131 Flashcards
healing as a pathological process
stimulated by a pathological stress such as physical injury, collagen deposition in scar tissue
genetic and immune factors as a pathological process
affect a cell/organ ability to adapt to environmental stresses leading to different susceptibilities to disease
environmental changes outside the acceptable physiological range gives rise to the cell stress response- give examples
osmotic stress
temp stress
oxygen/energy deprivation
injury / infection
homeostasis disruption
what happens when you fast
fatty acids are mobilised from adipose tissue this is a normal response from an energy store but long term can lead to atrophy
what occurs when you start lacking calcium
calcium is mobilised from bone matrix- leads to calcium deficiency in bones in the long term
physiological definition
the normal functions of living organisms
metaplasia
from one morphology to another , transformation of one differentiated cell type to another differentiated cell type. The change from one type of cell to another may be part of a normal maturation process
whats a ‘housekeeping’ gene
normal structural proteins (non essential proteins)
what happens to housekeeping genes during cell stress
they are downregulated so they stop producing non essential proteins
whats a cells stress gene
cell-organising/protective functions
eg heat shock proteins (HSPAs), NF-KB, AP-
they have a high degree of evolutionary conservation which promotes essential response to cell survival
what do HSPs do in cell stress
act as chaperones, protect proteins, assist refolding, prevent protein aggregation
what does ubiquitin do during cell stress
targets protein for destruction by specific proteases(proteasome) - to be recycled/eliminated to prevent them building up and causing disease like lewy body in dementia
what does chronic stress result in
visible aggregates of constituents known as inclusion bodies , eg lewt body ( aggregations of a-synuclein) in nerve cells
hyperplasia
increase in number of tissue cells due to increased cell division - can be normal eg in breasts for lactation
hypertrophy
increase in size of existing cells, matched by increase in functional capacity - eg in muscle cells
is the endometrial lining during menstrual cycle hyperplasia or hypertrophy
hyperplasia
are skeletal muscle fibres of athletes hyperplasia or hypertrophy
hypertrophy
colonic epithelial hyperplasia
normal colon is smooth single layer epithelial cells and short crypts. hyperplasia increases no of cells resulting in deeper crypts
transient colonic epithelial hyperplasia benefit
may help expel intestinal pathogens by increasing speed
benign prostatic hyperplasia (BPH)
hyperplasia of prostate cells
not a risk factor for carcinoma just normal adaptive response in most cases related to age
apoptosis overview
programmed cell death- a way of eliminating itself to protect the surrounding tissue from damage
necrosis overview
unable to adapt to stress is when this occurs- it releases contents such as enzymes into surrounding tissues damaging more cells
apoptosis phase 1
induction/signalling - anti-apoptotic protiens Bcl-2 deactivated
apoptosis phase 2
effector- mitochondrial permeability , looses ionic gradient needed
apoptosis phase 3
degradation- proteases- morphology- cells start to shrink and organelles disintigrate
apoptosis pahse 4
phagocytic- cell fragments are engulfed and removed - to prevent further damage to surrounding cells
is apoptosis a normal process +example
yes- as removal of autoreactive immune cells to prevent autoimmune diseases
intestinal cell turnover
embryogenesis and development
what happens when apoptosis isnt controlled properly
leads to caner
necrosis
uncontrolled cell death where enzymes and dna are released which will lead to an inflammatory response in surrounding tissues
necrosis triggers
any acute stressor eg metabolic stress, hyposxia, absence of nutrients, trauma
common molecule mechanisms that occur in necrosis
-reduction in ATp= cloudy swelling ,reducing biosynthesis
- increase in ca++ activates protein kinases, phospholipases start to break wall
- reduction in ability to scavange ROS causing further damage
- cells swell, lyse and burst
hypoxia
reduction or absence of normal o2 supply to an organ - fairly rapid necrosis
specific chemical agents that cause necrosis
carbon tetrachloride(CCl4)
paracetamol overuse
infarction definition
death of tissue
what does acute ischaemia and reperfusion injury lead to
increase in ca++ , phospholipase and lysozymes , cell damage and then necrosis
is apoptosis active or passive
active so ATP dependant - does not occur at 4 degrees
is necrosis active or passive
passive so occurs at 4 degrees
what happens to cytoplasm in apoptosis
shrinks
what happens to cytoplasm in necrosis
swelling
apoptosis in gel electrophoresis
non- random degradation of dna = ladder pattern on agrose gel as it is a controlled breakdown of dna
necrosis on gel electrophoresis
random digestion of dna = smear on agarose gel
dysplasia
abnormal growth or development
anaplasia
reversion of cell to primitive/undifferentiated state
neoplasia
formation of tumour
benign
not threatening to health or life
malignant
invasion of surrounding tissue/tendancy to metastasize
fixation- light microscope
halts biological activity and prevents tissue degradation and renders cells more amenable to staining
e.g. of fixatives for light microscope
formaldehyde and glutaraldehyde
embedding in light microscopy
supports tissue by embedding in stuff like paraffin wax or freezing or plastic resin
can cause artifacts
artifact
distortion in tissue
like fine lines, freeze thaw holes
cryostat
tissue frozen (-10-20c)
thickness 10-40um
collected on slides or free-floating
microtome
embedded in wax at rtp
thickness 5-40um
collected onto slides
vibratome
glued to holder rtp/chilled
thickness 40-400 um
collected on slides or free floating
haematoxylin
basic dye- so stains acidic structures purplish blue
nuclei, ribosomes
eosin
acidic dye- so stains basic structures red/pink
cytoplasmic proteins
giemsa stain
blood cell staining, nucleus dark blue to violet and cytoplasm pale blue
toluidine
basic stain
stain acidic components blue/purple
Massons trichrome stain
stains connective tissue, nuclei/basophilic structure blue, collagen green or blue, cytoplasm red
periodic acid- Schiff rxn
stains complex carbs purple
simple columnar epithelium function
absorptive
secretory
stratified epithelia function
protective function
e.g. skin
brain tissue function
thin axon for rapid-cell communication
smooth muscle tissue
elongated cells to maximise contractle properties
human tissue act
2004
regulated activities like removal, storage, use and disposal of human tissue.
lawful consent needed
tissue removed and stored for diagnosis not under act
4 cardinal effects of acute inflamation
rubor- redness
calor- heat
dolor- pain
tumor- swelling
rubor- redness
vessel dilation and increased blood flow to site
calor- heat in inflam
vessel dialtion and increased blood flow to site
dolor- pain in inflam
pressure on nerve endings/ chemical factors
response to acute inflammation
release of chemical mediators that stim production of exudate. this destroys infective agents and damaged tissue is partly liquified and removed from site
exudate (simple)
fluid
proteins
blood cells that mobilise local defences
exudate (complicated)
- salt, fibril, neutrophils (first on site of infection, phagocytic cells), macrophages( phagocytes+ produce cytokines,2nd wave response), dendritic cells (present antigen to t-cells), lymphocytes(cytotoxic and helper t-cells) ENTER WHEN BLOOD VESSELS BECOME LEAKY
exudation
when flow slows/vessels dilate, endothelial cells swell and partially retract, water salts proteins
transmigration/ diapedesis
The tissue macrophages release chemokines and cytokines which the leukocytes are attracted to , this is mediated by selectins on endothelial cells and integrins on leukocytes. Leukocytes then form pseudopodia and produce proteases to help move through the endothelial cells of veins to go into the tissue
how can chronic inflammation develop
- damaging stimuli persist and healing cant occur necrosis, organisation and repair all happening at once. tissues are infiltrated by activated lymphoid cells
- continued tissue damage- tissue-based immune response where lymphoid cells and macrophage are infiltrated
- macrophages are the main effector cell and they may form clusters called granulomas= granulomatous inflammation
tuberculosis
mycobacterium tuberculosis invades and replicates within macrophages which evades acute inflammation response. granulomas form in the lung surrounded by necrotic tissue
crohns disease
chronic intestinal inflammation
cycle of relapse and remission
complications are fibrosis and stricture (prevent food movement in gut)
no defined cause but could be wrong response to commensal microflora
microscopy
Subjective interpretation- human error
Cost of human labour
Widely available
Little training
Use antibodies for specific labelling
Difficult to assess multiple types of antigens at same time
Preserve tissue structure
Low throughput
flow cytometry
Automated reducing error
Cost of equipment
Less available
Require training
Use antibodies for specific labelling
Multiple cell types can be assessed at the same time
Loss of tissue structure during procedure
High throughput
ultrasound
high frequency sound waves
low resolution
CT
computerised tomography
uses x-ray to image quickly
less detail than ultrasound and MRI
MRI
magnetic resonance imaging
strong magnetic fields and radio waves
more detail but slower than CT
neoplastic transformation
loss of differentiation- cells become more like precursor cells
anaplasia
poorly differentiated cells
cells look dissimilar to normal tissues where there is also a lack of anchorage-dependant growth and loss of contact inhibition
protozoa
single celled animals, infect all tissues/organs. usually in tropic regions, bite transmission/ accidental ingestion
intracellular parasites or as extracellular parasites infection
asexual reproduction
how are viruses classified
type of nucleic acid, mode of replication, symmetry, presence of envelope
bacteria classification
practical characteristics such as size, shape, colour, immunologic, respiration. etc.
conventional specimen processing
details checked against request form
specimen grown on relevant culture media
incubated
commensal microorganisms
1 organism survives in another without causing harm (debated)
opportunistic infection
because of weakend immune system
why do microbes rarely lead to disease
an infection is dependent on mechanisms of both innate and required resistance as it is a conflict between 2 organisms
pneumonia
most common cause of infection-related deaths in USA and Europe
caused by large range of microorganisms (children usually viral and adults bacterial origin)
indistinguishable symptoms (lab id needed)
infection through inhalation, aspiration of normal flora, via blood
pneumonia symptoms
cough
chest pain
fever
confusion
shortness of breath
epidemiology definition
study of factors, implicated in disease progression that determines its frequency, distribution and severity in cohorts of individuals
endemic definition
diseases that occur at a constant rate within a given population
epidemic
incidence of disease above the endemic rate
pandemic definition
worldwide epidemic- new strains little immunity
influenza
influenza A undergoes major genetic changes rapidly so immunity becomes redundant
2009 pandemic was a re-assortment of genes between human, avian and pig flu strains
factors that influence disease distribution
person- age, gender, ethnic background, education, occupation
location- geographic, social
occurrence- episodic, cyclical, secular
epidemiology of cancer
- leading cause of death worldwide for 7.6 million deaths in 2008
- tobacco use is major risk factor, also alcohol, diet and inactivity
- more than 30% of cancer deaths can be prevented
examples of sample media
urine, faeces, cerebral fluid, sweat, saliva, arterial blood
internal quality assurance
daily/ every time a test is used, test results compared to monitor performance
external quality assurance
identical samples distributed to several labs and comparison of the labs to maintain high standards
precision
reproducibility- how many times do you get same results
accuracy
how close the measured value is to the actual value
sensitivity
how little of the analyte can be detected by the assay
specificity
how good is the assay at discriminating between the requested analyte and other interfering substances
common errors in collection of biochemical specimens
gender, diet, stress/anxiety/ menstrual cycle, strenuous exercise, time of day
Us and Es test
urea and creatinine and electrolytes
LFT test
alkanine phosphatase; alanine amino transferase, bilirubin, albumin
kidney function
- regulates extracellular fluid vol and electrolyte balance
- selective reabsorption of ions
- secondary endocrine function- hormones like renin
urea
breakdown product of protein in liver
creatinine produced?
muscles
normal GFR
100-120
whats GFR
glomerular filtration rate
what happens when GFR is reduced
serum urea and creatinine increase when GFR in kidneys is reduced (so less excreted)
ADH
from pituitary gland
causes reabsorption of water in collecting ducts, released after hypothalamus detects low water in blood
aldosterone
from adrenal gland
causes reabsorption of Na+ in nephron and water releases from renal via the renin-angiotensin-aldosterone system (RAAS)
distal
tubule far away from glomerulus
normal na levels
135-145 mmol/l
hyponatraemia oedematous symptoms
oedematous(swelling)
heart failure?
decrease in effective blood volume(water moved to brain)
aldosterone and ADH secreted
salt and water retained
hyponatraemia non-oedematous symptoms
too much water in collecting ducts of kidney
ADH released
hyponatraemia oedematous treatment
diuretic and restrict fluid + treat condition
hyponatraemia non-oedematous treatment
restrict fluid
hyponatraemia na levels
na> 135 mmol/l
hypernatraemia na levels
na>145 mmol/l
hypernatraemia causes
water depletion
excessive na intake
renal failure
hypernatraemia clinical signs
decreased blood pressure (increased if salt gain)
low urine output
dry mucous membranes
hypernatraemia treatment
oral water
IV 5% dextrose
hyperkalaemia K+ levels
K+ > 4.9 mmol/l
hyperkalaemia causes
renal failure
adrenal failure
renal failure
k+ release from damaged cells
hyperkalaemia treatment
calcium gluconate , insulin + glucose, dialysis
hypokalaemia k levels
K+ < 3.4 mmol/l
hypokalaemia causes
vomiting
diarrhoea
diruetics
hypokalaemia symptoms
weak cardiac arrhythmias
vomiting/ diarrohea
hypokalaemia treatments
oral or IV K (slowly with ECG monitoring)
anuric
no urine
oliguric
<400ml/day
acute renal failure (ARF) sympotoms
concentrated urine
serum urea and creatine increase
hyperkalaemia- nephron cant excrete K when GFR decrease
acute renal failure causes
pre-renal= blood supply to kidney failure
renal= damage to kidney tissue
post renal= obstruction blocks urinary drainage
acute renal failure treatment
treat underlying disease
dialysis if severe
chronic renal failure (CRF)
hyperkalaemia- nephron cant excrete k when GFR decreases
serum urea and creatinine high
management of CRF
sodium restriction
diuretics
dietary restriction of protein
oral ion exchange resin (k removal)
longer-term plans for dialysis or transplant
myocardial
heat muscle
infarction
death of tissue after lack of blood supply
morbidity
the condition of suffering from a disease/medical condition
left coronary artery
circumflex artery -left ventricle and atrium,
anterior interventricular branch
both ventricles
post interventricular branch
right coronary artery
both ventricles
marginal branch
right coronary artery
right ventricle after entering capillaries, blood drains into coronary veins then coronary sinus and empties into right atrium
tunica intima
endothelium
basement membrane
internal elastic lamina
tunica media
smooth muscle
external elastic lamina
tunica externa
elastic and collagen
usual reason for MI
atheromatous plaque residue with overlying thrombosis
cause of MI steps
- Initial damage to endothelium in arteries (>2mm diameter).
- Cholesterol-rich low density lipoproteins enter the intima and taken up by macrophages
- Fat-laden macrophages (FOAM CELLS) underneath endothelial cells = FATTY STREAK
- Macrophages release lipid (and chemical signals) into intima.
- Cells of intima release collagen in response to signals.
- Formation of a raised yellow smooth area = LIPID PLAQUE
- Fibrolipid cap forms
- Endothelium fragile and often ulcerates
- Platelets aggregate on plaque which stimulates thrombus formation
consequences of atheroma
- artery narrowing- ischaemia, hypoxia, angina pectoris, pain
- thrombus formation on plaque- Mi
- bleeding into the plague- can occur in coronary arteries
- aneurysm
arteriosclerosis
thickening/hardening o arery wall
atherosclerosis
thickening/hardening of high pressure artery wall caused by atheroma
atheroma
lipid-rich accumulation in arteries
acute MI
altered level of cardiac muscle biomarker, crushing chest pain, ECG changes, imaging evidence
how long does an MI ECG take to develop- impact
24hours
so may be difficult to interpret but show an elevated ST region
cardiac biomarkers
enzymes- creatine kinase, lactate dehydrogenase and aspartate amino transferase (not used since 2000)
muscle proteins- myoglobin (detectable 2/3 hours after Mi), troponin I and T
troponins
a complex with actin and myosin and regulates the concentration of striatedd muscles
3 forms= C, I, T
troponin c
binds calcium- regulates the action of the filaments during contraction
troponin I
inhibitory subunit- prevents contraction in the absence of calcium and troponin C
troponin T
binds the complex to tropomyosin
how to diagnose MI
cardiac damage causes release of cell components into bloodstream and you can measure the cTnT or cTnI to diagnose infarction
treatments for MI
thrombolytic agents - streptokinase
anticoagulant-heparin
coronary angioplasty
coronary bypass
coronary angioplasty
- catheter inflated in obstructed vessel to remove obstruction and enable blood flow
coronary bypass
graft of artery or vein to coronary artery which enables blood to glow around the obstruction
hyperglycaemia
diabetes, insulin released and the glucose enters cells
hypoglycaemia
hyperinsulinism, glycogen storage disease. Low blood glucose, glucagon release and the liver cells release glucose
diabetes mellitus
- Persistent hyperglycaemia
- Normal blood glucose values 4-6 mmol/l
- Now information out about diabetes being linked to dementia
- 9% of children population have diabetes
diagnosis of diabetes mellitus
urine glucose test
HbA1c
fasting blood glucose
random
oral
urine glucose test
10 mmol/l glucose overspill- glycosuria
HbA1c in diabetes testing
as glucose conc rises more HBA becomes glycated and % present as HbA1c increases, shows poorly controlled diabetes, but limitations include the fact other conditions show elevated HbA1c eg opiod abuse, iron deficiency
fasting blood glucose
> 7 mmol/l
random blood glucose
> 11 mmol
what happens to glucose when blood glucose is too high
turned into glycogen as the beta cells release insulin
what happens when blood glucose is too low
glycogen back into glucose via glucagon which is released via alpha cells
beta cells and insulin release
Glucose enters b cell- phosphorylated; glycolysis, pyruvate formed,
Atp is produced during this and the k channel closes so k+ rises in cell
The membrane depolarises and calcium channel opens so calcium rises in cell
Insulin granules exocytosis
insulin binding to receptors
insulin receptor is a tyrosine kinase receptor consisting of 2a and 2b subunits embedded in the plasma membrane.
Binding of insulin to the a-subunits results in phosphorylation of the b-subunits thus activating the kinase activity.
This results in glucose utilisation and further glucose uptake via a range of signal transduction pathways that increase the number of glucose transporters (GLUT 4) in the plasma membrane.
type 1 diabetes
- Body does not produce enough insulin
- 10% adults with diabetes have type 1
- 95% children with diabetes have type 1
- Mainly due to autoimmune mediated destruction of pancreatic-b-cells which results in insulin deficiency
- Weak family trait contracted at ages 9-13
- Only treated by insulin administration or pancreas transplant
type 2 diabetes
- Body produces insulin but cant use it well
-90% adults with diabetes have type 2
-2% of children with diabetes have type 2
-Characterised by insulin resistance on tissues
-Associated wit over nutrition, obesity, lack of excersize
-Strong family trait- environmental and genetic
-Usually seen in over 40s- is now seen in children sometimes
-Treatment- reduce calories, carbs and exercise, sulphonylureas- b cells secrete more insulin, bariatric surgery for weight loss
gestational diabetes
temporary during pregnancy
long term effects of diabetes
microvascular complications
neuropathy
nephropathy- atherosclerosis, arteriosclerosis
heart /brain complications
risk of alzheimers disease
retinopathy
neuropathy
defective blood supply to neurons, axon degeneration, sensation loss, diabetic trophic ulcers, ischaemia in feet
nephropathy
Atherosclerosis- aorta and renal arteries nephron ischaemia
Hyaline arteriolsclerosis- thickening of glomerular capillary basement membrane (glycation of proteins)
Expansion of mesangial matrix
Glomerular damage= increased permeability, proteinuria (renal failure), microalbuminuria
heart/brain complications in diabetes
Type 2 diabetes with blood glucose level of 190mg/dl have a 40% higher risk of dementia
Middle aged type 1 higher risk of brain lesions and slower cognitive function
Experiencing episode of extremely low blood sugar associated with risk of Alzheimer’s disease
retinopathy in diabetes
Hyaline arteriolosclerosis= membrane thickening in retinal blood vessels (retinal haemorrhage)
Cataracts- glucose attaches to lens proteins and form cloudy vision
components of blood
55% plasma
45% rbcs
buffy coat- wbc and platelets
plasma components
90% water
ph 7.4
electrolytes
plasma proteins
erythrocytes
Biconcave- mean diameter 7.8um and 25um at circumferential border
Larger surface are for oxygen diffusion
No nucleus
120 day lifespan
Oxygen and co2 transport
Each RBC has haemoglobin and enzymes
wbc types
neutrophils
monocytes
eosinophils
basophils
Sickle cell anaemia
– abnormal beta chain
-Haemoglobin chains tick when deoxygenated
-Erythrocyte deformed and stuck in capillaries
-Tissues are then starved of oxygen
-GAG to GTG ( glutamic acid to valine)
Thalassemias
Alpha or beta thalassemia
Reduced rate of synthesis of a or b globin chains
Erythrocytes small and stain weakly with eosin
Abnormal; erythrocytes made then destroyed- anaemia results
why do blood transfusions
-Needed to replace blood loss e.g. in surgery or trauma
-Needed to correct anaemia e.g. thalassaemias
-Need compatible blood for transfusion
complication of blood transfusions
- Wrong blood given to patient resulting in chest and abdomen pain, vomiting
- Iron overload- repeated transfusions without haemorrhage the iron deposits in organs
- Infection- new variant Creutzfeldt-Jakob disease, HIV
exogenous
from another person or the environment
endogenous
from another site in the patient- But it must be environmentally acquired before hospital admission
HAI
healthcare associated infection
With earlier discharges to reduce costs fewer are recognised while the patient is still in hospital,
In many hospitals it Is preventable e.g. puerperal fever (uterine tissue infection) came from physicians hands
most common HAI
-Pneumonia/ respiratory tract infection 22.8%
-UTI 17.2%
-Surgical site infection 15.7%
-Clinical sepsis 10.5%
-Gastrointestinal infections 8.8%
-Bacteraemia- bacteria in blood 7.3%
-Others: pressure sores, hepatits…
-Drug resistant examples include MRSA, VRE, MDRE
MRSA
methicillin-resistant staphylococcus aureus
Mostly resistance to common antibiotics so very difficult to treat especially when in the blood stream (bacteraemia)
‘search and destroy’- routine MRSA screening of staff and patients
Mandatory reporting of bacteraemia
Government targets to reduce MRSA bacteraemia
clostridium difficle
Gram positive anaerobic rod
Part of normal gastrointestinal flora
Antibiotics kill other gut flora so the c.difficle increases and produce toxins which cause diarrhoea and pseudomembranous colitis
High morbidity and mortality
c. difficile associated diarrhoea must be recorded.
vancomycin-resistant enterococci (VRE)
Enterococci are part of normal GI flora
Have resistance to other antimicrobials= multi drug resistance
sterilisation
is the process of killing or removing all viable microorganisms including the viruses and spores
-Heat 160-180 degrees glassware
-Autoclaves for equipment and dressing
-Irradiation for needles, gloves, vaccines
-Filtration for fluids
-Chemicals e.g. glutaraldehyde for endoscopes
disinfection
is the process of removing or killing most but not all viable organisms
- Chemical
- Boiling
- Low pressure steam
high risk patients include
-Very young and elderly
-Lack of vaccines
-Immune defects (HIV, diabetes…etc)
-Immunosuppressive drugs
-Lung, skin or urinary system disease
-Trauma
how infection can be eliminated
Environmental:
- Cleanliness= sterile equipment, dressings, IV fluid, blood products screened
- Human
Bacterially effective handwashing- alcohol based hand gels
Immunisation and health screening of staff
Bare below the elbows policy
how transmission of infection may be reduced
The health act 2006: code of practice for the prevention and control of healthcare associated infections in the uk, patients must be cared for in a clean environment
Airborne- check air conditioning, hospital operating theatre ultra clean air, isolation susceptible patients or infected person
Contact- aseptic behaviour, handwashing, alcohol based hand gels
Enhancing hosts ability to resist infection
Infection prevecardiac ntion and control teams to investigate HAI cervi
