Mechanism & Investigation of Diseases Flashcards
what does sensitivity tell us
tells us out of those who do have a disease, how many were tested positive
what does specificity tell us?
tells us out of those who do not have a disease, how many were correctly tested negative.
what does positive predictive value tell us
tells us out of those who were told they have the disease, how many actually do have
what does negative predictive value tell us
tells us out of those who were tested to not have the disease, how many truly do not
how to calculate positive likelihoood ratio?
sensitivity/1-specificity
how to calculate negative likelihood ratio?
1-sensitivity/specificity
how to calculate positive and negative predictive values?
PPV: (truly disease)/(tested positive)
NPV: (truly healthy)/(tested negative)
what is likelihood ratio used for?
to determine how good a test is at telling someone if they have the disease given a particular result.
what value of likelihood ratios are good?
if LR = 1 then test is useless
number should be much higher than 1.
what is a VUS in genomic study?
when someone has a variant of uncertain significance. means that they have a different genetic composition from ‘normal’, but we do not how that affects the person phenotypically
describe the components of the cellular innate defence
phagocytyes (macrophages) dendritic cells neutrophils NK cells other granulocytes like mast cells and, eosinophils and basophils
what do macrophages do
non-activated they help clear cellular debris
once activated they secrete cytokines that activate complement, endothelial cell adhesion molecules, and act as APC in lymph nodes
what kind of cells do NK cells target
tumour cells or virally infected cells
why is it that NK cells can kill tumour cells
because tumour cells lose MHC I expression
what surface molecule inhibit NK cell activity
MHC I
what can activated B cells become
plasma cells
memory b cells
APC
what is the first antibody that B cells secrete?
IgM
what is the process called when B cells increase their fit to the antigen
somatic hypermutation
what cells activate B cells?
T cells
what do CD4 and CD8 cells do?
CD4 express specific antigens on themselves, the circulate the body looking for APCs with matching antigen
once activate, they can activate B cells, or become CD8 cells, Treg cells or other Th cells
what cells express MHC II molecule?
immune cells like T cells, B cells, and APC
what cells express MHC I?
self cells
how is an immune response cleared?
after pathogen is cleared, cells stop becoming stimulated and naturally apoptose.
what are 2 mechanisms of cultivating self tolerance?
thymic central T cell selection
peripheral tolerance
what protein is key in central tolerance?
AIRE protein
what cell is key in peripheral tolerance?
Treg cells
what are 2 ways Treg cells can be made?
in the thymus or as progenitors of Cd4 t cells
what is the name of a primary loss of central self tolerance?
APECED
what is the name of the syndrome where peripheral tolerance is lost?
IPEX syndrome
2 other ways that self tolerance can fail other than central and peripheral self-tolerance loss
molecular mimicry
or chronic APC stimulation
describe type 1 2 3 4 hypersensitivity reactions and examples
type 1 - IgE mediated, mast cells, histamine release e.g. anaphylaxis
type 2 - IgG-IgM interaction on surface of target cell, tissue specific e.g. goodpastures, myesthaenia gravis,
type 3 - immune complex deposition e.g. SLE, RA, farmers lungs
type 4 - T cell mediated, organ specifice.g. Type 1 diabetes
what is the antigen targeted in goodpastures disease?
type 4 collagen
what is the pathophysiology of farmers lungs? what type HS?
type 3
patient breathes in allergen e.g. hay, triggers immune reaction, produces IgG antibodies against allergen whcih combine with allergen and forms immune complex which gets embedded in alveoli wall
chronic inflammation ensues, causing reduces lung function and clinical symptoms
acute management of anaphylactic shock?
Oxygen
adrenaline IM 0.5 mg in adults
antihistamine IV - chlorphenamine
corticosteroids IV
what must be measured after anaphylaxis?
serum tryptase
what are some primary immunodeficiencies
T cells, b cell
antibody, complement, neutrophil deficiencies
what type of infections are antibody, complement and neutrophils good at?
extracellular
what type of infections would someone be prone to if they are complement deficient?
pyogenic infections e.g. streptococcus and HIB
what type of infection would complement C5-9 deficiency lead to?
meningococcal
what does eculizumab inhibit?
complement
what does rituximab inhibit?
CD20 (B cell)
what treatment can be done for antibody, complement or neutrophil deficiencies
antibiotic, antifungal prophylaxis
Ig replacement
stem cell transplant
where is complement made?
liver
what type of infections would someone with T and B cell deficiencies be prone to?
viral, protozoal, intracellular infections, but also extracellular
how would someone with SCID present?
early on in life, around 6 months
with chronic LRTIs, fungal infections, PCP
what is the problem in autoimmune lymphoproliferative conditions?
failure to clear lymphocytes after infections, causing prolonged inflammatory state, causing autoimmune conditions
3 types of rejection in solid organ transplant
hyperacute
acute
chronic
mediators of each type of rejection in SOT?
hyperacute - preformed antibodies
acute - adaptive immune sytem T/B cells
chronic - antibodies, inflammatory system, fibrosis, scarring
e..g of hyperacute rejection?
preformed ABO antibodies
what is the most common cause of graft loss?
chronic rejection
how does chronic rejection happen?
takes months - years
build up of antibodies, macrophages and fibrosis of organs leading to chronic inflammation, scarring and damage of organ
how to prevent SOT rejection?
ABO matching
HLA matching if possible
immunosuppresion - acute or chronic treatment
what happens in GVHD?
grafts with immunocompetent cells attack host systems
what kind of transplants can cause gvhd?
BM transplant
blood transfusion with irridiation
stem cell transplant
pathophysiology of GVHD
damage host issue leads to cytokine release, causing recruitment of APCs which stimulate donor T cells. activated lymphocytes then cause immune reaction towards host tissue causing tissue destruction
factors associated with increased GVHD
alloreactivity sex mismatch donor parity age of recipient and donor stem cell source conditioning of recipient prior to transplant
2 types of GVHD
acute and chronic
where can acute gvhd occur?
particularly, skin, gut and liver
signs of acute liver gvhd?
asymptomatic raised LFTs - bilirubin, alt, ast, alk phos
symptoms of acute skin gvhd?
painful, erythematous +/- puritic macules
over soles, palms, trunk and limbs
symptoms of acute GI GVHD
anorexia, dyspepsia, abdominal pain, diarrhea, intestinal bleeding and ileus
where can chronic gvhd occur?
anywhere
how to prevent chronic gvhd?
choose best donor
deplete T cells from donor graft
suppress donor t cells with drugs
4 types of cell signalling
endocrine
paracrine
autocrine
juxtacrine
advantages of a multistep signal transduction system?
specificity
variability
amplification
redundancy
4 types of signal transduction pathways
type 1 - ligand gated
type 2 - g protein receptor linked
type 3 - tyrosine kinase linked
type 4 - intracellular
examples of each of the 4 types of signal transduction pathway and their ligands
type 1 - acetylcholine, nicotinic receptors
type 2 - acetylcholine, muscarinic
type 3 - EGF and EGFR
type 4 - steroid or thyroid hormones
what are g protein receptors usually involved with?
physiological regulation, senses, eyes smells, neurotransmitters
which type is cAMP pathway?
G protein coupled receptor
how is EGFR linked to cancer cells
EGFR is involved in cell proliferation, survival, angiogenesis, repair and metastasis.
cancer cell mutation causes mechanisms that result in over proliferation of the cell
5 mechanism related to EGFR that cancer cells exploit to cause over proliferation
increased EGFR expression
increased EGF production
heterodimerisation of HER1234 receptors
decreased degradation of receptor complex
mutation in EGFR causing it to be switched on permenantely
how does heterodimerisation of HER1234 allow cancer cells to proliferate?
homodimers require 2 signalling molecules to produce an effect, heterodimers only require 1 molecule. allowing the cell to do more with less
heterodimers are also more likely to be recyled instead of degraded, thus allowing more of the receptors to exist on the cell surface
what are some examples of anti cancer drugs that target EGFR?
Herceptin targets HER2, AKA trastuzumab
or tyrosine kinase inhibitors
how do type 4 signal transduction receptors work?
intracellular receptors, the signalling molecule is able to diffuse accross the cell membrane, binding to an intracellular receptor, forming a complex. this complex travels to the nucleus and acts as a transcription factor, controlling gene expression
what are the mediators of endothelial vasodilation and constriction?
NO, prostanoids vasodilates
endothelin vasoconstricts
describe the pathophysiology of atherosclerosis
damage to endothelium causes inflammatory response to the area, attracting macrophages. macrophages endocytose lipids and migrate under endothelium layer. eventually macrophage becomes foam cell as it consumes more lipids. within tunica media, it forms a large lipid rich core and starts to necrote as a fibrous plaque forms around it. plaque will be prone to rupture causing thrombus and exposure of endothelium, triggering clotting cascade and increasing risk of stroke and infarcts
what is the pro-clotting factor stored in endothelium called?
von willebrand factor
what values for +LR and -LR are useful?
for +LR: anything more than 1, higher is better
for -LR: less than 1, closer to 0 is btter
in what situations would doing tests be useful?
when pre-test probability is intermediate, not very sure of either
what kind of anaemia does CKD show?
normocytic
what is ESR?
distance fallen by RBC in a test tube after 60 mins
what causes RBC to fall further? i.e. higher ESR
“sticky” RBC causing them to clump and fall faster
what is a significantly raised ESR?
usually >100
what will be the ESR and CRP of someone with SLE?
high ESR low CRP
compared to an elderly person would a young person need to have higher or lower creatinine to have a lower EGFR?
higher
a rise in ALP but normal GGT indicates what kind of pathology?
bone
main causes of hypercalcaemia?
malignancy
ectopic PTH
boney mets
hyperparathyroidism
what is a common drug that can cause raised CK
statin
what is lactase dehydrogenase a marker of?
malignancy
whats the most important prognostic marker in sepsis
lactate
when analysing chest xray what is
DR
PE
ABCDEFGHI
Demographics/patient details/date
Rotation
Position
Exposure
Airways
Bones and soft tissue
Cardiac
Diaphragm
Effusions
Fields and fissures
Great vessels
Hilar and mediastinum
Impression (overall)
in anaphylaxis what is the strength dose route and volume of epinephrine required?
1:1000 0.5 mg 0.5ml IM
after anaphylaxis, how long does it take for tryptase to return to normal?
2 days
after anaphylactic shock what should patients be prescribed? how many? dose?
2x epipen, 0.3 mg
most common ECG finding in PE
sinus tachy
according to RCOG what is the pathway for pregnant woman with suspected PE?
clinical assessment, CXR, ECG, bloods
check for signs of DVT, if have DVT, give LMWH
if no signs of DVT, check if CXR is normal, if CXR is normal do V/Q if CXR is abnormal do CTPA. Once PE confirmed, give LMWH
what is a saddle embolus a sign of?
PE
what are indiciations for CT head within 1 hour, according to NICE?
GCS <13 at ED or <15 after 2 hours ?skull fracture ?basal skull fracture post traumatic seizure focal neurological deficit >1 episode of vomiting
what are some signs of basal skull fracture?
Battle’s sign
panda eyes
haemotypmanum
CSF leak
what are indiciations for CT C spine within 1 hour, according to NICE?
– GCS <13 on initial assessment
– Intubated
– Xrays inadequate (e.g. unable to position)
– Xray looks abnormal/suboptimal
– Definitive answer is needed (i.e. pre surgery)
– If they need multifocal CT as part of trauma investigation
– Alert and:
• 65+
• Dangerous mechanism
• Focal neurology in upper limbs
• Paraesthesia in upper limbs
what are the signs and symptoms of DiGeorge’s syndrome?
CATCH 22
22q11.1 deletion
cardiac abnormalities abnormal facies thymic aplasia cleft palate hypocalcaemia/hypoparathyroidism
pathophysiology of digeorge syndrome
malformation of the 3rd and 4th pharyngeal arches, these usually give rise to the aortic arch, thymus and parathyroid gland.
how is digeorge syndrome diagnosed
if clinically indicated, then usually by FISH
how does digeorge syndrome present?
facial defects, congenital heart defects, recurrent infections (protozoa or fungal), hypocalcaemia
what cells are responsible for acute rejection?
CD4 and CD8 t cells
signs of acute organ rejection
beginning few days to weeks after transplant, patient feels systemically unwell, then signs of target organ failure (e.g kidney, liver, lung),
primary pathophysiology in chronic rejection?
fibrosis or sclerosis of organ
why might a leukaemic patient develop a lichenoid rash post transplant?
GvHD
greatest risk factor for development of cancer?
diet
what is the main carcinogenic substance produced in chronic inflammation?
reactive oxygen species
which cancer does smoking not cause an increased risk?
endometrial
which UV band is the most common carcinogenic factor (A B C?)
UV-B
difference between oncogene and TSG?
oncogenes are mutated protooncogenes, these genes typically stimulate cell proliferation. only require 1 mutation to cause disease
TSG in health, suppress cell proliferation. require 2 mutations to cause disease
which type of gene is commonly implicated in inheritable cancer gene predispositions TSG or oncogenes?
TSG
what type of gene is BRCA1/2 TSG or oncogene?
TSG
what type of gene is BCR-ABL?
oncogene
how can PARP1 be used as a therapeutic target?
a mutated BRCA gene loses its ability to repair double stranded DNA breaks, but relies on PARP1 to repair single stranded breaks. in a cancer cell with BRCA mutation, by using a drug to inhibit PARP1, it will cause single stranded breaks to become double stranded breaks which makes the cell non-viable.
what does the BRCA1/2 gene do in health?
repair DNA damage,
how to calculate true positive rate?
sensitivity
how to calculate false negative rate?
1-sensitivity
how to calculate false positive rate
1-specificity
how to calculate true negative rate?
specificity
what are the 3 criteria in the billingham criteria
graft has too many immunocompetent cells
receipient expresses antigen not found in the donor
patient is immunosuppresed and unable to reject graft
types of 2nd messenger pathways
Ca2
DG, IP3
cAMP, cGMP
ras, JAK, Raf
what is transtuzumab also known as?
herceptin
