Medicine with Foundation Year

By

Ben McCartneyMYFYDr. Bowater and Dr. Winpenny

GENETICS AND REPRODUCTIVE MEDICINE

DNA

DNA is a double stranded, helical Molecule.

It is composed of nitrogenous bases connected to ribose sugar molecules which are linked together with phosphodiester bonds.

Each chromosome carries a DNA sequence that contains many genes. A gene is a functional unit.

WHAT IS THE GENOME?

Genome - the total DNA in a single cell, representing all of the genetic information of the organism.

It includes the sequence of DNA in the chromosome and any other cellular organelles.

A genome size is usually measured as the number of base pairs.

STRUCTURE OF THE CHROMOSOME

Long and short arm Condensed chromosomes can be stained to give light and dark

bands through G banding using Giemsa dye (sticks to AT rich regions)

Dye using fluorescent tag, shows extra or missing chromosome Each band is numbered Genes can be mapped

Karyotype - the number and visual appearance of the chromosomes in the cell nuclei of an organism or species.

CELL CYCLE

1. G1 you have only one copy of the chromosome, 2. Replication occurs in the S phase (DNA synthesis)3. G2 phase the cell checks the two copies in order to ensure there aren’t any errors

and any mistakes are repaired, this is a pause state.4. M phase (mitosis) occurs. The chromosomes are condensed to ease replication.

Unraveled DNA is useful in order for transcription and translation to take place. DNA is wrapped around histones and histones are wrapped around each other to

create a very tight format

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MITOSIS AND MEIOSIS

MITOSIS:

DNA condenses down, the chromosomes line up and then cell division occurs, the plasma membrane expands, the cytoplasm divides and you end up with two daughter cells. This is important in fetus development and in our lifetime. Our brain cells are not replaced.

1. Interphase DNA unraveled and replicated,

2. Prophase chromosomes condense and centrioles are pulled to opposite sides by spindles,

3. Metaphase chromosomes line up along the equator and attach to spindles,

4. Anaphase centromeres divide and separate chromatids,

5. Telophase chromatids are on opposite poles, cytoplasm divides

MEIOSIS:

The difference between meiosis and mitosis is that, meiosis is used to produce gametes (haploid sex cells) and there is a cross over between the two chromosomes.

ANEUPLOIDY AND NON-DISJUNCTION

Aneuploidy - the absence of whole chromosome(s) or the presence of additional chromosome(s), the chromosome number is not an exact multiple of the haploid number

usually arises from non-disjunction

It can occur when meiosis or mitosis is not carried out properly, one of this can be due to the chromosomes not lining up along the spindle. Non-disjunction can happen at either two stages of mitosis within meiosis.

The most common form is trisomy 21, which is downs syndrome. Some other forms of non-disjunction can cause the death of the fetus. 20% of fertilized eggs go on to have serious non-disjunction. The risk of having a downs syndrome baby increases with age of both the mother and father. And the risk goes down to 1 in 30 if you are a mother younger than 45. This is because the eggs are stuck in phase one of meiosis, and because the eggs are old, there is more chance of errors.

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TESTS FOR DOWN’S SYNDROME

We can carry out amniocentesis; a needle is inserted in the womb, and amniotic fluid is extracted, this is because skin cells are coming off the baby and are in the amniotic fluid so we can extract the baby’s DNA from that. 2-3 weeks are needed before the result of the test are available this is because we need to wait for the cell to reach the necessary cell cycle stage where non-disjunction occurs.

FISH analysis can detect simple trisomies within 24 hours. This is preferable for parents. FISH stands for fluorescence in situ hybridization, and it’s a probe using fluorescent labeled DNA that attach to specific points within the chromosome and this can occur very quickly, this is because you can do this at any stage within the cell cycle. The test is usually used to detect trisomy 13, 18 and 21 (only ones that produce living fetuses).

The first thing to do in order to carry our FISH is melt the DNA from metaphase cells and you need to have two single strands. Due to the human genome project, we have sequenced the entire chromosome, so we know the sequence of chromosome 21 and we can therefore design probes that can attach at different points specific to one chromosome. We then cool the DNA and wash off the probes using a solution to remove and probes that are not attached.

Human genome project succeeded due to the competition between two groups of scientists and the quick advancement in technology, as well as the improved relationship between IT and Biologist, as the computers could interpret the raw data quicker. This was done in order to create personalized drugs as well as commercial reasons such as insurance companies.

We can break up long strands of DNA using enzymes called restriction endonucleases. They don’t do this randomly, they do this at specific sequences, and they can recognize a palindromic sequence that is specific to each enzyme.

PCR is polymerase chain reaction, which is a useful technique to replicate and therefore amplify DNA. This can be used in order to identify the type of bacteria that causes a disease and therefore what treatment you require.

GENETICS AND COUNSELING

Genetic counseling can involve physical examination if relevant, spending time doing laboratory examination in conjunction with the physical examination, history taking and then drawing up a diagnosis.

There may be long term implication not just for the individual but also for the family members and counseling maybe a part of this process sometimes with screening programs.

Consultand = person who is seeking advice

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Proband = the affected individual.

They maybe the same person or maybe the proband is the child of the consultand. Single gene disorders deals with a family rather than an individual.

PEDIGREE DIAGRAMS

Doctors can use a pedigree analysis chart to show genetic disorders are inherited in a family. They can use this to work out the probability (chance) that someone in a family will inherit a condition. This is called pedigree analysis.

Male is put to the left or older sibling. Straight horizontal line means a couple or sibling, vertical line means child. Generations are indicated by roman numerals, oldest is I.

Huntington disease is an autosomal dominant disease, which means that the disease is expressed in the heterozygote, half of the offspring of the affected individual will be affected and that it’s passed on vertically.

Autosomal condition is when you have one normal copy of the gene and one mutant copy of the gene so the individual is a heterozygote, two different alleles at different locus within the gene, one mutant and one normal, then you are a heterozygote.

Huntington disease is the mutation in the genial chromosome 4, which is the Huntington gene, there is a CAG repeat sequence and this length varies between individuals, up to about 34 repeats is a normal allele and CAG codes of glutamine amino acid residue in the protein that is deposited in the organs. A run of more than 34 glutamines is problematic to brain cells as it causes the protein to aggregate causing the cell death within the brain. During meiosis these runs can become very unstable, so the copying process can become problematic and you end up with an even longer tracts of the repeat, so this results in an earlier development of the disease as we go down generations and this is known as anticipation.

Anticipation = onset (beginning) of the disease

TESTS

It’s possible to carry out a genetic test to tell patients at risk whether they can develop Huntington disease, which is an incurable disease, the advantages, are that if negative then any concern is removed. However is the results is positive then they can make plans for the future, which may involve reproductive planning or arranging surveillance to ease symptoms. The disadvantages are that if positive, it removes all hope since the disease is incurable, introduces uncertainty of when the disease will develop, can impact their children and also getting insurance, if the result is negative, then there is expectations of good result within life, and sometimes they make get survivor guilt.

Autosomal recessive conditions are more common when there blood relation. It’s expressed in the homozygote, and there is a low risk of individual offspring being affected. There is horizontal transmission. Homozygous means that you have two copies of the same mutant allele at the same locus.

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X linked diseases; if you are a female then you are a carrier (XX) if you are a male then you are affected (XY). X linked recessive conditions; there is no male-to-male transmission because males pass their Y-chromosomes to their sons. Females are rarely affected by X-linked recessive conditions.

Pre-implantation genetic diagnosis is the introduction of genetic testing into IVF. This guarantees the baby will be free from the genetic disease. Embryos are analyzed and ones that are disease free are then re-introduced to the uterus for pregnancy it’s therefore selecting embryos that are unaffected. Exclusion genetic testing, allows individuals not to find out their own status but guarantee that the disease will not affect their children. As part of the IVF process embryos are excluded from transfer if their carry chromosomal material from the at risk grandparents chromosome. The embryo is directly tested for the mutation but the medical team does not disclose any embryos have been excluded because they had a mutation. So the medical team will know for sure whether or not the parents will develop the disease but they do not disclose this information. This can only happen if there is genetic information available from the grandparents.

With the use of polymorphic markers we can guarantee embryos that are unaffected. These markers are variation between chromosomes, so each individual will have slightly different alleles at the same site, this means that you can distinguish between them.

IMMUNE SYSTEM

The primary function of the immune system is to eliminate pathogens and minimize the damage they cause.

EXTERIOR DEFENCES

TISSUES IN IMMUNE SYSTEM

Primary Development and maturation of immune cells (lymphocytes) Bone Marrow (B cells) Thymus gland (T cells).

Secondary Mature lymphocytes meet pathogens Spleen, adenoids, tonsils, appendix, lymph nodes, Peyer’s patches, mucosa-associated lymphoid tissue (MALT).

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INFLAMMATION

Response to tissue damage (trauma, radiation, invasion of pathogens)

Dolor (pain) Calor (heat) Rubor (redness) Tumor (swelling) Functio laesa (loss of function)

Increased blood supply to infected area Increased capillary permeability Migration of immune cells to site of damage

INNATE AND ADAPTIVE IMMUNE RESPONSE

CELLS OF THE IMMUNE SYSTEM

Innate:

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PMN/Neutrophil – Phagocytosis and killing of microbes Eosinophil – Killing of parasites Macrophage - Phagocytosis and killing of microbes, activation of adaptive IR Mast cell – Expulsion of parasites by release of histamine, allergy Natural killer cell – Lysis of virally infected cells Dendritic cell - activation of adaptive IR

Adaptive:

T lymphocyteso Originate from stem cells in bone marrow o Maturation takes place in Thymus gland followed by migration to

secondary lymphoid tissue o Express T cell receptors which recognize antigens present on surface of

antigen presenting cells (macrophages, dendritic cells, B cells) B lymphocytes

o Originate from stem cells in Bone marrow Maturation in bone marrow followed by migration to secondary lymphoid tissue

o Express surface receptor (antibody) specific for particular antigeno Following exposure to antigen, differentiation into plasma cells and

memory cells

PHAGOCYTOSIS

Phagocytes internalize antigens and pathogens and break them down. o Monocytes/macrophages – long-lived o PMN’s/neutrophils – short-lived

ANTIBODIES

Composed of two heavy and two light chains Surface bound on B cells, secreted by plasma cells

PRIMARY AND SECONDARY IMMUNE RESPONSE

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VACCINATION AND IMMUNISATION

A vaccine is a product that produces immunity from a disease and can be administered through needle injections, by mouth, or by aerosol.

A vaccination is the injection of a killed or weakened organism that produces immunity in the body against that organism.

An immunization is the process by which a person or animal becomes protected from a disease. Vaccines cause immunization, and there are also some diseases that cause immunization after an individual recovers from the disease.

Vaccines: Stimulate protective

adaptive immune response by expanding pool of specific memory cells

Subsequent natural infection induces fast, vigorous response

Harmless forms of the immunogen used to vaccinate e.g. killed or modified living organisms, fragments or toxoids

Vaccines must be safe and affordable

CYTOKINES

Molecules signaling between immune cells and other cells of the body Interferons

o Limit the spread of viral infections until adaptive IR has developed Interleukins

o Various functions, cell division and differentiation Colony stimulating factors

o Division and differentiation of bone marrow stem cells Chemokines

o Direct movement of leukocytes around the body

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Tumor necrosis factors (TNF) o Mediate inflammation and cytotoxic reactions

MENINGITIS

What is it?

Severe inflammation of the Meninges, which are the layers of tissue that surround the brain. Made up of:

The pia mater (closest to the CNS) The arachnoid mater The dura mater (farthest from the CNS). The meninges contain cerebrospinal fluid (CSF).

Meningitis is the inflammation of these linings.

CAUSES

Infectious causeso Bacteria (Life threatening)o Viruses (Less life threatening)o Fungi (e.g. Cryptococcus neoformans, Coccidiodes immitus)o Parasites

Non-infectious causes e.g. tumours, drugs, vaccines, Mollaret’s meningitis

BACTERIAL

Severe inflammation of the meninges caused by bacterial invasion. Can be acquired by a variety of methods:

o by person to person contacto By traumao Following surgeryo By spread from a septic site elsewhere in the body

Most cases community acquired Nesseria meningitidis (meningococcus) (most common) Streptococcus pneumoniae Haemophilus influenzae Hospital acquired meningitis rare – associated with different organisms

HOW DO ORGANISMS GET INTO THE CEREBRO-SPINAL FLUID?

Direct e.g. trauma/shunt with direct access into CSF

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Indirect across the blood brain barrier - bloodstream spread from site of infection

o Normally blood brain barrier with tight junctions between epithelial cells

o Reason how some organisms cross initially is not entirely clear - o Some suggestion of particular advantage in some organisms e.g.

specific pili in N. meningitidis that allow crossingo e.g. creation of local inflammatory response in small blood vessels that

disrupts barrier by injury to endothelial cells Inflammation of meninges allows blood brain barrier to become leaky A larger number of molecules of larger size can then can then cross the blood-

brain barrier

SIGNS AND SYMPTOMS

Early signs and symptoms may be very non-specific e.g. mild viral-like illness or confusion.

3P’s:o Pain in limbso Pale mottled skino Periphery cold (hands and feet)

Triad of fever, neck stiffness and loss of consciousness Rapid onset headache Photophobia (dislike of bright light) Phonophobia Possible signs of increased pressure in head (e.g. fits and seizures) Rash if septicaemic too (blood poisoning)– see below Kernig’s sign positive (unable to straighten leg due to hamstring stiffness) Non-blanching rash – can have meningitis without rash, but is a sign of

septicemia

TREATMENT AND TESTS

Give antibiotic as soon as meningitis suspected Do not wait to complete investigations before giving antibiotic Often GPs will give a shot of antibiotic in the community if they suspect

Blood testso Blood culture o Coagulation screeno Blood for PCRo Full blood count (numbers of white cells)o U+Es/CRP

Throat swab(s) Skin scrape of rash Lumbar puncture if not contraindicated by raised intracranial pressure

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Spinal Fluid: Sent to Biochemistry for protein and glucose levels Sent to Microbiology for:

o microscopy to look for cells in fluido Staining to look for bacteria among cells in fluido Culture to try and grow bacteriao Extra tests – antigen tests and PCR

CSF EXAMINATION

Normal CSF is clear and colourless Look at colour and clarity

E.g.:o cloudy in bacterial meningitiso Blood staining suggests intracranial bleed or traumatic LPo Yellow colour may suggest old blood in CSF

Count on a measured amount of CSF using a counting chamber which contains a grid

Count number of red cells and white cells Look for raised white cell count in meningitis Look as to whether white cells are lymphocytes or neutrophils

Condition Glucose Protein Cells Level

Acute bacterial meningitis

Low High White cells high, mainly neutrophils

Usually >300/mm3

Acute viral meningitis

Normal Normal or high White cells raised mainly lymphocytes

<300/mm3

TB meningitis Low High Mixed neutrophils and lymphocytes

<300/mm3

Fungal meningitis Low High <300/mm3

Malignant meningitis

Low High Usually mononuclear

Subarachnoid haemorrhage

Normal Normal or high Large number of red cells

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VIRAL

More common than bacterial Usually milder signs and symptoms than bacterial Pathogens include

o Enteroviruses (common by faeco-oral spread)o Herpes simplexo Varicella zoster (chickenpox)o Measleso Mumpso HTLV-1o Polyomavirus

TREATMENT

Most people with viral meningitis won't require hospital treatment. Viral meningitis is usually mild and can be treated at home with:

plenty of rest painkillers for the headache anti-emetics (anti-sickness) medicine for the vomiting

Most people take between 5 and 14 days to recover.

INVESTIGATION

Useful specimens are:

Faeces (for enterovirus) CSF (cell count, protein, glucose, viral culture and PCR) Throat swab (viral culture) Paired clotted bloods (serology looking for rise in antibody against a pathogen)

PCR is rapid, highly sensitive, does not require intact viral particles PCR is method of choice for enteroviruses and Herpes simplex Cell culture and serology are slow techniques Enterovirus grows poorly in cell culture

FUNGAL

Rare Usually immunocompromised

o Candida meningitiso Cryptococcal meningitis

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EXAMINATION

Gram stain Special stains – PAS/silver India ink stain for Cryptococcus Culture on special media that support the growth of fungi

PARASITIC

Very rare indeed Contact with contaminated water, food, soil

o E.g. amoebic meningitiso E.g. eosinophilic meningitis from Angiostrongylus (giant African Land

snails)

PREVENTION OF MENINGITIS

Prophylactic antibiotics to close contacts of cases of N. meningitidis and H. influenzae to try and prevent secondary spread

Vaccinations against N. meningitidis group C, Streptococcus pneumoniae and H. influenzae

BONES

STRUCTURE

Dense connective tissue o Support / movemento Protectiono Metabolic

Outer compact (dense) boneo Non-porous

Inner spongy (cancellous) boneo Trabecular structureo Allows room for blood vessels and marrowo Makes bone lighter

METABOLISM

Bone is constantly broken down (bone resorption) and remodeled (ossification) Osteoclasts break down mature bone Calcium released Osteoblasts fix systemic calcium and deposit as new bone cells (osteocytes)

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Osteoporosiso Inadequate formation of new boneo Imbalanceo Defined as a progressive bone disease characterised by a decrease in

bone mass and density leading to an increased risk of fracture

MOVEMENT AND JOINTS

Synovial ball and socket joint – articular bone surfaces covered with hyaline cartilage with an outer capsule enclosing the joint internally lined by a synovial membrane. The internal surface of the acetabulum and the head of the femour is covered with this. Capsule on the outside, internally that capsule is the synovial membrane.

Fibrous capsule – loose but strong, attached from labrum to neck of femur and reinforced by ligaments. N.B. reflected fibres along the neck bind down nutrient arteries

Synovial membrane - nourishes and lubricates the joint with synovial fluid Synovial fluid – viscous fluid secreted within synovial joints by membrane to

reduce friction between the articular cartilages during movement and nourishes joint.

Labrum is a cartilage extension of the acetabulum; it makes it deeper so it makes the joint a little bit more secure.

Cartilage is made out of chondrocyte cells. With Osteoarthritis the cartilage has worn off so the bones start to grind on each other. Osteoarthritis involves the gradual breakdown and eventual loss of the cartilage of joints. The joint capsule becomes thicker and more synovial fluid is produced making the joint swell.

There are numerous muscles involved with the movement of the hip

Flexors: Psoas and Illiacus and secondary hip flexors - rectus femoris and sartorious

Extensors: Gluteus maximus and the hamstrings Adductors: Adductors longus, brevis and magnus and gracilis and pectieus Abductors: Gluteus medius and gluteus minimus (also tilt the pelvis) Lateral rotators: Obturator internus, obturator externus, gemelli, quadratus and

sartorious Medial rotators: Gluteus medius and gluteus minimus

Individual muscles have a primary role but some have secondary, so they can carry out two motions. Muscles work together to initiate or restrict movement; the extensors work in opposition of flexors. The hamstrings can also limit movement.

Limitation of movement:

Extent of ball and socket joint Flexion – anterior part of the trunk/hamstrings

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Extension – ligaments

NERVE AND BLOOD SUPPLY TO HIP

Arteries that supply the hip joint are the Obturator artery branch supplies the head; this disappears, as we get older. And Retinacular arteries, they run back in the reflection of the capsule, the supply the head and the neck from the femur side.

In a young person if a fracture occurs we can just fix it in position as the head will still have a blood supply. In an older patient we will have to put in an artificial hip joint. Nerve supply from three places: the obturator nerve, the femoral and sciatic. The anterior is femoral, the back of the thigh is the sciatic and internal surface is the obturator. All nerves supply a motor and sensory proportion. Motor controls the muscle and sensory is about touch and pain.

DIABETES

Type 1, autoimmune, onset 10-13, genetics, insulin injection short and long acting, pancreatic islet transplantation

Type 2, insulin resistant, onset 40+, poor diet, diet and exercise as well as drug treatment Homeostasis maintenance of constant conditions internal environment irrespective of outside environment, negative feedback

HOMEOSTATIC SYSTEM

Detectors/Sensors – send signal to comparator (receptor cells, neural, measures variable in question)

Comparator – compares the value, generate the effect (CNS, Brain) Effectors – Muscular, hormones, activated by comparator to restore variable to

set point Negative feedback, reverse an effect, switch itself off Positive feedback, increases response, needs a way to switch itself off

Set point is actually a narrow range and not a single number

Resting blood glucose 3-4 mM

HORMONE SECRETION

Pancreas produces insulin and other hormones such as:

Alpha-cells - secrete glucagon Beta-cells - secrete insulin Delta-cells - somatostatin F cells – pancreatic polypeptide

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Gluconeogenesis – production of glucose from glycogen pyruvate, muscle soreness

Glycogenolysis – breakdown of glycogen stores to release glucose Glycogenesis – production of glycogen stores from glucose Glycolysis – breakdown of glucose to pyruvate generating ATP Lipogenesis – production of free fatty acids from pyruvate Lipolysis – production of glucose from free fatty acids

Insulin secretion: glucose enters Beta-cell via GLUT 2 down its concentration gradient, glycolysis occurs, ATP is produced, inhibition of K channels, leads to depolarization, Ca channels open, calcium moves in, causes insulin to be released from secretory granules via exocytosis Somatostatin and glucagon inhibits insulin release by working through adrenergic antagonist Insulin, dipeptide hormone, synthesized in RER, finalized in Golgi, half-life of 5 minutes, stimulated by glucagon, GLP, AA, parasympathetic, decreased by somatostatin and sympathetic Insulin receptor, multi merit protein, alpha and beta sub units, attached to tyrosine kinase system, insulin attaches to the two alpha units, stimulates receptor, allows glucose transporters to be put into the membrane, affect growth as they effect fat and protein synthesis Glucagon, released between meals, half-life 6 minutes, stimulated by AA, para/sympathetic, CCK, decreased by somatostatin and insulin.

DIABETES AND HOMEOSTASIS

Diabetes disrupts homeostasis by affecting the balance of glucose in the body.

Hypoglycemia results when the person's blood sugar falls too low and insulin levels rise too high. The diabetic does not have enough glucose to process the insulin and so this causes an imbalance with the blood stream having too much insulin and not enough glucose.

As diabetes is already a system out of balance, when normal sugar homeostasis is disrupted by either the pancreas not making enough insulin and/or the body's cells not responding to the insulin, glucose homeostasis is disrupted as the glucose levels rise.

Diabetes can disrupt the homeostasis of other aspects of body metabolism as well. Glucose cannot enter the cells - the role of insulin is to allow glucose to enter cells where it can be burned. So the cells simply "starve" while being bathed in glucose. Oxygen levels are not part of this. Cells that are starving for glucose start to burn fat, and produce breakdown products from fat called ketones. Protein is also burned for fuel. This results in wasting of fat and muscle - so in the face of excess sugar the body starves, and in the case of type I diabetes, may starve to death.

Another system which has disrupted homeostasis from diabetes is the body water regulation system. As sugar levels rise in the blood, water is pulled out of the cells, shrinking them. The brain doesn't function as well and foggy thinking happens. Water is pulled out of the vitreous of the eyeball, and it shrinks, causing blurring vision. The high glucose starts leaking through the kidney glomerulus and spilling into the urine, pulling

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water out with it - this happens as levels get to 300 and above. This is why diabetes causes the symptoms of thirst, excessive urination, blurry vision, and ‘foggy’ thinking.

The pancreas, a major endocrine organ, contains special cell types, called endocrine cells, which cluster together in the islets of Langerhans and secrete insulin and glucagon, the first step in blood glucose regulation. After a meal, if the endocrine system is working in homeostatic balance, blood sugars rise and insulin prompts the cells to take up the glucose. At this point, blood sugars can be used by many body parts, like the liver and skeletal muscles, for example, as an energy-giving carbohydrate. As the majority of the glucose is used and stored by the body, insulin production is inhibited. After this inhibition, a healthy person’s homeostatic mechanism causes the glucagon levels to rise, which causes stored glycogen to be reconverted back to glucose to maintain blood levels within the healthy range.

Insulin shock, which can lead to a diabetic coma, is a direct result from the relationship between homeostasis and diabetes. During insulin shock, which is also referred to as severe hypoglycemia, the person produces too much insulin and blood sugar levels cannot adjust. When the body’s dysfunctional homeostasis and diabetes disease is related to the more common cause of the mere physical underproduction of insulin, the body cannot flush the excess blood sugar from the blood stream. In this case, an external dose of insulin is needed for homeostatic balance. This form of diabetes more commonly leads to the body becoming increasingly unresponsive to natural mechanisms.

Another complication associated with the relationship between homeostasis and diabetes is ketoacidosis. In this case, when the extra sugar collects rapidly in the blood stream and cannot be used for cellular fuel because of lack of sensitivity, an overabundance of body fats are broken down to fuel the body. The fats contribute to high fatty acid levels in the blood, which increases the person’s hydrogen ion count and causes ketoacidosis. Severe metabolic acidosis can disrupt many organ systems and can lead to coma and death as well.

BIOCHEMICAL DIABETES

Diabetes patients urinate more than usual. Their urine contains excess amount of sugar.

Pathology is the study of disease.

Pathology is broken down into two branches, cell pathology (Morbid anatomy/histology/cytology) and laboratory medicine which is the bigger part of pathology (bacteriology, hematology, clinical biochemistry, immunology, cytogenesis, and molecular genetics).

Serum is when you allow the plasma to clot.

70% of all diagnoses depend on laboratory tests.

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ORGAN SPECIFIC

Kidney function test looks at different biochemical in the blood, sodium (extra-cellular ion), potassium (intracellular ion), urea (waste product of protein), and creatinine (break down product of phosphate in muscle).

Liver function test, to have a look at bilirubin, this is a breakdown of hemoglobin. Bilirubin is conjugated in the liver and it’s lost as bile, this is toxic in high concentrations. Liver makes protein, so protein levels may drop. Alanine transferase (ALT) is an enzyme that’s found in the liver, high levels mean damage to the liver. Alkaline phosphatase (ALP) pancreas cancer increases this.

Bone profile ALP, calcium, albumin keeps our pressure up, as well as transport things in the blood. Albumin transports calcium so when they are bounded together, it’s not biologically active.

DISEASE SPECIFIC

Diabetes, we can measure, random glucose level, fasting glucose, do an oral glucose tolerance test and measure hemoglobin A1C.

Glucose enters the urine via overflowing from blood; this is in effect of blood glucose concentration and the ability of renal tubules.

In diabetic people blood glucose is high as there is a lack of uptake due to the lack of response to insulin.

High glucose matters as it can have a diuretic effect, so it draws out water, and dehydration.

Glycation is the reaction between aldehyde (glucose) and amino groups on proteins creating a very reactive species, they may cause the implications of diabetes, such as loss of eyesight.

METABOLIC CONSEQUENCES

Dehydration – excess urination Acidosis – increase in acidity of blood and organs Hyperkalemia (high serum potassium) Hyperlipidemia Fruity smell is due to ketone bodies from fat metabolism.

Thyroid disease in diabetics is about twice as common as it is in the general public. Thyroxin is a hormone that is produced by the thyroids we can measure this. The pituitary produces TSH and this controls how much thyroxin is produced. T3 is the active from of thyroxin.

Tumor markers indicate disease:

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PSA: Prostate Tumor HCG: Testicular Tumor CA125: Ovarian Tumor CA 153: Breast Tumor

EPIDEMIOLOGY

Epidemiology is the study of how often diseases occur in different groups of people and why

The epidemiology of a disease is an integral part of its basic description, just like the clinical findings and pathology

Key assumptions: o Human disease does not occur at random o Human disease has causal and preventive factors that can be identified

through systematic investigation Epidemiology has three main aims:

o To describe disease patterns in human populations.o To identify the causes of diseases (also known as aetiology).o To provide data essential for the management, evaluation and planning

of services for the prevention, control and treatment of disease

Endemic disease: The constant presence of a disease or infectious agent within a given geographic area or population group; may also refer to the usual prevalence of a given disease within such area or group. The disease malaria is endemic to tropical areas of the world, such as those in South America or Africa. Malaria, however, is not endemic to Antarctica since it's not present there.

Epidemic: The occurrence of more cases of disease than expected in a given area or among a specific group of people over a particular period of time.This term is very relative. For example, 1000 cases of malaria in a tropical nation may not be an epidemic, but 1000 cases of malaria in England would be an epidemic. That's because the 1000 cases of malaria in an endemic tropical area is considered to be a normal, constant amount of cases of malaria for a set period of time. However, since malaria is not endemic to England, even a small increase in the number of people affected by malaria in England would be considered an epidemic.

Pandemic: An epidemic occurring over a very wide area (several countries or continents) and usually affecting a large proportion of the population.

PREVALENCE – snapshot of number of cases at a given timeo No. of existing cases at a particular point in time o Static concept; measures burden of diseaseo Particularly important when measuring diseases where new cases occur

relatively infrequently, but the disease lasts a long time (ie chronic) o Prevalence is the product of incidence and duration of disease.

INCIDENCEo No. of new cases during a specific period of time

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o Dynamic concept – measures risk o Direct indicator of risk

High incidence = high risk o Incidence can change as the result of changes in transmission or

changes in the rate at which people infected with a particular disease go on to develop that disease e.g. with TB it can take a while before the Mycobacterium Tuberculosis causes TB.

How would you calculate it? o I = Number of new cases ÷ Population at risk x time during which

cases were ascertained

MALARIA

An infection is the invasion of a pathogenic agent, which is able to propagate in or on the host, and can be caused by: bacteria, viruses, fungi and protozoan parasites. Tapeworm is not an infection; it’s an infestation.

The malaria parasite lives intracellularly and then can reproduce both sexually and asexually whilst spending most of their life cycle in a haploid state.

There are three different types of malaria caused by plasmodium species:o Tropical: P. falciparum – most dangerous, most common o Tertian: P. ovale, P. vivax o Quartan: P. malariae

Its host is only humans and they live in hepatic cells and then red blood cells and the female mosquitoes transmit them (anopheles). Its size is between 1-4 micro meters when in merozoite state.

Transmission only occurs through the female anopheles because it is the female that carries the eggs, and it needs to provide nutrients to these eggs which can be obtained from human blood.

It isn’t contagious, but, because the malaria parasite is found in red blood cells of an infected person, malaria can also be transmitted through blood transfusion, organ transplant, or the shared use of needles or syringes contaminated with blood. Malaria may also be transmitted from a mother to her unborn infant before or during delivery ("congenital" malaria).

Distribution: o P. ovale: mainly in tropical West Africa o P. vivax: worldwide between latitudes 16°N and 20°S o P. malariae: worldwide but patchy, mainly tropical and subtropical o P. falciparum: worldwide but mainly tropical and subtropical.

300 million cases each year with 1 – 2 million deaths per year and around half of them are children under the age of 8. This is because a newborn baby gets its immunity from

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the placenta and antibodies from breast milk however as that stops due to undeveloped immunity the risk of catching the infection increases.

The symptoms include:o Fever, shivering, pain in the joints, headache, generalized convulsions,

severe anaemia, and coma.

The fever is associated with the rupture of the red blood cells and the released merozoites. Sequestration of erythrocytes (red blood cells) in capillaries leads to organ damage and cerebral malaria. That’s because when the blood travels through our capillaries the spleen filters out old red blood cells. Old red blood cells are rigid and not so flexible. Infected red blood cells also rigid and have a different shape more spherical. This is seen especially P. falciparum where the infected red blood cells stick to then endothelial cells of capillaries.

THE LIFE CYCLE OF MALARIA:

1. A mosquito becomes infected when taking a blood meal from an already infected human. Gametocytes (macro (female) and micro (male)), mate within the gut of the mosquito and undergo meiosis and then migrate through the midgut wall of the mosquito and form an oocyst, within which thousands of sporozoites develop. These then move to the salivary gland of the female Anopheles.When a mosquito infected with the plasmodium parasite bites and feeds on a human, she injects saliva to stop the blood from clotting causing the injection of the parasite in the form of sporozoites into that individuals bloodstream. The sporozoites travel to the liver and enter the hepatocytes.

2. After Sporozoites have been injected into the human, it rapidly enters the blood stream, within 30-60 minutes it targets hepatocytes and they begin producing thousands of their haploid form called merozoites inside each hepatocyte (between day 5 and 16). (some can remain dormant within hepatocytes resulting in relapses up to years later). For example, In P. vivax and P. ovale some of the sporozoites do not immediately undergo asexual replication, but enter a dormant phase known as the hypnozoite. This hypnozoite can reactivate and undergo schizogony at a later time resulting in a relapse.

3. The hepatocytes will then rupture resulting in the release of the merozoites which will then re-enter the blood stream where they will invade the erythrocytes. Within the erythrocytes they will asexually replicate into a different form of merozoites repeatedly in the next 1-3 days (ring (due to its morphology), trophozoite and finally schizont). The resulting thousands of parasite infected cells causes the illness and complications of malaria.

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4. Some of the merozoites infected erythrocytes will begin to develop into sexual forms of the parasite called male and female gametocytes which will continue to circulate throughout the bloodstream.

5. When another Anopheles bites and infected human it will ingest the gametocytes. The human erythrocytes will then rupture in the mosquitoes gut releasing the gametocytes which will then further develop in mature sex cells known as gametes. The male and female gametes will fuse forming a zygote which will eventually develop into ookinetes which actively move and burrow into the mosquito mid gut wall forming oocysts.

6. The oocyst will grow and divide forming many active haploid formed called sporozoites. After 8-15 days these oocyst bursts releasing the sporozoites into the body cavity of the mosquito which will travel and invade the salivary glands ready for the next human to be infected.

Relapse can occur due to dormant stages where the cells don’t release the merozoites for years and can be activated.

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Malarial paroxysm (attack):

Cold stage: o Feeling of intense cold o Vigorous shivering o Lasts 15-60 min

Hot stage: o Intense heat o Dry burning skin and throbbing headache o Lasts 2-6 h

Sweating stage:o Profuse sweating and declining temperature o Exhausted and weak sleep o Last 2-4 h

The fever is caused by the release of waste product by the parasite. Fever costs a lot of calories, which is an issue for malnourished children. One complication of malaria is cerebral, especially with P. falciparum.

A diffuse encephalopathy (spread-out loss of brain function) that causes loss of consciousness that ranges from stupor to coma. The onset can be gradual or rapid. Patient will be unresponsive to pain, visual and verbal stimuli. Frequent cause of death, this is as a result of capillary blockage by the parasite so the brain does not receive enough nutrient and oxygen.

FEVER CYCLES:

P. vivax/P. ovale: o There is a 48 hour reoccurrence although it’s called tertian which refers

to three this because first day fever, second day no fever and third day fever.

P. malariae: o There is a 72 hour reoccurrence and it’s called a quartan malaria

because of the same logic. P. falciparum:

o There is irregular fever so there is no synchronisation.

TREATMENT

UNCOMPLICATED MALARIA

1. Determine which kind of species is causing the disease, this can be done by geographical location

2. Determine the clinical status on the patient – good/bad health 3. Knowledge of the geographic area where the infection was acquired4. Treatment:

o Chloroquine-sensitive P. falciparum: oral chloroquine

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o Chloroquine-resistant P. flaciparum: qunine sulphate + doxycycline /tetracycline/ clindamycin. Atovaquone-proguanil. Mefloquine

o P. Malaria: oral chloroquine o P. vivax and P. ovale: oral chloroquine. primaquine (liver stage; !G6PD

deficiency) o Chloroquine-resistant P. vivax: quinine sulphate +

doxycycline/tetracycline/mefloquine

COMPLICATED MALARIA

1. Only with P. falciparum; clinical criteria:o Impaired consciousness/coma o Severe normocytic anaemia o Renal failure o Pulmonary oedema o Acute respiratory distress symptom o Circulatory shock o Disseminated intravascular coagulation o Spontaneous bleeding o Acidosis o Haemoglobinuria o Jaundice o Repeated generalized convulsions o Parasitaemia > 5%

2. ICU admission and intravenous administration of anti-malarials: quinidine/quinine + doxycycline/tetracycline/clindamycin (oral or iv)

PREVALENCE

Prevalence: mainly in tropical countries: western Africa, Latin America, and Asia. We had malaria in Europe in Italy and England but the mosquitos need swamps to breed but they have been dried out. The word malaria comes from Old Italian, there was a lot of swamps that had mosquitos; it means bad air because they thought the bad smell of the swamps caused the disease.

The prevalence can be different even in one country for example in Namibia the south has very little cases of malaria but the north there are more cases. So this needs to be taken into account when treating the patient.

Pre-travel (vaccination and prophylaxis):

GP Travel Health Clinics: MASTA, TravelDoctor, TravelHealth.co.uk National Travel Health Network and Centre (NaTHNaC) London School of Hygiene and Tropical Medicine (LSHTM) Liverpool School of Tropical Medicine (LSTM) The Hospital for Tropical Diseases London

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Health Protection Agency, Centre for Infections

Post-travel (treatment):

GP Accident & Emergency The Hospital for Tropical Diseases London Liverpool School of Tropical Medicine (LSTM)

DIAGNOSTIC TESTS FOR TROPICAL DISEASES:

Microscopic examinations: o Blood specimens: stained/thick/thin smears (e.g.Plasmodium sp.) o Stool specimens: wet/stained preparations (e.g. helminth eggs) o Tissue specimens: biopsies (e.g. Leishmania sp.) o Sputum specimens: wet/fixed preparations (e.g. roundworm larvae) o Urine: sediment (e.g. Schistosoma haematobium eggs)

Isolation of organisms: o Tissue specimens: inoculation in culture (e.g. Leishmania sp., bacteria) o Blood specimens: inoculation in mice (e.g. Trypanosoma cruzi)

Detection of antibodies: o Blood specimens: CATT (e.g. Trypanosoma brucei spp.) o Serum/plasma specimens: IgM/IgA (e.g. Toxoplasma gondii)

Detection of parasite antigens: o Blood specimens: enzyme immunoassay (EIA) (e.g. parasite LDH,

Plasmodium sp.) o Stool specimens: enzyme immunoassay (EIA) (e.g. GIAP, Entamoeba

histolytica) Molecular diagnosis:

o Blood specimens: species-specific PCR (e.g. Plasmodium sp.) o Stool specimens: conventional/real-time PCR (e.g. E. histolytica/E.

dispar) Imaging tests:

o Chest: X-rays: pulmonary tuberculosis (pulmonary TB)

GI ANATOMY

The digestive is also called the alimentary or the gastrointestinal system. It prepares, moves and breaks down ingested food so it can be absorbed into the bloodstream to nourish cells and provide energy to the body, while indigestible products are disposed of as waste. There is the digestive tract as well as the accessory organs. The autonomic system, hormones and other chemicals control secretions.

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The tract itself is starting from the mouth and going to the anus. It’s a long epithelial (mucosa) lined muscular tube that is about 9 m long.

Mouth -> Pharynx -> Oesophagus -> Stomach -> Small intestine -> Large intestine/colon -> Rectum -> Anus

The accessory organs are:

Teeth Salivary glands Pancreas Liver Gall bladder.

THE GENERAL STRUCTURE OF THE DIGESTIVE TRACT: (FOUR MAIN LAYERS)

Mucosa – internal epithelium moistened by glandular secretions, connective tissue, and smooth muscle layer autonomic and not under voluntary control

Submucosa - Connective tissue with blood vessels, nerves, and lymphatics Muscularis externa – 2 smooth muscle layers

o Inner circular layer for crushing o Outer longitudinal layer for moving

Serosa - Outermost layer – visceral peritoneum its structure that goes over organs

It has a specific structural make up of layers that vary along the tract related to its function. For example in the oral cavity, pharynx, esophagus and the anus we aren’t absorbing anything. So their role is mainly for movement. We are therefore mainly concerned about protection that comes from the stratified epithelium and no serosa layer.

As we move down we get columnar epithelium and in the small intestine it becomes more and more highly folded to increase the surface area in order to aid absorption and expansion. So in the small intestine we have plica and villi, which are tiny projections that allow for better absorption.

DIGESTION

Digestion itself is a chemical and mechanical process. Physical and chemical modification of food depends on exocrine and endocrine secretions and controlled movement of food through the digestive tract.

Exocrine ducts that carry hormones to the external environment and outside of the body, the key thing is that they have ducts to get the hormones to where they need to be. The endocrines are ductless, and they release hormones into the internal environment and they are slower because they pass through the blood and extracellular fluid. Some gland have both function, the pancreas is one of them. The pituitary, thyroid, thymus are all endocrine glands.

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Processes:

Ingestion and initial breakdown that occurs in the mouth Propulsion/Peristalsis Voluntary movement – oral phase, muscles of mastication Involuntary movement, sequential smooth muscle contractions Physical/Mechanical Digestion Chemical Digestion

o Carbohydrates o Proteins o Lipids o Nucleic Acids

Absorption Defecation

In the oral cavity we have:

Lips (labia) - anterior opening. Cheeks - lateral walls (buccinators muscle). Hard and softpalate - roof/superior wall. Tongue - muscular floor/inferior.

Muscles of mastication consist of the temporal, the masseter that are on the side and then the pterygoid muscle. The ones that are on the side allow us to crunch whereas the pterygoid muscles allows us to move food side to side.

There are three main salivary glands:

Parotid Submandibular Sublingual

Deglutition (swallowing): 3 phases

Voluntary Pharyngeal Oesophageal

Pharynx is a very complicated muscle that is the common pathway for food, water and air. There is also the epiglottis that stops the food entering the airways.

It’s made up of 3 circular constrictor muscles and 3 small longitudinal muscles. They are sitting inside each other to allow expansion. Peristalsis.

Nasopharynx – relates to the nose and no part of digestive system Oropharynx – posterior to oral cavity

Laryngopharynx – relative to the larynx; it’s below the oropharynx and connected to the oesophagus.

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The oesophagus is a 25cm long muscular tube. The upper 1/3 is striated muscle and the lower 2/3 is smooth muscle. It has two sphincters that can squeeze around the food:

Upper oesophageal sphincter (cricopharyngeal sphincter) Lower oesophageal sphincter (cardiac sphincter)

It transfers food from pharynx to the stomach but there is no digestion or absorption. It moves the food to the stomach via peristalsis and relaxation. The stomach is made out of four main areas: Fundus, Body, Antrum, and Pylorus.

There is the cardiac sphincter that’s at the opening of the stomach and there’s the pyloric sphincter, which relates to the sphincter leaving the stomach. There is the lesser and greater curve. It consists of three muscle layers: longitudinal, circular and oblique with specialised mucosa that is highly folded to form rugae.

Mucosa of the stomach simple columnar epithelium: Mucous neck cells – produce a sticky alkaline mucus Gastric glands – secrete gastric juice Chief cells – produce protein-digesting enzymes (pepsinogens) Parietal cells – produce hydrochloric acid and intrinsic factor Endocrine cells – produce gastrin

The stomach acts as a food store as well as breaking down, mixing and churning food. Enzymatic digestion occurs with the help of HCl acid and pepsin that break down proteins to peptides. Absorbs water, sugar and amino acids. Intrinsic factor facilitates vitamin B12 absorption in the ileum. The processed food chyme is then emptied in to the small intestine. The small intestine is a coiled tube from pylorus to ileocaecal junction where the ileum joins the caecum. There is a valve there to stop backflow however if you have a deficiency in that valve you can have a condition called faecal vomiting. It’s about 6m long and chyme usually stays there between 1-6 hours. Its involved in Digestion, secretion, absorption – specialise folded mucosa.

Duodenum (C – shaped, 25cm) curves around the head of the pancreas. It’s the first place where absorption takes place. Due to the acidic nature of the chyme we can get peptic ulcers. The pancreas, liver and gall bladder have ducts that join together, this is called the ampulla of vater, and where it goes into the duodenum it’s called the sphincter of oddi.

Jejunum 40% (8ft) Ileum 60% (12ft)

Suspended from the posterior abdominal wall by the mesentery, which is the intestines with a blood supply that’s running through the peritoneum that attaches and wraps around the intestine.

Water absorbed along the length of the small intestine Absorption of sugars, fatty acids, amino acids, vitamins & minerals

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Absorption of Vitamin B12 & Bile salts - Terminal ileum Substances are transported to the liver by the hepatic portal vein or lymph

Hepatobiliary system:

Liver Gall bladder Associated ducts

o Hepatic ducts o Cystic duct o Common Bile duct

The liver is the largest gland in the body and it consists of four lobes suspended from the diaphragm and abdominal wall by the falciform ligament. It’s connected the gall bladder via the common hepatic duct. It has a role in metabolism and detoxifying drugs as well as degrading hormones and producing cholesterol and blood proteins such as albumin and clotting proteins.

The gall bladder made up of fundus, body and neck stores the bile that is produced in the liver via the cystic duct. Gallstones can cause blockage.

Bile introduced into duodenum in the presence of fatty food and emulsifies them. It also neutralises the acidity of the stomach. It’s made up of bile salts, pigments (breakdown of RBCs), water, mucus, and cholesterol.

Pancreas produces a range of digestive enzymes: fat (lipase), nucleic acids (nucleases) starch (pancreatic amylase) and protein digestion (trypsin, etc.) It also neutralises the acidic chyme. The endocrine aspect produces insulin and glucagon.

Large intestine is about 1.5m in length, contains two flexures – hepatic and splenic. Caecum, Appendix, Ascending, Transverse, Descending, Sigmoid, Anal Canal

Goblet cells produce mucus to act as a lubricant No digestive enzymes are produced Resident bacteria - digest remaining nutrients and release gases Water and vitamins K and B are absorbed Remaining materials are eliminated via faeces

Autonomic system has the parasympathetic (rest and digest) and sympathetic (fight and flight). Enteric nervous system.

METABOLISM AND BILE PRODUCTION

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GI PHYSIOLOGY

We start off from the mouth with the salivary glands there and the esophagus connects the mouth to the stomach, and then from the stomach we got the small intestine which is where most of the nutrients are absorbed, so amino acids, carbohydrates and fats. This leads to the large intestine, the ascending colon, and transverse colon, descending colon and sigmoid colon, which is where most of the water is absorbed before passing to the rectum to be excreted.

The Pancreas sits just under the stomach and it has direct connection to the duodenum and that’s where most of its content comes out and equally there is a connection of the liver via the gall bladder to the pancreas as well, these two tubes join together before emptying into a the duodenum.

Digestion is about breaking down food molecules, we do this by physical and chemical digestion. For the food to move down the esophagus; the esophagus is essentially a muscular tube and it contracts and allows the bolus of food to move into the stomach and once you are in the stomach, it too moves to churn the food. This controls the movement of food, it’s usually smooth muscle that contracts in a rhythmic manner (peristalsis).

There are two layers of the muscle to move the food both down and crush the food transversely at the same time. Chemical breakdown is due to enzymes, the majority of which are produced in the pancreas, but you can get enzymes that are produced elsewhere such as in the saliva and in the stomach. This is why the pancreas feeds at the top of the small intestine to allow time for the enzymes to act.

The absorption of protein and carbohydrates in general they are sodium dependent mechanisms so you need a concentration gradient of sodium to allow you to move amino acids from the lumen of the gut across into the blood.

BLOOD SUPPLY TO THE GUT

There are three major arteries that supply blood to the GI tract

Coeliac artery that supplies–Liver, stomach, spleen, gall bladder and pancreas Superior mesenteric artery –Most of large intestine, small intestine Inferior mesenteric artery –Terminal portions of large intestine, rectum

These arteries supply with nutrients so energy and oxygen to these tissues. Blood from the gut comes from the hepatic portal vein and that drains into the liver and the liver can then remove nutrients or to get rid of waste products by metabolizing and breaking them down. The liver also has a supply of the hepatic artery but that’s only 25% of its blood supply.

Most of the blood flow is regulated by the nervous system (autonomic) or by hormones.

Autonomic nervous system o Parasympathetic (vasodilator)

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o Sympathetic (vasoconstrictor) exercise - gut o Enteric (vasodilator)

Hormonal (endocrine) control o Adrenaline (epinephrine) vasoconstrictor o Gastrin (vasodilator)

Local (paracrine) control o Low pO2 (vasodilator)

DIGESTION

Digestion is in three phases: cephalic, gastric and intestinal.

Cephalic is about thinking: so the smell of food, the thought of food and chewing. Most of this phase is essentially neuronal and it’s all about nervous stimulus. The Medulla in the back of the brain controls it. This sends a signal to all the major areas, so it stimulates salivary secretion, movement of the stomach and also releases gastrin, which has an effect on other tissues. This stimulates the pancreas to produce enzymes and the gall bladder starts to contract and starts to move bile down to the duodenum. Its regulated by the vagal nerves i.e. the parasympathetic.

Once you put food in your mouth, there are receptors on the tongue; it starts to send signals and the sensation of taste adds stimulation of the pancreas and gall bladder. So enzyme and bile are produced more and move to the duodenum so by the time the food leaves the stomach, there are enough enzymes to have an effect. There is also bicarbonate secretion to neutralize the acid. The food moves from the mouth down the esophagus and into the stomach, the stomach expands and there are stretch receptors and that sends a nervous signal through the Medulla that again causes further enzyme and bile production. It also stimulates the production of pepsin and HCl in the stomach. The stomach then starts to contract and churn the food and starts that mechanical breakdown as well as starting to produce HCl that helps to kill any bugs that we might have taken in with the food. It also starts to help to break down protein. And pepsin is a hormone that is produced in the stomach and that helps breaks down the protein.

Once the food starts to leave the stomach we move onto the intestinal phase and that’s when it enters the duodenum and there are a number of receptors that are present, they also stimulate the production of certain hormones, secretin being one of them and cholecystokinin (CCK).

The amino acids, the fatty acids also stimulate the I cells within the duodenum and they are the ones that release CCK. It’s released through the blood stream, and is pumped around the body by the heart and goes to the pancreas and the gall bladder and it basically stimulates enzyme and bile secretion. Both of these then move into the duct system within these tissues, the pancreas and then the gall bladder and empty into the duodenum.

Acid that is coming from the stomach with pH of 2, this hits the duodenum and then secretin is stimulated as a result of that. So the acid content (H+) stimulate S cells in the duodenum and they secrete secretin which is the major stimulus of bicarbonate (HCO3

-),

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this therefore neutralizes the acidity to allow the enzymes to work effectively. The pancreas produces the bicarbonate and it’s also present in bile.

The food then passes into the jejunum and the ileum, by that point the food would have been broken down to manageable bits that allows it to be absorbed. CCK stimulates acinar cells in the pancreas; it causes enzyme secretion and production. Secretin stimulates duct cells and bicarbonate production. G cells in the stomach release gastrin and it’s brought about by the nervous signal that comes from the Medulla and brings about the release of peptide that causes G cells to produce gastrin. It travels through the bloodstream and had an effect on the stomach; it causes the stimulation of histamine release and also brings about the direct stimulation of acid secretion.

Salivary glands – allows us to taste:

Parotid: in the cheeks beside ear. Watery secretion Submandibular: Under jaw. Watery secretion Sublingual: Floor of mouth. Mucous secretion – immunity

Functions: Lubrication. Protection (lysozyme). Digestion (Salivary amylase)

They are controlled by the Medulla. There are a number of nuclei that control the salivary production so from the parotid gland it’s the cranial nerve 9 or glossopharyngeal nerve that controls the secretion. For the two subs its comes from cranial nerve 7. The facial nerve covers the first two thirds of the tongue where as the glossopharyngeal covers the back third.

GASTRIC ACIDS SECRETION

It’s produced by parietal cells. And HCl is essentially produced by an ATP pump. So it’s a proton ATPase. It requires potassium and K moves one way while the protons are pumped into the stomach.

The control of acid secretion is aided by histamines receptors on the parietal cells as well as control from gastrin secretion through CCK receptors and control from nervous input so Ach and parasympathetic system. Histamine receptors react to histamine, which is released from the enterochromaffin cells which is part of the stomach wall and that can be stimulated by gastrin or nervous input. We have nervous input itself and then we have gastrin that’s produced by G cells. It can be turned off by somatostatin.

HCO3- moves into venous blood leaving stomach – leads to rise in pH and fall in acidity

of urine after a meal (alkaline tide).

From a signaling mechanism, we have two, we have cyclic AMP protein kinase mechanism and we have a calcium mechanism. Essentially this leads to phosphorylation of protein kinases and that leads to the insertion of the protein pumps into the parietal cells. So you stimulate acid secretion by increasing the number of proton pumps that are stored in vesicles within the cells. We also have Cl channels that move in to produce the HCl.

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The stomach can turn this mechanism off itself as the food moves out. Too much acid can lead to acid reflux and ulcers in the duodenum.

We can stop this via Proton pump inhibitors (e.g. omeprazole) or H2 receptor antagonists (e.g. cimetidine ranitidine).

Gastric mucosal protection occurs by cells producing a bicarbonate and mucus to provide a barrier to allow the epithelial cells to be protected.

EXOCRINE PANCREAS

It’s a tree structure with the acinar cells at the top of the tree that secrete the enzymes and those enzymes move into the duct system and empty into the duodenum. The duct cells produce bicarbonate. Cystic fibrosis affects the pancreas. These patients cannot produce the bicarbonates so they have to take enzyme supplements before meals. CF is due to a mutation in the Cl channel, as this isn’t working properly, there is a chloride bicarbonate exchanger on the pancreatic cells, which allows movement of bicarbonate into the lumen, and Cl needs to be taken in for this to happen. The Cl channel allows chlorine to be taken back out so the exchange can occur. Bicarbonate secretion is stimulated by secretin. Enzyme secretion triggered by rise in intracellular calcium. Also triggers isotonic fluid secretion.

FAT ABSORPTION

It’s important that we have bile that is produced and stored by gall bladder. And bile is a waste product of liver metabolites. Bile is a mixture of cholesterol and bile acid and bile pigments. Water-soluble aspects of fat like glycerol and short-chained fatty acids can go directly into the capillaries. The non-soluble ones form these micelle cells, which are formed with bile salts, cholesterol and also lecithin. Things like monoglyceride and free fatty acids that are long chained, they have to form micelles that allow the absorption into the enterocytes and then they form chylomicron within the enterocytes, which then move through the lacteal or the lymphatic system which then distributes it around the blood as these chylomicrons are too big to go into the capillaries.

THE LIVER

It’s a hexagonal shape; there is the portal triad that is the hepatic portal vein that is blood coming from the gut, which has all the nutrients. There is the hepatic artery that feeds directly from the coeliac artery and then there is the bile duct, which all the waste product is pushed into that then feeds into the gall bladder.

The triads are on the outside; blood comes up and is pushed through the liver cell removing any waste and breaking down drugs, which then drains, into a central vein that then goes to the vena cava.

Functions:

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Metabolism o Carbohydrate o Protein o Lipid o Drugs

Catabolism o Haem one of the non-red blood cell to produce it

Synthesis o Haem o Liver proteins

Removal of toxic substances o Bilirubin, Bile o Drugs

Storage o vitamin A, B12, D, K o Glycogen o Iron o Ferritin

JAUNDICE

It is the deposition of bilirubin in the skin and sclera due to excess production or impaired secretion of bilirubin. It’s typically seen in the skin and they whites of the eye.

METABOLISM OF BILIRUBIN

Red blood cell (hemoglobin) after a while they stop working so we need to get rid of them and produce new ones, so they go to the spleen (and bone marrow) to be broken up to haem and globin. And the haem part goes through a pathway and forms bilirubin, which is a waste product. It’s also insoluble in water so the body cannot get rid of it. It’s not joined to anything so it’s called unconjugated bilirubin.

We need to make it water-soluble so we can either excrete it. So it goes to the liver and the bilirubin is added to this glucuronic acid and at this stage it becomes conjugated so now it’s water-soluble. Then it goes from the liver into the intestines and this is where most of the water is reabsorbed, so conjugated bilirubin is absorbed into the blood stream. And then it goes into the kidneys so we can wee it out and that’s 95% of it. About 5% of it doesn’t get re-absorbed and stays in the bowels and it’s excreted in the faeces and it’s turned to stercobilinogen and that’s what makes the faeces brown. These points are useful for symptoms.

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TYPES OF JAUNDICE

Pre-haptic (before the liver) so you must be breaking down too many red blood cells and that’s called hemolysis and this could be because of cancers or drugs or infection.

Hepatic so at the liver something stops conjugating the bilirubin so this can be caused by hepatitis, cirrhosis, cancers, and drugs.

Post-hepatic an obstruction after the liver so that’s why it’s also called obstructive jaundice

Type of Jaundice causes:

Pre-hepatic - Excess breakdown of erythrocytes e.g. sickle cell disease Hepatic - Liver disease e.g. alcoholic cirrhosis Post-hepatic (Obstructive) - Blockage of the biliary tree e.g. pancreatic cancer

The biliary tree connects the liver to the small intestine. The bilirubin is conjugated in the liver and it comes from the right and left hepatic duct and it form the common hepatic duct and then the gall bladder secreted bile and it joins with that and goes down the common bile duct and that all gets secreted into the intestine at the sphincter of oddi. So if there is a blockage anywhere in this biliary tree you get a buildup of bilirubin behind it as it can’t be passed into the intestine to be excreted.

Causes of obstructive jaundice:

Gallstone, which is made up of cholesterol Pancreatic cancer Pancreatitis

Symptoms of obstructive:

Yellow appearance

Itching this is due to a buildup of bilirubin and that spills over to the blood stream and that makes them itchy

Pale stools because as we said bilirubin goes into the gut and 5% continues in the bowels and then gives you the brown colour, so you get white faeces if this isn’t occurring.

Dark urine so as we said conjugated bilirubin is water-soluble, it makes the urine really dark brown.

Investigations of jaundice:

Blood tests Liver function tests (LFTs) ↑ bilirubin ↑ alkaline phosphatase (ALP) enzyme that’s in the walls of the biliary tree

which gets released so excess levels is due to gallstones, pancreatic cancer causing a blockage so the walls are damaged and the release this ↑ alanine

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transaminase (ALT) this is more specific to the liver also high in hepatic jaundice.

Abdominal Ultrasound

Dilated common bile duct (indicates obstruction) that can be caused by Gallstone, Pancreatic Cancer followed by CT scan.

Pancreatic cancer

Epigastric abdominal pain as the surrounding are pressed Jaundice Pale stools Dark urine Weight loss as with any cancer

CT scan to look for dilated ducts.

Treatment depends on whether it’s localised or spreading and usually when patients present symptoms the cancer has already spread so often it’s caught really late. If it’s caught early you can carry out surgery and remove the tumour, Whipple’s procedure. If it’s caught really late then it’s ensuring they are comfortable by providing adequate pain relief, maybe chemotherapy to shrink the cancer size. Or they can have endoscopic stenting done which is where they put a camera down your mouth, and down the intestine, up the biliary tree via the sphincter of oddi and then you can see what you’re dealing with and you can put a stent which is like a scaffolding, it just opens things up and may relieve some of their symptoms.

HOW DRUGS WORK

Pharmacokinetics is what the body does to drugs Pharmacodynamics is what the drugs do to the body

First of all you have to get the drug into the patient before it can exert any effect so a lot of pharmacokinetics is working out how to get the drug into the body.

HOW CAN YOU GET THE DRUG TO THE TARGET?

The drug must pass through at least one cell membrane barrier after administration and it can do this by

Lipid soluble drugs passively diffuse through phospholipid bilayer of membrane down a concentration gradient

Or drug mimics natural protein and is transported actively (levodopa) Or small water-soluble molecule (lithium) pass through ion channels

So passive diffusion of the drug depends on the ionized state of the drug so if unionized then its lipid soluble and passes through easily where as if it was ionized it would be water-soluble and pass through with difficulty.

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Level of ionization depends on the disassociation constant so whether it’s weak/strong acid or base and so the pH of body fluid.

Most drugs are weak acids or bases so for example aspirin (acetylsalicylic acid). In the acid stomach the pH is less than 5 so the aspirin molecule is uncharged rather than disassociated into the Asp-H+ so that passes through the gastric cell. When it gets in the pH 7.4 the drug becomes ionized and becomes water soluble it dissolves in the blood stream and travels to the site where it’s needed.

Unionized drugs Digoxin – cardiac drug. Prednisolone – corticosteroids to reduce inflammation No ionisable groups Not affected by pH Lipid soluble Easily pass through membranes

Permanently ionized (polar) drugs: Very acidic

o Heparin, lots of negatively charged GAGs stays in the blood steam due to its large size. Stops blood clot. IV administration.

o Cannot be absorbed orallyo Doesn’t cross placenta either, safer in pregnancy

Very basico Ipratropium (Atrovent) – asthma inhalero Stay in the lung due to its large size, less diffusion elsewhere so

possibly fewer systemic effects so it doesn’t affect anything else

EFFICIENCY

Bioavailability - the Proportion of parent drug that passes into systemic circulation after administration.

Oral determinants are:o Level of absorption, loss in faeceso First-pass metabolism

Calculate by comparing:o Amount in circulation after oral doseo Amount in circulation after iv dose

So taking regular blood tests to see how much of it has been absorbed.

Half-life is the time taken for the drug concentration to fall to half of its initial value. We want drugs to have a constant half-life since we’ll know how long it’ll stay in the body. Most drugs are first-order kinetics.

Alcohol has a half-life of an hour 10 mg/dl at 9 am 5 mg /dl at 10 am

So after 5 half-lives or 5 hours there will only be 3.125% of alcohol remaining, so 96.875 of it has been eliminated.

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HOW IT EXERTS AN EFFECT

When the drug gets to target site it must have some means of exerting an effect.

They can do this by many ways, one of which is receptor:

The receptor is a protein molecule on the surface of the cell and that binds to the drug, hormone or neurotransmitter and its principal role is to act as a recognition site. The receptor then sends a signal to the cell to elicit some sort of response.

Selectivity - propensity of drug to affect one type of receptors more than others.

You would like to design a drug that affects receptors that are of interest and not just all of the receptors in the body. For example:

Adrenaline stimulates both beta-1 and beta-2 adrenergic receptors Salbutamol more selective – greater affinity for beta-2

Drugs are never specific COX-2 inhibitors have some effect on COX-1

Patient with asthma:o Usually has salbutamol inhaler 200 mcgo Given salbutamol nebuliser (5mg)o Opens up airways via beta-2 receptorso But patient feels their pulse speed upo At high doses, salbutamol affects both beta 1 and 2 receptors.o Beta-1-receptor – increase heart rate

There is something called agonist and there is something called antagonist. So the agonist binds to the receptor and that’s governed by affinity and we measure efficacy so that’s the response. But the antagonist sits on the receptor and stops anything else from getting there so it elicits no response.

SITES OF DRUG ACTION

Directly on the cell Block transporters Change ion flow across channels Block enzymes

OR Most often Act via receptor binding Signalling via this receptor interface

The most wildly known receptors are called G-protein coupled receptors and this send a wide range or signals from outside of the cell into the cell. Most drugs target G-proteins or their downstream messenger. Once it’s bound to the receptor the signal can be transmitted in many different ways, it can open ion channel, it can activate a second messenger, it can trigger protein kinase to change synthesis of proteins in the cell or it

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can affect the gene transcription in nucleus. The receptor is merely a way of getting a signal through the cell to change something that is happening there.

Nicotine does number 1; it gets to the brain in 12ms.

Receptors and effect on DNA Corticosteroids - receptors on outside Conformational change after binding Steroid-receptor complex migrate to nucleus Interacts with DNA – change gene expression so the cell doesn’t produce so

many inflammatory mediators Reduces inflammation

CLINICAL EXAMPLES

If you took corticosteroids for asthma it would take hours or days for its effect to become apparent so they do not have an instant effect. They are given 1-2 times a day for several days before the patients have any benefit. So the patient will require other drugs for rapid relief symptoms such as:

• Salbutamol in acute asthma goes through second messenger• Prednisolone steroid tablets for 7 days

AGONIST – ANTAGONIST

Agonist Antagonist

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Drug + Receptor Drug + ReceptorActivation BindingCellular Response No response

There are different levels of agonism, so there is partial agonist, which causes activation but some response (not full). Examples: adrenergic stimulant - ephedrine cannot raise blood pressure as much as adrenaline.

Antagonist has no effect by itself but it binds to part of the receptor and prevents agonists from stimulating a response so it’s a blocking agent. Beta-blockers block the beta1 receptors on the heart so adrenaline cannot stimulate and get faster heart rate.

There are two types of antagonists:1. Competitive – it can be overcome by increasing agonist concentration so you

displace the antagonist so you can get the maximum response.2. Non-competitive – it cannot be overcome no matter how much agonist you add

as the antagonist has bound irreversibly to the receptor

TOLERANCE

Gradual decrease in effect over days / weeks Reduced clinical response to drug effect with chronic use Increase in dose necessary to achieve effect previously obtained with lower

dose

Alcohol tolerance occurs due to the liver producing more enzymes that breaks down alcohol.

Opioid tolerance:

Patient with cancer start with 20mg of morphine every 4 hours with good pain relief initially. On transfer to hospice the pain reoccurs so the dose is increased to 30mg with good effect and no further nausea.

Most people can start with 5-10 mg a day but if someone has been taking them for a while 10-30 mg is required to achieve the same response. Increase of dose by 30-50% if there is no response with regular review.

Receptor regulation

If you keep bombarding the receptor with morphine then the body will try and compensate so it might reduce the number or density of receptors on the cell as well as

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the way the receptors occupy or bind to the drug. This is as a result of homeostasis where the body tried to restore cell function to usual state.

Up regulation occurs after prolonged use of antagonist – increase beta-receptors after use of atenolol (beta- blocker)

Down regulation occurs after prolonged high concentration of agonist so the body reduces receptor number and affinity. Less response to salbutamol in chronically treated asthmatics.

Rebound phenomena

If you stop a drug suddenly and your receptors are down or up regulated that causes havoc. So you get withdrawal symptoms.

DRUGS AND TRANSPORT SYSTEMS

Some drugs don’t need receptors they can work on carrier pumps for example omeprazole on proton pump used to reduce gastric acidity and allows ulcers to heal.

Drugs can affect ions:o Indirectly through G protein receptorso Directly binding to channel protein

If you block the calcium channel then the muscle on your artery relaxes.Examples of direct effects:

Lidocaine (local anaesthetic) physically plugs the Na channel

Stops the electrical activity in the nerves No transmission of pain

DRUGS AND ENZYMES

It’s a widely used method, you can block an enzyme with a drug, and aspirin does this, it permanently knocks out platelets COX so clots aren’t formed. Can be reversible or irreversible.

ACE inhibitors:

Angiotensin II makes your blood pressure go up and make your heart rate speed up. The ACE inhibitor stops the production.

You can use it with patients with high blood pressure, heart failure and stroke.

NSAIDs & Aspirin

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Non-steroidal anti-inflammatory drugs Widely used in relieving pain NSAIDs binds reversibly to channel in cyclooxygenase (COX) enzyme But Aspirin irreversibly deactivates COX – acetylation of serine residue this is

important as we will need new platelets

COX deactivation Reduces conversion of arachidonic

acid to other inflammatory mediators

o Prostaglandinso Leukotrienes

Antipyretic lower the temperature Anti- inflammatory Analgesic

ASTHMA

Asthma is the chronic inflammation, which obstructs the airways. It’s managed by the use of various different types of inhalers. It’s susceptible to individuals. And it’s a widespread airflow obstruction.

Asthma is reversible either spontaneously or by treatment unlike chronic obstructive pulmonary disease.

SYMPTOMS OF ATHSMA

Wheezeo Diffuseo Polyphonico Bilateralo Particularly expiratory

Tachypnoea – rapid breathing it sign and can be observed over 30 for pneumonia

Tachycardia – fast heart rate Cyanosis – blue appearance due to lack of oxygen more deoxyhaemoglobin

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When you are having acute asthma you have to breathe fast because you can’t get air in as much and the heart rate goes up. Breathlessness is a symptom; it’s a feeling of uncomfortable breathing.

Additional information:

Whether they have a family history of atopic conditions such as eczema or hay fever, which go along side asthma. Or if anything worsens the symptoms after exposure or trigger such as pollen, dust, animals, exercise, chemicals, tobacco. Or whether symptoms are worsen after taking

NSAID non-steroidal anti-inflammatory drugs like brufen or voltaren are used as painkillers and can make asthma worse.

Beta-blockers they do the opposite of bronchodilators so they too can make asthma worse.

TREATMENT

Bronchodilators are reliever inhalers – reduce the airway constriction Inhaled steroids are preventative inhalers – reduce inflammation If you take your blue inhaler more than twice a week you should be on

inhaled steroids.

Now we have some bronchodilators that are required and used to prevent symptoms and they are long acting. Relievers are quick acting, with onset of about 5 minutes and lasts for half an hour.

One of the companies discovered that by adding a lipid tail to the drug, it binds to the membrane and keeps acting but the onset wasn’t as quick this is called serevent or salmeterol. This had to be taken twice a day so it wasn’t a reliever as such.

We try and control the symptoms to give good life quality and without having to give lots of medications.

Asthma treatment cascade: • Genetic predisposition – you can inherit it, it’s not autosomal dominant: there is

no treatment for this• Allergen/irritant exposure – cause the symptom: avoidance, which is impossible

the guidelines advice against this.• Inflammation – as a result of exposure: anti-inflammatory drugs• Inflammatory mediator release – as a result of inflammation: mediator blockers• Bronchoconstriction – airways are constricted as a result of these mediators:

bronchodilators

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ANTI-INFLAMMATORY DRUGS

The best kind is corticosteroids. Xanthines are weak drugs and new generation is PD4 inhibitors. Cromoglycates are used with children and they stabilize mast cells. You can give people with severe asthma immunosuppressant therapy such as cyclophosphamide which are extremely rare.

They work by having an effect on all inflammatory cells; they have a global effect. They reduce all inflammatory mediators and increase all anti-inflammatory mediators. They reduce eosinophils, macrophages and lymphocytes. And we have grade A evidence for their effect.

Side effects are: Weight gain, Water retention, Hypertension, Diabetes, Osteoporosis, Psychological, Growth in children, Bruising/skin thinning and gastric irritation

Inhalers are advantageous as you can deliver the drug directly to where it’s needed which reduced both the systemic exposure and systemic adverse effects.

But the difficulty is getting drugs into the lungs and we can do this via different type of inhalers. To administer we have:

Nebuliser – it’s job is to get the liquid drug into an aerosol Metered dose inhaler – puffers, drug is in a canister under pressure and

when pressed the exact dose is delivered, however its fired very quickly and you got to breath them in and get them through a 90 degree bend into the airways and it diverts, so they have to be the right size and the right velocity

Dry powder inhaler – they are drugs that are packets of dry powder that you breath in

The problem with them is that people don’t take them properly so they need to be trained.

Xanthines

They can be given orally or IV, they are weak anti-inflammatory and weak bronchodilators. They were used often in the past but not so much today. Some side effects are nausea and drug interaction.

PDE4 inhibitors

New generation theophyllines and are taken orally. It’s a Roflumilast and they are not licenced yet. Side effect is nausea.

Cromones

Stabilise the mast cells, which are one of the inflammatory cells and they stop them releasing the chemicals, which causes the problems. Mast cells release two chemicals: leukotrienes and histamine. So the drug stops their release. Used in children and have to be taken regularly.

Mediator blockers LTRA (LeukoTriene Receptor Antagonist) after steroids Anti-IgE

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Lipoxygenase inhibitors - not used in UK but similar to LTRA Antihistamines

Leukotriene inhibitors

Work by blocking leukotriene C4/D4 and block production 5 LO. They cause problems with smooth muscle constrictions.

Histamine

There is no clear clinical role, can be beneficial in patients with allergic asthma and it’s used orally, side effects is sedation.

Omalizumab

Monoclonal antibody – binds to circulating IgE which is an antibody involved in allergic reactions. So by blocking it we reduce the inflammation.

Bronchodilators B2 Agonists they work on beta-adrenergic receptors so they are similar to

adrenaline. Adrenaline works in sympathetic pathway. Anticholinergic

B2 agonists

They are fast acting effective bronchodilators that increase cAMP so the smooth muscle relaxes.

1. Short acting Salbutamol (ventolin) Terbutaline (Bricanyl)

2. Long acting Formoterol Serevent it’s a long actin slow onset drug

Combination

BTS treatment steps Step 1 – SABA short acting bronchodilators Step 2 – ICS 200-800mcg/day low dose steroids Step 3 – ICS + LABA high dose of steroids with long acting

o Better – continueo Bit better – add LTRAo No better change high dose ICSo LTRA or theophylline

Step 4 – ICS 2000mcg/day - LTRA + LABA + Theophylline

Step 5 – OCS oral cortisteroids

Some people with chronic condition do not take the inhalers at all.

NON-PHARMACOLOGICAL MANAGEMENT Primary prophylaxis – avoid

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o Allergen avoidance – no evidenceo Breast feeding – should be encouraged o Modified Milk formula – no benefito Other diet – studies ongoingo Microbiological exposure – no evidenceo Immunotherapy – prevents development of asthmao Smoking – parents should be encouraged to stop

Secondary prophylaxis – developing furthero Allergen avoidance

Environmentalo Smoking – should stopo Air pollution – probably – no firm evidence

GORD – should be treated, probably won’t help asthma High altitude - beneficial effects no

long term data Immunotherapy – reduce asthma and

symptoms, no comparison to other Rx

CONSULTATION SKILLS

I = Ideas C= Concerns E= Expectations

OBESITY

Overweight and obesity are defined as abnormal or excessive fat accumulation that may impair health. While some people are genetically more susceptible than others, the direct cause of obesity in any individual is always excess of energy intake over energy expenditure.

Underweight <18.5 Normal 18.5-24.9 Overweight 25.0-29.9 Obese 30.0-39.9 Very severe obesity >40

AETIOLOGY OF OBESITY

Behavioural factors

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o á In prevalence not due to increase in calorific value but due to decrease in activity levels

o High-fat dietso Snackingo Consumption of energy-dense foodso Alcohol consumptiono Smokingo Decrease in activity levels

Genetic factorso Mutations of melanocortin-4 receptor (MC4R)o Prader-Willi syndrome (childhood obesity with abnormal appearance

and CNS function)o Mutations in leptin gene

Specific causes (a few cases of obesity)o Endocrine factors (Hypothyroidism, Cushing’s syndrome,

Hypopthalamic tumours, Insulinoma)o Drug Treatments (Tricyclic antidepressants, sulphonylurea drugs,

corticosteroids, some oral contraceptive pills)

There are particular proteins that are thought to be involved in appetite control; leptin and ghrelin are an example. Ghrelin levels go up in-between meals so it’s a stimulant for eating; leptin on the other hand goes up with body fat so the more body fat you have the more leptin you have, it signals to the brain you have had enough to eat and its released by adipose tissue.

Metabolic syndrome is on the rise because of the rise in obesity, it’s a clinical name given to a number of different issues. There is a set of risk factors:

o A decreased ability to process glucose (insulin resistance, hyperinsulinism, glucose intolerance)

o Abdominal obesityo Atherogenic dyslipidemia (unhealthy lipid levels - á VLDL, â HDL-

cholesterol, á small, dense LDL) changes within your lipid composition in the blood leads to CVD

o Endothelial dysfunction (hypertension) constriction of the arteries so the blood pressure goes up

If you have any three of those then you have metabolic syndrome.

Obesity is the main cause that starts all of these issues.

ROLE OF ADIPOCYTE

Storage of free fatty acids that can be released on demand.

They are classed as endocrine tissue. It produces vast different components: metabolites, hormones, peptides that are all pumped into the blood. One of the main ones is a

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hormone called leptin, as fat cells increase, the amount of leptin goes up. It has a role in regulating what we eat and controlling appetite.

The fat cells also produce cortisone, which is a stress hormone. Also produced pro-inflammatory cytokines (TNF-α – Tumour necrosis factor-α, IL-6 – Interleukin which contribute to insulin resistance & vascular dysfunction). It also produces anti-inflammatory as well (adiponectin).

REGULATION AND CONTROL

Stretch receptors in the stomach and duodenum send a signal to the brain to let us know that we have had enough to eat. The absorption of nutrients is another signaling mechanism.

GLP-1 is released when we take food in.

In obesity these regulators aren’t working properly and we don’t have the same energy output, so more energy comes in that goes out.

Short-term regulation of food intake in order to stop us from over eating done by nervous impulses sent by stretch receptors:

CCK – pancreatic enzyme secretion, satiety signalo Released from small intestine in response to nutrients (e.g. FAs)o Influences satiety by action on CCK receptors located in peripheral

vagal afferent terminals GLP-1, PYY important for maintaining glucose homeostasis

o PYY released from intestine after meal in proportion to meal size. It’s a satiety signal.

o Evidence suggests peptide reduces food intake by action on inhibitory presynaptic NPY Y2 receptors on arcuate nucleus NPY neurons

Ghrelin stimulates food intakeo Released from stomach during fasting & before meals, falls within an

hour of food intakeo Activates NPY-expressing neurons in arcuate nucleus

Long-term regulation of food intake Glucostatic

o Hypoglycaemia (low blood sugar) produces hungero Increases firing of glucose-sensitive neurons in hunger centre while

also decreasing firing in neurons in satiety centreo Also activates orexin-containing neurons in LHA

Insulin satiety signal o Mechanism exists for transport of insulin across BBBo Insulin receptors expressed in appetite-controlling areas of the brain

(Arcuate nucleus)o Insulin deficiency leads to hyperphagia in uncontrolled type 1 diabetes

Leptin satiety signal o Leptin secreted by fat (adipose) cells, plasma leptin levels rise with

increasing fat stores

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o Leptin receptors expressed in appetite-controlling areas of the brain (arcuate nucleus)

o Leptin deficiency is uncommon cause of obesity, instead leptin resistance results from defects in transport across BBB or impaired intracellular signalling

o Interacts with insulin and its production, it inhibits insulin release whilst insulin stimulates leptin release.

The main controller is the brain in the hypothalamic area and there are certain areas that we know are important:

Satiety centreo Located in ventromedial nucleus (VMN)o Electrical stimulation of this centre elicits sensations of satiety (even in

presence of food)o Lesion of this centre causes continuous food intake (hyperphagia:

wanting to eat something) even in absence of need Hunger (feeding) centre Located in lateral hypothalamic area (LHA) Electrical stimulation of this area elicits voracious appetite (even after adequate

amount) Lesion of area causes complete and lasting cessation of food intake (aphagia) Paraventricular, dorsomedial & arcuate nuclei have major roles in appetite

control

If we look at the arcuate nucleus we have two types of neurons that cause us to decrease or increase food intake. If you stimulate these neurons they will elicit a response. There are interactions between these neurons.

Insulin, leptin and CCK cross the blood brain barrier and interact with these neurons and they do that by attaching to their receptors, and if you stimulate them, they will reduce food intake.

Ghrelin on the other hand which we know is a stimulant interacts with the neurons on the other side of arcuate nucleus and stimulation of those neurons leads to increase food intake.

Defective signalling of melanocortin system leads to obesity e.g MCR-4 mutations.

The neurons that increase food intake are orexigenic stimulate either neuropeptide Y or AgRP (Agouti-related protein), these are neurotransmitters that are being produced by these neurons that cause stimulations of neurons higher up the hypothalamus.

The AgRP have receptors to leptin and insulin but this time they inhibit these neurones. So not only are you stimulating neurones that reduce food intake, you are also inhibiting the neurones that increase food intake.

Equally if you stimulate these neurones like ghrelin does they can inhibit these neurones, so stimulation of food intake will inhibit the satiety neurones.

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TREATMENTS

Obesityo Weight reduction by behavioural change; reduce energy intake and

enhance energy expenditure Physical Inactivity

o Regular and moderate regimens of physical activity (e.g.30mins exercise daily)

Atherogenic and diabetogenic dietso Low intake of saturated fats, trans fats and cholesterolo Reduced intake of simple sugarso Increased intake of fruits, vegetables & whole grains

Management of metabolic risk factors: Atherogenic dyslipidaemia

o Elevations of triglycerides, apoB, small LDL particles &low HDL cholesterol

o Statins (3-hydroxy-3-methylglutaryl (HMG)-CoA inhibitors) prevents fat absorption

o Fibrates they effect the enzymes that are on tissues, allows the fat to be moved into the tissue.

o Orlistat Inhibits GI lipase action thus reducing fat uptake

Blood Pressureo ACE inhibitors or angiotensin receptor blockers believed to be better 1st

line therapy Insulin resistance and hyperglycaemia

o Preliminary reports indicate that metformin or thiazolidinediones reduce risk for type 2 diabetes

Prothrombotic stateo Elevations in fibrinogen, plasminogen activator inhibitor-1o Low-dose aspirin or other antiplatelet drugs

Proinflammatory stateo Elevated cytokines (e.g. TNFα & IL6) and acute phase reactants (C-

reactive protein & fibrinogen)

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o No specific anti-inflammatory drugs available

HISTOPATHOLOGY

Pathology consist of different branches, we use samples to find the manifestation of the disease:

Chemical pathology Clinical cytogenetic and molecular genetics Haematology Histopathology Immunology Medical Microbiology and virology

Histopathology refers to the microscopic examination of tissue in order to study the manifestation of the disease.

We receive a variety of small biopsies, so samples that have been removed from various organs and we answer any clinical questions by examining it under the microscope.

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We also examine whole organs that have been removed during surgical procedures such as ones taken from a cancer patient, for example gastrectomy or mastectomy. This isn’t cancer exclusive.

We also provide prognostic information such as depth of invasion or clearance of margins.

In order to examine the samples, we need to make then transparent, so we have to make the sample hard in order to be able to slice and stain it. We ink the specimen; we slice it and we have plastic sets that we put the tissues in. machines work over night with alcohol and zylon base that make the tissue really hard. The sample is then pushed down, more fluid goes down and you are left with a sample that can be sliced and the wax can be stretched on the slide to allow examination. We then have to stain it.

BREAST CANCER• Very common, most common in UK• 1 in 8 women incident rate • 2010 49,500 women and 400 men were diagnosed • Breast cancer has increased by 70% since the 70s• 11,700 people died from breast cancer but it has been reducing by 40%

ANATOMY

The breast sits on the chest outside the ribs and the pectoral muscle and mainly consists of fatty tissue and there are the lobules that produce milk. Some ducts that go to the nipple.

Milk is being produced and is secreted via the duct to the nipple has been compared to a daist with petals each breast has 15-20 lobes.

The lymphatic system runs along the veins and the arteries and picks up the fluid from inbetween the cells and flows towards the axilia (the armpit) where lymph nodes filter the fluid. This is a way of cancer dissemination.

SIGNS AND SYMPTOMS

Most common sign is a lump or thickening in breast. With the screening programme, cancer should be detected before a lump has been found.

Discharge or bleeding from the nipple Change in the size or contours of the breast due to tomour Inversion of the nipple Crusting of the nipple Redness of the skin called inflammatory response

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We have two types of cancer one that hasn’t spread through the walls of the ducts we call it in situ so its still there and hasn’t spread to the surrounding tissues Ductal Carcinoma in situ (DCIS).

We also have the Invasive Ductal Carcinoma (IDC) that has spread to the surrounding tissues and its 80% of breast cancer. The ductal or the lobules, doesn’t really matter.

Histopathologists look at the: Frozen section Gross dissection Microscopic examination Sentinel lymph node Interpretation of immunohistochemistry (prognostic and predictive markers)

In order to get a quick interpretation, the sample is frozen to -25 degrees Celsius; we then slice the sample that allows us to take a quick look. Surgeons do this during the operation in order to check clearance margins and to ensure the right tissue has been removed.

We have to also:

1. Orientate the specimen, to specify its location2. Ink the surface with one or multiple colours to know the orientation3. Palpate the tissue and identify the lesion4. Cut the tissue in transverse sections.

STAGING

TNM staging of breast cancer, this is the tumour node metastasis classification that is specific for each organ. For the breast this was decided to be the size of the tumour.

NOTTINGHAM PROGNOSTIC INDEX

The index is calculated using the formula:

NPI = [0.2 x S] + N + G

Where:

S is the size of the index lesion in centimetres N is the node status: 0 nodes =1, 1-3 nodes = 2,

4+ nodes = 3 G is the grade of tumour: Grade I =1, Grade II

=2, Grade III =3

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Score 5-year survival

>/=2.0 to </=2.4 93%

>2.4 to </=3.4 85%

>3.4 to </=5.4 70%

>5.4 50%

NODES

Sentinel lymph node, we have lymph nodes that filter our blood and fluids and they identify antigens and remove them from the circulation. Cancer cells can spread this way. We can remove the lymph nodes from the axilla and examine them. We used to remove the whole of the axillary tissue, which created problems, the fluid cannot be taken away and so it accumulates so you end up having lymphedema that is sensitive to trauma and it can lead to cancer.

The alternative solution came after realising the lymph goes through a node that can be identified which is called the sentinel lymph node. We inject the tumour with a colour or with a radioactive isotope then we wait for the fluid to be carried towards the axilla and it’ll stain the lymph node blue. So when they look at it, the blue node is visible and they can remove it.

We stain the tumour for the expression of oestrogen so that you might think it’s a hormonal dependant tumour. If the count is high, the patient will receive anti-oestrogen therapy.

A breakthrough was also the identification of this protein Her2. The cytoplasmic membrane expressing her2 will mean that the patient will receive Herceptin. If that is negative she cannot get drug as its very toxic. Her2 is the name chosen for that particular gene of the epidermal growth receptor family; its normal role is to regulate cell cycle and proliferation.

BREAST CANCER TREATMENT

1. Chemotherapy2. Radiotherapy3. Selective oestrogen response modifiers (TAMOXIFEN)4. Aromatase inhibitors (anastrozole- Arimidex) enzyme that synthesis

oestrogen in the female body and these are better for post-menopausal but it’s more expensive.

5. Herceptin (trastuzumab) her2 patients

PSYCOLOGY

Health is a state of complete, physical, mental, and social wellbeing and not merely the absence of disease and infirmity.

We think of health in 6 different ways:1. Not having symptoms2. Having physical or social reserves3. Having healthy lifestyles4. Being physically fit5. Psychological wellbeing6. Being able to function

Psychology is the scientific study of the mind and behavior.

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There is a strong link between physical and psychological health so one side should not be ignored.

Biomedical approach:o Assumes all disease can be explained using physiological processeso Treatment is for the disease, not the persono Psychological and social processes are separate; it separates body and

mind (dualism) Biopsychosocial approach:

o Does take into account biological, psychological and social factors when diagnosing and treating an individual

o Extended to include factors such as ethnicity and culture.o A holistic approach

Health behavioro Behaviours that affect our health positively or negatively.o They can be categorised as health protective behaviours and health

risk behaviours

Health psychology models Aim to explain why people carry out health behaviours and can be used to develop health behaviour interventions in clinical practice.

The expectancy-value framework means that they are based on the idea that people think rationally.

The so-called health belief models as beliefs can influence our health:

Susceptibility: the belief to whether you should carry out or stop an action that may harm your health. So it’s your belief on how susceptible you are on the negative effects.

Severity: how badly will the negative effect have an impact?

Costs: the cons and pros of the action

Cues to action: an event that has made them think about their actions

Health motivation: how motivated are they to change their health behaviour

Perceived control: how much control do they think they have to change their behaviour?

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THEORY OF PLANNED BEHAVIOUR

It’s still based on beliefs but goes further in that it says you have beliefs about something and the behaviour that you are carrying out, that leads to your intentions to carry on or stop doing it and then ultimately your intentions lead to your behaviour.

Behavioural beliefs: your thoughts on the behaviour that you are carrying out, so the pros and cons, this links to your attitude and your overall evaluation of the behaviour.

Normative beliefs is your beliefs on what others around you think of the actions you are carrying out this then leads to subjective norm which is the pressure you receive. You also want to please the people who are close to you.

Control belief again is how much control you have to want to make the change and whether you have the internal resources you need, so do you have the will power, have you got the external resources for example financially. That will mean you will know whether it’s easy or difficult to change.

We can intervene and educate patients to change their beliefs and allow them to make the change.

This is when someone is already doing something in terms of the behaviour. So this allows us to assess at what point they are at in order to change.

Pre-contemplation is when you are carrying out the health risk behaviour but you aren’t thinking about changing. You enter the model when you start thinking so contemplation.

Preparation is when you come up with a plan to make the change but no actions are taken.

Action is when you actually make the change but this can lead to relapse. But if you maintain the action for more than 6 months you move onto maintenance.

You can move onto stability if you carry on with the change and don’t carry out the health risk behaviour but at any point you may relapse and go back to contemplation.

The following 3 components should be considered in addition to the stages:1. Decisional balance (pros and cons)2. Self-efficacy (confidence) and temptations3. Processes of change (e.g. Counter-conditioning, raising awareness,

reinforcement management, re-evaluation of self and environment, helping relationships)

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