PP Flashcards

Question

Types of gangrene Look at notion

Answer 1

Can be dry or wet Dry is exposure to air and coagulative Wet is infection and liquefactive Gas - anaerobic bacteria

Answer 2

Oxidative Depletion of ATP

Answer 3

– Alternative blood supply – Speed of ischaemia – Tissue involved (heart/brain) – Oxygen content of the blood

Answer 4

• Foreign bodies (splinters, dirt, sutures) • Immune reactions • Infections (bacterial, viral, parasitic) and microbial toxins • Tissue necrosis (any cause) • Trauma (blunt and penetrating) • Physical and chemical agents (e.g., thermal injury, e.g., burns or frostbite, irradiation, environmental chemicals).

Answer 5

tumour: Vasodilatation which increases capillary hydrostatic pressure. Increased vessel permeability so plasma proteins move into interstitium This inc interstitial oncotic pressure. Fluid movement OUT of vessel INTO interstitium so OEDEMA. rubor, calor, dolor, loss of function C-Reactive Protein (common blood test – marker of severity) Fibrinogen a1 antitrypsin

Answer 6

1. Inc arteriole flow and capillary pressure Brief vasoconstriction Vasodilation of arterioles from chemical mediators such as histamines Inc rate of flow Capillary pressure rises so fluid moves out 2. Inc vessel permeability so inc fluid exudate Walls of venules become more permeable Plasma leaves Inc interstitial oncotic pressure Inc haematocrit in venules so inc resistance to flow Inc pressure Inc exudation of fluid into interstitium 3. Movement of neutrophils from blood into tissue Inc vessel permeability due to: Retraction of Endothelial Cells due to Histamine, Nitric Oxide, Leukotrienes Direct Injury - Burns, toxins, direct trauma Leucocyte Dependent Injury - Enzymes/toxic oxygen species released by activated inflammatory cells

Answer 7

When arterioles dilate flow accelerates in the capillaries and capillary pressure rises. These changes 1. increase the delivery of fluid and leucocytes to the area of injury. Vessel wall becomes more permeable. 2. Interstitial Fluid - Dilutes toxins 3. Exudate - Delivers Proteins eg fibrin – mesh limits spread of toxin and immunoglobulins can carry out adaptive immune response 4. Fluid drains to lymph nodes so delivery of antigens – stimulates adaptive immune response.

Answer 8

The primary white blood cell involved in acute inflammation Trilobed nucleus Steps 1. Chemotaxis - movement towards chemical attractant from injured cell, bacteria etc. 2. Activation - switches to a higher metabolic level and becomes stickier. 3. Margination, Rolling and Adhesion - Stick to walls of venules, then roll while binding to select ns, then trapped when receptors bind to integrins. 4. Diapedesis - crawl through venules by using collagenase which digests the basement membrane. 5. Recognition and attachment to bacteria using opsonins eg C3b or antigens. 6. Phagocytosis - engulf and digest bacteria. Phagosomes fuse with lysosomes, Produce secondary phagolysosomes.

Answer 9

Chemical Messengers Control and co-ordinate the inflammatory response Vasoactive amines - histamine in vasodilation and inc vascular permeability. Vasoactive peptides - bradykinin in vasodilation and inc vascular permeability. Mediators from phospholipids - prostaglandin in vasodilation and fever. Inhibited by NSAIDs as they inhibit cyclooxygenase. Complement components- C3a in inc permeability. Cytokines and chemokines - involved in Chemotaxis. TNF involved in cachexia. Endotoxins Vasodilation- Histamine + Serotonin (from platelets) Prostaglandins Permeability- Histamine, Bradykinin Chemotaxis - C5a, Bacterial products Pain - Bradykinin, Prostaglandins

Answer 10

Local complications: Damage to normal tissue due to by-products of phagocytosis. Obstruction of tubes and compression of organs due to exudate eg fallopian tubes Loss of fluid from surface wounds Pain causes muscle atrophy, psycho-social consequences and loss of function. Systemic complications: Fever - pyrogens eg Prostaglandins which act on hypothalamus to alter temperature to kill bacteria. Treat with NSAIDs. Leucocytosis - neutrophilia Acute phase response - Inducing rest by malaise, reduced appetite, altered sleep, tachycardia. Septic shock - Huge release of chemical mediators. Widespread vasodilatation = hypotension = tachycardia so eventually multi-organ failure.

Answer 11

Acute appendicitis - Blocked lumen due to Faecolith. Accumulation of bacteria + exudate Increased pressure -> perforation Pneumonia Bacterial meningitis Inflammation of meninges Many causative organisms: Group B Streptococcus, E.Coli, Neisseria meningitides Signs and symptoms: Headache, Neck stiffness, Photophobia, Altered mental state Abscess - Accumulation of dead and dying neutrophils with associated liquefactive necrosis. Can cause compression of surrounding structures so pain and blockage of ducts.

Answer 12

The response of living tissue to injury. It is immediate, short, innate,stereotyped, limits damage. 4 phases: Vascular- Changes in blood flow Accumulation of exudate Cellular Phase Delivery of neutrophils Controlled Chemical mediators Protective But can cause local and systemic complications

Answer 13

1 - Complete resolution Mediators have short half lives so Diluted/inactivated/degraded. Vessel calibre and permeability returns to normal. Neutrophils undergo apoptosis and get phagocytosed. Exudate drained via lymphatics If tissue architecture is preserved, can undergo regeneration. 2 – Repair with connective tissue (fibrosis) - If there has been substantial tissue destruction. 3 – Progression to chronic inflammation - Prolonged inflammation with repair

Answer 14

Biopsy and resection H and E Immunohistochemistry, immunofluorescence, electron microscopy Low or high power Benign - infection or inflammation Malignant- type of cancer Cancer - stage/grade, has it all been removed?, features that indicate chemo/radio?

Answer 15

H = purple - nuclei Eosin = pink - cytoplasm and extracellular matrix

Answer 16

Histology - solid tissue i.e. biopsy or resection Tissue structure - Look for specific things: – tumour invasion – tumour grade – special tests • Invasive • Expensive • Timely • More accurate Cytology - individual cells + fluid aspirate Eg smear test Individual cells • Benign vs Malignant - only one question • Less invasive • Cheap • Quick • Less accurate

Answer 17

1. When it takes over from acute inflammation 2. When it begins without any proceeding acute inflammation, e.g. in some chronic infections such as tuberculosis, in some autoimmune conditions such as rheumatoid arthritis, with prolonged exposure to some toxic agents 3. When it develops alongside and superimposed on acute inflammation, e.g., in on-going bacterial infection, persistent irritation

Answer 18

Macrophages - phagocytosis, antigen presentation, synthesise and release of many mediators, presenting antigens, stimulating angiogenesis, inducing fibrosis, inducing fever Lymphocytes- T and B cells. Helper T cells release cytokines to influence other inflammatory cells Cytotoxic T cells destroy pathogens B cells differentiate into plasma cells to produce antibodies to neutralise pathogens Eosinophils - release mediators in hypersensitivity reactions and attack large parasites Fibro/myofibroblasts - fibro produce connective tissue substances such as collagen, elastin and glucosaminoglycan. Differentiate into myo which contract. Giant cells - fusion of macrophages. Langerhans - nuclei in periphery - TB Foreign body - random, small body then phagocytoses or else sticks Touton - horseshoe - high lipid content leisons along with foam cells.

Answer 19

Fibrosis - fibroblasts are stimulated by cytokines to produce excess collagen . Initially helps wall off infected area and makes scar tissue but then replaces normal tissue which impairs function. Eg chronic cholecystitis, liver cirrhosis Involvement in Inappropriate immune response - when antibodies attack wrong targets, mediators are released that cause inflammation so it is a disease process eg RA. Atrophy - due to reduced function Impaired Function Eg inflammatory bowel disease Rarely = increased function (eg thyrotoxicosis in Graves’ Disease)

Answer 20

RA - immune system attacks body tissue and mediators are released that cause inflammation. Chronic cholecystitis - chronic cholecystitis - Repeated bouts of acute inflammation -> chronic inflammation, Fibrosis of gall bladder wall (thickened and pale). Cirrhosis - End stage damage to liver. Fibrosis and attempted regeneration. Alcohol, Hepatitis, Drugs & toxins, Fatty liver disease.

Answer 21

Ulcerative colitis - affects large bowel only. Continuous inflammation. Affects superficial wall (muscles and submucosa) only. No granulomata. More likely to have rectal bleeding than Crohns. Crohn’s disease- all of GI, discontinuous patches of inflammation, affects full bowel wall, sometimes granulomata, less likely to have rectal bleeding than UC. Both idiopathic Abdominal pain Altered bowel motion Weight loss

Answer 22

Granuloma - collection of macrophages that look like epithelial cells (epithelial histiocytes) with surrounding lymphocytes. A granuloma is the body’s way of dealing with particles that are poorly soluble or difficult to eliminate for some reason. Granulomatous inflammation is a type of chronic inflammation in which granulomas are seen.

Answer 23

Foreign body - Destruction and removal of foreign material Few lymphocytes Eg large splinter Immune mediated - Destruction and removal of pathogens (bacteria/fungi) - insoluble but antigenic particles that cause cell-mediated immunity Can be idiopathic Can undergo central necrosis Many lymphocytes Can be harmful as they occupy parenchymal space within an organ

Answer 24

Foreign body reaction Infections by mycobacterium eg tuberculosis and leprae as they are difficult to destroy due to thick cell wall and mycolic acids. Crohn’s Disease - Non-necrotising granulomata in GI tract Sarcoidosis - Non-necrotising granulomata in skin, lymph nodes, lungs - organs throughout body - idiopathic

Answer 25

Labile - Continuous replication of cells. Continuous cell cycle. Eg epithelium, haematopoietic tissue Stable - Normally low level of replication but can undergo rapid replication if required. Left cell cycle but can re-enter. Eg Liver, kidneys, pancreas, bone, endothelium, smooth muscle Permanent - Cells do not replicate. Left cell cycle. Eg neurons, skeletal muscle, cardiac muscle

Answer 26

Stem cells differentiate and self-renew. Replace dead/damaged cells. Totipotent- all cell types - embryonic stem cells Multi - several - haematopoietic Uni - one - epithelial

Answer 27

Cell to cell contact - contact inhibition Isolated cells replicate until they encounter other cells. Cadherins bind between cells and inhibit further proliferation. Defective in cancer. Local mediators - growth factors Polypeptides that act on cell surface. Causes cell to enter cell cycle and proliferate. Eg VEGF, epidermal GF, platelet derived GF, tumour necrosis factor. Hormones With local mediators and hormones communication can be: Autocrine Paracrine Endocrine - synthesised by endocrine organ and transported in blood to target.

Answer 28

Regeneration - if collagen framework intact labile or stable can regenerate using stem cells. Fibrous repair - happens if collagen framework destroyed, chronic inflammation or necrosis of permanent tissue.

Answer 29

1. Bleeding & Haemostasis 2. Inflammation Phagocytosis of necrotic tissue debris 3. Proliferation of: Capillaries (angiogenesis), Fibroblasts, Myofibroblasts (synthesise collagen), Extracellular Matrix - all make granulation tissue. This contracts and closes the defect. 4. Remodeling Maturation of scar: Reduced cell population, Increased collagen, Myofibroblasts contract to shrink scar

Answer 30

Type 1 - Bones, tendons, ligaments etc 4 - Basement membranes In myo/fibroblast cytoplasm Pre-pro collagen undergoes Vitamin C dependent hydroxylation to become pro-collagen which has cross-linked alpha chains that form triple helix. Leaves cell. C and N terminals of procollagen cleaved to form tropocollagen. Tropocollagen crosslinked and many of them together form collagen fibres.

Answer 31

Scurvy - Inadequate hydroxylation of pre-pro collagen. Defective triple helix = defective collagen. Bleeding gums, tooth loss, bruising of skin, fatigue Inherited: Ehlers-Danlos syndrome – a heterogeneous group of six inherited disorders where the collagen fibres lack tensile strength. Skin is hyperextensible and susceptible to injury Joints are hypermobile - joint dislocations. Wound healing is poor. Because the collagen in internal organs is also affected patients can suffer from rupture of the colon, large arteries, corneal rupture and retinal detachment. Osteogenesis imperfecta - COL1A or 2A gene mutation. They have blue sclerae as there is too little collagen in the sclerae making them translucent. also have hearing loss, dental abnormalities, hypermobility. Alport syndrome – usually an X-linked disease. Type IV collagen is abnormal and this results in dysfunction of the glomerular basement membrane, the cochlea of the ear and the lens of the eye. Patients, usually male, present with haematuria. This progresses to chronic renal failure. They also have neural deafness and eye disorders.

Answer 32

Primary - occurs in incised, closed, non-infected wound with apposed edges (sutured). Minimal clot and granulation tissue. Epidermis regenerates, dermis undergoes fibrous repair - disruption of epithelial basement membrane but death of only some epithelial and connective tissue cells. Secondary - Significant tissue loss, excisional, infected Unapposed edges (Infection/ulcer/abscess) Abundant clot, inflammation and granulation tissue Considerable wound contraction required (Myofibroblasts) Dermis requires significant repair Epidermis regenerates from edges

Answer 33

1.Haematoma which fills the gap and surrounds the bone injury. It provides a foundation for the subsequent cell growth. 2. A fibrin mesh and then granulation tissue is formed. Platelets and inflammatory cells release cytokines. These activate osteoprogenitor cells to osteoclastic and osteoblastic activity. 3. Soft callus (also called procallus or fibrocartilaginous callus) forms at about one week. It consists of fibrous tissue and cartilage within which woven bone begins to form. Forms a bulge around the fracture site. 4. Hard callus appears after several weeks. It is laid down by osteoblasts. The bone formed initially is woven bone. 5. Formation of lamellar bone which is stronger than woven bone. 6. Remodelling of the bone occurs in response to mechanical stresses placed on it. Bone not physically stressed is resorbed and the outline of the bone is re-established.

Answer 34

Local: Size, location, type - intention, regeneration or scarring Blood supply Local infection + Foreign bodies - persistent inflammation Systemic: Age Anaemia, hypoxia, hypovolaemia - poorer o2 delivery Obesity - inc wound tension Diabetes - microangiopathy Drugs - steroids inhibit collagen synth, antibiotics clear up inflammation and infection Vitamin C deficiency inhibits collagen synth Malnutrition - no protein synth

Answer 35

Insufficient Fibrosis Wound dehiscence Excessive Fibrosis Keloid Scar Adhesions Fibrous bands - cause obstruction of tubes Loss of function - Replacement of specialised tissue by fibrous tissue Disruption of architecture Excessive scar contraction - Constriction of tubes and flexed flexion deformities(contractures)

Answer 36

Haemostasis is the stopping of haemorrhage from injured vessel. Clotting is the process whereby blood becomes a solid mass when it makes contact with connective tissue. Haemostasis: The severed artery contracts to decrease the pressure downstream Platelet plug Blood clot from fibrin

Answer 37

Vessel wall is made up of 3 layers tunica intima (endothelium), tunica media (smooth muscle) and tunica adventitia (connective tissue). Does: Vasoconstricton Production of vWF - essential for platelet adherence Exposure of collagen and tissue factor initiates activation of clotting factors. They are present in Tunica Adventitia of the vessel wall. Endothelium secretes tissue plasminogen activator and thrombomodulin that oppose clotting

Answer 38

Platelets have no no nucleus - From cytoplasm of megakaryocytes - Life span = 7-10 days When vessel is injured: • ADHESION - Platelets adhere to collagen via vWF • ACTIVATION/SECRETION - Activated by collagen surfaces, ADP, thrombin, thromboxane A2. • AGGREGATION - Cross linking of platelets to form a platelet plug

Answer 39

Intrinsic(involves factors in blood) and extrinsic pathway( tissue factor - thromboplastin outside blood) Join by factor 10 Each step is conversion of a proenzyme (zymogen) to an active enzyme Amplification system to generate thrombin (IIa) Thrombin(enzyme) converts soluble fibrinogen into insoluble fibrin • Enmeshes initial platelet plug to make stable clot Fibrinolysis - releases D-dimers

Answer 40

3 basic tests • Performed on platelet poor plasma (centrifuged) Activated partial thromboplastin time (APTT) - intrinsic - factors 8,9,11,12 - if prolonged one of them is deficient - VIII (haemophilia A) and IX (haemophilia B) Prothrombin time (PT) - extrinsic factor 7 Thrombin time (TT) - fibrinogen to fibrin Deficiencies in Factors V, X, thrombin and fibrinogen prolong both the APTT and PT as they are in the common pathway

Answer 41

Dilution by blood flow fibrin degradation products - D dimers Protein C + Protein S: Thrombin binds to an endothelial cell receptor called thrombomodulin • The resulting complex activates protein C • This then inactivates Factors VIIIa and Va • Protein S is a cofactor for activated protein C Antithrombin - Plasma protein that inactivates thrombin and several other clotting factors Activated by heparin on the surface of endothelial cells Prevents the spread of a clot, by rapidly inactivating clotting factors, that are carried away from the immediate site of the clot by the flowing blood.

Answer 42

Thrombocytopenia symptoms- purpura, petechiae, mucosal bleeding, epistaxis, menorrhagia. causes: Dec production - marrow aplasia, sepsis Inc consumption- immune and non-immune Immune - Thrombocytopenic purpura (antibodies against enzyme which prevents multimers of VWF. Platelets stick to these multimers. Causes MAHA.) Non-immune - Hypersplenism ( Enlargement of the spleen– Reduction in the number of circulating blood cells). haemolytic uraemic syndrome (Low RBCs and platelets, Bloody diarrhoea, fever, vomiting, kidney failure). DIC (Pathological activation of coagulation. Numerous microthrombi are formed which leads to consumption of clotting factors and platelets so MAHA. Always has trigger eg malignancy, sepsis, pre-eclampsia). Thrombotic disorder - Thrombophilia Congenital - deficiency in natural anticoagulants (protein C, protein S and antithrombin) Abnormal factor 5 - factor v Leiden - resistant to activated protein C. Acquired = antiphospholipid syndrome (due to antiphospholipid antibodies)

Answer 43

Acquired - DIC Thrombus forms in vessels leading to ischaemia, necrosis and organ damage. Inc bleeding due to consumption of platelets and clotting factors. Clotting tests affected – usually raised PT/INR, raised APTT, low fibrinogen and raised D dimers Congenital: H A - X-linked recessive • Congenital lack of factor VIII, Prolonged APTT and normal PT • Treated with recombinant factor VIII B - Congenital reduction in factor IX, Treated with infusions of recombinant FIX, otherwise similar – Recurrent haemarthroses – Joint pain and deformity – Prolonged bleeding post dental extraction VWD - autosomal dominant, VWF deficient - binds to factor 8 and helps activity. Also responsible for platelet adhesion to vessel wall. Causes inc bleeding time and APTT (intrinsic pathway). Symptoms: Spontaneous bleeding from mucous membranes (nosebleeds) • Excessive bleeding from wounds eg dental • Menorrhagia Unlike H spontaneous joint or muscle bleeds are rare. Vessel wall abnormalities

Answer 44

Anti-platelet Aspirin - blocks formation of thromboxane A2 in platelets Clopidogrel/ticagrelor – block platelet ADP Complications- bleeding Warfarin - Warfarin – stop, give Vitamin K - affects clotting factors that require Vit K which are factors 2(thrombin),7,9,10 (factor 7 dec due to lack of Vit K first as it has shortest half life). Heparin – stop, give protamine sulphate which binds to heparin and stops it from working. Heparin activates antithrombin lll which dec activity of F10 and thrombin.

Answer 45

Formation of a solid mass of blood within the circulatory system. Clot = mass of blood outside the vessel wall

Answer 46

1. Vessel Wall Damage 2. Blood flow - turbulent 3. Blood components - hypercoagubility

Answer 47

Wall Atheroma Inflammation Direct injury Damage to heart Blood flow Stasis - Narrowing, immobility, LBP Turbulent blood flow – Defects in wall and heart valves, Components Hypercoaguable- smokers, pregnancy, trauma

Answer 48

tPA = tissue plasminogen activator Plasminogen to plasmin Plasmin degrades fibrin and dissolves thrombus Fibrin degradation products eg. D dimers (detected in blood tests)

Answer 49

Lysis - break down when small, Fibrinolytic system active, Blood flow re-established Propagation - Progressive spread of thrombosis Distally in arteries Proximally in veins Organisation - Ingrowth of fibroblasts and capillaries, lumen obstructed Recanalisation - One or more channels form through area of organising thrombus, incomplete blood flow Embolism - Part of thrombus breaks off  Travels through bloodstream  Lodges at distant site

Answer 50

congestion  oedema  ischaemia  infarction Cavernous sinus thrombosis Subclavian vein thrombosis Budd Chiari and IVC thrombosis Uteroplacental thrombosis Deep vein thrombosis, DVT

Answer 51

ischaemia  infarction  depends on site and collateral circulation Cerebral A. Carotid A. Coronary A. Mesenteric A Renal A. Femoral/ Iliac / Popliteal A.

Answer 52

Embolism is the blockage of a blood vessel by solid, liquid or gas at a site distant from its origin. >90% of emboli are thrombo-emboli Other types: Air - medical equipment Amniotic fluid - tear in amniotic membrane - pregnancy - causes haemorrhage Nitrogen - scuba Tumour cells Fat + bone marrow- bone fractures

Answer 53

Veins - causes pulmonary embolism in pulmonary artery Massive PE = death Small = is in peripheral artery, infarct Multiple = hypertension Heart - thromboembolism due to endocardial thrombus (causes MI), vegetations, atrial fibrillation. Fragments into aorta and then affects systemic arteries such as renal (renal infarcts), mesenteric (bowel ischaemia). From carotid arteries development of atherosclerotic plaque with thromboemboli causes ischaemic stroke. From Abdominal aorta - Atherosclerotic plaque or aneurysm with development of thromboembolism causes acute limb ischaemia. From iliac/femoral causes limb ischaemia.

Answer 54

Mobilise+leg compression Thrombolysis - streptokinase CT PA for pulmonary embolism Heparin DOACs are anti factor 10, eg rivaroxaban - better than warfarin(easily bleed by overdosing, need lots of blood tests) Mechanical Embolectomy

Answer 55

Atherosclerosis – a disease of large and medium sized arteries that begins in the intima. Plaques are formed in the arterial wall and these are filled with atheroma. The plaques often calcify. Arteriolosclerosis = hardening of the arterioles. This disease affects arterioles throughout the body but especially those of the kidney. It has little or no connection with atherosclerosis and usually occurs secondary to severe hypertension or in diabetes mellitus. Atheroma is the necrotic core of the atherosclerotic plaque. It consists of dead cells, debris and cholesterol crystals.

Answer 56

1. Chronic endothelial insult 2. Lipid droplets from LDLs, and monocytes cross and accumulate in the intima. The lipids become oxidised and the macrophages ingest the lipid - foam cells 3. Smooth muscle cells migrate into the lesion from the media and start to proliferate - fatty streak. 4. Some smooth muscle cells lie over the plaque forming a ‘roof’. This roof is reinforced by collagen, elastin etc - fibrous cap. As the endothelium stretches gaps appear between the endothelial cells. Platelets adhere to the gaps. 5. Cells in the centre of the plaque die and necrosis develops. The dead cells release cholesterol and cholesterol crystals appear in the plaque. Small blood vessels grow into the plaque from the adventitia and the plaque may undergo calcification.

Answer 57

Cells: endothelial cells - Altered permeability to lipoproteins platelets - migration of smooth muscle cells (PDGF) neutrophils - Secrete proteases - inflammation macrophages - foam cells + smooth muscle cells migration smooth muscle cells - foam cells, synthesise collagen Lymphocytes - migration of smooth muscle cells Lipid: intracellular (foam cells) and extracellular (pools) Extracellular matrix: collagen, elastin, proteoglycans

Answer 58

Fatty streak Lipid deposition, slightly raised yellow area in the intima simple plaque / fibroatheroma Raised yellow/white, irregular outline, widely distributed, enlarge and coalsece Complicated plaque Yellow and red (haem and thrombosis), irregular, rough, hard and calcified

Answer 59

Fatty streak - Proliferation of smooth muscle cells Accumulation of foam cells Extracellular lipid Simple plaque - Fibrosis (fibrous cap), Necrosis, Cholesterol clefts complicated plaque - Disruption of the internal elastic lamina, Damage extends into the media, New vessels grow into plaque (from adventia), Plaque fissuring

Answer 60

1. Ulceration – the fibrous cap is eroded from underneath and the core of the plaque is exposed to the blood - highly thrombogenic. 2. Thrombosis on the plaque – often on ulcerated - occlude lumen. 3. Spasm at the site of the plaque – caused by vasoconstrictors released from thrombi. 4. Embolisation – of pieces of exposed atheroma or overlying thrombus. 5. Calcification – in and around the plaque making the artery even stiffer. 6. Haemorrhage – of one of the new vessels within the plaque. expands the plaque = vessel occlusion or break the plaque open. 7. Aneurysm formation – a local dilatation may result when elastic tissue within the arterial wall is destroyed - weakens the wall - rupture. 8. Rupture of the atherosclerotic artery – with resulting bleeding. This occurs as a result of a weakened media.

Answer 61

• Heart - myocardial infarction, chronic ischaemic heart disease, arrhythmias, cardiac failure and sudden cardiac death • Brain – transient ischaemic attacks (TIAs), cerebral infarction, multi-infarct dementia, • Kidneys – hypertension, renal failure, • Legs – peripheral vascular disease, gangrene, Acute limb ischaemia • Bowel - ischaemic colitis, malabsorption, acute bowel ischaemia. Abdominal Aorta - Aneurysmal formation, rupture These conditions are either due to narrowing/blockage of vessels or embolism of plaque material or thrombus that has formed on a plaque.

Answer 62

Age Gender - women protected by oestrogen until menopause Hyperlipidaemia - high plasma cholesterol + high LDL Cause: Apolipoprotein defects - ApoA1, ApoE Lipoprotein lipase LDL receptor mutations Signs - corneal arcus, tendon xanthomas, xanthelasma Treat: Dec cholesterol + LDL in diet Statins Low fat + high fibre Aspirin Cigarette smoking Hypertension Diabetes mellitus - IHD, cerebro and peripheral vascular disease Alcohol Infection - Chlamydia pneumoniae, Helicobacter pylori, Cytomegalovirus

Answer 63

• Statins (lipid lowering) • Anti-hypertensives • Exercise • Normal BMI • Non smoker • (Alcohol) – in moderation! • Balanced diet to reduce diabetes risk - Mediterranean • Diabetic medication • CANTOS – targeting inflammation in atherosclerosis – Canakinumab (monoclonal Ab targeting IL-1Beta)

Answer 64

Size of population: • cell proliferation • cell differentiation • cell death by apoptosis G0 - permanent exit G1 - cellular contents duplicated S-chromosomes duplicated G2 - checks for error, inc in cell size and proteins Restriction point - End of G1- nutrients, GF, DNA damage G2 checkpoint- cell size and replication Metaphase checkpoint - spindle attachment Cyclin dependent kinases - phosphorylase proteins to allow passage through restriction points.

Answer 65

1. Hyperplasia – cells increase in number - only in labile or stable eg bone marrow or liver. Reversible. 2. Hypertrophy – cells increase in size 3. Atrophy – cells become smaller 4. Metaplasia – cells are replaced by cells of a different type. Not across germ layers. Not in striated muscle or neurones. Still fully differentiated. Aplasia –The complete failure of a specific tissue or organ to develop Hypoplasia –The congenital underdevelopment, or incomplete development, of a tissue or organ Involution –The normal programmed shrinkage of an organ Dysplasia – The abnormal maturation of cells within a tissue

Answer 66

Hyperplasia: Physiological- hormonal or compensatory (tissue damage) - inc bone marrow production in hypoxia, After birth hyperplasia for lactation. Pathological - psoriasis - epidermis thicker Hypertrophy: more cellular components. Physio - heart in athletes, Smooth muscle hypertrophy in uterus in pregnancy, Skeletal muscle. Path - anoxia in heart, in BPH obstructed urinary flow so trusser muscle works harder so bladder hypertrophy. When one kidney removed compensatory hypertrophy. Atrophy: Cellular - shrinkage of cell but survival. Red function + components Organ - loss of parenchyma and replaced by connective tissue. Remove cause. Physio - dec in size of uterus after birth, thymus gland from 20yrs Path - disuse eg after fracture. denervation. senile due to inadequate blood supply in permanent tissue eg brain in artherosclerotic cerebrovascular disease. Pressure. Immunological - pernicious anaemia causes gastric mucosa to lose glands that produce intrinsic factor? Metaplasia: columnar epithelium (fragile) undergoes metaplasia to become squamous epithelium (more resilient) but mucus secretion lost. common on surface linings. Physio - Myeloid metaplasia of the spleen - splenic tissue to bone marrow tissue when it is destroyed by disease. Stratified squamous more resistant in Salivary gland ducts and pancreatic ducts, Renal pelvis and renal stones. In smoking replace by squamous which cannot produce mucus - squamous cell carcinoma Barrera oesophagus- Acid reflux causes replaced by secretory glands - oesophageal adenocarcinoma. Fibroblasts in skeletal muscle to osteoblasts - Traumatic myositis ossificans.

Answer 67

Thymus aplasia - immune conditions in infants Aplastic anaemia - bone marrow cells fail to proliferate - embryonic Hypoplasia - embryonic - congenital - not opp - renal hypoplasia, testicular hypoplasia, chambers of heart Atreasia - oesophageal and duodenal Reconstitution- several cells involved. Small blood vessels in healing. Involution - thymus, pronephros Dysplasia -cervical cancer

Answer 68

1. Resistance to apoptosis 2. Angiogenesis 3. Resistance to growth stop signals 4. Self sufficiency in growth signals 5. Cell immortalisation due to telomeres- no limit on proliferation 6. Metastasise Enabling- genetic instability - alterations in chromosomal segregation that causes accelerated accumulation of mutations that are present in malignant neoplasms.

Answer 69

Tumour = Any clinically detectable lump or swelling Neoplasm = means ‘new growth’. an abnormal growth of cells that persists after the initial stimulus is removed. Malignant when it invades surrounding tissue and can spread. Metastasis = Malignant neoplasm that has spread from its original site to a new non-contiguous site. Cancer = a malignant neoplasm

Answer 70

dysplasia - pre-neoplastic alteration in which the cells show disordered tissue organisation Reversible Can exhibit considerable pleomorphism pleomorphism - increasing variation in size and shape of cells and nuclei. Differentiation = the process of becoming different by growth or development. Progression - neoplasm emerges from single founding cell. characterised by the accumulation of yet more mutations.

Answer 71

Behaviour- Malignant can spread Macro - Benign grow in a local area and so have a pushing outer margin. Malignant have an irregular outer margin and may show areas of necrosis and ulceration. Micro - Benign closely resembles the parent tissue - well differentiated - low grade. With worsening differentiation individual cells have increasing nuclear size and nuclear to cytoplasmic ratio, increased nuclear staining (hyperchromasia), more mitotic figures and pleomorphism.

Answer 72

In-situ = no invasion through epithelial basement membrane. Invasive means it’s penetrated.

Answer 73

Neoplasia is caused by accumulated mutations in somatic cells. The mutations are caused by initiators, which are mutagenic agents, and promoters, which cause cell proliferation. In combination result in an expanded, monoclonal (single founding cell) population of mutant cells. Can be inherited instead of external mutagenic agent (chemicals eg smoking + alcohol, radiation, infection eg HPV).

Answer 74

Genes targeted by cancer causing mutations: Growth promoting proto-oncogenes Growth inhibiting tumour suppressor genes Genes that regulate apoptosis - abnormalities so less cell death Genes involved in DNA repair - Impair the ability of the cell to repair non-lethal genetic damage so cells acquire mutations at accelerated rate - mutator phenotype. proto-oncogenes become abnormally activated (oncogenes then to oncoproteins) = neoplasm formation. Drive proliferation. Sometimes they impart a completely new function on the affected gene (Gain-of-function” mutations). Need 1 damaged allele. Tumour suppressor genes, which normally stop cell proliferation become inactivated. Need 2 damaged alleles.

Answer 75

benign or malignant, the type of tissue the tumour forms and sometimes the gross morphology (e.g. cyst or papilloma). Benign neoplasms end in –oma. Malignant ones end in –carcinoma if epithelial or -sarcoma if stromal. Some neoplasms are called “-blastomas”, - children - immature precursor cells.

Answer 76

- Bladder – transitional cell carcinoma - Oesophagus – squamous cell carcinoma, adenocarcinoma - Stomach/Bowel – adenocarcinoma - Skin – squamous cell carcinoma, malignant melanoma, basal cell carcinoma - Lung – adenocarcinoma, squamous cell carcinoma, small cell carcinoma - Breast/Prostate – adenocarcinoma - Brain –astrocytoma - Thyroid/Pancreas/Uterus – adenocarcinoma - Cervix – squamous cell carcinoma

Answer 77

Invasion Breach of the basement membrane with progressive infiltration and destruction of the surrounding tissues Metastasis Spread of tumour to sites that are physically discontinuous from the primary tumour 1) GROW AND INVADE AT THE PRIMARY SITE with breach of the basement membrane. (2) ENTER A TRANSPORT SYSTEM AND LODGE AT A SECONDARY SITE; (3) GROW AT THE SECONDARY SITE TO FORM A NEW TUMOUR (COLONISATION) CELLS MUST EVADE DESTRUCTION BY IMMUNE CELLS.

Answer 78

• Altered adhesion Reduction in E-cadherin expression (so sticks to other cells less) +Changes in Integrin expression(basement membrane) • Stromal proteolysis Altered expression of proteases, notably matrix metalloproteinases (MMPs). Degrade basement membrane to allow for invasion. • Motility Propels itself forward into stroma. Involves changes in the actin cytoskeleton. cell takes on a phenotype more akin to a mesenchymal cell/stromal cell so known as epithelial to mesenchymal transition. Niche

Answer 79

Regional drainage: of blood, lymph or coelomic fluid (fluid in body cavities). Lymphatic metastasis = lymph nodes as it drains there - Breast cancer goes to the ipsilateral axillary lymph nodes. transcoelemic spread - other areas in the coelemic space or adjacent organs blood-borne metastasis - next capillary bed. Seed and soil phenomenon: INTERACTIONS BETWEEN MALIGNANT CELLS AND THE LOCAL TUMOUR ENVIRONMENT (I.E. THE NICHE) AT THE SECONDARY SITE.

Answer 80

Metastases are most common malignant bone tumours - axial - haematogenous spread osteolytic lesions due to destruction of the bone tissue osteosclerotic metastases as it causes increased production of disorganised abnormal bone - prostate cancer

Answer 81

Local: 1. Direct invasion and destruction of normal tissue 2. Ulceration at a surface leading to bleeding 3. Compression of adjacent structures 4. Blocking tubes and orifices 5. Raised pressure due to tumour growth or swelling (brain) Systemic: Inc tumour burden + cytokines secretion = dec appetite and weight loss (cachexia), malaise, Immunosuppression(could be due to direct destruction of bone marrow), thrombosis. Production of hormones(usually benign). Paraneoplastic Syndrome - not readily explained symptoms eg Hypercalcaemia (myeloma), Syndrome of Inappropriate ADH Secretion causes hyponatraemia (small cell lung cancer). Miscellaneous - neuropathies, pruritus, fever, clubbing, myosotis, hypoglycaemia.

Answer 82

Intrinsic: heredity (inherited mutation - BRACA 1 gene causes breast cancer), older age (more exposure to extrinsic factors and immune system gets worse) and gender (hormonal - oestrogen) extrinsic: environment - chemicals, radiation and infection behaviour - high BMI, low fruit and vegetable intake, lack of physical activity, tobacco use, and alcohol use

Answer 83

Chemicals - initiators: aromatic amines eg 2-napthylamine - dye industry and smoke - bladder cancer, natural products e.g aflatoxin in fertilisers - liver cancer, asbestos - buildings - mesothelioma. Pro-carcinogens converted to carcinogen by cytochrome P450 enzymes in liver. Need promoters for proliferation. Radiation UV light - doesn’t penetrate further than skin - skin cancer Ionising - radon - damage DNA ( single and double strand breaks) or generate free radicals. Infections: Affect genes that control cell growth eg HPV - cause cervical carcinoma- express E6 that inhibits p53 so cell cannot undergo apoptosis. Or cause chronic tissue injury - regeneration acts as promotor for mutations or new mutations from DNA replication errors eg Hep B and C cause chronic liver cell injury, H pylori causes chronic gastric inflammation, parasitic flukes cause inflammation in bile ducts and bladder mucosa. HIV lowers immunity so allows carcinogenic infections to occur.

Answer 84

1) there is a long delay between carcinogen exposure and malignant neoplasm onset (2) the risk of cancer depends on total carcinogen dosage (3) there is sometimes organ specificity for particular carcinogens 6 hallmarks: 1) can produce their own Growth signals 2) resistance to growth stop signals 3) no limit on division 4) angiogenesis 5) resistance to apoptosis 6) can invade tissue

Answer 85

Tumour Suppressor Genes both alleles must be damaged for transformation Abnormalities in these genes leads to failure of growth inhibition Example - Retinoblastoma gene - key negative regulator of G1/S cell cycle checkpoint. Proto-Oncogenes Oncogenes are created by mutations in proto-oncogenes and encode proteins called oncoproteins that have the ability to promote cell growth in the absence of normal growth promoting signals. Example - RAS DNA repair genes Caretaker genes prevent accumulation of DNA damage. Chromosome aggregation during mitosis can be abnormal in malignant cells due to accelerated mutation rate - genetic instability- caretaker gene are TS genes that maintain stability.

Answer 86

First, somatic cells are exposed to environmental carcinogens (chemicals, radiation, infections) that are initiators and cause mutation. Promoters cause sustained proliferation so there is a monoclonal population of mutant cells. During progression the cells acquire further activated oncogenes or inactivated tumour suppressor genes - cells with all the hallmarks.of cancer.

Answer 87

Cirrhosis is associated with hepatocellular carcinoma, and ulcerative colitis is associated with colorectal cancer due to prolonged injury and inflammation to the organs.

Answer 88

In inherited cancers germline mutations cause malignant neoplasms indirectly by affecting DNA repair. Hereditary Non-Polyposis Colon Cancer (HNPCC) Syndrome - autosomal dominant - Germline mutation affects one of several DNA mismatch repair genes eg MSH2,MSH6. Familial breast carcinoma - BRCA1/BRCA2 genes - repairing double strand DNA breaks Familial adenomatous polyposis (FAP) - Fault in the APC gene Retinoblastoma- RB gene - autosomal dominant

Answer 89

Neoplasias can be sporadic or familial. For familial cancers, the first hit was delivered through the germline and affected all cells in the body. The second hit was a somatic mutation. For sporadic both hits must be somatic and occur in the same cell.

Answer 90

Adult - Lung, female breast (15-54), prostrate (men-45+), bowel carcinomas Children - leukaemia and lymphoma Most cancer deaths = lung cancer

Answer 91

Tumour stage is a measure of the overall burden of the malignant neoplasm. T = size of primary tumour N = extent of regional lymph node involvement M = metastatic spread via the blood • Stage 1 = early local disease • Stage 2 = Advanced local disease (N0, M0) • Stage 3 = regional metastasis (N1, M0) • Stage 4 = advanced disease with distant metastasis (M1) Ann arbor - breast carcinomas Stage 1,2,3 tubule formation (3 means very poorly differentiated) Stage 1,2,3 nuclear pleomorphism Stage 1,2,3 abnormal mitoses Dukes - colorectal cancer Duke A - small - going through through muscle wall B - eroding completely through muscle wall C - lymph node involvement D - liver metastases (or any other metastases)

Answer 92

Grade describes the degree of differentiation of a neoplasm. G1 = well-differentiated G2 = moderately differentiated G3 = poorly differentiated G4 = undifferentiated or anaplastic

Answer 93

Surgery Neoadjuvant- Treatment is given prior to surgical excision to reduce the size of the primary tumour Adjuvant- Treatment is given after surgical removal of a primary tumour to eliminate subclinical disease Radiotherapy Kills rapidly dividing cells in G2 of the cell cycle by triggering apoptosis by causing DNA damage which is detected by cell cycle checkpoints. External beam - aimed at tumour. Internal - systemic (radioactive iodine) or local (brachytherapy- capsules near tumour). There are lifetime dose limits. Fractionated doses to limit damage to normal tissue.

Answer 94

Chemotherapy Kills cancer cells that have spread. Used in combination. Cisplatin - cross link DNA strands, antibiotics eg Doxorubicin inhibits DNA synthesis by inhibiting DNA topoisomerase, antimetabolites eg flurouracil mimic DNA substrates and plant-based disrupt mitotic spindle formation. Hormone Therapy Selective oestrogen receptor modulators (SERMs) – Tamoxifen – Bind to oestrogen receptors so block oestrogen. Treatments targeted to specific molecular alterations eg target oncogenes - Imatinib which inhibits fusion protein in CML. Immunotherapy - immune checkpoint inhibitors, T-cell transfer therapy, monoclonal antibodies, treatment vaccines (oncolytic virus therapy - cancer cells cannot kill herpes simplex)

Answer 95

Various substances are released by cancer cells into the circulation (and in urine and faeces) Measured for diagnosis, monitoring tumour burden, assess response to therapy and recurrence. Hormone - Human Chorionic Gonadotrophin (hCG), calcitonin - testicular tumours, medullary thyroid carcinoma Specific proteins - Prostate specific antigen (PSA)– prostate carcinoma Fetoproteins - alpha-fetoprotein - hepatocellular carcinoma Mucins and glycoproteins - CA-125 - ovarian carcinoma

Answer 96

Meant for healthy people with no symptoms at all. Benefits: Attempts to detect cancers as early as possible when the chance of cure highest More effective treatment Reduce complications and death Can help people make better health decisions eg stop smoking. Risks: Lead time bias Length time bias Selection bias Not always accurate - over diagnosis Anxiety Could still go on to develop condition even with neg test

Answer 97

Must be sig public health problem Treatment and cure with early detection Safe, inexpensive Result in better health outcomes Measures of performance • Incidence • Reduction in mortality • Interval cancers Sensitivity- ability to identify positive people as positive Specificity- identify neg as neg

Answer 98

Cervical - HPV - 25-64 Breast - 47-73yrs Bowel - 60-74 yrs

Answer 99

Adenocarcinomas: Oncogenes - both build up drug resistance EGFR - more Asian - mutations cause activation of TH signalling pathway- cell diff and proliferation - gefitinib which is anti TK inhibitor - better than platinum based chemo drugs - PCR - deletion ALK - fusion of gene - IHC or PCR - young not smokers - ATP kinase inhibitors eg crizotinib KRAS - PCR - smokers - on going clinical trials Small and non small cell: Tumour suppressor genes p53 mutations Small cell: Tumour suppressor RB1 mutations

Answer 100

BRAF mutation - V600E mutation - Activation of MAPK pathway • Anti BRAF drugs = dabrafenib and trametinib medication Tumour resistance can develop on BRAF inhibitors alone, so combine with MEK inhibitor (trametinib) If lacking BRAF mutation- IHC Block PDL1 ligand on tumour cells so T cells can detect and kill cancer cells - increase in cytokine production and cytolysis. - Nivolumab and Pembrolizumab - drug resistance and side effects.

Answer 101

IHC Cancer cells produce Growth factors to stay alive and proliferate - PDGF (stromal cell proliferation) and TGF beta (angiogenesis, produces ECM, suppress immune response) Block TK receptors on growth factors to prevent proliferation Block PDL1 ligand Metastatic urothelial carcinoma – PDL1 Head and neck cancers mets – PDL1 Colorectal cancer – DNA mismatch repair enzymes

Answer 102

Mutate proto-oncogenes to oncogenes so result in cell proliferation • Mutate Ts genes (double hit) e.g. p53, Rb, APC, WT1, BRCA1 &2 gene, MSH and MLH • Overexpress anti-apoptotic factors e.g. Bcl2 (Normally bcl2 inhibits apoptosis) • Inhibit pro-apoptotic signals (e.g. p53, caspases) • Overexpress growth factors and/or growth factor receptors. • Mutate DNA repair mechanisms (MLH and MSH)