Everything Flashcards
Which four clinical signs contributed to your assumption that Harley was hypovolemic?
Weakness, collapse, tachycardia, weak pulse
In which cellular space is fluid accumulating in pitting oedema?
Interstitial / extracellular space
How does snake venom affect the cardiovascular system?
Release of fibrinolytic and thrombin-like enzymes to cause widespread clotting, depletion of fibrinogen and, later, widespread microhaemorrhages.
Define hypovolemia
Loss of fluid from the intravascular compartment; characterised by Na+ loss
Why were hypertonic fluids contraindicated in Harley’s case?
Because they work by drawing fluid out of the interstitial space into the blood to restore blood volume. However, Harley may have had snake venom in this compartment.
Would isotonic fluids help more with intravascular volume expansion or extravascular dehydration?
It would contribute equally.
What is one toxic mechanism of PLA2 in snake venom?
Inhibit the electron transfer chain and solubilise mitochondrial enzymes
Name three toxic components of snake venom
Hyaluronidase, collagenase, phospholipse, amino acid oxidases
Define petechiae
Small haemorrhages in the skin
Define ecchymoses
Converging petechiae visible in the mucous membranes
Two mechanisms by which snake venom can interrupt neuromuscular transmission are
Blocking (antagonising) the AChR, preventing release of ACh from pre-synaptic nerve
What is the major risk associated with giving antivenom to a dog?
Allergic reaction to the equine or sheep protein that would also be in the solution
How does snake venom spread around the body?
Spreads locally via diffusion, spreads to the blood via the lymphatics, spreads systemically via the blood
Why shouldn’t you shake antivenom?
Destroys the proteins within, also causes the liquid to foam making it difficult to draw up.
Describe the role of iodine in thyroid hormone production
Iodine converted to iodide in the GIT, which is then absorbed and travels to the thyroid. Here, it iodinates tyrosine residues on the thyroglobulin molecule to create mono-iodotyrosine and di-iodotyrosine.
What is the mechanism of action of a cyanogenetic goitrogen?
Acts to inhibit iodine uptake by thyroid, preventing synthesis of T3 and T4. Get overstimulation of thyroid with TSH in the absence of T3 and T4, leading to hyperplastic/hypertrophic thyroid.
What is the mechanism of action of a thiouracil goitrogen?
Prevent incorporation of iodine into thyroid hormones
Loose CT has a high or low ratio of cells to fibres?
High
Dense CT has a high or low ratio of cells to fibres?
Low
Three types of CT proper?
Loose, adipose, dense
Two types of extracellular material?
Amorphous and fibrous
Describe a mesenchymal cell (light microscope level)
- stellate
- cytoplasmic processes
- oval/round nucleus
- multipotent
- small numbers in adults
Describe a fibroblast (light microscope level)
- stellate or spindle
- ovoid nucleus
- abundant basophilic cytoplasm
- synthesises collagen
Describe a fibrocyte (light microscope level)
- flattened, elongated spindle shape
- small
- elongated nucleus
- minimal cytoplasm as not active
What are some contents of mast cell granules?
Heparin, histamine, serotonin, proteases
Describe a B cell (light microscope)
Fat ovoid cell with abundant basophilic cytoplasm. Radially arranged chromatin in eccentric nucleus.
Do stereocilia have motility?
No
Name to lateral membrane specialisations for adherence
Desmosomes
Zona/macula adherens
What attaches epithelial cells to basement membrane?
Hemidesmosomes
Explain merocrine secretion
Vesicles containing secretory product open onto cell surface and discharge
Explain holocrine secretion
Entire secretory cell breaks down to release its product (e.g sebaceous glands)
Explain apocrine secretion
Part of apical cytoplasm is lost together with secretory product e.g sweat glands, mammary, prostate
In flexion, legs go backward or forward?
Backward
In extension legs go backward or forward?
Forward
A horse kick is an example of which kind of movement?
Abduction
Which joint is known as the ‘hock’? Which bones constitute the hock?
The tarsal joint - talus + calcaneus + centrale
Which is the main weight-bearing bone immediately distal to the stifle in a dog?
The tibia
How many sesamoids in a single paw? Where are they?
9 in total:
1 in digit 1
2 each in digits 2 - 5
Which phalanx is missing in digit 1?
Phalanx II
What is the name for the articular surface of the humerus and scapula?
The glenoid cavity
Which two bones meet at the antebrachial joint?
The radius, and the carpal bone Radiale
The most medial carpal bone is?
Ulnare
The large lateral foramen in the pelvis is called?
The obturator foramen. Contains nerves, femoral artery, etc
When viewed laterally, the femoral head points cranially or caudally? What about the distal condyles?
Cranially - the surface that articulates with the tibia and fibula points caudally
The surface between the lateral and medial femoral condyles on the distal caudal aspect of the femur is called?
The popliteal surface.
The malleolus structures of the tibia and fibula occur at the proximal or distal end? Which is larger - medial or lateral?
Distal. Medial is the larger.
When standing, the fibula is medial or lateral to the tibia?
Lateral.
The tibial tuberosity occurs on the cranial aspect and points medially or laterally?
Laterally
What is the vertebral formula for a dog?
C 7 T 13 (T 11 is usually anticlinal) L 7 S 3 (fused) C 20 - 23
What does the head of the rib articulate with?
Both the caudal costal fovea of the cranial rib, and the cranial costal fovea of the caudal rib
What does the tubercle of the rib articulate with?
The transverse process of the caudal rib
The clavicle runs from__ to ___?
The clavicle runs from the shoulder joint to the cranial end of the sternum
Which bone is the hoof of a horse analogous to?
Metacarpal III
To which bones does ‘crus’ refer?
Tibia and fibula
To which bones does ‘manus’ refer?
The forepaw / hand structure
Define sesamoid.
A stiffening in a ligament that helps to reduce friction of joints and increase mechanical efficiency
What is the navicular bone?
A sesamoid bone present i horses and other heavy, hoofed animals. Occurs between P2 and P3
What is the difference between a condyle and a trochlea?
Condyles are usually rounded, trochleas are groove shaped. Both provide articular surfaces for the bone.
Are epicondyles usually rough or smooth?
Rough
Are tubercles found in forelimbs? What about trochanters?
Tubercles are tuberosities of the forelimb. Trochanters are tuberosities of the hindlimb
What is a splanchnic bone?
A bone that forms within viscera e.g penis bone in dogs
Name three major ligaments from cranial - caudal
Nuchal, supraspinous, sacrosciatic
Body water is approximately __% of body weight. __% bodyweight is intracellular and __% bodyweight is extracellular.
Body water is approximately 60% of body weight. 40% bodyweight is intracellular and 20% bodyweight is extracellular.
Of the extracellular body water (comprising a total of 20% bodyweight), ___ is interstitial fluid and ____ is plasma.
Of the extracellular body water (comprising a total of 20% bodyweight), 3/4 is interstitial fluid and 1/4 is plasma.
List two ions that are in high concentration intracellularly, and three that are low.
High: K+, Mg2+
Low: Na+, Cl-, Ca2+
What is the osmolality of all three body compartments?
~290mOsmol/kg ( or /L)
Dehydration represents a ____% loss of body water
Dehydration represents a 5 - 15% loss of body water
If the molarity of NaCl is 0.15M, what is the molality?
0.3 molal = 300mOsm
Define osmolality
The concentration of particles per kg
At 5 - 8% dehydration, what clinical signs would you expect?
Tacky MMs, reduced skin turgor
Define osmolarity
Concentration of particles per litre. It is independent of particle size or weight.
What is fick’s law? Which biological process does it describe?
(Surface area of membrane x difference in concentration across the membrane) / thickness of membrane
Describes osmosis of particles in the context of bulk flow
In what situation might your blood become hypotonic?
Secretory diarrhoea - where ions are being lost but not water e.g cholera
Describe continuous capillaries, including where they are found
10-15nm clefts between enothelial cells and caveolae. Found in the muscle, skin, lung, fat, connective tissues
Describe fenestrated capillaries including where they are found
Have fenestrae as well as clefts and caveolae. Found in kidneys, intestines, endocrine glands, joints
Describe discontinuous capillaries including where they are found
Have wide clefts (100 - 1000nm) between adjacent endothelial cells that are permeable to large molecules. Also have large fenestrations. Found in the bone marrow, liver, spleen.
Which capillary type has caveolae?
Neural
Which of Starlings forces contributes least to the overall flow?
The colloid pressure of the interstitial fluid
If a particle moves via diffusion-limited exchange, will increasing blood flow increase its exchange?
No
Which kind of endothelial gap are plasma proteins most likely to penetrate?
Caveolae
What sort of epithelium does an initial lymphatic have?
Simple squamous
List the four major functions of the lymphatic system.
- Control of blood and ECF volume by returning excess filtered fluid and proteins
- Main pathway for fat absorption as well as lipid soluble vitamins A, D, E, K
- Pathway for immune cell circulation
- Role in turnover of extracellular matrix proteins e.g hyaluronan and glycosaminoglycans
Lymph enters the initial lymphatic by:
Mechanical deformation of the valves, causing them to open
How does lymph move?
- deformation of tissues (extrinsic pump - may include pulse pressure changes, peristalsis, respiration)
- contraction of collecting lymphatic smooth muscle (intrinsic pump)
- presence of valves in collecting lymphatic to prevent backflow
- pumps create suction to draw lymph from initial lymphatics into collecting
What constitutes a lymphangion?
A segment of collecting lymphatic bounded by an upstream and downstream valve with a smooth muscle wall.
List four causes for lymphoedema.
- High hydrostatic pressure in veins
- Low oncotic pressure of blood
- Inflammation
- Obstruction of lymphatic drainage
Which structures are drained by the R lymphatic duct
- head and neck
- thoracic cavity
- upper limb R side
What are the three main types of membrane lipid?
- Phospholipids (phosphoglycerides, sphingolipids, glycosphingolipids)
- Cholesterol - the more there is the less flexible the less permeable the membrane will be
- Glycolipids - external leaflet only
List and describe the four factors affecting membrane fluidity
- Membrane lipid tail length - the longer the tails, the less fluid
- Degree of unsaturation of fatty acid tails - the more saturated, the less fluid as unsaturated tails have a kink, meaning they don’t pack together as tightly
- Amount of cholesterol present - reduces both fluidity and permeability though is necessary structural component
- Temperature - increasing temp increases fluidity
Give two examples of mechanically-gated ion channels.
- Ion channel in the inner ear opened by sound waves
- Ion channels in smooth muscle opened by stretch
- pacinian corpuscle?
Fatty acids with one or more double bonds in their hydrocarbon tail are ____?
Unsaturated.
What is the difference between integral and peripheral plasma membrane proteins?
Integral proteins traverse the membrane (except integral monotopic), are ampipathic.
Peripheral proteins are non-covalently bound to one side of the bilayer, often to an integral membrane protein.
What makes up the glycocalyx? What is its function?
The sugar moieties of cell membrane glycoproteins or glycolipids. Mediates cell-cell interactions such as surface recognition and attachment.
Contrast pinocytosis and endocytosis.
Pinocytosis is not receptor mediated, requires energy and is continuous. Endocytosis only occurs in presence of the correct ligand. Endocytic vesicles have clathrin or caveolin structure.
What is serum?
Plasma without the clotting factors. Obtain by collecting sample without anticoagulant
How to get plasma?
Collect blood in EDTA tube and spin.
Describe CO2 transport in the blood.
11% free in plasma 89% in RBC - 21% bound to Hb - 64% as HCO3- ion inside RBC (has high carbonic anhydrase concentration) - 4% dissolved in RBC cytoplasm
Lifespan of cat RBC?
~ 80 days
Lifespan of dog RBC?
~ 100-120 days
Lifespan of horse, cow, sheep RBC?
~ 150 days
What is the lifespan of a platelet? What cell do they come from?
Megakaryocytes in the bone marrow produce membrane blebs that become platelets. 8 - 10day life span
What do the dense granules of platelets contain?
ADP, serotonin, Ca2+
What do the alpha granules of platelets contain?
Thrombospondin, fibrinogen
Name three sites of haematopoiesis in the adult
- The red marrow region (ends) of long bones
- Pelvic flat bones
- Vertebrae
Name the cells of the myeloid lineage (7 types)
Erythrocytes (++ erythropoietin) Thrombocytes (++ thrombopoietin) Basophils Eosinophils Monocytes Dendritic cells Neutrophils
What special kind of cell replication do megakaryocytes undergo to produce platelets?
Endomitotic replication
- replicate DNA and expand cytoplasm but don’t divide
Which glycoprotein is responsible for regulating erythropoiesis? Where is it produced and by which cell type?
Erythropoietin - produced in the renal cortex and medulla by renal peritubular cells (fibroblast-like)
What are the three main effects of EPO on erythropoiesis?
- Increases mitotic rate of haematopoietic progenitor cells
- Reduces maturation time for erythroblasts
- Increases rate of RBC release from bone marrow
Give a brief summary of blood clotting
Exposed collagen of injured blood vessels activates platelets, and they aggregate at the site. Prothrombin is converted to thrombin, which then converts soluble fibrinogen to fibrin, which forms a mesh of fibres over platelet plug.
What are the sites of haematopoiesis in the embryo? What about the foetus?
Embryo - yolk sac, liver, spleen
Foetus - liver, spleen, bone marrow
Reticulocytes are erythrocytes that still possess which structures?
Mitochondria and ribosomes
What are three cytokines secreted by macrophages?
IL-1, IL-6, IL-8, TNFalpha
What lineage are dendritic cells?
Some are from myeloid while others are from lymphoid lineage
Which granulocyte is typical of hypersensitivity/allergic response?
Basophil
What do acute phase proteins do?
Activate complement, opsonise pathogens
Name four cells that aren’t usually seen in the blood
Plasma cell, macrophage, dendritic cell, mast cell - all activated forms usually present in tissue
Which two classes of leukocytes are AGRANULOCYTES?
Monocytes, lymphocytes
Name three antimicrobial peptides of the innate immune system
- cryptidins
- defensins
- cathelicidins
What do the primary granules of neutrophils contain?
Peroxidase, lysosyme, hydrolytic enzymes
What do the secondary granules of neutrophils contain?
Collagenase, lactoferrin, phospholipase
What are the three mechanisms by which neutrophils kill pathogens?
- Phagocytosis and formation of a phagolysosome
- Extracellular release of granule contents and protease contents
- Release of neutrophil extracellular traps (NETs) along with myeloperoxidase and neutrophil elastase
What are three antibacterial proteins neutrophils produce?
Lactoferrin, lysosyme, defensins
What is the lifespan of a neutrophil in the blood? What about the tissues?
4 - 10h in the blood, 1 - 2 days in tissue
What are some of the secretory products of basophils? Are they effective at killing bacteria?
Histamine, heparin, serotinin, hyaluronic acid. They are inefficient bacteria killers, and cannot phagocytose in any significant way
What are two cytokines secreted by basophils?
IL-4 and IL-13
How do mast cells degranulate?
Multivalent antigen binds two IgEs on their cell surface at once, cross linking causes degranulation
List six PAMPs
- LPS present on gram negative cell wall
- Bacterial porins in outer membrane of gram negative cell wall
- Peptidoglycan
- Lipotechoic acids found in gram positive cell wall
- Flagellin
- Double stranded RNA (viral )
Which MHC molecule do CD8 T cells express?
MHC I
Which MHC molecule to CD4+ T cells express?
MHC II
What do Th17 cells do?
Activation of epithelial cells and fibroblasts, recruit neutrophils
List three TLRs and their ligands
- TLR2 => peptidoglycan
- TLR4 => LPS
- TLR5 => flagellin
What is an autacoid? What are some possible actions of autacoids
Autacoids are biological factors which act locally for a brief duration near the site of synthesis. May have systemic effect if a significant concentration is reached. Effects include modulation of smooth muscle tone and length, increasing glandular secretion and sensitising nerves for pain and itch
List three mediators of vasodilation.
Any of: histamine, prostaglandins, NO, bradyknin, substance P
List three mediators of increased vascular permeability
Any of: histamine, complement, leukotrienes, chemokines
List three mediators of neutrophil attachment
Any of: IL-1, TNFalpha, leukotrienes, chemokines
List three mediators of fever
IL-1, TNF alpha, PGE2
Give two causes of tissue necrosis in acute inflammation
- Released ROS
2. neutrophil metalloproteinases and collagenases
Give three factors that stimulate histamine release
- IgE binding mast cell, cross-linking
- complement C3a and C5a action
- Physical trauma
Also
Substance P
What drug might you use for atopic dermatitis, uriticaria, stings??
H1 blocker
What four sensations does histamine induce?
Redness, wheal, flare and itch
Give two examples of autacoids
Histamine
Bradykinin
Give three actions of bradykinin
- Stimulates vasodilation
- Promotes vascular permeability
- Stimulates pain sensation via causing substance P release
What are the three kinds of eicosanoid
Thromboxanes, prostaglandins and leukotrienes
What are the three major processes leading to acute inflammation?
- Vasodilation
- Increase in vascular permeability
- Cellular recruitment and activation
Describe serous inflammation
The least severe kind. Minimal increase in vascular permeability. Modified transudate e.g burns, blisters
Describe catarrhal inflammation
Serous exudate formed on a mucosal surface. Has mucous, inflammatory cells, debris. Occurs in intestine, respiratory tract.
Describe fibrinous inflammation
Caused by larger increase in vascular permeability - fibrinogen included in the effusion, polymerises into fibrin. Occurs on serosal and mucosal body surfaces.
Describe suppurative inflammation
Production of large amounts of purulent exudate including neutrophils, pathogen, necrotic tissue. Characteristic response to pyogenic bacteia. May occur in lumen, body cavity, or within an abscess.
Define phlegmon
Spreading, diffuse, suppurative inflammation present in loose CT e.g cellulitis
Define empyema
Accumulation of pus within a body cavity especially pleura
List three ‘stop’ signals for inflammation
Resolvins, lipoxins, protectins, IL-10, TGF beta
What are the three major characteristics of chronic inflammation?
- Change to inflammatory cell population (more lymphocytes and macrophages, less neutrophils)
- Inflammatory tissue damage e.g necrosis
- Tissue repair and regeneration e.g fibrosis, scarring, granulation tissue
Are abscesses acute or chronic inflammation?
They may be either.
Three features of lymphoplasmacytic inflammation
- Perivascular cuffing
- lymphoid follicles
- autoimmune, hypersensitivity reaction common
Typical pathogens to cause pyogranuloma? What cell types predominate?
Actinomyces, Actinobacillus. Would typically be macrophages and neutrophils
Typical pathogens to cause caseating granuloma? What cell types would predominate?
M. bovis
Typically macrophages, lymphocytes, plasma cells, fibrovascular connective tissue
Possibly mineralised
What are three mechanisms for tissue damage during chronic inflammation?
- Bacterial or viral toxic damage
- Damage by inflammatory mediators e.g proteases and ROS
- Direct cell-mediated destruction
- Tissue ischaemia due to thrombosis and vascular damage
Describe granulation tissue
Loose oedematous connective tissue containing fibroblasts and leukocytes interspersed by capillaries arranged perpendicular to the surface
What are the three phases of granulation tissue?
- Inflammatory phase
- clearance of debris
- replacement with fibrin coagulum, which serves as scaffold for next phase - Proliferative phase has two components: angiogenesis and fibroplasia, occuring simultaneously
- Maturation phase
Describe angiogenesis in the context of granulation tissue
Hypoxic conditions stimulate VEGF, FGF and angiopoietin release form local endothelial cells, macrophages, platelets. Get activation of endothelial cells and collagenase production allowing breakdown of basement membrane. The cells proliferate into the hypoxic area, secreting proteases to assist. Canalise and anastamose with others to form loops with progressive re-arrangement and maturation.
Describe fibroplasia in the context of angiogenesis
Fibroblasts migrate along the fibrin scaffold under the influence of PDGF, FGF and TGFbeta. Initially secrete extracellular matrix as fine reticulin type III collagen network, replacing the fibrin coagulum.
Describe the maturation phase of granulation tissue formation
Collagen III replaced with collagen I, re-organised along lines of tension. Wound contracts and tensile strength increases. Fibroblasts atrophy, microvasculature regresses.
Describe primary intention healing
Wound edges are in direct opposition. Minimal granulation tissue formation. Epithelium covers defect via mitosis and migration, fuses in midline under scab. Granulation tissue forms from day 3, by day 5 collagen fibres are present. Smaller defects = less granulation tissue = faster healing.
When does secondary intention healing occur?
In incidences of extensive tissue loss where the defect is too large for epithelial migration
List 5 factors that influence healing
- Presence of infection and necrosis
- Nutrition e.g vitamin C deficiency inhibits collagen maturation
- Movement and pressure on the wound
- Persistent foreign body
- Impaired blood supply
- Hormones such as glucocorticoids can inhibit collagen synthesis
- Concurrent disease
- Age
Why are cells showing hydropic degeneration pale?
They have lost much of their intracellular protein due to membrane damage, and so less to take up the stain
What are myelin figures?
Aggregates of phospholipids that have detached from the cell membrane
List three causes of pathological glycogen accumulation in the liver
- Steroid hepatopathy
- Diabetes mellitis
- Glycogen storage disorder
What is an example of an inherited lysosomal storage disorder? It is possible to acquire the same condition later in life?
Alpha-mannisidosis (a type of glycoproteinoses) in cattle and cats - defective catabolism of CHO component of N-linked glycoproteins. See swollen neuronal cell bodies with foamy cytoplasm and peripheral nuclear displacement.
It is possible that an animal could ingest swainsonine via a plant which inhibits alpha-mannosidase, producing the same condition.
What are mallory bodies?
Retained misfolded protein bodies in hepatocytes.
Define amyloid.
An insoluble, extracellular, fibrillar glycoprotein deposit
What is fibrinoid change?
Entry and accumulation of plasma proteins +/- complement +/- immunoglobulin secondary to vascular endothelial injury. Accumulation in the tunica intima, tunica media and perivascular connective tissues. Especially small arteries and arterioles
What is collagenolysis? What are some causes?
Lysis of collagen fibrils. Causes include mast cell tumours, insect bites, eosinophilic collagenolytic granulomas
Give some examples of pathological apoptosis.
- secondary to radiation damage
- atrophy of glandular parenchymal cells secondary to blockage of duct
- viral infections
- malignant tumour cell killing by immune system
Why is there no inflammatory response to apoptosis?
Expression of phosphatidylserine molecules on exterior of cell - this is recognised by neighbouring cells and is a stimulus for phagocytosis
Inflammatory mediators such as arachadonic acid are not released
What is karryorhexis?
Blebbing, budding or fragmentation of the nucleus following rupture of the nuclear envelope
Outline the cellular mechanism for oncosis
Deprivation of oxygen or nutrients causes cell to switch to anaerobic metabolism and swell with water drawn in by increased lactic acid concentration
Eventually get failure of the Na/K ATPase pump
Get sodium flowing into the swollen cell down its concentration gradient
Damage to the cell and organelle membranes catalyses Ca2+ release from mitochondria/influx from extracellular space causing activation of ATPases, endonucleases, proteases and phospholipase, all of which play a role in breakdown of cell contents
Define pyknosis
Shrunken, darkly staining nuclei
Define karyolysis
Fading of nucleus due to activation of RNAses and DNAses
When does coagulative necrosis occur?
When hypoxia or intracellular acidosis has lead to denaturation of both structural AND enzymatic proteins, preventing proteolysis of the dead cells.
Define dry gangrene
Coagulative necrosis induced by ischaemia. Tissue eventually mummifies due to dehydration
Define wet/gas gangrene
Tissue necrosis (usually coagulative) that is then colonised by bacteria causing liquefaction and putrefaction
What does liquefactive necrosis refer to?
Rapid enzymatic degradation of dead cells involving both autolysis and heterolysis. Characteristic of pyogenic bacterial infection.
What is malacia?
Liquefactive necrosis in the brain, characterised by softening of the tissues usually due to hypoxic damage leading to oncosis. Tissues are pale, soft and swollen
What is caseous necrosis?
Following oncosis, dead tissue is converted to grossly dry, granular, cream-white friable tissue +/- mineralisation
Two histological features of fat necrosis are?
Dystrophic mineralisation of calcium salts and released fat
Precipitation of free cholesterol into needle-like crystals
Define dystrophic mineralisation
Deposition of calcium salts into tissues that have undergone oncotic necrosis - regardless of normal Ca:P concentrations.
Define metastatic mineralisation
Deposition of calcium salts into living tissues when Ca:P ratio is abnormal or there is a defect in Ca:P metabolism
Normal TP range in most mammals?
60 - 80 g/L
What is the difference between multiunit and visceral smooth muscle?
Multiunit is innervated by a single nerve terminal, never contracts spontaneously.
Visceral occurs in bundles, connected by gap junctions, and may contract spontaneously. Depolarisation of one cell will spread to the others - functional syncytium
Which parts of the sarcomere get smaller when it contracts?
I band (actin only) and H band (myosin only)
What does the A band of the sarcomere encompass? Is it lighter or darker in H&E?
The absolute length of the myosin myofibrils, which does not change . Darker in H&E
What does the Z line represent?
Line of attachment for actin filaments
With which muscle fibre type are postural muscles associated?
Type I - red cells
Thinner, more myoglobin and mitochondria
Myosin has low ATPase activity > slower contraction
Which region of the sarcomere do intercalated discs likely correspond to?
Z line
Name three components of the intercalated disk, and what they do
- Fascia adherens - anchors actin to nearest sarcomere
- Macula adherens desmosome to stop separation of cardiomyocytes during contraction
- Gap junctions to allow electrochemical charge to spread from cell - cell
What is the function of astrocytes?
Provide mechanical and metabolic support to neurons
What is the function of oligodendrocytes?
Synthesise myelin sheath of CNS axons
What is the function of microglia?
Phagocytic function
What is the function of ependymal cells?
Simple cuboidal/low columnar epithelial cells that line ventricles of brain and central canal of spinal cord. Often ciliated.
Is the I band lighter or darker in H&E?
Lighter
How do K+ and Cl- both contribute to the equilibrium potential of a neuron?
The intracellular concentration of K+ is higher than extracellular
There are constitutively open K+ channels in the neuron cell membrane
K+ leaks out of these down its concentration gradient
Cl- cannot leave, so its electrical charge hols some K+ inside the cell
The balance between K+ leaving and staying form the equilibrium potential for potassium (-70mV)
What event contributes to the falling phase of the AP?
Opening of voltage-gated K+ channels, and rush of K+ out of the neuron
What is the refractory period? What are its phases?
The period of time post-depolarising that the neuron is unresponsive to further stimulation. Composed of the Absolute refractory period (all Na+ channels are inactivated) and the Relative refractory period (some Na+ channels may be opened with further stimulation). Ensures the AP only travels in one direction
Define graded potential
Local change in RMP which occurs over short distance. May summate or cancel each other out. Amplitude is variable - is related to the magnitude of the stimulus
Define EPSP and IPSP
EPSP is a small wave of Na+ ion influx as a result of ion channel activation. IPSP is the same but inhibitory - may increase neuron permeabilty to Cl- or K+, hyperpolarising it.
Compare temporal and spatial summation of EPSPs
Temporal summation occurs when two or more EPSP are generated within a short timeframe. They may summate to an AP
Spatial summation occurs when two or more EPSP are generated within a small enough time frame and close proximity - may summate to an AP
What is the effect on ion permeability caused by activation of m1AChR?
K+ permeability of the cell is decreased - brings membrane closer to threshold
What is the effect on ion permeability caused by activation of m2AChR?
K+ permeability of the cell is increased, brings membrane further from threshold
Give some factors that might affect the amount of NT released into the synapse
Effectiveness of Ca2+ channels in the presynaptic membrane
Integrity of the SNARE complex
Function of choline acetyltransferase
What is an axoplasm?
An artery for protein transport from the perikaryon down the axon. Slow and fast systems exist.
How many molecules of ACh need to bind the nAChR to cause activation?
Two
Smaller or larger motor units offer finer muscle control?
Smaller
How might the somatic nervous system achieve a gentle contraction?
By recruiting only the proportion of muscle fibres (e.g half) of the total muscle that it needs.
List the three outer layers of muscle and what they enclose.
Epimyseum = lies immediately beneath the fascia. Encloses the entire muscle Perimyseum = encloses fascicles (bundles of fibres ) Endomyseum = encloses individual fibres
Which molecule in the contractile apparatus has a Ca2+ binding site?
Troponin - binding causes conformational change in TROPOMYOSIN which then moves from the actin-binding site allowing myosin access
Which molecule of the contractile apparatus is rope-like?
Tropomyosin
What happens after myosin binds actin?
Myosin is ‘loaded’ with the energy from splitting an ATP, and still has an ADP + P attached. When it binds actin, a conformational change occurs - the power stroke - pulling actin over the myosin and shortening the sarcomere. ADP and P are released.
What causes myosin to release the actin?
A new ATP molecule binds the myosin, and the myosin head releases the actin. Hydrolysis of the ATP molecule provides the energy to ‘cock’ the myosin head again.
How does this relate to rigor mortis?
No new ATP to bind myosin - actin stays bound, muscle remains contracted (stiff)
Furthermore, no ATP to pump Ca out of sarcoplasm, so contraction continues
What are the three roles for Ca2+ in skeletal muscle contraction?
- Influx of Ca2+ at the presynaptic terminal to allow fusion of NT vesicles with presynaptic membrane
- Released from the SR in response to AP arriving at the T tubules. Binds troponin C causing tropomyosin to release actin, allowing myosin to bind
- Pumped back into the SR via Ca2+ ATPases, allowing tropomyosin to reassociate with actin and muscle to relax
What are the three roles of ATP in skeletal muscle contraction?
- Provides energy for myosin power stroke
- Binding to myosin allows release of actin and muscle relaxation
- Drives the Ca2+ ATPase that pumps Ca2+ back into the SR
A small amount of ATP is stored in skeletal muscle, and used within the first 6 seconds. What are the next three sources of ATP for skeletal muscle ?
- Creatinine kinase forms ATP from creatinine phosphate and ADP - first 10 sec
- Glycolysis used to generate ATP - low level production, durable over longest time. Starts at 30 seconds
- ATP generated via anaerobic glycolysis (glucose oxidised to lactic acid) from 70 seconds onward, tires after about 2min
Slow twitch fibres have ____ oxidative capacity, ___ glycolytic capacity, ___ mitochondria, _____ blood supply, ____ contraction force, ____ resistance to fatigue
Slow twitch fibres have high oxidative capacity, low glycolytic capacity, plentiful mitochondria, better blood supply, lesser contraction force, greater resistance to fatigue
Fast twitch fibres have ___ oxidative capacity, ____ glycolytic capacity, _____ mitochondria, _____ blood supply, ____ contraction force, ____ resistance to fatigue
Fast twitch fibres have less oxidative capacity, more glycolytic capacity, fewer mitochondria, lesser blood supply, greater contraction force, poor resistance to fatigue
List three differences between cardiac and skeletal muscle contraction
- Contraction is not initiated by neuronal input, though is modulated by it
- All myocytes are interconnected electrochemically by gap junctions at intercalated disk
- AP has longer duration
What is the function of pacemaker cells in heart?
They are rhythmically active, capable of depolarising by themselves and passing the AP along to Purkinje fibres and cardiomyocytes. Regulate the baseline HR.
How does extracellular Ca2+ influence cardiomyocyte contraction?
The presence and concentration of Ca2+ contributes to the strength of contraction
Other than [Ca2+], what influences heart contraction strength?
ANS innervation
Hormones e.g adrenaline
Extent of cardiac stretch
What are dense bodies?
Sites of attachment for actin
They are attached to the cell membrane
They transduce the contraction of the sarcomeres to the smooth muscle cell as a whole - actin contracting pulls on the dense bodies making the cell smaller
Which muscle type doesn’t have T tubules?
Smooth - has caveoli instead
Multiunit smooth muscle has ____ gap junctions, _____ response to stretch, _____ response to hormonal influence
Multiunit smooth muscle has fewer gap junctions, poor response to stretch, minimal response to hormonal influence
Visceral/single unit smooth muscle has ____ gap junctions, ____ response to stretch, hormones and local pacemaker potentials.
Visceral/single unit smooth muscle has more gap junctions, strong response to stretch, hormones and local pacemaker potentials.
All muscle fibres are innervated in ____ smooth muscle, but only a few are innervated in _____ smooth muscle.
All muscle fibres are innervated in multi unit smooth muscle, but only a few are innervated in single unit smooth muscle.
List the three ways smooth muscle cells achieve an increase in intracellular Ca2+
- Voltage gated Ca2+ channels at the cell membrane
- Ligand gated Ca2+ channels at the cell membrane
- Ca2+ channels at the ER (activated later, by second messenger systems)
Describe cross bridge cycling in smooth muscle
Ca2+ binds to calmodulin which activates myosin light chain kinase. Myosin light chain kinase uses ATP to phosphorylate myosin, changing its conformation and increasing myosin’s affinity for actin. Myosin ATPase then cycles, allowing binding of actin, power stroke and release.
Which enzyme is upregulated by circulating cortisol and corticosteroids to cause hepatic lipidosis?
Glycogen synthetase
What is required for amyloidosis to develop?
A source of inflammation in the body, increasing SAA production
Production of a defective SAA protein
What do muscle spindles detect? Where are they located?
Stretch of skeletal muscle. Located within the fleshy part of the muscle
What do golgi tendon organs detect? Where are they located?
Tension of skeletal muscle. Located at the junction of muscle and tendon.
What are the three sources of sensory innervation conveyed by afferent neurons to the spinal cord?
Skeletal muscles of the area
Other nearby muscles especially the antagonist
Tendons, joints, skin and other structures directly affected by the muscle’s action
What are the fibres inside a muscle spindle called?
Collectively, they are known as ‘intrafusal’ fibres, and the fibres of the surrounding skeletal muscle are ‘extrafusal’. There are two types of intrafusal fibres - Nuclear bag fibres, which detect the onset of stretch, and nuclear chain fibres which detect sustained stretch.
Describe the stretch reflex in one sentence
Stretch of a muscle is detected by muscle spindle and through the stretch reflex the stretching muscle is stimulated to contract, and the antagonist is stimulated to relax
Describe the tendon reflex in one sentence
Excessive tension of a muscle is detected by the golgi tendon organ at the musculo-tendonous junction, and relayed to the spinal cord causing inhibition of further APs to the original muscle, relaxing it, and propagation of new APs to the antagonist muscle, causing it to contract
True or false - drug concentration can affect its selectivity.
True
At the cellular level, do antagonists have efficacy?
No
What is potency? Is it affected by affinity?
Potency is the amount of drug that is required to have the effect. It is usually affected by affinity (higher affinity, more potent) though not always. Specific for a given tissue type.
What is EC50?
The dose of the drug at 50% of its maximum effect. Specific to tissue type.
As antagonists have no efficacy, how would you measure their potency?
By adding them to a solution then adding the agonist at varying doses. The higher the dose of agonist required to outcompete the antagonist, the more potent the antagonist is. Requires competitive, reversible binding of drug to target. The concentration of agonist required to regain the full response = pA2 or pKb
Pharmacodynamics relates to:
Affinity, selectivity, potency and efficacy. Know where drug acts and predict response.
Pharmacokinetics relates to:
How often to dose based on ADME, potency and efficacy. Know long term consequences of use
Which sympathetic nerve is unusual in that it does not synapse at the SNS ganglion chain?
The ACh nerve innervating the adrenal gland
Which SNS nerve is unusual in that it uses ACh as its post-ganglionic transmitter?
The nerves innervating sweat glands
From which area of the spine do SNS neurons arise?
Thoraco-lumbar
From which areas of the spine to PNS neurons arise?
Cranial, sacral
How does the SNS indirectly affect the body?
Via release of adrenaline from the adrenal gland. This is how it modulates arteriolar diameter and bronchiolar diameter
Which receptor does NA have greatest selectivity for?
alpha1 adrenergic
Which receptors does adrenaline have greatest selectivity for?
beta1 and beta2 adrenergic
What is meant by the ‘alpha’ effect of adrenaline in the blood?
A rise in BP due to adrenaline’s actions on the alpha1 receptors to cause vasoconstriction, and beta1 receptors to increase HR.
What is meant by the ‘beta’ effect of adrenaline in the blood?
PNS homeostatic innervation of the heart brings HR back down, and this unmasks the effect of adrenaline binding the beta2 adrenoceptors to cause vasodilaton. BP falls as adrenaline has higher affinity for the beta2 than alpha1.
What happens when NA is given IV?
Get spike in BP due to its action on alpha1 adrenoceptors to cause vasoconstriction. There would be some action on the beta1 adrenoceptors too, however this is not obvious due to the PNS-mediated homeostatic mechanism which reduces HR to combat the rise in BP. Thus we see a reasonable spike in BP with minimal change in HR. NA can’t cause adrenaline release from the adrenal gland, as its being given in the blood.
What happens when give adrenaline + phentolamine IV?
Get large drop in BP due to adrenaline action on beta2 adrenoceptors. Homeostatic mechanism mediated by SNS is to raise HR to bring BP back up. We get adrenaline’s effect on beta1 receptors + this homeostatic mechanism to produce a greater increase in HR than adrenaline alone.
What is phentolamine?
An alpha-adrenoceptor antagonist. Not commonly used medically as not very specific ??
What happens when we give noradrenaline and phentolamine IV?
No change in BP, as this was mediated by alpha1 which has been blocked. We do see a small increase in HR due to NA’s action on beta-1 - absence of PNS homeostatic response unveils this small effect.
What is propanolol? What effect might it have on NA and A administered IV?
A beta adrenoceptor antagonist - would block increase in HR and vasodilation of peripheral arterioles as mediated by adrenaline or noradrenaline in the blood.
List the contents of a noradrenaline vesicle. Other than NA, are any of them physiologically significant?
Noradrenaline, neuropeptide Y, ATP, dopamine-B-hydroxylase. There is evidence to suggest that NPY and ATP can participate in signaling if NA is not present or functional.
Which drugs prolong NA effect at the synapse? What is the mechanism?
90-95% of NA is taken up by the presynaptic nerve. Blocking this pathway can prolong the effects of NA. Drugs that do this are cocaine, desipramine. Causes rapid accumulation of NA in the cleft
What other effects might you get from cocaine?
Increased dopamine signalling in the CNS as the uptake receptor for NA and dopamine is the same
Effects on peripheral NS including tachycardia
Which enzyme breaks down NA at the presynaptic nerve?
Monoamine oxidase (MAO)
Which enzymes metabolise NA in the peripheral tissues?
MAO
Catechol-o-methyltransferase
Which drugs might you use to cause slow accumulation of NA in the cleft? What is the mechanism?
MAO inhibitors will cause slower, more progressive NA accumulation than cocaine or desipramine. E.g moclobemide.
What are the two mechanisms by which indirectly acting sympathomimetics increase NA effect? What are some examples?
Have affinity for the NA reuptake carrier at the presynaptic nerve
- Enter the nerve terminal, cause release of NA vesicles
- As they work, compete with released NA for uptake, prolonging its effect in the synapse
Examples are amphetamine, ephedrine
What is phenylephrine?
An alpha adrenoceptor agonist
What is isoprenaline?
A beta adrenoceptor agonist
What is the effect on NA dose required to increase BP and HR in the presence of phentolamine?
Phentolamine is an alpha adrenoceptor antagonist.
You need more NA to produce BP increase, though no effect on HR.
What is the effect on NA dose required to increase BP and HR in the presence of propanolol?
Propanolol is a beta adrenoceptor antagonist.
You need more NA to produce an increase in HR, though no effect on BP
What feature of isoprenaline limits its clinical use?
It isn’t very specific for beta2 adrenoceptors - so if used to cause bronchodilation, get a certain amount of cross-reactivity with beta1 adrenoceptors causing heart palpitations
Which drug is commonly used to help asthmatics with their asthma?
Salbutamol, and beta2 agonist. Has higher specificity than isoprenaline. Causes fewer heart palpitations, though still get some.
What is an alpha-2 adrenoceptor agonist? What is the effect produced?
Clonidine - has affinity for alpha 1, but mostly alpha2. Causes inhibition of NA release at the presynaptic neuron, dampening down SNS transmission. Causes sedation as passes into CNS to inhibit neurological activity there.
Which alpha1 antagonist is preferred to phentolamine? Why?
Prazosin - more specific for alpha1. Provides relief for hypertension, though can permit wide blood pressure fluctuations when posture changes, causing dizziness and potentially fainting
What does yohimbine do? What is its use in veterinary medicine? What other names is it known by?
Yohimbine is an alpha2 antagonist - prevents inhibitory signalling. May be used to reverse Clonidine sedation. Also called xylazine a.k.a Rompun.
List three effects of alpha1 adrenoceptor activation.
- Vasoconstriction
- Constriction of sphincters in GIT
- Dilation of pupil via constriction of radial muscle
List three effects of beta1 adrenoceptor activation
- Increase in HR
- Renin secretion by the kidneys
- Glycogenolysis in the liver
List two effects of beta2 adrenoceptor activation.
- Vasodilation of skeletal muscle arterioles
2. Bronchodilation via relaxation of adjacent smooth muscle
What is one effect of beta3 adrenoceptor activation?
Lipolysis in adipocytes
As a drug IV, is NA useful?
Not really - has greatest affinity for alpha1, followed by beta1, but has limited potency from the blood
An a drug IV, is adrenaline useful?
Has similar affinity for alpha1, beta1, and beta2. Endogenous location is bloodstream, so has high potency in IV dose. Stimulates HR, blood flow, cellular metabolism and improves airway function - lifesaving!
Beta1 and beta2 adrenergic receptors are both Gs GPCR. What determines the difference in their effects?
- The location of the receptor in the body (what tissue type, and in what density)
- The affinity of the ligand for the receptor
What is the presynaptic neurotransmitter at the adrenal gland?
ACh
If you pre-treat with atropine and give a large dose of ACh, what is the outcome on BP?
Atropine is a mAChR antagonist - so the drop in BP caused by ACh will be prevented. At high doses, circulating ACh may act on the nAChR at the adrenal gland, and cause release of adrenaline from the adrenal gland. Therefore expect big jump in BP due to action of adrenaline.
If you give moderate ACh dose IV, what is the outcome on BP?
Drops, due to ACh acting on mAChR in the heart to reduce rate and contractility
Which is the dominant AChR available to circulating ACh?
mAChR
List four effects of mAChR antagonists on a living organism
- Tachycardia - lost PNS tone
- Inhibition of SLUD
- Dilation of pupil
- Agitation, restlessness, coma, depression (CNS effects)
List two clinical applications for atropine
- Bradycardia
2. Carbamate poisoning
What sort of drug is hyoscine?
A mAChR antagonist
What sort of drug is ipratopium?
A mAChR antagonist
What sort of drug is pilocarpine?
a mAChR agonist
What sort of drug is carbachol?
a mAChR agonist
What sort of drug is bethanecol?
a mAChR agonist
What sort of drug is physostigmine?
A reversible AChE antagonist
What sort of drug is neostigmine? Provide two uses.
A reversible AChE antagonist.
- Treatment of myasthenia gravis (prolong ACh at synapse)
- Reversal of non-depolarising neuromuscular blockers (increases available ACh which then outcompetes)
What are the two categories of nAChR antagonist?
- Neuromuscular blocking drugs (action at NMJ)
2. Ganglion blocking drugs (action at sympathetic ganglion)
What are the two categories of NMJ blocking drugs (nAChR antagonists). Give a drug for each category.
- Non-depolarising blockers - vecuronium, tubocurare
2. Depolarising blockers - suxamethonium
What is an example of a nAChR antagonist that blocks at the ganglion?
Hexamethonium
Which drugs may be reversed with neostigmine?
Vecuronium, d-tubocurare
Give an example of an nAChR agonist?
Nicotine
What sort of G protein is mAChR 3? What signal transduction mechanism does it activate?
Gq protein
- PLC breaks PIP2 into IP3 + DAG
- DAG activates PKC
- IP3 mobilises Ca2+, which causes downstream effects such as GIT contraction
What sort of G protein is mAChR 2? What signal transduction mechanism does it activate?
Gi protein
- inhibits adenylate cyclase activity to reduce cAMP production
- lower cAMP levels in cytosol reduce HR and force
How does ACh cause vasodilation, when acting from the blood?
Binds M3 on vascular endothelial cells
Downstream signaling switches on NO synthetase causing NO production
NO diffuses to vascular smooth muscle, causes relaxation > vasodilation
Give five examples of autacoid molecules.
1. Histamine 2 Bradykinin 3. Prostaglandins 4. Leukotrienes 5. Thromboxane 6. Eicosanoids
Give four cell types that produce histamine. Is it stored for release, or made on demand?
Mast cells, basophils, ECL cells in stomach, histaminergic neurons. Stored in granules.
What sort of receptor are the histamine receptors?
GPCRs
What are some clinical uses for H1 antagonists?
Hay fever tx Atopic dermatitis Urticaria Anaphylaxis Angioderma Bites and stings
What is a clinical use for H2 antagonists? Name two such drugs
Reduce HCl secretion in the stomach - ranitidine, cimetidine
Why must bradykinin synthesis occur after an initial increase in vascular permeability in inflammation? What other molecules are involved ?
Because Hageman factor, is only activated once outside the blood. Hageman factor is required to convert prekallikrien to kallekrien, which can then convert Kininogen to bradykinin.
What sort of receptors are bradykinin receptors?
GPCRs - has B1 and B2
What does icatibant do? what condition might it be used for?
B2 bradykinin receptor antagonist - used to reduce effects of excessive circulating bradykinin in inherited angioderma
Eicosanoids are synthesised de novo (not stored). What is the signalling mechanism for this?
Influx Ca2+ into cell > PLA2 releases AA from phospholipids in cell membrane > COX acts on AA to produce prostanoids, LOX acts on AA to produce leukotrienes
In which cells is LOX mostly found?
Leukocytes
Which prostaglandin is produced by most cells of the body?
PGE2
Give an example of two prostanoids acting in synergy
PGE2 and PGI1 both increase sensation and duration of pain (hyperalgesic)
What kind of receptor are eicosanoid receptors?
GPCRs
How do NSAIDs work? Give an example
Aspirin - Inhibit COX
How do glucocorticoids work? Give an example
Dexamethosone
Bind intracellular receptor to change gene expression
Inhibit PLA2 and COX
- inhibit synthesis of prostanoids and leukotrienes
Inhibit cytokine synthesis and adhesion molecule expression
How long is the pre-implantation period? What event typically occurs at the end?
Fertilisation - 1 weeks
Blastocyst hatches from zona pellucida
In which week do the three germ layers appear? What is one other event from that week?
Week 2. Also should have implantation
What is one major event of the third week?
Formation of the extra-embryonic membranes
What are the three requirements for implantation?
- Blastocyst hatches from zone pellucida
- Pregnancy recognised by mothers body
- Formation of the extra-embryonic membranes
Define morula
Solid ball of blastomeres within the zona pellucida. Formed through cleavage.
Define blastocyst
Blastomeres are arranged within the zona pellucida to form blastocoele containing inner cell mass and fluid
What four forces facilitate rupture of the zona pellucida?
Blastocyst growth
Fluid accumulation in blastocoele
Enzymatic degradation via trophoblast enzymes
Blastocyst contraction
What other names is the inner cell mass known by?
Embryonic disc = epiblast = embryo proper
Where does the hypoblast layer come from?
The proliferating inner cell mass. Once the hypoblast has formed, the ICM is called the epiblast.
Which structure indicates the beginning of gastrulation?
The primitive streak (formed from epiblast cells). It also gives the embryo polarity for the first time.
Where do endoderm cells come from?
A coelom forms between the epiblast and hypoblast layers. Epiblast cells migrate medially, through the primitive streak and through the coelom to the hypoblast layer. They push the hypoblast cells laterally, and become the endoderm
Where do mesoderm cells come from?
As for endoderm, except they remain in the coelom and migrate laterally to fill it
Where does ectoderm come from?
The remaining epiblast cells after mesoderm and endoderm have formed
Where is somatic mesoderm relative to the somites? ?What does it occur beside
lateral to somites
Ectoderm
Where is splanchnic mesoderm relative to the somites? ?What does it occur beside
Lateral to somites
Endoderm
What structures does the ectoderm form in the adult?
Epidermis
Nervous tissue
Brain and spinal cord
Peripheral nerves and other neural crest derivatives
What structures does the mesoderm form in the adult?
Connective tissues
Muscle
Epithelial linings of cardiovascular, urinary and reproductive systems
What structures does endoderm form in the adult?
Epithelial linings of GIT and respiratory system
Digestive organs
Glands of digestive system
What major event occurs simultaneously to gastrulation?
Formation of the notochord (primitive streak)
What events begin as a result of notochord formation?
Head, nervous system formation
Somite formation
What is the ultimate fate of the notochord?
Becomes nucleus pulposus of the intervertebral discs
List the four extra-embryonic membranes
Chorion, amnion, yolk sac, allantois
What is the function and origin of the chorion?
Trophectoderm and mesoderm
Mediates attachment to uterus
Eventually fuses with allantois
What is the function and origin of the amnion?
Trophectoderm and mesoderm
Fluid filled sac that protects the embryo via shock absorption
What is the function and origin of the yolk sac?
Endoderm
Provides nutrients for the embryo
Contributes primitive germ cells
What is the function and origin of the allantois?
Primitive gut
Fluid filled sac that collects waste from the embryo
Eventually fuses with the chorion to form the allantochorionic membrane which is the foetal contribution to the placenta
What is neurulation?
Notochord-induced transformation of the ectoderm into nervous tissue. Confers first appearance of gut, heart and nervous system
What is neuroectoderm?
Tall, columnar ectodermal cells over the notochord which form at the beginning of neurulation. Form a neural plate with neural folds at either end and a neural groove in the centre.
What event/s complete formation of the neural tube?
Closure of the anterior and posterior neural pores
What is the position of the neural crest cells?
Dorsolateral to the neural tube, beneath the ectoderm.
What are some products of the neural crest cells?
Pigment cells of skin
Neurons and glial cells of the PNS
Adrenal medulla cells
Meninges, bone, fascia and teeth in head
What major event is occuring at the same time as neurulation?
Cranial and caudal folding of the embryo. The cranial fold forms subcephalic pocket
What are the three placodes? what tissue do they form from?
Ectoderm
- nasal placode > nasal chambers
- optic /lens placode > lens
- otic placode > inner ear
Which tissue forms somites?
Paraxial mesoderm
What do the somites give rise to?
First 7: mesodermal structures in the head
Caudal to those: axial skeleton and its associated musculature, overlying dermis
What does the intermediate mesoderm form?
Occurs lateral to the somites - forms urinary and reproductive system
What is the fusion of somatic mesoderm and ectoderm called?
Somatopleure
What is the fusion of splanchnic mesoderm and endoderm called?
Splanchnopleure
What structure occurs between the somatopleure and the splanchnopleure? what does it give rise to?
The extra-embryonic coelom- gives rise to the cavities of the body (pleural, pericardial, peritoneal)
Define agenesis
Developmental abnormality where there is not enough tissue - something has not formed.
Define aplasia
Failure of a structure to develop in utero
The most severe form of hypoplasia
Define segmental aplasia
Aplasia of tubular structure e.g intestine, uterus
What other term could be used to describe segmental aplasia of the intestine?
Intestinal atresia
Define hypoplasia
Failure of an organ or tissue to reach its full size
Give two veterinary example of hypoplasia
Hypoplasia of uterus i female calves due to ‘freemartinism’ masculinising them
Cerebellar hypoplasia due to BVDV infection or FIP infection in utero
Congenital micropthalmia in piglet due to hypovitaminosis A in utero
What is a common feature of unilateral hypoplasia, dysplasia, aplasia of paired structures?
Hyperplasia/hypertrophy of the unaffected structure
Define dysplasia
Abnormal development resulting in disorganisation of cells and hence architectural distortion of a tissue or organ. Effect on function is chaotic though may require microscope to identify
Under what circumstances may dysplasia occur post-natally?
Infection with a virus in first few weeks of life in species that are still undergoing development e.g kitten, puppy
Define atresia
Absence or closure of a normal opening
What are the potential consequences of atresia ani?
Distension of distal rectum and colon Possibly mucosal ulceration and perforation Leading to septic peritonitis Grossly see abdominal distension Extreme discomfort
Define atrophy
Decrease in cell size or tissue mass after normal growth has been achieved
Cell decreases size and metabolic activity in order to survive in presence of external stressor
Define hypertrophy
Increase in cell size, or increase in tissue mass due to increase in cell size
All cells
Define hyperplasia
Increase in tissue mass due to increase in cell number
Labile and stable cells only
Define metaplasia
Transformation of a mature, differentiated cell type into another cell type
Provide two examples of physiological atrophy
- Involution of lymphoid organs (thymus at puberty, LNs in old age)
- Involution of corpus luteum in ovary during oestrous
- Involution of uterus following parturition, involution of mammary secretory parenchyma following lactation
What are the seven major mechanisms of pathological atrophy?
- Decreased blood supply
- Decresaed workload
- Loss of innervation
- Loss of endocrine stimulation
- Obstruction of secretory or drainage ducts
- Inadequate nutrition or wasting diseases
- Ageing
Provide an example of decreased blood supply causing atrophy
PSS
Pressure atrophy
Provide an example of decreased workload causing atrophy
Disuse atrophy of limb in a cast for extended period
Provide an example of loss of innervation causing atrophy
Atrophy of the left dorsal cricoarytenoid muscle in laryngeal hemiplegia in horses due to damage of the left recurrent laryngeal nerve
* fastest form of atrophy*
Provide an example of loss of endocrine stimulation causing atrophy
Atrophy of the prostate gland following castration of male dog
Atrophy of adrenal cortex due to long term corticosteroid therapy and reduced ACTH secretion
Provide an example of duct obstruction causing atrophy
Obstruction of pancreatic duct causing parenchymal atrophy. May be compounded by increase in pressure reducing bloodflow.
Provide an example of inadequate nutrition or wasting disease causing atrophy
Chronic conditions such as cancer cause atrophy of adipose, muscle, viscera especially liver, pancreas and myocardium
Provide an example of aging causing atrophy
Of reproductive organs and CNS in old animals and people
What is lipofuschin?
Lipofuschin is polymers of lipids and phospholipids complexed with proteins
Why does lipofuschin accumulate in atrophic and aged cells?
It is the residue formed from peroxidation and polymerisation of unsaturated fatty acids and the phospholipid component of cell membranes. Is indigestible. The more organelle breakdown, the more lipofuschin there will be
Name three ultrastructural features of atrophic cells
- Reduced size and number of organelles
- Reduced number of secretory vesicles
- Additional autophagosomes that may contain lamellar lipofuschin
List four features of atrophic tissue under light microscope
- False appearance of hypercellularity due to crowding of small cells
- Increased prominence of ducts, connective tissue
- Fatty infiltration
- Lipofuschinosis
List five gross features of atrophic organs
MAY BE
- Smaller, lighter
- Firmer
- May be pale due to fat or fibrosis deposit
- May be brown-yellow due to lipofuschinosis
- May have wrinkled CT capsule
What is serous atrophy of fat?
When fat stores are being mobilised so quickly the fat becomes gelatinous, translucent, sometimes pale pink due to oedema and increased prominence of local capillaries
Under what circumstances is serous atrophy of fat seen? Which organ will commence this process last (i.e in most severe demand)
Extreme starvation/cachesis
Serous atrophy of the bone marrow is only seen in most advanced stages
List three mechanisms for villous atrophy
- Significant loss of surface epithelial cells e.g viral infection, transient hypoxia
- Necrosis or impaired mitosis of crypt stem cells e.g viral infection, prolonged hypoxia >2h
- Dysregulation of crypt cell proliferation and enterocyte maturation e.g lymphoma, food hypersensitivity
List two consequences of villous atrophy
- Reduced SA for absorption > malnutriton
2. Reduced absorption of food > osmotic drag of water into lumen > diarrhoea
What pathogen is responsible for progressive atrophic rhinitis in pigs? Which species are affected, and which age?
Pasteurella multocida +/- other bacteria
Typically 6 - 12 week piglets
What clinical signs might a pig with atrophic rhinitis display?
Sneezing Nasal discharge Haemorrhage Nasal deformity Failure to thrive Predisposition to secondary bacterial infection
What is the pathogenesis of atrophic rhinitis
P. multocida cyclotoxin causes:
- atrophy of the renal mucous secreting glands
- resorption of nasal turbinate bone
-. reduced formation of new bone
- proliferation of fibroblasts
- deposition of collagen
Leading to progressive atrophy of the nasal turbinates and deviation of snout to more severely affected side.
Define abiotrophy. Give an example
Genetically programmed, premature or accelerated degradation of mature cell types causing atrophy of affected organ or tissue
Autosomal recessive cerebellar abiotrophy in dogs, lambs, piglets and calves
- especially purkinje cells
What ultrastructural features are associated with cellular ageing?
Irregular nuclear shape Vacuolation of mitochondria Reduced ER Distorted golgi Accumulation of lipofuschin
What are advanced glycation end products? Why do they accumulate? what is one veterinary example?
The result of non-enzymatic glycosylation reactions causing cross-linking of adjacent proteins. Accumulation of abnormally folded proteins. Due to reduced proteasome function of older cells.
E.g Age-related glycosylation of lens proteins causes senile cataracts
Give two examples of physiological hypertrophy
- Hypertrophy of pancreatic acinar cells in response to high protein diet
- Hypertrophy of uterine smooth muscle cells in response to oestrogen in late pregnancy
Give two examples of pathological atrophy
- Hypertrophy of cardiac muscle in response to chronic high BP > narrowing of lumen, reducing stroke volume and cardiac output. Prone to hypoxic damage and energy defecit
- Hypertrophy of intestinal smooth muscle proximal to ab obstruction or stricture > reduced lumen size
Which two factors impose the upper limit on hypertrophy?
Distance for O2 diffusion into tissues
Size of cell permits efficient metabolic rate
List four signals for hyperplasia
- Hormonal stimulation
- Cytokine signalling
- Growth factor signalling
- Increased expression of growth factor receptors
List three advantages of hyperplasia
- Repair of injured tissues
- Compensate for lost cells
- Respond to increased workload
- Protect a structure that is being damaged
What is the difference between hyperplasia and neoplasia?
Hyperplastic response will stop once cause has been removed or tissue mass has been restored
What are the common stimuli for hyperplasia?
Increased hormonal stimulation
Compensation ( increased workload )
Provide two examples of physiological hyperplasia
- Mammary gland hyperplasia in late pregnancy under influence of oestrogen, progesterone and prolactin
- Mild hyperplasia of adrenal cortices in response to sustained stress causing increased ACTH secretion
Provide two examples of pathological hyperplasia
- Goitre due to low iodine
- see fronds of hyperplastic follicular epithelium, no colloid in follicles - Mammary fibroadenomatous hyperplasia in young, intact female cats due to endogenous progesterone
- Benign prostatic hyperplasia in dogs due to testosterone
What is the general outcome of metaplasia?
Usually change of a specialised, vulnerable cell type into a less specialised, more resistant type - typically within the same germ line. Most common in epithelia e.g squamous metaplasia of upper alimentary tract mucous cells. Generally confers loss of function
What is the most common kind of metaplasia?
Squamous metaplasia.
What does glandular metaplasia usually involve? Give an example
Transformation of epithelial cells into mucous secreting cells e.g chronic inflammation of the gastric fundus causes mucous metaplasia of the gastri epithelium e.g parasitism. Get reduced HCl secretion and impaired digestion.
What does mesenchymal metaplasia usually involve? Give an example.
Metaplasia of one connective tissue type into another e.g metaplastic bone formation in pulmonary connective tissues of old dogs and cattle
What does dysplasia mean in the acquired sense? When is it most commonly seen?
A proliferative response of cells and tissues in which there is abnormal tissue architecture and cellular atypia
Most commonly in chronically ill/inflamed epithelium
What are 5 possible features of dysplasia under the light microscope?
- Disorderly tissue architecture, irregular cell orientation
- Loss of normal regular progression from deep germinative to superficial mature cells
- Increased mitotic rate, mitoses in more superficial cell layers
- Cellular pleiomorphism
- Hyperchromatic cells
Give an example of acquired dysplasia
Dysplasia of transitional mucosa of bladder in chronic cystitis, dysplasia of mammary epithelium in chronic mastitis
What can anaplasia refer to in the acquired sense? Is it reversible?
Loss of differentiation - irreversible
Give three microscopic features of anaplasia
Hyperchromatic, irregular nuclei with prominent nucleoli
High mitotic rate
Abnormal mitoses present
