SBI241 - All content.docx

**SBI241 -- All content (Week 1 -- 12)** Cell Biology **Plasma membrane --** Phospholipids main structure - Acts a barrier separating inside and outside of the cell - Controls the flow of substances in and out of the cell - Helps identify the cell to other cells and participates in in...

**SBI241 -- All content (Week 1 -- 12)** Cell Biology **Plasma membrane --** Phospholipids main structure - Acts a barrier separating inside and outside of the cell - Controls the flow of substances in and out of the cell - Helps identify the cell to other cells and participates in intercellular signalling **Membrane Transport** *[Passive transport]* -- Does not require energy\* [Simple diffusion] -- Movement of solutes from an area of high concentration to low concentration. High -\> Low [Facilitated diffusion] -- Down the concentration gradient and 'facilitated' by integral proteins (carriers and channels) [Osmosis] -- Water travels through a selective permeable membrane so that concentrations of a solute are the same on both sides of the membrane, crucial for normal fluid balance [Filtration] -- Pressure pushes water and solutes against cell membrane **Active transport** [ ] -- requires energy *[Active transport carriers (pumps)]* - Can transport molecules against the concentration gradient - It is a sodium-potassium pump *[Transport by vesicle formation]* - Endocytosis Pinocytosis Phagocytosis - Exocytosis **Cytoplasm** - Is a ground substance/matrix in which various cellular components are found - 75-90% water plus solid compounds, mainly carbohydrates, lipids and inorganic substances and it is the substance in which chemical reactions occur. **Nucleus -** Brain of the Cell as it contains DNA **Cell division** - Ages and dies. Remaining cells divide to replace the cells which are lost. Occurs through a process call *[mitosis]* -- a cell passes through an ordered series of events in which the cell duplicates its contents and divides into two cells - *[Meiosis]* -- type of cell division which occurs in sexual organs, testes and ovaries & leads to formation of gametes. **[Mitosis]** -- Only last for roughly 1 hr on a 24 hour time span *[4 phases/stages]* - Prophase - Metaphase - Anaphase - Telophase Before and after it has divided, the cell enters a stage -- Interphase (G1, S and G2 sub-phase) - Extra organelles are manufactured by the replication of existing organelles, DNA also goes through replication. - Cell build-up of store energy that is required for cell division. **[Meiosis]** -- Has 8 stages = 2 cycles of cell division - *[Human cells]* = 23 pairs of chromosomes (22 pairs of autosomes + 1 set of sex chromosomes) - *[Reproduction]* = Ovum is penetrated by sperm, DNA copy from both parents is combined, ensuring that the resulting zygote has the correct amount of DNA. Egg and sperm undergo meiosis to ensure that they only contain one copy of chromosomes  **[Endoplasmic Reticulum]** -- found around the nucleus - Membranous network attached to Nuclear membrane - Site of protein synthesis, smooth and rough endoplasmic reticulum **[Ribosome]** -- site of protein synthesis - Made of RNA and protein - Produces proteins from genetic material - *[Free ribosomes]* -- Floating in the cytoplasm - *[Attached ribosomes]* -- Bound to the endoplasmic reticulum **[Golgi Apparatus]** - Network of flattened, smooth membranes - Packages proteins from the endoplasmic reticulum into secretory vesicles - Vesicles transport proteins to other organelles or releases them from the cell RNA carries DNA information. **[Lysosomes]** - Storage vesicles containing enzymes - Break down old organelles and digest foreign substance - Plays a role in [apoptosis] **[Peroxisomes]** - Similar structure to lysosomes, only smaller - Detoxification of harmful substances and neutralises dangerous free radicals. **Mitochondria** - Powerhouse of cell, surrounded by double lipid bilayer membrane - Participate in oxidative phosphorylation and ATP production - Contains own RNA, DNA and ribosomes - ATP = stores and transfers energy **[Cellular metabolism]** [Anabolism] -- energy using uses energy to construct. [Catabolism] -- energy releasing deconstructing, releases energy. [Cytoskeleton] -- Maintains cell's shape and internal organisation and permits movement of substances within the cell. **Cellular respiration** 1. Aerobic -- with oxygen. 2. Anaerobic -- lack of oxygen, unsustainable for a long period of time. **Types of Tissues** **Basic tissue types** 1. Connective tissue 2. Epithelial tissue 3. Muscle tissue 4. Nervous tissue **Epithelial** - Diverse group of tissue that include both surface epithelia and solid organs - Functions are: - Forming a protective barrier - Regulation of the exchange molecules between compartments (selective diffusion and absorption) - Synthesis and secretion of glandular products **Connective tissues** - Tissues that provide general structure, mechanical strength, space filling, physical and metabolic support for specialised tissues. - Three structural properties with corresponding construction materials: - Tensile strength - Elasticity - Volume i.e. bulk/substance **Specialised connective tissue: Bone & cartilage** - **Bone** is made up of collagen and a cellular matrix with cells that synthesise them. Provides a rigid protective and supporting framework resulting from the deposition of calcium salts within the collagen and matrix - **Cartilage** occurs in different forms and provides a smooth articular surface at bone ends as well as structural support in special area i.e. trachea and pinna. **Muscle** - Specialised contractile cells that generate force through contraction - Movement is generated by interaction of proteins actin and myosin. - Muscle cells can be divided into [3 types:] - Skeletal muscle -- Attached to bones, involved in movement of skeleton. Can be contracted voluntarily, controlled by somatic nervous system - Smooth muscle -- visceral muscle, found in internal viscera. Under controlled by autonomic nervous system. - Cardiac muscle -- found in the heart, striated muscle. **Nervous Tissues** - Provides rapid and precise communication between different parts of the body via the action of specialised nerve cells called neurons = they are interconnected and function together and process information and then generates appropriate response signals - Main parts of Nervous system: - Central Nervous system (CNS) -- Brain and spinal cord - Peripheral Nervous system (PNS) -- Nerves which run between the CNS and other tissues. \*Inflammation is the body's immediate reaction to tissue injury or damage, because when tissue injury or damage occurs, this stimulates the body's inflammatory and immune response spring into action to promote the healing process and to start immediately. \* **Homeostasis** - Ability of physiological systems to maintain conditions within the body in a constant state. Maintain the organism's internal environment within tolerance limits and to provide a stable environment for cells to carry out normal functions. - Goal of homeostasis is to maintain the internal environment at/or near a set point. **Vital Signs as a measure of homeostasis** - Resp rate, depth and rhythm, oxygen saturation, pulse rate and rhythm, blood volume and pressure, and temperature are regarded as essential part of monitoring patients. - Changes in vital signs = homeostatic imbalance. **SBI 241 -- week 2 notes** **Classes of microorganisms** - Bacteria - Viruses - Fungi - Protozoa - Parasitic worms **Healthcare acquired infections** - Direct - Droplet - Indirect - Airborne/aerosol - Vector-dependant - Faecal-oral **PROCESS OF INFECTION**\ Colonisation Infection Spread **FACTORS FOR INFECTION** - Mechanism of action - Infectivity - Pathogenicity - Virulence - Immunogenicity - Toxigenicity **Host Defences**  **Classes of infectious microorganisms** - Viruses - Bacteria - Fungi - Protozoa - Helminths **Bacteria** **Gram Staining** - Staining procedure in which a dye colours all bacteria a deep purple. Alcohol applied and washes off purple colour from SOME bacteria while others retain the colour. - This provides useful information on which antibiotics to choose - *[Gram positive bacteria]* -- have a thick layer of peptidoglycan, found in cells walls of bacteria - *[Gram negative bacteria]* -- Only has a thin peptidoglycan layer + outer membrane outside the cell wall **Bacterial Toxins** - *[Exotoxins]* -- Enzymes released during bacterial growth. Damages cell membranes, inhibit protein synthesis. [Immunogenic: antitoxin production] - *[Endotoxins]* -- Lipopolysaccharides from outer membrane of dead gram-negatives, released during cell lysis or destruction of the bacteria. Pyrogenic effects, septic shock. **Septicaemia** -- Refers to the presence of microorganisms in the blood. **Bacteraemia** = presence of bacteria in the blood causing failure of the body's defence mechanisms Symptoms of Gram-negative septic shock is produced by the release of endotoxins release of vasoactive peptides and cytokines that affect blood vessels + producing vasodilation = reduces blood pressure, caused decreased oxygen delivery and produces septic shock. **Obligate intracellular parasites** - Dependent on host cells - No metabolism - Permissive host cell - Usually a self-limiting infection **Viral replication** - DNA or RNA - Protein receptor-binding site - Viral DNA enters nucleus and is transcribed into mRNA - Clinical symptoms will reflect the alteration of the function of the infected cells like influenza virus binds to a receptor on respiratory epithelial cells = causes symptoms of an upper respiratory tract infection **Cellular effects of viruses** - Inhibition of host cell DNA, RNA or protein synthesis - Disruption of lysosomal membranes - Promotion of apoptosis - Transformation of host cells into cancerous cells **Fungi = either moulds or yeast** - Singled cell = yeast - Double cell = moulds Diseases caused by fungi are call mycoses Dermatophytes = fungi that invades the skin. Infection control -- prevent and treatment **Vaccines** - Induction of long-lasting protective immune responses that will not result in disease in a healthy recipient. Vaccines could be either: - Attenuated organism - Killed/inactive organism - Extracts of Antigens - Toxins **Immune system** +-----------------------------------+-----------------------------------+ | **The lymphatic system** | **Circulatory system** | +===================================+===================================+ | - Tonsils | - Bone marrow -- where all | | | immune cells are formed. | | - Thymus gland | | | | - Lymphocytes/white blood cells | | - Lymph nodes | | | | - Phagocytic cells (white blood | | - Spleen | cells) | | | | | - Appendix | - Dendritic cells | | | | | | - Thrombocytes (platelets) | | | | | | - Complement proteins | +-----------------------------------+-----------------------------------+ **Types of immunity** *[Non-specific (innate)]* - Immunity that is present from birth. Eg. Blood cells, physical barriers, chemical and mechanical barriers *[Specific (acquired/adaptive)]* - Immunity that develops as a result to exposure to infectious organisms: - Humoral immunity or antibody mediated immunity (involves B cell actions) - Cell-mediated immunity (involves T cell actions)  **Immunodeficiency** -- insufficient to protect the host - *[Clinical presentation]* -- development of unusual or recurrent, severe infections *[Autoimmunity]* -- misdirected against the body's tissues - Breakdown of tolerance -\> body recognises self-antigens as foreign *[Allergy]* -- exaggerated hypersensitivity response to environmental antigens - Clinical presentation -- watery eyes, vomiting, runny nose. \*severe reactions -- skin rashes, swelling of lips, tongue or throat, SOB, dizziness/fainting. \* **Inflammation** Occurs in response to tissue injury *[Purpose:]* - Prevent & limit infection & further damage - Initiate healing and adaptive immune response *[Characteristic changes:]* - Localised vasodilation & increased capillary permeability - Movement of WBC, complement and plasma proteins to site of injury. **5 signs of inflammation** - Heat - Redness - Swelling - Pain - Lose of function **Mast cell** - Cellular bags of granules located in the loose connective tissues close to blood vessels. skin, digestive lining and respiratory tract - Activation: - Physical injury - Chemical agents - Immunologic processes LEADS TO =\> [Degranulation] and [synthesis] of lipid-derived chemical mediators **Phagocytosis** - Process which a cell ingest and disposes of foreign material **Neutrophils** - Most abundant white cells - Life span = 4-8 hrs in circulation & 4-5 days in tissues - Major defence against bacterial infection *[Diapedesis]* -- neutrophils & monocytes squeeze through the pores in the blood capillaries to enter tissues, moved by AMAEBOID-type of motion *[Chemotaxis]* -- neutrophils move towards the source of certain chemicals = chemo-attractants. - Bacterial or viral toxins - Degenerative products of inflamed tissue - Products of complement system *[Opsonization]* -- process by which bacteria are made visible for neutrophils to be ingested  **SBI241 -- week 3**  **Renal Failure** - *[Acute]* = sudden, sharp decline in renal function, can be reversible - *[Chronic]* = gradual decline in renal function over time = irreversible **Chronic Kidney disease (CKD)** - Irreversible loss of renal function that affects all organ system which can be caused by a variety of different pathophysiological conditions - Can lead to a development as a complication of systemic diseases (Hypertension, Diabetes) or as a complication of many renal diseases (Chronic glomerulonephritis). **Renal diseases** 1. Glomerular Diseases 2. Tubular Diseases 3. UTI -- Urinary Tract Infection 4. UTO -- Urinary Tract Obstruction **Glomerular Diseases** - *[Acute glomerulonephritis]* -- Large, inflamed glomeruli with decreased capillary lumen and rapid onset of haematuria and proteinuria. - *[Chronic glomerulonephritis]* -- Glomerular scarring and eventual loss of functioning nephrons, gradual development of uremia may be first sign. **Glomerulonephritis: Clinical Manifestation** - Hypertension - Renal Failure - Two major changes distinctive of more severe glomerulonephritis are: - [Haematuria] with RBC casts - [Proteinuria] exceeding 3-5g/day with albumin as the major protein. - [Gross proteinuria] = associated with nephrotic syndrome **Tubular diseases** - Result in decreased excretion/reabsorption of certain substances or reduced concentrating capability. - [Renal Tubular acidosis] = Disorder affecting acid-base balance **Urinary tract infection** - Inflammation of the urinary epithelium caused by bacteria from gut flora - Can occur anywhere in the urinary tract. - Common pathogens: - Escherichia colo - Staphylococcus saprophyticus  **Pyelonephritis** *[Acute pyelonephritis]* = Acute infection of the renal pelvic most commonly by Escherichia coli and Proteus Mirabilis. Ascends from the lower urinary tract. - Men = prostatitis and prostatic hypertrophy because urethral obstruction predispose to bacterial infection - Can also be caused by blood infection *[Chronic Pyelonephritis]* = Persistent or recurring episodes of acute pyelonephritis that leads to scarring. **Urinary Tract Obstruction** -- can be caused by calculi or tumours - Renal calculi are stones in the urinary tract and the causes of upper urinary tract obstruction. Formed by combination of various crystallized substances - Men are more at risk than women - Symptoms may depend on the location of the renal stone - Silent stones causing obstruction may lead to CKD. *[Certain systemic diseases that can cause CKD. ]* - Diabetes - Hypertension - Lupus CKD = decreases GFR and tubular functions **GFR** - Measurement of GFR is a good indicator of kidney function - Calculate GFR = calculate clearance of a substance by kidneys over a period of time - *[Creatinine]* -- breakdown product of muscle is normally cleared from the blood by the kidney, through the process of filtration. Kidneys not working = level of creatinine in blood increases **eGFR** - Estimated glomerular filtration rate is based = creatinine, age, body, size, gender and race. Common formula in clinical practice: - Cockcroft-Gault equation - Modification of Diet in Renal Disease (MDRD) equation **Evaluation** - CKD is based on risk factors, history and presenting signs and symptoms - Elevated serum creatinine and serum urea concentrations are consistent with CKD - Markers of Kidney damage include urine protein, albumin and examination of urine sediment - Ultrasound, CT and x-rays will show small kidney size - Renal biopsy confirms the diagnosis **Management Principles** The mainstay of management involves: - Dietary control - Fluid evaluation - Sodium, potassium and phosphate restriction - Adequate kilojoule intake - Management of dyslipidaemias - Iron, folic acid and erythropoietin replacement therapy as needed - Angiotensin-converting enzyme (ACE) inhibitors or receptor blockers are often used to provide renal protection and to control systemic hypertension. **Alzheimer's Disease** - Most common type of dementia - The risk of developing Alzheimer increases with age. As it progresses, lack of concentration and disorientation occur. - Inability to retrieve semantic memories occurs early and manifests as difficulty in finding the words to formulate or follow speech, failure to recognise or identify people or objects. **Pathophysiology** - Characterised pathologically by death of pyramidal cells, neuritic plaques, neurofibrillary tangles, particularly in the hippocampus, temporoparietal and front cortices. - The patients exhibits memory loss, poor judgement, disorientation, confusion and changes in personality. Can lead to mood swings and violent outburst. **Dementia** - Set of symptoms that include gradual loss of memory, mood change and problems with communication and reasoning. - Occurs when the brain is damaged by certain diseases like Alzheimer's Disease or a series of small strokes **Encoding the memory** - Short-term memory is stored in the frontal lobe but only temporarily (seconds to minutes) and the info needs to be consolidated into long-term memory because the space is limited. - Long-term memory resides in the hippocampus and last years/lifetime. - PLASTICITY = ability to alter the anatomy and function in response to changes in its activity patterns. New neurons and synapses are produced in the areas involved in memory. - LTP = repeated stimulation results in increased strength of that synaptic connection. **Role of inflammation** - Aggregates and larger deposits of plaques and tangles elicitan inflammatory - This response assists in the clearance of the aggregated peptide but may also stimulate the secretion of mediators that cause damage. **SBI241 -- Week 4** **AUTONOMIC NERVOUS SYSTEM** [CENTRAL]     ⁃    Brain and spinal cord (cervical, thoracic, lumbar and sacral) [PNS]     ⁃    cranial and peripheral nerves [Somatic nervous system ]     ⁃    Voluntary (conscious control - walking and chewing)     ⁃    Effectors are skeletal muscles     ⁃    Controlled at all level of the nervous system [Autonomic nervous system]     ⁃    involuntary movements like beating of the heart.     ⁃    effectors are smooth muscle - cardiac muscle     ⁃    *[hypothalamu]s controls and integrates the ANS, during emotional stress higher centres* [Major divisions:]     ⁃    sympathetic division     ⁃    parasympathetic system [Sympathetic predominance ]     ⁃    exercise     ⁃    anger     ⁃    fear [Parasympathetic Predominance ]     ⁃    digestion     ⁃    sleep     ⁃    relaxation **Neurotransmitters and Receptors** *[therapeutic manipulation major transmitters:]*     1.    acetylcholine     2.    noradrenaline *[effects are mainly aimed at:]*     1.    stimulating or blocking receptors     2.    modifying the concentration of neurotransmitter at their site of action:     ⁃    change rate of synthesis - increase/reduce concentration     ⁃    change storage or rate of release - increase/reduce concentration     ⁃    block re-uptake - increase concentration     ⁃    block degradation- increase concentration     3.    change number of receptors *[Cholinergic receptors: ]* Nicotinic- Ligand-gated ion channel Muscarinic *[Adrenergic receptors]* - alpha or beta(beta has 1-3) **PAIN** pain is a protective mechanism, a subjective experience with distinct discriminative and emotional components. pain changes in the level of autonomic nervous system activation - increase HR, BP, ventilation, nausea/vomiting and sweating. Damage to internal organs can result in activation of sympathetic nervous system which causes elevation in CV respiratory responses. Pain receptors are all free nerve endings. these do not adapt - stimulus is present, receptors will always fire and send signals to the brain. *[C-fibres]* - slow chronic pain signals *[A-fibres]* - very quick pain signals. sends signals to spinal cord then brain.  *[Acute pain]* - severe sudden onset, prolonged and continues until healing begins, associated to a medical condition or injury *[Chronic pain]* - pain that continues even through healing may be complete. although the pain may remain as intense as acute pain, there is little or no autonomic response. usually lasts longer than 3 months **types of pain** *[Superficial pain]* - occurs due to nociceptor stimulation in the skin due to large number of nociceptors in skin, pain is easily located. Acute superficial pain = sharp, pricking sensation *[Deep pain]* - dull and prolonged pain. can be either somatic or visceral. [somatic pain] - emanates from structures like bones, muscles, joints and tendons. [visceral pain] - produced when nociceptors in organs like kidneys, stomach, gallbladder and intestines are stimulated. **Built-in analgesia**     ⁃    individuals react to pain differently.     ⁃    brain can suppress the input of pain signals     ⁃    works at the brain and spinal cord level **Analgesia system** many transmitter substances are involved: Enkephalin and Serotonin are most important. Enkephalin - caused both pre-synaptic and post synaptic inhibition of incoming pain fibres where they synapse in the dorsal horns. **Referred pain** when a person feels pain in a part of the body that is fairly remote from the tissue causing pain e.g. pain in one of visceral organs often is referred to an area on the body surface. knowledge of the different types of referred pain is important in clinical diagnosis because in many visceral ailments the only clinical sign is referred pain. *[Phantom limb pain]* pain sensed by amputees where the removed limb once was. Possible explanations:     ⁃    the brain continues to receive 'signals' from the amputated limb     ⁃    painful limbs create 'pain memories' before amputation.     ⁃    tissue damage leads to increased sensitivity in nociceptors stimulating neighbouring nerves not originally involved in the initial injury *[Neuropathic pain]* arises from nervous system. phrase for pain that occurs because of central or peripheral nervous system damage/dysfunction. *[postoperative pain]* anxiety and apprehension prior to surgery leads to high level of pain postoperative. unresolved pain leads to a complicated post-surgical recovery. *[cancer pain]* very high prevalence of pain in patients with cancer. causes of cancer pain are wide and varied but most common cancer pain is caused by bone metastases *[Assessment of pain]* evaluate of pain is often difficult. useful aid is to ask for location, type and duration of the pain. *[children]* = inadequately treated for pain, harder to assess pain than in older child or adult. assessments need to be context by the child's age, developmental stage, family and cultural situation and previous pain experience. *[infants and toddlers]* - observers can estimate pain by various scale considering behaviours, vital signs and sleep patterns. [McGill pain questionnaires ] most common multidimensional pain assessment. Contains series of adjective for patients to use to describe their pain (sensory, affective and evaluative). rating scale of 0-5 Assessment of pain is based on 3 measures:     1.    the pain rating index     2.    number of words selected     3.    present pain index [Pain Management]     1.    treat the cause of pain, not just symptoms     2.    make accurate assessment of pain extent and type     3.    dose at regular specified intervals - especially with chronic pain     4.    integrate analgesia into a comprehensive patient management plan with a multidisciplinary approach     5.    Stepwise management: doses should be stepped up the 'analgesic ladder' as required for increasing pain or development of tolerance     6.    prevent side effects - especially w/ opioids. **Opioid analgesics** [Mechanism of action of opioids ] - at spinal cord level, stimulation of opioid receptors inhibits release of substance P from dorsal horn neurons, thus inhibiting efferent transmission - at supra-spinal levels, opioids activate opioid receptors widely distributed in the CNS, especially in the kombucha system, thalamus, hypothalamus and midbrain - *[Tolerance]* - opioid effects may be due to both a gradual loss of inhibitory functions and an increase in excitatory signalling. - *[Withdrawal effects]* - may be due to a rebound increase in cAMP formation activated via delta opioid receptors by chronic administration of opioid **Effects of opioids in the CNS**     ⁃    analgesia     ⁃    suppression of cough reflex     ⁃    suppression of respiratory centre in medulla (common cause of death from OD)     ⁃    sedation and sleep = narcotic analgesics     ⁃    Euphoria - contentedness     ⁃    dysphoria - hallucinations     ⁃    miosis - pupillary constriction     ⁃    nausea/vomiting     ⁃    hypotension and bradycardia     ⁃    significant analgesics and anti-inflammatory effects **Adverse Drug reactions**     ⁃    respiratory depression     ⁃    excessive sedation     ⁃    dysphoria     ⁃    constipation     ⁃    nausea/vomiting     ⁃    tolerance and dependence Cause of death - acute toxicity after an overdose of an opioid such as heroin is respiratory failure **Non-opioid analgesics- NSAIDS** common non-opioid drug is paracetamol NSAIDS - anti-inflammatory actions thus reduction of inflammation leads to analgesia. decreases risk of thrombosis effective for mild-moderate pain. allows reduction of opioid dosage when combined with opioid analgesics in patients with moderate pain. **Adjuvant Analgesics** [Tricyclic antidepressants] - useful for neuropathic pain and are combined with opioids for cancer-associated nerve pain. [Corticosteroids] - dexamethasone help relieve pain associated with inflammation and swelling [Psycho active drugs] - benzodiazepines, useful for sedating anti-anxiety and muscle relaxing properties. [Bisphosphanates] - useful for metastatic or osteoporotic bone pain Clonidine [Non-pharmacological analgesics techniques.]     ⁃    RICE     ⁃    physiotherapy/massage     ⁃    hydrotherapy     ⁃    Transcutaneous electrical nerve stimulation (TENS)     ⁃    Acupuncture - releases endorphins and enkephalins **STROKE - Cerebrovascular accident (CVA)**     ⁃    occurs as a direct result of impaired blood flow to the brain     ⁃   *[ Ischaemic stroke]* - because of vessel occlusion     ⁃  *[  hemorrhagic stroke]* - ruptured vessel     ⁃    primarily a disease of old age, can happen to anyone with these risk factors: hypertension and type 2 diabetes [Risk factors for stroke:]     ⁃    Age     ⁃    Gender     ⁃    family history of stroke     ⁃    Hypertension     ⁃    hyperlipidaemia     ⁃    diabetes     ⁃    cigarette smoking     ⁃    obesity     ⁃    poor diet     ⁃    drinking too much alcohol     ⁃    lack of exercise     ⁃    TIA and Atrial Fibrillation [Pathophysiology: Ischaemic stroke]     ⁃    when a blood clot blocks an artery to the brain = causes interruption of blood flow to the brain cells     ⁃    high cholesterol level causing a furring of the arteries with fatty deposits. [pathophysiology: hemorrhagic stroke ]     ⁃    occurs when a blood vessel in or around the brain bursts, causing bleeding and increased pressure in the skull resulting in compression and eventual ischaemia to brain tissue     ⁃    untreated hypertension is a common cause of this stroke [SIGNS OF STROKE ] Face Arms Speech Time [manifestation of stroke] - Depends on the artery obstructed or the area of the brain suffering from anoxia. - Different sites of obstruction create different occlusion syndromes and if the area is damage is unilateral (one side of the brain) then symptoms will typically only be seen on the contralateral (opposite) side of the body.  [Manifestations of stroke: ICH] - Headache with immediate lapse into an unresponsive state - Headache with consciousness maintained - Sudden lapse into unconsciousness - Immediate prognosis is grave but if the person survives -- recovery possible. [Intracerebral haemorrhage ] - Head trauma - Hypertension - Ruptured aneurysms - Bleeding into tumour - Bleeding disorders - Anticoagulation medications [Subarachnoid haemorrhage] - Blood escapes from defective or injured vasculature into the subarachnoid space - Often causes significant haematomas leading to increased intracranial pressure - Impairs the circulation of the CSF - Compresses and displaces brain tissue - Mortality is 50% at one-month post haemorrhage [Increased intracranial pressure] 3 main components occupy the cranial vault: 1. Blood 2. Cerebrospinal fluid 3. Brain tissue Skull does not allow for expansion because these components are in a fixed space, any increase in volume of one must be compensated by a decrease in the volume of the others. More volume squashed into the same confined space leads to increases in *[intracranial pressure ]* **SIGNS OF INCREASED ICP** **Transient ischaemic attacks (TIA)** Mini-stroke is a temporary interruption in blood flow to the brain that can result in numbness, temporary paralysis and impaired speech. Symptoms usually resolves within 24 hours, TIA is a warning of an impending and more serious cerebrovascular accident. [Evaluation] ABCD score predicting early risk of stroke after TIA A -- AGE: 60+ = 1 B -- Blood Pressure: 140/90+ = 1 C -- Clinical features: Unilateral weakness = 2, speech impairment without weakness = 1. D -- Duration: 60 mins + = 2, 10 -- 59 mins = 1 D -- Diabetes = 1 Pt history, CT Scan, MRI, angiography, lumbar puncture CT scan should be performed as soon as possible but at least within 24 hrs of symptoms commencing if the pt is at high risk of stroke. [Care and acute management] - Frequent monitoring of pt vital signs using ADDS score - Maintain BP and BGL - Ax neurological function regularly using GCS - Keeping the pt nil by mouth until an assessment of the swallowing reflex can be carried out - Undertaking a nutritional status ax - Preventing pressure sore formation - Protecting the patient from injury due to possible seizures, motor and visual deficits. [Treatment] All types = supportive, maintain cerebral perfusion Ischaemic = Thrombolysis, aspirin SAH = treat raised ICP, stop bleeding Non-pharmacological management - Carotid endarterectomy - Thrombectomy - Dietary plan lowers cholesterol levels - Smoking cessation and reduce alcohol intake - Regular monitor of BP and BGL. [Care and long-term management] - Physiotherapist - Occupational therapist - Speech pathologist - Dietitian - Social worker - Psychologist **SBI241 -- Week 5** **Myocardial Infarction -- Risk factors** +-----------------------------------+-----------------------------------+ | *[Conventional | *[Conventional | | non-modifiable]* | modifiable]* | +===================================+===================================+ | - Age | - Dyslipidaemia and | | | atherosclerosis promoting | | - Male or postmenopausal female | diet | | | | | - Family history | - Hypertension | | | | | | - Smoking | | | | | | - Diabetes mellitus and insulin | | | resistance | | | | | | - Obesity (abdominal) | | | | | | - Sedentary lifestyle | +-----------------------------------+-----------------------------------+ | Non-Traditional | | | | | | Inflammatory factors | | +-----------------------------------+-----------------------------------+ - Presence of some of the 5 risk factors of abdominal obesity, fasting glucose, HDLs, triglycerides and hypertension diagnostic of 'metabolic syndrome' predisposing to CVD - Abdominal obesity -- strongest link with coronary heart disease - Physical activity + weight loss = protective against it NOTE: statins are thought to be cardio-protective partly due to an anti-inflammatory effect.  **Angina** Pain or other sensation caused by myocardial ischemia. - Last for 3-5mins with no permanent damage. - Substernal from heaviness or pressure to severe pain - Radiates from neck to lower jaw, left arm, left shoulder. **Pathophysiology** 1. Narrowing of major coronary artery by greater than 50% ischaemia, especially exercise. 2. Atherosclerosis more common cause 3. Within 10 seconds of occlusion anaerobic respiration forms lactic acid 4. Falls are then viable for approximately 20-40mins **Angina types** *[Stable angina]* - Due to gradual luminal narrowing and hardening of vessel wall, reducing ability to dilate in response to increased myocardial demand during stress or exercise usually relieved on rest. *[Unstable angina]* - Usually a pre-myocardial infarction condition. Does NOT relieve on rest *[Prinzmetal's angina]* - Caused by vasospasm. Atherosclerosis may or may not be present occurs during sleep **Myocardial Infarction: Pathophysiology** *[Ischaemia continues]* = cell death. Attempt at repair: within 24 hrs leucocytes remove necrotic tissue. *[Haemodynamic changes]* - Ejection fraction decreases, EDV increases, venous pressures increase - Congestion occurs *[Granulation tissue then scar tissue form]* - 10-14 days the newly formed collagenous tissue is still weak and susceptible to injury - 6 weeks scar tissue is usually strong but lacks ability to contract or conduct impulses. **Myocardial infarction** - Usually pain like angina but more intense, may be 'silent' especially in elderly or those with diabetes - Peripheral vasoconstriction and diaphoresis indigestion common, nausea/vomiting may occur. - BP initially decreases, then SNS may temporarily increase BP & HR. - Abnormal heart sounds from ventricular dysfunction - Pericardial friction rub may occur from inflammation - Dullness in lung percussion and inspiratory crackles from pulmonary congestion may occur - Angiotensin II released and contributes to pathogenesis - Vasoconstriction - Fluid retention - Catecholamine release and coronary artery spasm - Myocyte growth and fibroblast formation of collagen, resulting in myocardial 'remodelling' **Evaluation for myocardial infarction** 1. Chest x-ray 2. Cardiac enzymes 3. ECG 4. Angiography 5. Echocardiography **ECG changes**  **Complications of Myocardial Infarction** 1. Arrhythmias 2. Death 3. Recurrent MI 4. Stroke 5. Heart failure **Myocardial Infarction management:** - Oxygen and aspirin, sublingual glyceryl nitrate and IV morphine - Admission to coronary care unit - May give ACE-inhibitors or beta blockers - Coronary artery bypass graft - Thrombolytics or percutaneous angioplasty (PTCA) and stenting Aim is to increase coronary perfusion and decrease myocardial workload and demand for oxygen - Decrease work of heart by decrease BP, HR, Contractility and end diastolic volume - Decrease blood clot formation - Address dyslipidaemia **Management of ACS -- acute coronary syndromes** *[Initial assessment of ACS]* should involve a 12-lead ECG with clinical interpretation within 10 mins of first presentation; care is guided by a suspected ACS assessment protocol; cardiac-specific troponin concentration is measured on presentation and at defined periods thereafter. *[Long term management recommendation]* if appropriate, dual antiplatelet therapy with aspirin (100-150mg/daily) and either [clopidogrel or ticagrelor] for 12 months irrespective of whether coronary revascularisation was performed. Highest tolerated dose of statin should be initiated and continued indefinitely. Lifestyle education, cardiac rehab programs and chest pain actions plans = long-term management strategy. **[HEART FAILURE]** Syndrome encompassing several different types of cardiac dysfunction that result in inadequate perfusion of tissues with oxygen and blood-born nutrients. Characterised by an underlying structural abnormality or cardiac dysfunction that impairs the ability of left ventricle (LV) to fill with or eject blood, particularly during physical activity. Symptoms of Congestive Heart Failure -- dyspnoea and fatigue can occur at rest or during physical activity. **Pathophysiology of Heart Failure** -- both ventricles can fail independently - Can be acute or chronic - Often associated with systolic and diastolic congestion and with myocardial weakness - Acute HF, sudden decrease in the amount of blood pumped out from both ventricles, reducing oxygen supply to the tissues. - Chronic HF, progression of the disease is gradual and early stages may have no symptoms of HF. - Right side of Heart fails = Right-sided heart failure (RSHF), causes peripheral congestion. - Left side of Heart fails = Left-sided heart failure (LSHF), causes pulmonary congestion. **Investigations for Heart Failure:** 1. ECG 2. Chest x-ray 3. Echocardiogram/Transesophageal echocardiogram. 4. Cardiac enzymes 5. Brain natriuretic peptide (BNP) or N-terminal pro-B-type natriuretic peptide (NT-proBNP) blood test. **Echocardiogram** - Commonly used to diagnose HF and determine the causation of HF. - Non-invasive procedure using ultrasound waves. - Provides a semi-quantitative assessment of left ventricular systolic and diastolic function. Valvular disorders can be usually be accurately delineated and pulmonary artery systolic pressure can be estimated. **TYPES OF HEART FAILURE** 1. Left heart failure -- congestive heart failure = systolic failure 2. Right heart failure = diastolic failure  **Clinical features of Right-sided heart failure** Poor ventricular contraction causes blood to "back-up' in *[systemic circulation. ]* 1. Peripheral oedema 2. Hepatosplenomegaly 3. Pleural Effusion 4. Ascites  **Clinical features of Left-sided heart failure** Poor ventricular contraction causes blood to 'back up' in the *[LUNGS]* 1. Pulmonary congestion and oedema 2. Cough 3. Dyspnoea/orthopnoea/PND **Pharmacological management** Ace inhibitors and beta blockers commenced at a low dose and then titrated until target dose is achieved or tolerated dose is reached. Blood pressure, pulse, urea and electrolytes are measure before and after starting ACE inhibitors and beta blockers and after each dose increment. Diuretic like Furosemide, used to decrease fluid load in patients with HF. Anticoagulant and anti-arrhythmia medication are used in patients with HF with arrhythmias (e.g. AF). **Non-pharmacological management** Moderate physical activity as the condition allows, weight reduction through physical activity and healthy eating to reduce BMI. Reduction of salt intake is essential as excessive intake can cause fluid retention and lead to an exacerbation of cardiac problems. Careful monitoring of fluid intake prevents fluid overload. Patients may be placed on fluid restriction as directed on their care plan. Daily weight monitoring with any sudden increase in weight is reported and documented. **Complications of Heart failure** 1. Renal failure 2. Hypokalaemia/hyperkalaemia 3. Hyponatraemia 4. Impaired liver function 5. Thromboembolism 6. Atrial and ventricular arrhythmias 7. Sudden death **SBI 241 -- Week 6** **Atherosclerosis and Hypertension** *[Vascular bed]* Blood vessels can dilate, constrict, pulsate and form a closed delivery system for the blood, which begins and ends at the heart. [STRUCTURE:] *[Blood vessels]*, except capillaries, are composed of three distinct layers: - [Tunica externa/tunica adventitia] -- Outer layer, largely composed of collagen fibres that protect and support the blood vessels and secure them to the surrounding tissues. Supplied with sympathetic nerve fibres and lymphatic vessels. - [Tunica media] -- middle layer, contains smooth muscle and elastic tissue. Sympathetic nervous system also innervates the smooth muscle layer and controls the diameter of the blood vessel. Constriction and dilation causes blood pressure to increase or decrease. - [Tunica interna] -- inner layer and lined with endothelium. Makes the inner surface smooth, thus minimising friction as blood flows through the vessel. *[Endothelium]*, lines all vessels and make up the main part of the capillary wall, has dynamic function: - Endothelium is involved in both coagulation and antithrombosis, as well as fibrinolysis, immune function, vasodilation or constriction, tissue growth and wound healing. - In particular, the endothelium is involved in a delicate balance between coagulation and anticoagulation as a result of the production of many chemical mediators. Some of this cause vasodilation, such as prostacyclin, nitric oxide and endothelium‐derived relaxing factor, and some cause vasoconstriction, such as endothelin, angiotensin II and thromboxane. - A healthy intact endothelium tends toward anticoagulation, but if damaged, the balance switches in favour of clot formation. This arrangement generally works well with clots forming where blood vessels are damaged, thus preventing blood loss and enabling the repair process to begin. *[Arteries]* -- thick walls and narrow lumen, responds to hormonal and neural signals. 3 groups are: 1. Elastic arteries 2. Muscular arteries 3. Arterioles *[Veins]* -- Thinner walls, contain fewer elastic and collagen fibres and less smooth muscles. Lumen is larger. *[Arteriosclerosis]* -- abnormal thickening and hardening of artery walls, lipids may be present. *[Atherosclerosis]* -- Form of arteriosclerosis with soft deposits of intra-arterial fat and other variations depending on the severity of condition. = Causes coronary heart disease and cerebrovascular disease. Risk factors: - Hypertension - Obesity - Smoking - Alcohol - Diabetes - Male gender **Pathophysiology of Atherosclerosis** *[Endothelial injury]* Endothelium becomes inflamed Smooth muscle cell and collagen migrate over the fatty streak = forms a fibrous plaque. - inflammatory cells → further inflammation → more endothelial damage - macrophages become foam cells and form fatty streaks - endothelium changes → platelet aggregation and vasoconstriction →decreased blood flow The fibrous plaque now formed may calcify, protrude into the lumen, obstruct blood flow, and become an 'unstable' plaque. An unstable plaque is prone to rupture and thus become a 'complicated' plaque. After rupture platelet adhesion occurs and tissue clotting factors are also released. A thrombus rapidly forms and may cause complete blockage of the vessel. **Clinical manifestations of atherosclerosis** [Partial obstruction] = transient ischaemic events, stress or exercise. [Further obstruction] = Infarction with manifestations depend on the vessels involved e.g. [coronary and cerebral vessels] = heart attack and stroke. [Peripheral artery obstruction] = associated with pain and disability especially lower limbs. **Management of atherosclerosis** Modification of lifestyle factors + Control of diabetes and HT + improvement of serum lipids + aspirin may be indicated. [Dyslipidaemia] metabolic disorder characterised by increased concentrations of plasma cholesterol and triglycerides. Primary lipoproteins found in blood of fasting individuals = VLDL, LDL (bad) and HDL (good). **Deep Vein Thrombosis (DVT)** [Thrombus] - develop in the superficial or deep veins of the legs. The blood flow is sluggish in the affected vessels, and the clotting cascade takes place. Triggers the inflammatory response, causing tenderness, swelling and erythema at the affected site. Thrombus can become loose and travel through the circulation as an *[embolus]*, may travel to the lungs causing = pulmonary embolism. [Hypertension] -- repeated measurements of over 140/90 [Secondary h]ypertension is caused by: Kidney disease, endocrine imbalance [Malignant hypertension] -- Occurs in younger groups with renal and collagen disease [Isolated systolic hypertension] -- occurs when combination of factors is seen in the elderly and is due to the increase in cardiac output, increased peripheral resistance and renal vascular resistance. [Risk factors for hypertension:] - family history - age and gender - abdominal obesity - Alcohol intake - Glucose intolerance - High sodium intake - Sedentary lifestyle - Low potassium, calcium and magnesium intake. [Clinical Manifestations of hypertension:] Considered as a silent condition, early on. Symptoms arise due to associated damage of organs as well as vascular changes: - Heart disease - Renal insufficiency - Brain dysfunction - Impaired vision - Impaired mobility - Vascular occlusion and oedema [Chronic hypertension leads to:] 1. Vascular remodelling 2. Renal changes 3. Cardiac hypertrophy These causes increased risk of, Myocardial infarction, kidney disease and stroke. [Evaluation of hypertension] 1. Repeated high BP measurement 2. History and physical examination 3. Blood analysis - Na+, K+, Cl-, HCO3- - Urea, creatinine, uric acid - Haemoglobin - Fasting glucose - Total cholesterol, LDL, HDL 4. ECG Hypertension: Management  **SBI241 -- Week 7** **Respiratory Failure** alveolar ventilation in not sufficient to maintain normal arterial blood gases. Oxygen Saturation (Sp02) = The majority of oxygen (around 98%) is attached to haemoglobin (Hb). A pulse oximeter can gauge what percentage of haemoglobin is carrying oxygen. **Causes of respiratory failure** *[Acute]* -- life-threatening derangements in arterial blood gases and acid-base status *[Chronic]* -- less dramatic as it is not readily apparent. pH may not be low because of [renal compensation. ] Type 1 -- where pO2 is low (hypoxaemia) and pcO2 is normal or low Type 2 -- where pO2 is low and pC02 is high (hypercapnia) **DISORDERS OF THE PULMONARY SYSTEM** +-----------------------------------+-----------------------------------+ | **Obstructive airway diseases** | **Restrictive airway diseases** | +===================================+===================================+ | - Asthma | - ARDS (adult respiratory | | | distress syndrome) | | - COPD = Chronic bronchitis and | | | Emphysema | - Idiopathic Pulmonary Fibrosis | | | | | - Cystic Fibrosis | - Interstitial Lung Disease. | | | | | - Bronchiectasis | | +-----------------------------------+-----------------------------------+ **Obstructive Airway Diseases** Involves a degree of obstruction to air flow. *[Asthma and COPD]* -- the obstruction to airflow is associated with narrow airways and increased airflow resistance. Resistance increase, more gas molecules collide = causing wheeze sound. *[Spirometry]* measures the force and volume of a maximum expiration after a full inspiration. - The volume of air that can be forced out is referred to as the forced vital capacity (FVC), and the volume that can be exhaled in the first second of expiration is the forced expiratory volume (FEV1). Indication = severity of obstruction, less than 80% is obstructed. *[Peak expiratory flow rate]* measures the force of expiration in litres per minute. It measures the patient's maximum expiratory flow rate via their mouth. Quick and simple assessment of the airways. Effort is dependent. **Asthma** Caused by different things varying between people and characterised by chronic airway inflammation. defined by the history of respiratory symptoms such as wheeze, shortness of breath, chest tightness and cough that vary over time and in intensity, together with variable expiratory airflow limitation. *[Epidemiology]* There are large variations in the incidence and prevalence of asthma according to geographical regions. *[Aetiology]* Family predisposition - Many genes have been identified that may play a role in susceptibility and pathogenesis of asthma. Triggers -- substances or situation. [Extrinsic asthma] - airway inflammation is a consequence of hypersensitive reactions associated with an allergen, that is, pollen, dust mites or food. [Intrinsic asthma] - linked to hyper‐responsive reactions to other forms of stimuli; for example, infection, sudden exposure to cold, exercise, stress or cigarette smoke. **Pathophysiology of asthma**  - airways respond in an abnormal, exaggerated way to inflammatory mediators, such as an allergen or irritants or triggers like pollution, exercise, cold air or respiratory infection (bacterial or viral). - [Histamine, interleukins, prostaglandins, leukotrienes and nitric oxide. ] *[Clinical presentation]* - Bronchoconstriction - Expiratory wheezing - Dyspnoea - Cough - Prolonged expiration - Tachycardia - Tachypnoea - Severe episodes involve some hypoxaemia the accessory muscles of ventilation and wheezing is heard during both inspiration and expiration. *[Management of Asthma]* - Allergen or irritant -- stimuli should be minimised - Most drugs target various chemical mediators and pathways involved in asthma pathogenesis. - Effective asthma management requires patient education and awareness. - *[Relivers]* - salbutamol or terbutaline (short-acting β2-agonist) and ipratropium bromide (anti-muscarinic antagonist). - *[Controllers]* - salmeterol and eformoterol, both long-acting β2-agonist drugs. - *[Preventers]* - inhaled corticosteroids (e.g. fluticasone propionate), leukotriene-receptor antagonists (montelukast) and cromones (cromoglycate and nedocromil). **COPD -- Chronic Obstructive Pulmonary disease** progressive chronic disease characterised by irreversible obstruction of the airways. Characterised by persistent respiratory symptoms and airflow limitation, which is due to airway or alveolar abnormalities, that are usually caused by significant exposure to noxious particles or gases, with the most common cause being cigarette smoking. **Pathophysiology** characterised pathophysiologically by emphysema, chronic bronchitis or commonly the coexistence of both. *[Immunological processes:]* - Neutrophils, macrophages and CD8+ T-lymphocytes play a major role in the airway inflammation and lung damage. - Proinflammatory cytokines such as IL-6, IL-8, IL-1β and tumour necrosis factor alpha (TNF-α) are also released in the COPD airway. - Eosinophilic airway inflammation occurs in approximately 30% of individuals with the disease. *[Chronic bronchitis]* - The inflammation, swelling, and mucus frequently and significantly inhibit the airflow to and from the lung alveoli by narrowing and partially obstructing the bronchi and bronchioles. defined as hypersecretion of mucus and chronic productive cough for at least 3 months of the year (usually the winter months) for at least 2 consecutive years. caused by cigarette smoking and by exposure to inhaled noxious particles. It differs from episodes of acute bronchitis, which are usually caused by infection and are reversible, whereas chronic bronchitis is an irreversible condition of progressive decline. *[Emphysema]* - A few patients with emphysema are deficient in α1-antitrypsin, which inhibits the elastase. abnormal permanent enlargement of gas-exchange airways accompanied by destruction of alveolar walls. Obstruction results from changes in lung tissues, rather than mucus production and inflammation as in chronic bronchitis. major mechanism of airflow limitation is loss of elastic recoil. *[Cause]* - cigarette smoking, although air pollution and childhood respiratory infections are contributing factors. *[Management of COPD]* - reduce the risk of exacerbation and minimise symptoms. - Cessation of smoking. - Short-acting bronchodilators. - Influenza vaccinations. - Inhaled glucocorticoids and long-term oxygen therapy are recommended as severity, symptoms and exacerbation frequency increase. - Pulmonary rehabilitation is recommended for severe cases. - Watch out for pulmonary infections (pneumonia)! **SBI241 -- Week 8** **PEPTIC ULCER DISEASE**\ *[Gastric Ulcer]* - The ability of the gastric mucosa to protect and repair itself seems to be defective; *[Duodenal ulcer]* - in duodenal ulcers, hypersecretion of acid and pepsin is responsible for the erosion of the duodenal mucosa. *[Gastric juice]* - comprised of pepsin, hydrochloric acid, mucus and intrinsic factor. major stimulant to gastric acid secretion is [protein]. - prostaglandins E2 and I2 inhibit acid secretion - [hormone gastrin + the neurotransmitter acetylcholine + the local hormone histamine] = directly stimulate acid secretion by parietal cells. **Gastritis** -- Inflammatory disorder of the gastric mucosa 1. *[acute gastritis]* -- Caused by chemical injury e.g. NSAIDs, corticosteroids, iron tablets, alcohol, corrosive substances. Ischaemia physical stress like burns, shock, trauma. Initial response to H. pylori infection, HSV or CMV. Pathological features: - Surface epithelial degeneration - Regenerative hyperplasia of pit-lining epithelium - Vasodilatation/congestion - Neutrophil response 2. *[chronic gastritis]* - Chronic fundal gastritis - Chronic antral gastritis **Helicobacter-associated gastritis** - gram negative rod & bind to epithelium Survives the acidic environment as it is associated with intestinal metaplasia, causes risk of developing gastric adenocarcinoma *[Gram negative organism]* Buffering mechanism: urease and ammonia H. pylori virulence factors: - Motility - Ammonia production and adhesion - Toxins (local tissue damage) Acute inflammatory response: polymorphs, chemokines, ROS Glandular loss Diagnosis: - Urea breath test - Gastric biopsy: Histology, PCR or Serology - Culture -- uncommon Complications: - Peptic ulcer - Dysplasia - Intestinal metaplasia \*\*It is a spiral (helical)-shaped organism that has evolved to inhabit the highly acidic environment of the stomach, particularly the pylorus.\*\* - The bacterium adheres to the gastric epithelial cells, it breaks down endogenous urea, creating a protective cloud of ammonia and bicarbonate that enables it to protect itself against the effects of gastric acid. - The ability of the bacterium to degrade urea and release carbon dioxide forms the basis of the H. pylori breath test, which is used to detect infestation and also to monitor the effectiveness of drug-mediated eradication. **Peptic ulcer** A break or ulceration in the protective mucosal lining of the lower oesophagus, stomach or duodenum. *[ACUTE & CHRONIC ulcers]* Superficial - Erosions Deep - True ulcers *[Loss of balance between:]* +-----------------------------------+-----------------------------------+ | *[Aggressive factors | *[Defensive | | ]* | mechanism]* | +===================================+===================================+ | - NSAIDs | - Tight intercellular junctions | | | | | - H. Pylori infection | - Mucus | | | | | - Alcohol | - Mucosal blood flow | | | | | - Bile salts | - Epithelial renewal | | | | | - Acid | - Bicarbonate secretion | | | | | - Pepsin | | +-----------------------------------+-----------------------------------+ *[Morphology:]* - Clear-cut edges that overhang the base - Base: necrotic tissue and PMNs, granulation tissue, fibrous tissue ◦ Arteries within fibrous base can be obliterated - If muscularis propria replaced by fibrous tissue→ shrinkage of tissue (cicatrisation)→ deformities.  **Duodenal ulcer** Most common of the peptic ulcers *[Developmental factors: ]* - Helicobacter pylori infection toxins and enzymes that promote inflammation and ulceration - Hypersecretion of stomach acid and pepsin - Use of NSAIDs - High gastrin levels - Acid production by cigarette smoking **Gastric ulcer** tend to develop in the antral region of the stomach, adjacent to the acid-secreting mucosa of the body *[Pathophysiology:]* The primary defect is an increased mucosal permeability to hydrogen ions Gastric secretion tends to be normal or less than normal. *[Drugs that neutralise or inhibit acid secretion]* 1. Antacids 2. Cytoprotective agents 3. Proton pump inhibitors 4. H2-receptor antagonist **Helicobacter pylori treatment regimens** Helicobacter pylori causes chronic active gastritis, is associated with the development of gastric and duodenal ulcers, and is a recognised risk factor in the development of gastric carcinoma. Eradication of H. pylori is considered first-line treatment because it vastly improves the odds of non-recurrence of the ulcer. **INFLAMMATORY BOWEL DISEASE** 1. Crohn's disease 2. Ulcerative colitis *[Pathogenesis:]* inappropriate mucosal immune activation *[Contributing factors:]* genetics, epithelial defects and microbiota *[Clinical features: ]* - Diarrhoea - Fever - Abdominal pain - Bloody stool - Weight loss *[Diagnosis]* - Colonoscopy - Biopsy **Ulcerative colitis** -- Chronic relapsing inflammatory disease. Unkown aetiology Chronic inflammatory disease that causes ulceration of the colonic mucosa. - Sigmoid colon and rectum. *[Morphology]* - Diffuse superficial inflammation (mucosa & submucosa) - Shallow ulcers - Crypt abscesses - Crypt atrophy - Psuedopolyps *[Symptoms]* - Diarrhoea 10-20 days, blood stools and cramping *[Treatment]* - Broad-spectrum antibiotics and steroids - Immunosuppressive agents - Surgery *[Complications:]* - Haemorrhage - Electrolyte disturbances - Toxic megacolon - Extra-GI involvement: - Skin pigmentation, pyoderma - Liver-fatty change, cirrhosis - Eye-iritis, uveitis - Joint-arthritis, ankylosing spondylitis, arthralgia \*\*INCREASED COLON CANCER RISK **Crohn's Disease** -- causes 'skip lesions' Unknown aetiology Mouth to rectum distribution, common in small intestine - Granulomatous colitis, ileocolitis or regional enteritis - Idiopathic inflammatory disorder; affects any part of the digestive tract, from mouth to anus - Difficult to differentiate from ulcerative colitis - Ulcerations can produce longitudinal and transverse inflammatory fissures that extend into the lymphatics - Anaemia may result from malabsorption of vitamin B12 and folic acid - Can cause transmural inflammation = fistula formation -- can form between loops of bowel, bladder and skin. Treatment is similar to ulcerative colitis *[Morphology]* - Skip lesions - Cobblestones appearance of mucosa-oedema and deep fissures - Thickened bowel wall obstruction (transmural inflammation) *[Complications:]* - Malabsorption - Fistula formation - Perforation - Toxic megacolon - Adenocarcinoma (very rare)  **Drug therapy for IBD** Current therapy for these conditions: - *[Corticosteroid]* prednisolone and budesonide - *[5-aminosalicylates (5-ASA)]* balsalazide, mesalazine, olsalazine and sulfasalazine - *[Immuno-suppressants]* azathioprine, mercaptopurine and methotrexate Crohn\'s disease is an indication for the use of the TNF-α antagonists adalimumab and infliximab. **SBI241 -- Week 9** **Diabetes Mellitus** - a group of disorders with abnormal glucose metabolism in common. characterised by chronic hyperglycaemia and other disturbances of carbohydrate, protein and fat metabolism. While diabetes indicates an increased urine output, mellitus is Latin for honey --- hence the urine is sweet (contains glucose) and copious. [3 main categories of diabetes mellitus] 1. *[Type 1]* -- absolute insulin deficiency 2. *[Type 2]* -- insulin resistance with an insulin secretory deficit 3. *[Gestational diabetes]* **Type 1 Diabetes Mellitus** results from autoimmune destruction of beta (β) cells in the islets of Langerhans. This is thought to be the result of a gene--environment interaction, with the strongest genetic risk markers in the human leucocyte antigen (HLA) region of chromosome 6. Genetic factors may increase susceptibility to environmental causes of diabetes. Before hyperglycaemia occurs, 80--90% of the insulin-secreting beta cells of the islets of Langerhans must be destroyed. This is because the remaining cells can increase their production of insulin to compensate, but with so few beta cells remaining, insulin production is no longer adequate. With a lack of insulin, there is a relative excess of glucagon (produced by alpha cells). **[Hyperglycaemia]** and **[ketonemia]** can result from insulin deficiency alone, but a relative excess of glucagon clearly facilitates the metabolic alterations seen in diabetes. [Clinical manifestations] 1. Polyphagia -- excessive eating 2. Polydipsia -- excess thirst 3. Polyuria -- excess urination *[Evaluation and treatment]* [polydipsia, polyuria, polyphagia, weight loss and hyperglycaemia] (usually determined by a glucometer) are present in fasting and postprandial states. [Management] requires individual planning according to type of disease, age and activity level, but all individuals require some combination of: - Insulin - meal planning - exercise.  **Type 2 Diabetes Mellitus** *[Diagnosis]* Generally, two abnormal test results that demonstrate hyperglycaemia are required to make the diagnosis of diabetes: - either two fasting venous blood glucose levels of equal to or over 7.0 mmol/L, or two random venous blood glucose levels of equal to or over 11.1 mmol/L. The diagnosis can also be made with just one abnormal fasting or random blood glucose level if symptoms of hyperglycaemia are present. A plasma fasting blood glucose level of less than 6.1 mmol/L indicates diabetes is unlikely. Diabetes can also be indicated by the presence of glucose in the urine (glycosuria), but this should be confirmed using blood tests. *[Oral Glucose Tolerance Test]* Requires overnight fasting followed by consumption of a glucose drink which contains 75 grams of glucose; blood glucose levels are monitored after fasting and then again 2 hours after glucose ingestion. [Result:] If the person does not have diabetes, the blood glucose level will rise as the glucose drink is absorbed into the bloodstream, but should then decrease to below 7.8 mmol/L after 2 hours. In a person with diabetes, the fasting blood glucose level is raised, and the blood glucose level remains over 11.1 mmol/L after 2 hours. **Pre-Diabetes** A condition in which glucose homeostasis is between the normal level of control and that seen with diabetes. *[Impaired fasting glucose]* - the fasting blood glucose level is raised, but the response to the oral glucose tolerance test appears normal. *[Impaired glucose tolerance]* - the fasting blood glucose level is normal, and there is a hyperglycaemic response to the oral glucose tolerance test, but to a lesser extent than seen with diabetes. Pre-diabetes should be considered as a warning that type 2 diabetes is developing and modifiable lifestyle factors should be changed. **Pathophysiology** *[Insulin Deficiency]* -- shortage of insulin *[Insulin resistance]* -- Ineffective response to insulin at the target cells. Obesity - insulin is less able to facilitate the entry of glucose into the liver, skeletal muscles and adipose tissue. Excessive energy intake predisposes an individual to type 2 diabetes by contributing to obesity. **Monitoring Blood Glucose Control** *[Glucometer]* - allows patients to monitor the effectiveness of their lifestyle measures and diabetes medications. *[HbA1c]* Measuring glycated haemoglobin (HbA1c) is used as a general indication of glycaemia over recent weeks. - Glucose molecules bind to haemoglobin, to form glycated haemoglobin - this is an irreversible reaction, so once the glucose is bound, it remains attached. A build-up of glycated Hb within the red cells reflects the average level of glucose to which the cells have been exposed during their 120-day life. **Complications** +-----------------------------------+-----------------------------------+ | **ACUTE** | **CHRONIC** | +===================================+===================================+ | - Hypoglycaemia | - Neuropathy | | | | | - Diabetic ketoacidosis | - Nephropathy | | | | | - Hyperglycaemic hyperosmolar | - Retinopathy | | state | | +-----------------------------------+-----------------------------------+ **Hypoglycaemic shock** Excess insulin, beyond what is required, leads to hypoglycaemia, which can result in severe activation of sympathetic nervous system responses. If the liver can produce sufficient glucose through gluconeogenesis, then the blood glucose can return to normal. However, if the hypoglycaemia becomes too low, without sufficient glucose to balance, this can lead to severe neuronal dysfunction, which may lead to coma and death.  **Diabetic ketoacidosis** The inability of glucose to enter cells can lead to usage of lipids as cell fuel instead of glucose. As a result, ketone bodies are formed, which are highly acidic, and can lead to ketoacidosis. The severe lack of glucose in cells can also lead to production of glucose, which can occur by both glycogenolysis --- breakdown of glycogen stores into glucose, and by gluconeogenesis --- creation of glucose from non-glucose sources. This may lead to hyperglycaemia, which causes glycosuria and polyuria, with the dehydration contributing to acidosis. **Hyperglycaemic hyperosmolar state** Hyperglycaemic hyperosmolar state or HHS is an uncommon but significant complication of type 2 diabetes with a high overall mortality of approximately 15%. The hyperglycaemic hyperosmolar state, there is sufficient insulin to prevent breakdown of fat stores for production of glucose and therefore ketoacidosis is avoided. HHS is a medical emergency, as it can lead to drowsiness, stupor, coma and death. Treatment mandates aggressive fluid and electrolyte resuscitation and strict control of serum glucose level. **Chronic complications** **[Cardiovascular disease]** *[Dyslipidaemia]* - relates to the development of atherosclerosis. Elevated triglycerides and low-density lipoprotein (LDL) cholesterol are more prevalent in those with diabetes than those without the condition. *[High density lipoprotein]* - tends to protect vessels, is present in only low concentrations in individuals with diabetes compared with the general population. This overall lipid profile is more atherogenic in those with diabetes. The presence of other risk factors, including [hypertension,] increases vulnerability to [atherosclerosis].  **Thyroid Dysfunction** *[Hyperthyroidism]* It is a condition where thyroid hormone levels are higher than normal. When these high levels result in a hypermetabolic state, this is known as [thyrotoxicosis]. All forms of thyrotoxicosis share common physiological effects on the individual that are caused by the high thyroid hormone level. These effects are the result of an increase in adrenergic stimulation and increased metabolic effects: - Tachycardia - Palpitations - Nervousness - Insomnia - Heat tolerance - Moist skin - Tremor - Increased systolic blood pressure *[Grave's Disease]* - is the most common cause of hyperthyroidism. It is an *[autoimmune]* condition.  **Clinical Manifestations** All signs and symptoms of thyrotoxicosis; plus Immunological stimulation causes several physiological changes unique to *[Graves\' disease:]* - TSH receptor antibodies stimulate thyroid cells, increasing gland size and vascularity. - TSH receptors are found on tissue within the orbit. This causes enlargement of the ocular muscles, and results in eyeball protrusion, paralysis of extraocular muscles and damage to the retina and optic nerve which can lead to blindness. These changes result in exophthalmos (protrusion of the eyeball), periorbital oedema and extraocular muscle weakness leading to diplopia (double vision). **Diagnosis** Thyroid hormone is measured as the hormones that are not protein bound, namely free thyroxine (T4) and free triiodothyronine (T3). In primary hyperthyroidism (which is the most common form of hyperthyroidism) thyroid hormone levels are raised and as a result TSH will decrease. **Treatment** Treatment needs to consider two issues: 1. achieve symptom control 2. reduce thyroid hormone levels where possible. To reduce thyroid hormone, antithyroid medication is commonly the first- line therapy: *[Carbimazole and propylthiouracil (PTU]*) interfere with thyroid hormone production and secretion from the thyroid cells. Both medications can cause liver disturbances and monitoring of liver function is essential Could cause agranulocytosis, patients are to immediately report sore throats, mouth ulcers and other signs of infection [Radioactive iodine therapy or surgery may be required.] Thyroidectomy when performed by experienced thyroid surgeons carries a small risk of permanent hypoparathyroidism of \< 2% and recurrent laryngeal nerve damage of \< 1%. Current treatment for Graves\' disease does not reverse the ocular changes. Corticosteroids and surgical intervention may be required in severe cases. *[Thyrotoxic crisis]* rare but dangerous worsening of the thyrotoxic state, in which death occurs within 48 hours without treatment. usually occurs in individuals who have undiagnosed or partially treated Graves\' disease. *[The systemic symptoms of thyrotoxic crisis include: ]* - hyperthermia - tachycardia - high-output heart failure - agitation or delirium - nausea, vomiting - diarrhoea contributing to fluid volume depletion **Hypothyroidism** *[Primary causes ]* 1. congenital defects 2. defective hormone production resulting from autoimmune thyroiditis, iodine deficiency or antithyroid drugs 3. Inadvertent loss of thyroid tissue after surgical or radioactive treatment for hyperthyroidism. 4. Causes of secondary hypothyroidism are related to either pituitary or hypothalamic failure **Clinical manifestations -- affects all body systems** The decrease in thyroid hormone lowers energy metabolism, heat production and delays neuromuscular processes within the body. The individual develops a low basal metabolic rate, cold intolerance, lethargy, tiredness, constipation, thinning brittle hair and slightly lowered basal body temperature. The decrease in thyroid hormone leads to excessive TSH production and goitre.  **Evaluation and Treatment** The clinical symptoms of hypothyroidism, a decrease in serum-free T4 is nearly always present. TSH concentration increases because of loss of negative feedback from thyroid hormone. [Hormone replacement therapy] is the treatment of choice. Therapy may be increased gradually over months to avoid precipitating acute cardiac events in the elderly. Thyroxine needs to be taken separately from food, vitamins and mineral supplements to ensure adequate absorption. **SBI241 -- Week 10** **Spread of infection** - Direct - Droplet - Indirect - Airborne/aerosol - Vector-dependant - Faecal-oral *[Process of infection ]* Colonisation Infection Spread *[Factors for infection]* - Mechanism of action - Infectivity - Pathogenicity - Virulence - Immunogenicity - Toxigenicity  **Classes of infectious microorganisms** - Viruses - Bacteria - Fungi - Protozoa - Rickettsiae, chlamydiae and mycoplasmas - Helminths **Bacteria** *[Gram staining]* -- provides useful information on which antibiotics to choose A staining procedure in which a dye colours all bacteria a deep purple. Alcohol is applied and this washes off the purple colour from some bacteria, while others retain the purple colour. Finally, a red counter stain is applied which colours gram-negative bacteria (that did not retain the purple dye) red. - *[Gram-positive --]* have a thick layer of peptidoglycan, found in the cell walls of bacteria. - *[Gram-negative --]* have only a thin peptidoglycan layer and have an additional outer membrane outside the cell wall  **Bacterial toxins** **EXOTOXINS** - Enzymes released during bacterial growth - *[Examples:]* cytotoxins, neurotoxins, pneumotoxins, enterotoxins and haemolysins - Damage cell membranes, inhibit protein synthesis - Immunogenic: antitoxin production **ENDOTOXINS** - Lipopolysaccharides from outer membrane of dead gram- negatives, released during cell lysis or destruction of the bacteria - Pyrogenic effects, septic shock **Bacteraemia or Septicaemia** - the presence of microorganisms in the blood, while bacteraemia is the presence of bacteria in the blood as a result of a failure of the body's defense mechanisms. *[Symptoms of gram-negative]* septic shock are produced by the release of endotoxins: release of vasoactive peptides and cytokines that affect blood vessels, producing vasodilation, which reduces blood pressure, causes decreased oxygen delivery and produces septic shock. While the mechanisms are somewhat different, the symptoms of gram- positive shock are similar. **Viruses** **Viral infection and injury** - Obligate intracellular parasites - Dependent on host cells - No metabolism or incapable of independent reproduction - Permissive host cell - Virion binds to receptors on the plasma membrane - Usually a self-limiting infection - Spreads cell to cell *[Viral Replication]* - DNA or RNA - Single or double stranded - Protein receptor-binding site - Virus uncoats - Most RNA viruses directly produce mRNA - Viral DNA enters nucleus and is transcribed into mRNA Infection with a virus begins with a virion binding to a specific receptor on the cell membrane of a host cell. The virus then changes the activity of the host cell such that viral replication occurs. *[The clinical symptoms]* will reflect the alteration of the function of the infected cells --- for example, the influenza virus binds to a receptor on respiratory epithelial cells, causing symptoms of an upper respiratory tract infection.  *[Cellular effects of viruses]* - Inhibition of host cell DNA, RNA or protein synthesis - Disruption of lysosomal membranes - Promotion of apoptosis - Fusion of infected, adjacent host cells - Alteration of antigenic properties of host cells - Transformation of host cells into cancerous cells - Promotion of secondary bacterial infections **Fungi** **Fungal infection and injury** Large eukaryotic microorganisms with thick cell walls (do not contain peptidoglycan) Exist as single-celled yeasts, multi- celled moulds, or both (dimorphic) *[Pathogenicity:]* - Adapt to host environment Wide temperature variations, digest keratin, low oxygen - Suppress the immune defences Diseases caused by fungi are called mycoses - Superficial, deep or opportunistic - Fungi that invade the skin, hair or nails are known as dermatophytes ▪ The diseases they produce are called tineas (ringworm) Tinea capitis, tinea pedis and tinea cruris Deep fungal infections are life threatening and are commonly opportunistic. *[Laboratory Diagnosis and infection control]* *[Detection of microorganisms]* *[Prevention]* - Good hygiene - Washing hands - Isolation and quarantine **Vaccines** Induction of long-lasting protective immune responses that will not result in disease in a healthy recipient. Vaccines could be either - Attenuated organism - Killed/inactive organism - Extracts of antigens - Toxins *[Treatment]* - Antimicrobials - Antivirals - Antibacterial - Fungicidal drugs - Antiparasitic drugs  **Antibacterial drugs** - Inhibit synthesis of cell wall - Inhibit synthesis of nucleic acids - Inhibit protein synthesis - Modify metabolism - Can be bacteriostatic or bactericidal *[Antimicrobial resistance]* - Inactivation of the drug - Reduced membrane permeability - Alteration of the drug target - Active efflux of the antimicrobial drug - Transfer of resistance genes between bacteria - Exacerbated by: overuse of antimicrobials failure to take full course *[Healthcare-acquired infections]* - acquired by individuals during a stay in a healthcare setting, and in some cases may not become apparent until months after discharge from hospital. - Endogenous flora - Exogenous source *[Most common sites]* - UTIs, surgical wound infections, IV cannulas **Urinary tract infections** an inflammation of the urinary epithelium usually caused by bacteria from gut flora. Can occur anywhere along the urinary tract including the urethra, prostate, bladder, ureter or kidney. *[Most common pathogens:]* - Escherichia coli - Staphylococcus saprophyticus *[Many people are at risk of developing a UTI:]* - premature newborns, - pre-pubertal children, - sexually active and pregnant women, - women treated with antibiotics that disrupt vaginal flora, - oestrogen-deficient postmenopausal women, - individuals with indwelling catheters, - and those with diabetes mellitus, neurogenic bladder or urinary tract obstruction. *[Cystitis]* is more common in women because of the shorter urethra and the closeness of the urethra to the anus (increasing the possibility of bacterial contamination from the intestines). UTI may occur alone or in association with pyelonephritis, prostatitis or kidney stones. **Acute Cystitis** -- inflammation of the bladder *[Manifestations:]* - frequency - dysuria - urgency - lower abdominal and/or suprapubic pain *[Treatment]* - antimicrobial therapy - increased fluid intake - avoidance of bladder irritants - urinary analgesics *[Urine cultures and susceptibility not mandatory except in the following groups:]* - pregnant women - aged-care facility residents - patients who have recently taken antibiotics or have failed treatment patients who have recurrent infection - patients who have travelled internationally within the past 6 months. **Pyelonephritis** *[Acute pyelonephritis]* - Acute infection of the renal pelvic interstitium - Vesicoureteral reflux - kidney stones - E. coli, Proteus, Pseudomonas *[Empirical therapy:]* Gentamicin PLUS amoxy/ampicillin Penicillin hypersensitivity: gentamicin only Gentamicin contraindicated: ceftriaxone OR cefotaxime Higher doses required in critically ill patients - Targeted therapy - Convert to oral therapy early - Total duration of therapy (IV + oral) is 10-14 days - Repeat C/S 1-2 weeks after treatment *[Chronic pyelonephritis]* - Persistent or recurring episodes of acute pyelonephritis that leads to scarring - Risk of chronic pyelonephritis increases in individuals with renal infections and some type of obstructive pathological condition (Vesicoureteral reflux and kidney stones). **Recurrent Urinary Tract Infections -- Adults** *[Recurrence:]* - Relapsed infection (same organism) - Re-infection Early recurrence (within 2 weeks) is usually regarded as relapse rather than reinfection Investigate for functional or anatomical abnormalities Empirical Treatment: - Amoxycillin + clavulanate OR cephalexin OR trimethoprim Resistance or Pseudomonas aeruginosa- ciprofloxacin OR norfloxacin **Urinary tract infections -- Children** - May be associated with anatomical abnormalities - All require urine C/S - Acute pyelonephritis common in children but difficult to distinguish from cystitis in young children **Prevention of CAUTI (Catheter-associated UTI)** - Limit use of catheters - Insert using aseptic technique - Ensure flow of urine - Maintain closed drainage - Catheter care - Remove the catheter ASAP - Suprapubic catheters preferred for long term usage - Antimicrobial-coated urinary catheters don't work! - Routine prophylactic antibiotics at placement don't work! - Addition of antimicrobials or antiseptics to drainage bag not recommended **Pneumonia** **Lower Respiratory Tract Infections** **Tuberculosis** - Mycobacterium tuberculosis (acid-fast bacillus) - Airborne transmission - Tubercle formation - Caseous necrosis - Positive tuberculin skin test (PPD) - In 2011 there were 1.4 million deaths worldwide - TB can be successfully treated on an outpatient basis with a 6‐month course of a combination of antibiotics **Pneumonia** - infection of the alveoli and small airways - Inflammation and oedema cause the alveoli to fill with debris and exudate - Consolidation in the alveoli disturbs gas exchange in the alveoli; as a result, the patient may become hypoxaemic and breathless - Pneumonia can also have a non-infectious cause and develop secondary to aspiration of irritating substances Infection of the lower respiratory tract caused by bacteria, viruses, fungi, protozoa or parasites. - *[Risk factors]* for pneumonia include advanced age, individuals who are immunocompromised, underlying lung disease, alcoholism, altered consciousness, smoking, malnutrition and immobilisation. The causative microorganism influences how the individual presents clinically, how the pneumonia should be treated and the prognosis. Hospital acquired pneumonia have higher mortality rate than community-acquired pneumonia **Causes of pneumonia**  The most common community-acquired pneumonias are caused by bacteria, particularly those caused by Streptococcus pneumoniae (also known as the pneumococcus), which has a relatively high mortality rate in the elderly. - Mycoplasma pneumoniae is a common cause of pneumonia in young people living in close contact, such as in dormitories. - Influenza is the most common viral community-acquired pneumonia in adults and children; respiratory syncytial virus and parainfluenza virus are common aetiological microorganisms. **Bacteria** *[Streptococcus Pneumoniae]* - gram-positive coccus; the cocci are usually arranged in pairs (diplococci). In a large percentage of the population this organism is part of the normal flora of the mouth and throat; however, it can cause pneumonia *[Pathophysiology]* Pneumonia can also occur when bacteria are spread to the lungs in the blood from bacteraemia (bacteria within the blood) that can result from infection elsewhere in the body or from intravenous drug abuse. Legionella and viral/mycobacterial pneumonias = route of infection is through inhalation of microorganisms released by infected individuals via cough, sneeze or talks. *[In healthy individuals]*, pathogens that reach the lungs are expelled or held in check by mechanisms of defence: Cough reflex and mucocilliary escalator, and the alveolar macrophages. If this fails, there is a full-scale activation of the body\'s defence mechanisms, including the release of multiple inflammatory mediators, cellular infiltration and immune activation. These inflammatory mediators and immune complexes can damage bronchial mucous membranes and alveolar--capillary membranes, causing the alveoli and terminal bronchioles to fill with infectious debris and exudate (fluid moving into a site of inflammation). In addition, some microorganisms release toxins from their cell walls that can cause further lung damage. *[Clinical manifestations]* The accumulation of exudate in the alveoli leads to dyspnoea, ventilation-- perfusion mismatching and hypoxaemia. Many cases of pneumonia are preceded by an upper respiratory infection = often viral. *[Symptoms:]* - Fever - Chills - productive or dry cough - malaise - pleural pain - sometimes dyspnoea and haemoptysis (blood in the sputum). Physical examination may reveal signs of pulmonary consolidation, such as dullness to percussion (creation of vibrations, typically by tapping the chest) and inspiratory crackles. Individuals may also demonstrate symptoms and signs of underlying systemic disease or sepsis. *[Management]* Antibiotics are used to treat bacterial pneumonia; however, resistant strains of pneumococcus are on the rise. Antibiotics are chosen based on the likely causative microorganism according to the clinical presentation and history. Infections with opportunistic microorganisms may be polymicrobial (many species of microorganism) and require multiple drugs, including antifungals. Adequate hydration and good pulmonary hygiene (e.g. deep breathing, coughing, chest physiotherapy) are important aspects of treatment for all types of pneumonia. **Viruses** *[Viral pneumonia]* - Can be a primary infection or a complication of another viral illness, such as chickenpox or measles (spread from the blood). The virus not only destroys the ciliated epithelial cells but also invades the goblet cells and bronchial mucous glands. Sloughing of destroyed bronchial epithelium occurs throughout the respiratory tract, preventing mucocilliary clearance. Bronchial walls become oedematous and infiltrated with leucocytes. In severe cases, the alveoli are involved, with decreased compliance and increased work of breathing. *[Management]* Viral pneumonia is usually treated with supportive therapy alone; however, antiviral medication may be needed in severe cases: Oseltamivir or Zanamvir **SBI241 -- Week 11** **Cancer** It is a complex disease characterized by deregulation of cell proliferation and apoptotic mechanisms, stromal and micro-environmental changes, angiogenesis and cell metastasis. *[Biology of cancer]* - DNA of a cell becomes altered, causing the cell to grow uncontrollably. Carcinogenesis is a multistep mechanism and is caused by an accumulation of errors *[Causes of Cancer]* -- linked to interactions between genes and the environment e.g. chemicals, viruses, radiation and heredity. *[Staging of cancer]* - linked to the spread of the cancer (metastasis). This provides an indication of the likely prognosis for the patient. *[Treatment:]*\ Whilst there are different treatments for different cancers, there are certain principles and types of treatment that are generally accepted as standard. **Cell Cycle** Most cells will pass through an ordered series of events in which the cell duplicates its DNA and then divides into two cells This process of cell division must be highly ordered and tightly regulated. +-----------------------------------+-----------------------------------+ | *[Normal Cells]* | *[Cancer cells]* | +===================================+===================================+ | - Predictable, orderly growth | Uncontrolled, disorderly growth | | | | | - Cells mature with specialised | Develop abnormally and fail to | | functions | perform specialised functions | | | | | - Cell production = cell death | Cells production = cell death | | | | | - Cells cease to grow when come | Cells lose contact inhibition and | | in contact with other cells | grow outside tissue boundaries. | +-----------------------------------+-----------------------------------+ **Benign vs malignant tumours** +-----------------------------------+-----------------------------------+ | *[Benign ]* | *[Malignant]* | +===================================+===================================+ | - Grows slowly | - Grow rapidly | | | | | - Well-defined capsule | - Not encapsulated | | | | | - Not invasive | - Invasive | | | | | - Well differentiated | - Poor differentiated | | | | | - Low mitotic index | - High mitotic index | | | | | - Do not metastasise | - metastasise | +-----------------------------------+-----------------------------------+ When cells go rogue *[Apoptosis]* -- Cell death / suicide Viral infection, exposure to ionising radiation and signal by cytotoxic T cells can all induce apoptosis. internal cell stresses can lead to apoptosis via the cell's own mitochondria. *[Immune surveillance --]* Body's own defences  Proto-oncogenes Cancer cell = oncogenes accelerate cell growth and division Tumour suppressor genes Cancer cell = damage to both genes leads to cancer **Chemicals** -- causing cancer \*\* tobacco use is associated with increased risk of cancers of the lung, mouth and oesophagus *[Diet]* - Many toxic, mutagenic and carcinogenic chemicals can be found in the human diet (notably preservatives and food colours). *[Alcohol]* - Linked with increased rates of incidence of oral cancer and cancer of the pharynx, larynx, oesophagus and liver --- particularly if taken with large quantities of tobacco in the form of cigarettes, cigars and in pipes. Alcohol consumption has also been linked to breast cancer and colorectal cancer. **Viruses**  R**adiation** Cancer spreads either by *[Haematogenous spread]* or *[Lymphatic spread]* **SYMPTOMS AND COMPLICATIONS** *[Local]* - Unusual lumps or swelling (tumour) - Haemorrhage (bleeding) - Pain and/or ulceration - Compression of surrounding tissues may cause pressure symptoms - Erosion - Angiogenesis *[Systemic]* - Weight loss - anaemia - Poor appetite - Fatigue and cachexia - Excessive sweating **Cancer Staging** **Diagnosis and evaluation** 1. Clinical staging 2. Imaging techniques 3. Biopsy 4. Blood tests **Cancer Screening** Early detection of cancer can lead to better outcomes. This has led to many screening programs for common cancers. In some cases, even precancerous conditions can be picked up. E.g. - Breast Cancer = breast self-examination and mammography - Cervical cancer = cervical smear - Bowel cancer = Faecal occult blood test *[Cancer prevention]* - Smoking - Diet - Alcohol - Occupation - UV radiation - Sexual behaviour HPV vaccine which has been shown to be effective in preventing precancerous changes and is recommended for adolescents between 9 and 18 years of age in Australia. **CANCER TREATMENT** **Chemotherapy** Conventional chemotherapy kills all rapidly dividing cells High (and sometimes toxic) doses of these drugs are usually given with the hope that all cancer cells will be killed An unavoidable consequence of this approach is killing of normal actively dividing cells *[Major side effects]* This results in the most common side effects of chemotherapy: - myelosuppression (decreased production of blood cells, hence also immunosuppression), - mucositis (inflammation of the lining of the digestive tract) - alopecia (hair loss) Other serious side effects are - Severe Nausea and Vomiting  Infertility - Secondary Tumours *[Targeted therapy]* Newer anticancer drugs act directly against abnormal proteins in cancer cells; this is termed targeted therapy The first molecular target for targeted cancer therapy was the cellular receptor for the female sex hormone oestrogen, which many breast cancers require for growth [Tamoxifen was the first drug developed as a targeted therapy] *[Signal Transduction Inhibitors]* - Imatinib mesylate (Gleevec®) is approved to treat gastrointestinal stromal tumour (a rare cancer of the gastrointestinal tract) and certain kinds of leukaemia. - It targets several members of tyrosine kinase enzymes that participate in signal transduction. **TYPES OF CANCER** *[Carcinomas]*, the most common types of cancer, arise from the cells that cover external and internal body surfaces. Lung, breast, and colon are the most frequent cancers of this type *[Sarcomas]* are cancers arising from cells found in the supporting tissues of the body such as bone, cartilage, fat, connective tissue, and muscle *[Leukemias]* are cancers of the immature blood cells that grow in the bone marrow and tend to accumulate in large numbers in the bloodstream *[Lymphomas]* are cancers that arise in the lymph nodes and tissues of the body's immune system **Leukemia** -- malignant disorder of the blood and blood-forming organs Excessive accumulation of leukemic cells 1. *[Acute leukemia]* -- Presence of undifferentiated or immature cells, usually blast cells 2. *[Chronic leukemia]* -- Predominant cell is mature but does not function normally. *[Acute Lymphoblastic Leukemia]* -- Aetiology The exact cause of ALL is unknown,