelet
dont give crystalloids/ colloids much anymore due to hypotermia
explain the trauma TRIAD OF DEATH
patient becomes acidotic due to vasocontriction, hypotension (and hypoperfusion) causing anaerobic respiration.
this leads to decreased heart performance
this leads to hypothermia (also due to cold fluid admin. and exposure)
hypothermia causes decreased coagulation
this has the effect of exacerbating the acidosis
what is an immunoassay?
biochemical test that measures the conc. or presence of proteins (or other macro molecules) with antibodies
advantages of monoclonal immunoassay?
recognizes single epitote (foreign target antigen)
little batch variability
high specificity
pros and cons of immunoassay
pros:
automated therefore fast
sensitive
widely applicable e.g. BNP
cons:
cross-reactive: hard to produce an antibody that only reacts to the epitote you want
some are manual
heterophilic antibodies screw results
clinical application for immunoassay?
cancer diagnosis and prognosis
microarrays advantages
can look at 1000s of antigens at the same time so cost effective
microarray diadvantages
imprecise
not yet robust enough for clinical practice
define proteomics
study of the full set of proteins encoded by the human genome (30,000 genes)
which lab tests are used in proteomics
2D electrophoresis (protein material in disease sample is compared to non-diseased sample mass spec (produces peptide finger print) microarrays
which lab tests are used in metabolomics?
mass spec
NMR
what are the limiting factors in the -omics?
huge amount of data with complex interpretation
statistical significance not proven yet
define genomic test
test nucleic acid to answer a diagnostic / prognostic question
diagnostic genetic testing is what? and what are the practical problems
finding the gene mutation to confirm the diagnosis (usually 100% sensitive)
multiple genes cause same phenotype
different phenotypes
unknown genes
what is it that causes degenerative disorders of the CNS?
aggregates of misfolded proteins
where these deposit determines what kind of problem you get
on post-mortem what are you able to see in Alzheimers?
senile plaques: short amino acid called amyloid Beta. this comes from a much bigger pre-cursor protein
Tau protein (particularly in FTLD): these cause nerve cells to die off
how can we slow the accumulation of amyloid beta in alzheimers
inhibit the enzyme that is breaking down the large protein precursor into amyloid beta
why do tau proteins aggregate in dementia?
enzymes cause phosphorylation of tau which reduces micro tubule biding and promotes aggregation (because they’re hydrophobic)
what is seen on microscopy in PD?
lewy bodies
neural loss
what could be a diagnostic biomarker in PD?
alpha-synclein
how could vaccination work as a therapy in degenerative disorders?
infusion of antibodies into patients could reduce symptoms
how do lysosomal storage disorders lead to symptoms?
loss of function of an enzyme leads to progressive accumulation of metabolite within lysosomes leads to organ disfunction
in which cells is the pathology in Gaucher’s disease?
accumulation of metabolites in macrophages -> skeletal problems and anaemia. also spleen and liver problems
treatment for Gaucher’s disease?
replace defective enzymes (B-glucosidase)
what is hunter syndrome?
enzyme deficiency that causes skeletal deformities, developmental delay and recession, cardiac and lung abnormalities and hepatosplenomagaly
how do pharmacological chaperones treat lysosomal storage defects?
stabilizes proteins in the endoplasmic reticulum to prevent protein misfolding
define iron deficiency anaemia and symptoms
effects of iron overlaod
liver cirrhosis
diabetes
cardiomyopathy
endocrine dysfunction
how does iron enter a cell?
transferrin
what is haemachromotosis?
elevated transferrin iron saturation and elevated ferritin leads to complications of high iron (cariomyopathy, diabetes, cirrhosis, arthritis) and hypogonadotrop ic hypogonadism
treatment for haemachromotsis?
regular phlebotomy and reduced iron diet
acute and chronic effects of copper overload?
acute : GI spasm, kidnet damage, rhabdomyolysis, haematemesis
Chronic : cirrhosis, diabetes, renal damage, neurophsychiatric problems
Wilsons disease is a problem of…
copper retention: due to failure of the copper to get into the bile it isnt excreted
symptoms/ signs of Wilsons
cirrhosis, extra-pyramidal symptoms, cardiomyopathy and nephocalcinosis
name a copper deficiency disorder
Menke’s disease
severe developmental delay and hair/ skin/ nail defects
sensitivity = …
true positives / (true positives + false negatives)
i.e. who has the disease
specificity = …
true negs / (true negs + false positives)
i.e. who hasnt got the diease
define positive predictive value and give equation
% of people who actually have the disease out of those who tested positive
positive predictive value = true pos. / (true pos. + false pos.)
define likelihood ratio
likelihood of the result meaning there is disease vs. there being no disease
equation for positive likelihood ratio
LR+ = sensitivity / (1- specificity)
equation for negative likelihood ratio
LR- = ( 1 - sensitivity) / specificity
roughly what LR+ is considered useful ?
> 10
roughly what LR- is considered useful?
the lower the better , 1 is USELESS
describe endocrine signalling
uses hormones which are secreted into the blood so they can be carried to their site of action. they are present at very low levels.
act via receptors on or in target cells
the same hormone can have a heterogeneous response depending on the cell
what is paracrine signalling?
the chemical acts on the adjacent cell
what is autocrine signalling? e.g.?
target site is on the same cell - amplification process
T-cell lymphocytes
what is juxtacrine signalling?
contact-dependent signalling
i.e. grow when not touching, stop on contact (cancer doesnt have this)
define ligand
extra-cellular signalling molecule
what is a third messenger system and what is another name for it?
molecule that transmit messages from outside the nucleus to inside or visa verse
also called DNA binding molecules
why do most signal transduction therapies target the beginning of a pathway?
the higher up the pathway the more specific and the less unpredictable outcomes
define second messenger
small molecules synthesised in cells in response to an external signal which are responsible for intracellular signal transduction e.g. Ca2+
4 ways specificity of biosignalling can be influenced
- different interactions between ligand and receptor
- cell- specific expression of receptors (only some cells will express the correct receptor)
- cell- specific expression of signal transduction proteins (so the same signal - receptor combination can have different effects in the cell)
- cell-specific expression of effector proteins - there can be a varied response depending on what the cell does in response to the signal
how does a direct ligand-gated channel work?
a signal, acting as a ligand, binds to a receptor changing its shape such that a specific ions can now flow through
around 40% of medical drugs use what kind of signal transduction?
G-protein coupled type
which type of signal transduction is used in most of our senses? (smell, sight, taste)
GPCR
explain how a mutation in the V2R gene on the X chromosome results in congenital diabetes insipidus in males
normally AVP (anti-diuretic hormone) binds to the V2 vasopressin receptor (GPCR) and stimulates water reabsorption. if the V2R gene is inactivated then this cannot happen so cannot generate appropriately concentrated urine
what area are tyrosine kinase-linked signals important
cell growth, differentiation and survival
how could the inhibition of EGFR have therapeutic effects in cancer patients?
EGFR is expressed to varying degrees in a variety of cancers e.g. colorectal, pancreatic, head and neck, renal, breast. by introducing an anti-body to bind to extracellular domain of EGFR , growth factor can be blocked
what are the 4 types of receptor in signal transduction?
- direct ligand gated channel
- G protein coupled receptor
- tyrosine kinase- linked
- intracellular steroid / thyroid type
where are intracellular receptor proteins found?
in the cytosol or nucleus
what type of molecules can reach intracellular receptors?
small or hydrophobic
two examples of hormones that work on intracellular receptors?
thyroid
steriod
how do intracellular signals have an effect on the body?
act as transcription factors, turning on specific genes
what are the 5 components of the innate immune system?
- physical / chemical barriers
- phagocytic leukocytes
- dendritic cells
- natural killer T cells
- plasma proteins (complement)
2 components of adaptive immunity
- humoral (B cells which mature into antibody secreting plasma cells)
- cell mediated (T cells that mature into effector helper T and cytotoxic T cells)
how are specific antibodies made?
randomly through recombination of regions of the immunoglobulin genes.
B cells that make antibodies against foreign molecules AND self are allowed to be made.
there is then a process of negative selection where the B cells making self antibodies are DESTROYED
how can the process of antibody production lead to autoimmune disease
the negative selection process doesnt always destroy the B cells that produce antibodies with a low affinity to self
what makes autoimmunity pathogenic?
it is normal for there to be autoantibodies in individuals. it is pathogenic when:
- there is activation of T/B cells and amplification of autoantibody responses
- there is increased or novel exposure of ‘self’ antigen
4 functions of antibodies
- opsonisation -> phagocytosis
- cytotoxicity
- immune complex formation
- mediate inflammation
pathophys of Goodpastures syndrome
AKA anti-GBM disease
anti-GBM antibodies bind to the basement membrane of capillaries causing the WBC to attack it.
leads to inflammation of the vessels -> glomerulonephritis and alveolar capillartitis
anti-body mediated AID is what type of hyper-sensitivity?
type II
how do streptococcal cell wall antigens cause acute rheumatic fever?
they cross react with cardiac heart muscle
what antigens are present in Goodpastures syndrome?
collagen type IV basement membrane
type III hypersensitivity is mediated by what?
immune complexes:
ineffective clearance of immune complexes by the innate immune cells leads to an inflammatory response
what are the two general ways the immune system can be over active?
failure to switch off
wrong target
allergy is what kind of hypersensitivity?
type I
describe sensitisation in a type I hypersensitivity reaction
antigen comes into contact with a B cell
it is presented to a T helper cell
IgE is produced for that antigen
a mast cell is coated in this IgE
what is it that causes the inflammatory response in type I hypersensitivity?
degranulation of the mast cell on re-rexposure
what dose of adrenaline do you give in anaphylaxis? 3 other things?
0.5ml of 1 in 1000 IM
fluid bolus
chlorphenamine 10mg IV
hydrocortisone 200mg IV (for the late phase)
when would you do a mast cell tryptase test and why?
1hr after onset of anaphylaxis
to monitor progress
3 medications to give on discharger following anaphylaxis?
oral prednisolone
antihistamine (10/ 20mg PRN)
CONSIDER adrenaline autoinjector x2
4 tests available for allergy follow up?
RAST testing for specific IgE
skin prick
oral challenges
intradermal testing
what is Bayes theorem ?
the pre-test characteristics of a patient must be considered along with the test result to work out the post test probability of having a disease
if the likelihood ratio of a test is 10, what is the approx. change in probability with a positive result?
add on 45%
if the likelihood ratio of a test is 2, what is the approx. change in probability with a positive result?
add on 15%
with what pre-test probability might you not want to do the test and why?
very low- would you treat even if positive?
very high- just treat anyway
why is there increased lactate in sepsis?
- macrophage activity
- decreased clearance of lactate
- increased anaerobic respiration
what is adult respiratory distress syndrome? what does it look like on CXR?
injury to the basement membrane of the alveoli causes them to fill with fluid
diffuse opacity
when and why would you do a tryptase test?
24 hrs after anaphylaxis to rule out mastocytosis (excess mast cells)
what is von willebrand factor and where is it stored?
blood glycoprotein involved in haemostasis
stored in the endothelial cells
how does von williebrand factor work?
released into plasma when endothemilum is damaged
traps passing platelets
how does the endothelium regulate vWf to prevent clots?
releases nitrous oxide to prevent adhesion (can i bind here please? NO!)
how is vasculitis classified?
small, medium and large
what is the most common vasculitis?
GCA
how is vision lost in GCA?
occultion of the blood supply to the eye
how is GCA diagnosed? and treated?
biopsy
steroids
what is Bechet’s disease?
small vessel inflammation in veins and arteries that causes mouth ulcers, genital sores, eye inflammation , rashes
what changes are associated with endothelial dysfunction?
reduced NO bioavailability pro-vaso-constriction pro-coagulopathy pro-inflammation pro-oxidative stress
what type of vascular disease is anti-neutrophil cytoplasic antibdies (ANCA) associated with?
small vessel vasculitis
what are the systemic symptoms of small vessel vasculitis?
ENT- saddle bridge nose
lungs- wheeze, breathlessness, dry cough, haemoptysis
skin- ulcers, rash, necrosis
eys- dry, red gritty, painful eyes with or w/o vision loss
nerves- loss of sensation
bowels- bleedins, diarrhoea, abdo. pain
how are macrophages primed?
NK cells and T cells release IFN-gamma when a barier has been penetrated
this upregulates the expression of MHCII
how do marophages kill bacteria?
recognise PAMP: increase reactive o2 molecules and lysosome number
other than phagcytosis, what do macrophages do when primed?
release cytokine that have the following affect:
- active compliment cascade
- active vascular endothelium
- increase anti-bodie production
- recruits other cells
where are NK cells made?
bone marrow
what can NK cells do?
kill tumour and virally infected cells
how do macrophages and NK cells have an amplification effect?
macrophages activate NK cells and NK cells release IFN-gamma which activates macrophages
where are neutrophils made and what attracts them?
bone marrow
TNF-a
what is the ‘bridge’ between innate and adaptive immune systems?
dendritic cells:
awaits sampling by t cells at lymph nodes
what is meant by ‘contexualised’ discrimination? (immune system)
our bodies will allow the retention of harmless ‘non-self’ e.g. in the gut
how is peripheral tolerance achieved?
Tregs made in the peripheries and tolerogenic DCs can turn off self reactive T-lyphocytes by cell- cell inhibition
what are t-regs and what ar the types?
CD4+ T lymphocytes which suppress potentially deleterious activities of T lymhocytes thymic tregs (central tolerance) peripheral tregs- induced in peripheries `
AIRE deficency is an example of what mechanism of auto-immunity?
failure of central tolerance: non-expression of self antigen -> organ specific auto-immunity and chronic mucocutaneous candidiasis
give an example of a disorder of Treg cells?
IPEX syndrome
define primary immundeficincy
loss OR GAIN in function
what type of infection are neutrophils, compliment and antibodies responible for clearing?
EXTRAcellular
Tx for anti-body, compliment , neutrophil deficiency?
abx prophylaxis
anti fungal prophylaxis (particularly in compliment)
replacement Ig
what could be a non-congenital cause of neutrophil deficiency
chemo/ radio therapy
bone marrow failure
how are t cells involved in extra cellular infection clearing?
B cell actvation
how do t cell deficient patients present/
persistent viral infection (t cells clear intracelluar infections)
protazoal infections +/- bacterial infections
tx for t lymphocyte deficiency ?
abx prophylaxis
anti fungal prophylaxis (particularly in compliment)
replacement Ig
haematopoietic stem cell transplant
how can phagocyte deficiency lead to non-infectious resp. failure?
cells arent cleared so get a build up surfactant
3 types of rejection, their time periods and what mediates it?
hyper-acute: straight away- anti-bodies (pre-existing)
acute: days/ weeks - T-cells and anti-bodies
chronic: months/ years - compliment, ab, adhesion molecules
what does chronic rejection cause?
FIBROSIS
atherosclerosis
inflammation/ scarring
what are the three criteria for graft v host disease?
graft has immunologically competent cells
host appears foreign to the graft, i.e. it has alloantigens that stimulate the graft
host is unable to mount an effective immune response to the graft
3 ways to prevent rejection?
ABO matching (prevents hyper acute)
HLA matching e.g. with family members
immunosuppression: destroy T cells with serotherapy, prednisolone
what is graft v host disease?
when bone marrow/ stem cells rejects host
RARE: liver transplant (there are lots of immune cells here)
who is at risk of GVHD?
neonates
immunocompetent
which organs does acute GVHD effect?
skin (painful rash, blisters)
liver (raised LFTs and possibly jaundice)
gut (anorexia, dyspepsia, bleeding, diarrhoea)
what factors increase risk of GVHD?
sex mismatch
previous pregnancies
peripheral cells worse than core cells
age
what investigation is used to determine extent of liver fibrosis?
biopsy is the gold standard
what can LFTs tell you about fibrosis?
AST/ALT ratio
why do blockages form in the liver in cirrhosis?
regeneration leads to nodule formation
which cells cause pulmonary fibrosis?
abnormal activation of fibroblasts
what will the U&Es look like in chronic renal failure?
high phosphate (kidneys cant clear it) low calcium
two main causes of high calcium
malignancy (boney mets or ectopic parathyroid tissue)
hyperparathyroidism
define carcinogenesis
process of a normal cell becoming a cancer cell
what is the smallest detectable tumour?
1cm
why do cells not normally metastasize to other parts of the body? e.g. why no liver cells on skin?
cellular proteins and surface glycoproteins have a contact inhibition system
define hypertrophy
increase in size of tissue due to increase in size of cells
define hyperplasia
increase in size of tissue due to increase in number of cells
define metaplasia
replacement of one fully differentiated tissue with another due to persistant injury. when this stimulus is removed it will return to initial state
define dysplasia
archetectual and cytological changes similar to malignancy.
some features of cancer but not cancer yet- can also return to normal if stimulus removed
3 steps in chemical carcinogenesis
- initiation- chemical damage to DNA and repair had failed before replication
- Promotion- reversible process that requires multiple exposure. if a promotor is removed the cancer could stabilise
- Progression- irreversible process that involves multiple complex DNA changes
2 types of non-ionising radiation that could cause cancer?
radio-waves
UV
which tissue is particularly sensitive to ionising radiation?
breast, thyroid, bone marrow
why are male pilots more likely to have daughters than sons?
exposure to radiation
y chromosome is more susceptible to it
which UV type has the most effect on DNA and which is the most clinically relevant?
UVC is the most potent but us mostly absorbed by the air so is negligible.
UVB is the most important in cancer
how does non-ionising radiation cause changes in DNA?
and how do cells normally stop this?
electron excitation
nucleotide excision repair pathway
what % of cancers are thought to be due to infection globally?
15%
what does EBV increase risk of?
Hodgkins and burkett’s lymphoma
example of exogenous hormones causing cancer
HRT, COCP*- over exposure to oestrogen linked with breast cancer
only if this is used after oestrogen would normally be lowered
whats the difference between somatic and germline mutation
germline- error in every bit of DNA. can be hereditary but not always
somatic- in the tumour there is a mutation but this is not present in the other cells (unless present in the germline cells). this cannot be passed on
somatic mutations and germline mutations can affect the same genes
how can mutations occur in normal cell division?
mis-segregation
mitotic recombination
how many cancers are familial?
10%
why is it dificult to get chemo to cancer cells?
they are very hypoxic so arent well supplied by our blood vessels. only about 20% of cells can be reached
