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Block 1 – Foundations + Immunology + Infectious Diseases Learning Objectives Arunan Sriravindrarajah The following lecture objectives were ordered thematically TABLE OF CONTENTS Anatomy ................................................................................................................................................................. 4 Introduction to Anatomy ........................................................................................................................... 4 Introduction to Skin, Bones, Joints and Skeletal Muscle .............................................................. 4 Introduction to Viscera, Smooth and Cardiac Muscle .................................................................... 4 Introduction to Arteries, Veins and Lymphatics ............................................................................... 5 Introduction to Central Nervous System ............................................................................................ 6 Introduction to Peripheral Nervous System ....................................................................................... 7 Autonomic Nervous System ..................................................................................................................... 8 Introduction to Limbs ................................................................................................................................. 9 Upper Limb – Bones and Joints ............................................................................................................ 10 Upper Limb – Shoulder and Arm Muscles ......................................................................................... 10 Upper Limb – Forearm and Hand Muscles ........................................................................................ 10 Upper Limb – Vessels ............................................................................................................................... 11 Upper Limb – Nerves + Lesions ........................................................................................................... 11 Lower Limb – Bones and Joints ............................................................................................................ 11 Lower Limb – Muscles .............................................................................................................................. 12 Histology ............................................................................................................................................................... 13 Introduction to Cells and Tissues ......................................................................................................... 13 Epithelial Tissue .......................................................................................................................................... 13 Connective Tissue and Muscle .............................................................................................................. 14 Vessels – Arteries, Veins, Lymphatics, Nerves ............................................................................... 15 Biochemistry ......................................................................................................................................................... 16 DNA and RNA Structure........................................................................................................................... 16 RNA Transcription and Translation ...................................................................................................... 17 Protein Structure and Function ............................................................................................................. 17 Enzymes, Substrates, Products and Modes of Inhibition ............................................................ 17 Major Nutrients and Nutrient Sensing Systems ............................................................................. 18 Metabolic Pathways for the Conversion of Major Nutrients to Usable Energy .................... 18 The Role of Oxygen in Making Energy Available from Major Nutrients ................................. 19 Feast and Famine – How Nutrients are Stored and Made Available When Required ....... 19 Pharmacology ....................................................................................................................................................... 20 What is Pharmacology? ........................................................................................................................... 20 How Drugs Work ........................................................................................................................................ 20 Quantitation of Drug Effects and Pharmacodynamics.................................................................. 21 Principles of Pharmacokinetics .............................................................................................................. 22 Adverse Reactions to Drugs (ADR) ..................................................................................................... 22 Non-Medical Use of Drugs ...................................................................................................................... 23 Antimicrobial Drugs ................................................................................................................................... 23 Pathology .............................................................................................................................................................. 24 Homeostasis – The Balance Between Health and Disease ......................................................... 24 Tissue Renewal and Repair .................................................................................................................... 25 Acute Inflammation ................................................................................................................................... 25 The Process of Anatomical Pathology and Laboratory Diagnostics ......................................... 26 Neoplasia 1 ................................................................................................................................................... 27 Neoplasia 2 ................................................................................................................................................... 28 Chronic Inflammation ............................................................................................................................... 29 Physiology ............................................................................................................................................................. 30 Homeostasis and Its Control Mechanisms ........................................................................................ 30 Biological Membranes and Their Roles in Intracellular Homeostasis ..................................... 31 Intracellular Signal Transduction ......................................................................................................... 31 Intracellular Communication ................................................................................................................. 32 Pregnancy ..................................................................................................................................................... 33 Growth and Division of Cells .................................................................................................................. 34 Genetic Medicine.................................................................................................................................................. 35 Chromosome and Cell Genetics ............................................................................................................ 35 Strategies for Prevention and Treatment of Genetic Disorders ............................................... 36 Genes, Mutation and Cancer ................................................................................................................. 36 Embryology ........................................................................................................................................................... 37 Early Human Embryonic Development .............................................................................................. 37 Birth Defects ................................................................................................................................................ 39 Dentistry ............................................................................................................................................................... 40 Dental Infection .......................................................................................................................................... 40 Oral Health ................................................................................................................................................... 41 Adolescence and Young Adulthood ...................................................................................................................... 41 Adolescence and Young Adulthood 1 .................................................................................................. 41 Geriatrics .............................................................................................................................................................. 41 The Ageing Process ................................................................................................................................... 41 Ethics of Infection Control .................................................................................................................................... 42 Ethics of Infection Control 1 .................................................................................................................. 42 Immunology .......................................................................................................................................................... 42 Introduction to an Immune System ................................................................................................... 42 Antigen Capture and Presentation....................................................................................................... 43 Lymphocyte Antigen Receptors and Development of Immune Repetoire ............................ 44 Activating T-Cells, Cytokines and Chemokines .............................................................................. 46 Th1 and Th2 Effector T-Cells ................................................................................................................. 47 Th17 Effector T-Cells, Treg and CD8 T-Cells ................................................................................... 48 Immune Control of Viruses .................................................................................................................... 48 Activating B-Cells ....................................................................................................................................... 50 Actions of Antibodies ................................................................................................................................ 50 Immunological Tolerance ........................................................................................................................ 51 Immune System Diseases + Vaccines and Immune Therapies ............................................... 52 Infectious Diseases ............................................................................................................................................... 53 Communicable Diseases in a Global Context .................................................................................. 53 Medically Important Bacteria I.............................................................................................................. 55 Medically Important Fungi ...................................................................................................................... 57 Medically Important Parasites ............................................................................................................... 58 Medically Important Bacteria 2 ............................................................................................................. 60 Introduction to Viruses ............................................................................................................................ 62 Mechanisms of Bacterial Pathogenesis .............................................................................................. 63 Mechanisms of Viral Pathogenesis....................................................................................................... 64 Laboratory Diagnoses of Infectious Diseases.................................................................................. 65 Mechanisms of Transmission of Infectious Diseases .................................................................... 66 Seminars ............................................................................................................................................................... 67 Introduction to Population Medicine ................................................................................................... 67 Indigenous Health I.......................................................................................Error! Bookmark not defined. Introduction to Imaging .......................................................................................................................... 67 The Software: Genetic Information, Its Expression and Variation ......................................... 68 Introduction to Patient-Doctor: Observing People ........................................................................ 68 Introduction to MD .................................................................................................................................... 68 The Australian Health System ............................................................................................................... 68 Cultural Impacts of Health Outcomes ................................................................................................ 69 Principles of Nutrition ............................................................................................................................... 70 Introduction to Immunology and Infectious Diseases ................................................................. 70 Cervical Cancer ........................................................................................................................................... 70 Control of Infectious Diseases .............................................................................................................. 71 ANATOMY INTRODUCTION TO ANAT OMY An introduction to the: o Discipline of anatomy o Importance in medicine o Organisation of course o Resources available; and o Some tips to get the most out your anatomy time - ... Be able to describe the basic anatomical planes and movements of the body - ... INTRODUCTION TO SKIN, BONES, JOINTS AND SKELETAL MUSCLE Describe the organisation of somatic structures – skin, subcutaneous tissue, deep fascia, bones, muscles, compartments, somatic nerve supply - ... Describe the function and structure of skin, skin appendages, tension lines in skin, and the ‘rule of nines’ - ... Describe the function and classification of bones, including reference to bone markings, compact and spongy bone, periosteum, bone marrow, bone growth, and bone repair after injury - ... Describe the function and classification of joints, including reference to ligaments and associated structures, the mobility and stability of joints, how joints function in movement, and the effect of injury to joints - ... Describe the function of skeletal muscle, attachments of skeletal muscle to other structure, the actions of skeletal muscle, the structure and functions of tendons, aponeuroses and synovial sheaths, and the effect of injury to muscle - ... INTRODUCTION TO VISCERA, SMOOTH AND CARD IAC MUSCLE Define the terms ‘viscera’ (singular ‘viscus’), ‘visceral systems’, ‘parenchyma’, ‘stroma’, ‘endocrine glands’, ‘exocrine glands’, ‘lumen’, ‘hilum’ - ... Classify viscera as hollow or solid and as single or paired - ... Describe the layered structure of a typical hollow viscus, with reference to the mucosa, submucosa, muscularis and adventitia or serosa - ... Summarise the characteristics of smooth muscle - ... Summarise the characteristics of anatomical sphincters and functional sphincters - ... Summarise the general characteristics of serous membranes and explain how they allow parts of a visceral system to be fixed or mobile - ... Outline the general plan of the neurovascular supply of paired and unpaired viscera - ... Summarise the function of the autonomic (sympathetic and parasympathetic) nerves and sensory afferent nerves of the viscera - ... INTRODUCTION TO ARTE RIES, VEINS AND LYMP HATICS Define the terms: o Circulatory System ... o Cardiovascular System o ... Lymphatic System o Artery o Vein o Lymph Vessel o Arteriole o Capillary o Elastic Artery o Medium (Muscular) Artery ... ... ... ... ... ... ... ... o Small Artery o Venule o Small Vein o Medium Vein o Large Vein o Avascular Structure o Valves (in Veins) o Plexus (of Veins or Nerves) o Anastamoses ... ... ... ... ... ... ... ... ... Describe the general structure of a blood vessel, with reference to the endothelium, the wall or tunica (intima, media and adventitia) and vasomotor fibres - ... Outline differences in blood vessel walls in relation to blood pressure - ... INTRODUCTION TO CENT RAL NERVOUS SYSTEM Describe the specialised structure of neurons - ... Differentiate between central and peripheral nervous systems - ... Outline the characteristics of grey and white matter - ... Describe the organisation of the spinal cord with specific reference to, gray and white matter segregation, sensory, motor and reflex pathways - ... Identify the brainstem as made up of the midbrain, pond and medulla - ... Outline the function of the thalamus, hypothalamus, cerebellum, hippocampus, amygdala and the basal ganglia - ... Describe the macroscopic appearance of the cortex of the brain and be able to identify the following regions: frontal lobe, temporal lobe, parietal lobe and occipital lobe - ... Be able to differentiate between a sulcus and a gyrus - ... Outline the overall function of the cortex and describe the concept of anatomical localisation of function - ... INTRODUCTION TO PERI PHERAL NERVOUS SYSTEM Describe the peripheral nervous system - ... Outline the basic structure of the spinal cord, vertebral segmentation and spinal roots - ... Describe a "typical" peripheral nerve cell in terms of soma, fibres, dendrites and axons - ... Describe the organisation of fibres in terms of the location of nerve roots, peripheral ner ves and spinal nerves - ... Define dermatomes and myotomes and describe their basic organisation and clinical significance - ... Outline the regions innervated by the key dermatomes (C6-8, T4, T10, L1, L5, S1-2) - ... Describe the most commonly performed tests of spinal reflexes (biceps, brachioradialis, triceps, patellar, Achilles) and name the spinal nerve associated with each - ... List the spinal levels associated with each of the following motor function: o Abduction of the Shoulder o Flexion of the Elbow o Extension / Flexion of the Wrist o Movement of Each of the Fingers o Extension / Flexion of the Hip o Extension / Flexion of the Knee o ... Dorsiflexion / Plantarflexion of the Ankle ... ... ... ... ... ... AUTONOMIC NERVOUS SY STEM Explain why the autonomic nervous system can also be referred to as the "Visceral Motor System" and briefly outline its main characteristics (speed, targets, innervations pattern and numbers of synapses in pathways) - ... Describe and differentiate between the sympathetic and parasympathetic arms of the autonomic nervous system and describe when one or the other is likely to be predominating in activity - ... Outline the projections of the sympathetic and the parasympathetic arms of the autonomic nervous system - ... Describe the location of the lateral horn or the (intermediary lateral gray matter) and what is contained within this region of the spinal cord - ... Describe the sympathetic chain or trunk and sympathetic ganglia - ... Describe the pathways taken by the sympathetic supply to the following structures and name the structures found within each of these areas o T1-L2/3 local structure ... o Above T1 and below L2/3 (i.e. the distant structure) o Medial visceral structures ... ... Describe the vagus nerve (cranial nerve X) with reference to its anatomical location, branching, and parasympathetic activity - ... Describe the parasympathetic projection with respect to pre-and postganglionic neuron and parasympathetic ganglia - ... Describe the involvement of the autonomic nervous system in the execution of integrated functional responses to emotional stimuli - ... INTRODUCTION TO LIMBS Explain the general function and classification of musculoskeletal structures - ... Describe the individual musculoskeletal structures found within the limbs and their region relationship to each other - ... Outline the anatomy of the upper limb - ... Outline the anatomy of the lower limb - ... Identify and explain structures in terms of: o Schema and significance o Overall level of major body part o System or regional level o Individual structure level; and o Further levels such as substructure, microscopic or molecular structure - ... Describe the general features of the upper and lower limbs - ... Outline the upper limb in terms of bones, joints, muscles as well as overall topography and functionality - ... Outline the lower limb in terms of bones, joints, muscles as well as overall topography and functionality - ... UPPER LIMB – BONES AND JOINTS Identify the general and some specific features of the bones of the upper limb including the scapula, clavicle, humerus, radius, ulna, and hand bones - ... Identify the major features of the joints of the upper limb including the shoulder, elbow, radio-ulnar, wrist and some hand joints - ... Describe the classification, positions and movements of the major joints of the upper limb and the scapula - ... Describe the correlation of the structure of the bones and joints of the upper limb with radiographic images - ... UPPER LIMB – SHOULDER AND ARM MUS CLES Identify the individual muscles of the shoulder region - ... Identify the individual muscles of the arm region - ... Describe and demonstrate the action of the individual muscles or groups of muscles of the shoulder and arm regions on the scapula, shoulder joint and elbow joint - ... Identify the location of the muscles or muscle groups of the shoulder and arm region and their correlation with radiographic images of the shoulder and arm region - ... UPPER LIMB – FOREARM AND HAND MUS CLES Identify the individual muscles of the forearm region - ... Identify the individual muscles of the hand - ... Describe and demonstrate the action of the individual or groups of muscles of the forearm or hand region on the elbow, radio-ulna, wrist and hand joints - ... Identify the location of muscles or muscle groups of the forearm and hand regions and their correlation with radiographic images of the forearm and hand - ... UPPER LIMB – VESSELS Identify the major arteries of the upper limb in a cadaver specimen - ... Identify the major relationships of the arteries of the upper limb in a cadaver specimen - ... Identify the deep and superficial components of the venous system of the upper limb in a cadaver specimen - ... Identify the major arteries and veins of the upper limb in contrast radiographs - ... UPPER LIMB – NERVES + LESIONS Identify the plexus of the upper limb (brachial plexus) and its key relationships - ... Identify the major nerves of the upper limb and the courses and key relationships of each - ... LOWER LIMB – BONES AND JOINTS Describe the general function of bones and joints of the lower limb - ... Outline the classification of bones and joints of the lower limb - ... Describe the various components of the joints in the lower limb - ... Outline the movements associated with each of these joints - ... LOWER LIMB – MUSCLES Describe the general attachments and actions of the following muscle groups: o Hip-thigh Iliopsoas (i.e. Ilacus and Psoas Major [+ Psoas Minor]) Tensor Fascia Lata Gluteus Maximus Gluteus Medius Gluteus Minimus Lateral Rotators (e.g. Piriformis, Quadratus Femoris, Superior and Inferior Gemelli, Obturator Internus, Obturator Externus) Sartorius Adductor Magnus Adductor Longus Adductor Brevis Gracilis Biceps Femoris Semimembranosus Semitendinosus o ... ... ... ... ... ... ... ... ... ... ... ... ... ... Leg-foot Tibialis Anterior ... Peroneus Longus Peroneus Brevis Extensor Hallicus Longus Extensor Digitorum Longus Gastrocnemius ... ... ... ... ... Soleus Plantaris Tibialis Posterior Flexor Digitorum Longus Flexor Hallicus Longus Internal Muscles of the Foot (as a group) ... ... ... ... ... ... HISTOLOGY INTRODUCTION TO CELLS AND TISSUES Outline the broad principles of preparing tissues for histological examination - ... Describe the general structure of a typical human cell - ... Identify the main cell organelles and outline their functions - ... Describe how specialised cell structures relate to cell functions - ... Outline the ways in which cells interact to form tissues - ... Outline the main characteristics of epthelial and connective tissue, skeletal muscle and neural tissue - ... Define the terms 'necrosis' and 'apoptosis' - ... EPITHELIAL TISSUE Define the term ‘epithelium’ and the terms ‘apical’, ‘basal’ and ‘lateral’ as they are used in describing epithelial cells - ... Describe the structure and function of the apical plasma membrane modifications (microvilli, cilia, stereocilia) on epithelial cells - ... Describe how and why epithelial cells are joined to one another and the structure and functions of the different types of junctional complexes between the lateral plasma membranes of cells - ... Describe the different classifications of epithelium, their locations in the body and how their structure relates to function - ... Summarise the differences between epithelium and endothelium - ... CONNECTIVE TISSUE AND MUSCLE Define the term ‘connective tissue’ - ... List the constituents of connective tissue - ... Describe the main characteristics and functions of fibroblasts - ... List the types of permanent resident cells in connective tissue - ... List the types of transient cells in connective tissue - ... Outline the main characteristics of loose (or areolar) and dense connective tissue and give examples of tissues in which each might be found - ... Outline the main constituents of specialised connective tissues, with particular reference to bone, cartilage, tendons and ligaments - ... Outline the characteristics of elastic fibres and their role in the stability of joints - ... Describe the structure of skeletal muscle with reference to the term ‘sarcomere’ - ... Describe the structure of skeletal muscle fibres with reference to myofibrils, myofilaments, actin, myosin and z-lines - ... Describe the structure of smooth muscle - ... Describe the structure of cardiac muscle - ... Summarise the structural and functional differences between skeletal, smooth and cardiac muscle - ... VESSELS – ARTERIES, VEINS, LYM PHATICS, NERVES Describe the general features of vessel walls, with reference to the tunica intima, media and adventitia - ... Summarise the distinguishing structural and functional characteristics of elastic and muscular arteries - ... Describe the structure and function of arterioles - ... Summarise the distinguishing structural and functional characteristics of continuous, fenestrated and discontinuous capillaries (the last are also known as sinusoids) - ... List major examples of organs or tissues in which these three types of capillaries are located - ... Summarise the structural and functional differences between arteries and veins - ... Summarise the distinguishing structural and functional characteristics of large and medium veins and venules - ... Define the term ‘atherosclerosis’ - ... Describe the general features of neurons, with reference to nerve cell bodies, dendrites and axons - ... Describe the general features of a typical neural synapse - ... Describe the general structural and functional characteristics of myelinated and unmyelinated axons, including reference to the nodes of Ranvier - ... Describe the structural organisation of a peripheral nerve, with reference to the terms ‘fascicle’, ‘endoneurium’, ‘perineurium’ and ‘epineurium’ - ... Summarise the composition and distribution of grey matter and white matter in the spinal cord, cerebellum and cerebrum - ... Outline the structure and function of neuroglia, with reference to astrocytes, oligodendrocytes, microglia, ependymal and choroid plexus - ... Outline the structure and function of the cerebral meninges, with reference to the dura mater, arachnoid mater, subarachnoid space and pia mater - ... BIOCHEMISTRY DNA AND RNA STRUCTUR E Describe the building blocks of DNA: purines and pyrimidines, 2-deoxyribose and inorganic phosphate - ... Summarise key developments in the discovery of the double helix structure of DNA - ... Describe the synthesis and reproduction of DNA and the importance of the double helix structure - ... Explain the meaning of the genetic code - ... RNA TRANSCRIPTION AND TRANSLATION Outline the structure of RNA - ... Describe the structures of messenger RNA, ribosomal RNA, transfer RNA and micro RNA and describe their functions in transcription and translation - ... Outline the composition and the process of production of ribosomes - ... Outline the process of reverse transcription and PCR - ... Define the term ‘ribozyme’ - ... PROTEIN STRUCTURE AND FUNCTION Describe the hierarchy of protein structures - ... Outline the major secondary structure motifs in proteins - ... Describe how protein structure is related to function - ... List the features of collagen and collagen diseases - ... List the features of amyloid and amyloid deposition diseases - ... List the features of prions and prion disease - ... ENZYMES, SUBSTRATES, PRODUCTS AND MODES OF INHIBIT ION Define the term ‘enzyme’ - ... Describe the modes of enzyme inhibition: competitive, non-competitive and uncompetitive - ... List important drugs and toxins that target enzymes - ... Summarise modes of regulation of enzymes - ... MAJOR NUTRIENTS AND NUTRIE NT SENSING SYSTEMS Describe the basic characteristics of the major nutrients, with reference to their structures, their functions and their significance - ... Outline the fate of proteins, carbohydrates and lipids after ingestion - ... Outline the biochemical and pathological consequences of disordered amino acid metabolism (taking phenylketonuria as an example) and disordered carbohydrate absorption (taking lactase deficiency as an example) - ... Outline the process whereby the body detects or senses nutrients - ... Outline the significance of nutrient sensing with reference to appetite, food selection, satiety, coordination of hormonal and digestive responses, control of growth and nutrient storage - ... Describe the mechanism of glucose sensing - ... Outline the nature and role of Class C G-protein coupled receptors as an example of a nutrient-sensing receptor - ... METABOLIC PATHWAYS F OR THE CONVERSION OF MAJOR NUTRIENTS TO U SABLE ENERGY Describe the concept and function of ATP - ... Summarise the processes of cellular uptake of glucose, amino acids, fatty acids, triacylglycerols and cholesterol - ... Summarise the processes of aerobic and anaerobic metabolism of glucose - ... Outline the process of fatty acid oxidation - ... Outline Kreb’s citric acid cycle with reference to its place in the metabolism of major nutrients - ... Outline the process of amino acid deamination - ... Outline the role of thiamine in metabolism - ... THE ROLE OF OXYGEN I N MAKING ENERGY AVAI LABLE FROM MAJOR NUT RIENTS Outline the process of the cellular uptake of oxygen and nutrients - ... Outline the role of mitochondria in energy production - ... Outline the process of intracellular electron transfer - ... Outline the role of oxygen binding proteins - ... Outline the relationship between oxygen reduction and ATP synthesis - ... FEAST AND FAMINE – HOW NUTRIENTS ARE ST ORED AND MADE AVAILA BLE WHEN REQUIRED Describe how major nutrients (carbohydrates, protein and fat) are stored - ... Summarise the processes of synthesis and breakdown of glycogen - ... Outline the processes of synthesis and breakdown of protein in skeletal muscle and liver - ... Outline the process of gluconeogenesis - ... Outline the process of triglyceride breakdown to fatty acids and the different fates of fatty acids - ... List the major types of ketone bodies (acetoacetate, beta-hydroxybutyrate, acetone) - ... Outline the actions of insulin, glucagon, IGF-1 and cortisol - ... PHARMACOLOGY WHAT IS PHARMACOLOGY ? Define the terms ‘pharmacology’, ‘toxicology’, ‘pharmacodynamics’, ‘pharmacokinetics’, ‘clinical pharmacology’ and ‘therapeutics’ - ... Define the terms ‘therapeutic effect’, ‘adverse effect’ and ‘therapeutic index’, and explain the meaning of high therapeutic index and low therapeutic index - ... Outline the process of drug discovery and development - ... Define the term ‘clinical trials’ and summarise the purpose of Phase I, Phase II, Phase III and Phase IV clinical trials - ... Outline the purpose of genotyping for drug response and drug toxicity - ... HOW DRUGS WORK Outline the range of mechanisms by which available drugs produce their effects - ... Explain how the mechanism of action of a drug underlies dose response relation ship and possible side effects - ... Summarise the mechanisms of drug action as either mimicking/replacing an endogenous substance, activating a receptor, inhibiting an enzyme, binding to and inactivating cytokines or inactivating immune cells - ... Outline an example of a drug (and the condition for which it is used) to demonstrate each of the mechanisms described above - ... Explain that for some drugs (e.g. Keppra-anticonvulsant) the mechanism of action is unknown, despite the efficacy of the drug in clinical use, and the limitations this pose on the prediction of side effects - ... QUANTITATION OF DRUG EFFECTS AND PHARMACODYNAMICS Define the terms 'agonist', 'antagonist', 'potency', 'EC50' and 'pA2' - ... Describe concentration response curves and be able to identify the EC50 and compare potency of agonists - ... Using adrenergic receptor agonists as an example, explain the concept of drug selectivity - ... Using atropine as an example, explain the mechanism of action of drugs which as defined as 'antagonists' - ... Define the terms 'pharmacodynamics' - ... Using blood pressure regulatory drugs and bronchodilators as examples, explain the pharmacodynamics of short and long acting drugs - ... In terms of the pharmacodynamics of anticoagulant drugs explain the need for close monitoring following the commencement of therapy - ... Describe the pharmacodynamics of lipid lowering drugs - ... Describe the concept of 'therapeutic drug monitoring' and explain where such practice maybe necessary - ... PRINCIPLES OF PHARMACOKINETICS Understand the simple concepts of drug disposition - ... Understand the importance of understanding pharmacokinetics to achieve optimal drug delivery - ... Understand the idea that various clinical states can affect pharmacokinetics and pharmacodynamics - ... ADVERSE REACTIONS TO DRUGS (ADR) Define 'adverse drug reactions' and their classification (Type A-E) and outline the strategies to identify and minimise the occurrence of adverse drug reactions - ... Define the following terms related to adverse drug reactions: 'toxicity', 'secondary effects', 'intolerance' and 'idiosyncratic reactions' - ... Outline the process through which the side effect profile of a drug is determined - ... Describe the content of 'prescribing information' listed in MIMS and the phases of clinical trials on which prescribing information is based - ... Describe the concept of ‘pharmacoepidemiology’ and ‘pharmacovigilance’ using the VIGOR study as an example - ... Define 'polypharmacy', outline the risk factors associated with polypharmacy and the general approach to deprescribing to reduce the extent of polypharmacy where possible - ... Define 'drug overdose' and outline the principles of management (using paracetamol as an example explain the toxicology of overdose) - ... NON-MEDICAL USE OF DRUGS Describe the effect of cannabis in terms of mechanism of action, CNS target and pharmacological effects - ... Describe the effect of cocaine in terms of mechanism of action, CNS target and pharmacological effects - ... Describe the effect of Ecstasy (MDMA) in terms of mechanism of action, CNS target and pharmacological effects - ... Describe the effect of opioids (with Heroin as an example) in terms of mechanism of action, CNS target and pharmacological effects - ... Describe the effect of tobacco (or nicotine as the only active constituent) in terms of mechanism of action, CNS target and pharmacological effects - ... Describe addiction as a biological phenomenon with specific reference to the mesolimbic dopamine theory - ... ANTIMICROBIAL DRUGS Explain that the principles of antimicrobial therapy are based on exploitation of the physiological difference between the host (human) and the pathogenic organism in order to achieve toxicity in the pathogen without causing harm to the host - ... Outline the strategies in the mechanisms of action in the targeting of bacterial, viral, parasitic and fungal pathogens - ... Identify and describe the mechanism of action for an antibiotic, antifungal, antiviral, anthelmintic and anti-malaria drug of current use - ... PATHOLOGY HOMEOSTASIS – THE BALANCE BETWEEN HEALTH AND DISEASE Define the terms ‘atrophy’, ‘hypertrophy’, ‘hyperplasia’, ‘metaplasia’, ‘dysplasia’, ‘necrosis’, ‘apoptosis’ - ... Explain that all cells must be able to adapt to stress in order to maintain energy production, perform their functions and replicate, with respect to stresses affecting the whole individual (e.g. traumatic injury, temperature extremes, drugs, chemicals, xenobiotics, irradiation, excessive physical or functional demand) - ... Explain the following concepts: o In a complex organism (e.g. a human), the response to stress is either adaptation or disease ... o Reversible injury may cause adaptive responses at the cellular and organism level in order to copy with stress o Adaptation can be physiological or pathological, but reverts to normal with removal of stress o Forms of adaptation include atrophy, hypertrophy, hyperplasia, metaplasia and dysplasia o ... ... ... If a cell is unable to cope with the stress, cell death may result through one of two distinctly different processes – apoptosis and necrosis ... Describe the intracellular steps leading to necrosis, with particular reference to coagulative necrosis and its variants liquefactive necrosis and caseous necrosis - ... Outline the mechanisms involved in the apoptosis cascade (programmed cell death) - ... Outline the function of apoptosis as a response to exogenous insults from viruses, irradiation and toxins, and the place of apoptosis in normal development and cell turnover - ... TISSUE RENEWAL AND R EPAIR Define the terms ‘healing’, ‘regeneration’, ‘healing by first intention’, ‘healing by second intention’, ‘granulation tissue’ (‘soft callus’), ‘fibrosis’ (‘hard callus’), ‘angiogenesis’, ‘inflammation’ - ... Outline the control mechanisms of cell proliferation and tissue growth - ... Outline the basic cell cycle and the concept of stem cells - ... Outline the regenerative capacity of different types of cells (labile cells, stable cells and permanent cells) and give examples of tissue renewal (turnover) in blood cells, small intestinal epithelial cells and skin cells - ... List the stages of healing, with reference to the timescale of inflammation, granulation tissue formation, wound contraction and remodelling - ... List the differences between healing by first intention and healing by second intention - ... Summarise the principal steps of healing by first intention, the processes that occur in each step and the timescale of each step, with reference to the rate of healing and the tensile strength of a healing wound - ... ACUTE INFLAMMATION Explain the relevance of acute inflammation to medicine and dentistry - ... Define the term 'inflammation' and describe the roles of the inflammatory response and the cardinal signs of inflammation - ... Describe the position of inflammation within the wider context of host protective responses against micro-organisms - ... Explain the distinctions between acute and chronic inflammatory processes - ... Describe the roles of leukocytes (particularly polymorphonuclear leukocytes and granulocytes) in the inflammatory process - ... Mechanisms underlying the cardinal signs of inflammation - ... The stereotypic nature of acute inflammation - ... Components of the acute inflammatory response - ... Describe soft tissue injury, the recommended treatments of soft tissue injury and the process through which long-term complications are reduced - ... Explain the role of 'exudation' in the inflammatory process - ... Describe what is meant by the following statement: 'Inflammation: friend or foe'? - ... THE PROCESS OF ANATOMICAL PATHOLOGY AND LABORATORY DIAGNOSTICS Outline the place of pathology in clinical medicine - ... Outline the scope of each of the following areas of pathology: o Anatomical pathology (including forensic pathology, histopathology and cytology) o ... Chemical pathology o Genetics o Haematology o Immunopathology o Microbiology o General pathology ... ... ... ... ... ... NEOPLASIA 1 Define the terms ‘tumour’, ‘neoplasm’ or ‘neoplasia’, ‘benign [tumour or neoplasm]’, ‘malignant [tumour or neoplasm]’, ‘pleomorphism’, ‘hamartoma’, ‘metastasis’ - ... List different types of tumours according to their tissue of origin (epithelial, mesenchymal, mixed, teratogenous} and behavior (benign/malignant} - ... List the general features of benign versus malignant neoplasms - ... Outline the main routes of metastasis, giving an example of each: o Lymphatic ... o Haematogenous (via systemic veins, portal veins, pulmonary veins, systemic arteries) o Transcoelomic o Intra-epithelial o Perineural ... ... ... ... Outline the clonal theory of metastasis and the metastatic cascade - ... Explain, in general terms and through the use of examples, the ways in which tumours affect the host clinically: o Disfigurement ... o Mechanical interference with normal function o Interference with organ or tissue function by replacement of tissue with cancer (or metastatic cancer) cells o Disruption of an epithelial surface due to invasion, necrosis and ulceration o Weight loss (cancer cachexia) o Paraneoplastic effects ... ... ... ... ... o Endocrinopathies o Psychological disturbances ... ... Outline the effects of the host on the tumour - ... NEOPLASIA 2 Outline the main features of the epidemiology of cancer: o Approximate incidence of and mortality from cancer (overall) in Australia ... o The four most common sites of cancer in new cancer cases for males and females o The four most common sites of cancer in cancer deaths for males and females ... o ... Incidence of common cancers as a function of age o Common examples of geographic variations in cancer incidence o Examples of risk factors for cancer: environmental and occupational exposures, smoking, alcohol abuse, obesity, heredity ... ... ... List examples of pre-neoplastic conditions and the related cancers - ... Outline factors implicated in the aetiology of cancer, with reference to: o Radiation Chemical carcinogens o Oncogenic viruses and their mechanism of carcinogenesis o Hormones o Chronic inflammation ... o ... ... ... ... Explain how a tumour arises from clonal expansion of a single precursor cell that has undergone genetic damage, outlining that non-lethal cumulative genetic damage may result from inherited (germline) or acquired (somatic) mutations - ... List the mechanisms by which nuclear damage may give rise to a malignant phenotype - ... List the ways in which mutations of proto-oncogenes can stimulate cells to proliferate - ... Outline the mechanisms of action of proliferative oncogenes, inhibition of tumour suppressor genes, stimulation of genes that prevent apoptosis, loss of DNA repair gene function, and increase in telomerase activity - ... Outline examples of screening programs that can lead to early detection of cancer - ... Explain the components of the diagnosis of neoplasia, with reference to: o Patients’ presenting symptoms ... o Methods of obtaining tumour tissue or cells for histological diagnosis o The meaning and importance of the terms ‘grading’ and ‘staging’ of a tumour o Techniques for examining, identifying and characterising tumour tissue or cells (standard histological techniques, immunohistochemistry, chromosomal analysis, molecular diagnosis, flow cytometry) ... ... ... CHRONIC INFLAMMATION Outline the factors that determine the response to injury - ... Define the terms ‘resolution’, ‘organisation’, ‘suppuration’, ‘granuloma’, ‘granulation tissue’, ‘regeneration’, ‘repair’, ‘healing’, ‘chronic inflammation’, abscess’, ‘ulcer’, ‘pyogenic’ - ... Describe the possible forms of progression of acute inflammation with reference to the mechanism for each: o Resolution o ... Organisation ... o Healing o Suppuration o Chronic inflammation ... ... ... Outline the characteristics of granulation tissue - ... List the characteristics that are common to all chronic inflammatory lesions - ... Outline the characteristics of chronic suppurative inflammation, with reference to osteomyelitis as an example - ... Summarise the characteristics of an abscess and an ulcer - ... List the three types of chronic granulomatous inflammation (immune, foreign body and unknown origin), outlining their causes and histological characteristics and giving an example of each - ... Outline the characteristics of mixed-type chronic inflammation, with reference to rheumatoid arthritis as an example - ... PHYSIOLOGY HOMEOSTASIS AND ITS CONTROL MECHANISMS Define the term ‘homeostasis’ - ... Outline the concept of feedback mechanisms in relation to the control of environmental conditions - ... Define the term ‘thermoregulation’ and describe the major thermoregulation pathways as an example of homeostasis, with reference to the temperature set-point and endogenous and exogenous factors that can influence it - ... Outline the physiological processes for maintaining fluid balance and osmolarity as another example of homeostasis, with reference to processes for the regulation of extracellular fluid volume and osmolarity - ... Outline the role of vasopressin (or anti-diuretic hormone – ADH) in fluid balance and the abnormal state that occurs in the syndrome of inappropriate ADH secretion (SIADH) - ... BIOLOGICAL MEMBRANES AND THEIR ROLES IN I NTRACELLULAR HOMEOST ASIS Outline the properties and structure of biological membranes and explain the role of these membranes in the functioning of a cell - ... Describe Integral Membrane Proteins (IMP) in terms of structure, function and location within a biological membrane - ... Outline the composition of the cytosol and extra-cellular fluid - ... Outline the role of the electrochemical gradient in determining the direction of movement of solutes across biological membranes - ... Define the movement of materials across a biological membrane as either passive or active (primary and secondary) and the biological conditions under which one process is likely to function over the other - ... Outline the transporters: including NaK-ATPase, NaH-exchanger and HATPases, NaK2Cl-cotransporter, SGLT1 and GLUT2, and aquaporins - ... Using Diabetes Mellitus, Diabetes Insipidus and Barters syndrome as examples, describe the expected water homeostasis when membrane transport systems fail to appropriately function - ... INTRACELLULAR SIGNAL TRANSDUCTION Describe intracellular signalling in terms of the processes that take place in the target cell - ... Define membrane potentials as the separation of opposite changes across a plasma membrane and explain the process by which action potentials can propagate along a membrane - ... Describe electrical coupled signalling using insulin secretion by pancreatic β cells as an example of electrical signalling process by the K+/ATP channel - ... Describe the process of chemical signalling cascade associated with the activation of voltage gates Ca2+ channels with specific reference to the role of Ca2+ in muscle contraction and Malignant Hyperthermia - ... Describe G-protein coupled receptors and the role of IP3 and cAMP as second messengers. Using Ventolin and Cholera toxin as opposing examples describe the effects of exogenous substances in the activation of cAMP/phospodiesterase signalling cascades - ... Describe Tyrosine receptor Kinase signalling and the activation of the Ras/MAPK phosphorylation pathways - ... INTRACELLULAR COMMUNICATION Define intercellular signalling - ... Distinguish between electrical and chemical signalling and identify an example of each - ... Describe the role of neurotransmitters; using acetylcholine as an example, describe the process of chemical signal activation of muscles in response to neural signals - ... Outline the effects of nerve characteristics on the flow of current in an action potential, with reference to the sciatic nerve as an example of a largediameter, well-insulated nerve - ... Summarise the mechanisms of endocrine signalling, whereby an active agent (hormone) is released into the circulatory system and bound to its target tissue at another site of the body - ... Outline the three types of endocrine signalling: o Paracrine system, where the active agent is released into the local environment and acts on the target tissue without uptake into the circulation (e.g. epithelial cells and fibroblasts); ... o Exocrine system where the active agent acts on the same cell type as that from which it originated (e.g. epithelial tissue secretions acting on other epithelial cells); and o Autocrine system, where the secretion acts as a self-regulatory feedback mechanism and the signal acts on the same cell that secreted the active agent ... ... Outline how the HPA and HPT axes exemplifies paracrine, exocrine and autocrine processes - ... Describe the ionic signalling processes that occur at the neuromuscular junction; with reference to these processes, o ... With reference to the above ionic signaling processes that occur at the neuromuscular junction, explain the mechanisms by which neuromuscular transmission is affected by botulinum toxin and organophosphates and in myaesthenia gravis o ... Describe the molecular basis of electrical excitability - ... Describe the molecular basis of nerve conduction and apply it to the mechanisms by which tetrodotoxin affects nerve conduction - ... Outline the effects of myelination and of fibre diameter on conduction rate - ... Outline the features of hormonal signalling as illustrated by the regulation of plasma glucose levels by insulin - ... PREGNANCY Describe the physiological maternal adaptations that take place after the implantation of the blastocyst, including the production of chorionic gonadotropin, the formation of placenta and altered oestrogen/progesterone levels - ... Outline the metabolic adaptations that take place during pregnancy with specific reference to the following: o Increases in basal metabolic rate; o Altered glucose and fat metabolism; o Increase in body weight; and o Increase in oxygen consumption ... Outline the cardiovascular adaptations that take place during pregnancy with specific reference to increase in blood volume and the associated benefits of this adaptation - ... Describe the roles of relaxin, oestrogen and progesterone in systemic vasodilatation, retention of sodium by the kidneys and water reabsorption in order to increase total blood volume in pregnancy - ... Explain the changes that occur in pregnancy in the individual components of the following equations describing cardiac output: o CO = HR x SV o ... MAP = TRP x CO ... Describe the haematological changes that take place during pregnancy - ... Describe the respiratory adaptations that take place during pregnancy - ... Describe the renal adaptations that take place during pregnancy - ... GROWTH AND DIVISION OF CELLS Define the terms ‘cell growth’ and ‘cell proliferation’ and outline the difference between the two processes with specific reference to development of cancer - ... Explain the importance of checkpoints in cell cycles and describe how they regulate cell growth - ... Define the processes that take place at the following phases of the cell cycle: G1, interphase, S-phase, G2, and M-phase and cytokinesis - ... Explain the role of cyclin-dependent kinases (Cdks) and the process by which they control the cell cycle, with specific reference to phsophorylation - ... Identify the point at which the cell is committed to the syntheis of the genome and the completion of cell division and the cyclins that are essential in this process - ... Define the term ‘mitogen’, list examples of mitogens, and outline the role of mitogens in cancer formation with reference to breast and prostate cancer - ... Explain the process by which cell death allows for tight control of cell numbers - ... Outline processes by which cancer cells are able to escape the tight control of the cell cycle and proliferate unchecked (e.g. self-secretion of mitogens, increased expression of mitogenic receptors) - ... Using p53 as an example, describe the consequences of a cell's escape from apoptosis - ... GENETIC MEDICINE CHROMOSOME AND CELL GENETICS Summarise the steps in the cell cycle - ... Outline the role of soma and germ cells - ... Outline the mitotic cycle - ... Outline the meiotic cycle – meiosis I and II: o Reproductive cycle in males and females o ... Crossing over/recombination ... Outline how problems may arise in meiosis, and their consequences structural rearrangements e.g. inversions, translocations - ... Outline female and male gametogenesis - ... List methods used to visualise chromosomes - ... Outline the genetic mechanisms underlying Klinefelter Sydnrome, Trisomy 13 and 21, Williams-Beuren syndrome and Prader-Willi Syndrome, and list the main clinical characteristics of these conditions - ... STRATEGIES FOR PREVE NTION AND TREATMENT OF GENETIC DISORDERS Outline the epidemiology of genetic disorders - ... Summarise the levels of treatment of genetic disorders with reference to the following, giving clinical examples: o The family ... o Clinical phenotype o Biochemical disorders o Mutant protein o Mutant gene ... ... ... ... Outline major ethical dilemmas arising in the diagnosis and treatment of genetic disorders - ... Outline basic prenatal genetic diagnostic strategies - ... GENES, MUTATION AND CANCER Outline how mutations convert proto-oncogenes to oncogenes and list a clinical example for each of the following causes: o Environmental factors ... o Viruses o Spontaneous cellular events o Inherited errors ... ... ... List types of mutations: point, deletion, addition, gene amplification and chromosome translocation - ... Outline the cellular mechanisms by which oncogenic proteins exert their effects - ... Outline the function of tumour suppressor genes - ... Outline the range and nature of genetic mutations in breast cancer - ... EMBRYOLOGY EARLY HUMAN EMBRYONI C DEVELOPMENT Define the following terms: 'oocyte', 'zygote', 'blastocyst', 'polar body', 'monozygotic', 'dizygotic', 'cytotrophoblast', 'syncytiotrophoblast', 'embryo' and 'fetus' - ... Describe the first week of human development from the point of fertilization on day 0 to the point of implantation on day 7 - ... Describe the stages of development where the embryo is referred to by the following terms: ‘oocyte’, ‘morula’ and ‘blastocyst’ - ... Describe the pathogenesis of ectopic pregnancies with specific reference to the site of implantation and likely outcome for fetus and mother - ... Explain how home pregnancy and early pregnancy tests work with specific reference to hCG and progesterone production respectively - ... Describe the process of in vitro fertilisation and the potential for genetic diagnosis prior to implantation - ... Describe the process of gamate intrafallopian transfer - ... Describe the phenomenon of multiple gestations and outline the difference between monozygotic and dizygotic twins - ... Describe the process of implantation with reference to the following: o Size of implanting blastocyst o Formation of the placenta o Formation of the foetal membranes o Cellular make up, function and formation of chorionic villi - ... Describe molar pregnancy - ... Describe the 'gastrulation' phase of pregnancy and describe three distinct layers (ectoderm, mesoderm and endoderm) that make up the human embryo at the gastrulation phase of development - ... Describe the 'neurulation' phase of embryonic development with specific reference to the landmark days in the formation of the neural tube - ... Describe the 'organogenic' period of embryonic development, define the process of organogenesis and the weeks of embryonic development this takes place in - ... Describe the fetal period of development with reference to changes that take place in both the fetus and the mother - ... Describe the hormonal fluctuations that take place during 9-38 weeks of the pregnancy - ... Explain the potential for progesterone to play a role in maintaining at risk pregnancies as well as the predictive power of the maternal blood progesterone level in estimating the ultimate outcome of the pregnancy - ... Describe the role and possible risks of chorionic villus sampling in identifying genetic abnormalities at 10 weeks - ... Describe the process of amniocentesis with reference to both the risks and benefits of the procedure - ... Describe the fetus at 13 weeks - ... Describe ultrasounds at 16-18 weeks as anomaly scans and the range of conditions that can be detected - ... Define the age at which a birth is defined as 'premature', the problems with prematurity, the associated risks to prematurely born babies and their likelihood of survival - ... BIRTH DEFECTS Outline the potential adverse outcomes of pregnancy: o Birth defects ... o Perinatal deaths o Neonatal deaths o Premature birth o Low birth weight ... ... ... ... Define primary prevention and secondary prevention in the context of neural tube defects - ... Define anencephaly and spina bifida as the failure of the neural tube to close at either end - ... Describe the role of folic acid in the prevention of neural tube defects - ... Outline the time frame when major malformations are likely to occur - ... Outline the proportion of birth defects defined as of 'clear genetic origin', exogenous and 'potentially preventable' and 'unknown' - ... Outline the genetic causes of achondroplasia, Down syndrome, cystic fibrosis and Turner syndrome - ... Describe the association of maternal rubella infection in the first 16 weeks of gestation with birth defects - ... Outline the birth defects caused by the following agents: thalidomide, isotretinoin, anticonvulsants (e.g. valproic acid) and alcohol - ... Describe the process used to detect whether a drug is teratogenic - ... List the conditions and associated drugs which have teratogenic effects in humans - ... DENTISTRY DENTAL INFECTION Principles of pathogenesis of dental caries and periodontitis - Dental Caries involve: o Bacteria accumulating on teeth form plaque o Bacteria metabolise carbohydrates present and produce acid as a by-product o Acid dissolves enamel Periodontitis results from accumulation of Dental Plaque at border of tooth; initially will be Gingivitis but can progress to Periodontitis, which involves: o Destruction of ligament / bone supporting the teeth o Chronic disease resulting in eventual tooth loss - The main clinical manifestations of dental infection in terms of underlying patho-physiological processes - Acute Inflammation, which includes: o Swelling (fluid is the inflammatory exudate) o Redness (dilation of vascular supply to open up microcirculation) o Heat (bringing warm blood to cool surface) o Pain (due to inflammatory mediators; also due to increased pressure in the area) ORAL HEALTH Major oral diseases and their distribution in the Australian population - 40% of children aged 5-6 years already have caries Dental health is significantly correlated with social disadvantage lower socioeconomic people can find it difficult to afford dental care and hence will have worse dental health Low education/ income a risk factor for development of caries The disparities in oral disease burden between different demographic groups and the current evidence linking oral and systemic disease - Dental health is significantly correlated with social disadvantage lower socioeconomic people can find it difficult to afford dental care and hence will have worse dental health Oral disease will lead to pain and problems sleeping / eating, which can increase risk of systemic disease - The major challenges facing the prevention and management of oral disease in Australia - The highest risk sub-populations are those who are in the lower socioeconomic bands of society o These lower socioeconomic sub-populations are more likely to have poorer literary and reading skills, so messages should be kept simple and easy to comprehend o These lower socioeconomic bands of society are less likely to have access to medical care and are less likely to learn the prevention and management techniques for oral disease ADOLESCENCE AND YOUNG ADULTHOOD ADOLESCENCE AND YOUN G ADULTHOOD 1 The theories of development - ... The factors affecting development of temperament throughout the lifespan, including individual as well as gender differences in adolescence - ... GERIATRICS THE AGEING PROCESS Define ageing - ... Understand why it is important for doctors to understand ageing in terms of epidemiology, as a risk factor for disease, and as a modulator of the presentation, management and outcomes of disease - ... Understand the physiology, pathology and pharmacology of ageing - ... Understand some theories on the mechanisms of ageing - ... Understand the rationale for and possible outcomes of lifestyle and pharmacologic interventions that may alter the ageing process - ... ETHICS OF INFECTION CONTROL ETHICS OF INFECTION CONTROL 1 Understand the major risk factors for healthcare associated infections (HAIs) including patient, healthcare worker, environmental and organizational factors - ... Understand common HAI prevention and control policies, the evidence (if any) or logic behind them, implementation and barriers to their full compliance - ... Understand the ethical and economic implications of HAIs and their prevention including potentially conflicting priorities for resource allocation, and between the interests of individuals and the (hospital/general) community - ... Understand the roles and responsibilities of healthcare staff, hospital administration and health bureaucrats - ... IMMUNOLOGY INTRODUCTION TO AN IMMUNE SYSTEM Describe the difference between innate and adaptive immunity - Innate immunity is nonspecific immunity that provides immediate protection against infection o The innate immune response is identical with repeat exposure Adaptive immunity is a specific immunity to a particular pathogen that develops over days to weeks o The adaptive immune response improves with repeat exposure - Outline the properties and components of the innate immune system - Properties of Innate Immune System o Develops rapidly on exposure to infection (i.e. within minutes) o Recognises components shared by groups of different pathogens (e.g. Gram Positive bacteria, Gram Negative bacteria, etc.) o Limited Diversity (small number of receptors encoded in germline DNA) o Non reactivity to self (receptors fail generally to recognise self molecules) o Response independent of prior exposure o No memory (not improved by repeated infections) - Components of Innate Immune System: o Cellular barriers (e.g. skin, epithelium, anti-bacterial chemicals (e.g. lysosome) o Cells Phagocytic cells: Neutrophils & macrophages Dendritic cells: activate adaptive immunity Innate lymphoid cells (e.g. Natural Killer Cells) o Plasma Proteins Complement protein system Mannose binding lectin (MBL): opsonisation Pentaxins: C reactive protein (CRP): opsonisation o Cytokines (e.g. TNF, IL-1 & chemokines) Outline the properties and components of the adaptive immune system - Properties of Adaptive Immune System o Develops slowly on exposure to infection o Specificity for molecules ( or antigens) of microbes & non-microbial antigens (e.g. Allergens) o Enormous Diversity (large number of receptors (~107) produced by somatic recombination of gene segments o Dependent of prior exposure o Memory (improved by repeated infections) o Non reactivity to self (self-reactive receptors on lymphocytes are deleted in primary lymphoid organs) Components of Adaptive Immune System o Cells B lymphocytes or B cells T lymphocytes or T cells Unique membrane receptor on each “clone” of lymphocytes o Plasma proteins Antibodies or Immunoglobulins (Ig) produced from B cells - Identify primary and secondary lymphoid tissues and list the ways in which they contribute to adaptive immunity - Primary Lymphoid Organs have the following functions: o Site for the development and maturation of B and T lymphocytes o Generation of receptor diversity o MHC restriction for T cells o Development of self tolerance Primary Lymphoid Organs are: o Bone Marrow - Site of B-Cell maturation o Thymus - Site of T-Cell maturation Secondary Lymphoid Organs (e.g. Spleen, Lymph Nodes, Tonsils, Cutaneous Immune System, etc.) are the sites for the generation of immune responses o Their function is to trap antigens (which are transported from the peripheries) and provides sites for lymphocytes to interact with antigen and initiate adaptive immune responses - - ANTIGEN CAPTURE AND PRESENTATION Describe the function of different types of immune cells – T cells and dendritic cells - Dendritic Cells are the main antigen presenting cells (APC) that binds with an antigen and express them in a manner that can be read by other cells o Endogenously synthesised antigens are presented on Class 1 MHC molecule (hence, particularly relevant for virus-infected cells) o Exogenous antigens are presented on Class II MHC molecule o - - T-Cells will be able to interact with the Class I or Class II MHC molecules that are expressing the antigen; this will help activate the T-Cell T-Cells are important for cell-mediated immunity o Effector T-Cells carry out acute function (i.e. kill antigen / antigen-infected cells) o Memory T-Cells provide ability to react quickly in future if antigen presents again o T-Cells have their effect through release of antigen non-specific cytokines (e.g. TNF-Alpha, Inteferon-Gamma, Interleukins) and membrane contact (e.g. CD40 Ligand that activates BCells, Fas Ligand) Viruses inside cells are protected from antibodies (i.e. B-Cell response) o However, T-Cells can bind to these virally infected cells as they present a MHC Class 1 molecule that can be read by the T-Cells Explain what is meant by ‘MHC complex’ and how the immune response is regulated - MHC Complex refers to a set of cell surface molecules that controls a major part of the immune system o Antigens are presented on the MHC Complex of Antigen Presenting Cells, where it then interacts with T-Cell Receptors (TcR) on T-Cells in order to activate the T-Cells Immune Response is regulated by requiring T-Cells to have a co-stimulatory signal for activation (in addition to the binding with the Antigen on the MHC Complex) o For CD4+ T-Cells (Class II) [i.e. Helper T-Cells], the Activated APC (e.g. Dendritic Cell) provides the Co-Stimulatory Ligand B7 that reacts with the CD28 Receptor on the CD4+ T-Cell to activate the T-Cell Note: T-Cell expresses ‘CTLA4’ ~24 hours after activation, which then acts as an inhibitor rather than a stimulator; this competes with the stimulator (CD28) and prevents excessive activation of the T-Cell o For CD8 T-Cells (Class I) [i.e. Cytotoxic T-Cells], expansion requires co-stimulation of CD4+ TCells (in addition to the initial cross-priming by the Dendritic Cells) - Outline how protein antigens are processed via endogenous and exogenous antigen pathways - Endogenously synthesised antigens are presented on Class 1 MHC molecule (hence, particularly relevant for virus-infected cells) Exogenous antigens are presented on Class II MHC molecule - LYMPHOCYTE ANTIGEN RECEPTORS AND DEVELOP MENT OF IMMUNE REPET OIRE Summarise B and T cell receptor structure and outline the associated signalling molecules - All T and B Cells look the same until you look at their receptors Structure of Immunoglobulin (i.e. Antibody [i.e. Antigen Receptor]) o There are four chains (2 identical heavy chains, 2 identical light chains) o A single light and heavy chain are held together by disulfide bonds, and together form an Antibody Fragment (Fab) Fab (Antibody Fragment) is different across different antibodies; these differences confer different binding properties (also referred to as N Terminus) Note all antibodies contain a component that is identical across all antibodies (labelled “Fc”) (also referred to as C Terminus) o There five different types of heavy chains (each of which will result in a different type of Immunoglobulin [i.e. IgM, IgG, IgA, IgE, IgD]) o There are two different types of light chains (Kappa and Lambda) o Each light and heavy chain will have a variable part and a constant part Constant part of the light chain will be the same for all Kappa or all Lambda light chains - Variable region of light chain will vary across every different Immunoglobulin molecule o IgBeta and IgAlpha on either side of receptor are associated proteins that assist in triggering activation of the cell o When B-Cell is activated, the transmembrane segment (connecting the receptor to the cell surface) is deleted enabling secretion of the receptor (i.e. secretion of the antibody) In T-Cells: o Variable region of T-Cell Receptor (TcR) (i.e. Binding Region) consists of the 2 chains (H & L or & ) that are encoded by separate gene fragments (Variable, Diversity, Junctional) that recombine to form a mRNA encoding functional variable region unique to each clone of B & T cells o A limited no of V, D & J genes can lead to a large number possible recombinations & unique variable region There are ~100 different Variable, ~6 different Junctional and 23 different Diversity gene fragments in the Heavy Chain Additional variation is added by changes at the end of V, D & J segments during recombination o CD3 protein complex on T-Cells signals activation from the antigen specific T-Cell Receptor to Nucleus Summarise the classes of antibodies and the development of receptor repertoires - Different structures of different classes of Immunoglobulin (Ig) result in each Ig having different capabilities / functions o IgM is similar in structure to 5 IgG molecules put together and held together by short peptides called “J-chains” This provides the Primary Immune Response o IgA is similar in structure to 2 IgG molecules put together and held together by short peptides called “J-chains” This provides the Mucosal Immune Response IgM and IgG activate complements (i.e. C1q) o This means when antigens bind to these immunoglobulins, the shape of the antibody changes to reveal a binding site called “C1q” o C1q triggers a cascading signal that covalently binds peptides to the antibody, which will target them to cells IgD is less well understood; it is present on naive B Cells, but is down regulated once the B Cell is activated IgG coats (i.e. opsnise) antigens and has receptors for phagoctyes -> this increases the attractiveness of the antigen for phagocytes o This provides the Secondary Immune Response IgE is relatively similar in structure to IgG (both monomers), though its function is to protect against Helminths (i.e. parasites) o Hypersensitivity of IgE though will result in allergies - - - Explain clonal selection theory - Clonal Selection Theory states that in a pre-existing group of lymphocytes (specifically B cells), a specific antigen only activates (i.e. selection) its counter-specific cell (i.e. B-Cell) so that that particular cell is induced to multiply (producing its clones) for antibody production o The theory is an explanation of the mechanism for the generation of diversity of antibody specificity There are four tenets of this theory: o Each lymphocyte bears a single type of receptor with a unique specificity (by VDJ recombination) o Receptor occupation is required for cell activation - o o The differentiated effector cells derived from an activated lymphocyte will bear receptors of identical specificity as the parental cell Those lymphocytes bearing receptors for self molecules will be deleted at an early stage ACTIVATING T-CELLS, CYTOKINES AND CHEMOKINES Outline mechanisms of antigen recognition of MHC-peptide complex by T cells - T-Cell Receptor (TcR) on T-Cells will bind with the antigen presented by the MHC Complex (Class I or II) of the Antigen Presenting Cell o CD4+protein molecule on the surface of T-Cells recognise MHC Class II, whilst CD8 protein molecule on the surface of T-Cells recognise MHC Class I o CD4+ T-Cells are known as T-Helper Cells as one of their main roles is to send signals to other types of immune cells to arrive o CD8 T-Cells are known as Cytotoxic T-Cells as they will destroy the infected cell or infectious particle Interaction of antigen with CD3 complex of proteins (on either side of TcR) will trigger a signalling cascade that activates the T-Cell - Outline T cell activation (through co-stimulation) and responses to activation - T-Cell activation requires two steps: o Signal 1 – Antigen Recognition by the TcR of the Peptide-MHC Complex o Signal 2 – Co-Stimulation of CD28 receptor on T-Cell by Antigen Presenting Cell (APC will only provide co-stimulation when it has been activated) Activation of the T-Cells will result in growth / proliferation of T-Cells o This will occur through the interaction between T-Cell growth cytokines (e.g. IL-2) (which are released by CD4+ T-Cells) with related receptors on the T-Cell Failure to receive the co-stimulatory signals will result in no response from the T-Cell Release of cytokines and expression of CD40Ligand (which activates B-Cells) is short-term (~1-3 days) only - - Summarise T cell differentiation into effector and memory T cells, cytokine and cytokine receptor expression - Activation of the T-Cells will result in growth / proliferation of T-Cells o This will occur through the interaction between T-Cell growth cytokines (e.g. IL-2) (which are released by CD4+ T-Cells) with related receptors on the T-Cell Initial T-Cell proliferation will be mainly Effector T-Cells (with small level of Memory T-Cells) o This level of Effector T-Cells will increase until a certain point at which it peaks o Reduction in T-Cell levels occur because: IL-2 Growth Factor ceases being released after 2 days Inhibitory Receptor CTLA4 is expressed on T-Cells that prevent co-stimulation of CD28 receptor (which is needed for T-Cell activation) Elimination of antigen prevents activation of T-Cells Fas Ligand expressed by T-Cells reacts with Fas on T-Cells to institute T-Cell death, so there isn’t an excess of T-Cells after the elimination of the antigen T-Cell levels will decline leaving behind a small, but expanded memory pool of T-Cells Activated T-Cells express IL-2 and IL-2 receptor; these interact result in growth / proliferation of TCells o IL-2 Receptors also exist on Natural Killer Cells; these will proliferate too and activate upon receiving IL-2 o Activated T-Cells will also release other cytokines such TNF-Alpha, IL-4, IL-5, IL-13, InterferonGamma, etc. - - Summarise migration of T cells to sites of infection and inflammation - Naive T-Cells will migrate to the Lymphoid Organs (e.g. Lymph Node, Spleen) where they survey Dendritic Cells (DC) from the periphery Once activated by the antigens presented by the DC, the activated T-Cell will circulate to the site of infection / inflammation to eliminate the infection o These T-Cells reduce expression of the Lymph Node homing receptor (CD62L) and increase expression of adhesion molecules o The site of infection will also express Integrin (e.g. VLA-4) that attracts the activated T-Cell (and / or Memory T-Cell) - TH1 AND TH2 EFFECTOR T-CELLS Summarise the function of T cells in cell-mediated immunity - T-Cells can have the following functions: o Th1 –Intracellular pathogens o Th2 – Parasites / B-Cell Help o Th17 – Bacteria, Fungi, Mucosal Infections o Treg – Regulatory T-Cells Summarise the differentiation, role, activation and regulation of Th1 and Th2 cells - Th1 T-Cell develops from Naive T-Cell when this is exposed to IL-12 (which binds on receptor of activated T-Cell (IL-12 Receptor (IL-12R)) o IL-12 is released from the Antigen Presenting Cell IL-12 also activated Natural Killer Cells, which then release Interferon-Gamma, which activates the Th1 Cell o Binding of IL-12 to the IL12R activates master transcription factor (T Bet) which controls multiple other downstream genes, which results in the differentiation of the Naive T-Cell to a Th1 T-Cell Identifying the T Bet will enable identification of T-Cell as Th1 Alternatively, review the cytokine production from the end T-Cell to identify the functional type of T-Cell (i.e. releases Interferon-Gamma) Th1 T-Cell releases Interferon-Gamma, which activates macrophages (in addition to antiviral properties) and drives B-Cells to produce more antibodies; they also release: o IL-2, which is essential for T-Cell proliferation o TNF, which is critical in driving the inflammatory response o IL-3 and GM-CSF, which drive production of granulocytes (and monocytes too in GM-CSF) Th1 are inhibited by IL-10 (which are produced by Th2 T-Cells) Th2 T-Cell response was developed to control multi-cellular organisms (e.g. parasites) and hence will stimulate multiple arms of the immune response o Parasitic antigen will be expressed in the context of IL-4, which is essential to create a Th2 TCell IL-4 may be expressed by Mast Cells, Basophils, Eosinophils, Natural Killer Cells and Th2 T-Cells o IL-4 binds to IL-4 Receptor [IL-4R) which activates transcription factor GATA3 (which results in the differentiation of Naive T-Cell into Th2 T-Cell) Th2 T-Cells can be identified by observing an activated GATA3 (which increases expression of IL-4R) o Th2 will characteristically produce IL-4, IL-5 and IL-13 IL-4 = essential for generating Th2 responses and critical for providing T-Cell help for antibodies; will also drive B-Cells to switch from producing IgM to IgE IL-5 = Essential for eosoniphils IL-13 = pro-inflammatory cytokine; also important for maturing of B-Cells - - o Th2 also produce IL-3 and GM-CSF, which drive production of granulocytes (and monocytes too in GM-CSF) Th2 are inhibited by Inteferon-Gamma (which are produced by Th1 T-Cells) TH17 EFFECTOR T-CELLS, TREG AND CD8 T-CELLS NEED TO VIEW THIS LECTURE SLIDES IN PARTICULAR AS LEARNING OBJECTIVES NOT ALIGNED TO ACTUAL SLIDES B cell activation by antigens - Naive B cells express membrane-bound antibodies, IgM & IgD, that function as antigen-specific receptors o Cross-linking IgM & IgD receptors by antigen triggers signals that are relayed across cell membrane by Iga and Igb this triggers a signalling cascade that activates the B-Cell o Ag-recognition plus Th cells & other stimuli induce clonal expansion (proliferation of antigenspecific cells) & differentiation General primary and secondary antibody responses - Primary antibody response occurs on first exposure to antigen Secondary antibody response occurs on subsequent exposures to antigen; this response is faster and bigger than the primary response (and will continue to get bigger with each subsequent exposure) o IgG is released faster and in greater levels compared to primary antibody response (where the initial response was IgM followed by IgG) o Antibody has a higher affinity to antigen in the secondary response B cell responses to antigen activation - Proliferate (i.e. expansion of antigen-specific clone) Low level IgM secretion (which is important for protection against bacteria) Increased expression of B7 costimulators (which co-stimulates / activates T-Cells) Express cytokine receptors (which can receive cytokines from T-helper Cells) Migrate from follicles (i.e. location to activate Th Cells) T helper cell function in antibody response to protein antigens - T-Helper Cells can help activate B-Cells through its CD40Ligand o This will help B-Cells mature / proliferate , synthesis / secrete antibodies and initiate heavy chain (i.e. class) switching (from IgM to another Ig class) T-Helper cells release cytokines that bind to receptors on the B-Cells (this stimulated B-Cell proliferation and Antibody production) o Cytokines will also determine outcome of class switching o Benefit of class switching is that different microbes are eliminated most efficiently by different immune responses - IMMUNE CONTROL OF VIRUSES Describe host immune responses to virus infection - - Host has three lines of defence: o Physical Barriers (E.g. skin, acid in stomach, cilia and mucous in respiratory tract, etc.) o Innate Immune Response o Adaptive Immune Response (requires time to develop and be implemented (e.g. >4 days)) Immune responses are designed to block infection and eliminate infected cells Summarise the role and components of the innate immune response - Innate immunity is the initial response to viruses; this does not require prior exposure or amplification to be effective Principle mediators of innate immunity include: o Type I Interferons (IFN) Inhibit viral infection and replication by inducing an “anti-viral state” (through inhibiting protein synthesis by the cell) Enhance cytotoxic T lymphocyte (CTL) activity against virally infected cells (by increasing their expression of MHC Class I) Increase cytotoxic activity of NK cells o Natural Killer (NK) cells Viruses can cause cell to reduce level of MHC Class I expressed All cells generally express MHC Class I, and so NK Cells only attack and destroy those target cells with abnormal levels of MHC Class I Note: There is no antigen-specificity in Natural Killer (NK) Cells and so is critical for innate immunity o Inflammatory mediators such as cytokines (e.g. Interferon-Alpha, Interferon-Beta, IL-1, IL-6) Summarise the role and components of the adaptive immune response - Adaptive immunity is the antigen specific immune response which is a critical host response against virus infection Principle mediators of the adaptive immune response against viruses are: o Antibodies Antibodies are effective against viruses primarily during the extracellular phase of their lifecycle Most effective type of anti-viral antibodies that function during the extracellular phase are “neutralizing” antibodies (i.e. prevents virus binding to its cell-surface receptor) o Antibody Dependent Cell-Mediated Cytotoxicity Infected cell expresses antigen on surface of cell which binds with antibody Antibody then binds with NK cells which will kill the infected cell o Cytotoxic T lymphocytes (CTLs) (CD8 T-Cells) Key effector cells which are involved in clearing established viral infections Elimination of viruses that reside within cells is mediated by CTLs which recognize and lyse infected cells CD8 CTLs recognize antigenic peptides presented MHC Class I o T-Helper Cells (CD4+ T-Cells) CD4+ T cells are important in providing “help” for the antibody, CTL & inflammatory responses via the secretion of cytokines CD4+ T cells recognize antigenic peptides presented by cell-surface MHC class II molecules - Summarise the major mechanisms used by viruses to counter host immune responses - Hide from the immune system o Infection of “immune privileged” sites to avoid antigen presentation and immune recognition o Establishment of a latent “dormant” infection (e.g. Herpes Simplex) Directly infect and destroy/alter cells of the immune system o HIV infects human CD4+ T cells Encode immunomodulatory gene products that directly modulate specific components of the innate and/or adaptive immune responses o Virus can release homolog for IFN-Receptor and prevent IFN-Type I from binding with uninfected cell and changing it to a anti-viral state (similarly, other viral homologs can bind to other molecules part of the immune system) o Intracellular inhibitors of cytokine signalling - o o Antigenic variability (i.e. change the antigen expressed, so necessary antibody keeps changing) Inhibition of generation and / or transport of antigenic peptides / Inhibition of MHC class I surface expression ACTIVATING B-CELLS Summarise the role of antibodies in humoral immunity, including the phases of antibody response and T-dependent and T-independent mechanisms - Humoral immunity protects by neutralising and eliminating extracellular bacteria and microbial toxins o Humoral immunity is mediated by antibodies Antibodies are secreted by B cells & their progeny o Naïve B cells recognize antigens but do not secrete antibodies Naive B cells express membrane-bound antibodies, IgM & IgD, that function as antigen-specific receptors o Activation of B cells that have recognized antigen stimulates their differentiation into antibody secreting cells Secreted antibodies have same specificity as membrane receptors o B cells differentiate into effector cells that secrete antibodies Heavy chain class (isotype) may be changed (class switch) during differentiation Repeated exposure to same (protein) antigen may induce antibodies with increasing binding affinity (affinity maturation) T helper cells play a major role ‘helping’ B cells respond to protein antigens (i.e. “T-dependent antibody responses”) o This T-Dependent response induces heavy chain isotype switching and affinity maturation Polysaccharides, lipids and other non-protein antigens stimulate antibody production without T cell help (i.e. “T-independent antibody responses”) o Antibodies produced in response to T-independent antigens show relatively little heavy chain isotype class switching, affinity maturation and memory - - - Outline feedback inhibition of antibody secretion - B cell responses are inhibited when sufficient IgG has been produced IgG-antigen complexes simultaneously bind Ig receptors and Fc Receptor on B cell membrane o Binding of Fc Receptor inhibits B cell activation, which shuts off antibody production ACTIONS OF ANTIBODIE S Summarise the effector functions of antibodies, including the major features and functions of the five antibody classes - Effector Functions of Antibodies include: o Neutralisation of microbes and toxins (i.e. blocking microbes and toxins from binding to host cells) o Opsonisation and phagocytosis of microbes o Antibody-dependent cellular cytotoxicity o Complement Activation Lysis of microbes Inflammation Phagocytosis of microbes opsonised with complement fragments Major features and functions of the five antibody classes are: o IgA Function: Mucosal Immunity (control pathogens that target these areas for entry in the body) Structure of antibody is a Dimer Two different sub-types exist (IgA1, IgA2) - o o IgD Function: Native B-Cell antigen receptor This antibody is not secreted and exists only in trace amounts Function: Defence against helminths (and also causes hypersensitivity reactions) Has a very high affinity and hence the concentration in serum doesn’t need to be too high Structure of antibody is a Monomer IgE o IgG o Function: Broadest range of functions (e.g. opsonisation, complement activation, antibody-dependent cell-mediated cytotoxicity, neonatal immunity, feedback inhibition of B-Cells) Has the highest serum concentration Structure of antibody is a Monomer Function: Very important in activating the complement pathway Structure of antibody is a Pentamer IgM Outline the complement system, including the three activation pathways - Complement System comprises proteins essential for protection against infection o Elimination of many (extracellular) bacteria is greatly enhanced by complement activation o Complement Activation will result in: Opsonisation and Phagocytosis Complement-mediated Cytolysis Stimulation of Inflammatory Reactions Activation of Complement System involves activating inactive protein enzymes triggering a cascade that eventually results in the generation of effector molecules that eliminate microbes Three Pathways of Complement Activation (all of which have the same biological outcome) are: o Classical Pathway Triggered by IgM and IgG bound to microbes or in Antigen-Antibody complexes o Alternative Pathway Triggered by C3b and factor B bound to microbes o Lectin Pathway Triggered by Mannose binding protein (lectin) binding multiple mannose residues in some microbe cell walls - Outline the major strategies used by pathogens to evade antibody dependent immunity - Mutate surface antigens during infection (e.g. E-Coli) Mutate surface antigens between infection (e.g. Influenza) Inhibit Complement Activation Resist Phagocytosis IMMUNOLOGICAL TOLERANCE Explain the principle of self-tolerance - Self Tolerance is the specific ability of the immune system NOT to respond to self antigens Summarise the mechanisms of central and peripheral tolerance - Central Tolerance o Deletion of auto-reactive lymphocytes in the primary lymphoid organs (i.e. Thymus, BoneMarrow) Peripheral Tolerance - o o Anergy = Control of the activation of T & B cells in the secondary lymphoid organs (i.e. Lymph Nodes, Spleen) (by preventing co-stimulation) Suppression of auto-reactive T cells by regulatory T- cells (Tregs) Outline the role of Treg cells - Treg T-Cells (which arise from the Thymus) will regulate CD4+ T-Cells and minimise auto-immune diseases Treg T-Cells recognise self-reactive antigens upon recognition, they will release a series of inhibitory cytokines (especially TGF-Beta) which inhibit self reactive T-Cells from both activating initially and subsequently from having an effect o Treg T-Cells express IL-2 Receptors on their surface which assist in their regeneration / proliferation - Describe the factors underlying auto-immunity, with reference to clinical examples - Auto-immunity involves a breakdown in Self Tolerance leading to immune responses against self antigens o Precipitated by interaction of environmental factors (e.g. infections or drugs) (60%) with a genetically susceptible host (40%) Auto-immunity can occur due to a failure in the development of the various self-tolerance mechanisms o Failure to delete auto-reactive lymphocytes in the primary lymphoid organs can occur when there is lack of expression of self-antigens in these organs (e.g. due to absence of AIRE genes); this can lead to Auto-Immune Polyglandular Syndrome 1 [APS1]) This will result in autoimmunity against organs / tissue other than the primary lymphoid organ (e.g. intolerant to pancreas and insulin) o Costimulatory pathways can be activated by other antigens also being present at the same time; this can thus cause the activation and proliferation of self-reactive T-Cells o Inhibition of Treg T-Cells can cause autoimmunity (e.g. IPEX is very rare genetic mutation of the FoxP3 Transcription Factor that inhibits differentiation of naive T-Cells into Treg T-Cells; this causes severe immunodysregulation in addition to auto-immune and other diseases) - Summarise the mechanisms of auto-immunity - - This will involves two steps: o Step 1: Development of an autoimmune response which may be shut down by protective tolerance mechanisms o Step 2: Development of clinical autoimmune disease in a genetically susceptible host due to a failure in self tolerance Causes of auto-immunity include: o Cross reactivity between self and foreign antigens (termed molecular mimicry) o Drug or viral induced changes in self antigens o Sudden release of sequestered self antigens o Mutation in genes responsible for immune regulation and cell death (deletion of self-reactive T cells) (e.g. AIRE, FoxP3 mutation) List the relationship between major auto-immune diseases and MHC (HLA) - Most Autoimmune diseases will be related to MHC (HLA); particular HLA alleles will significantly increase the relative risk of contracting specific auto-immune diseases (e.g. 90x RR of Ankylosing Spondylitis with B27 HLA Allele) IMMUNE SYSTEM DISEAS ES + VACCINES AND IMMUNE T HERAPIES Summarise the major manifestations of immune system dysfunction, with reference to underlying mechanisms - - Hypersensitivity to Foreign Antigens o Type I: IgE and Mast Cells (e.g. Atopy due to degranulation of Mast Cells and later influx of Eosinophils) o Type II: Antibody and Complement (e.g. Autoimmune Diseases) o Type III: Antigen-Antibody Complexes (e.g. Vasculitis) o Type IV: T-Cell Mediated (e.g. Contact Dermatitis) Autoimmunity to Self Antigens Outline management strategies for immune system dysfunction - Stimulation of immunodeficient systems (e.g. IVIG) and suppression of hypersensitive immune systems (e.g. Corticosteroids, Cytotoxic Agents, Antiproliferative Agents, etc.) Management strategies include: o Primary prevention o Remove / treat cause o Manipulate immune response o Replace deficient elements o Block effector pathways o Treat symptoms - Summarise the major techniques used for immune system modulation, with reference to underlying mechanisms - IVIG (i.e. Intravenous Immunoglobulin) are produced from blood donations and used for treatment of patients with antibody deficiency TNF-Antagonists can be used to disrupt inflammatory pathway and hence mitigate autoimmune disease that causes inflammation (e.g. RA) Immunosuppressants (e.g. Corticosteroids, Antiproliferative Agents) Immunotherapy to ‘desensitise’ patient to triggers o Involves giving small doses of allergens that gradually increase o Starting dosage should be small enough to avoid an acute allergic reaction but big enough to result in body becoming tolerant to the allergen Monoclonal anti-IgE therapy, given IgE is critical for the hypersensitivity reaction Vitamin D has been proven to very important for normal immune function, as Vitamin D deficiency predisposes patients to autoimmune and allergic diseases Alternative medicines for immune system are common, though lack evidence - - INFECTIOUS DISEASES COMMUNICABLE DISEASE S IN A GLOBAL CONTEXT Define the following terms: ‘communicable disease’, ‘parasitism’, ‘indigenous flora’, ‘commensal flora’, ‘quarantine’, ‘antisepsis’ - Communicable Disease = disease that can be passed from one sufferer (host) to another unaffected individual Parasitism = Pathogen uses the host to provide the resources necessary to grow and reproduce to the detriment of the host’s wellbeing Indigenous Flora = Bacteria, protozoa, fungi and viruses that peacefully coexist with the host [may provide benefits too [symbiotic relationship]) o Unless they gain access to sterile sites, where they can cause infection Commensal Flora = In a state of good health, the indigenous flora exists in harmless association with the human body (“commensal) Quarantine = Isolation of sufferers of an infectious disase to prevent its spread - - - Antisepsis = Killing of bacteria (and other organisms) to prevent infection Summarise the main characteristics of sub-cellular infectious agents (viruses – obligate intracellular parasites), prokaryotic organisms (bacteria) and eukaryotic organisms (fungi, protozoa, helminths) - Viruses o Small infectious agents that contain DNA or RNA o Only propagate inside a living cell (in a parasitic manner) o Classified on the basis of genetic structure (DNA vs. RNA), symmetry of protein shell (i.e capsid) and presence vs. absence of lipid membrane Prokaryotic Organisms (e.g. Bacteria) o Simple single celled organisms with a cell membrane, cell wall and cytoplasm containing both DNA and RNA (but NOT having organelles or defined nucleus) o Classified on the basis of genetic structure, cell wall structure and biochemical characteristics Eukaryotic Organisms (e.g. Fungi, Helminths) o Single and multi-celled organisms with a cell membrane, DNA, RNA, organelles and a defined nucleus Prions o Protein that can assume two different structural forms whereby one form is normal, whilst the other form is self-replicating and transmissible - - - List examples of infections caused by indigenous flora - Urinary Tract Infection caused by E-Coli in Large Intestinal Flora Boils / Surgical Wounds caused by Staphlococcus aureus in Skin Flora Meningococcal septicaemia caused by Neissera meningitides in Pharyngeal Flora Note: Indigenous Flora are more prone to invade sterile sites and cause disease when host is immunocompromised Outline the modes of transmission of microbes between hosts - Respiratory or Salivary Spread Faecal-Oral Spread Venereal Spread Vector Spread (e.g. mosquitios) Vertebrae Reservoir Vector- Vertebrae Reservoir Outline the mechanisms by which pathogenic microbes cause disease - Secretion of toxins Disordered function of cells and / or cell death Bulk effects (e.g. abscesses) Host response to infection causing tissue damage List Koch’s postulates - The four Koch postulates are: o The microbe must be present in every case of the disease o The microbe must be isolated from the diseased host and grown in pure culture o The disease must be reproduced when a pure culture is introduced into a non-diseased susceptible host o The microbe must be recoverable from an experimentally infected host Limitations are that not all microbes can be grown in a laboratory or have experimental animal models to test these postulates on - Outline major developments in the study of infectious diseases: o Contagion theory o Contagion Theory was that epidemic diseases were caused by a transmissible ‘toxin’ or by minute infective agents This provided the basis for the idea of infectious diseases caused by microbes Germ theory and Koch’s postulates o Germ theory indicates that a specific microbe is responsible for particular diseases This identification enabled more rational and accurate approaches to disease control Koch’s Postulates provided a means of testing whether a specific microbe (i.e. ‘Germ’) was responsible for a particular disease The sanitary movement o This was the idea that provision of clean air and water could prevent communicable diseases This was based on the fact that unhygienic conditions were the environment from which particular diseases would arise Solid growth media and staining techniques o Toxin mediated disease This was used to cultivate and view / identify microbes o Secretion of toxins by the microbe result in the disease (e.g. cholera, tetanus, diphtheria) Immunity to infection, with reference to innate and adaptive immunity o Innante immunity refers to the bodies immediate, non-specific response to prevent infection Adaptive immunity refers to the development of cell-mediated immunity (e.g. TCell, B-Cell) that commences a few days after initial exposure Viruses o This was a different type of microbe that could cause disease The mechanism, mode of transmission and approach to treat is different to bacteria Vaccines and immunization programs o Widespread scourge of Polio created a drive for governments to develop a cure Polio vaccine was develop and widespread immunisation programs were implemented Other vaccines were subsequently developed and included in immunisation programs Antibiotics and antibiotic resistance o Antibiotics were able to kill bacteria and reduce the morbidity / mortality of many diseases However, widespread and frequently inappropriate use of antibiotics has led to the development of diseases that are increasingly resistant to antibiotics International agencies o These international agencies will focus on infectious disease prevention and treatment in many poorer countries in the world This will include the provision of vaccination programs Emerging infectious diseases New spectrum of infectious diseases continue to emerge in the wake of social and environmental changes MEDICALLY IMPORTANT BACT ERIA I Outline the classification of bacteria by the following criteria: o o o o o Staining (i.e. Gram-postive vs. Gram-negative) Shape (i.e. Rods vs. Cocci) Respiration (i.e. Aerobic vs. Anaerobic) Reproduction (i.e. Clusters [Staph] vs. Chains [Strep] vs. Pairs [Dip]) Genomic similarity (i.e. DNA sequence similar to reference sequences) Outline the rationale and importance of Gram staining - Gram-positive bacteria have a thick Peptidoglycan Layer in their cell wall whilst Gram-negative bacteria have a thin/minimal Peptidoglycan Layer in their cell wall Different cell walls will require different types of treatment Outline the main features of some clinically important Gram-positive bacterial infections o Staphylococcus aureus o Also known as ‘Golden Staph’ Gram-positive cocci in clusters Drug resistant forms exist (e.g. Methicillin-Resistant [MRSA]) Will release toxins and can cause severe life-threatening diseases that progress quickly such as: Endocarditis Toxic Shock Syndrome Osteomyelitis and Septic Arthritis Necrotising Pneumonia Pyogenic Infections Infection tends to localise; abscess formation is common Commonly be commensal flora in the nasal mucosa and skin Streptococcus pyogenes o Also known as ‘Group A Strep’ Gram-positive cocci arranged in long chains This results in superficial and deep tissue infections and will result in a clear zone of haemolysis Commonly be commensal flora in the Upper Respiratory Tract, GIT and Lower Genital Tracts Will release toxins and can cause: Supprative infections (e.g. “Strep Throat” [i.e. Pharyngitis], Impetigo) Systemic Infections (e.g. Arthritis, Sepsis, Osteomyelitis) Scarlet Fever Poststreptococcal Sequelae (e.g. Acute Glomerulonephritis) Spread through direct contact, respiratory droplets or exposure to contaminated materials More common in winter Streptococcus pneumoniae o Also known as ‘Pneumococcus’ Gram-positive cocci arranged in pairs Common coloniser (~30%) of the Upper Respiratory Tract in healthy people Exists in an Encapsulated (more difficult to phagocytose) and Unencapsulated format May cause Pneumonia or Meningitis (in addition to Otitis Media or Sinusitis) and will result in partial haemolysis Person-to-person spread is rare More common in winter Bacillus anthracis Gram-positive rods arranged in long chains o Cause of ‘Anthrax’; virulence based on release of range of toxins Spore forming bacteria Mycobacterium tuberculosis o Weakly Gram-positive rod Acid-fast bacteria stained by ZN stain Difficult to culture and slow growing Intracellular pathogen Cause of Tuberculosis Localised collection of Granulomas (i.e. pool of macrophages) prevent further spread Recurrences of disease may occur following immunosupression ~33% of the world population are infected Person-to-person spread by aerosol occurs Multi-drug resistant forms are emerging Listeria monocytogenes o Gram-positive rods that are short, non-branching, non-sporing Virulence from being intracellular pathogen and releasing haemolysin This can cause: Neonatal Sepsis (leading to stillbirth) Meningitis Gastoenteretis Found in soil and gut flora (~1-5% of healthy people) Transmission – foodborne and vertical (i.e. mother to baby) Corynaebacterium diphtheriae o Club-shaped non-motile Gram-Positive rods Major pathogen causing Diptheria (in addition to Pharyngitis, Cervical Lymphadenitis, Myocarditis) Virulence from production of Diptheria toxin Coloniser of upper respiratory tract of humans Spread by respiratory transmission Clostridium botulinum Anaerobic spore forming bacteria (in contrast to the all the other bacteria which are Aerobic) Ubiquitous in environment and part of normal flora of GIT Virulence based on release of range of toxins and haemolysic enzymes Toxins block neurotransmitter (ACh); this is responsible for all the symptoms (will cause death if heart and lungs are affected) Botulinum toxin is the most poisonous substance in the world Usually a food-borne disease Wound Botulism is an emerging infection resulting from unrefined (i.e. black-tar) heroin use MEDICALLY IMPORTANT FUNGI List the major groups of medically important fungi o Superficial mycoses o Examples include the yeast Malasezzia furfur (which causes Pityriasis or ‘Sun Fungus’) Cutaneous mycoses o Examples include the moulds Trichophyton or Microsporum (which causes Dermatophytoses or ‘Tinea’) Sub-cutaneous mycoses Examples include the dimorphic fungi Sporotrix (which causes Sporotrichosis) o Systemic mycoses Examples include the yeast Cryptococcus (which causes Cryptococcosis) or the dimorphic fungi Coccidioides (which causes Coccidiomycosis) Often cause systemic infections Mode of transmission includes inhalation from the environment Outline the main features of opportunistic mycoses and their clinical consequences - Examples include the yeast Candida (which causes Candidiasis) or moulds Rizopus, Mucor and Aspergillus (which causes Zygomycosis) Usually affect immunocompromised hosts Clinical manifestations may be acute, subacute or chronic; Whilst this is usually a local infection, it can become systemic Define the terms ‘yeast’, ‘mould’ and ‘dimorphic fungi’ - Yeast = Unicellular fungi that reproduce by budding or by fusion Moulds = Multicellular fungi consisting of hyphae Di-Morphic = Mould phase at room temperature (~20-24 degrees Celsius), but Yeast phase in the host (~37 degrees Celsius) Outline the main features of some clinically significant fungal infections: o Tinia o Erythematous, scaly lesions Onychomycosis (i.e. discoloured and brittle nails) Note: Tinea can occur in all the different parts of the body (e.g. feet, skin, crotch, beard, scalp) Candida o Onychomycosis (brittle and discoloured nails) Scaly erythamatous lesions (especially between the fingers) Note: Involvement can be Orally, Vaginally [i.e. Thrush], Fingers, Nails, GIT or Systemic Sporotrichosis o Chronic infection of subcutaneous tissue and adjacent lymphatics Granulomatous inflammation with intradermal microabscesses Nodular discharging lesions Occasionally spreads to muscles, bones and lungs Cryptococcus Lung infections resulting in influenza-like presentation or pneumonia Meningitis Disseminated infection affecting skin, kidneys, bones, prostrate, etc. MEDICALLY IMPORTANT PARASITES List the major groups of medically important parasites: - Protozoa; there are four main groups: o Sporozoa (e.g. Malaria) o Ciliates (e.g. Balantidium gastroenteritis) o Amoebae (e.g. Amoebic Dysentery) o Flagellates (e.g. Giardia) Helminths; there are three main groups: o Nematodes (e.g. Roundworm) - - o Cetodes (e.g. Tapeworm) o Trematodes (e.g. Flatworms) Arthopods (e.g. insects and arachnids) Mites and lice (may live permanently in the host) Define the terms ‘protozoa’ and ‘helminth’ - Protozoa are single-celled eukaryotes; these undergo both sexual and asexual reproduction Helminths are multi-celled eukaryotes (e.g. worms); these are large organisms with complex body organisation Outline the main features of some clinically significant parasitic infections: o Entamoeba histolytica o Cyst is the infective form for humans This parasite causes ulcers in mucosa of large bowel, leading to amoebic dysentery; there will be: Colicky abdominal pain Frequent bowel movements with blood-tinged mucous ~2-8% will develop extraintestinal abscesses (most commonly in liver) Giardia lamblia o Most common protozoan infection in developed countries Infection can range from asymptomatic to severe diarrhoea Diarrhoea arises from inflammation of the intestinal epithelium and interference with normal absorption Transmission via food, water and person-to-person contact Malaria o ~300-500 million clinical cases per year leading to ~1.2-1.5 million annual deaths Vector-borne disease (i.e. mosquito) Caused by Plasmodium species There are four sub-types of Plasmodium (i.e. falciparum, vivax, ovale and malariae) Each of these sub-types will have a different severity, duration and complications Sporozoites of Plasmodium will invade liver and red blood cells where they divide and become Merozoites; red blood cells will rupture causing further release / spread of Merozoites Clinically manifests with waves of high fever followed by normal temperature; the fever is synchronised with the release of Merezoites Exception is Plasmodium falciparum where fever is continuous Hookworm (Ancylostoma duodenale) o Hookworm (Ancylostoma duodenale) found in all tropical locations; >1 billion people infected worldwide Morbidity is greater than mortality Larvae penetrate the skin and migrate via the lungs to the intestine Extra-intestinal stages are mostly asymptomatic Chronic infection results in iron deficiency anaemia due to blood loss through ingestion by the worm and bleeding at bite site This will result in fatigue and impair growth in children Infection is readily treated, though re-infection is common Hookworm may be seen in faecal specimens collected ~24 hours prior to examination Lymphatic filariasis Found in all tropical regions; >1 billion people affected worldwide Lymphatic filariasis is a disease of poverty o This parasite is responsible for ‘Elephantitis’ Filarial nematodes infect deep lymphatic tissues of the host and are transmitted by mosquitos Larvae travel through bloodstream to the lymphatics only at night (10pm2am) Severe inflammation in response causes scarring and blocks lymph nodes causing chronic tissue swelling (i.e. Elephantitis) Readily treated by anti-parasitic drugs; WHO campaign currently underway to eliminate this parasite globally Pig tapeworm (Taenia solium) o Taenia solium found where raw or under-cooked pork is consumed and where pigs are free to consume human waste Carriage of adult worm in intestine is generally asymptomatic However, the main problem is that larval forms may migrate from the intestine and lodge in different tissues causing a condition known as Cysticercosis Most common and dangerous site of larval deposition and cyst formation is in the brain (which may manifest as Epilepsy) Lifecycle involves pig (the intermediate host) ingesting Tapeworm eggs from human faeces These hatch in the pig and form cysts in the pic muscle Ingestion of undercooked pork allows hatching of these cysts in human intestine Schistosomiasis (i.e. Trematode) o This is a Trematode (flatworm / fluke) infection transmitted by freshwater snails Larvae (cercaria) released from the snails penetrate the skin of people exposed to fresh water The Cercaria travel via the bloodstream to the liver, where they mature into adult worms Adult worms join in sexual union and travel to final sites (which vary depending on the genus of Schistosomiasis); this can be: o Mesenteric Veins surrounding the intestine (eggs excreted in faeces) o Veins surrounding the bladder (eggs excreted in urine) Skin penetration can cause irritation and allergic sensitisation Laying large number of eggs in those final veins can cause chronic inflammation; this may cause bleeding in urine / faeces Eggs may also enter bloodstream and deposit in key organs (e.g. brain, liver, lung), where a granuloma will then develop to surround it Body louse Body louse (Pediculus humanus) pass through three larval stages before becoming an adult All stages feed on the blood of the host Adult lice live for ~1-2 months Skin irritation (and potentially allergic sensitisation) may occur at bite site MEDICALLY IMPORTANT BACTERIA 2 Outline how bacteria are named - Bacteria are named “Genus species” o Genus name is capitalised followed by the species name in lower case Outline the main characteristics of some clinically important Gram-negative bacterial infections: o Neisseria gonorrhoeae (gonococcus) and meningitidis (meningococcus) o Gram-negative cocci in pairs with adjacent sides flattened together Both are pathogenic N. meningitides can cause meningitis, sepsis and pharyngitis N. gonorrhoea can cause gonorrhoea, urethritis, epididymitis and pelvic inflammatory disease Gonorrhoea appearance under microscope is very characteristic and can be easily diagnosed based on microscopy of discharge Gonorrhoea results in a painful, purulent urethral discharge Meningitis involves a diffuse skin rash (this can be a sign of sepsis!) Neisseria species are commensal in the nasopharynx and are transmitted via respiratory spread Escherichia coli o Gram-negative non-spore forming rods Most are considered normal flora in the GIT Common pathologies caused are Urinary Tract Infection (UTI), Meningitis, Neonatal Sepsis and Intestinal Infection Four different types of E-Coli each result in different types of Intestinal Infection (e.g. watery vs. blood diarrhoea, small vs. large intestine, etc.) Most common type is Enterohaemorrhagic E-Coli (EHEC) which commences with non-blood diarrhoea and abdominal cramps before progressing to bloody diarrhoea (most people then resolve, but 6% will get acute renal failure) Klebsiella o Virulence from the large polysaccharide capsule Common pathologies include UTIs, Lobar Pneumonia, Lung / Liver Abscesses, Sepsis Antibiotic resistance is common Salmonella (including typhoid) o Intracellular pathogen Refrigeration prevents growth but does NOT kill bacteria Pathologies include gastroenteritis, extra-intestinal infections (especially in immunocompromised, Enteric Fever [i.e. Typhoid and Paratyphoid] [from S. typhi and S. paratyphi A or B] Typhoid is a life threatening systemic infection Humans are the only host; transmission via faecal-oral route, food, water, animal contact Possible prolonged excretion of bacteria after clinical recovery Typhoid may travel through bloodstream and infect variety of organs; can eventually cause death via haemmoraghing and / or haemodynamic shock Non-typhoid Salmonella (i.e. S. enteritidis, S. typhimurium) cause a range of diseases such as self-limiting gastroenteritis Shigella o Non-motile, non-lactose fermenting Gram-negative rods Shiga toxin damages intestinal and glomerular endothelium Three common species (Shigella sonnei, Shigella flexneri, Shigella dysenteriae [most severe] Common pathologies are dysentery (i.e. frequent, low-volume stool with blood, mucous and pus in addition to abdominal cramps) Humans are only reservoir Spread via faecal-oral, water, food (especially with poor sanitation) Infectious dose is low (10-100 bacteria) Children are most susceptible Bordetella pertussis o Cause of Whooping Cough (i.e. Pertussis) Virulence from release of a range of toxins affecting various parts of the immune system and body Humans are only reservoir Transmission via respiratory droplets Legionella o Gram-negative aerobic non-encapsulated fastidious bacilli Optimum temperature 20-45 degrees Celsius (grows best in warm water sources such as cooling towers, air-conditioning systems, etc.) Legionalla pneumophilia is the cause of Legionnaire’s disease Virulence from invading alveolar macrophages; this is a intracellular pathogen with high mortality (~5-30%) Transmission via inhalation of aerosol, fine droplets, mist (no human-to-human transmission) Treponema pallidum (Syphilis) o Thin, tightly coiled spirochetes with pointed ends Poorly stained with Gram stains; do not grow on routine bacterial cultures Can be detected by dark-field microscopy Intracellular pathogen with slow replication that cannot survive outside host Virulence from outer membrane protein and antiphagocytic coating Primary Pathology of Chancre (i.e. painless ulceration / sore) and secondary pathology of tissue destruction (due to the body immune response) This is a disease of blood vessels and perivascular areas Transmitted via sexual contact or placenta Long incubation period (and bacteria may persist for years in host [i.e. latent infection]) Leptospira Most important species is Leptospira interrogans Directly invades through broken skin without local lesion Replication in tissues, liver (leading to jaundice) and kidneys (leading to renal failure) Diseases include Flu-like illness, meningitis and haemmorage as well as the severe Weil’s Syndrome Zoonotic infection where humans are accidental hosts Reservoirs are in rodents and farm animals Transmitted through contact with animal urine in water INTRODUCTION TO VIRU SES Define the term ‘virus’ - Viruses are filterable, submicroscopic organic particles consisting of nucleic acid (DNA or RNA) surrounded by a protein shell Outline the structure of a virus structure and the composition of the virus genome - Virion (i.e. Virus particle) has the following structure: o Nucleic Acid (DNA or RNA) o Capsid (i.e. Proteinaceous Shell) o Envelope (i.e. lipid membrane surrounding the capsid that is derived from host membranes; note this only exists in some but not all viruses) Capsid has three structural arrangement o Helical (i.e. spiral arrangement around a hollow core) o Icosahedral (i.e. regular polygon with 20 equilateral triangle faces) - - o Complex (Regular vs. Irregular) Virus genome can be: o DNA Genome Majority of DNA viruses have double stranded DNA as the genome material A small number of DNA virus groups may have single stranded DNA (either ‘positive’ or ‘negative’ sense) o RNA Genome Most RNA viruses are single stranded genomes (either positive or negative) A small number of RNA viruses have double stranded genomes Retroviruses and Hepadnaviruses replicate through a double-stranded DNA genome intermediate o Note: Proteins can be translated via positive single stranded RNA or mRNA; all other types of genomes must be converted into one of these two types of genomes to be translated to a protein List the steps in the virus multiplication cycle - Attachment o Virion binds to a potential host cell; this is a specific interaction between the capsid or envelope protein and a cell surface protein Cell Penetration o Movement of the virus particle across the plasma membrane Uncoating o Loss of capsid proteins and release of viral nucleic acid Biosynthesis o Synthesis of viral proteins encoded in the nucleic acid and synthesis of viral nucleic acid Assembly o Association of viral structural proteins and nucleic acid to form virions Release o Exit of the virus from the infected cell - List the effects of viruses on cells - Cell death (i.e. Cytopathic Effect) (may be induced via Apoptosis or Necrosis) Transformation (i.e. cell phenotype develops properties similar to cancer cells) Latent infection (remain within the cell in a potentially active state, but with no obvious effect on cell function) List important modes of virus transmission - Respiratory and salivary Faecal-Oral (which can be person-to-person or via contaminated food / water) Vector-mediated (e.g. mosquitos) Sexual Blood-borne (which can be perinatal or sharing contaminated blood products) MECHANISMS OF BACTER IAL PATHOGENESIS Outline basic mechanisms of bacterial pathogenesis - There are four steps in successful infection: o Acquire virulence genes (pathogens often contain genes not present in related nonpathogenic bacteria) o Switch virulence genes on o Avoid immune system o Damage host tissue and spread through host List bacterial mobile genetic elements - Plasmid o This is extra-chromosomal DNA that can replicate independently o Leads to virulence factors such as Anthrax Toxin and Exfoliatin Prophage o This is a not lytic bacteriophage that enables genetic material of bacteria to be integrated and replicated with the host genetic material (i.e. Transduction) o Leads to virulence factors such as Shiga-like Toxin and Cholera Toxin Pathogenicity Island o This is a segment of the chromosome harbouring clusters of virulence genes o Leads to virulence factors such as Enterotoxin and Cytotoxin - - Outline bacterial protection and attack strategies - Protection strategies include: o Hiding (within a capsule, in biofilms, inside phagocytes, etc.) o Camouflage / molecular mimicry o Immune evasion (e.g. antigenic variation) o Suppress immune response (e.g. suppress phagocyte recruitment, reduce vascular permeability, inhibit phagocytosis) Attack strategies include: o Enzyme production (e.g. proteases, coagulases, collagenase, hyaluronidase) o Microbial toxins (e.g. exotoxins, endotoxins) - Outline some host factors that alter susceptibility to infection - Immune status Age Genetics Nutritional status Overall health MECHANISMS OF VIRAL PATHOGENESIS Outline the mechanisms of spread of viruses through the host - Direct spread o This will be to tissues adjacent to the site of entry into the host o Scratching and rubbing may promote infection and spread Lymphatic spread o Transported via the lymphatic system to lymph nodes, where it may replicate o It can then spread to the blood through the efferent lymphatic system Blood spread o Blood is a very efficient means of spread, as this supplies virtually every organ / tissue o There can be either primary viraemia (i.e. soon after infection) and /or secondary viraemia (i.e. after growth in primary target organ) o Secondary Viraemia is greater in magnitude (>100x) and duration that Primary Viraemia and is often accompanied by clinical signs and symptoms - - List major genetic determinants of viral virulence - Expression of particular receptors that enable infection of cells by virus Effectiveness of immune system / macrophages in the body Outline the meaning of the term ‘tissue tropism’ - Tissue tropism refer to the breadth of the cells / tissues of the host that can support the growth of the particular virus / bacteria Summarise mechanisms of viral disease production (with reference to clinical examples): o Viral destruction of tissues and organs o Virus may trigger necrosis of cell (e.g. polio) or trigger apoptosis of the infected cell Virus-induced immunopathology Immune response (i.e. cytokines / antibodies from immune system) may be the primary cause of signs and symptoms of disease (e.g. Influenza, Measles) Outline factors related to persistent and latent infections - Persistent infections are more likely if: o Infection delivers immunosuppresion o Host is immunodeficient o Foetus / Neonate was infected (and hence becomes tolerant to infection) o Virus stimulated non-neutralising antibody that blocks neutralisation o Virus rapidly generates immune escape mutants (e.g. HIV) Latent infections are more likely if: o Virus hides in part of body without immune response (e.g. Herpes Simplex hides in dorsal root ganglion) o Virus integrates its genome into host cell DNA - Outline mechanisms of viral oncogenesis - Viruses from many families are capable of transforming cells (increases risk of oncogenesis) Risk of oncogenesis is increased if patient is: o Younger o Exposed to carcinogens (e.g. smoking) o Immunocompromised LABORATORY DIAGNOSES OF INFECTIOUS DISEAS ES Outline the rationale for laboratory testing in the detection and diagnosis of infectious diseases - Assists in establishing the diagnosis Guides patient management and helps select appropriate antimicrobials Public Health and Infection Control implications (i.e. notifiable diseases, contact tracing, etc.) Outline techniques used to identify pathogens - Microscopy (may involve Gram, Fluorescent and other stains or direct examination) Antigen detection (i.e. using a known antibody and seeing which antigens will bind to this antibody) o This can be performed using the rapid Point-of-Care Tests (POCT); any positive results need to be confirmed by standard laboratory analysis Nucleic acid amplification based methods (e.g. PCR) (used to detect microbial DNA) Microbial DNA sequencing (which compared DNA to database with reference sequences) Microbial culture o Develop colony on culture and examine macroscopically and microscopically o Bacteria identified using biochemical, immunological and molecular techniques - Outline processes used to test antibiotic susceptibility - Antibiotic susceptibility can be tested using either a diffusion or dilution test o o Diffusion test involves placing antibiotics on agar plate of bacteria and seeing the diameter around the antibiotic where bacteria doesn’t grow (larger the diameter, more effective the antibiotic) Dilution test involves identifying the MIC (minimum in-vitro concentration of antibiotic that inhibits growth of the bacteria); the lower the MIC, the more effective the antibiotic Outline the process of antibody detection - Serology / Antibody Response Detection will involve using a known antigen and seeing which antibodies will bind to this antigen o For example, Enzyme ImmunoAssay (EIA) can be used for this o This will also involve adding an anti-human antibody with a coloured substrate too to the antibody / antigen, as this will bind to the antibody-antigen complex and hence be visible (but it won’t bind and hence NOT be visible if the antibody doesn’t bind to the antigen) Increases in the antibody concentration (measured via MIC) over time (i.e. higher in convalescent serum vs. acute serum) can indicate an increase in the level of immune response over this period; this indicates presence of infection (and corresponding immune response) - MECHANISMS OF TRANSM ISSION OF INFECTIOUS DISEASES To introduce concepts of direct and indirect transmission routes and factors influencing disease transmission - Direct transmission includes skin and sexual contact Indirect transmission includes contact with infect blood or contaminated food / water Factors influencing disease transmission include: o Host susceptibility (e.g. immune status, age, genetics, etc.) o Transmission routes and level of sanitation o Presence of carriers / asymptomatic infectious phase o Size of infectious dose o Nature of disease / virulence o Reproductive rate of infectious agent (i.e. potential to spread in a population) To explain possible outcomes after exposure to an infected agent and the meaning of incubation, latent and infectious periods - Exposure to an infect agent may result in: o Patient immune response killing infective agent and preventing disease o Patient becoming an asymptomatic carrier o Patient developing disease due to infective agent Incubation Period = Time between exposure to the infected agent and the first appearance of signs / symptoms Latent Period = Time between exposure to the infected agent and becoming infectious Infectious Period = Period in which host can transmit infective agent to another person To discuss the contribution of symptomatic sources, asymptomatic carriers and vectors in disease transmission - Symptomatic sources are known and observable and their symptoms may act to transmit the disease (e.g. sneezing faciliatates respiratory spread) Asymptomatic carriers do not have symptoms, but can be dangerous as they will not be quarantined and yet will be infecting many others (e.g. Typhoid Mary) Vectors may be unavoidable resulting in a rapid spread of disease (e.g. Plague); furthermore, there may be a lack of knowledge that they are transmitting the disease - To explain the importance of transmission dynamics and outbreaks for communicable disease control and prevention at patient-to-patient and population levels - Infection control aims to break the chain of transmission by minimising exposure to potentially infectious body fluids o Standard precautions involve taking general precautions to prevent spread (e.g. hand hygiene, PPE, etc.) o Transmission-based precautions are implemented when standard precautions are insufficient Understanding the transmission dynamics of a disease is important for developing the appropriate prevention strategies to control and prevent the disease from spreading - SEMINARS INTRODUCTION TO POPU LATION MEDICINE TBA - ... INTRODUCTION TO IMAGING Outline the role of imaging in the clinical setting and when imaging maybe preformed in the patient-doctor setting - ... Outline the principles of imaging techniques including X-ray, CT and MRI and identify some advantages and disadvantages of each modality - ... Describe how an X-ray image is formed and situations where an anteriorposterior, posterior-anterior or lateral image is preferable - ... Define multi-planar reconstruction and describe the benefits achieved by this medical imaging technique - ... Describe the advantages and disadvantages to be considered when choosing CT or an MRI. Describe the difference between a CT and MRI image and be able to recognise each - ... Outline the safety considerations with MRI imaging - ... Describe the difference between a T1 and a T2 MRI image and be able to recognise each - ... Describe a basic method of interpretation of a musculoskeletal image - ... THE SOFTWARE: GENETI C INFORMATION, ITS E XPRESSION AND VARIAT ION Outline the organisation of the human genome, with reference to: o Chromosomes and genes o The genetic paradigm o The double helix structure of DNA o The genetic code o Development of technologies for visualising genes - ... Outline patterns of human inheritance: autosomal dominant, autosomal recessive, X linked, non-classical - ... List basic techniques for examining the genome: gene sequencing and gene disease identification - ... Summarise ethical and social implications of genetic testing and individualised medicine - ... Identify useful internet resources for further learning about genetics - ... INTRODUCTION TO PATI ENT-DOCTOR: OBSERVING PEOPLE Introduction to Patient-Doctor Theme - ... INTRODUCTION TO MD TBA - ... THE AUSTRALIAN HEALT H SYSTEM Explain what is meant by the terms: o Population Health ... o Social Determinants of Health o Health Equity o ... Health Care System ... o ... Describe the major features of the Australian Health Care System with reference to: o The major components of the system ... o The distribution of resources across system components o The principle of universal access to health care and how it is achieved o The division of health care responsibilities among different levels of government o Co-existing public and private sector health care ... Access to Health Care ... ... ... ... Outline the strengths and weaknesses of the Australian Health Care System with reference to: o Addressing social determinants of health ... o Access to health care o Division of responsibilities among different levels of government o Co-existence of public and private sector health services ... ... ... CULTURAL IMPACTS OF HEALTH OUTCOMES Understand that cultural identity is an important social determinant of health and may play a significant role health in health outcomes for the individual patient and specific populations - ... Understand that cultural identity may affect the experience of health care delivery - ... Understand that stigma, discrimination and social exclusion can create ill health and influence health outcomes - ... Understand the impact of discrimination (overt or subtle; individual or systemic) on interactions between patients and health professionals and have some learned some skills for sensitive and effective communication - ... Recognise that Indigenous Australia is diverse in its language, culture and demographics - ... Understand the significant role of Aboriginal Health Workers (AHWs), and other Indigenous community workers, in helping provide Aboriginal patients with the best possible care throughout their life - ... PRINCIPLES OF NUTRIT ION Outline the nutritional requirements of early childhood - ... List the advantages and disadvantages of breastfeeding and bottle feeding - ... Outline how to take a dietary history - ... Outline how to use child growth charts to track height and weight - ... INTRODUCTION TO IMMU NOLOGY AND INFECTIOU S DISEASES TBA - ... CERVICAL CANCER Explain in broad terms the nature of cancer - ... List the pathological stages in the development of squamous cell cancer of the cervix - ... Describe the way cervical cancer incidence varies within and between populations - ... List the major risk factors for cervical cancer - ... Explain how human papilloma virus (HPV) causes cervical cancer - ... Give a simple account of the way the human immune system can act to prevent cancer - ... Describe the key features of the Australian cervical screening program - ... Describe the expected outcomes of the Australian program of immunisation against HPV - ... CONTROL OF INFECTIOU S DISEASES Summarise, in general terms, trends in mortality from infectious diseases in Australia since the early part of the 20th Century - ... Summarise, in general terms, trends in the occurrence of major vaccinepreventable diseases and tuberculosis in NSW - ... List the six leading infectious disease causes of mortality worldwide - ... List the major approaches to the control of infectious disease - ... Outline in general terms the role of public health legislation (public health, quarantine and food acts, etc) in the control of infectious disease - ... Define ‘surveillance’ as applied to the monitoring of infectious diseases, and give examples of sources of data for infectious disease surveillance (disease notifications from clinicians, laboratories and others; data on emergency department presentations; death registrations; sentinel surveillance system data; specific surveys) - ... Outline the process of investigating an acute disease outbreak - ... Explain the importance of investigating infectious disease outbreaks - ... Using Salmonella as an example, define the terms ‘epidemiologic cluster’ and ‘genotyping cluster’ - ... Using tuberculosis as an example, outline the importance molecular epidemiology in investigating infectious disease clusters - ... Outline the importance of the shift in pathogen concept from genus/species/serotype to virulence profile/subtype in determining direction of transmission of infectious disease - ... Explain the significance of the statement, ‘No antibiotic is effective against all types of microbes’ - ... Outline the reasons for using combinations of antibiotics - ... Define what is meant by ‘resistant microorganisms’ and outline their mechanisms of exerting resistance - ... Define the term ‘cross resistance’ to antibiotics - ... Outline the evolution of antibiotic resistance, list the factors that promote resistance and list the reasons why antibiotic susceptibility testing is important - ...