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Mechanisms of Disease


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Six causes of acute inflammation
Microorganisms Foreign Particles Necrotic Tissue Physical agents Chemicals Hypersensitivity
Three Changes of acute inflammatory response
Haemodynamic changes - Peripheral hyperaemia Alterations of vessel permeability - direct injury & inflamm. mediators Recruitment and migration of neutrophils - Accumulation of PMNs
Cellular Response in Acute inflammation
Margination Adhesion (Selectins, Integrins, Ig Gene Superfamily) Emigration Chemotaxis
What do PMNs recognise?
Dead tissue Foreign material Opsonins Ig/complement (Fc & C3b receptors)
Phagocytic Killing mechanisms
Oxygen Dependent Oxygen independent
Inflammatory mediators
Complement Kinins Arachidonic Acid (PG & Leukotrienes) PAFs Cytokines Acute Phase Proteins
Systemic effects of acute inflammation
Pyrexia Malaise Weight loss Reactive Lymphoid Lymph-hyperplasia Acute Phase Response
Benefits of inflammation
Dilution of toxins entry of Ab Fibrin network formation Nutrients & Oxygen Delivery of neutrophils Immunse response stimulated Entry of drugs
Problems caused by inflammation
Destruction of tissue Swelling Blockage of tissues Fluid loss Pain Inappropriate inflammation
Outcomes of acute inflammation
Resolution Suppuration (pus) Organisation Calcification Chronic Inflammation Septicaemia Death
Examples of Pro-inflammatory cytokines
IL1 IL6 IL8 TNF Alpha
Definition of Chronic Inflammation
Long standing inflammation Characterised by mononuclear/chronic inflamm. cells Results in destruction, fibrosis or repair Granulomatous inflammation specific pattern
Causes of Chronic inflammation
Primary (infection/irritation/autoimmune) Progression of acute Recurrent acute
Patterns of chronic inflammation
Lymphatic Granulomatous Mixed acute/chronic
Cells involved in chronic inflammation
Macrophages Lymphocytes Plasma cells Eosinophils
Macrophage Functions
Phagocytosis Cytokine production Tissue destruction & repair APC
Three stages of wound healing
Inflammation Tissue formation Tissue remodelling
Three processes of Wound healing
Cellular migration ECM reorganisation & remodelling Cell proliferation
Three types of cell
Labile (skin) Stable (Liver) Permanent (Cardiac)
Important Collagen types & location
Type 1 - Bone, tendon, scars Type 2 - Cartilage Type 4 - Basement membrane
Three parts of ECM reorganisation & remodelling
Remodelling (Macrophages) Angiogenesis (IL8) Granulation Tissue (perfused, fibrous connective tissue)
From Wound to Scar Development
Incision Blood clot Acute inflammation Granulation tissue forms Epithelium proliferation Myofibroblasts invade Collagen & Glycoproteins produced Cell population falls & vessels reduced Collagen matures & contracts
Healing by primary intention
Edges of wound opposed & fixed Epidermis regenerates
Healing by Secondary intention
Wound not closed Initial contraction Epidermis regenerates at base Granulation tissue bed Longer process, more scarring, more contraction
What cells cause scar contraction in remodelling, and over what time?
Myofibroblast Over many months (Poorly understood)
Local factors affecting wound healing
Site Size Tissue Type Apposition Infection Blood supply Foreign material Radiation damage
General factors affecting wound healing
Age Chronic Diseases Drugs CVA status Dietary insufficiency
Complications of tissue repair
Scarring cosmetics Contracture Loss of architecture & function Dihescence
What do Cadherins do?
Cell-Cell Adhesion
What do Intergrins do?
Cell-Stroma adhesion
What are the stages of malignant spread
Invade BM Passage through ECM Intravasation Immune interaction Platelet adhesion Adhesion to endothelium/BM Extravasation Angiogenesis
Routes of metastatic Spread
Lymphatics Vascular Trans-Coelomic Spread
Common Sites of vascular metastatic spread
Lung Liver Bone Brain
Local Benign Effects of Neoplasms
Compression Obstruction Ulceration Space occupying lesion
Local malignant effects of neoplasms
Destruction of local tissue Obstruction or constriction Ulceration Infiltration SOL
Systemic effects of neoplasms
Haematological (anaemia, low WBC & Thrombosis) Endocrine (excessive / ectopic) Skin (pigmentation, pruritis) Neuromuscular (Balance, sensory) Cachexia Malaise Pyrexia
Why do neoplasms kill?
Local effects (Brain perforation, haemorrhage) replacement of essential body organs
By what mechanism do cells invade & spread
Altered cell adhesion (Cadherins) Altered cell stromal interactions (integrins) Secretion of proteins (MMPs etc)
Common secondaries in brain
Breast Bronchus Testicular Malignant Melanoma
Common secondaries in Bone
5B\'s Bronchial Breast Byroid Brostate Bidney
Common secondaries in Lung
Osteosarcoma Breast Stomach Large intestine Kidney cannonball Testes
Common secondaries in Liver
GI Breast Bronchial
Tumour Suppressor Genes
c-myc src ras c-erb her-2
Essential Alterations for malignancy (Mag 7)
Self-sufficiency in growth signals Insensitivity to negative growth signals Defects in DNA repair Evasion of apoptosis Limitless replicative potential Sustained angiogenesis Ability to invade & metastasise
Definition of Dysplasia
Premalignant condition (still confined by BM) Atypia (alteration to cell size, shape etc) Alt. Differentiation (CIN)
Cytological features of malignant cells
Poor differentiation Many mitotic figures Increased chromatin Cell & nuclear pleomorphism
Extrinsic Carcinogens
Radiation Chemical Virus
Three Chemical Carcinogens
Polycyclic Hydrocarbons (tobacco smoke) Aromatic amines Nitrosamines
Two Radiation carcinogens
Ionising (Xrays etc) Non-Ionising (UV)
Inherited Susceptibility to Neoplasms
Xeroderma Pigmentosum (Bad skin) Ataxia Telangiectasia (Bad skin) Down\'s syndrome (increased risk of ALL)
Inherited Tumours
Retinoblastoma Familial Polyposis Coli Breast Cancer Neurofibromatosis
Stages of Carcinogenesis
Initiation (Stimulus / unstable genome) Promotion (hormones etc) Progression (6+ gene alterations)
What is the Ann Arbour Staging System
I - One group of nodes involved II - two seperate groups, same side of diaphragm III - Nodes on both sides of diaphragm + spleen IV - Bone Marrow, Lungs, other sites A - No symptoms B - Itching & Fever
Dukes Staging for Colorectal cancer
A) Not through muscularis propria B) Extended through MP C) Lymph node involvement
TNM Staging
T1 < 2cm, T2 2-5cm, T3 Skin/chest wall involvement N0 - no axillary nodes N1 - nodes M0 - No mets M1 - (demonstrable) mets
Tumour marker for Ovarian cancer
Tumour marker for testicular cancer
Beta-hCG Alpha-fetoprotein
Tumour marker for Prostate
PSA Acid Phosphatase
Tumour marker for GI
Carcinoembryonic Antigen
Factors in Radiotherapy
Type of radiation Rate of delivery Cumulative dose Target tissues Phase of cell cycle Repair mechanisms Oxygenation
Successful Haemostasis Depends on
Vessel Wall Endothelial Cells Platelets Coagulation Cascade Fibrinogenesis / Fibrinolysis
Coagulation is controlled by
Site restriction & dilation Antithrombin III / Thrombomodulin Negative Feedback by thrombin Release of t-PA Metabolism of active coagulation factors in the liver
Causes of excessive Bleeding
Congenital Liver Disease Vitamin K Deficiency DIC
Congenital clotting factor deficiencies
Von-Willebrands Disease (Autosomal Dominant - low factor VIII) Haemophilia A (X-linked recessive, low factor VII) Haemophilia B (Factor IX deficient)
Causes of excessive clotting
Thrombocytosis Sticky platelets Cancer SLE Acquired (Protein S&C deficiency)
Constituents of a thrombus
Platelets Fibrin Trapped cells
Definition of thrombus
Solid mass of blood constituents formed in circulation in life
Predisposing factors to thrombosis
Vessel wall abnormalities Changes in blood constituents Changes in blood flow
Clinical effects of arterial thrombosis
Cuts off blood supply to part of an organ causing ischaemic necrosis (infarction) Source of emboli MI / Stroke
Fates of thrombus
Propogation in direction of blood flow Fibrinolysis & removal Organisation into scar tissue Recanalisation
What is an embolism?
A mass which travels through vascular tree & becomes lodged so as to obstruct blood flow
Types of Embolism
Air Amniotic Fluid Atheroma Fat Foreign Material Nitrogen Tumour Cells
DVT Prophylaxis
Heparin & Leg compression
DVT Treatment
Heparin & Warfarin
Arterial Thrombosis Prophylaxis
Arterial Thrombosis Treatment
Streptokinase t-PA
What regulates cell growth?
Rate of population growth Signal molecules Cell-Cell interactions Cell-Matrix interactions General factors (Nutrition, blood supply etc)
Phases of cell cycle
G0 G1 S G2 M
Different Cellular Responses in Growth & Differentiation
Hyperplasia (more cells) Hypertrophy (big cells) Atrophy (Shrinking cells) Metaplasia (Reversibly changing mature cells) Hypoplasia (incomplete development of an organ)
Causes of Atrophy
Reduced workload Loss of nerve supply Reduced blood supply Inadequate nutrition Loss of endocrine stimulation Ageing
What is atherosclerosis
Chronic arterial disease characterized by intimal accumulation, resulting in narrowing of arterial lumen, weakening of wall, sudden local thrombus formation
What accumulates in atherosclerosis
Lipid Inflammatory cells Vascular smooth muscle cells ECM
Three types of atheroma
Fatty Streaks Simple (Fibrous) Plaque Complicated plaque
Describe a simple plaque
Peripheral proliferating vessels Raised Irregular outline Central Necrosis Enlarged & coalesced
Four complications of a plaque
ARSE Aneurysm Rupture Stenosis Embolism
Effects of Atheroma
IHD Cerebral Ischaemia (Cerebral Infarct, TIA or Multi Infarct dementia) Mesenteric Ischaemia Aortic aneurysm & rupture (& Peripheral Vascular disease - intermittient claudication)
Non Modifiable risk factors for atheroma
Age Family Hx Male
Modifiable risk factors for Atheroma (The \'Deadly Quartet\')
Hyperlipidaemia Hypertension Cigarette Smoking Diabetes
Pathogenesis of Atheroma
Lipid & Lipoproteins - Oxidisation leads to... Endothelial dysfunction & Altered Cell Adhesion - Vasoconstriction & cell adhesion / chemoattractants Macrophages & other Inflam cells - Inflammatory response Inflammation & Cytokines - More recruitment ECM - Proliferation & migration of vascular smooth muscle
What causes silent lesion to rupture
Degradation of cap by proteases from macrophages etc
5 Causes of cell injury
Hypoxia Chemical Physical Immune Nutrition
Pathogenesis of reversible cell injury
Loss of ATP - failure of Na/K ATPase Increased glycolysis Increased lactic acid Detachment of ribosomes etc
Microscopic features of reversible cell injury
Cellular swelling Loss of microvilli Blebbing ER swelling Myelin figures Clumping of chromatin Mitochondrial swelling
Pathogenesis of Irreversible Cell Injury
Massive Ca accumulation Enzyme activation
Microscopic features of irreversible cell injury
Rupture of lysosomes & autolysis Mitochondrial swelling Lysis of ER Defects in cell membrane Nuclear Pyknosis, Karyolysis, Karyorhexis
Free radicals generated by
Irradiation Normal metabolism Transition Metals Nitric Oxide Toxins
Free radicals removed by
Spontaneous decay Antioxidants Storage proteins Enzymes
Free radical Injury
Membrane lipid peroxidation DNA damage Interaction with proteins
Three Patterns of Necrosis
Coagulative (Ischaemia) Liquefactive (Brain) Caseous (TB) (Fat)
Triggers for Apoptosis
Withdrawal of growth stimuli Death signals DNA damage
Ann Arbour is used for...?

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