ICS Flashcards
what two categories do most autopsies fall under in most countries?
those performed under instruction of a legal authority
those performed with permission from deceased’s relatives to gather info on the nature and extent of the deceased’s disease
why are medico-legal autopsies performed?
to determine the cause of death and to collect evidence to use in prosecution of those responsible for the death
when are clinical autopsies performed?
on patients who die in hospital
why are clinical autopsies performed?
certified cause of death given by clinicians with primary responsibility for the patient shows a 30% discrepancy with cause found at autopsy
how can clinical autopsy be useful?
more accurate data about cause of death: clinical audit, education of clinicians and national allocation of health resources, determining extent of disease and response to treatment
what is an advantage of clinical autopsy?
simple and cost-effective compared to modern methods of in-vivo imaging
what is happening to the rate of hospital autopsies?
declining
what is the prevalence of types of autopsy in the UK?
hospital - less than 10%
medico-legal - more than 90%
when are deaths ‘presumed natural’?
cause of death not known
not seen by doctor in last illness (within 14 days)
when are deaths ‘presumed iatrogenic’?
peri/postoperative deaths
anaesthetic deaths
abortion
complications of therapy
when are deaths ‘presumed unnatural’?
accidents industrial death suicide unlawful killing neglect custody deaths war/industrial pensions
doctors and referrals for autopsy
have no statutory duty to refer
common law duty
GMC guidance
registrar of BDM and referrals for autopsy
have a statutory duty to refer
where do referrals for autopsy come from, other than doctors and registrars of BDM?
relatives
police
anatomical pathology technicians
other properly interested parties
what types of pathologists perform autopsies?
histopathologists and forensic pathologists
what types of autopsies do histopathologists perform?
hospital and coronial autopsies
when do histopathologists perform coronial autopsies?
natural deaths drowning suicide accidents road traffic deaths fire deaths industrial deaths peri/postoperative deaths
what types of autopsies do forensic pathologists perform?
coronial autopsies
when do forensic pathologists perform coronial autopsies?
homicide
death in custody
neglect
these if they may be due to action of a third party: drowning, suicide, accidents, road traffic deaths, fire deaths, industrial deaths, peri/postoperative deaths
what is the role of the coronial autopsy?
to answer:
who was the deceased?
when did they die?
where did they die?
how did they come about their death?
what year was the coroner’s act established?
1988
what is S19 of the Coroners Act (1988)?
allows coroner to order an autopsy where death is likely due to natural causes to obviate need for inquest. no power to authorise special investigations
what is S20 of the Coroners Act (1988)?
allows coroner to order an autopsy where death is clearly unnatural and inquest will be needed. can authorise special investigations
when were the Coroners Rules established?
1984
what is R5 of the Coroners Rules (1984)?
autopsy as soon as possible
what is R6 of the Coroners Rules (1984)?
by a pathologist of suitable qualification and experience
what is R10 of the Coroners Rules (1984)?
report findings promptly and only to coroner
what is R11 of the Coroners Rules (1984)?
autopsy only on appropriate premesis
when were the Amendment Rules established?
2005
what are the Amendment Rules (2005)?
pathologist must tell coroner what materials have been retained
coroner authorises retention and sets disposal date
coroner informs family of retention
family has choices
coroner informs pathologist of family’s decision
pathologist keeps record
autopsy report must declare retention and disposal
what choices do family have in the Amendment Rules (2005)?
return material to family
retain for research/teaching
respectful disposal
when was the Coroners and Justice Act established?
2009
what changes are in the Coroners and Justice Act (2009)?
affects S19/20 - coroner can defer opening the inquest and launch investigation instead
enshrines a system of medical examiners
little practical change to the pathologist
inquests have conclusions, not verdicts
when was the Human Tissue Act established?
2004
what does the Human Tissue Act (2004) require?
S16(2): autopsies only to be performed on licensed premises
license holder
consent from relatives for any use of tissue if not subject to coronial legislation or retained for criminal justice purposes
public display requires consent from deceased
what are the penalties of the Human Tissue Act (2004)?
3 years imprisonment and/or a fine
what are the stages of the autopsy?
history/scene external examination evisceration internal examination reconstruction
what is involved in external examination?
identification
disease and treatment
injuries
how is someone identified in an external examination in autopsy?
formal identifiers gender, age body habitus jewellery body modification clothing
what are the steps involved in evisceration?
Y shaped incision open all body cavities examine all organs in situ remove thoracic and abdominal organs remove brain
what is studied in internal examination in autopsy?
heart and great vessels lungs, trachea, bronchi liver, gallbladder, pancreas spleen, thymus, lymph nodes genitourinary tract endocrine organs central nervous system
what is inflammation?
local physiological response to tissue injury - usually a manifestation of disease
how can inflammation be classified?
time course (acute and chronic) and differences in cell types
what is acute inflammation?
initial tissue reaction to a wide range of injurious agents. often transient, it is similar whatever the causative agent
how long can acute inflammation last?
few hours to few days
what are the principal causes of acute inflammation?
- microbial infections (pyogenic bacteria, viruses)
- hypersensitivity reactions (parasites, tubercle bacilli)
- physical agents (trauma, ionising radiation, heat, cold)
- chemicals (corrosives, acids, alkalis, reducing agents)
- tissue necrosis
- bacterial toxins (ischaemic infarction)
how do microbial infections cause acute inflammation?
- viruses kill individual cells by intracellular multiplication
- bacteria release specific exotoxins and endotoxins
- hypersensitivity reactions e.g. parasitic infections and TB
when do hypersensitivity reactions occur?
- when an altered state of immunological responsiveness causes an inappropriate or excessive immune reaction that damages the tissues
- cellular/chemical mediators similar to inflammation
how do physical agents cause acute inflammation?
physical trauma, UV or other ionising radiation, burns or excessive cooling
what are the essential macroscopic appearances of acute inflammation?
- redness (rubor)
- heat (calor)
- swelling (tumor)
- pain (dolor)
- loss of function
what is rubor?
- redness
- due to dilation of small blood vessels within the damaged area
what is calor?
- heat
- due to hyperaemia, leading to vascular dilation and delivery of warm blood to the area and systemic fever (due to the chemical mediators of inflammation)
- only seen in peripheral parts of the body
what is tumor?
- swelling
- due to oedema and the physical mass of inflammatory cells migrating to the area and formation of new connective tissue
what is oedema?
accumulation of fluid in the extravascular space as part of the fluid exudate
what is dolor?
- pain
- due to stretching/distortion of tissues due to oedema and pus under pressure in an abscess cavity, and chemical mediators of acute inflammation
what chemical mediators of acute inflammation contribute to pain?
bradykinin, prostaglandins and serotonin
what is loss of function?
movement of an inflamed area is consciously and reflexly inhibited by pain
severe swelling may physically immobilise tissues
who added loss of function to the Celcus list?
Virchow (1821-1902)
what happens in the early stages of acute inflammation?
oedema fluid, fibrin and neutrophil polymorphs accumulate in the extracellular spaces of the damaged tissue
how is acute inflammation histologically diagnosed?
presence of the neutrophil polymorph
what three processes occur in the acute inflammatory response?
- changes in vessel calibre and flow
- increased vascular permeability and formation of fluid exudate
- formation of cellular exudate - emigration of neutrophil polymorphs into extravascular space
what feature of normal blood flow keeps blood cells away from the vessel wall?
in blood vessels larger than capillaries, blood cells flow in the centre of the lumen (axial flow) and the area near the vessel wall carries only plasma
what lines small blood vessels?
single layer of endothelial cells - may be uniform or have thinning areas (fenestrations)
how does ultrafiltration occur under normal conditions?
oxygen, CO2 and nutrients transfer across the wall by diffusion
high colloid osmotic pressure inside the vessel due to plasma proteins favours fluid return to vascular compartment
high hydrostatic pressure at the arteriolar end forces fluid into the extravascular space, which returns into the capillaries at the venous end due to low hydrostatic pressure
what happens to ultrafiltration in acute inflammation?
increased capillary hydrostatic pressure and escape of plasma proteins into the extravascular space leads to more fluid leaving the vessels than is returned to them
why does the blood flow through all of the capillaries in acute inflammation?
opening of precapillary sphincters
what is exudation?
the net escape of protein-rich fluid
what is the fluid exudate?
protein rich fluid that escapes from vessels in acute inflammation
what are features of the fluid exudate?
high protein content (up to 50g/L)
immunoglobulins, coagulation factors
what are immunoglobulins responsible for in fluid exudate?
destruction of invading microorganisms
what are coagulation factors responsible for in fluid exudate?
fibrinogen causes fibrin deposition on contact with extravascular tissues
acutely inflamed organ surfaces are completely covered with fibrin
what is the turnover of the fluid exudate?
large turnover - constantly drained away by local lymphatic channels to be replaced by new exudate
what are causes of immediate transient increased vascular permeability?
chemical mediators, e.g. histamine, bradykinin, nitric oxide, C5a, leucotriene B4, platelet activating factor
what are causes of immediate sustained increased vascular permeability?
severe direct vascular injury, e.g. trauma
what are causes of delayed prolonged increased vascular permeability?
endothelial cell injury, e.g. x rays, bacterial toxins
give examples of tissue sensitivity to chemical mediators
CNS vessels are insensitive to chemical mediators, but vessels in the skin, conjunctiva and bronchial mucosa are sensitive to them, e.g. histamine
what are the steps in neutrophil polymorph emigration?
- margination
- pavementing
- pass between endothelial cells
- pass through basal lamina and migrate into the adventitia
what is margination of neutrophils?
caused by loss of intravascular fluid and increase in plasma viscosity with slowing down of flow at the site of acute inflammation
neutrophils flow in plasmatic zone
what is pavementing of neutrophils?
adhesion of neutrophils to the vascular endothelium, occurring at sites of acute inflammation
where does pavementing occur?
only seen in venules
how does pavementing occur?
interaction between paired adhesion molecules on leukocyte and endothelial surfaces
how do neutrophils migrate through the vessel walls?
active amoeboid movement through the walls of venules and small veins
pseudopodia are inserted between endothelial cells, through the basal lamina and into the adventitia
why are endothelial cells not damaged by pseudopodia insertion?
the defect is self-sealing
what is diapedesis?
red cells escaping from vessels - this is passive and depends on hydrostatic pressure
what does large presence of red cells in the extravascular space imply?
severe vascular injury e.g. tear in vessel wall
what is chemotaxis?
neutrophil polymorphs being attracted towards certain chemical substances in solution
what compounds may be chemotactic for neutrophils?
complement components, cytokines and products produced by neutrophils
what causes up-regulation of adhesion molecules on the surface of endothelial cells?
histamine and thrombin released by the original inflammatory stimulus
what do endogenous chemical mediators cause?
vasodilation emigration of neutrophils chemotaxis increased vascular permeability itching and pain
what is the best-known chemical mediator in acute inflammation?
histamine
what does histamine cause?
vascular dilation
immediate transient phase of increased vascular permeability
how and where is histamine stored?
preformed granules
mast cells, and also basophils and eosinophils
what stimulates histamine release?
complement components C3a and C5a
lysosomal proteins released from neutrophils
what are other chemical mediators of acute inflammation, apart from histamine?
- lysosomal compounds
- eicosanoids
- 5-hydroxytryptamine (serotonin)
- chemokines
what are the 4 enzymatic cascade systems contained in the plasma?
- complement
- kinins
- coagulation factors
- fibrinolytic system
what are 4 features of the enzymatic cascade systems contained in the plasma?
- safer to have inactive precursors than active mediators
- each step results in amplification of the response
- larger number of regulators can modulate the response
- each step results in end products with different activities
what activates the kinin, fibrinolytic and coagulation systems?
coagulation factor XII (Hageman factor)
what does the coagulation system produce? what happens to it?
fibrin, which is degraded by plasmin into fibrin split products
what does the kinin and fibrinolytic system produce? what happens to them?
- kinin system produces kinins
- fibrinolytic system produces plasmin - both activate the complement system, which produces activated complement
what activates the complement system?
kinins and plasmin produced by the kinin and fibrinolytic system
what occurs in the kinin system?
- activated factor XII and plasmin activate the conversion of prekallikrein to kallikrein
- kallikrein stimulates the conversion of kininogens to kinins
what can activate prekallikrein?
- activated factor XII
- plasmin
- leukocyte proteases e.g. trypsin
how can the complement system be activated in acute inflammation?
enzymes that activate complement are released during tissue necrosis
classical and alternative pathways
what activates complement in the classical pathway?
formation of antigen-antibody complexes
what activates complement in the alternative pathway?
endotoxins of Gram-negative bacteria
what are the chemical mediators of vascular dilation?
histamine prostaglandins PGE2/I2 VIP nitric oxide PAF
what are the chemical mediators of increased vascular permeability?
transient phase - histamine
prolonged phase - bradykinin, nitric oxide, C5a, leukotriene B4 and PAF, prostaglandins
what are the chemical mediators of adhesion of leukocytes to endothelium?
IL-8, C5a, leukotriene B4, PAF, IL-1 and TNF-alpha up-regulate adhesion molecules on endothelium
what are the chemical mediators of neutrophil polymorph chemotaxis?
leukotriene B4, IL8, others
what chemical mediators do tissue macrophages secrete when stimulated by local infection or injury?
IL-1, TNF-alpha, E-selectin, IL-8 and neutrophil attractant 78
what is the role of the lymphatics in acute inflammation?
lymphatic channels become dilated as they drain away the oedema fluid of the inflammatory exudate
limits extent of oedema
carry large molecules and some particulate matter
what are terminal lymphatics?
blind-ended, endothelium lined tubes present in most tissues in similar numbers to capillaries
where do terminal lymphatics drain into? what is the pathway of lymph?
collecting lymphatics
terminal lymphatics -> collecting lymphatics -> lymph nodes
what is a feature of the lymphatic endothelium that is important in inflammation?
basal lamina is incomplete and junctions between cells are simpler and less robust than capillary endothelial cells
gaps open up passively and allow large protein molecules to enter
where are antigens carried to?
carried to regional lymph nodes for recognition by lymphocytes
what brings about amoeboid movement?
contraction of cytoplasmic microtubules and gel/sol changes in cytoplasmic fluidity
what is amoeboid movement dependent on?
- active mechanisms depend on calcium ions and are controlled by intracellular concentrations of cyclic nucleotides
what is chemotaxis?
directional movement of an organism in response to a chemical stimulus
what activates the complement alternative pathway? what does this produce?
- bacterial lipopolysaccharides
generates component C3b (opsonising properties)
what activates the classical complement pathway? what does this produce?
- antibodies binding to bacterial antigens
- component C3b
what is the role of neutrophil polymorphs in adhesion to microorganisms?
binding of immunoglobulins to microorganisms by their Fab component leaves the Fc component exposed
neutrophils bind to the Fc fragment of the immunoglobulins via their surface receptors
what is phagocytosis?
process of a cell using its plasma membrane to engulf a large solid particle to produce a phagosome
briefly describe phagocytosis
- adhesion of particle to the cell surface by opsonisation
- the phagocyte ingests the attached particle by sending pseudopodia around it
- pseudopodia meet and fuse, so particle is in a phagocytotic vacuole (phagosome)
- lysosomes fuse with phagosomes to form phagolysosomes
- intracellular killing of microorganisms occurs
how may the microbicidal agents in neutrophil polymorphs be classed?
- those that are oxygen-dependent
- those that are oxygen-independent
what are oxygen-dependent mechanisms in neutrophil polymorphs?
- neutrophils produce hydrogen peroxide, which reacts with myeloperoxidase in cytoplasmic granules in presence of a halide, e.g. Cl- to produce a potent microbicidal agent
- peroxide anions (O2-)
- hydroxyl radicals (OH)
- singlet oxygen (1O2)
what are oxygen-independent mechanisms in neutrophil polymorphs?
- lysozyme (muramidase)
- lactoferrin
- cationic proteins
- low pH in phagosomes
what does lactoferrin do in neutrophil polymorphs?
chelates iron required for bacterial growth
what does the release of lysosomal products do?
- damages local tissues by proteolysis by elastase, collagenase etc.
- activates coagulation factor XII
- attracts other leukocytes into area
what are pyrogens?
compunds that produce systemic fever by acting on the hypothalamus
what is the role of mast cells in acute inflammation?
- on stimulation by the C3a/C5a complement components, they release preformed inflammatory mediators stored in their granules
- metabolise arachidonic acid into newly synthesised inflammatory mediators e.g. leukotrienes, prostaglandins, thromboxanes
what are beneficial effects of the fluid exudate?
- dilation of toxins
- entry of antibodies
- transport of drugs
- fibrin formation
- delivery of nutrients and oxygen
- stimulation of immune response
why is fibrin formation in acute inflammation beneficial?
- may impede the movement of microorganisms, trapping them and facilitating phagocytosis
- matrix for the formation of granulation tissue
what is the lifespan of neutrophils? where may they die?
- 1-3 days, constantly replaced
- most die locally
- some leave site via lymphatics
- some are actively removed by apoptosis
what do monocytes transform into?
- upon leaving the blood vessel, they transform into macrophages
- become more metabolically active, motile, phagocytic
what is the proportion of neutrophils to macrophages during acute inflammtion?
- macrophages appear within a few hours of inflammation
- macrophages don’t predominate until later stages where neutrophils have diminished and macrophages have proliferated
what is the role of macrophages in acute inflammation?
clear away tissue debris and damaged cells
how do neutrophils and macrophages release their content?
- discharge lysosomal enzymes into ECF
- by exocytosis or entire cell contents are released when cells die
what are the harmful effects of the fluid exudate released in acute inflammation?
- digestion of normal tissues
- swelling
- inappropriate inflammatory response
what is an example of harmful swelling due to fluid exudate in children?
swelling of the epiglottis in acute epiglottitis due to haemophilus influenzae infection may obstruct the airway
what is an example of harmful swelling due to fluid exudate in an enclosed space?
- cranial cavity
- acute meningitis or a cerebral abcess may raise intracranial pressure
- raised pressure may impair blood flow into the brain
- leads to ischaemic damage or force the cerebral hemispheres against tentorial orifice and the cerebellum into the foramen magnum
what are the possible outcomes of acute inflammation?
- resolution
- suppuration
- repair and organisation
- chronic inflammation
what is resolution in relation to acute inflammation?
- complete restoration of the tissues to normal after an episode of acute inflammation
- usual outcome
what are conditions that favour resolution of acute inflammation?
- minimal cell death and tissue damage
- occurrence in an organ or tissue with regenerative capacity vs one that can’t
- rapid destruction of the causal agent
- rapid removal of fluid and debris by good local vascular drainage
what is an example of an acute inflammatory condition that usually resolves completely?
acute lobar pneumonia
what is the sequence of events leading to resolution?
- phagocytosis of bacteria by neutrophils and intracellular killing
- fibrinolysis
- phagocytosis of debris and carriage through lymphatics to lymph nodes
- disappearance of vascular dilation
what is suppuration? what causes it?
- formation of pus, a mixture of living, dying and dead neutrophils and bacteria, cellular debris and sometimes globules of lipid
- excessive exudate
what is usually the causative stimulus for suppuration?
- must be persistent
- infective agent, usually pyogenic bacteria
what are examples of pyogenic bacteria?
- staphylococcus aureus
- streptococcus pyogenes
- neisseria species
- coliform organisms
what can suppuration lead to?
- discharge of pus
- repair and organisation
what is an abscess?
- pus accumulates in a tissue
- surrounded by pyogenic membrane, consisting of sprouting capillaries, neutrophils and fibroblasts
how do abscesses die/get removed?
- often burst; abscess cavity collapses and is obliterated by organisation and fibrosis, leaving a small scar
- surgical incision and drainage
how is an empyema formed?
- pus accumulates inside a hollow viscus
- mucosal layers of outflow tract of the viscus may be fused together by fibrin
what is a sinus tract?
an abnormal connection lined by granulation tissue, between an abscess and the skin/mucosal surface
what is a fistula?
- formed when deep-seated abscesses discharge pus along a sinus tract
- it is an abnormal passage connecting two mucosal surfaces or one mucosal surfaces to the skin surface
what often causes sinuses?
foreign body materials (indigestible by macrophages)
what is the treatment of fistulas?
surgical elimination of foreign body material
how may fibrous walls of long-standing abscesses become complicated?
dystrophic calcification
what can cause organisation and repair in acute inflammation?
- excessive necrosis
- suppuration
what is an outcome of organisation and repair in acute inflammation?
fibrosis
what is organisation in acute inflammation?
organisation of tissues is their replacement by granulation tissue as part of the repair process
what are the circumstances favouring organisation and repair?
- large amounts of fibrin formed (which can’t be removed completely by fibrinolytic enzymes from plasma or neutrophil polymorphs)
- large amount of tissue becomes necrotic or dead tissue isn’t easily digested
- exudate and debris can’t be removed or discharged
what happens in organisation in acute inflammation?
- new capillaries grow into the inert material (inflammatory exudate)
- macrophages migrate into zone, fibroblasts proliferate, leading to fibrosis and possibly scar formation
what causes fibroblasts to proliferate?
TGF-beta
what is an example of organisation and repair in acute inflammation?
in pleural space following acute lobar pneumonia
what causes progression from acute to chronic inflammation?
persistent causal agent
what are some systemic effects of inflammation?
- pyrexia
- constitutional symptoms
- weight loss
- reactive hyperplasia of the reticuloendothelial system
- haemotological changes
- amyloidosis
what is pyrexia?
- polymorphs and macrophages produce endogenous pyrogens
- pyrogens act on the hypothalamus to set thermoregulatory mechanisms at a higher temp
what endogenous pyrogen has the greatest effect?
interleukin-2
what stimulates the release of endogenous pyrogen?
- phagocytosis
- endotoxins
- immune complexes
what are constitutional symptoms?
- malaise
- anorexia
- nausea
why does weight loss occur due to inflammation?
- negative nitrogen balance
what are examples of haemotological changes due to inflammation?
- increased erythrocyte sedimentation rate
- leukocytosis
- anaemia
what is increased erythrocyte sedimentation rate? why does it occur?
- non-specific finding in many types of inflammation
- due to alterations in plasma proteins leading to increased rouleaux formation of red cells
when does neutrophilia occur?
pyrogenic infections and tissue destruction
when does eosinophilia occur?
allergic disorders and parasitic infection
when does lymphocytosis occur?
chronic infection, viral infections, whooping cough
when does monocytosis occur?
infectious mononucleosis and certain bacterial infections, e.g. TB and typhoid
why may anaemia occur in inflammation?
- blood loss in the inflammatory exudate
- haemolysis
- anaemia of chronic disorders due to toxic depression of bone marrow
how may secondary amyloidosis occur?
long-standing chronic inflammation may cause amyloid to be deposited in tissues by elevating serum amyloid A protein
what is chronic inflammation?
- inflammation extended over a long period of time
- type of cellular reaction differs from acute inflammation
- lymphocytes, plasma cells and macrophages predominate
- granulation and scar tissue are formed
- usually primary
what cells predominate in chronic inflammation?
lymphocytes, plasma cells and macrophages
what are causes of chronic inflammation?
- primary chronic inflammation
- transplant rejection
- progression from acute inflammation
- recurrent episodes of acute inflammation
what is the most common type of acute inflammation to progress to chronic inflammation?
suppurative type
what are examples of chronic abscesses?
- osteomyelitis (abscess in the bone marrow cavity)
- empyema thoracis that has been inadequately drained
what causes a chronic abscess?
- pus forms abscess cavity that’s deep seated or drainage is delayed/inadequate
- abscess develops thick walls of granulation and fibrous tissues over time
- rigid walls fail to come together after drainage
- stagnating pus becomes organised by ingrowth of granulation tissue, then replaced by fibrous scar
what are examples of indigestible material?
- keratin from ruptured epidermal cyst
- fragments of necrotic bone in the sequestrum of chronic osteomyelitis
what are the most indigestible forms of material? give examples
- inert foreign body materials
- surgical suture, wood, metal, glass, prostheses
what type of chronic inflammation do foreign bodies provoke?
- granulomatous inflammation
- cause macrophages to form multinucleate giant cells
what is an example of recurrent episodes of acute inflammation becoming chronic inflammation? what happens in this?
- chronic cholecystitis, due to gallstones usually
- replacement of gallbladder wall muscle by fibrous tissue
- predominant cell type becomes the lymphocyte instead of the neutrophil polymorph
what are specific causes of chronic inflammation?
- resistance of infective agent to phagocytosis and intracellular killing
- endogenous materials
- exogenous materials
- some autoimmune diseases
- specific diseases of unknown aetiology
- primary granulamatous diseases
what are examples of resistance of infective agent to phagocytosis and intracellular killing causing inflammation?
TB, leprosy, brucellosis, viral infections
what are examples of endogenous materials causing inflammation?
necrotic adipose tissue, bone, uric acid crystals
what are examples of exogenous materials causing inflammation?
silica, asbestos fibres, suture materials, implanted prostheses
what are examples of some autoimmune diseases causing inflammation?
organ-specific disease, non-organ-specific autoimmune disease, contact hypersensitivity reactions
what are examples of organ-specific diseases causing inflammation?
Hashimoto’s thyroiditis, chronic gastritis of pernicious anaemia
what are examples of non-organ-specific diseases causing inflammation?
rheumatoid arthritis
what are examples of contact hypersensitivity reactions causing inflammation?
self-antigens altered by nickel
what are examples of specific diseases of unknown aetiology causing inflammation?
chronic inflammatory bowel disease, e.g. UC
what are examples of primary granulomatous diseases causing inflammation?
Crohn’s disease, sarcoidosis
what are macroscopic appearances of chronic inflammation?
- chronic ulcer
- chronic absess cavity
- thickening of the wall of a hollow viscus
- granulomatous inflammation
- fibrosis
what are microscopic features of chronic inflammation?
- cellular infiltrate consists of lymphocytes, plasma cells and macrophages
- some eosinophil polymorphs, neutrophil polymorphs are scarce
- production of new fibrous tissue from granulation tissue
- continuing destruction of tissue at same as regeneration
- tissue necrosis
what does tissue healing involve?
regeneration and migration of specialised cells
what are features of repair?
- angiogenesis
- fibroblast proliferation
- collagen synthesis -> granulation tissue
what regulates healing and repair? what do they do?
- low molecular weight proteins called growth factors
- bind to receptors on cell membranes, triggering series of events to lead to cell proliferation
what is the function of EGF?
- epidermal growth factor
- regeneration of epithelial cells
what is the function of TGF-alpha?
- transforming growth factor alpha
- regeneration of epithelial cells
what is the function of TGF-beta?
- transforming growth factor beta
- stimulates fibroblast proliferation and collagen synthesis
- controls epithelial regeneration
what is the function of PDGF?
- platelet derived growth factor
- mitogenic and chemotactic for fibroblasts and smooth muscle cells
what is the function of FGF?
- fibroblast growth factor
- stimulates fibroblast proliferation, angiogenesis and epithelial cell regeneration
what is the function of IGF-1?
- insulin-like growth factor-1
- synergistic effect with other growth factors
what is the function of TNF?
- tumour necrosis factor
- stimulates angiogenesis
what does the lymphocytic tissue infiltrate contain?
B and T lymphocytes
how do macrophages move through tissue?
amoeboid motion
what is a difference between macrophages and neutrophil polymorphs?
- macrophages are longer lived
- macrophages can ingest a wider range of materials
- macrophages can harbour viable organisms if they can’t kill them by lysosomal enzymes
what are examples of organisms that can survive inside macrophages?
- mycobacteria (Mycobacterium tuberculosis, M. leprae)
- Histoplasma capsulatum
where are macrophages derived from?
blood monocytes that have migrated out of vessels
what system are macrophages part of?
mononuclear phagocyte system/reticuloendothelial system
what is involved in the activation of macrophages?
- increased size
- protein synthesis
- mobility
- phagocytic activity
- increased content of lysosomal enzymes
what cytokines do macrophages produce?
- interferon alpha and beta
- interleukin-1
- interleukin-6
- interleukin-8
- TNF-alpha
what is a granuloma?
aggregate of epithelioid histiocytes
- may contain other cell types, e.g. lymphocytes and histiocytic giant cells
what are examples of granulomatous diseases?
TB and leprosy
what is the appearance and arrangement of epithelioid histiocytes?
- large vesicular nuclei
- plentiful eosinophilic cytoplasm
- elongated
- arranged in clusters
what is the function of epithelioid histiocytes?
- full purpose not known
- produce ACE
- measurement of ACE in blood can act as a marker for systemic granulomatous disease, e.g. sarcoidosis
how can the appearance of granulomas be augmented?
- caseous necrosis (e.g. TB)
- conversion of some histiocytes into multinucleate giant cells
what does the association of granulomas with eosinophils indicate?
parasitic infection, e.g. worms
what are effector T lymphocytes derived from?
- non-sensitised T lymphocytes by transfer factor
- T lymphocytes
what do effector T lymphocytes produce?
- lymphotoxins
- inflammatory mediators to produce increased vascular permeability
- migration inhibition factors to affect macrophages
what are memory cells derived from?
- effector T lymphocytes
- transformed B lymphocytes
what are transformed B lymphocytes derived from?
- B lymphocytes
what are antibodies derived from?
- transformed B lymphocytes
what are monocytes derived from? where?
haemopoietic stem cell -> promonocyte -> monocyte
what can monocytes differentiate into when they enter tissues?
- connective tissue histiocyte
- alveolar macrophages
- peritoneal macrophage
- Kupffer cell of liver
- melanophage of skin
- lipophage
- osteoclast in bone
- microglial cell in brain
- specialised histiocytes, e.g. epitheliod cell
- histiocytic giant cell
where/when do histiocytic giant cells tend to form?
- where particulate matter that’s indigestible accumulates
- foreign materials are too large to be ingested by just one macrophage
how many nuclei do histiocytic giant cells contain?
over 100
how do histiocytic giant cells form?
‘by accident’ when 2 or more macrophages attempt to engulf the same particle simultaneously - cell membranes fuse and cells unite
what is the activity of histiocytic giant cells like?
- little phagocytic activity
- no known function
how are Langhans giant cells arranged? where are they seen?
- horseshoe arrangement of peripheral nuclei at one pole of the cell
- seen in TB and other granulomatous conditions
what are foreign body giant cells? when are they seen?
- large cells with nuclei randomly scattered throughout cytoplasm
- particulate foreign body material
- often seen in granulomas
- don’t have a defining feature
what are causes of granulomatous disease?
- specific infections
- materials that resist digestion
- specific chemicals
- drugs
- unknown
what are examples of specific infections that cause granulomatous disease?
- mycobacteria
- fungi
- parasites, larvae, eggs, worms
- syphilis
what are examples of materials resisting digestion that cause granulomatous disease?
- endogenous (keratin, necrotic bone, cholesterol crystals, sodium urate)
- exogenous (talc, silica, suture materials, oils, silicone)
what are examples of specific chemicals that cause granulomatous disease?
beryllium
what are examples of drugs that cause granulomatous disease?
- hepatic granulomas due to allopurinol
- phenylbutazone
- suphonamides
what are examples of unknown factors causing granulomatous disease?
- Crohn’s disease
- sarcoidosis
- Wegener’s granulomatosis
exudate vs transudate
- exudate has a high protein content due to increased vascular permeability
- transudate has a low protein content due to vessels having normal permeability
acute vs chronic inflammation
- acute inflammation has a rapid onset and usually resolution, and neutrophil polymorphs are the most abundant cells
- chronic inflammation has an insidious onset, prolonged course and slow resolution, and lymphocytes, plasma cells and macrophages are the most abundant cells
granuloma vs granulation tissue
- a granuloma is an aggregate of epithelioid histiocytes
- granulation tissue is an important component of healing. comprises small blood vessels in a connective tissue matrix with myofibroblasts
fibrin vs fibrous
- fibrin is deposited in blood vessels and tissues or on surfaces due to action of thrombin on fibrinogen
- fibrous describes the texture of a non-mineralised tissue where the principal component is collagen
how do irritants and corrosive chemicals cause inflammation?
- corrosive chemicals (acids, alkalis, oxidising agents) provoke inflammation through gross tissue damage
- infecting agents may release specific chemical irritants leading directly to inflammation
how does tissue necrosis cause inflammation?
- death of tissues from lack of oxygen or nutrients due to inadequate blood flow (infarction)
- edge of recent infarcts often show acute inflammatory response, due to peptides released from dead tissue
what are time course mechanisms as causes of increased vascular permeability?
- immediate transient chemical mediators
- immediate sustained severe direct vascular injury
- delayed prolonged endothelial cell injury
what are immediate transient chemical mediators as causes of increased vascular permeability?
- histamine
- bradykinin
- nitric oxide
- C5a
- leucotriene B4
- platelet activating factor
what are causes of delayed endothelial cell injury?
- xrays
- bacterial toxins
how does the acute inflammatory response spread following injury to a small area of tissue?
chemical substances being released from injured tissues, spreading outwards towards uninjured areas
what chemical mediators of acute inflammation are released early in the response? what do they cause?
- histamine and thrombin
- up-regulation of adhesion molecules on surface of endothelial cells
- very firm neutrophil adhesion to the endothelial surface
what is the role of the neutrophil polymorph?
phagocytoses bacteria
what are terms used to describe macroscopic appearances of acute inflammation?
- serous
- suppurative (purulent) inflammation
- membranous inflammation
- pseudomembranous inflammation
- necrotising (gangrenous) inflammation
what is the function of B lymphocytes?
on contact with an antigen, they become progressively transformed into plasma cells (produce antibodies)
what is the function of T lymphocytes?
- cell mediated immunity
- on contact with an antigen, they produce a range of soluble factors called cytokines, which recruit and activate other cell types
what are Touton giant cells? when are they seen?
- central ring of nuclei, peripheral to which there is lipid material
- seen when macrophages attempt to ingest lipids
- seen in xanthomas/dermatofibromas of the skin
what is the role of acute inflammation in the CVS?
- response to acute myocardial infarction
- generation of some complications of MI e.g. cardiac rupture
what is the role of chronic inflammation in carcinogenesis?
- initiation and propogation of cancer
how is chronic inflammation involved in MIs?
- myocardial fibrosis
how does inflammation contribute to development of atheromas?
- macrophages adhere to endothelium
- migrate into arterial intima and with T lymphocytes, express cell adhesion molecules which recruit other cells into the area
- macrophages process lipids that accumulate in atheromatous plaques
how does inflammation feature in the tissue injury associated with neurodegenerative disorders of the CNS?
- chronic inflammation is involved in MS
- perivascular cuffing by plasma cells and T lymphocytes is seen in zones of white matter, where macrophages break down myelin
what factors does cell survival depend on?
- constant supply of energy
- intact plasma membrane
- biologically safe and effective function of cellular activities
- genomic integrity
- controlled cell division
- internal homeostatic mechanisms
at what rate do cells replicate in the human body?
c. 10000 new cells per second
what are types of mechanisms of cellular injury?
- energy failure
- failure of membrane functional integrity
- membrane damage
- blockage of metabolic pathways
- mechanical disruption
- DNA damage or loss
what can energy failure in a cell be caused by?
- oxygen and glucose lack
- mitochondrial failure
what can failure of membrane functional integrity be caused by?
- damage to ion pumps
- complement or perforin
- bacterial toxins
what can membrane damage be caused by?
- free radicals
what can blockage of metabolic pathways be caused by?
- interruption of protein synthesis
- respiratory poisons
- hormone/growth factor lack
what can mechanical disruption be caused by?
- trauma
- osmotic pressure
what can DNA damage or loss be caused by?
- ionising radiation
- chemotherapy
- free radicals
what are some major types of cellular injury?
- trauma
- thermal injury (hot or cold)
- poisons
- drugs
- infectious organisms
- ischaemia and reperfusion
- plasma membrane failure
- DNA damage
- loss of growth factors
- ionising radiation
how do most physical agents cause passive cell destruction?
- gross membrane disruption
- catastrophic functional impairment
how do trauma and thermal injury kill cells?
- disrupting cells
- denaturing proteins
- cause local vascular thrombosis with tissue ischaemia and infarction
how does freezing damage cells?
- mechanically; membranes are perforated by ice crystals
how do chemicals cause cell injury?
- act as toxins to specific metabolic pathways
- local damage
- local and systemic damage
how do caustic agents cause rapid local cell death?
- extreme alkalinity or acidity
- corrosive effect on tissue by digesting proteins
how does trauma cause cellular injury?
- mechanical disruption of tissue
how does carbon monoxide cause cellular injury?
- prevents oxygen transport
how does contact with strong acid cause cellular injury?
- coagulates tissue proteins
how does paracetamol overdose cause cellular injury?
- metabolites bind to liver cell proteins and lipoproteins
how do bacterial infections cause cellular injury?
- toxins and enzymes
how does ionising radiation cause cellular injury?
- damage to DNA
what happens in the blockage of cellular respiration? what do cyanide ions do?
- prevention of oxygen utilisation leads to death of many cells
- cyanide ions bind to cytochrome oxidase and interrupting oxygen utilisation
- cells with higher metabolism are most vulnerable
what is an example of the effects of glucose deprivation on cells?
- cerebral neurones are highly dependent on glucose
- in diabetes mellitus, there’s inadequate use of glucose due to lack of insulin
why does blockage of protein synthesis damage cells?
- constant requirement to replace enzymes and structural proteins
what is an example of the effects of blocking protein synthesis on cells?
- ricin is a potent toxin from the castor oil plant
- acts on the ribosomal level
- antibiotics, e.g. streptomycin, chloramphenicol and tetracycline interfere with protein synthesis
what are examples of loss of growth factor/hormonal influence affecting cells? how can this affect organs?
- growth factor deficit, receptor loss/blockade, tyrosine kinase inhibitors
- affected cells undergo apoptosis
- hormone withdrawl
- organ may shrink (atrophy)
what is an example of a tyrosine kinase inhibitor drug?
imatinab
what are the effects of impaired blood flow (ischaemia)?
- causes inadequate oxygen delivery
- mitochondrial production of ATP ceases
- anaerobic glycolysis leads to acidosis due to accumulation of lactate
- acidosis promotes calcium influx
why does anaerobic glycolysis lead to acidosis?
accumulation of lactate
what cells are most vulnerable to effects of ischaemia?
those with high metabolic activity e.g. cortical neurones and cardiac myocytes
what is reperfusion injury? why does it occur?
when blood flow is restored after ischaemia, the oxygen leads to a burst of mitochondrial activity and excessive release of ROS (free radicals)
what are free radicals?
atoms or groups of atoms with an unpaired electron
- avidly form chemical bonds
what are properties of free radicals?
- highly reactive
- chemically unstable
- present only at low concentrations
- participate in or initiate chain reactions
how can free radicals be generated?
- deposition of energy
- interaction between oxygen and a free electron in relation to oxidation-reduction reactions
how are free radicals generated by deposition of energy?
electron is replaced, resulting in free radicals
what are the body’s mechanisms for protection against free radical damage?
- free radical may be scavenged by endogenous or exogenous antioxidants
- superoxide radicals may be inactivated by copper-containing enzyme superoxide dismutase, generating hydrogen peroxide, which is converted to water by catalase
what are clinicopathological events involving free radicals?
- toxicity of some poisons (e.g. carbon tetrachloride)
- oxygen toxicity
- tissue damage in inflammation
- intracellular killing of bacteria
what are mechanisms of cell membrane damage?
- complement-mediated cytolysis
- perforin-mediated cytolysis
- specific blockage of ion channels
- failure of membrane ion pumps
- free radical attack
what is verapamil?
- calcium channel blocker
- used in treatment of hypertension and ischaemic heart disease
what can depletion of ATP affect?
- membrane ion pumps that are dependent on ATP
how can chemical agents deplete ATP?
- interfering with mitochondrial oxphos
- by consuming ATP in their metabolism
what are the actions of ouabain?
- naturally occurring toxin
- Na/K ATPase is inhibited
what does failure of membrane ion pumps lead to?
- cell swelling (oncosis or hydropic change)
how can membrane proteins/layers be altered?
- reactions with phospholipid or protein moieties
- phospholipids may be altered through peroxidation by ROS and phospholipases
- membrane proteins altered by cross-linking induced by free radicals
what happens when membrane damage leads to lysosome permeability?
release of contents precipitates further cell damage/death
what is the process of neoplastic transformation that results in tumours?
- non-lethal DNA damage is inherited by daughter cells
- a clone of transformed cells with abnormal growth characteristics is formed
what are the types of DNA damage?
- strand breaks
- base alterations
- cross-linking
what are the effects of different numbers of strand breaks?
- one: repair can be accomplished accurately
- double: no template
- multiple double-strand breaks: rejoin incorrectly, leading to chromosome translocation or inversion
what is a mutation?
DNA strand no longer transcribes correctly
what causes DNA strand cross-linking?
- ROS cause linkage between the complementary strands
- leads to an inability to separate strands and make new copy
- DNA replication is blocked
what do alkylating agents and platinum-based drugs do to DNA strands?
- alkylating agents cause cross-linkage
- platinum based drugs cause strand breaks
what is reproductive death? when do cells die?
- where double strand breaks lead to misrepairing or failure to repair
- combination of genetic instability and lethal mutations leads to cell death after 2-3 mitotic cycles
- smaller proportion of cells die immediately by apoptosis/necrosis
how do ATM mutations affect cells? what is an example?
- loss of function mutations of the ATM gene impair excision repair of double-strand breaks
- explains the enhanced radiation sensitivity of patients with ataxia telangiectasia
what is xeroderma pigmentosum? what is it caused by?
- extreme skin sensitivity to sunlight, causing tumors
- mutated ERCC6 gene
what are two common patterns of sublethal cellular alteration?
- hydropic change
- fatty change
what happens in hydropic change? what is it caused by?
- cytoplasm becomes pale and swollen due to accumulation of fluid
- disturbances of metabolism e.g. hypoxia or chemical poisoning
are changes in hydropic change reversible?
yes, but they may cause irreversible damage if causal injury is persistent
what is fatty change? what is it caused by?
- vacuolation of cells
- due to the accumulation of lipid droplets due to a disturbance to ribosomal function and uncoupling of lipid from protein metabolism
what is commonly affected by fatty change?
- liver
- due to hypoxia, alcohol, diabetes, etc
is fatty change reversible?
moderate degrees are, but severe fatty change may not be
what is autophagy? what happens in it?
- cellular response to stress, e.g. deficiency of nutrients or growth factor-mediated effects, or organelle damage
- cell components are isolated into intracellular vacuoles and processed through to lysosomes
- means of staving off cell death
what can autophagy lead to?
- may progress to cell death if stimulus is more severe
- cell metabolic pathways may switch to apoptosis
what are the two distinct mechanisms by which cells die?
- necrosis
- apoptosis
what is a key outcome difference between apoptosis and necrosis?
in apoptosis the cell membrane remains intact and there is no inflammatory reaction
what happens to mitochondria during necrosis?
- anaerobic conditions lead to acidosis, leading to calcium inflow
- calcium uptake by mitochondria exceeds their storage capacity and leads to disruption of the inner membrane
- ATP production ceases and contents leak into cytosol
- exacerbated by reperfusion, leading to ROS production
what are the distinct morphological types of necrosis?
- coagulative
- colliquative
- caseous
- gangrene
- fibrinoid
- fat necrosis
what is the commonest type of necrosis?
coagulative necrosis
why do cells retain their outline in coagulative necrosis?
- after devitalisation, they retain their outline as their proteins coagulate and metabolic activity ceases
what is the gross appearance in coagulative necrosis?
- depends on cause of cell death and vascular alteration
- tissue texture is normal/firm initially
- becomes soft later due to macrophage digestion
what is the microscopic appearance in coagulative necrosis?
- first few hours: no discernable abnormality
- progressive loss of nuclear staining until it ceases to be haemotoxyphilic
- loss of cytoplasmic detail
- collagenous stroma is more resistant to dissolution
tissue retains a faint outline of its structure until the damaged area is removed by phagocytosis
where does colliquative necrosis occur? why?
- brain
- lack of substantial supporting stroma - necrotic neural tissue may totally liquefy
what happens in colliquative necrosis?
- glial reaction around the periphery
- site of necrosis is eventually marked by a cyst
what is caseous necrosis? when is it commonly seen?
- pattern of necrosis where the dead tissue is structureless
- TB
what is the histological appearance of caseous necrosis?
amorphous eosinophilic area stippled by haematoxyphilic nuclear debris
what is gangrene?
necrosis with putrefaction of the tissues, sometimes due to action of certain bacteria, e.g. clostridia
what bacteria is associated with gangrene?
clostridia
why do gangrenous tissues appear black?
deposition of iron sulphide from degraded haemoglobin
why is intestinal necrosis liable to proceed to gangrene?
clostridia are very common in the bowel
what is the difference between wet and dry gangrene?
- dry gangrene is due to blockage of blood supply to local tissues
- wet gangrene is due to infection
what is the cause of gas gangrene?
infection by clostridium perfringens
what is the cause of synergistic gangrene?
infection by combinations of organisms, e.g. bacteroides and borrelia vincentii
what is fibrinoid necrosis?
- arterioles are under such pressure that there’s necrosis of the smooth muscle wall
- seepage of plasma into the media, with deposition of fibrin
what is the histological appearance of fibrinoid necrosis?
with H&E staining, the vessel wall is a homogenous bright red
what are causes of fat necrosis?
- direct trauma to adipose tissue and extracellular liberation of fat
- enzymatic lysis of fat due to release of lipases
what happens after trauma to adipose tissue?
- release of intracellular fat elicits an inflammatory response
- polymorphs and macrophages phagocytose fat
- development of fibrosis
- may produce a palpable mass
what happens to fat released in acute pancreatitis?
- release of pancreatic lipase leads to fat cells having stored fat split into fatty acids
- fatty acids combine with calcium to precipitate out as white soaps
- may lead to hypocalcaemia
how are cells classified according to their potential for renewal?
- labile cells
- stable cell population
- permanent cells
what are labile cells? give examples
- good capacity to regenerate
- e.g. surface epithelial cells
- lost from surface, replaced by deeper layers
what are stable cell populations? give examples
- divide at a very slow rate
- retain capacity to divide when needed
- e.g. renal tubular cells and hepatocytes
what are permanent cells? give examples
- cells with no effective regeneration
- e.g. nerve cells and striated muscle cells
what happens in stem cell differentiation?
- mitotic division
- one of the daughter cells progresses along a differentiation pathway according to needs and functional state of the tissue
- other daughter cell retains stem cell characteristics
where are stem cells located in the epidermis?
- basal layer immediately adjacent to the basement membrane
- hair follicles
- sebaceous glands
where are stem cells located in the intestinal mucosa?
- near the bottom of the crypts
where are stem cells located in the liver?
- progenitor cells
- between hepatocytes and bile ducts
what kind of damage are stem cells vulnerable to? what could this lead to?
- radiation injury
- death
- mutations propagated to daughter cells with risk of neoplastic transformation
what happens in the process of healing (in epidermis)?
- cells proliferate and spread out as a thin sheet until the defect is covered
- contact inhibition: stimulus to proliferate is turned off when they form a confluent layer
- when in place, the epidermis is rebuilt from the base upwards
what is contact inhibition?
the switching off of proliferation when cells form a confluent layer.
- controls growth and movement
what protects the epidermis during healing?
a scab (layer of fibrin)
what is an example of a procedure done in plastic surgery to help skin heal?
- done when using split skin grafts
- whole of the epidermis is removed and positioned as the donor graft
- necks of adnexa glands are left in place to generate a replacement at the donor site
what is organisation in relation to repair?
- repair of specialised tissues by the formation of mature fibrovascular connective tissue
what happens during organisation?
- granulation tissue is formed in the early stages, often on a scaffold of fibrin
- any dead tissue is removed by phagocytes
- granulation tissue contracts and accumulates collagen to form the scar
- remodelling occurs
what is the feel/appearance of an organised area?
- firmer than normal
- shrunken or puckered
what are the steps in granulation tissue formation?
- capillary endothelial cells proliferate and grow into the area to be repaired
- initially, endothelial cells are solid buds, and open into vascular channels
- vessels are arranged as a series of loops arching into the damaged area
- fibroblasts are stimulated to divide and secrete collagen/other matrix components
- acquire bundles of muscle filaments and attachments to adjacent cells (myofibroblasts)
what are myofibroblasts?
modified cells displaying features and functions of both fibroblasts and smooth muscle cells
- secrete collagen framework
- wound contraction
what is granulation tissue?
combination of capillary loops, supported by myofibroblasts
- inflammatory cells may be present
- actively contracts to reduce wound site
- distinct from a granuloma
what is a proud flesh?
excessive granulation tissue protruding from a surface
how and why does wound contraction occur?
- reduces volume of tissue for repair
- may be reduced by 80%
- contraction of myofibroblasts
- myofibroblasts are attached to eachother and to adjacent matrix components, so granulation tissue contracts as a whole and indraws surrounding tissues
when can wound contraction become problematic?
- if tissue damage is circumferential around the lumen of the tube, contraction may cause stenosis/obstruction due to a stricture
- contracture
- burns to the skin can lead to contraction which can cause cosmetic damage and impaired mobility
what is contact inhibition?
- when cells form a confluent layer, the stimulus to proliferate is switched off
- controls growth and movement
what is contracture?
tissue distortion resulting in permanent shortening of a muscle
what is the process of healing for an incised wound (first intention healing)?
healing occurs with minimal delay if both sides are brought together acccurately
some small blood vessels will be occluded by thrombosis
1. fibrin deposited locally binds the two sides
2. coagulated blood on the surface forms the scab and keeps the wound clean
3. join is weak, and is formed rapidly and is the framework for the next stage
4. over next few days, capillaries proliferate to bridge tiny gap, fibroblasts secrete collagen as they migrate into the fibrin network
5. by 10 days, the strength of the repair enables removal of sutures
6. basal epidermal cells proliferate to spread over any gap
7. if edges of wound are gaping, the epidermal cells creep down sides
8. epidermal cells stop growing and are resorbed when wound is healed, or they form a keratin filled cyst
what may form at the end of a wound healing after incision?
- implantation dermoid (keratin-filled cyst)
- made of epidermal cells
what is healing by second intention (tissue loss) characterised by?
- phagocytosis to remove any debris
- granulation to fill in defects and repair specialised tissues lost
- epithelial regeneration to cover the surface
when do keloid nodules form?
- dermal injury sometimes followed by excessive fibroblast proliferation and collagen production
- mass several cm across may follow surgery/injury, particularly burns
what are keloid nodules determined by? what population are they prevalent in?
- genetically determined
- prevalent amongst blacks
what are the steps of repair by second intention?
- loss of tissue
- granulation tissue
- organisation
- early fibrous scar
- scar contraction
what are the initiating signals of skin healing and repair?
- hypoxia
- release of growth factors from platelet degranulation
what does the release of initiating signals of skin healing and repair trigger?
trigger the production of cytokines:
- EGFs
- keratinocyte growth factor
- macrophages
- dermal fibroblasts (stimulate keratinocyte proliferation and mobility)
what is released to stimulate keratinocyte proliferation and mobility?
macrophages and dermal fibroblasts
what do keratinocytes and macrophages produce? what does this lead to?
vascular endothelial growth factor, inducing angiogenesis
what do platelets, macrophages and keratinocytes release during wound healing? what does it facilitate?
platelet-derived growth factor
- local accumulation and activation of macrophages
- proliferation of fibroblasts
- matrix production
what does TGF-beta influence in wound healing?
control of myofibroblasts and collagen formation
what is regeneration of skin adnexal glands and hair controlled by?
- complex cellular configurations
- controlled by homeotic (patterning) genes
- genes control the growth and differentiation genes
healing of fetal skin vs adult skin
- damage to fetal skin is healed completely
- in the adult, the homeotic genes aren’t activated, so there is imperfect repair
- adult epidermis can respond to produce hairs, but wounded dermis can’t produce required signals
what is an erosion?
loss of part of the thickness of the mucosa
how are mucosal erosions regenerated?
- viable epithelial cells are immediately adjacent to the defect and proliferate rapidly
- can be recovered in hours if cause has been removed
what happens when patients bleed from erosions?
- patient can lose much blood from multiple gastric erosions before healing
- if endoscopy to identify the cause of haematemesis
is delayed, then erosions may evade detection
what is ulceration?
loss of the full thickness of the mucosa - defect often goes deeper to penetrate the muscularis propria
what happens during mucosal ulceration?
- damaged blood vessels bleed and surface of the ulcer becomes covered with fibrin
- macrophages remove any dead tissue by phagocytosis
- granulation tissue produced in the ulcer base, and capillaries and myofibroblasts proliferate
- mucosa regenerates at margins (destroyed muscle can’t be regenerated) and spreads out on to floor of the ulcer
why must mucosal ulcers regenerate at the margins?
destroyed muscle can’t be regenerated
what happens in chronic ulceration?
- oscillation between further ulceration and repair
what happens when chronic ulceration heals enough?
fibrous scar tissue that has replaced muscle will contract, with distortion of stomach and possible obstruction
when may haemorrhage occur in chronic ulceration?
larger arteries lying in the path of advancing ulceration may rupture
what is enarteritis vascular intima?
- may be a zone of inflammation around the ulceration
- if the inflammation abuts the vessel this leads to a reactive proliferation of the vascular intima
- there is obliteration of the lumen
what happens immediately after a fracture?
- haemmorage within the bone from ruptured vessels in the marrow cavity and around the bone in relation to the periosteum
- haematoma forms
what does a haematoma in a fractured bone do? what is the process of healing of a bone fracture?
- facilitates repair by providing a foundation for the growth of cells
- replaced by a fracture callus
- woven bone (callus) is replaced by lamellar bone
- lamellar bone is remodelled to restore the normal trabecular pattern of the bone
what is involved in the initial phases of fracture repair?
- devitalised fragments of bone and soft tissue damage nearby is present
- removal of necrotic tissue and organisation of the haematoma
what are the capillaries in the haematoma accompanied by? what do they do?
fibroblasts and osteoblasts
- deposit bone in an irregularly woven pattern
what is a callus?
mass of new bone deposited by fibroblasts and osteoblasts
- may have islands of cartilage
what are internal calluses and external calluses?
- internal calluses are within the medullary cavity
- external calluses are at the periosteum
what factors can delay or arrest the repair of a fracture?
- movement
- interposed soft tissues
- gross misalignment
- infection
- pre-existing bone disease
how does movement affect fracture healing?
- movement between two ends leads to excessive callus and prevents/delays tissue union
- persistent movement prevents bone formation and collagen is laid down instead to give fibrous union
how are false joints at a fracture site formed?
- persistent movement prevents bone formation
- collagen is laid down instead to give fibrous union
how do interposed soft tissues affect fracture healing?
- interposed soft tissue between broken ends delay healing
- increase risk of non-union
how does gross misalignment affect fracture healing?
- slows rate of healing
- prevents a good functional result
- increases risk of osteoarthrosis in adjacent joints
what is a compound fracture?
skin over a fracture is broken
what is a pathological fracture? what can it be caused by?
bone broken was weakened by disease
- primary disorder of bone
- secondary involvement of bone by another condition, e.g. metastatic carcinoma
where can hepatic regeneration come from?
- hepatocytes
- liver progenitor cells
- bone marrow-derived stem cells
when can damage to the liver not be repaired?
when there is damage to the hepatic architecture and the hepatocytes
when may liver damage proceed to cirrhosis?
when there is an imbalance between hepatocyte regeneration and failure to reconstruct the architecture
what happens when there the liver’s architecture is damaged?
- confluent loss of liver cells and architectural damage leads to healing by fibrous scarring and nodular regeneration of liver cells
- leads to cirrhosis
what happens when the kidney is damaged?
- its epithelium can be regenerated, but it’s architecture can’t
what happens when tubular epithelium, the glomeruli and the interstitia are damaged?
- tubular epithelium: loss after an ischaemic episode/toxins may lead to renal failure but there’s enough epithelium to repopulate tubules
- inflammatory/other damage to the glomerulus is permanent and leads to scarring and loss of filtration capacity
- interstitial inflammation can come to fibrosis
are muscle fibres replaceable?
- cardiac and smooth muscle cells are permanent
- vascular smooth vessels are replaceable
- voluntary muscle has limited capacity for regeneration from satellite cells
where can voluntary muscle be regenerated from?
satellite cells
what happens when just contractile proteins in muscle cells are lost?
new ones can be synthesised within the old endomysium
what is gliosis?
proliferation of glial cells in response to injury
what happens if a peripheral nerve is transected?
- axons degenerate proximally for 1-2 nodes
- distally there is Wallerian degeneration, followed by proliferation of Schwann cells in anticipation of axonal regrowth
what happens if there is good realignment of two cut ends of a peripheral nerve?
axons may regrow down previous channels (now occupied by proliferated Schwann cells)
- full recovery is unusual
what happens if there is poor alignment or amputation of cute ends of a peripheral nerve?
- ends of axons still proliferate, in a disordered manner
- produce an amputation neuroma
- may be painful and require removal
what is an amputation neuroma?
a tangled mass of axons and stroma that grows when a there is poor alignment of cut ends of a peripheral nerve
- can be painful
what are factors that can impair healing and repair of tissues?
- age (young and elderly)
- nutritional disorders
- neoplastic disorders
- Cushing’s syndrome and steroid therapy
- diabetes mellitus and immunosupression
- vascular disturbance
- denervation
how does nutrition affect wound healing?
wound healing is influenced by ability to synthesise protein and collagen, which are affected by nutrition
how is collagen synthesis affected by nutrition?
- vitamin C is needed for the hydroxylation of proline in collagen synthesis
- scurvy leads to reduced wound healing, fragile capillaries and haemorrhages
how is protein synthesis affected by nutrition?
- dietary deficiency or protein loss
how can severe malnutrition affect wound healing?
impairs the response to infection, may be fatal
how can Cushing’s syndrome and steroid therapy affect tissue injury?
increased circulating corticosteroids
- have immunosuppressive actions, so injury and infection may have more severe effects
- steroids impair healing by interfering with formation of granulation tissue and wound contraction
how do diabetes mellitus and immunosuppression affect tissue damage?
- increase susceptibility to infection by low-virulence organisms
- increase risk of tissue damage
how can diabetes mellitus affect cells in tissue damage?
- affects polymorph function
- may lead to occlusion of small blood vessels and cause neuropathy
- direct effect on keratinocytes (reduced motility)
- affects myofibroblasts
how can vascular disturbance affect tissue injury/healing?
- adequate supply is necessary for normal cellular function, but may not be enough when demand increases
- deficit of oxygen may lead to tissue damage and impaired healing
how can denervation damage tissues?
- unresponsiveness to repeated minor trauma
- lack of pain of intercurrent infection or inflammation
what happens to a blood clot after death?
blood cells and vessel wall cells release their hydrolytic enzymes and the clot is dissolved
what are the post-mortem clot layers?
- lower, deep-red layer
- upper, clearer layer
- platelets are distributed throughout
- this happens because red cells tend to settle out before the clot forms
what is a thrombus?
a solidification of blood contents that forms within the vascular system during life
what do alpha granules in platelets contain?
substances involved in the process of platelet adhesion to damaged vessel walls
- fibrinogen
- fibronectin
- platelet growth factor
- antiheparin
what do dense granules in platelets contain?
substances causing platelets to aggregate
- ADP
what activates platelets? where can the activating substance be found?
collagen
- damaged vessel walls
- with polymerising fibrin
what happens when platelets are activated?
- platelets change shape and extend pseudopodia
- granules release their contents
- platelets form a mass that covers the vessel wall defect until endothelial cells have regenerated and repaired the vessel permanently
what happens when platelets are activated in an intact vessel?
thrombus
what is Virchow’s triad?
three disposing situations that may result in thrombus formation
what are the three factors in Virchow’s triad?
- changes in the intimal surface of the vessel
- changes in the pattern of blood flow
- changes in the blood constituents
what are the rules of Virchow’s triad?
not all three are needed for thrombosis to occur; any one of them is sufficient
what is the atheromatous plaque like in its earliest phase?
may consist of a slightly raised fatty streak on the intimal surface of any artery
how does the atheromatous plaque develop with time?
enlarges and becomes sufficiently raised to protrude into the lumen
what are the effects of an atheromatous plaque?
- its enlarging over time leads to increased turbulence in blood flow
- turbulence causes loss of intimal cells, which which exposes the plaque to blood cells.
- turbulence also predisposes to fibrin deposition and to platelet clumping, which exposes collagen, causing platelets to settle on the surface
what are the steps in/leading to thrombosis?
- atheroma (turbulence and lipid-filled cells)
- ulceration (loss of endothelial cells and exposure of collagen)
- platelet adherence (platelet adherence and activation)
- thrombosis (thrombus formed of alternating layers of platelets, fibrin and red cells)
what are the layers of a thrombus?
- platelet layer
- precipitation of a fibrin meshwork with trapped red cells
- lines of Zahn
what are the lines of Zahn?
alternating bands of white platelets and red blood cells in thrombi
what is propagation in relation to thrombosis? how does it differ in arteries and veins?
- thrombi grow in the direction of blood flow
- greatest degree of turbulence occurs at the downstream side of arterial thrombi, as the blood passes over the thrombus
- greatest degree of turbulence occurs at the upstream side of venous thrombi
does atheroma occur in veins? why/why not?
blood pressure is lower in veins than in arteries
what initiates thrombus formation?
most venous thrombi begin at valves, because of the turbulence produced when they protrude into the vessel lumen and their potential damage by trauma, stress and occlusion
why is thrombosis likely in surgery/MI?
blood pressure falls; usually, there is laminar flow and most blood cells are kept away from diseased walls/damaged valves
when/why may DVT occur?
- venous return from legs is reliant upon calf muscle contraction/relaxation which massages the veins and returns blood to the heart
- immobilisation of elderly patients increases risk of DVT
when are the effects of thrombosis apparent?
only if thrombus is large enough to affect the blood flow significantly
what are the clinical effects of arterial thrombosis?
- loss of pulses distal to the thrombus
- all signs of impaired blood supply: cold, pale and painful area and eventually tissue death and gangrene
where do most venous thromboses occur?
95% occur in leg veins
what are the clinical effects of venous thromboses? why does this occur?
- area becomes tender, swollen and reddened (due to arteries carrying blood to the area still but veins not being able to carry it away)
- tenderness is due to developing ischaemia in the vein wall
- general ischaemic pain develops as the circulation worsens
what condition is often associated with thrombus formation?
MI is associated with it in coronary arteries
- often responsible for many sudden deaths
what are possible fates of thrombi?
- resolution
- organisation by into a scar by macrophages (remove thrombus) and fibroblasts (collagen), leaving a nodule/web that narrows the vessel
- intimal cells may proliferate and capillaries may grow into the thrombus (occlusion becomes recanalised)
- thrombus causes death before detection
- fragments may break off into circulation (embolism)
what is an embolus?
mass of material in the vascular system that’s able to lodge in a vessel and block its lumen
where may material of an embolus arise from?
- within body
- outside
what states can the material of an embolus be?
solid, liquid or ogaseous
what does an embolus do in the body?
travel in circulation, passing through the vascular system until it reaches a vessel that’s narrow enough to prevent further passage
how much material of emboli is from thrombi?
90%
what is a pulmonary embolism?
emboli from venous thrombi that are in the pulmonary circulation
what is a paradoxical embolus?
pulmonary emboli that arrive in the arterial circulation through an arterial-venous communication
- e.g. perforated septum in the heart
- very rare
what are consequences of small pulmonary emboli? what can accumulated damage lead to?
- can go unnoticed and be lysed in the lung
- become organised and cause a permanent respiratory deficiency, which may only be noticed due to accumulated small emboli
- accumulated damage can lead to pulmonary hypertension
what are effects of large pulmonary emboli?
- acute respiratory and cardiac problems
- chest pain and SOB
- infarction
what are effects of massive pulmonary emboli?
sudden death
- long thrombi from leg veins
- have shape of vessels from where they’re from
what is recanalisation?
consequence of thrombosis where there’s ingrowth of new vessels which join up to restore blood flow
- leads to scar and residual thrombus
what is a systemic embolism?
emboli arising from the arterial circulation
where do the thrombi for systemic emboli usually arise from?
heart or atheromatous plaque
what are causes of thombosis in the heart?
- MI leading to clotting and turbulence
- AF
where do emboli from the heart usually originate from? what does this lead to?
- left atrium/ventricle
- can travel to any site in the systemic circulation
where may larger systemic emboli lodge?
bifurcation of the aorta as a saddle embolus
- cuts off blood supply to the lower limbs
- rapid diagnosis needed before there’s irreversible damage
where may smaller systemic emboli lodge?
- nearer the periphery to cause gangrene of the digits
- kidneys/spleen with no symptoms
- intestine, down the SMA - death of sections of small bowel
what are potential origins of systemic arterial emboli?
- atheromatous plaque with thrombus
- atrial thrombus
- valve vegetation
- thombus; old MI (adynamic)
- thrombus; recent MI
what are effects of systemic arterial emboli?
- cerebral infarct (stroke)
- renal infarct
- ischaemic bowel
- ischaemic foot (dry gangrene)
how do systemic arterial emboli affect kidneys/spleen differently compared to the intestine? why?
- whole sections of small bowel can die, leading to perforation and peritonitis
- death of small area of kidney/spleen only produces a small scar
- in intestine, the whole organ needs to be intact to function properly, unlike the kidney/spleen
where are embolic atheromas often seen?
- fragments of atheromatous plaque may embolise; often seen in lower limbs of arteriopathic patients
how can embolic atheroma fragments be recognised histologically?
cigar-shaped clefts left behind when the cholesterol crystals dissolve out during histological processing
what are platelet emboli?
- early stages of atheroma involve mainly platelet deposition
- emboli from early legions may be composed just of platelets
- usually very tiny, no severe clinical signs
what is a TIA?
transient ischaemic attack
- lasts for less than 24 hours and is associated with complete clinical recovery
- risk markers for subsequent major strokes
what are infective emboli? what are their effects?
in infective endocarditis, vegetations consist of microorganisms and are extremely friable
- infective agent may weaken the vessel wall, causing a mycotic aneurysm
how may fat embolisms arise?
- severe trauma with fracture to long bones
- extensive soft tissue injury
- severe burns
what is the mechanism of fat embolism formation?
- fat from bone marrow may be released into circulation
- systemic effects of trauma may cause changes in stability of fat held in micellar suspension, causing free fat in circulation
what are causes of gas embolism?
- caisson disease
- surgical
- suicide attempts
- disconnected from IV lines and air enters
what is caisson disease? what happens in it?
- experienced by divers
- transferring too quickly from high to low pressure environments
- at high pressure, increased volumes of gas dissolve in blood and in rapid decompression they come out as bubbles
- oxygen and CO2 redissolve but nitrogen bubbles remain and enter bones and joints and lodge in lungs
what happens in amniotic embolism?
- increased pressure in uterus during labour
- amniotic fluid may be forced into maternal uterine veins
- travel in circulation and lodge in lungs
how can amniotic embolisms be recognised histologically?
contain shed skin cells of the infant
what happens in tumour embolism? what are its consequences?
- small and break off as tumours that penetrate vessels
- don’t cause immediate physical problems
- major route of dissemination of malignancies through the body (metastasis)
what is embolism of foreign matter? what are their effects?
- foreign matter may contaminate fluids injected intravenously e.g. talc
- elicit granulomatous reaction in organs
what are common and serious disorders in which thromboembolic mechanisms participate?
- myocardial infarction
- cerebral infarction
- pulmonary embolism
what is ischaemia?
the result of impaired vascular perfusion, depriving the affected tissue of vital nutrients, e.g. oxygen
what does recovery from ischaemia depend on?
- duration of the ischaemic period; brief episodes might be recoverable
- the metabolic demands of the tissue; cardiac myocytes and cerebral neurones are most vulnerable
what is infarction? is it reversible? what does it usually result from?
death of tissue due to ischaemia, within the living body
- is reversible, but tissues vary in their ability to repair and replace the loss
- usually from thromboembolic phenoma completely occluding the artery supplying the affected tissue
what is shock?
state of circulatory collapse resulting in impaired tissue perfusion
what are vascular lesions causing ischaemia?
- thrombosis
- embolism
- spasm
- atheroma
- compression
- vasculitis
- steal
- hyperviscosity
what can spasm be due to? what can is cause?
- contraction of smooth muscle in the vessel wall, due to decreased nitric oxide production by vascular endothelial cells due to cellular injury or loss
- spasm of coronary arteries can lead to angina
- relieved by glyceryl trinitrate
- arterial spasm responsible for ischaemia of fingers in Raynauds
what is responsible for ischaemia of the fingers in Raynauds?
arterial spasm
are arteries or veins more susceptible to occlusion by external compression? when does this occur?
- veins, due to thin walls and low intraluminal pressure
- strangulated hernias, testicular torsion and torsion of ovaries containing cysts or tumors
what is vascular steal? when does it occur? is it common?
blood is diverted (stolen) from a vital territory
- proximal to an area of atheromatous narrowing on its own, insufficient to cause ischaemia, the arterial stream is diverted along another branch vessel to meet increased demands of competing territory
- territory supplied by the atheromatous vessel becomes ischaemic
- uncommon
what is vasculitis?
inflammation of vessel wall
- narrows lumen
- may be complicated by superimposed thrombosis
what can increased whole blood viscosity cause?
ischaemia at arteriolar, capillary and venular level
how does viscosity affect small/large vessels?
- contribute little to flow characteristics of large blood vessels
- affect small vessels more
what can hyperviscosity of blood be caused by?
- myeloma (tumour of plasma cells) due to high conc. of antibodies in plasma and rouleaux formation by red cells
- hypergammaglobulinaemia from myeloma
what is the distinction between infarction and necrosis?
- necrosis is the general term for death of tissue within the living organism
- only death of tissue due to restricted blood supply is infarction
what areas of the body have a dual blood supply?
- liver; hepatic veins and portal veins
- lungs; bronchial arteries and pulmonary arteries
- some areas of the brain around the circle of Willis
what is reperfusion injury? why does it occur?
- tissue effects of ischaemic injury that occur when perfusion is re-established
- blood encounters tissue where transport mechanisms across the cell membrane have been disrupted and calcium transport out of the cell and organelles has been impaired
- triggers activation of oxygen-dependent free radical systems that clear away dead cells
- polymorphs and macrophages import their own oxygen free radicals into the area
what do experimental studies reveal about the mechanisms of reperfusion injury?
- involves intracellular mechanisms of apoptotic cell death
- may be due to disruption of cell-matrix interactions
how can reperfusion be prevented experimentally?
- with antioxidants; only small effect on amount of tissue loss
what does an infarct look like after less than 6 hours?
- ECG changes
- no visible changes grossly or histologically
- electron microscopy would reveal swollen mitochondria
what does an infarct look like after more than 24 hours?
- pallor visible
- inflammatory reaction at edge
- striations disappear from cardiac myocytes
- with H&E, the RNA is broken down and the cytoplasm stains pink
what does an infarct look like after several days to weeks?
- dead myocytes removed by macrophages and polymorphs
- replacement by fibrous tissue
- amorphous, acellular appearance apart from many inflammatory cells
what is the gross appearance of the tissue of an infarct several days/weeks old?
- if small blood vessels have also become ischaemic, they may die and blood escapes into the infarct, giving it a patchy/confluent red appearance
- remains pale with a red hyperaemic rim and becomes progressively paler in healing if there is no bleeding into the area
when is the tissue at its weakest during infarction? what could happen?
after a few days
- rupture of healing infarct and consequent haemopericardium and cardiac tamponade
what is the appearance of an infarct after a few months?
fibrous scar forms
- grey, contracted area consisting of callagenous fibrous tissue
- no longer functional
what is the functioning of a fibrous scar like? give an example
- organ is intact and hole is mended, but scarred area is no longer functional
- adynamic, can lead to further problems
- e.g. in heart this can be an aneurysm as the scar is subjected to cyclic pressure loads and becomes stretched without contractile ability
what are the shapes of infarcts? why may these occur?
depends on territory of perfusion of the occluded blood supply
- lungs: wedge shaped
- kidneys: triangular (conical in 3D)
- spleen: less predictable due to less regular blood supply and overlap
- brain: fluid filled cyst remains due to dead tissue being cleared away efficiently
what is gangrene?
when whole areas of a limb or region of the gut have their arterial supply cut off and large areas of mixed tissues die in bulk
what are the two types of gangrene?
dry and wet
what is dry gangrene? give an example
tissue dies and becomes mummified and healing occurs above it
- dead area drops off
- sterile process
- common fate of gangrenous toes due to diabetes
what is wet gangrene?
bacterial infection supervenes as a secondary complication
- gangrene spreads proximally
- patient dies from overwhelming sepsis
how does torsion cause gangrene?
gut may twist on a lax mesentery or ovary/testis may twist on pedicle; occludes venous return
- organ swells
- oedema further compresses the drainage
- arteries continue to pump blood into the organ, but ishaemia supervenes and infarction develops
what is gas gangrene?
from infection of ischaemic tissue by gas-producing anaerobic bacteria e.g. clostridium perfringens
how can frostbite cause capillary ischaemia?
damaged in exposed areas and contract so severely that the area they usually supply becomes ischaemic and dies
how does exposure to cold without freezing cause capillary ischaemia? what is an example?
causes capillary contraction followed by a fixed dilation
- mechanism of damage in trench foot and related conditions
what can capillaries be blocked by? how can this lead to ischaemia?
- parasites
- abnormal cells in sickle cell disease
- abnormal proteins that precipitate in the cold (cryoglobulinaemia)
local ischaemia and infarction
what is DIC?
disseminated intravascular coagulation
what happens in DIC? how can this lead to capillary ischaemia?
- thrombosis is activated without effective counterbalance
- minute thrombi may form throughout the body
- bleeding may occur at multiple sites due to consumption of clotting factors
what factors can cause capillary ischaemia?
- frostbite
- cold without freezing
- blockage
- DIC
what factors increase susceptibility to ischaemia?
- only one arterial supply (end arteries)
- differing metabolic arteries
- watersheds
what is an example of an end artery? what can ischaemia of this lead to?
retinal artery
- blindness
what tissues are vulnerable to low-flow infarction?
- watershed areas
- tissues perfused by a portal vasculature
- tissues distal to pathological arterial stenoses
- metabolically active tissues
what are watershed areas? where are they usually located?
tissues at the interface between the adjacent territories of two arteries
- usually at the fringes of the territories perfused by the arteries
- no collateral circulation
what are examples of watershed areas?
- splenic flexure of the colon; at the interface between territories of SMA and IMA
- regions of cerebral hemispheres at the interface between territories of major cerebral arteries
- myocardium between sub-endocardial myocardium (oxygenated from blood in ventricles) and that which is perfused by coronary arteries
what types of patients may develop ischaemic lesions in watershed areas?
severely shocked and hypotensive patients
what is a portal vascular arrangement?
tissues are perfused by blood that has already passed through one set of capillaries
why are portal vascular arrangements vulnerable to ischaemia?
drop in intravascular pressure across the first set of capillaries and reduction in oxygen saturation
- tissue perfused by second set of capillaries is vulnerable to ischaemia
what are examples of portal vasculature? what can happen to each?
- anterior pituitary, perfused by blood that’s already perfused the median eminence of the hypothalamus; pituitary infarction
- renal tubular epithelium, perfused by blood from glomerular capillaries; renal tubular necrosis
- parts of the exocrine pancreas, perfused by blood that’s perfused islets of Langerhans; acute pancreatitis
how can arterial stenoes cause infarction?
- if blood pressure and flow falls, and there is atheromatous narrowing/arterial stenosis, then tissue distal to stenosis may become infarcted
- patients who are severely shocked may develop ischaemic changes in many organs w/o sign of total vascular occlusion
where can transient arterial spasm cause infarction?
vulnerable tissues e.g. brain and heart
how does metabolic activity affect risk of infarction?
cells with large metabolic requirements are more vulnerable to ischaemic damage and infarction
what are examples of highly metabolically active cells vulnerable to infarction? can they be permanently damaged?
- cerebral neurones; irreversible damage occurs within few minutes
- cardiac myocytes; irreversibly damaged if coronary arteries cannot supply requirements during tachycardia associated w/ exertion
what is atherosclerosis?
disease characterised by formation of focal elevated lesions in the intima of large and medium-sized arteries
what are the lesions in atherosclerosis called?
atherosclerotic plaques
what is the level of danger in atherosclerosis?
- plaques alone are usually benign asymptomatic lesions, even in large numbers
- life-threatening ischaemic damage may occur to organs when an occlusive thrombosis forms on a spontaneously disrupted plaque
how has the prevalence/incidence of atherosclerosis changed?
- frequency has increased over the past 50 years
- more common in parts of the Middle and Far East, especially where a western style has been adopted and where diabetes is common
when does formation of atherosclerotic lesions start?
in young children, especially in societies with a high dietary fat intake
what is the earliest significant lesion in atherosclerosis? what does it look like?
fatty streak
- yellow linear elevation of the intimal lining
- composed of masses of lipid-laden macrophages
are fatty streaks clinically significant?
no
what are the outcomes of fatty streaks?
- disappear from arterial intima
- in patients at risk, they develop to atherosclerotic plaques
what is the appearance/composition of an atherosclerotic plaque?
lesion with a central lipid core with a cap of fibrous tissue covered by arterial endothelium
- connective tissue in cap (mainly collagens) provide structural strength and are produced by smooth muscle cells
- inflammatory cells reside in the fibrous cap
- rich in cellular lipids and debris
- soft, semi-fluid, highly thrombogenic lesions bordered by a rim of foam cells
- fragmented and destroyed internal elastic lamina
- cholesterol
- thinned media
what are foam cells? what is their appearance?
macrophages that have phagocytosed oxidised lipoproteins via a specialised membrane-bound scavenger receptor
- large amounts of cytoplasm with a foamy appearance
what can serve as a marker for atherosclerotic vessel disease in angiograms or CT images?
dystrophic calcification of the plaque
- can be extensive
- occurs late in the process of plaque development
what is the most important risk factor for atherosclerosis?
hypercholesterolaemia
how does hypercholesterolaemia affect atherosclerosis?
can cause plaque formation and growth in the absence of other known risk factors
- if plasma cholesterol levels in a population were below 2.5 mmol/L, symptomatic atherosclerosis would be almost non-existent
what are risk factors for atherosclerosis other than hypercholesterolaemia?
- smoking
- hypertension
- diabetes
- male gender
- increased age
- obesity
- sedentary lifestyle
- low socioeconomic status
- low birth weight
- miroorganisms
how can infection increase risk of atherosclerosis?
- cumulative effect
- infections with common bacteria e.g. chlyamydia pneumoniae, cytomegalovirus, influenza and dental pathogens
- switch on evolutionarily conserved pathways of inflammation
- high fat diets and obesity promote translocation of commensal-derived endotoxin from the gut into the general circulation and induce inflammation, insulin resistance and atherosclerosis
what mediates LDL uptake in peripheral tissues?
receptors
what is the major pathway of lipid metabolism?
dietary TGs and chylomicrons are converted into VLDL in liver, released and converted into IDLs, then LDLs, and then into tissues.
HDL apoprotein accepts cholesterol from tissues and can then be absorbed by specific receptors in the liver or recycled into LDL
what are the effects of high-fat diets and obesity on atherosclerosis risk?
- may promote translocation of commensal-derived endotoxin from the gut into the general circulation and there induce inflammation, insulin resistance and atherosclerosis
how many steps are involved in the development of atherosclerosis?
generally, 2
what is the first step in the development of atherosclerosis?
injury to the endothelium of the arterial wall
what is the second step in the development of atherosclerosis?
tissue response of the vascular wall to the injurious agents
what causes plaque formation over many years?
chronic or episodic exposure of the arterial wall to processes causing atherosclerosis
what changes do injured endothelial cells at lesion formation sites go through?
functional alterations
- enhanced expression of cell adhesion molecules for monocytes, e.g. E-selectin and ICAM-1
- increased thrombogenicity
what do changes in injured endothelial cells allow? what is the inflammatory process?
- inflammatory cells and lipids to enter the intimal layer and form plaques
- large amounts of macrophages and T cells accumulate in plaque tissue in later stages
- foam cells die through apoptosis, spilling their lipid into an enlarging lipid core
what follows the inflammatory reaction in injured endothelial cells in lesion-formation sites?
tissue repair
- growth factors (esp. PDGF) stimulate the proliferation of intimal smooth muscle cells and synthesis of collagen, elastin and mucopolysaccharide by smooth muscle cells
- fibrous cap encloses lipid-rich core
- growth factors secreted by platelets, injured endothelium, macrophages and smooth muscle cells
what is the link between haemorrhage and plaque growth?
haemorrhage results from rupture or leakage of microvessels within the plaque
- large haemorrhages can cause rapid expansion of plaques and clinical symptoms
what are clinical manifestations of atherosclerosis?
- progressive lumen narrowing due to high-grade plaque stenosis
- acute atherothrombotic occlusion
- embolisation of the distal arterial bed
- ruptured abdominal atherosclerootic aneurysm
how can progressive lumen narrowing manifest as atherosclerosis?
- stenosis of more than 50-75% of the lumen leads to critical reduction of blood flow to the distal arterial bed
- reversible tissue ischaemia develops
- e.g. stable angina pectoris and intermittent claudification
- pain may also occur at rest
how can acute atherothrombotic occlusion manifest as atherosclerosis?
- plaque rupture exposes highly thrombogenic plaque components to the blood stream
- activation of the coagulation cascade adn thrombotic occlusion occurs rapidly
- total occlusion leads to irreversible ischaemia, causing necrosis
how can embolisation of the distal arterial bed manifest as atherosclerosis?
- small thrombus fragments may embolise to the arterial bed distal to the ruptured plaque.
- embolic occlusion may cause small infarctions
how can ruptured abdominal atherosclerotic aneurysm manifest as atherosclerosis?
- rupture of a weakened dilated atheromatous abdominal aneurysm causes retroperitoneal haemorrage and death
what is the morphology of vulnerable plaques?
thin fibrous cap, large lipid core and prominent inflammation
what causes weakening and rupture of a plaque’s fibrous cap and then thrombosis?
proteolytic enzymes, cytokines and ROS
what are the characteristics of plaques that progress to highly stenotic lesions?
large fibrocalcific component with little inflammatory activity
what is growth?
the process of increase in size due to synthesis of specific tissue components
what are types of growth in a tissue?
- multiplicative
- auxetic
- accretionary
- combined patterns
what is multiplicative growth of tissue? where does it occur?
involves an increase in numbers of cells by mitotic cell divisions. occurs in all tissues during embryogenesis.
what is auxetic growth of tissue? where does it occur?
increased size of individual cells.
- growing skeletal muscle
what is accretionary growth of tissue? where does it occur?
increase in intercellular tissue components
- bone and cartilage
what is combined patterns of growth of tissue? where does it occur?
combined multiplicative, auzetic and accretionary growth
- seen in embryological development
- differing rates and directions of growth at different sites of the developing embryo
what is differentiation?
process whereby a cell develops a distinct specialised function and morphology (phenotype)
- coordinated and selective expression and repression of specific genes and gene products to produce a cell with a specilised function
how does the ability to differentiate change in cells?
- fertilized ovum can produce daughter cells that give rise to all cell types in the body and extraembryonic tissues
- differentiation potential is restricted so that tissue-specific stem cells
what is morphogenesis?
highly complex process of development of the structural shape and form of organs, limbs, facial features from primitive cell masses during embryogenesis
what must happen for morphogenesis to occur?
- primitive cell masses must undergo coordinated growth and differentiation
- movement of some cell groups relative to others
- apoptosis to remove unwanted features
what does tissue growth depend on in fetal and adult life?
balance between increase in cell numbers due to proliferation and decrease due to death
- balance of proliferation, differentiation and apoptosis
what are non-proliferative cells?
- quiescent
- differentiate and adopt specific phenotypes capable of carrying out specific functions
what is cell growth like in fetal life?
rapid and all cell types proliferate
- still constant cell death
what is cell growth like in post-natal and adult life?
cell proliferation ability and replication rates are reduced
- some cells divide rapidly and continuously
- some divide only when stimulated due to cells lost/dying
- some can’t divide at all
what is regeneration?
enables cells/tissues destroyed by injury or disease to be replaced by functionally identical cells
what categories do mammalian tissues fall into according to regenerative ability?
- labile
- stable
- permanent
what are labile cells? what are they susceptible to?
proliferate continuously in post-natal life
- short lifespan and rapid turnover
- lost cells are rapidly replaced by stem cells
- susceptible to toxic effects of radiation or drugs
what are examples of labile cells?
- haemopoietic cells of bone marrow
- lymphoid cells
- epithelial cells of skin, mouth, pharynx, oesophagus, gut, exocrine gland ducts, cervix and vagina, endometrium, urinary tract
how can regenerative potential of the skin be exploited in treatment?
- surgeon removes layer of skin including dividing basal cells from an unburned donor site
- dividing basal cells in the graft and donor site ensure regeneration of squamous epithelium at both sites
what are stable cells?
divide infrequently under normal conditions
- their stem cells are stimulated to divide rapidly when they’re lost
what are examples of stable cells?
- liver cells
- endocrine gland cells
- bone cells
- fibrous tissue
- renal tubules
what are permanent cells?
normally only divide during fetal life
- active stem cells don’t persist long after fetal life
- can’t be replaced when lost
what are examples of permanent cells?
- neurones
- retinal photoreceptors in the eye
- cardiac muscle cells
- skeletal muscle
which phase does DNA synthesis occur in?
S phase
what are the stages of the cell cycle?
G1: preparation for DNA synthesis
S: DNA synthesis
G2: preparation for mitosis
M: mitosis
what causes apoptosis in the cell cycle?
failure of a phase to complete leads to cell cycle arrest
what is the pharmacological interruption of the G1 stage?
- cyclophosphamide
- corticosteroids
- L-asparaginase
what is the pharmacological interruption of the G0 stage?
vincristine
what is the pharmacological interruption of the S phase?
- cyclophosphamide
- methotrexate
- cytosine arabinoside
what is the pharmacological interruption of the M stage?
- vincristine
- cyclophosphamide
what are CDKs? what do they do?
cyclin-dependent kinases
- activate target proteins by phosphorylation
- timely production and activation of proteins involved in cell cycles is regulated by CDKs
what regulates CDK activity?
cyclins (proteins)
what do cyclins do in the cell cycle? give an example
- transitions from one phase of the cycle to the next are initiated by rises in levels of specific cyclins
- transition from G0 to G1 is triggered by external factors, e.g. growth factors, leading to increased levels of cyclin D
what are CDKIs? what increases their levels? what does this do?
CDK inhibitors
- problems such as abnormal DNA replication, leads to rises in CDKIs
- prevents CDKs from triggering the next phase of cell division until the problem is resolved
how can generation times vary?
from 8 hours (gut epithelial cells) to 100 days+ (hepatocytes)
- duration of individual phases of cycle is usually constant
when is therapeutic interruption of the cell cycle used? what symptoms can it cause?
- used to inhibit rapid division of cancer cells
- administered systemically so there’s often inhibition of other rapidly dividing cells
- anaemia, bleeding tendency and suppression of immunity (due to inhibition of bone marrow cells and lymphoid tissue)
what is apoptosis?
physiological cellular process in which a defined and programmed sequence of intracellular events leads to the removal of a cell without the release of products harmful to surrounding cells
what does the coexistence of apoptosis alongside mitosis within a cell population ensure?
- continuous renewal of cells
- tissue is more adaptable to environmental demands
what are characteristics of apoptosis?
- energy dependent
- biochemically specific
- enzymatic digestion of nuclear and cytoplasmic contents
- phagocytosis of breakdown products within cell membrane
which disorders are caused by defective apoptosis?
neoplasia, autoimmunue disease
which disorders are caused by increased apoptosis?
- AIDS
- human immunodeficiency virus proteins may activate T-helper lymphocytes, inducing apoptosis
what are apoptosis and necrosis induced by?
- apoptosis: physiological or pathological stimuli
- necrosis: pathological injury
what is the extent of apoptosis and necrosis?
- apoptosis: single cells
- necrosis: cell groups
what are the biochemical events in apoptosis and necrosis?
- apoptosis: energy-dependent fragmentation of DNA by endogenous endonucleases; lysosomes intact
- necrosis: energy failure; impairment of ion homeostasis; lysosomes leak lytic enzymes
what is the cell membrane integrity in apoptosis and necrosis?
- apoptosis: maintained
- necrosis: lost
what is the morphology in apoptosis and necrosis?
- apoptosis: cell shrinkage and fragmentation to form apoptotic bodies with dense chromatin
- necrosis: cell swelling and lysis
what is the inflammatory response in apoptosis and necrosis?
- apoptosis: none
- necrosis: usual
what is the fate of dead cells in apoptosis and necrosis?
- apoptosis: phagocytosed by neighbouring cells
- necrosis: phagocytosed by neutrophil polymorphs and macrophages
what is the outcome of apoptosis and necrosis?
- apoptosis: cell elimination
necrosis: defence, preparation for repair
what external signals trigger apoptosis?
- detachment from the extracellular matrix
- withdrawal of growth factors
- specific signals from other cells
what are intracellular signals that trigger apoptosis?
- DNA damage
- failure to conduct cell division correctly
what are inhibitors of apoptosis?
- growth factors
- extracellular cell matrix
- sex steroids
- viral proteins
what are inducers of apoptosis?
- growth factor withdrawal
- loss of matrix attachment
- glucocorticoids
- some viruses
- free radicals
- ionising radiation
- DNA damage
- ligand-binding at death receptors
what is apoptosis inititated by?
extrinsic and intrinsic pathways
what is the intrinsic pathway of apoptosis? what does it do?
- integrates multiple external and internal stimuli
- leads to alterations in the relative levels of pro and anti apoptotic members of the Bcl-2 family
what members of the Bcl-2 family are involved in apoptosis?
Bcl-2
Bax
what does the Bcl-2 family do in apoptosis?
- Bcl-2 inhibits many factors that induce apoptosis
- Bax forms Bax-Bax dimers that enhance apoptotic stimuli
where was the Bcl-2 first discovered?
at the t(14;18) chromosomal breakpoint in follicular B-cell lymphoma
what is the ‘molecular switch’ in apoptosis?
- ratio of Bcl-2 to Bax
- determines cell’s susceptibility to apoptotic stimuli and determines whether the cell will survive and the tissue will expand or undergo apoptosis
what stimuli does the intrinsic pathway lead to?
- growth factors
- biochemical stress (e.g. DNA damage)
what is p53? what does it do?
multifunctional protein which induces cell cycle arrest and initiates DNA damage repair
- can induce apoptosis via activation of pro-apoptotic members of the Bcl-2 family
what is the extrinsic pathway of apoptosis? what happens in it?
specific mechanism for the activation of apoptosis characterised by ligand binding at death receptors on the cell surface
- ligand binding promotes clustering of receptor molecules on cell surfaces, and a signal transduction cascade resulting in caspase activation
what are death receptors?
members of the TNFR gene family, e.g. TNFR1 and Fas (CD95)
what is the role of the extrinsic pathway in the immune system?
eliminates lymphocytes that would otherwise produce self-antigens
what are caspases?
proteases which are normally present as inactive procaspase molecules
what is the role of caspases in apoptosis?
- triggering of apoptosis leads to activation of initiator caspases e.g. caspase 8
- caspase 8 cleaves other procaspases to produce active executioner caspases which degrade targets e.g. cytoskeletal framework/nuclear proteins
- caspase-3 activates DNAse which fragments DNA
- nucleus shrinks (pyknosis) and fragments (pyknosis)
- cell shrinks, retaining an intact plasma membrane; alterations of it induce phagocytosis
- dead cells not phagocytosed fragment into smaller membrane bound apoptotic bodies
what are initiator caspases?
first activated after apoptosis is triggered
- caspase 8
what does caspase-3 do?
activates DNAase which fragments DNA
what is pyknosis?
shrinkage of the nucleus
what is karyorrhexis?
fragmentation of the nucleus
does apoptosis trigger an inflammatory reaction? why/why not?
no, probably because the membrane is intact
what is apoptosis recognised as morphologically?
death of scattered single cells which form rounded, membrane-bound bodies; eventually phagocytosed and broken down by adjacent unaffected cells
what are examples of the alterations in tissue form and shape caused by cell removal by apoptosis?
- interdigital cell death responsible for separating the fingers
- cell death leading to the removal of redundant epithelium following fusion of palatine processes
- cell death in the dorsal part of the neural tubes during closure
- cell death in the involuting urachus, to remove redundant tissue between the bladder and umbilicus
what developments can failure of apoptosis lead to?
syndactyly (webbed fingers), cleft palate, spina bifida, bladder diverticulum (pouch) or fistula (open connection)
how does apoptosis contribute to development?
regression of Muellerian ducts, and removal of vestigial remnants from lower evolutionary levels, e.g. pronephros
what are diseases caused by?
- entirely genetic: inherited or prenatally acquired defects of genes
- multifactorial: interaction of genetic and environmental factors
- entirely environmental: no genetic component to risk of disease
what is the age of onset for genetic and environmental causes of disease?
- genetic: usually early
- environmental: any age
what is the familial incidence for genetic and environmental causes of disease?
- genetic: common
- environmental: unusual, unless exposed to the same agent
what is the remission for genetic and environmental causes of disease?
- genetic: none
- environmental: often, when cause can be eliminated
what is the incidence for genetic and environmental causes of disease?
- genetic: relatively uncommon
- environmental: common
what is the clustering like for genetic and environmental causes of disease?
- genetic: in families
- environmental: temporal or spatial or both
what is the linkage to inherited factors for genetic and environmental causes of disease?
- genetic: common
- environmental: relatively rare
what are categories of predisposing factors and precursors of disease?
- predictable
- probable
- predispose
- permissive effect
what are predictable predisposing factors?
many diseases are the predictable consequence of exposure to the initiating cause; host factors make little contribution to the outcome
what are probable predisposing factors?
diseases may be probable consequences of exposure to causative factors
- not absolutely inevitable
- other factors can influence the outcome
what conditions do ulcerative colitis and hepatic cirrhosis predispose to?
- UC predisposes to carcinoma of the colon
- hepatic cirrhosis predisposes to hepatocellular carcinoma
what are pre-neoplastic conditions?
diseases predisposing to tumours
what are pre-neoplastic lesions?
lesions from which tumours can develop
what is a congenital predisposition to ankylosing spondlyitis?
ankylosing spondylitis is a disabling inflammatory disease of the spinal joints of unknown aetiology
- more common in people with the HLA-B27 haplotype
what is a permissive effect?
diseases may predispose to others and allow environmental agents that aren’t normally pathogenic to cause disease
what are opportunistic infections?
occur in patients with impaired defence mechanisms, allowing infection by normally non-pathogenic organisms
what are prenatal factors contributing to disease risk?
- transplacental transmission of environmental agents
- nutritional deprivation
what are examples of diseases due to transplacental transfer of environmental agens?
- fetal alcohol syndrome
- congenital malformations due to maternal rubella infection
what is the Barker hypothesis?
an adults risk of disease is programmed partly by nutritional deprivation in utero
- deprivation could have profound effects during critical periods of fetal morphogenesis
why does incidence of many diseases increase with age?
- probability of contact with an environmental cause increases with duration of exposure risk
- disease may depend on cumulative effects of one or more environmental agents
- impaired immunity with ageing increases susceptibility to infections
- latent interval between between the exposure to cause and appearance of symptoms may be decades
give examples of diseases that have a significant genetic component?
- breast cancer
- Alzheimer’s disease
- diabetes mellitus
- osteoporosis
- coronary atherosclerosis
why may there be slow progress in characterising genetic components of diseases?
may be polygenetic and have environmental factors
why may there be a high incidence of a disease in a country/region?
- higher prevalence of a genetic predisposition in racial/ethnic groups
- environmental factors
what does the incidence of disease in the migrant racial group rising after moving from a low incidence country to a high one suggest?
likely that environmental factors are responsible for the high incidence in the indigenous population
what does the incidence of disease in the migrant racial group staying the same after moving from a low incidence country to a high one suggest?
higher incidence in the indigenous population is due to genetic factors
what are racial characteristics?
polymorphisms possessed by large groups of people of common ancestry; clustered
what are the polymorphisms of greatest relevance to disease susceptibility?
- HLA types
- blood groups
- cytokine genes
how was MHC discovered?
clinical and experimental observations on the fate of organ transplants
what is the MHC?
major histocompatibility complex
- genes
- on chromosome 6
- designated human leucocyte antigen genes
what are HLA genes?
human leucocyte antigen genes
- expressed on cell surfaces as antigens
- they are involved in graft rejection
what are the classes of HLA types?
Class I and class II
what are class I HLA types?
expressed on surface of all nucleated cells
- in all diploid cells there are pairs of allelic genes at each of three loci: genes are called A, B and C
what is the role of class I HLA types?
to enable cytotoxic T lymphocytes to recognise and eliminate virus-infected cells
what are class II HLA types?
expressed on the surface of cells that interact with T lymphocytes by physical contact, e.g. antigen-presenting cells
- pairs of allelic genes at each of three loci are called DP, DQ and DR
what is the role of class II HLA types?
initiation of immune responses
what is the association between autoimmune disease and HLA types?
- strong combination of HLA-DR3 and HLA-B8
- normally, class II types are not expressed on epithelial cells
- in organs affected by autoimmune disease, the target cells for immune destruction express class II
give examples of diseases associated with HLA types?
- allergic disorders
- ankylosing spondylitis
- coeliac disease
- Graves’ disease
- Hashimoto’s thyroiditis
- insulin-dependent diabetes mellitus
- Rheumatoid disease
what HLA type are allergic disorders associated with?
A23
- requires environmental allergen
what HLA type is ankylosing spondylitis associated with?
B27
- associated in ~90% of cases
what HLA types is coeliac disease associated with?
DR3 and B8
- gluten sensitivity
what HLA types is Graves’ disease associated with?
DR3 and B8
- due to thyroid stimulating immunoglobin
what HLA type is Hashimoto’s thyroiditis associated with?
DR5 - aberrant HLA class II expression on thyroid epithelium
what HLA type is insulin-dependent diabetes mellitus associated with?
DR3, DR4, B8
- immune injury to beta-cells in pancreatic islets
what HLA type is rheumatoid disease associated with?
DR4
- autoimmune disease
what are examples of blood group-associated diseases?
- duodenal ulceration and group O
- gastric carcinoma and group A
how are cytokines associated with disease?
incidence/severity of chronic inflammatory diseases is linked to polymorphisms within or adjacent to cytokine genes
what inflammatory diseases has TNF gene polymorphisms been associated with?
Graves’ disease of the thyroid and systemic lupus erythematosus
where is the TNF gene?
chromosome 6 between HLA classes I and II loci
what is a heterozygote advantage?
confers protection against an environmental pathogen
what is a racial association of CF? what is the explanation?
caucasians
- hypothesised that defective gene increases resistance to intestinal infection by Salmonella bacteria
what is a racial association of sickle cell anaemia? what is the explanation?
blacks
- sickle cells resist malarial parasitisation
- HbS gene more common in blacks in areas of endemic malaria
what is a racial association of haemochromatosis?
what is the explanation
caucasians
- mutant HFE protein may have conferred protection against European plagues cause by Yersinia bacteria
what does effective morphogenesis require?
mechanisms to signal the direction of differentiation to cells within different parts of the embryo and intracellular mechanisms that yield the selective, coordinated gene expression to distinguish cell types
what is artificial twinning?
at the 4/8 cell stage embryos can be artificially separated into separate cells groups, each capable of forming a complete organism
how can a ‘fate map’ of development of cells be constructed?
observing the effects of selective marking/obliteration
what is determination?
developmental path of cells is planned long before differentiation
what must determining cells have/do?
- have differences that are heritable from one cell generation to another
- be committed and commit its progeny to specialised development
- change its internal character
what is induction?
pattern of differentiation in one cell type may be controlled by another
what are examples of induction?
- action of mesoderm on ectoderm at different sites to form parts of the neural tube
- action of mesoderm on skin at different sites to form epithelium at differing thickness and accessory gland content
- action of mesoderm on developing epithelial cells to form branching tubular glands
- action of uretic bud to induce metanephric blastema in kidney formation
how do body cells differ?
not in the range of genes present, but in how those genes are expressed
on what levels can the synthesis of a gene product be controlled?
- transcription (formation of mRNA)
- transport (export of mRNA from the nucleus to ribosomes in the cytoplasm)
- translation (formation of gene product within the ribosomes)
what are transcription factors? what are they regulated by?
protein products of gene products of small number of control genes
- regulated by other transcription factors, acting as master control genes
what is a homeotic mutation? what does it show?
transformation of one body part into another that is usually found on a different body segment
- importance of the position of a cell within an embryo at a given time and of genetically predefined programmes of development
what are homeobox genes?
shared amino acid sequence domains
- are transcription factors influencing morphogenesis
what is epigenetic regulation?
alterations in the structure of DNA which modulates the expression of specific genes and are heritable from a cell to its progeny
what is DNA methylation?
best understood epigenetic regulator of gene expression
- occurs in lengths of DNA rich in sequential adjacent cytosine and guanine bases (CpG islands) which occur in the promotor region upstream of the coding region of specific genes
what does DNA methylation do?
inhibits transcription and gene expression
- stable and preserved during DNA replication
- patterns of methylation are passed from cells to their progeny
- provides a heritable mechanism of gene expression regulation
what may disturbances in DNA patterns likely to lead to?
cancer
how do histones exert epigenetic gene expression?
post translational modification (e.g. methylation, acetylation) of histones alters chromatin structure
- may signal to transcriptional machinery whether or not a genomic region is active or silenced
- may be passed from a cell to its progeny
- plays some role in cell determination and differentiation
what is the differentiation potential of the zygote?
zygote and cells from its first two divisions are totipotent, and are able to form all cells of embryo and placenta
what is the differentiation potential of the early blastocyst?
embryonic stem cells derived from the early blastocyst are pluripotent - producing almost all cells derived from the endoderm, mesoderm and ectoderm
- not cells from placenta/supporting tissues
what is the differentiation potential of most individual tissues?
have either multipotent or unipotent stem cells
- multipotent: generate small numbers of cell types
- unipotent: only one cell type
what is transdifferentiation? what is an advantage of it?
inducing stem cells from one organ system into cells of other organ systems
- avoids immunological rejection of transplanted organs
how is a differentiated state of a cell maintained?
- epigenetic changes regulating gene expression
- interactions with adjacent cells, through secreted paracrine factors
- secreted factors (autocrine factors), including growth factors and extracellular matrix
what are modulations?
minor alterations to the differentiated state which may occur if the local environment changes
reversible interconversions between between closely related cell phenotypes
what is an example of a modulation?
alteration in synthesis of certain liver enzymes in response to circulating corticosteroids
what are examples of modulations during cell maturation in neonatal development?
- production of surfactant by type II pneumonocytes under the influence of corticosteroids
- synthesis of vitamin-K dependent blood clotting factors by the hepatocyte
- gut maturation affected by EGF
what is the summary of normal differentiation and morphogenesis?
- determination and differentiation occur in cell by transcriptional modifications to the expression of the genome
- expression of genes is modified
- differentiated state is maintained or modulated
- external factors may alter differentiated state of the cell at any time
how is expression of individual genes modified, in summary?
- positional information carried by a small number of control gene products, causing local alterations in growth and differentiation
- migrations of cells and modifications mediated by adjacent cells (paracrine factors) or endocrine factors
how is the differentiated state maintained or modulated, in summary?
- interactions with extracellular environment and matrix
- epigenetic modification that can be passed from a cell to its progeny
how does an individual cell increase tissue/organ size in response to increased functional demand?
- hypertrophy
- hyperplasia
- combination of above
what is hypertrophy?
increasing cell size without cell replication
what is hyperplasia?
increasing cell numbers by cell division
what is ploidy?
permanent cells increasing their DNA content
what is an important component of hyperplasia that is often overlooked?
decrease in cell loss by apoptosis
what are examples of physiologically increased growth of tissues?
- muscle hypertrophy
- hyperplasia of bone marrow
- hyperplasia of breast tissue
- hypertrophy and hyperplasia of uterine smooth muscle
- thyroid hyperplasia
when/why can muscle hypertrophy happen?
in athletes
- skeletal muscle of the limbs
- in left ventricle (due to sustained outflow resistance)
when/why does hyperplasia of bone marrow cells happen?
individuals living at high altitude
- produces increased erythrocytes
- stimulated by increased production of growth factor erythropoietin
when/why does hyperplasia of breast tissue occur?
puberty, pregnancy and lactation
- due to oestrogens, progesterone, prolactin, growth hormone and human placental lactogen
when/why does hypertrophy and hyperplasia of uterine smooth muscle occur?
puberty and pregnancy
- stimulated by oestrogens
when/why does thyroid hyperplasia occur?
due to increased metabolic demands of puberty and pregnancy
what are apparently autonomous hyperplasias?
in some apparently hyperplastic conditions, cells appear autonomous and continue proliferating despite lack of stimulus or control mechanism
what are examples of apparently autonomous hyperplasias?
- psoriasis; marked epidermal hyperplasia
- Paget’s disease of bone: hyperplasia of osteoblasts and osteoclasts leading to thick but weak bone
- fibromatoses: proliferations of myofibroblasts, occasionally forming tumour like masses
what is Paget’s disease of bone?
hyperplasia of osteoblasts and osteoclasts resulting in thick but weak bone
what is fibromatoses?
apparantly autonomous proliferations of myofibroblasts, sometimes forming tumour-like masses
what are examples of tumour like masses formed in fibromatoses?
- palmar fibromatosis (Dupuytren’s contracture), - desmoid tumour
- retroperitoneal fibromatosis
- Peyronie’s disease of the penis
what are examples of non-regenerative hypertrophy and hyperplasia in the myocardidum?
right ventricular hypertrophy
- response to pulmonary valve stenosis, pulmonary hypertension or ventricular septal defect
left ventricular hypertrophy
- response to aortic valve stenosis or systemic hypertension
what are examples of non-regenerative hypertrophy and hyperplasia in arterial smooth muscle?
hypertrophy of arterial walls
- occurs in hypertension
what are examples of non-regenerative hypertrophy and hyperplasia in capillary vessels?
proliferative retinopathy
- complication of diabetes mellitus
what are examples of non-regenerative hypertrophy and hyperplasia in bone marrow?
erythrocyte precursor hyperplasia
- response to increased erythropoietin production
what is an example of non-regenerative hypertrophy and hyperplasia in cytotoxic T lymphocytes?
hyperplastic expansion of T-cell populations
- involved in cell-mediated immune responses
what is an example of non-regenerative hypertrophy and hyperplasia in the breast?
juvenile hypertrophy (females) - exaggerated pubertal enlargement
gynaecomastia (males)
- due to high estrogen levels (e.g. in cirrhosis, iatrogenic, endocrine tumours)
what is an example of non-regenerative hypertrophy and hyperplasia in the prostate?
epithelial and connective tissue hyperplasia
- relative excess of oestrogens stimulates oestrogen-sensitive central zone
what is an example of non-regenerative hypertrophy and hyperplasia in the thyroid?
follicular epithelial hyperplasia
- most commonly due to a thyroid-stimulating antibody (Graves’ disease)
what is an example of non-regenerative hypertrophy and hyperplasia in the adrenal cortex?
cortical hyperplasia
- response to increased ACTH production
what is an example of non-regenerative hypertrophy and hyperplasia in myointimal cells?
myointimal cell hyperplasia in atheromatous plaques
- proliferate in response to platelet-derived growth factor
what do matrix metalloproteinases do?
selectively degrade extracellular matrix proteins
what is intussusception?
existing vascular channels may be bisected by an extracellular matrix ‘pillar’, with the two channels subsequently being extended towards the angiogenic stimulus
what do myofibroblasts do in angiogenesis?
often follow new blood vessels into damaged tissues, where they proliferate and produce matrix proteins e.g. fibronectin and collagen to strengthen the scar
- eventually contract and differentiate into fibroblasts
what may contraction of an angiogenetic scar cause?
- deformity and reduced movements of limbs affected by extensive scarring following skin burns around joints
- bowel stenosis and obstruction caused by annular scarring
- detachment of the retina due
what happens in the epidermis in skin healing?
PDGF acts synergistically with EGF and the somatomedins (IGF1 and 2) to promote proliferation of basal epithelial cells
what happens in the dermis in skin healing?
- myofibroblasts proliferate in response to PDGF and TGF beta
- collagen and fibronectin secretion is stimulated by TGF beta, and fibronectin aids migration of epithelial and dermal cells
what are factors mediating wound healing?
- blood coagulation and platelet degranulation, releasing growth factors
- GF are chemotactic for macrophages, which migrate into the wound to phagocytose bacteria and necrotic debris
- epidermal basal epithelial cells are activated by released growth factors from platelets,
- dermal myofibroblasts
- epidermal cells by paracrine and autocrine mechanisms
- and saliva
- nutrients and oxygen and circulating hormones and growth factors diffusing from blood vessels contribute to epidermal growth
- GF from platelets stimulate cell division in myofibroblasts
- fibronectin stimulates migration of dermal myofibroblasts and epidermal epithelial cells
- angiogenic GF stimulate proliferation and migration of new blood vessels into wound area
what happens in cardiac hypertrophy?
- after an infarct, there is death of a segment of muscle which is replaced by scar tissue
- the remainder of the myocardium must work harder for a given cardiac output, so there is compensatory hypertrophy without cell division
what are the types/patterns of cardiac hypertrophy?
right ventricular hypertrophy secondary to left ventricular failure and pulmonary hypertension
what is atrophy?
decrease in size of an organ or cell by reduction in cell size and/or reduction in cell numbers, often by apoptosis
what is needed for atrophy to occur?
- cessation of growth
- active reduction in cell size and/or decrease in cell numbers, mediated by apoptosis
when do physiological atrophy and involution occur?
- as part of morphogenesis
- branchial clefts, thyroglossal ducts and notochord undergo involution during development
- involution occurs in genitourinary tract development
- involution of thymus gland in early adult life
- atrophy of various tissues including bone, gums, cerebrum and reproductive system parts in late old age
what are categories of pathological condition in which atrophy may occur?
- decreased function
- loss of innervation
- loss of blood supply
- pressure atrophy
- lack of nutrition
- loss of endocrine stimulation
- hormone-induced atrophy
how does atrophy occur in decreased fuction?
- marked muscle atrophy due to decrease in muscle fibre size
- extensive physiotherapy may be required
- bone atrophy may lead to osteoporosis and bone weakening
how does atrophy occur in loss of innervation?
- occurs when there is loss of anterior horn cells of the spinal cord
how does atrophy occur in loss of blood supply?
- due to tissue hypoxia
- epidermal atrophy is seen in skin of the lower legs in patients with circulatory stagnation related to varicose veins or atheromatous narrowing of the arteries
how does atrophy occur in pressure atrophy?
- when tissues are compressed by exogenous agents (atrophy of skin and soft tissues over the sacrum) or endogenous factors
- major factor is local tissue hypoxia
how does lack of nutrition cause atrophy?
- may cause atrophy of adipose tissue, the gut, pancreas and muscle
- cachexia
what is cachexia?
severe atrophy similar to that seen in severe starvation
- may be seen in patients in late stages of severe illnesses
- may be influenced by cytokines e.g. TNF
how does loss of endocrine stimulation cause atrophy? give examples
- if endocrine stimulation of a target organ is inadequate, atrophy may occur
- e.g. adrenal gland atrophies if there’s decreased ACTH secretion by the anterior pituitary
why may there be decreased ACTH secretion by the anterior pituitary gland?
- destruction due to tumor/infarction
- therapeutic use of high concentrations of corticosteroids (feedback reduction)
how does hormone-induced atrophy occur?
- may be seen in the skin, due to growth-inhibiting actions of corticosteroids
- all steroids when applied topically may be absorbed through skin to produce systemic side effects
what is hypoplasia?
the failure in attainment of the normal size or shape of an organ due to a developmental failure
- failure in morphogenesis
what is an example of hypoplasia?
failure in development of the legs in adult patients with severe spina bifida and neurological deficit in the lower limbs
what is metaplasia?
transformation of one type of differentiated cell into another fully differentiated cell type
- metaplastic daughter cells replace original cells, giving rise to a tissue type that may be more able to withstand adverse environmental changes
what can cause metaplasia?
- occurs in context of alterations in the cellular environment, esp. if associated with chronic cellular injury and repaiar
- inappropriate activation or repression of groups of genes involved in maintenance of cellular differentiation
- mutations in genes
what are examples of metaplasia in epithelial tissues?
include a change to squamous epithelium
- ciliated respiratory epithelium of trachea and bronchi in smokers
- ducts of the salivary glands and pancreas, and bile ducts in presence of stones
- transitional bladder epithelium in presence of stones, and in presence of ova of the trematode schistosoma haematobium
- transitional and columnar nasal epithelium in vitamin A deficiency
what happens in Barrett’s oesophagus? what is it caused by?
- glandular metaplasia: replacement of normal squamous epithelium of the oesophagus by columnar glandular epithelium, sometimes showing overt intestinal differentiation
- caused by chronic reflux of gastro-duodenal contents into the oesophagus
what are examples of metaplasia in mesenchymal tissues?
osseous metaplasia (bone formation)
- following calcium deposition in atheromatous arterial walls
- in bronchial cartilage
- following long-standing disease of the uveal tract of the eye
what is metaplasia often associated with? why?
- subsequent development of malignancy within the metaplastic tissue
- due to environmental changes that caused metaplasia can also induce dysplasia, which may lead to tumor formation
what is a congenital disorder?
a disorder present at birth
what is trisomy?
the presence of additional whole chromosomes
what is trisomy 21? what is its incidence? what are the symptoms?
Down’s syndrome
- 1 in 1000 births
- mental retardation, flattened facial profile and prominent epicanthic folds
- short hands and a transverse palmar crease
- abnormalities of the ears, trunk, pelvis and phalanges
what is Trisomy 18? what is its incidence? what are the symptoms?
Edwards’ syndrome
- 1 in 5000 births
- ear, jaw, cardiac, renal, intestinal and skeletal abnormalities
what is trisomy 13? what is its incidence? what are the symptoms?
Patau’s syndrome
- 1 in 6000 births
- microcephaly, microphthalmia, hare lip, cleft palate, polydactyly, abnormal ears, rocker bottom feet, cardiac and visceral defects
what is Klinefelter’s syndrome? what is its incidence? what are the symptoms?
47XXY
- 1 in 850 male births
- testicular atrophy, absent spermatogenesis, eunuchoid bodily habitus, gynaecomastia, female distribution of body hair, mental retardation
what are variations of Klinefelter’s syndrome? what are their symptoms?
48XXXY, 49 XXXXY, 48XXYY
- rare
- cryptorchidism, hypospadias, severe mental retardation, radio-ulnar synostosis
what are double Y males? what is the incidence? what are the symptoms?
47XYY
- form 1 in 1000 male births
- phenotypically normal, most are over 6 feet tall
- subtle behavioural abnormalities
what is Turner’s syndrome? what is the incidence? what are its symptoms?
gonadal dysgenesis, 45X
- 1 in 3000 female births
- one half are mosaics (45X/46XX), some have 46 chromosomes and two X chromosomes but one is defective
- short stature, primary amenorrhoea, infertility, webbing of the neck, broad chest, widely spaced nipples, cubitus valgus, low posterior hairline and coarctation of the aorta
what are multiple X females? what is their incidence? what are their sympoms?
47XXX, 48XXXX
- 1 in 1200 female births
- mental retardation, menstrual disturbances, some are normal and fertile
what are true hermaphrodites?
most 46XX, some 46XX/47XXY mosaics
- both testicular and ovarian tissue
- varying genital tract abnormalities
what is cri-du-chat syndrome? what is its incidence? what are the symptoms?
46XX, 5p- or 46XY, 5p-
- 1 in 50000 births
- deletion of the short arm of chromosome 5 (5p-)
- microcephaly, severe mental retardation, round face, gross hypertelorism and epicanthic folds
what are the three categories of single gene disorders?
- enzyme defects
- defects in receptors or cellular transport
- non-enzyme protein defects
what are enzyme defects in relation to single gene disorders?
- altered gene may result in decreased enzyme synthesis or synthesis of a defective enzyme
- failure to synthesise the end products of a reaction catalysed by an enzyme may block normal cellular function
what is an example of an enzyme defect single gene disorder?
albinism
- caused by absent melanin production due to tyrosinase deficiency
what are examples of accumulation of enzyme substrate in enzyme defect single gene disorders?
- accumulation of galactose and tissue damage in galactose-1-phosphate uridyl transferase deficiency
- accumulation of phenylalanine, causing mental abnormality in phenylalanin hydroxylase deficiency
- accumulation of glycogen, mucopolysaccharides in lysosomes in enzyme deficiency states of lysosome storage disorders
what can defects in receptors/cellular transport in single gene disorders cause?
- insensitivity to substances e.g. hormones
- cellular transport deficiencies may lead to disorders e.g. CF
what disorders can non-enzyme protein defects in single gene disorders lead to?
- failure of production of important proteins/production of abnormalities in proteins has widespread effects
- sickle cell anaemia caused by abnormal haemoglobin
- marfan’s and ehlers-danlos syndromes caused by defective collagen production
what are deformations or disruptions?
anomalies of normal development caused by extrinsic physical forces (e.g. uterine constraint or amniotic bands)
what are malformations?
intrinsic failures of morphogenesis, differentiation or growth
what is a syndrome?
collection of specific anomalies typically seen together but without an obvious single initiating localised defect
what is a sequence?
a constellation of typical individual features, but in which these features are secondary to an identified single localised primary anomaly, which leads to secondary effects elsewhere
what is the Potter sequence? why is it a sequence and not a syndrome?
- various primary causes of a decreased volume of amniotic fluid (oligohydramnios) all lead to fetal compression
- deformations of the hands, feet, hips and facies
- there is a sequential casual relationship between oligohydramnios, fetal compression and resultant deformities
what are the potential outcomes of defects in embryo division?
- conjoined twins
- fetus in feto
what is fetus in feto?
one of the fused twins develops imperfectly and grows on the other, either externally or within the abdominal cavity
- some extragonadal teratomas in neonates may belong to this group
what are teratogens?
physical, chemical or infective agents that interfere with growth and differentiation, resulting in fetal abnormalities
- extent and severity of fetal abnormality depend on the nature of the teratogen and the developmental stage of the embryo
when are the effects of teratogens on organogenesis most severe?
early organogenesis (4-5 weeks of gestation)
what is the teratogenic effect of irradiation?
microcephaly
what is the teratogenic effect of thalidomide?
- amelia/phocomelia (absent/rudimentary limbs)
- heart, kidney, GI and facial abnormalities
what is the teratogenic effect of folic acid antagonists, e.g. 4-amino PGA?
- anencephaly
- hydrocephalus
- cleft lip/palate
- skull defects
what is the teratogenic effect of anticonvulsants?
- cleft lip/palate
- heart defects
- minor skeletal defects
what is the teratogenic effect of warfarin?
nasal/facial abnormalities
what is the teratogenic effect of testosterone and synthetic progestagens?
- virilisation of female fetus
- atypical genitalia
what is the teratogenic effect of alcohol?
- microcephaly
- abnormal facies
- oblique palpebral fissures
- growth disturbance
what is the teratogenic effect of rubella?
- cataracts
- microphthalmia
- microcephaly
- heart defects
what is the teratogenic effect of cytomegalovirus?
microcephaly
what is the teratogenic effect of herpes simplex?
- microcephaly
- microphthalmia
what is the teratogenic effect of toxoplasmosis?
microcephaly
what is Kartagener’s syndrome? what can it lead to?
- defect in ciliary motility due to absent or abnormal dynein arms
- affects cell motility during embryogenesis
- sinus inversus
- complications in later life: bronchiectasis and infertility due to sperm immobility
what is sinus inversus?
congenital lateral inversion of the position of body organs
what is Hirschprung’s disease? when is it seen?
- condition leading to marked dilation of the colon and failure of colonic motility in the neonatal period, due to the absence of Meissner’s and Auerback’s plexuses
- caused by selective failure of craniocaudal migration of neuroblasts in weeks 5-12 of gestation
- 10 times more frequent in Down’s syndrome children
what is cryptorchidism?
- undescended testis
- may be associated with severe forms of Klinefelter’s syndrome
- often an isolated anomaly in an otherwise normal male
- increased risk of neoplasia
what is agenesis (aplasia)?
failure of development of an organ or structure
which types of agenesis of individual organs are recorded/have happened?
- renal agenesis
- thymic agenesis
- anencephaly
what is renal agenesis? why does it occur?
- unilateral or bilateral (if bilateral then baby may survive for only a few days)
- due to a failure of the mesonephric duct to give rise to the ureteric bud, and consequent failure of metanephric blastema induction
what is thymic agensis? where may it be seen?
- seen in DiGeorge syndrome
- consequent poor T-cell production leading to severe deficiency of cell-mediated immunity
what is DiGeorge syndrome? what causes it? what is it associated with?
- deletion of part of chromosome 22 (22q11.2 deletion syndrome)
- thymic agenesis, cardiac and palatine abnormalities, learning difficulties and hypoparathyroidism
what is anencephaly?
- severe neural tube defect where the cerebrum and often the cerebellum are absent
- lethal
what is atresia?
failure of development of a lumen in a normally tubular epithelial structure
what are examples of atresia?
- oesophageal atresia
- biliary atresia
- urethral atresia
what is oesophageal atresia?
- may be seen in associatioin with tracheo-oesophageal fistulae
- due to anomalies in development of structures from the primitive foregut
what is biliary atresia?
uncommon cause of obstructive jaundice in early childhood
what is urethral atresia?
- very rare
- may be associated with rectourethral or urachal fistula or congenital absence of the anterior abdominal wall muscles
what is hypoplasia?
failure in development of the normal size of an organ
- may affect only part of an organ, e.g. segmental hypoplasia of the kidney
what is an example of hypoplasia?
- relatively common
- affects osseous nuclei of the acetabulum
- causing congenital dislocation of the hip due to a flattened roof to the acetabulum
what is maldifferentiation (dysgenesis, dysplasia)?
failure of normal differentiation of an organ
- often retains primitive embryological structures
what is an example of maldifferentiation?
- renal dysplasia due to anomalous metanephric differentiation
- primitive tubular structures can be admixed with cellular mesenchyme and smooth muscle
what are ectopic and heterotopic tissues?
usually small areas of mature tissue from one organ that are present within another tissue
what is an example of etopic/heterotopic tissues?
endometriosis
- endometrial tissue is found around the peritoneum
- causes abdominal pain during menstruation
what is a choristoma?
related form of heterotopia
- one or more mature differentiated tissues aggregate as a tumour-like mass at an inappropriate site
what is an example of a choristoma?
complex choristoma of the conjunctiva
- varying proportions of cartilage, adipose tissue, smooth muscle and lacrimal gland acini
what could a conjunctival choristoma consisting of lacrimal gland elements alone be considered as?
ectopic (heterotopic) lacrimal gland
what are conditions caused by neural tube defects?
- anencephaly
- hydrocephalus
- spina bifida
what is an established factor leading to neural tube defects?
dietary deficiency of folate (vitamin B9) during early stages of embryogenesis
what may female pseudohermaphroditism be due to?
exposure of the developing fetus to the masculinising effects of excess testosterone or progestagens, causing abnormal differentiation of the external genitalia
what are causes of female pseudohermaphroditism?
- an enzyme defect in the fetal adrenal gland, leading to excessive androgen production at the expense of cortisol synthesis (consequent adrenal hyperplasia due to feedback mechanisms increasing ACTH secretion)
- exogenous androgenic steroids from a maternal androgen-secreting tumour or administration of androgens during pregnancy
what are the causes of male pseudohermaphroditism?
- testicular unrespsonsiveness to hCG or LH, due to reduction in receptors to these hormones; causes failure of testosterone secretion
- errors of testosterone biosynthesis due to enzyme defects
- tissue insensitivity to androgens
- abnormality in testosterone metabolism by peripheral tissues, in 5-alpha reductase deficiency
- defects in synthesis, secretion and response to Muellerian duct inhibitory factor
- maternal ingestion of oestrogens and progestins
what is the main symptom of male hermaphrotidism?
small and atrophic testis, and a female phenotype
when do the important stages of development of lips, palate, nose and jaws occur?
first 9 weeks of embyonic life
how do maxillary processes grow?
from 5 weeks of gestatioinal age, they grow anteriorly and medially and fuse with developing fronto-nasal process at two points below the nostrils, forming the upper lip
how does the palate develop?
develops from the palatal processes of the maxillary processes, which grow medially to fuse with the nasal septum in the midline at 9 weeks
what is the Hayflick limit?
maximum number of possible cell divisions
- ascribed to the shortening of telomeres with each successive cell division
how do Hayflick limits differ between mammals?
- small and short lived mammals have low limits
- larger and long lived species have high limits
how can short-lived cells and stem/progenitor cells minimise deleterious effects? can long-lived cells do this?
- divide any cytoplasmic debris between daughter cells at each division
- no; accumulated debris has detrimental effects on function
what is the Hayflick limit?
maximum number of possible cell divisions
- ascribed to the shortening of telomeres with each successive cell division
how do Hayflick limits differ between mammals?
- small and short lived mammals have low limits
- larger and long lived species have high limits
how can short-lived cells and stem/progenitor cells minimise deleterious effects? can long-lived cells do this?
- divide any cytoplasmic debris between daughter cells at each division
- no; accumulated debris has detrimental effects on function
what is the link between ageing and death and socioeconomic groups? what can this suggest?
- many diseases are more common in people from lower socio-economic groups; they exhibit ageing changes and die earlier than age and sex matched people from higher socio-economic groups
- disadvantaged in diet, housing and social welfare, etc
what is the evidence for genetic factors in ageing?
- genetic programmed processes in embryogenesis, infancy, adolescence and maturity
- ageing has a genetic component, but limits can be modified by the environment
what are the mechanisms for the genetic component of ageing?
- statistical association between longevity and certain alleles of the apolipoprotein E and forkhead box 03A genes, but total variation in longevity explained by variants is small; not clear if they confer a positive benefit or reflect the absence of deleterous variants
- e4 allele of APO-E is associated with Alzheimer’s and CV illness
- extreme old age is associated with variations in the human telomerase reverse transcriptase gene
- centenarians and offspring maintain longer telomeres
- was believed that longevity was a maternal trait, inherited through mitochondrial genes, but this has been disputed
what is the link between ageing and death and socioeconomi groups? what can this suggest?
- many diseases are more common in people from lower socio-economic groups; they exhibit ageing changes and die earlier than age and sex matched people from higher socio-economic groups
- disadvantaged in diet, housing and social welfare, etc
what is an example of interaction of genetic mechanisms with environmental factors?
Dutch children who survived chronic starvation lived longer than populations not starved
what are the cellular and subcellular mechanisms that are suggested to cause cumulative damage?
- protein cross-linking
- DNA cross-linking
- true mutations in DNA, making essential genes unavailable or functionally altered
- damage to mitochondria
- other defects in oxygen and nutrient utilisation
how do wear and tear theories explain why cardiac and CNS failures are common causes of death?
functionally important cells in crucial tissues have very limited ability to regenerate
what does the wear and tear theory depend on?
statistical view of ageing
- we are all exposed to the same amount of wear and tear
- we have a narrow range of life expectancy that gives us a characteristic lifespan
what is the role of free radicals in ageing?
- created in neutrophils and macrophages
- usually, there are enzymatic and quenching processes in cells to dispose of them
- the greater the exposure to free radical inducers, the greater the chance of damage
how do telomeres change in length over age? what effect does this have?
- decreases with age
- short telomeres permit chromosomal fusion
- chromosomal fusion correlates with higher incidence of karyotypic aberrations in cells from elderly individuals and in senescent cells in culture
in which human cells are the telomeres replicated by telomerase?
germ cells and embryos
what is the frailty syndrome?
- pragmatic solution to understanding the diverse phenomena of ageing
- describes a state of non-specific vulnerability recognisable in the elderly
what is the pathological expression of frailty syndrome?
the elderly person who dies after a gentle and gradual deterioration
- post-mortem examination reveals no single cause or simple combination of causes
what causes frailty syndrome?
- consequence of changes in inflammatory responses
- neurohormonal dysregulation and metabolic alterations
what does sarcopenia in frailty syndrome lead to?
- critical feature of frailty syndrome
- reduced metabolic rate and chronic poor nutrition
- further loss of muscle bulk and established frailty cycle
how do different grades of cancer affect people years later?
- in the first few years, grade 3 has a steep drop in survival %. It then plateaus out. If it was going to kill the patient, then it would have earlier.
- Grade 1/2 can still kill patients many years later as there is a steady drop in % survival.
what are causes of fluctuating cognitive function?
- subdural haemotoma
- cerebral abscess
- insulinoma producing hypoglycaemia
- meningioma
- acute aortic regurgitation
- hypertensive encephalopathy
- alcohol intoxication
what is a tumour (neoplasm)?
lesion resulting from the autonomous or relatively autonomous abnormal growth of cells that persists in the absence of the initiating stimulus
what is neoplastic transformation? what does it involve?
- nucleated cell type in the body forming a tumour or neoplasm (new growth)
- accumulation of genetic alterations (e.g. mutations, deletions, translocations, rearrangements, amplifications)
- accumulation of epigenetic changes (e.g. promotor methylation silencing transcription)
what do the changes in neoplastic transformation produce?
cells that can escape permanently from nrmal growth regulatory mechanisms
what are malignant tumours?
tumours that possess potentially lethal abnormal characteristics enabling them to invade and metastasise to other tissues
what is the incidence of malignant tumours?
develop in about 25% of the human population
- risk increases with age, but some can occur in infancy
what is the mortality rate of malignant tumours? how does it vary?
- high mortality rate
- 1/5th of all deaths in developed countries
- varies between specific tumour types
what are the most common malignant neoplasms?
- lung cancer is the most frequent one in the UK and USA
- followed by colorectal cancer
- breast cancer in women and prostate cancer in men is common
what do solid tumours consist of?
- neoplastic cells
- stroma
