Phase 2 - ICS Flashcards
How do you differentiate between acute and chronic inflammation
Acute - typically involves neutrophils and is sudden onset - short-lived - usually resolvesChronic - typically involves macrophages and lymphocytes; usually slow onset - longer-lived - may never resolveAcute inflammation can become chronic inflammation but some inflammation can start as chronic e.g. TB
What cells involved in inflammation?
Neutrophil polymorphsMacrophagesLymphocytesEndothelial cellsFibroblasts
Characteristics of neutrophil polymorphs
- Short lived cells - 2 or 3 days* polylobed nucleus* First on the scene of acute inflammation* Has cytoplasmic granules full of enzymes (lysosomes) that kill bacteria + are phagocytic* Usually die at the scene of inflammation* Release chemicals that attract other inflammatory cells such as macrophages
Characteristics of macrophages
- Long lived cells (months to years)* Phagocytic properties* Ingest bacteria and debris* May carry debris away* May present antigen to lymphocytes* can be found in biopsies even months after inciting incident* can have different names in different tissues e.g. Kupfer cells, alveolar macrophages, microglial cells etc.
Characteristics of lymphocytes
- Long lived cells (years)* Produce chemicals which attract in otherinflammatory cells* Immunological memory for past infectionsand antigens* plasma cells create antibodies
Role of endothelial cells in inflammation
- Line capillary blood vessels in areas of inflammation* Become sticky in areas of inflammation soinflammatory cells adhere to them* Become porous to allow inflammatory cellsto pass into tissues (pulls apart to form holes)* Grow into areas of damage to form newcapillary vessels
What causes characteristic appearance of inflammation
substances like histamine cause all capillaries in inflamed area to open and fill with blood - becomes red and swollen - much more fluid in the area than is normal
What happens in septic shock
All capillaries in body open so BP drastically falls - there is not enough blood in the body to fill every capillary at once
What is a granuloma?
particular type of chronic inflammation with collections of macrophages surrounded by lymphocytes- only significant as it may be due to myobacterial infection like TB/leprosy etc.- seen in Crohn’s and sarcoidosis- could be seen around foreign material in tissues
Sequence of acute inflammation
- injury or infection* neutrophils arrive and phagocytose and release enzymes* macrophages arrive and phagocytose* either resolution with clearance of inflammation or por- gression to chronic inflammation* examples of acute (neutrophil-mediated) inflammation -acute appendicitis, frostbite, Streptococcal sore throat
chronic inflammation
- either progression from acute inflammation or starts as‘chronic’ inflammation such as infectious mononucleosis(thus better term is macrophage/lymphocyte-mediatedinflammation)* no or very few neutrophils* macrophages and lymphocytes, then usually fibroblasts* can resolve if no tissue damage (e.g. viral infection likeglandular fever) but often ends up with repair and formation of scar tissue
role of fibroblasts in inflammation
produce collagenous tissue in scarring following some types of inflammation
how does ice reduce inflammation
it closes precapillary sphincters, closing some capillaries
what do anti-inflmmatory medicines like aspirin and ibuprofen do to reduce inflammation?
inhibit prostaglandin synthetase- prostaglandins are chemical mediators of inflammation so less prostaglandin release means less inflammation
How do corticosteroids reduce inflammation?
they bind to DNA and down regulate mediators/genes of inflammation
What is resolution and when does it occur?
It is when there is a complete recovery from inflammation/injuryOccurs when the initiating factor is removed AND the tissue is undamaged OR able to regenerate
What is repair and when does it occur?
Repair is what happens when:The initiating factor is still present OR tissue is damaged AND unable to regenerate
Which cells can regenerate?
- hepatocytes* pneumocytes* all blood cells - helpful in chemotherapy* gut epithelium* skin epithelium* osteocytes - via remodelling
which cells can’t regenerate?
- myocardial cells* neurones(reason why strokes, MI and nerve damage is so problematic)
What happens when cells can’t regenerate properly? In regards to tissue function what causes this?
Fibrous tissue forms Commonly this is because the tissue can’t regenerate (e.g. heart muscle) or the damage is happening repeatedly/over a long period of time (e.g. repeated alcohol abuse - can cause cirrhosis of liver)
What are the 2 types of skin wounds and their characteristics?
1st intention - edges of skin can be brought together to form a clean scar when healed - just a line of tough collagen in the dermis which causes typical scar tissue texture2nd intention - edges of skin can’t be brought together - tissue has to grow into the gap (granulation tissue forms) - results in lots of collagen, bigger scar
what is the alternative to fibrosis that occurs in the CNS?
Gliosis - replacement formed by glial cells not fibrous tissue - still not functioning brain tissue
Types of autopsies and their distinctions and statistics
Hospital autopsy - cause of death known but clinician wants to know more - conducted with relatives’ consent - less than 10% of autopsies performed- requires medical certificate of cause of death (mccd)Medico-legal autopsies:* Coronial autopsy - unknown cause of death but presumed to be due to natural causes - the deceased was not seen by a doctor within the last 14 days before death* Forensic autopsy - suspected or known unnatural cause of death- more than 90% of autopsies fall within the medico-legal section
how many deaths are actually autopsied?
around 40% of deaths referred to coroneronly around 10% go on to autopsy
Which deaths referred to coroner?
- presumed natural but unkown cause of death* presumed iatrogenic cause (even if it was a known risk the patient agreed to)* presumed unnatural e.e. accidents, suicide, murder, neglect, deaths in custody/anybody who dies within a prison establishment, industrial death, death related to war/industrial pensions
Who makes referrals to coroners?
- Doctors - no statutory duty to refer but encouraged by common law duty and GMC* registrar of births, deaths and marriages (BDM) - statutory duty to refer* any properly intrested party e.g. relatives, police, anatomical pathology technicians
Who performs autopsies?
Histopathologists - hospital and coronial autopsiesForensic pathologists - forensic autopsies (trained to deal with legal aspect as well)
What is the role of the coroner?
To answer 4 questions via a systematic scientific examination (the autopsy):- who was the deceased- when did they die- where did they die- how did they die (not why did they die) - to determine this last question is the main purpose of autopsy as the first three questions already usually have known answers
Name 2 key coronial legislations, their dates and key things mentioned within them
Coroners Rules - 1984* autopsy as soon as possible* by a pathologist of suitable qualification and experience (this wasn’t clarified)* report findings promptly and ONLY to coroner (it is a coroner’s report only)* autopsy must only be conducted in appropriate premisesCoroners Act - 1988* allows coroner to order autopsy where death is likely natural to obviate need (SLIDES GLITCHED OUT NEED TO COME BACK AND FIX THIS)
What 2 amendments where made to coronial legislation and when?
In 2005:- pathologist must tell coroner precisly what materials have been retained- coroner authorities retention and sets disposal date- coroner informs family of retention- family has choice on what happens:* return material to family* retain for teaching/research* respectful disposal- coroner informs pathologist of family’s decision- pathologist has to keep record- autopsy report must declare retention and disposalCoroners and justice act - 2009:- NOT fully enacted- coroners can now defer opening the inquest and instead launch an investigation- enshrines system of medical examiners- little practical change to pathologists- inquests now have conclusions NOT verdicts- autopsies only on licensed premises- by license holder- any tissue retained needs consent from family EXCEPT when subject to coronial legislation or for criminal justice reasons- public display requires consent from the deceased- PENALTY: 3 years imprisonment and/or fine
stages of autopsy?
- get history/scene- external exam- digital autopsy - if needed:* evisceration* internal exam- reconstructiondigital photography also taken at examinations and evisceration stages
What is examined in external examination (in autopsy)?
- Identification* formal identifiers* gender, age* body habitus* jewellery* body modifications* clothing- disease and treatment- injuries
What happens in evisceration during autopsy?
- y-shaped incision- open all body cavities- examin all organs in situ- remove thoracic and abdominal organs- remove brain
What is examined in internal examination during autopsy?
- heart + great vessels- lungs, trachea, bronchi- liver, gallbladder, pancreas- spleen, thymus, lymph nodes- Genitourinary tract- Endocrine organs- CNS
What prevents clots from forming within vessels?
- Laminar flow - cells travel in the centre of arterial vessels and don’t touch the sides2. Endothelial cells are not ‘sticky’ when they are healthy
What is thrombosis?
The formation of a solid mass from blood constituents on an intact vessel in a living personORsolid mass of blood constituentsformed within intact vascular systemduring life
Stages of thrombosis
(First injury)Platelet aggregationClotting/coagulation cascadeFormation of fibrin mesh
What is fibrin
It is a large protein molecule which forms a mesh which can trap red blood cells and form the final clot- platelets release chemicals when they aggregate which cause platelets to stick together and start the coagulation cascade
What kind of feedback is involved in thrombosis
Positive feedback loops
What causes thrombosis?
- Change in vessel wall- change in blood flow- change in blood constituentsVirchow’s triad! stasis, vasc injury, hypercoagulabilityusually a combination of 2 or 3 of these (e.g. endothelial cell injury from smoking causing endothelial cell injury - change in vessel wall and change in blood flow over injured/absent cells)
Common type of thrombosis and measures taken to prevent it
Deep vein thrombosisearly mobilisation after operation, low dose subcutaneous heparin
What is an embolism?
The process of a solid mass in the blood being carried through the circulation to a place where it gets stuck and blocks the vessel. - solid mass is usually a thrombus- can be caused by air bubbles too, cholesterol crystals (athreromatous plaque), tumour, amniotic fluid (rare in women with precipitate labour), fat (from severe trauma with multiple fractures??)
Where can an embolus go if it enters the venous system and why
It can travel through the vena cava, through the right side of the heart and into the lungs but will get stuck there as vessels will split into capillaries through which only single RBCs can fit. Lungs act as a filter for venous emboli
Where can an embolus in the arterial system can go?
Anywhere downstream of its entry point
What is ischaemia?
A reduction of blood flow to a tissue (without any other implications)
What is an infarcation?
The reduction in blood flow to a tissue that is so reduced that it cannot support the maintenance of cells resulting in cell death- usually a macroscopic event caused by arterial thrombosis- most organs have a single artery supplying them so are very susceptible to infarction
Which organs are less susceptible to complete infarction and why?
These organs have more than one source of arterial supply (acts as backup even if one artery blocked)Liver - supplied by portal venous and hepatic arteryLung - supplied by pulmonary venous and bronchial arteryBrain - multiple arteries connect to circle of Willis
What is atherosclerosis?
The accumulation of fibrolipid plaques in systemic arteries (in the walls)
Why is atherosclerosis an issue?
It reduces the blood flow in important areas e.g. the heart which can cause infarcts and necrosis. It would also increase the pressure of blood when it is being forced through the narrower lumen which increases risk of thrombosis and further atherosclerosis.
At what ages does atherosclerosis typically present and in what forms?
- fatty streaks in aorta can be seen in late teens/early 20s. These don’t necessarily lead to atherosclerotic plaques.- 30s/40s/50s - established atherosclerotic plaques form- 40s-80s - complication from atherosclerosis (thrombosis, intraplaque haemorrhage (plaques have blood vessels in them) etc.)
Risk factors for atherosclerosis
- hypertension- hyperlipidaemia- cigarette smoking (vaping can also contribute as it contains nicotine)- poorly controlled diabetes mellitus (typically type 1 tends to be better controlled than type 2 so type 2 diabetic are more affected typically)- deprivation (atherosclerosis is more common in the north of the UK and research has correlated it with deprivation, especially in males)(- age)
What do atherosclerotic plaques consist of?
- fibrous tissue- lipids (cholesterol) - shows up as often needle shaped clear spaces in histology sections (lipids dissolve during processing)- inflammatory lymphocytes are also found in plaques, however it is not an inflammatory condition
Explain disease process of atherosclerosis
- plaque forms under endothelium, often from thrombus formation- plaque can cause irregularity in blood flow increasing chance of endothelial damage in the area- thrombosis over plaque causes bigger plaques to form- plaques can hemorrhage causing more atherosclerosis- when the vessel is significantly occluded, it can cause angina- when the vessel is mostly/fully occluded, can cause myocardial infarction/other infarcts/necrosisPeople don’t typically get symptoms and seek help till the later stages by which point it could be too late
Where is atherosclerosis found in the human body?
In high pressure, arterial systems (aorta + systemic circulation)It is NOT found in low pressure circulation (pulmonary circulation)
What theories are there on the pathogenesis of atherosclerosis?
- Lipid insulation theory (DISCREDITED)- idea that cholesterol from the lumen got under endothelium and formed plaques- radio labeling cholesterol showed that plaque cholesterol is made by the body and doesn’t come from diet* Endothelial damage theory- endothelial cells are delicate and metabolically active- they are easily damaged by cigarette smoke, nicotine, CO, shearing forces at arterial divisions (worsened by hypertension), hyperlipidaemia, the products of glycosylation- causes endothelial ulceration, leads to thrombosis and microthrombi- platelets contain lots of cholesterol so this generates atherosclerotic plaques
Complications of atherosclerosis
- infarction due to occlusion- parts of plaques can break off causing embolism (can cause smaller infarcts downstream which could add up to cause significant damage later)- atherosclerosis in the aorta weakens the wall. This can cause the wall to rupture causing an aortic aneurysm which often leads to death(there is now screening in place for everyone over a certain age to reduce the incidence of this happening)
What is apoptosis and when does it occur?
Programmed cell death- occurs when the cell senses a certain amount of DNA damage
What is necrosis and when does it occur?
The destruction of cells (usually a large amount together) by an external factor- occurs from * infarcts, * contact with toxic venom from reptiles and insects, * frostbite, * pancreatitis (pancreas is autodigested by the enzymes it produces - the debris gets trapped retroperitoneally causing bruising)
Why is apoptosis important?
In normal cell turnover, it prevents resting cells with accumulated genetic damage from dividing. If cells with genetic damage divide they may produce cells which eventually develop into cancer cells.- it also removes older fully differentiated cells so they can be replaced by newer cellsIn development - removes unneeded cells (e.g. webbing between fingers)
What triggers apoptose? Give one mechanism.
P53 is a protein in cells which can detect DNA damage and then trigger apoptosis- high levels of P53 suggests a lot of DNA damage
What happens with apoptosis in cancer?
Cancer cells have very low rates of apoptosis and are typically longer lived than normal cells. There is mutation of the P53 gene causing increase in tumour size and an accumulation og genetic mutations.
How does a cell apoptose?
The cell triggers a series of proteins which lead to the cascade release of digestive enzymes (MANY of which are caspases) within the cell which autodigest the cell.
What happens with apoptosis in HIV?
The HIV virus can induce apoptosis, typically in CD4 helper cells (t helper cells) which reduces their number and results in an immunodeficient state (AIDS).
How does the body respond to necrosis?
The only thing the body can do is try and clear up the debris by macrophages phagocyting dead cells (or microglial cell in the brain). Necrotic tissue is usually replaced by fibrous scar tissue though fibrosis doesn’t happen in the brain.
What is a congenital defect?
A defect present at birth
What can cause congenital defects?
Issues with apoptosis and/or cell migrationCan be caused by inherited genetic abnormalities or an acquired (non-genetic, caused by environmental factors) abnormality, genetic or physical
What controls cell migration during development?
Homeobox genes - code for particular regions and control migration. Issue with this can be caused by genetic abnormalities or environmental problems (e.g. if the environment prevents the right chemicals from diffusing at the right time)
Examples of congenital abnormalities caused by migration issues during fetal development
Spina bifida - three main types:- spina bifida occulta - small gap in spine but no opening on back so often not noticed till late childhood or adulthood- meningocele - meninges protrude out as a sac through an opening in the back - could cause nerve damage- myelomeningocele - meninges AND spinal cord protrude out as a sac through an opening in the back - likely nerve damageCleft palateVentricular septal defect - can cause heart murmur (fairly common in babies) - most cases of this close up within 1st year of life
Types of genetic abnormalities, examples and complications where known
Chromosomal abnormalities - mostly not viable with life- main viable one is Down’s syndrome (trisomy 21)- people with Down’s tend to get cataracts and dementia earlier - lens and beta amyloid genes are found on chromosome 21Mendilian inheritance - abnormality caused by a sngle geneAutosomal inheritance - e.g. Familial adenomatous polyposis (FAP) - characterized by cancer of the large intestine (colon ) and rectum- recessive e.g. - cystic fibrosisPolygenic inheritance - more common (difficult to identifiy exactly what is causing what result)- can be late presenting e.g. Huntington’s (caused by accumulation of Huntingtin protein)
Examples of acquired congenital abnormalities
- Growth hormone irregularities (gigantism if increase occurs in childhood, acromegaly if increase occurs after puberty - a decrease causes dwarfism)- Achondrplasia - causes abnormality of fibroblast growth factor receptor protein - slows bone growth in growth plate - leads to dwarfism
Define hypertrophy
The increase in size of a tissue caused by an increase in the SIZE of constituent cells
Define hyperplasia
Increase in size of a tissue caused by an increase in the NUMBER of constituent cells
Example of hypertrophy
Increasing the size of skeletal muscle- skeletal muscle can’t divide but each muscle fibre can increase in size - caused by either an increase in sarcoplasm (sarcoplasmic hypertrophied muscle) or an increase in myofibrils as well as sarcoplasm (myofibril hypertrophied muscle). Muscle with increased myofibrils is stronger than sarcoplasmic hypertrophied muscle
What can cause hypertrophy?
- mutation in myostatin gene (e.g. certain cattle)- training (e.g. body builder)
