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Pathology
Week 1 - Endocrinology
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The ENDOCRINE SYSTEM and nervous system are the two major control systems of the
vertebrate body
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Enable you to respond and adapt to changes in external
environment (eg: food intake, water availability, temperature change, “stressors”etc)
Hormone - A chemical messenger produced and secreted by a specialized endocrine gland that
is transported in the bloodstream to a distant target organ/cell where it elicits a physiological
response
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3 classes of hormones: Proteins/peptides - e
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Growth hormone
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g
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Modified amino acids - e
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Adrenaline and thyroid hormones
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Rate of metabolism - by target tissue, blood, liver, kidney
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Target cell recognition - specific receptors - are protein, have high affinity for hormone,
binding starts chain of events that results in biological response
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Hormone affect specific target cells - peptide hormones bind receptor proteins on the
membrane
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Time-frame of response - Neurotransmitter - Milliseconds
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Protein - minutes to hours
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Hormone actions - Affect growth, development, metabolic activity and function of tissues
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May act on several tissues or just one specific target tissue
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g
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g
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Regulation of hormone secretion:
By physiological changes - Blood glucose regulates insulin & glucagon release from pancreas
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Blood calcium regulates
parathyroid hormone release from parathyroids
By endogenous rhythms - e
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Ultradian - cycles in minutes, Circadian - daily cycles and
infradian cycles - monthly cycles
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Some positive feedback
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Pituitary Gland “Conductor of the Endocrine Orchestra”
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Hypothalamus - master gland, regulates pituitary - Hypothalamus controls release of various
pituitary hormones
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g
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End organ insensitivity /resistance
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g
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Dietary e
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Iodine deficiency - thyroid malfunction
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g Destruction of thyroid tissue in Hashimoto’s
Disease, e
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destruction of adrenal cortex in Addison’s Disease
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g
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o Iatrogenic (=doctor-caused) - e
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removal of parathyroid glands during thyroidectomy (can be
fatal)
o Idiopathic - unknown cause
 Treatment - Hormone replacement - Steroids or Thyroid Hormone - Straightforward Absorbed
in GI
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 Hypersecretion
 Causes:
o Functional tumour - e
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Prolactin secreting pituitary adenoma
o Ectopic hormone-secreting tumour - e
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Oat cell carcinoma of lung secreting ACTH => cortisol
excess (Cushing’s Disease)
o Immunological - Grave’s Disease, antibodies that bind and activate TSH receptor on thyroid
o Substance abuse - Anabolic steroid use, exogenous source of high hormone levels
 Treatments:
o Surgical removal of the gland that is hyper-secreting e
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Hyperthyroidism
o Irradiation of Gland – reduce function, will need replacement therapy
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g
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g
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GH receptor
mutation=> non-functional, normal/raised GH levels, Very low IGF
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g
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 Slow growing pituitary tumour - often first affects gonadotrophins (LH, FSH), followed by GH
deficiency, finally low TSH and low ACTH
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(undersecretion of multiple
pit
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Pressure on the optic chiasm => visual field loss
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 Antidiurectic hormone - ADH or vasopressin:
o Effects – PHYSIOLOGICAL HOMEOSTASIS - Increases water retention (kidney), Decreases
osmotic pressure of blood
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o Regulation of ADH secretion - release follows activation of physiological homeostasis osmoreceptors in hypothalamus, volume receptors in atria of heart
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 ADH Pathophysiology:
1
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o Symptoms - Polyurease - copious, dilute urine, polydipsia - thirst and excessive drinking
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o Treatment - replacement therapy with synthetic ADH analogue
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Hypersecretion - Syndrome of inappropriate ADH (SIADH)
o Symptoms - decrease in frequency of urination, excessive fluid retention
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Pathological - ADH secreting
tumour, brain disorder/damage
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Tumor removal
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Growth and maturation (essential) - Embryo development,
CNS development, Linear growth (promotes effects of growth hormone)
Hypothyroidism - lack of thyroid hormone - in adults causes weight gain, cold intolerance,
lethargy, depression, puffy skin and muscles, sluggish reflexes, muscular weakness, reduced
cardiac output
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Causes - Primary failure of thyroid gland, Secondary due to hypothalamic or anterior pituitary
failure, Secondary due to autoimmune damage to gland, Secondary due to lack of dietary
iodine
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Common - affects 2% women
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Primary - due to hyper
secreting thyroid tumour
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Treatment - Anti-thyroid drugs” that interfere with T3/T4 synthesis
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Thyroid ablation using radiaoactive iodine
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GHsecreting pituitary tumour - GH excess, in young results in gigantism, in adults leads to
thickening of bones and soft tissues, coarsening of features
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) Secreted by
adrenal cortex - Cortisol - (essential for adaptation to stress, mobilises glucose, antiinflammatory actions) Aldosterone (maintains balance of Na/K in blood)
Disorders - Adrenal atrophy due to either Addison's disease or long-term corticosteroid
therapy
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Addisons disease - Deficiency of adrenocortical hormones - affects about 1 in 50,000 people
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g
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Treatment:
replacement therapy with cortisol (and mineralocorticoid if needed)
Cushings syndrome - hypersecretion of cortisol - Due to: Raised pituitary ACTH secretion
(=Cushing’s Disease) Inappropriate ACTH secretion from tumour (pituitary or elsewhere)Raised
cortisol secretion from tumour in adrenal cortex, BUT most common cause of CS is exogenous
cortisol medication
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Cardiovascular disease
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Week 2 - Gut disease
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Gut - The most metabolically active organ in the animal or human body, Dominated by a
diverse microbiota, Involved in disease onset
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Gut flora - Gut bacteria can be compromised- stress, ageing, infection, poor diet, antibiotics
etc
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Inflammatory bowel disease (IBD) - the name of a group of disorders that cause the intestines
to become inflamed
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Peak occurrence 15-40 years of age
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Unknown cause, seen as autoimmune
disorders
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Ulcerative colitis:
Pathology: inflammatory reaction, haemorrhage, remission periods
Aetiology: unknown, bacteria?
Clinical features: bloody diarrhoea, pain, fever, weight loss
Diagnosis: blood in stools, loss of mucosal detail, inflammatory exudate
Complications: colon perforation, conjunctivitis, abscesses, mouth ulcers, skin lesions
Treatment: sulphasalazine, adrenal steroids, colectomy
Chrohn's Disease - Chronic inflammatory disorder, Peak occurrence is 15-35 years old, Involves
a granulomatous reaction, Varies in the level of inflammatory response
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Mycobacteria?
Antibiotic associated diarrhoea - Occurs because of a compromised commensal gut flora
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Elderly are especially
prone, All groups of antibiotics may cause AAD, but those with broad-spectrum coverage—in
particular cephalosporins, extended-coverage penicillins, and clindamycin—are the most
common
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Ampicillin, clindamycin,
cephalosporins are most frequently implicated antibiotics, 2 types of toxin are produced
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g
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Irritable bowel syndrome (IBS) - A common gut complaint (up to 20%) Stress/ Gut
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A ‘functional’ disorder (i
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no tissue damage but function is affected)
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More prevalent in females
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Linked to intestinal yeasts - candida albicans - most recognised candida species
involved as a human pathogen
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Bowel cancer - second most common site for tumors in humans
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Aetiology is unknown, but at least 12 bacterially produced

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carcinogens are known, 75% in distal colon, Affects women more frequently than men
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Links with bacteria - production of carcinogens and tumour promoters, protective
effects, effects of 'anti nutrients'
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Pneumatosis cystoides intestinalis - fermentation by colonic bacteria
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Over production of hydrogen is characteristic, SRB, MB, AB, Hydrogenotrophic
bacteria seem to be absent in the gut of PCI sufferers
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Gastroenteritis - Involves mild inflammation of the GI tract, Usually due to transient pathogens
from food or water that is contaminated, Nausea and vomiting, Fever, Diarrhea, Loss of
appetite, Abdominal pain, Abdominal cramps, Bloody stools
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Bacterial pathogens - Invasive - EPEC, shigellas, salmonellae
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Autistic spectrum disorders - A spectrum of developmental disorders - impairments in
interaction, communication and development of imagination
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Reports show
children with ASDs suffer from intestinal dysfunction, but no direct evidence of human gut
microflora imbalance
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The gut contains: ‘+ve’ & ‘-ve’ bacteria (pathogens) Probiotics are
‘+ve’ bacteria, yogurt or drinking yogurts, capsules
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Examples of
probiotics: Lactobacilli, bifidobacteria
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Approaches - Resistance to gastric acidity, hydrolysis by mammalian
enzymes and GI absorption
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Found in
human breast milk, manufactured in GOS and lactulose, some occur naturally in asparagus,
onion, artichoke etc
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Reduces blood flow to tissues
causing Ischaemia (MI/stroke)
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Pathology of

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thrombosis - inappropriate blood clotting, Haemorrhage - insufficient blood clotting
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Hypoxia - lack of oxygen, Ischemia - lack of blood flow
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Haemostasis - 5 stages - Vessel spasm, platelet plug formation, coagulation, clot retraction and
fibrinolysis
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An injury to the vessel wall exposes the subendothelium which includes collagens (long
polypeptides)
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Coagulation is the process where fibrin (stringy
stuff) is formed to bind all the cells together into a more stable clot
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At sites of damage the subendothelial collagens are exposed
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This initial interaction isn’t very strong, so just slows the platelet down rather than
stopping it
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The
receptor GPVI is then able to bind collagen triggering a signalling cascade that causes the
increase in intracellular calcium that has 3 effects- The granules are secreted, releasing their
contents to further activate nearby platelets, The fibrinogen receptor (aIIbb3) is converted
from a low affinity state to a high affinity state (more able to bind fibrinogen), Ca2+ levels
increase causing shape change
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Fibrinogen is a plasma protein, its
release from platelets boosts the local concentration
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Polymerisation of fibrinogen to fibrin
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Thrombin is a protease –
an enzyme that cuts proteins
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Coagulation factors - Some coagulation factors work in
the intrinsic pathway, some in the extrinisc pathway and some in the common pathway
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Fibrinolysis - dissolution of the blood clot - blood flow re-established for permanent tissue
repair
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Blood stopped from clotting by - Healthy endothelium - Healthy endothelium – covers
collagens, produces NO and PGI2, produces t-PA
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Blood flow to carry away clotting factors Factors present in blood that inhibit clotting factors,
e
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Anti-thrombin III
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Arterial thrombosis - Caused by inappropriate activation of platelets, most common cause is
rupture of an atherosclerotic plaque
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Myocardial infarction - blockage of coronary arteries
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Signs Tachycardia, low grade fever, pale clammy skin, hypo or hypertension, altered heart sounds
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Treatment - Thrombolytic
therapy, anti-platelet therapy, b-blockers, PCTA, CABG
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Anti-platelet drugs
- help prevent arterial thrombosis - Aspirin, ADP receptor antagonists, Fibrinogen receptor
blockers, Phosphodiesterase inhibitors
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PCTA - ballon used to expand artery to reduce effect of plaque
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Peripheral arterial disease - narrowing of leg arteries
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Sign - Poor pulses in feet, thin skin, leg hair loss, redness with legs
below heart height, paleness when elevated, ulcers (poor healing)
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9 – 1
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9 indicative of PAD),
ultrasound, MRI
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Foot care
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Ischaemic stroke - blockage of carotid/cerebral arteries - Symptoms - FAST (face asymmetries,
arm weakness, slurred speech, time!)
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Signs - Muscle weakness, paralysis, loss of sensation
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Treatment - Thrombolytic therapy, anti-platelet therapies, carotid endarectomy
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Venous thrombosis - in large veins of leg, caused by activation of coagulation cascade
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Signs - Tenderness, swelling, redness, heat (unilateral)
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Diagnosis - Ultrasound, venogram
(x-ray with contrast dye), elevated D-dimers (by-product of fibrinolysis)
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Warfarin - blood thinner - inhibits cycling of vitamin K, acts on liver - liver synthesises some
clotting factors if Vitamin K is present, slow acton, used to kill rats
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Diabetes mellitus:
A group of disorders characterized by abnormalities of metabolism (fat and protein as well as
carbohydrate) resulting from deficiency of or resistance to the action of insulin
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Recent increase in amount of people suffering
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Blood Glucose test - Random levels - Non diabetic <80mmol/l, diabetic >11
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Fasting non diabetic <6
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0mmol/l
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Type 1 - insulin dependent - weight loss, plouria, polydypsia, ketosis (keto-acidotic coma)
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Insulin - 51 aa polypeptide hormone composed of two chains, A and B, joined by disulphide
bonds (MW ~6000)
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Insulin stored in
beta cell secretory granules complexed with zinc (zinc + six insulin molecules)
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Uses - in picture
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Now produced by recombinant technology
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Forms a
suspension (no IV injection ) and has the effect of prolonging the length of action
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Insulin lispro/aspart/glulysine are short acting
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Glucose utilisation in tissue is impaired or abolished due to lack of insulin
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When blood glucose rises >12mmol/l (renal threshold) glucose re-absorption
saturated and ‘glucose spill over’ into urine occurs
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Excessive NEFA (0
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0mmol/l " 34mmol/l)
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2mmol/l " 10-20mmol/l)
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4 " 7
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Type 2 - risk increases with BMI
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Estimated approx 750,000 people in UK are
currently un-diagnosed
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16% by recurrent infection
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Insulin secretory defect - may be the
major factor in the genetic transmission of diabetes
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Usually defined in
terms of insulin-mediated glucose uptake in muscle
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Closely associated with obesity, particularly central (abdominal) obesity
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Treatment/management - weigh control,
reduce fat content, reduce refine CHO, moderate alcohol consumption
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Structure of heart - 2 atria: thin walls, collect blood returning to heart via venous system,
pump blood into ventricles
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Congenital heart defects - Ventricular septal defects
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Blood mixes between the ventricles but more blood shunted left to right
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Tetraology of fallot - 4 abnormalities resulting in insuffieciently oxygenated blood pumped to
body - narrowing of pulmonary valve, thickening of wall of right ventricle, displacement of
aorta over ventricular septal defect, ventricular septal defect opening between left and right
ventricles
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Anchored by
strong fibres that prevent them turning inside out
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Semilunar valves at exits of heart (where aorta leaves LV and where pulmonary artery leaves
RV)
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Valves close when ventricles relax so preventing blood from flowing back into ventricles
Bicuspid aortic valve - most common cardiac valvular anomaly - predisposes to calcification
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Aortic stenosis - caused by rheumatic heart disease
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May require heart surgery
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Treatment for valvular diseases - surgery - replacement with mechanical valves
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relaxation phase (atria and ventricles in diastole) ~ 0
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Atrial systole ~ 0
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Ventricular systole ~ 0
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Heart beat - Cardiac muscle cells can contract without any signal from nervous system
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The sinoatrial (SA) node, or pacemaker, maintains heart’s pumping rhythm
by setting rate at which all cardiac muscle cells contract
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Function: generates electrical impulses
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Impulses pass to the atrioventricular (AV) node (another region of specialised muscle
tissue), a relay point between RA and RV
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1 s) to ensure atria
contract first and empty completely before ventricles contract (phase 2 of cardiac cycle)
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The SA node sets tempo for entire heart, but is influenced by a variety of signals and
hormones via two sets of nerves that oppose each other in terms of being able to adjust the
heart rate
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g
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Positive chronotropic factors increase heart
rate, adrenaline (epinephrine) increases heart rate (fight-or-flight hormone released from the
adrenal glands)
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Electrocardiogram - plot of time-dependence of changing
potential differences between the electrodes place on body
surface
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QRS complex: represents impulse spreading
from AV node to ventricles via Purkinje fibres (ventricular
depolarization)
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Blood vessels - carried in a closed system of vessels that
begins and ends at the heart
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Arteries carry blood away from the
heart
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Capillaries directly
serve cells in tissues/organs
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Within organs arteries
branch into arterioles (small vessels that convey blood to capillaries)
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Can be up to 70 µm in
diameter
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Networks of capillaries (capillary
beds) infiltrate each tissue
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Small vessels ~1 mm long and 3-10 µm in
diameter (just large enough for a single RBC to squeeze through)
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A series of pocket valves allows blood to flow only towards the heart
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Venous system is large volume, low pressure (typically <10% of that in arterial system) system
consisting of vessels with a larger inside diameter than corresponding arteries
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Arteries and veins distinguished by the direction in which they carry blood and not by the type
of blood they carry
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Following blood loss, venous blood volume, not arterial volume decreases in order to
maintain arterial pressure and capillary blood flow
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Lymphatic system serves to return excess fluid to
the blood, transport large molecules (e
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Fat from
gut and high molecular weight hormones) to the
blood, produces and transports leukocytes to
blood
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Blind-ending lymphatic capillaries drain interstitial
spaces and join to form tree-like structure with
branches reaching all tissues
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Lymphatic pressures often slightly lower than
surrounding tissue pressures, thus interstitial fluid
passes easily into lymphatic vessels
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Some vessels contract rhythmically to
drive fluid away from tissues
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Lymph enters blood circulation via thoracic duct or right subclavian vein into very low
pressure region of venous system, close to heart
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Results from malignant changes to one or
more lymphocytes
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May also spread or first appear outside the lymphatic system (extranodal disease)
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Some tumours respond to chemotherapy whilst others require radiotherapy
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Causes: Primary (inherited) – 1/10,000 people, Secondary
(injury or damage to the lymphatic system) - ~100,000 people in UK, Infection, Cancer
treatments, Accidental damage, Reduced mobility/paralysis, Cancer
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Transport capacity is sufficient and lymphoedema not present
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Usually, the limb or affected area is almost normal in
size
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Fibrosis and
lymphoedema marks the beginning of the hardening of the limbs and increasing size
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The tissue is hard (fibrotic) and unresponsive; some patients consider undergoing
reconstructive
surgery, called "debulking“
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Hypertension - Definition: High blood pressure (bp >140/90 mm Hg on three consecutive
occasions)
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Usually refers to arterial blood pressure measured at upper arm with
sphygmomanometer
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Secondary
hypertension - hormonal dysruption, kidney disease, obesity, liver disease
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g
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Drugs - vasodilators, ACE inhibitors, Ca2+
channel blockers, diuretics
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Caused by deposition of fat, cholesterol and other
substances in the artery wall in the form of plaques
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Development - Initiated by damage to the endothelium, Infiltration of macrophages and
development of fatty streaks, Accumulation of intracellular lipid (foam cells), Deposition of
extracellular lipid, Fibrosis and calcification, Rupture of fibrous cap and thrombosis
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Detected by an angiography - x-ray study
of arteries
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Surgery - endarterectomy
to remove plaque, PCTA, CABG
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Principal symptom of ischaemic heart disease
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Commonest form: angina pectoris
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g
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Also get angina at rest (unstable angina)
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Myocardial infarction - Definition: death of heart tissue (myocardial necrosis) following
cessation of blood supply
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Infarction
usually regional following occlusion of single coronary artery
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Type 2: MI
secondary to ischaemia due to increased oxygen demand or reduced supply (e
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Coronary
artery spasm, coronary embolism, arrhythmias, hypertension)
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Type 4: MI
associated with coronary angioplasty or stents
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Symptoms:
crushing retrosternal chest pain, shortness of breath, sweating, nausea and vomiting
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Treatment: thrombolytic drugs (e
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streptokinase, tPA)
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Results in the death of brain (neuronal) tissue
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Ischaemic stroke (80% of cases)
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carotid artery) become blocked following
formation of blood clot (thrombus)
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Ruptured blood
vessels flood and put pressure on brain leading to death
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Causes - Ischaemic heart
disease (coronary artery disease, MI): 50-70%
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Hypertension: 5%
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Class II: slight, mild limitation of activity; patient is comfortable at rest
or with mild exertion
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Class IV: any physical activity brings on discomfort and symptoms occur at rest
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Drugs - diuretics,
cardiac glycosides, vasodilators, ACE inhibitors
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Intermittent disease
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Hyper-responsiveness to: Irritant chemicals, cold air - exercise, allergens - pollen, cats,
bacterial flagellin, digestive enzymes in faeces, respiratory infections
Asthma is an inflammatory disease, associated with bronchial hyper-responsiveness
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Innervation of airways - parasympathetic nuerone causes acetylcholine on M3 muscarinic
receptor, which causes an inositol triosphosphate increase, which causes Ca2+ to cause a
contraction
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Innervation of mucus-producing cells - Parasympathetic neurones react with acetylcholine (M3
muscarinic receptor), produces mucus

Sympathetic neurone, releases noradrenaline which activates B2 - adrenoceptor, decreases
mucus production
Regulation of airways and glands - Parasympathetic nerves cause bronchoconstriction and
mucus secretion
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Circulating adrenaline acts on B2adrenoceptors on smooth muscle cells to cause bronchodilation
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Summarised in the pictures
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First-line drugs
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Usually inhaler, but can be
given orally or injected
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o Xanthine drugs - Theophylline in tea, Aminophylline
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Used in
conjunction with other drugs for difficult asthma
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o Muscarinic receptor antagonists - Ipraopium bromide, Muscarinic antagonist
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Given by inhalation
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o Salbutamol is selective for B2-adrenergic receptors
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Salbutamol is selective to B2-adrenoceptors because it contains a butyl
group
 Anti-inflammatory drugs o Glucocorticoids - not bronchodilators, effective in preventing recurrence
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Its inhaled, need
several days of therapy for full effect
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Therefore decereases
the synthesis of leuoktrienes, prostaglandins and platelet-activating factor
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o Nonsterodial anti-inflammatory drugs induce asthma in some people
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Respiratory tract infections
 The common cold - viral infection of the upper respiratory tract
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Excessive production of nasal secretions and mucous membranes become inflamed
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Paranasal sinuses are in
communication with the nasal cavity through narrow openings called ostia
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Obstructs the
ostia and the clearance of the mucus from the paranasal cavities into the nasal cavity
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 Influenza - Important cause of acute upper respiratory tract infection
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Can spread into lower respiratory
tract and cause severe shredding of bronchial and alveoli cells, which can lead to pneumonia,
can cause death quickly
o Treatment - Antiviral drugs, prevention by immunisation
 Pneumonia - Serious infection or inflammation of lungs
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Lack of O2 in
blood
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Asymptomatic carriers with limited numbers in nose and throat, may be secondary bacterial
infection afecter infection by influenza
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Released from bacteroal
and binds to cholesterol in the plasma membranes of cells and created pores in the cells
damaging them
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Other causes include
viruses, mycoplasmas, fungi and chemicals
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Tuberculosis - TB - infectious disease in the lungs
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Bacterium lives and multiplies inside phagosomes in macrophages
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o Diagnosis - Tuberculin skin test, if negative vaccine given, mainly effective in children
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Some untreatable due to
multidrug resistance
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Mosr infected people develop minor symptoms
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Increased susceptibility in HIV
infection
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Chronic Obstructive Pulmonary Disease
 2 types: Chronic bronchitis and emphysema
o Irreversible, inflammatory disease, involves neurtrophils, macrophages and t-lymphocytes
o Diagnosis - pulmonary function test, arterial blood gases, chest x-ray
o Mechanism - Cigarette smoke attracts monocytes to lung (which differentiate into
macrophages) - activates neutrophils which secrete elastase, leads to either mucus
hypersecretion and reducded ciliary beating causing chronic bronchitis or degrades elastin and
collagen causing emphysema
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Mucus hyper secretion and cilia on
epithelial cells stop beating
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Cough and difficulty in breathing
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 Emphysema - Inflammation leads to destruction of terminal bronchioles and elastic fibres in
walls of alveoli by neurtophil elastase
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o Causes - Smoking, genetic deficiency of alpha1-antitrpsin which inhibits neutrophil elastase
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Decreased chloride ion secretion and viscous mucus in airways
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Cannot clear effectively inhaled bacteria
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Irreversible airway damage and respiratory failure
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Lung transplantation
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Cationic liposome-DNA
complexes - Liposome enhances fusion with plasma membrane of cell and positive charge
binds to DNA
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Gene therapy is
disappointing so far
Cough
 Reflex mechanism to remove foreign material from airways
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Impulses from receptors pass
through vagus nerve to the brain stem and initiate the cough reflex
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 Treatment - treat underlying cause, eg asthma, antitussive drugs
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 Deep vein thrombosis in legs, arms, ect, causes embolis, travels through right side of the heart,
blocks pulmary artery, shortness of O2
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Treatment - fibronolytic therapy - used for pre-existing thrombosis, thrombolytic drugs
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Week 6 - Cancer
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Is a collection of diseases with the common feature of an uncontrolled increase in cell number
lading to invasion of the surrounding tissues and spread to other parts of the body
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Cancers are clonal in origin - one cell becomes billions of cells
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Mutations in proto-oncogenes lead to a gain of function
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o Ras was one of the first oncogenes discovered
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In cancer, Ras is often mutated (and becomes an oncogene) and is switched on
all the time
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Most common oncogene found in cancer, 20-30% of all
tumours have a mutant version
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Tumour cells are effectively immortal and can rebuild telomere using the
enzyme telomerase
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o Examples of tumour suppressor genes include p53 and BRCA
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Mutations in tumour suppressor genes lead to loss of function
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p53 is the most common mutated gene in
cancer - found in 50% of all human cancers
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Apoptosis is also the
mechanism through which chemotherapy and radiotherapy kills cancer
cells
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The pro-survival members of the family are commonly over-expressed in cancer (gain of
function)
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Invasion and metastasis - 90% of deaths due to the spread of cancer to distant sites, a process
called metastasis
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The acquisition of invasive properties is what distinguishes
malignant from benign cells
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Process: Tumour grows until it starts to invade neighbouring tissues
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Cells cross into the
bloodstream and begin to circulate
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Malignant cancer cells get the ability to move and start to break away from the main tumour,
they crawl through the extracellular matrix until they reach a blood vessel
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How cancer kills:
 Interference with normal organ function - blockage/obstruction, deprivation of nutrients,
pressure
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Causes of cancer:
 Cancer can be causes when DNA is damaged, which occurs regularly, and the damage is not
repaired properly, leading to a mutation
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Mainly in non-coding regions, or in areas where they have no effect
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 DNA Mutations:
o In gene coding regions - point mutations, small insertions/deletions
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o Amplifications/deletions of chromosomal regions
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 Risk factors of cancer - Smoking, diet, obesity, alcohol, sun exposure, family history, child
bearing, sexual activity, age
...

 Table summarises types of cancer
...

o Promotion - additional mutations promote further proliferation
...

o Progression - growth and invasion of the tumour
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 Also the TNM grading scheme
...
N = is invasion of the lymph nodes from 0-2
...

Treatments for cancer:
 Surgery - If all the tumour cells are removed it can provide a cure
...
Not effective if
the cancer has spread
...

 Radiotherapy - Radiation to damage cell DNA
...
Generation of free
radicals species in cells - DNA strand breaks
...
Can
cause tissue damage and new mutations as it can damage healthy cells
...
Only treatment option for metastatic
cancer
...
Can cause side effect like ausea, hair loss, and bone marrow toxicity
...


Week 7 - Immune System
How immune system works:
 4 main tasks
o Immunological recognition
o Immune effector function
o Immune regulation
o Immunological memory
 Innate and adaptive immunity:
o Innate immunity - responses are generic, occur at the same speed and efficiency each time
...
Recognise an invading pathogen
...

o Adaptive immunity - second level of defence, increases in strength and effectiveness, foreign
agent is recognised in a specific manner and the immune system acquires memory of it
...
On primary exposure to pathogens it amplifies the immune response
to contain pathogens, makes immune response more specific to particular pathogens
...

 Secondary immune responses - T and B cells remember that the body has come into contact
with the pathogen before
...
Vaccines harness this property of
the immune response
...
All cells
derived from a common multipotent stem cell population
...
These cells are then committed to that linage
...
Primary
lymphoid organs, e
...
Bone marrow, thymus - immune cell development
...
g
...

 Innate immunity - Phagocytosis occurs - carried out by macrophages, neutrophils, dendritic
cells
...
Initiation of the immune
response and associated inflammation
...
Circulate in blood for 10hours prior to
migrating to tissue
...

o Mast cells - 2 types mucosal in gut and lung and connective tissue cells in most tissues
...
Activated mast cells can
increase vascular permeability, vasodilation, smooth muscle cell contraction and attract
neutrophils
...
2 kinds of active
immunity
...
Humoral immunity - mediated by
antibody - transferred by antibody, antibodies can bind
exposed epitopes on antigens
...
Antibodies interact specifically with relatively small parts of
molecules
...

Small antigens are referred to as haptens
...

Antibody is produced by B cells
...

3 actions of antibody Neutralisation - Block biological activity of target molecule e
...

Opsonisation- Interact with special receptors on various cells, including macrophages,
neutrophils, basophils and mast cells allowing them to "recognise" and respond to the antigen
...

Memory B cells - confer immunological memory, ensuring that secondary response to
pathogen is rapid
...
Different types - CD4 and CD8
...
Role
is to provide help for effector cells
...

Cytotoxic t cells express adhesion molecule CD8, respond to intracellular antigen
...

T cells recognise antigen via the T cell receptor
...
The T cell receptor only recognises
antigens in the form of peptides bound to MHC molecules
...

o Immunodeficiency - when immune system is depressed or absent and an individual is unable
to mount a normal immune response to protect the body
...

 Secondary or acquired - a loss of previously functional immunity due to infection, radiation,
splenectomy, aging, malnutrition or drugs
...
Involves
similar mechanisms to those used to attack pathogens
...
4 types of autoimmunity
...

Autoimmune reactions leading to autoimmune diseases can involve - autoreactive T cells and
autoantibodies
...

Self-tolerance - ability of immune system to not attack normal body tissues, autoimmunity is
therefore regarded as a breakdown in self-tolerance
...

Organ specific - Immune response is directed to a target antigen that is unique to a single
organ or gland
...
Causes cellular lysis and inflammatory
response in target organ
...

E
...
Type 1 diabetes (Insulin-dependent diabetes mellitus) - insulin producing cells destroyed
...
Mechanism - T cell mediated destruction of the cells that make insulin
...
CD8+T cells recognise a protein from
insulin producing b-cells in the pancreas
...

Symptoms - Increased plasma glucose, glucose in urine, thirst, weight loss, increased urin
production, increased use of fats as source of energy - increases ketones in bloodstream which
can cause convulsions due to lowered blood pH
...


E
...
Myasthenia gravis - Type 2 autoimmune disease - serious muscle weakness - Target
antigen is acetylcholine receptors on motor end-plates of muscles
...
Antibody
dependent mechanisms cause cellular damage leading to progressive muscle weakening
...

Treatments - Acetylcholine esterase inhibitors to try and build up concentrations on
acetylcholine, immunosuppressive drugs, plasmapheresis - treatment of blood plasma
...
g
...
Disables rapid depolarisations along nerve fibres
...

Systemic autoimmune diseases - directed against different areas of the body, have varying
symptoms
...
Caused by generation of auto-antibodies called
rheumatoid factors
...
Bind normal IgG in
circulation and complexes are deposited in joints
...
No cure for chronic
autoimmunity one established as tissue is never cleared
...
Palliative therapy is only option
...

Modification of the immune response by immunomodulatory therapy
...
Injection of insulin in type 1 diabetic
patients)
General current treatments - For organ specific immunity - removal of target organ is
beneficial
...
Dealing with problem T cells Most cause non-specific suppression of the immune system i
...
no distinction between
beneficial and pathologic immunity
...

PNS - Peripheral nervous system, nerves that extend from the brain and spinal cord
...
Characterised by degeneration of the cerebral ganglia
...

 Loss of dopaminergic neurones in basal ganglia – Symptoms do not appear until striatal DA
levels decline by ~80%
 Basal ganglia comprise five subcortical nuclei that regulate movement control - Caudate
Nucleus, Putamen, Globus Pallidus, Subthalamic Nucleus, Substantia Nigra
 DA decline causes a DA:ACh imbalance - Imbalance results in disruption of basal
ganglia:striatum feedback loop
...

 More common in men, initially manifests as muscle rigidity and loss of facial expression and
vocal tone
...

 Causes - multi-factorial disease, multi-system disease, no single underlying cause
...
Cons - Non-DA neurones are

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now known to show the first signs of presymptomatic degeneration in P
...
Cons - 90% of cases are idiopathic
...
Cons: PD has been prevalent prior to the use of such toxins
Therapeutics - L-dopa is the typical first line treatment ; replaces dopamine in brain
...
Selefiline - selective, irreversible MAO-B inhibitor
...
DBS - deep brain stimulation
Alzheimer's disease - degenerative disorder of the cerebral cortex
...
First
manifestation is failing memory
...

Taupathy - Microtubule-associated tau-protein is a critical cell structure component
...
Intracellular fragments eventually give rise to extracellular neurofibillary
tangles
Hypotheses - Cholinergic - Pros: Cholinergic neurones appear selectively affected
...
Amyloid
beta (Ab) peptides - Pros: Ab deposition precedes AD symptoms; APP gene located on
Chromosome 21 and trisomy 21 patients all exhibit AD by 40
...
Tau fragment (‘tauopathy’)Pros: Tau locations correlate with
neurone loss
...

Hypothetical/future approaches - improve neuronal survival with neurotrophic factors, inhibit
amyloid plaque formation, inhibit excitotoxicity
...

Generalised seizures - involve the whole brain and produce abnormal electrical activity in both
hemispheres
...
2 types - Grand mal (tonic-clonic
seizures) and petit mal (absence seizures)
Grand mal - Limb extension and rigidity, respiration stops, defaecation,
micturation and salivation often occur (~1 min)
...
Patient gradually regains consciousness after a few more minutes
and is likely to feel confused, ill and disorientated
...
Patient typically ceases
any action, stares vacantly ahead, unaware of surroundings, dangers, other people
...

Partial seizures - discharge begins and typically remains restricted to a local brain area
...

Treatments - Sodium channel blocks - Action potential generation is dependent upon the
opening of voltage-gated sodium channels
...
Enhancement of GABA action– Enhancement of GABAmediated Cl- channels increase inhibitionand attenuates seizures
...

Neuropathology of schizophrenia - imaging techniques have revealed enlarged cerebral
ventricles
...
Not a progressive disorder
...

Aetiology of schizophrenia - Inherited genetic factors
...
In twins: Dizygotic (fraternal) 17%; Monozygotic (identical) 48%
...
g
...
Environmental factors -Birth
complications, viral infection, inner cities, immigration, cannabis use
...

Treatments - Drugs block typically dopaminergic function – Dopamine hypothesis of
schizophrenia: excessive mesocorticolimbic dopamine activity
...
g
...
Effects on negative
symptoms for some newer drugs - e
...
Clozapine
...

First line therapy – risperidone, Second line therapy - amisulpride, aripiprazole, olanzapine,
quetiapine
...
Treatment resistant
patients – clozapine
...

 Picorna-like viruses - ssRNA - positive sense (mRNA like), icosahedral capsid
...
g Poliovirus,
norovirus, rhinovirus
...

 HIV 1 - Human immunodeficiency virus type 1
...
Has an envelope, associated with AIDS
...

Originated in primates, transmitted by humans
...

o Retroviruses have a ~10 kb RNA genome consisting of at least the genes Gag, Pol and Env
...

o Antiviral therapeutics developed to treat HIV infection - Protease inhibitors, fusion inhibitors,
Integrase inhibitors ect
...

Cytokine storm - release of pro-inflammatory cytokines and chemokine's from infected
macrophages - attracts more monocytes, macrophages and neutrophils
...

o SARS - Severe acute respiratory syndrome coronavirus
...

Disease Associated: Severe Acute Respiratory Syndrome
...
Treatment: Some types of interferon used, but no licensed antivirals
...

 TTV - only infects humans and primates
...
Transfusion-transmitted virus
...
Has no envelope but has a
protein shell on the outside, DNA on the inside
...
No treatment or
vaccine, Environmental host and vector unknown
...

o PrPc helps transmit a myelin maintenance signal via an unknown receptor
Myelin acts as an insulating sheath and shields the long axons of some neurons
Mice lacking PrPc are resistant to disease, but develop only a mild myelinopathy
...
Change PrP
shape to match their own
...


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o
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Ingested - infection - pathogen reaches gastrointestinal tract and rapidly multiplies
...

Vector-borne - ticks, lice, fleas ect
...

Prevention - Hygiene and sanitation, Vaccines - inactivated, attenuated and toxoid,
prophylaxis, insecticides for vector control, quarantine, antimicrobial coatings
...
g
...
Samples from
blood, urine ect
...

Treatment - antibiotics - target specific compnents of bacterial cellular machinery, inhibit
growth or cause bacterial death, combination of antibiotics may help prevent evolution of
resistance and treat infections caused by MDR bactera, different antibiotics for different
diseases, concern of resistance
...

TB - Airborne disease - only 5% of infections lead to disease
...
Mainly in bronchi in lungs, spread through coughing
...
Tubercles - can escape immune detection, body tries
to contain the pathogen in tubercles, small granulomas consisting of epithelioid cells and giant
cells
...
Treatment - triple therapy
over 6months - isoniazis, pyrazinamide, rifampicin
...

E-coli - ingestion - gram negative rod, facultative anaerobe, non-pathogenic strains can cause
disease in immunocompromised, pathogenic strains infect gastrointestinal tract
...
Causes gastroenteritis - water balance disturbed, symptoms such as diarrhoea
and vomiting
...
Treatment - rehydration antibiotics
...

Bacteria enter body via fleat bites or inhalation of contaminated droplets, spread via
lymphatics to nodes, bacteria enter bloodsteam
...

Treatment - antibiotics, quarantine, flea and rodent control
...
Spread through cervix of women and urethra of men
...
Invade non-ciliated epithelial cells by phagocytosis
...
Treatment - antibiotics, safe sex

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