PM1A Spring term Flashcards

Question

What can happen to cells in Hypo / Hypertonic solution

Answer 1

Cells can swell in hypo and hypertonic solutions – look what happens If you put a cell in a hypotonic solution (meaning more water on the outside of the cell), water will move into the cell and cell will swell. It can pop aswell. If you put the cell in a hypertonic solution, (cell has more water than outside does), then water will move out of the cell and cell will shrink Both are dangerous Putting a cell in an isotonic solution (has the same conc of water as the cell), nothing will happen

Answer 2

Respiratory System: provides O2 needed for oxidation (energy provision) Gastointestinal tract: breaks down nutrients, pass to liver via portal vein Musculoskeletal system: locomotion, maintenance of posture, breathing, protection Cardiovascular system pumps blood around the body (delivers O2/ nutrients removes CO2/ waste) Renal system: controls the contents of the extracellular fluid Endocrine and Nervous System: co-ordinates organ system activity by hormones or electrical signals

Answer 3

The primary function of the organ system is to maintain homeostasis

Answer 4

Homeostasis is ‘the control or stabilization of the internal environment’ Body water accounts for about 60% of the total body weight 1. Extracellular fluid (ECF) (~33%) represents the internal environment: Plasma (8%) fluid component of blood Interstitial fluid (ISF) (24%) fluid surrounding cells Transcellular fluid (1%) ‘other’ fluid eg. CSF, joints, ocular 2. Intracellular fluid (ICF) (67%) fluid within cells (cytosol)

Answer 5

The central theme of this concept is that the internal environment of a metazoan (multicellular animal) is regulated within close tolerances for a number of critical factors. Conformers: more ‘primitive’ organisms that are restricted to more constant environments Regulators: able to control internal environment and therefore can exploit physiologically hostile and variable environments Conformers – Cannot easily adjust the conditions of their internal environment.

Answer 6

Changes in ICF are secondary to those in ECF and are driven by changes in osmotic activity

Answer 7

Changes to internal environment due to the inability or failure of regulatory systems lead to ill health and threaten survival Example: the mammalian brain requires a constant supply of 02 and glucose; block of blood supply can lead to death within 30 s Many micro-organisms cause infectious disease by disturbing the internal environment Example: cholera toxin stimulates Cl- secretion into the lumen of the intestine. Na+ follows to increase osmotic activity and causes copious watery defecation, which can lead to lethal dehydration

Answer 8

Examples: 1. O2 buffering function of haemoglobin (Hb) Hb has a high affinity for O2 and only releases O2 when the local concentration is low 2. Respiratory control of CO2 End product of aerobic respiration: C6H12O6 + 6O2 ￫ 6H20 + 6CO2 ΔHc 2880 KJ hyperventilation decreases plasma [CO2] hypoventilation increases plasma [CO2] NB : Co2 in the blood can either be bound to hemoglobin while the free form of co2 is dissolved in the blood in form of carbonic acid. Hyperventilation – leads to decreased levels of plasma co2 – release of co2 decreases the levels of carbonic acid, increasing the PH of the blood. . These effects leads to for example involuntary contraction of muscles , shaking etc.

Answer 9

3. Maintenance of electrolytes (see next lecture) 4. Blood sugar (glucose) regulation 5. Acid-base balance (see Renal Physiology lecture) 6. Blood pressure regulation 7. Temperature regulation The hypothalamus represents the body’s thermostat, receiving afferent inputs from peripheral and central thermoreceptors: initiate thermoregulatory responses (vascular changes, shivering, sweating)

Answer 10

Homeostasis is maintained by feedback system 1. Negative feedback Effector system opposes the initiating stimuli eg. an increase in BP causes a compensatory decrease in BP 2. Positive Feedback Effector system reinforces or amplifies the initiating stimuli eg. formation of a blood clot stimulates further clotting

Answer 11

Negative feedback Almost all physiological regulatory mechanisms rely on negative feedback systems to maintain a variable within a given range following a disturbance. Characterised by: 1. a set point for the physiological parameter being regulated 2. a sensor to monitor the regulated variable 3. the ability to detect any error between the sensor and the set point by a comparator 4. an effector to bring about a compensatory chang

Answer 12

Blood sugar (glucose) homeostasis is under hormonal control

Answer 13

Effector system that reinforces or amplifies the initiating stimuli i) formation of a blood clot stimulates further clotting causes ii) oxytocin stimulation of uterine contraction during labour Q. Can you see why the vast majority of physiological systems use negative feedback? A. Positive feedback provides an unstable, increasing stimulus-response cycle. If not stopped can be dangerous and even letha

Answer 14

An enzyme is a catalyst of a biological system – enzymes make the reactions go faster Nearly all enzymes are proteins (amino acids Enormous catalytic power – can speed up reactions heavily Perform specific types of reaction

Answer 15

Peptidases (or proteases)-break peptide bonds - e.g., trypsin (breakdown of food) Lipases-break down fats - e.g., pancreatic lipase (breakdown of food) Phosphatases-remove groups (signaling cascades) - e.g., fructose-1,6-bisphosphatase (gluconeogenesis) Kinases-add phosphate groups (signaling cascades) - e.g., hexokinase (glycolysis)

Answer 16

Angiotensin I-Converting Enzyme converts angiotensin I (inactive) to angiotensin II (active) Inhibitors of Angiotensin I-Converting Enzyme are used to treat hypertension e.g., captopril, lisinopril. Angiotensin is a short peptide and it regulates blood pressure Angiotensin 2 raises blood pressure

Answer 17

Phosphofructokinase specifically adds a phosphate group to fructose-6-phosphate Phosphofructokinase is an enzyme of the metabolic cycle called “Glycolysis” In this case, phosphofructokinase adds a phosphate group to the one position on the molecule

Answer 18

Feedback inhibition Regulatory proteins Covalent modification-

Answer 19

Often an allosteric interaction (where the molecule doesn’t bind to active site); normally reversible Examples in metabolic pathways; Glycolysis In this pathway, A is being converted to B to C. You have 5 different enzymes regulating this pathway Now, the buildup of F may go back and inhibit Enzyme 1 and this is called feedback inhibition – stops the enzyme. This might be because the body does not want to produce too much F so in order to stop the overproduction of F, F would come back and inhibit the first enzyme. This is just an example, it doesn’t mean its always the first enzyme. Just an example

Answer 20

A process where a molecule i.e a functional group is chemically bonded to the protein altering its activities or properties. Enzymes can be covalently modified Example of reversible reaction Mammals store glucose as glycogen When we want energy, we can break down glycogen into energy using the phosphorylase enzyme. This phosphorylase enzyme only becomes active when it is phosphorylated with the phosphate (Pi) molecule. This releases a glucose-1-phosphate from the glycogen molecul We don’t want enzymes to be activated when they are made because they can be destroy the body right away. What the body does is that it produces these enzymes as inactive precursors which we call zymogens

Answer 21

We don’t want enzymes to be activated when they are made because they can be destroy the body right away. What the body does is that it produces these enzymes as inactive precursors which we call zymogens Trypsin is made as trypsinogen by the body which is its inactive form It is only when trypsin encounters another enzyme called enterpeptidase(in the small intestine) that a cleavage takes place and this leads to an active form of trypsin. Trypsin will then work in the small intestine instead of typsin self digesting the pancreas where it is made

Answer 22

Enzymes don’t change themselves They stabilise the transition states It’s the enzymes job to facilitate the transition state Helps the reaction to progress Enzyme will bind to the substrate until it forms the product The product is released by the enzyme

Answer 23

Active sites usually represent a very small portion of the enzyme Active sites are 3-dimensional (3D) Substrates are bound by multiple weak interactions Active sites are pockets within the enzyme - particular amino acids in the pocket drive the creation of microenvironments for catalysis water usually excluded unless necessary for catalysis NB : Active site is a very small portion of enzyme They are 3d not 2d Substrates are bound by multiple weak interactions, making them stable Active sites are pockets inside the enzyme where substrates bind to

Answer 24

Two main models of enzyme interaction They fit really nicely together – fit perfectly like lock and key

Answer 25

This works different We have substrate and enzyme They don’t look like they will fit What happens is when they come together, the enzyme will change shape so that they fit nicely Its not like a lego binding- its induced – the shape changes slightly to accommodate the whole substrate

Answer 26

Simvastatin Atorvastatin - HMG-CoA reductase inhibitor interfere with the cholesterol synthesis pathway lower cholesterol-cardiovascular disease Aspirin Ibuprofen Paracetamol - Cyclo-oxygenase inhibitors COX-1; COX-2 Inhibit prostaglandin synthesis Paracetamol-COX-2 Ramipril Benazepril Enalapril Fosinopril Lisinopril Moexipril Perindopril Quinapril Trandolapril - ACE inhibitor - Prevent production of angiotensin II - Angiotensin II is a potent vasoconstrictor Causes hypertension Inhibitors used to treat hypertension

Answer 27

Specialized Assays to Detect Diseases/Conditions HIV Test Enzyme-Linked Immunosorbant Assay (ELISA) Humans produce antibodies to viral proteins Assay specific antibodies are coupled to enzymes

Answer 28

Biological washing powders Contain lipases and peptidases to digest fat and protein in stains Modified to work at lower temperatures Pregnancy test kits Measure chemical markers of pregnancy in blood or urine Human chorionic gonadotropin (hCG) This is released into blood and urine from trophoblast cells of the fertilised ovum after implantation Liver Function Test Blood test used to measure total protein, albumin and several enzymes in serum Two enzymes involved in amino acid metabolism are assayed: Alanine aminotransferase Leaks into blood from damaged liver cells e.g. viral hepatitis, paracetamol overdose, fatty liver (alcohol abuse) Aspartate aminotransferase Also raised in liver damage

Answer 29

An enzyme and substrate are mixed Loss of a substrate or production of a product is then monitored 1. Absorbance 2. Fluorescence 3. High Performance Liquid Chromatography 4. Mass Spectrometry

Answer 30

Angiotensin 1 is an inactive peptide Converted into angiotensin 2 So, using HPLC, if we run down angiotensin down the column, it will stick to the column initially Something called acetonitrile (don’t need to know) will interfere with the hydrophobic interactions and will knock off the angiotensin from the column Eventually after 20 mins, it gets knocked off and you get a nice peak If you run down the purified angiotensin 2, you get that second graph and they look pretty much the same But if you look in the third graph, overlay them both, you will see slight shift that angiotensin 2 leaves the colum just before angiotensin 1 It is a shorter enzyme because it has lost 2 amino acids as shown on previous slide so now its not as hydrophobic and didn’t bind to the column as well so it comes off easier We can use HPLC to see how much angiotensin 1 has been converted into angiotensin 2. Can measure area under the curve to see how much as been produced

Answer 31

Interested in the initial rate As time goes on, we get something called a plateau or tailing off Tailing off can happen due to product inhibition reverse reaction substrate depletion

Answer 32

The rate of a reaction is referred to as the velocity, V V is usually expressed as µmol of product formed per minute; µmol/min The specific activity of an enzyme: expressed as µmol of substrate converted per minute per mg of protein µmol/min/mg protein

Answer 33

In one min, there are 60 secs We have the value for 20 secs There are three lots of 20 secs in a minute 3 x 0.05 is 0.15

Answer 34

Enzyme concentration affects how an enzyme works Here we have 3 substrate concentrations More substrate = more faster reaction, most substrate is then represented by the green

Answer 35

Initial Velocity is Dependent on Substrate Concentration Plotting velocity against substrate concentration We get a curve Why does it tail off at one point? Because even if you add more substrate, the active sites of all the enzymes have been saturated, meaning they are full. This means even if you add in hundreds of substrates, the reaction cannot go any faster because the enzymes are working at their full capacity. The leftover substrates are just waiting for their turn The only way to increase rate of reaction would be to add in more enzymes

Answer 36

This is an important equation for calculating the maximum velocity of an enzyme In practice, its almost impossible to calculate that V max (maximum velocity)because in the graph previously, the dotted line is the maximum velocity but in practice, we cannot get enough substrate into the tube at the right concentration to get the maximum velocity. This is because enzymes are super fast and we cannot get it at a high enough concentration

Answer 37

You will end up with a straight line if you convert all the previous values (that generated a curve graph) using y = mx + c This is done in labs Just draw the line straight line back

Answer 38

Why do we do this? A lot of drugs on the market inhibit enzymes To test these inhibitors, we need to see how they affect the reactions We use these v max and km to see how it changes We need to see how much the drug inhibits the enzymes Gives us info also about biological pathways

Answer 39

Vmax is the maximal rate of enzyme reaction (µmol/min) KM is the substrate concentration that give 50% of the maximum velocity Vmax reveals TURNOVER NUMBER of an enzyme Definition: Turnover number is the number of substrate molecules converted to product per enzyme molecule in unit time when the enzyme is saturated Vmax = k2 [ET] k2 = Vmax/[ET] k2, turnover number (kcat) Why are these values important? Km is the conc of substrate required that give 50% of max velocity. V max can be used to work out turnover number of enzyme - read definition. Some enzymes turnover slower than others ofc

Answer 40

What is an Isozyme? enzymes come from different genes perform identical reactions glucose to glucose-6-phosphate isozymes have slightly different amino acids sequences Physiological Example Hexokinase Isozymes Involved in glucose metabolism Hexokinase I, II and III (wide distribution), KM = 0.04 mM Hexokinase IV (glucokinase, liver), KM = 10 mM NB : Different types of the SAME enzyme will have different KMs Hexokinase I, ii, iii all hve very small concentration of KM meaning that at very small concentrations (0.04), the 50% enzyme velocity will be achieved. But in hexokinase iV, you need 10mM concentration to achieve the same 50%

Answer 41

Here, the question asks us to consider the activity at 10mM The information is telling us KM of the two hexokinases is 0.04 and 10mM so by definition, that means the hexokinase iv is at 50% of vmax because its number is 10mM (given in the question) Therefore A is correct

Answer 42

Graph - If you are fasting, I, ii and iii would be active all the time. These enzymes are found throughout all of the cells. You need to be breaking down glucose for energy for survival all the time Whereas the one in the liver (iv) is less active because the glucose in the liver isnt there When you are well fed however, the iv enzyme becomes more active because glucose will be stored in the liver – enzyme becomes activated The role of Hexokinase IV is as follows 1. When glucose is abundant, hexokinase IV is more active 2. As liver contains hexokinase IV, more glucose-6-phosphate is produced 3.Glucose-6-phosphate is used for the synthesis of glycogen 4.Glycogen is an efficient way the body stores glucose

Answer 43

Most enzymes have optimal ph – ph at which they work best This ph optimum depends on where the enzymes are found Enzymes found in stomach will have acidic ph (lower than 7). They work best at low ph because stomach is acidic Red line – optimal ph is 7. an example of such enzyme would be one that is found on the surface of the cell for example. This is because the extracellular fluid around it is neutral – round about a ph of 7. So it needs to work best in ph of 7 The blue is working optimum at about 5 which is working at a more acidic ph – this could be an endosome or a lysosome Ph is important because enzymes have active sites. Enzymes are made up of amino acids as they are protein. As the PH changes, all of the R groups, side chains etc that are facilitating the binding of the substrate to the enzyme will ionise etc so if ph changes they will not be able to catalyse the reaction

Answer 44

If temperature increases, the bonds holding the active site in place will break and the enzyme will lose its shape The active site shape will be lost Substrate and enzyme cannot bind Reaction cannot be catalysed Enzyme denatures and you cannot reverse that Different enzymes have different optimum temperatures Enzymes inside a thermophillic bacterial enzyme will naturally work good at higher temperatures since its temperature of surroundings will always be higher so needs to work good in the high temps

Answer 45

kcat measured in seconds KM measured in concentration kcat/KM = concentration per second This value tells us about an enzymes substrate specificity, catalytic efficiency and kinetic perfection The higher the kcat/KM value, the better the enzyme works on that particular substrate These criterion are useful numbers to define enzymes and make comparisons between enzymatic assays Especially useful when comparing the effects of inhibitors on enzymatic reactions

Answer 46

Inhibition is an important natural way to control metabolic pathways; knowledge can be used to our advantage We can use drugs to inhibit enzymes to treat disease Inhibitors can be used to study the mechanisms by which enzymes catalyze reactions-especially in the absence of 3D structures – we need to design drugs that are 3D Inhibitors can have other commercial applications including weed killers, pesticides

Answer 47

Inhibitor binds to enzyme Binding can be covalent or non-covalent Very slow dissociation Active site or allosteric site of Not to be confused with irreversible enzyme inactivation e.g., denaturation

Answer 48

Here the inhibitor just binds on and off Rapid kinetics On and off quickly Prevents substrate from entering active site Sometimes the substrate can sneak in still This is reversible as not permanent

Answer 49

1. Competitive inhibitors 2. Non-competitive inhibitors 3.Mixed inhibitors 4. 4. Uncompetitive inhibitors Each of these can be reversible or irreversible Competition is more to do with it sits

Answer 50

Compete with substrate for active site Always bind to active site So either an enzyme substrate (ES) complex can form or an enzyme inhibitor (EI) complex can form Both are competing with each other, so both can form Remember that equation Compete with substrate for active site Always bind to active site So either an enzyme substrate (ES) complex can form or an enzyme inhibitor (EI) complex can form Both are competing with each other, so both can form Remember that equation. When you lower the amount of enzyme substrate complexes, it means that the reaction is slowed because the substrate is binding less The more the inhibitor that you add, the less the enzyme substrate complexes can form – lowers the rate of catalysis If you add more substrate, the substrate will outcompete the inhibitor meaning it will "win" more times If you add more inhibitor molecules then the inhibitors will win more meaning there will be more inhibition

Answer 51

Substrate against velocity With no inhibitor, the substrate concentration increases rapidly, reaches Vmax. If we do that in the presence of an inhibitor, then the shape of the curve is slowed (blue line) because there will be competition As the substrate concentration increases, it will overcome that inhibition and eventually the two lines meet at the top Basically v max can be reached if you increase substrate conc sufficiently Vmax is identical but KM is increased because the substrate concentration required to reach 50% of maximum enzyme capacity is increased when you also have inhibitors competing for the same active sites 2nd graph below is drawing a different way using a straight line

Answer 52

Irreversibly binds to an enzyme (glycopeptide transpeptidase)required for bacterial wall synthesis Covalently attaches to a serine residue of the enzyme Gram-negative bacteria Escherichia coli, Haemophilus influenza, Proteus mirabilis, Neisseria gonorrhoeae Used to treat: bacterial infections; tonsillitis, bronchitis, pneumonia, gonorrhea, and infections of the ear, nose, throat, skin, or urinary tract

Answer 53

Inhibitor of dihydrofolate reductase Does not bind covalently-has very slow dissociation Interferes with the production of folic acid (required for the synthesis of nucleosides, especially thymidine) Therefore, blocks DNA synthesis and have an anti-proliferative effect Used to treat: cancer, psoriasis, Crohn’s disease, rheumatoid arthritis

Answer 54

Peptide-based inhibitor of HIV protease HIV protease (Retropepsin) is an aspartyl peptidase and is essential for the life cycle of HIV Viral proteins are synthesized as poly-protein which are then cleaved by HIV protease into mature proteins High mutation rates of reverse transcriptase make drug resistance and big problem for the drug industry

Answer 55

A non-competitive inhibitor binds to the enzyme at a site other than the active site. The inhibitor and substrate can simultaneously be attached to the enzyme. The substrate and the inhibitor have no effect on the binding of the other and can bind and unbind to the enzyme in any order. The inhibitor and the substrate do not bind to the same site. (2nd Diagram) When you have the substrate AND inhibitor bound to the same enzyme, the reaction cannot be catalysed. Inhibitor locks it in an incative site – prevents catalysis Adding MORE substrate in this case will NOT overcome inhibition, because the inhibitor is binding elsewhere

Answer 56

When you have the inhibitor, vmax is changed because the inhibitor is binding elsewhere KM is identical (2nd Diagram) This is how the straight line graph would look like You should be able to look at the graphs and say this is competitive and this is non competitive Understand why the vmax and km would change or not change Inhibition cannot be overcome by increasing the substrate concentration

Answer 57

An inhibitor of acetylcholine esterase: catalyzes the hydrolysis of acetylcholine (important neurotransmitter) Used to treat: mild to moderate dementia of the Alzheimer’s type and dementia due to Parkinson's disease

Answer 58

An inhibitor of aromatase; enzyme involved in the production of oestrogens Oestrogens stimulate the growth of many breast cancers As it is non-competitive and irreversible effects can persist even after drug is discontinued

Answer 59

This is just to summarise – learn these In presence of competitive inhibitor, we have identical v-max and increased km In non competitive inhibitor, Kms remain identical but V max is reduced

Answer 60

A more complex type form of inhibition Mixed type inhibition is similar to non-competitive inhibition. However, the binding of the substrate or the inhibitor affect the affinity of each other for the enzyme. This means that the binding of the substrate to the enzyme is reduced in the presence of the inhibitor The inhibitor affect the binding of substrate and the turnover number (kcat) of an enzyme The inhibitor affects both the KM and Vmax of the enzyme

Answer 61

Reduced vmax Km increased

Answer 62

This is a very rare class of inhibition: An uncompetitive inhibitor binds only to the enzymesubstrate complex and enhances the binding of substrate (reducing KM). The resultant enzymeinhibitorsubstrate complex has a reduced activity and only forms the product slowly, so that Vmax is also reduced NB : Inhibitor only binds if the substrate is already bound Increases the amount of enzyme-substrate complexes

Answer 63

Parallel lines Reduced vmax Km also decreased

Answer 64

Highly effective in the treatment of bipolar disorder and also has multiple effects on embryonic development, glycogen synthesis, hematopoiesis Uncompetitive inhibitor of inositol monophosphatase Interferes with phosphatidylinositol signaling pathways Lithium also affects many other enzymes

Answer 65

Haloperidol is used to treat a variety of mental health problems Haloperidol is used to treat a variety of mental health problems Selective monoamine oxidase B inhibitor (degrades phenylethylamine) Interferes with neurotransmission; other reported effects

Answer 66

Although some examples of true uncompetitive and non-competitive inhibitors exist, in most cases, the kinetics are not quite that simple For uncompetitive inhibition: Inhibitor binding should only occur if the active site is occupied by substrate. However, in most cases, the inhibitor will have some affinity for the unoccupied enzyme as well For non-competitive inhibition: the inhibitor affinity should be unchanged regardless of whether substrate is bound or not. However, the affinity for the inhibitor usually changes when substrate is bound to the enzyme in reality True competitive inhibition is common, but, in reality, competitive and mixed inhibition is likely

Answer 67

Immunology is a branch of biomedical science that covers the study of all aspects of the immune system in all organisms. It deals with the physiological functioning of the immune system in states of both health and disease.

Answer 68

The immune system includes all cells, tissues, and molecules that mediate resistance to infections. This includes our skin which acts as a barrier Immunity if the body`s ability to fight off harmful micro-organisms (pathogens) that invade it, e.g. fungi, protozoans, bacteria, viruses. It also includes the body’s availability to fight off tumour cells The immune system includes all cells, tissues, and molecules that mediate resistance to infections Immunity if the body`s ability to fight off harmful micro-organisms (pathogens) that invade it, e.g. fungi, protozoans, bacteria, viruses.

Answer 69

Immune response is the collective and coordinated response to the introduction of foreign substances in an individual mediated by the cells and molecules of the immune system.

Answer 70

Defence against invading microbes Defence against the growth of tumour cells kills tumour cells Homeostasis Destruction of abnormal or dead cells (e.g. dead red or white blood cells)

Answer 71

Lymphocytes (white blood cells) which include T-lymphocytes B-Lymphocytes, plasma cells natural killer lymphocytes Monocytes, Macrophages Granulocytes neutrophils eosinophils basophils

Answer 72

Lysozyme – helps body to remove bacterial pathogens Antibodies – bind to any types of pathogens but also to our own cells that have become tumours Complement Cytokines Interleukines Interferons – these signal to our body that there is something wrong and cells are infected with virus

Answer 73

Innate (non-adaptive) First and second line of immune response relies on mechanisms that exist before infection takes place Acquired (adaptive) Third line of response (if innate fails) relies on mechanisms that adapt after infection. This is the body’s defence system after they have got the infection

Answer 74

The non-specific (innate) immune system includes chemical and physical barriers (the first line of defence) and responses such as inflammation (the second line of defence). Skin – barrier Ciliated cells – have extensions called cilia that actively remove the pathogens Lysosomes – enzyme present in the saliva helping us to digest pathogens Coughing and vomiting – can help get rid of the pathogens Blood clot – prevents bacteria from going inside body Mast cells – release histamine We will go through mast cells in a bit

Answer 75

Present from birth in all individuals and based on genetic make-up Relies on already formed components Rapid response: within minutes of infection Not specific; same molecules / cells respond to a range of pathogens Has no memory ; same response after repeated exposure

Answer 76

The skin serves as a physical barrier and prevents the passage of microbes and is acidic (4.5- 5.5) The surface of the skin contains `good` bacteria that can outcompete pathogens Sweat contains bacteriostatic substances – prevent bacteria from dividing (e.g. lactic acid). The respiratory passage is lined with ciliated cells and covered in a layer of mucus The mucus traps invading microbes and debris, cilia remove particles Acidic pH in the stomach and digestive enzymes destroy most of the foodborne pathogens `good` gut microbiota outcompete pathogens

Answer 77

If a pathogen is able to pass the first line of defence (infection), the second line of defence deals with the pathogen The second line of defence is cellular and involves white blood cells (natural killer (NK) cells, neutrophils, macrophages, mast cells, basophils, and eosinophils) The second line of defence is non-specific (phagocytosis) and is followed by inflammation. Phagocytosis = ingestion and digestion of pathogens

Answer 78

Mast cells – release histamine – triggers inflammation. Also involved in many allergic reactions like hayfever Natural killer cells (on the right) – recognise and kill CELLS that are infected with virus Basophils, Eosinophil and Neutrophils – all classed as granulocytes since they contain different types of granules – role is to release digestive enzymes, histamine and heparin Macrophages, and Dendritic cells – these are known as phagocytes – engulf, ingest and destroy the microbe/release cytokines

Answer 79

Cytokines (Greek: cyto: cell; kinos: movement): regulatory proteins secreted by white blood cells Cytokines bind to specific receptors on target cells triggering signal transduction pathways and altering the gene expression patterns Cytokines and their receptors exhibit very high affinity for each other – they like binding to each other

Answer 80

Cytokines can be pro- or anti-inflammatory TNF-alpha is the most important mediator of inflammation!

Answer 81

1.rubor (redness) 2.dolor (pain) 3.calor (heat) 4.tumor (swelling) 5.functio laesa (possible dysfunction/loss of function of the organs or tissues involved) – if the infection is severe

Answer 82

This happens at the organ level As a result of injury caused by physical or chemical agent or pathogenic microorganism, capillaries widen. Inflammation also causes increased capillary permeability and it attracts white blood cells. This results in increased blood flow, release of fluid and migration of white blood cells to injury Systemic response is also happening – fever, making of new white cells etc. By increasing temperature of the body, immune system moves the temperature out of range so that it is not optimal for the pathogen. Their cell division rate will be lower

Answer 83

Slow response during 1st infection because several things need to happen to build that immunity. The body has never seen this bacteria before Fast in secondary infections Has memory – can remember the infection from last time Involves antibodies Is specific adaptive immunity has two types: humoral and cell mediated Adaptive immunity is the basis of all vaccination strategies

Answer 84

Cell-mediated response - Eliminates intracellular microbes that survive within phagocytes or other infected cells Humoral response - Mediated by antibodies Eliminate extra-cellular microbes and their toxins

Answer 85

Antibodies recognize antigens An antigen is a toxin or other foreign substance which induces an immune response in the body, especially the production of antibodies.

Answer 86

Antibodies recognize antigens Can be membrane bound or soluble Belong to the gamma-globulin fraction of serum proteins Y-shaped or T-shaped polypeptides 2 identical heavy chains (dark blue) 2 identical light chains (light blue)

Answer 87

Formation and maturation in the bone marrow (hence the name “B cell”) naive B cells (not really mature B cells) move into the lymphatic system and circulate throughout the body Each B cells has one of millions of distinctive surface antigen-specific antibodies. An antigen is a toxin or other foreign substance which induces an immune response in the body, especially the production of antibodies. When a naive B cell encounters an antigen, it divides and becomes either a memory B cell or an effector B cell / plasma cell.

Answer 88

Once formed in the bone marrow, T progenitor cells migrate to the thymus (hence the name `T cell`), mature and become T cells express T cell receptors (TCRs) and other receptors called CD4 and CD8 receptors All T cells express T cell receptors, and either CD4 or CD8, not both CD4+ cells are T helper cells CD8+ cells are cytotoxic T cells (killer T cells) T cell receptors can only recognize antigens bound to Major Histocompatibility Complex. class 1 (MHCI) and class 2 (MHCII)

Answer 89

Macrophages and Dendritic cells

Answer 90

Macrophages and Dendritic cells are Antigen presenting cells (APC's) Macrophages and DCs express pattern recognition receptors (TLRs)

Answer 91

Vaccination: A process of induction of immunity to a pathogen by deliberate injection of a weaken, modified or related form of the pathogen which is no longer pathogenic.

Answer 92

When you vaccinate, this leads to activation of the innate immune system first, then you have the activation of the adaptive immune system and this leads to primary antibody response Then we have formation of memory cells – if we are exposed to the same antigen and infection again, then we have a strong and very quick secondary antibody response

Answer 93

hypersensitivity reactions immunodeficiency

Answer 94

Hypersensitivity : excessive, undesirable reaction by the immune system Causes cell damage through excessive immune response to antigens overreaction to infectious agents Allergy: overreaction to environmental substances Autoimmunity: overreaction to self

Answer 95

Loss or inadequate function of various components of the immune system Can occur in any part or state of the immune system, e.g. physical barrier, phagocytes, B lymphocytes, T lymphocytes, complement, natural killer cells The immuno-compromised host has an impaired function of immune system is at high risk of infection Congenital ID has genetic causes (e.g. SCID) Can be acquired (e.g. AIDS, malnutrition, leukemia, pharmacological intervention)

Answer 96

Blood: a liquid that fills the vascular compartment and serves to transport dissolved materials and blood cells throughout the body The average human has 4 to 6L of blood NB : Blood is a liquid tissue All other tissues are solid state Blood only liquid tissue – moves from one place to another Transports desired materials throughout body Blood very important Blood carries blood cells and also oxygen Blood has plasma and also red blood cells as you can see – plasma is that yellow liquid layer – liquid part of the blood. 50% is plasma. Bottom part are the red blood cells – bottom of the tube as they are heavy Buffet coat in the middle – called fatty layer – platelets and white blood cells are in this layer You can achieve this by centrifugation Hematocrit – percentage of all the red blood cells after your centrifugation – shows how many red blood cells we have in the body Haemoglobin – protein that carries oxygen in the red blood cells MCV – what is the size and volume of red blood cells? Red cell count – how many red cells we have in the blood – this is important as these carry oxygen and can lead to anaemia. Morphology – this is to do with the shape of the red blood cells too because they should be a biconcave shape – this makes a difference as the biconcave shape is the best shape for carrying the oxygen Total white blood cells count – all the cells that are white blood cells Differential white cell count – the individual numbers of each type of cell

Answer 97

Respiration – generation of energy Supply of oxygen to tissue and cells – every cell gets blood Removal of carbon dioxide from tissues and cells Transport Nutrients to the tissues and cells Waste products from cells to the kidney and liver Messages such as hormones around the body Protection from infection: the immune system Repair of tissue damage e.g. blood clotting Thermoregulation – maintain body temperature

Answer 98

Neutrophils are the most abundant white blood cells

Answer 99

Blood formation occurs in bone marrow - spongy tissue inside bones that produces blood cells RED marrow in flat bones produces most blood cells YELLOW marrow in long bones produces some white and other cells Bone marrow consists of blood cells that are at various stages of development Supporting tissue is called stroma

Answer 100

Haematopoiesis: production of blood cells. Megakaryopoiesis or thrombopoieis: production of platelets (from megakaryoblasts). Erythropoiesis: production of RBCs. Granulopoiesis: production of the granulocytes. Monocytopoiesis: production of the monocytes. Lymphopoiesis: production of the lymphocytes. Haemopoietic growth factors produced by the stromal cells in the bone marrow, with the exceptions of erythropoietin (produced in the kidney) and thrombopoietin (produced in the liver). Totipotent: stem cell with the ability to become any cell in the body (ie fertilized ovum). Pluripotent: stem cell with the ability to become nearly all cells in the body (from the 3 germ layers). Multipotent: stem cells with the ability to become a number of different cells of the same family eg. in the bone marrow able to become any of the different blood cells. Oligopotent: stem cells with the ability to differentiate into a few different cells types. Eg. Common myeloid precursor: myeloid precursor, can become any of the myeloid cells (platelets, RBCs, granulocytes or monocytes). Common lymphoid precursor: lymphoid precursor, can become any of the lymphoid cells (lymphocytes, natural killer cells or lymphoid dendritic cells). Myeloblast: immature precursor cells that can become any of myeloid cells (granulocytes or monocytes). Not usually found in the circulation and recognisable by their large size and large primative nucleus. Lymphoblast: immature precursor cells that can become any of the lymphoid cells (lymphocytes or natural killer cells). Not usually found in the circulation and recognisable by their large size and large primative nucleus. Notice the location, sizes, shapes, nuclei shapes and colours (on staining) of the different cell types. Note that Mast cells are not a type of basophil (as previously thought), however they are the tissue equivalent cell as basophils.

Answer 101

Red blood cells (Erythrocytes) Biconcave disks – see structure 8-12µm in diameter, ~90fL volume No nucleus (anucleate) – allows O2 to be packed in No mitochondria 4-6 x 1012/L about 25 trillion in the average human with 5L of blood, varies ♀ ♂ Long life span - 120 days Function Transport of oxygen and carbon dioxide around the body Critical role in respiration (glucose and O2 making energy, H20 and CO2

Answer 102

Responsible for the red appearance of RBCs About 250 million haemoglobin molecules per RBC Each haemoglobin has 4 polypeptide chains EACH with a cofactor called a haem group, that has an iron atom at the centre (each haemoglobin therefore carries 4 oxygen molecules) Each iron atom binds one molecule of O2 Co-operativity in O2 binding and release Binds to O2, CO2 and NO (can also bind CO) and transports these molecules around the body

Answer 103

We get iron through iron rich food Goes into the blood circulation Iron cannot travel on its own Must bind to a protein in order to be carried over Transferrin is the protein which will then go to the different places in the body Transcript: Iron is obtained through diet and iron rich food gets digested in intestine Straight away, it will get into the blood stream through capillaries Iron cannot travel on its own Must bind to a protein in order to be carried over That protein is called transferrin It will go to bone marrow to produce red blood cells because that is a predominant role These red blood cells will be released to the blood stream and can carry oxygen and carbon dioxide and carry out respiration Next they can go to the spleen – older cells can be broken down by the spleen and when they are breaking down these molecules, metabolites like bilirubin will be produced – important for producing bile salts which are in turn important for digestion. Bilirubin comes from spleen and will go to liver – produces bile – helps everything to be broken down in the small intestine Some of the bilirubin will be restored/recycled again into the blood by the liver Some bilirubin will go to kidneys and kidneys will use it to produce erythropoietin – this helps growth of red blood cells The erythropeotin will go into the blood stream, go to bone marrow and help growth of red blood cells

Answer 104

The pulmonary system is the blood vessels surrounding the lungs. The pulmonary artery brings blood from the heart to the lungs (but this is deoxygenated), and the pulmonary vein carries the oxyenated blood back to the heart to be pumped around the body. The capillary bed surrounds the alveoli. Air enters via nose / mouth, travels down trachea to the 2 bronchi, then bronchioles, to the alveoli. Air enters the lungs, goes to bronchi, then bronchioles and then to alveoli. Alveloi contain many capillaries. As concentration of oxygen is high in alveoli and low in blood, oxygen will enter blood through simple diffusion. Blood travels all around body and delivers oxygen to every cell These cells respire and produce CO2 Co2 enters blood CO2 travels around blood and back to capillaries. Now, there si a higher concentration of CO2 in the blood than capilarries and so CO2 will enter capillaries and go out the lungs through exhalation

Answer 105

Once in the plasma, O2 is taken into RBCs and binds Hb (co-operatively) for transport around the body Co-operative binding – once one molecule of O2 has bound, it is easier to bind the 2nd and 3rd molecules.

Answer 106

CO2 follows the concentration gradient from the tissues into the interstitial fluid and then plasma. 7% of the CO2 travels back dissolved in the plasma, but 90% enters the RBC. Once in the RBC some CO2 binds to Hb, but most reacts with the water in the RBC to become carbonic acid (catalysed by carbonic anhydrase). The HCO3- travels in the plasma and the H+ binds to Hb so the pH of the blood isn’t altered. In the lungs the reverse happens – the HCO3- and the H+ recombine to carbonic acid and then dissociates into CO2 and H20. The CO2 follows the concentration gradient out of the blood into the alveolar sacks and is exhaled. How is CO2 being transported? It is a metabolic byproduct of respiration When co2 is produced, it will come to the interstitial fluid right in between the cells, Goes into capillaries Some will straight away bind to haemoglobin and be carried to the lungs, Some will react with water and produce carbonic acid Carbonic acid will get hydrolysed to produce H+ ions. These will bind to the haemoglobin molecules plus bicarbonate This bicarbonate is an important component in the blood in order to keep the buffer nature Bicarbonate in the blood and H+ ions in the haemoglobin will react together and produce carbonic acid. Carbonic acid will release the water then carbon dioxide will be released – goes to the outside and exhaled

Answer 107

Reduced Hb/RBCs A reduced haemoglobin concentration in blood Several classifications  Low haematocrit  Small red cells Different sizes Most common causes Poor diet – iron deficiency Chronic blood loss Malabsorption of iron Pregnancy Signs and Symptoms: Fatigue, pallor, tachycardia Inflammation of the tongue Dysphagia - painful swallowing

Answer 108

Elevated level of RBCs Abnormally increased production in bone marrow Can show increased haematocrit & haemoglobin Haematocrit is more than 48% in women & 52% in men Haemoglobin is more than 16.5g/dL (women) & 18.5g/dL (men) Most common causes Due to various diseases Tumours (in kidneys & liver) producing EPO Due to inherited problems Chronic hypoxia (reduced O2 levels) Signs and Symptoms: Fatigue, weakness Headache Itching and bruising in the body Also includes Chronic blood loss: internal bleeding eg GI, heavy menstruation…

Answer 109

Each of the different types of WBC have different characteristics – nucleus shape, granules (what stain with). 5 different types Most important is neutrophils

Answer 110

Approximately twice the size of red blood cells Multi-lobed nucleus (polymorphonuclear) Granulated cytoplasm that stains with both basic and acidic dyes 2.5-7.5 x 109/L Largest population of leukocytes Life span - 6 hours to a few days Phagocytic (engulfing) Function Vital role in protection from bacterial infections Phagocytosis of bacteria Called neutrophils because their granules are neutral staining.

Answer 111

* Approximately the same size as neutrophil * Bi-lobed nucleus * Granulated cytoplasm that stains with acidic dye, eosin red (name) * Large pink-staining granules (histamine, plasminogen, DNase, RNase etc) * 0.04-0.44 x 109/L * Life span - 8-12 days * Phagocytic Functions * Immune-protection * Phagocytosis of antibody-coated pathogens * Attacks parasites (specific feature) * Allergic responses Called eosinophils because their granules stain with eosin.

Answer 112

* Slightly smaller than neutrophil * Lobed nucleus * Heavy granule contents in cytoplasm stains with basic dye, methylene blue (name) * Contains large purple-staining granules (histamine, heparin, proteolytic enzymes) * 0.01-0.1x109/L * Not phagocytic (unlike neutrophils & eosinophils) * Life span - a few hours to a few days Function * Release of histamine during inflammation * Cause allergic reactions (specific feature) Called basophils because their granules stain with methylene blue. Note that mast cells are not a type of basophil (as previously thought).

Answer 113

* Large kidney-shaped nucleus * Larger than neutrophil and contain a large population of lysosomes * 0.2-0.8 x 109/L * Life span - last many months * Activated into macrophage * Macrophage engulfs foreign/damaged materials Function * Vital role in protection from infections * Ingest bacteria, dead cells and cellular debris * Phagocytosis Monocytes Don’t do anything in the blood UNTIL theres an infection or injury If there is, they will change shape and become macrophages

Answer 114

* Large and relatively round nucleus that fills the cytoplasm * Slightly smaller than neutrophil * 1.5-3.5 x 109/L * Life span - can persist for many years, especially B memory cells * Divided into two types of cells due to function - T & B cells * T-cells for direct immunity & B-cells into plasma cells to produce antibodies Function * Central role in the immune system - protecting from infections, especially for viral infections * T lymphocytes attack pathogens directly and B-cells produce antibodies

Answer 115

Cancer of the WBCs Uncontrolled growth of one WBC type occurs in the bone marrow causing - a raise in cell count of affected WBC type 4 main classes of leukaemia 4 main classes of leukaemia: Acute myeloid leukaemia (AML) Acute lymphoblastic leukaemia (ALL) Chronic myeloid leukaemia (CML) Chronic lymphoid leukaemia (CLL) Blast cells are immature WBCs that don’t usually appear in the peripheral blood (they are larger and have a large nucleus). If you see these cells – that means there is cancer ( if AML, ALL are seen) CML and CLL are normally seen in the blood but get elevated during cancer

Answer 116

Reduction in a type or all of WBCs Mainly due to bone marrow failure Causes Microbial (mainly viral) infections Chemotherapy, radiotherapy and other medications Immunosuppressive drugs Sepsis (complete collapse of immune system) 4 main classes of leukaemia: Acute myeloid leukaemia (AML) Acute lymphoblastic leukaemia (ALL) Chronic myeloid leukaemia (CML) Chronic lymphoid leukaemia (CLL)

Answer 117

* Small anucleate cellular fragments of large precursor cells called megakaryocytes * Produced in bone marrow * 2-4µm diameter * Appear in blood films as dark-staining granules * 150-400 x 109/L * Life span - 5-10 days Function * Roles in blood clotting (haemostasis) Activated platelets change from a smooth discoid shape to sending out filopodia and forming lamellipodia. Pseudopodia are projections of membrane. There are several different types of projections. Filopodia are slender projections like those shown here. Filopodia help establish platelet-platelet contacts. Lamellipodia are large flat spreading projections that help platelet coverage. Fibrin (produced by the coagulation cascade) binds the blood cells together more strongly.

Answer 118

The spleen is an ovoid organ found in the upper left abdominal cavity (5-13cm). Spleen is the largest “filter” of blood in the body, removing old or damaged blood cells (engulfed by phagocytes) NB : 3 μm windows separate splenic cords from venous sinuses. Cells that can no longer deform to squeeze through the windows are filtered from the blood and destroyed. Phagocytes engulf the cells. Of the RBCs, the protein is broken down to amino acids which are transported around the body for new protein synthesis, the iron is transported back to the bone marrow for new RBC formation. The porphyrin ring is converted to bilirubin which is transported to the liver for processing and excretion. 4 million blood cells destroyed every second, 2.5 million of which are RBCs.

Answer 119

The circulatory system is highly delicate and damage can cause it to leak. The blood vessels and the blood work together to prevent minor injuries resulting in death due to bleeding through a normal physiological mechanism called ‘blood clotting or haemostasis

Answer 120

Haemostasis - the cessation of bleeding (Haemo - blood; stasis - standing) Haemorrhage - the excessive flow of blood (Haemo – blood; rhage – burst forth) Physiological regulation – haemostasis – if you get an injury, it will clot Pathological (disease) response – thrombosis or haemorrhage Thrombosis is a blood clot that forms in the blood vessels unnecessarily – can lead to heart attack or stroke

Answer 121

Vessel spasm – when you get an injury, you start to bleed. A vessel spasm is when the blood flow starts to reduce itself – the vessel will constrict in that area to reduce the blood flow manually 2- platelets are small circulating blood cells – they are normally pushed towards the edges of the lumen and are closely monitoring the epithelium cells of the blood vessels (the cells that make up the wall of the blood vessels). When there is damage when you hurt yourself, they become activated and clump together in order to make a platelet aggregate (platelet plug) and that will seal the area. 3- At the same time, the clotting cascade will be activated at the damaged site. Both the extrinsic and intrinsic pathway and at the end of the cascade, a thrombin will be produced. This is a multifunctional enzyme which will convert the fibrinogen (which we have in large quantities in the plasma) into fibrinopeptides and that will tangle all the platelets, some white cells, some red cells in order to make an insoluble clot to seal the area permenetly 4 – we need to shrink the clot – cant stay there forever – clot needs to shrink to bring together the edges of the wound to promote healing – clot retraction 5- existing clot needs to removed totally – clot dissolution – clot gets diluted and removed from the system

Answer 122

1st stage of clotting Endothelial injury initiates vessel spasm or constriction- vessel shrinks Spasm reduces the blood flow to prevent excessive bleeding It is a transient event and lasts only less than a minute TXA2 from platelets and other mediators released at the damaged site contributes to spasm

Answer 123

2nd stage of clotting Platelets bind to collagen at the damaged site Platelets get activated, change shape and release their granule contents (e.g. ADP) Platelets synthesise and release thromboxane A2 (TXA2). So ADP and TXA2 are all being released Secondary activation of additional platelets – more and more platelets are being activated Platelet plug is formed to temporarily seal the damaged site Clot should be stabilised in order to continue protection. .

Answer 124

Activated platelets change from a smooth discoid shape to sending out filopodia and forming lamellipodia. Pseudopodia are projections of membrane. There are several different types of projections. Filopodia are slender projections like those shown here. Filopodia help establish platelet-platelet contacts. Lamellipodia are large flat spreading projections that help platelet coverage. Fibrin (produced by the coagulation cascade) binds the blood cells together more strongly. Negative regulation of a system is just as important as activation. If activation and inhibition aren’t balanced the system will be inappropriately stimulated / understimulated. Prostacyclin and NO are produced by healthy endothelium ie at sites where we don’t want platelet activation to occur. Where the endothelium is damaged there will be a lack of PGI2 and NO and thus the activatory signals will dominate. PGI2 is formed by the same enzyme as thromboxane A2 (COX). See later for how this complicates aspirin use. PECAM-1 in an inhibitory receptor found on the surface of platelets that helps maintain platelets in a quiescent state. Basically, if an area does not contain prostacyclin and nitric oxide, then platelets will get activated there. The damaged areas don’t have any of that so platelets get activated there. This means clotting cant occur at random places. These two are being produced by healthy epithelial cells

Answer 125

3rd Step of clotting Conversion of fluid blood into gelatinous clot Occurs on the surface of platelets Cofactors required in several steps Two pathways; intrinsic & extrinsic (both lead to FX - FXa) Intrinsic - relatively slow Extrinsic - much faster (injury) Activation of one factor leads to activation of the next (cascade) Thrombin converts fibrinogen into fibrin Factor XIIIa stabilises the clot by cross linking the fibrin Calcium chelation (citrate or EDTA) for blood storage

Answer 126

Fibrin is a protein Fibrin forms long polymers Fibrin is the stringy stuff in scabs. Next time you have a scab, break it in half and see if it seems fibrous – that’s the fibrin (the product of coagulation Thrombin - Thrombin catalyses the conversion of fibrinogen to fibrin Thrombin is an enzyme. Thrombin is a protease – an enzyme that cuts proteins. How does an enzyme that chops up proteins stick proteins together to form a polymer? Fibrinogen is a long protein When thrombin is produced, it is a proteolytic enzyme It will convert the fibrinogen into a fibrinopeptide by cleaving a small peptide regions in the fibrinogen. All fibrinopeptides will join together and form a long polymer – that’s going to tangle all the platelets

Answer 127

4th stage of clotting Post-clotting event Induced by large amount of platelets in the blood clot Integrin molecules on the platelet surface are involved in this process Retract the clot and squeeze out the serum This helps to bring the wound edges together and induce healing

Answer 128

5th stage of clotting Once blood loss has been controlled and the vessel walls have been pulled together, blood flow must be re-established in order for permanent tissue repair to take place The process by which the clot dissolves is called fibrinolysis Like coagulation, fibrinolysis is a series of steps controlled by activators and inhibitors Plasmin is the key enzyme involved in this process α2- plasmin, an inhibitor for plasmin to control its activity to local clot NB : Clot needs to dissolve We have plasminogen in the plasma all the time – in the inactive form We also have tissue plasminogen activator too in the plasma After the clot is formed, the tissue plasminogen activator will convert the plasminogen into plasmin – active form of plasminogen This will bind to blood clot or fibrinopeptide – and chopping them into small pieces – clot is degraded and dissolved

Answer 129

Healthy endothelium – covers collagens, produces NO and PGI2, produces t-PA Clotting factors circulate in an inactive form Blood flow to carry away clotting factors Factors present in blood that inhibit clotting factors e.g. Anti-thrombin III, protein C and S Consumption of clotting factors at site of damage Fibrinolysis

Answer 130

Thrombosis - clotting at wrong place or time (increased clotting) Bleeding/haemorrhage – insufficient haemostasis (reduced clotting)

Answer 131

There is high pressure in the arteries and this can cause slight damage Will cause platelets to aggregate and clot formation which will stop artery flow – can lead to stroke and heart attack or DVT This is why someone is having a heart attack or stroke or anything, we will prescribe antiplatelet drugs In venous thrombosis, the coagulation cascade will play major role but platelets will play minor role that’s why anticoagulants are given for DVT 1. Arterial Thrombosis: MI & ischaemic stroke. Inappropriate activation of platelets in the arteries. E.g. by rupture of an atherosclerotic lesion 2. Venous thrombosis: Deep vein thrombosis Inappropriate activation of coagulation in the veins Virchow’s Triad (three factors) Stasis (haemodynamics) Endothelial damage Hypercoagulability – increased coagulation naturally Minimal role for platelets Embolism of venous thrombi travel to other organs such as lungs NB : Venous circulation returns to the heart via the vena cava, passes through the heart and onto the capillary beds of the lungs where emboli could get stuck, resulting in pulmonary embolism (life threatening). If you don’t move muscles, the platelets can get activated and then blod clot can form. It can break off and go to anywhere into the body e.g. heart or lung

Answer 132

Anti-platelet drugs (e.g. aspirin & clopidogrel) - mainly for arterial thrombosis Anti-coagulant drugs (e.g. warfarin) – mainly for venous thrombosis Fibrinolytic drugs (t-PA or alteplase) – dissolving clots mainly for ischaemic stroke

Answer 133

Good health Unpaid volunteers Excluding risk factors (jaundice, hepatitis, travel in malarial areas, risk factors for HIV or CJD) Screening of blood Screening for compatibility of donor and recipient

Answer 134

Red cells within 35 days Platelets within 7 days Plasma with 3 days

Answer 135

ABO group Rhesus group (mainly D) Red cell Ab Hep B surface Ag Hep C HIV Treponema pallidum (syphilis) HTLV-I and HTLV-II (causes leukaemia) Other important diseases e.g. COVID-19 CROSS-MATCHING

Answer 136

Cell membranes contain many molecules Glycolipids (e.g. ABO Ag) Proteins (e.g. Rhesus Ag) Glycoproteins Lots of different roles eg. channels, receptors, identification Important to the immune system Immune system ignores ‘self’ molecules Immune system recognises non-self molecules on the surface of cells / bacteria / viruses etc

Answer 137

RBC Ag’s are sugar chains attached to the surface of the RBC via the lipid ceramide Note that the surface antigen is a sugar chain. Antigens don’t have to be proteins. Ceramide is a lipid molecule (anchoring the sugar chain to the membrane). Blood group O doesn’t have nothing on the surface, it still has the H antigen. Blood group A has the A antigen ie the carbohydrate chain with an N-acetyl galactosamine. Blood group B has the B antigen ie the carbohydrate chain with a galactose on the end. Blood group AB has both the A and B antigens on the surface of the RBCs.

Answer 138

Immune molecules (proteins) that recognise foreign molecules (Ag) Trigger an immune response When Abs are produced, they are screened against ‘self’ and those that are against ‘self’ are destroyed. Naturally occurring Ab circulate in the plasma of subjects who lack the corresponding Ag (i.e. From early in life – maternal antibodies) 5 types- Antibodies with slightly different structures. These include, Immunogloulin G and Immunoglobulin M IgM is made of 5 of the IgGs stuck together. This makes IgM much bigger than IgG. This is important as size determines where each type can be found. This way if you have the antigen (ie it is self), the Ab raised against it will be destroyed. If you don’t have the antigen (ie non-self) the Ab raised will be kept, ready to attach to the antigen if it ever appears.

Answer 139

People of blood group A will have A antigens on the surface of their RBCs. Therefore, they will destroy any Ab made against self (anti-A), but will keep antibodies made against non-self (anti-B) in their plasma. The antibodies made will be the IgM type (the big ones). IgM is made by natural immunity. This is the production of antibodies without being exposed to the antigen. IgG antibodies are made after exposure to an antigen, such as when you get an infection.

Answer 140

Rh antigens are transmembrane proteins that pass through the membrane 12 times. There are lots of different antigens (RhD most common) and the gene is autosomal recessive (so most people are rhesus positive) Rh antibodies (IgG) are only present in the plasma IF a Rh negative person is exposed to Rh antigen (i.e. non-self) triggering an immune response.

Answer 141

An individual with a particular blood group can recognise red cells carrying a different blood group antigen and produce antibodies to them Natural immunity IgM antibodies (large) are produced without prior exposure to the ABO antigen (anti-A or anti-B) Adaptive immunity IgG antibodies (small) are produced upon exposure to other RBC antigens e.g. RhD It is important that donors and recipient’s blood are matched for blood group prior to transfusion

Answer 142

ABO antibodies in the serum are formed naturally. Their production is stimulated when the immune system encounters the "missing" ABO blood group antigens in foods or in micro-organisms. This happens at an early age because sugars that are identical to, or very similar to, the ABO blood group antigens are found throughout nature. ABO antibodies are absent at birth and start to appear around 3-6 months as result of stimulus by bacterial polysaccharides (but the ABO antigens are present on the RBC surface from birth).

Answer 143

Acute transfusion reactions are a result of mixing ABO blood groups together. Acute Transfusion Reaction caused by ABO mismatch Within minutes: Agglutination by IgM Complement mediated lysis Release of Hb (haemoglobinuria) Breakdown to bilirubin Toxic (Fever, chills, nausea, clotting within blood vessels, necrosis of kidneys) Most incompatible blood transfusions arise from clerical errors and mistaken patient identity

Answer 144

caused by mismatch of non-ABO antigens Usually due to repeated transfusion of ABO matched blood that is incompatible for other blood group antigens e.g. Rh, Kidd, Kell and Duffy Usual class of antibody is IgG (less effective at activating complement - less aggressive symptoms) Fever, low haemoglobin, increased bilirubin, mild jaundice and anaemia Should be prevented by proper cross-matching

Answer 145

O group (specifically O-) is the universal donor AB group (specifically AB+) is the universal recipient A person who is group A has A antigens on the surface of their RBCs. In their plasma they will have anti-B antibodies (IgM). If they are given RBCs with the B antigen on the surface (ie groups B or AB) the anti-B in their plasma will attack the donated cells. They will not attack either group A or group O RBCs. O is the universal dOnor.

Answer 146

Since there are many blood groups (>20) and variants (>400) with varying degrees of antigenicity and rarity, the suitability of blood for transfusion is double checked by cross-matching Blood cells from the donation are mixed with plasma from the recipient Agglutination indicates that the donor blood is incompatible

Answer 147

Symptoms caused by destruction of red blood cells Most common antigen involved - RhD (very antigenic and high frequency) Enlarged liver and spleen as a result of red cell lysis Symptoms of anaemia Jaundice caused by elevated bilirubin (breakdown product of haemoglobin – toxic, may cause brain damage) NB : Haemolysis = breakdown of haem (RBCs). The RBCs of the foetus are being attacked and destroyed. Damaged or destroyed RBCs are filtered from the blood by the spleen (hence the enlarged spleen and liver). Liver and spleen are also sites of extramedullary haematopoiesis ie. Sites of blood cell production in embryonic and foetal stages. As more cells are destroyed these sites increase their production to try and keep up.

Answer 148

Haemolytic disease of the newborn is only a risk in RhD negative mothers. RhD positive mothers will recognise any Rh as self and so not produce an antibody response to it. If RhD positive cells enter the mothers circulation she will recognise the RhD as foreign and make antibodies to it. These anti-RhD antibodies (IgG as adaptive immunity) will circulate in the mother quietly waiting to see the antigen again. If the mother carries another RhD positive foetus the anti-RhD (IgG) is small enough to cross the placenta and enter the foetal circulation. Here the antibodies attack and destroy the foetal RBCs, leaving the foetus very anaemic. The build up of waste products like bilirubin are toxic to the brain and can result in brain damage.

Answer 149

Anti-D antibody is injected to RhD- mother after birth of first child Neutralises RhD+ red cell from foetus No anti-RhD antibodies raised in mother Second RhD+ child does not develop haemolytic disease of the foetus/ newborn Haemolytic disease of the new born can be prevented if the foetal RBCs can all be mopped up before an immune response is raised. Immediately after birth a RhD negative mother is injected with anti-D. The anti-D antibody mops up all the foetal RhD positive RBCs and prevents the immune response happening, so no IgG are made.

Answer 150

Haematopoietic Stem Cell Transplants (Bone marrow transplants) “Tissue-typing” from a saliva sample Bone marrow harvest or peripheral blood stem cell donation (PBSC) Recipient has chemotherapy / radiotherapy to destroy their bone marrow Donated stem cells can be injected by IV and migrate to the bone marrow to repopulate it Recipient takes immunosupressive medication

Answer 151

1. Central Nervous System (CNS) Brain and spinal cord 2. Peripheral Nervous System (PNS) Divided into: Autonomic Nervous System (largely outside of voluntary control) (ii) Somatic (motor) nervous system (under conscious control)

Answer 152

The brain may be divided into 3 major regions: Fore Brain (Prosencephalon) cerebrum, thalamus Mid Brain (Mesencephalon) cerebral peduncle, substantia nigra Hind Brain (Rhombencephalon) pons, medulla, cerebellum

Answer 153

Fore Brain (Prosencephalon) cerebral hemisphere, thalamus Thalamus: ‘sense’ information processing function Hypothalamus: regulates endocrine system via hormone release from pituitary gland

Answer 154

Mid Brain (Mesencephalon) cerebral peduncle, substantia nigra (relays information from auditory and visual system and body movement)

Answer 155

Hind Brain (Rhombencephalon) pons, medulla, cerebellum pons = ‘bridge’ (between cerebrum and cerebellum) medulla oblongata = ‘long oblong’ (controls respiratory, BP) cerebellum = ‘little brain’ (controls movement & balance)

Answer 156

Brain and spinal cord surrounded by tough meninges (dura and also arachnoid, pia mater) Cerebrospinal fluid (CSF) lies between arachnoid and pia mater; cushioning, protective and homeostatic function

Answer 157

Delicate structure with central grey area (2 dorsal and 2 ventral horns) and surrounding white matter (nerve fibres connecting spinal cord to brain) Dorsal means top Ventral means bottom Where the nerves come out the spinal cord

Answer 158

4 spinal nerves/segment: involved in communication and reflexes Afferent nerve fibres enter via dorsal root e.g. sensory pain information via DRG cells Efferent nerve fibres exit via ventral root e.g. to skeletal muscle (somatic NS) or glands (ANS)

Answer 159

The CNS has two main types of cell: 1) Neurones 2) Non-neuronal cells Neuronal functions Neurones have become highly specialized to serve two primary functions: 1) the rapid transmission of information from specific sources to selected targets 2) the integration (i.e. summation) of information from many sources The anatomy of neurones is directly related to these functions Non-neuronal cells (i) Astrocytes: supportive function for CNS neurones, contribute to the protective blood brain barrier (BBB) (ii) Oligodendrocytes: form the myelin sheath around axons in the CNS (iii) Microglial: phagocytotic action in the CNS (iv) Ependymal cells: epithelial cells in the fluid-filled spaces of the brain and central canal of the spinal cord. Possess microvilli which help circulate CSF around the CNS

Answer 160

Dendrites: receive information from other neurones = ‘convergence’ Presynaptic terminals ~80% dendritic ~20% somatic Axon: transmit information to other neurones or non-neuronal cells (eg. muscles) Neurones are the functional units of the nervous system giving rise to two types of processes: (numerous) dendrites (receive convergent information) and (typically) a single axon (transmits information via divergent signalling)

Answer 161

This is an action potential An action potential is fired when we reach the threshold We go from a resting potential of about -70 to about +50 We are injecting current in order to fire an action potential Depolarization – going from a minus number to a positive number Repolarization – going from a positive back down to minus

Answer 162

The potential at which the tendency of an ion to move down its concentration gradient is exactly balanced by the membrane potential is called the equilibrium potential. If an ion is at the equilibrium potential, it wont move in or out of the cell Equilibrium potential (E) is calculated using the Nernst equation Generation of the nerve action potential is dependent on the pre-existence of a resting membrane potential (RMP) Resting membrane potential is calculated from the sum of effects of all permeable ions

Answer 163

Equilibrium potential (E) for ion (I) is calculated using the Nernst equation: EI = - RT ln [C]in zF [C]out Or EI = - 2.3 RT log [C]in zF [C]out R = gas constant (8.31 J/K/mol) T = absolute temperature (in Kelvins) F = Faraday constant (96 487 C/mol) z = charge on the ion (K+ = +1 etc) [C]out = extracellular ion concentration [C]in = intracellular ion concentration So So what they did here was: the RT/zF values are ALWAYS the same so if you plug them in, it gives you 26.7mV. Then you just have to do the log of the [C]in/[C]out (values that will be given to you). Use the calculator and that’s it C in means concentration of inside and C out means concentration of outside

Answer 164

Conc of ions inside and outside the cell Lets look at sodium: extracellular fluid conc is 142 and inside is 10 The concentration gradient is therefore 142 divided by 10 = 14.2 We can do that for any ions

Answer 165

The AP is determined by the action of 2 major currents: 1. Sodium (Na+) current – inward, depolarizing current 2. Potassium (K+) current – outward, hyperpolarizing current The 2 most important ions are Na and K Sodium goes INTO cell Potassium goes OUT

Answer 166

we can control the opening and closing of the channels by gates Gates are controlled by voltage In the resting phase A, sodium channel is shut, potassium channel is shut. No movements either way Then, In B sodium channel opens and sodium goes into the cell. Potassium channel remains shut so this increase in charge depolarizes the cell away from its minus value towards the positive value Then in C, gate on the inside is closed then we essentially we stop losing sodium. Potassium channel is open so potassium leaves cell (positive potential inside the cell to more and more negative as potassium leaves) Then in D, sodium channel is shut, potassium channel closing slowly. We get an overshoot because this potassium channel is quite slow to close

Answer 167

If threshold is exceeded, APs have similar magnitude and duration = ‘all-or-nothing’ principle In the period Na+ channels are open or inactivated, an AP cannot be elicited = absolute refractory period In the period K+ channels are open, membrane is hyperpolarized and a stronger stimuli is required to elicit an AP = relative refractory period NB : If the threshold is exceeded, an action potential will happen. Action potentials have the same height. Its all or nothing. If the threshold is reached, the action potential will happen. If it is not reached, it will not happen and the action potential will not fire Refractory period is when the neuron recovers and no action potential can happen. ARP in the diagram is the Absolute Refractory Period – period in which sodium channels are opened or inactivated – action potential cannot happen at this point. You are already at the highest point, therefore you just cannot have another action potential starting at this point In the relative refractory period, if you put enough stimulation during this time, you can get another action potential. But, in the ARP, no matter how much stimuli you put in, you cannot get another action potential. This is important because we want to space out the action potentials as much as possible

Answer 168

Myelination determines conduction velocity In the CNS: oligodendrocytes myelinate axons In the PNS: Schwann cells myelinate axons Myelin is a phospholipid which wraps around and insulates the axon. Myelin around the nerves is like an insulator and makes the transmission a lot quicker Know the cells that make up the myelin sheath

Answer 169

Myelin decreases the capacitance of the axon, and restricts the generation of action potentials to the nodes of Ranvier Action potentials conducted with little decrement and at great speed from one node of Ranvier to the next If u have a look at the red line, as you increase the thickness of myelin sheath, the rate of conduction gets quicker. In comparison, the unmyelinated neurons (blue) transmit much less slower

Answer 170

Neurones signal by action potentials (APs) AP generation depends on the existing resting membrane potential (established by membrane ion channels and pumps which maintain electrochemical ion gradients) APs are rapid (< 1 ms), all-or-nothing events generated by stimulation above a threshold value at the axon hillock APs are initiated by a rapid increased Na+ permeability, which depolarizes the membrane and terminated by a slower increase in K+ permeability, which repolarizes the membrane Na+ channel inactivation means the neurone cannot fire during the absolute refractory period. Prolonged K+ channel activation makes it is more difficult for AP to fire during the relative refractory period. Large-diameter axons conduct faster than small-diameter axons; myelination speeds conduction velocity by salutatory conduction In the CNS, oligodendrocytes myelinate axons In the PNS, Schwann cells myelinate axons As APs are all-or-nothing (i.e. identical), information is encoded by firing frequency (measured in Hertz); e.g. increased pressure or pain stimuli produces higher frequency firing

Answer 171

synapses types Between axons and axons Between axons and dendrites Between axons and soma Between dendrites and dendrites

Answer 172

Neurones send and receive signals to and from other cells at specialised junctions called synapses. These are either: chemical (>99% in mammalian NS) or electrical (open channels that conduct directly e.g. gap junctions) Chemical synapses Axons of presynaptic neurones make contact with target postsynaptic cells (neurone, muscle cell or gland) at: dendrites (axo-dendritic synapses) soma (axo-somatic synapses) other axons (axo-axonal synapses) The presynaptic cell releases chemical neurotransmitters which act on receptors on postsynaptic cells to propagate neuronal signals.

Answer 173

This is a chemical synapse You have the pre synapse (before the synaptic cleft) – labelled in blue You have the post synapse (after the synapse) Synaptic cleft is in the middle White circles are the neurotransmitter vesicle The acetylcholine is packaged into these vesicles The vesicle fuses with the presynaptic membrane, contents are released across the synaptic cleft, and attaches to the post synaptic receptor

Answer 174

1) Excitatory neurotransmitters – swich system on increase nerve activity cause depolarization initiate excitatory post-synaptic potentials (EPSPs) 2) Inhibitory neurotransmitters – switch system off decrease nerve activity cause hyperpolarization initiate inhibitory post-synaptic potentials (IPSPs) Examples: g-aminobutyric acid (GABA), opioids, acetylcholine Whether or not an AP is generated depends upon the balance of EPSPs and IPSPs converging on a neurone at any given moment = **synaptic integration**

Answer 175

Acetylcholine packaged into its vesicle Calcium comes in through voltage gated calcium channels Acetylcholine released You have different types of receptors – muscarinic and nicotinic receptors- they are named after things that turn them on. For example, nicotinic receptors are turned on by nicotine If you activate a nicotinic receptor, you can see that it lets sodium down its concentration gradient and depolarises the cell

Answer 176

Example: acetylcholine at nicotinic acetylcholine receptor (nAChR) 1. We have a receptor that is inactive – gate is shut 2. Acetylcholine comes along, attaches to receptor to the binding site and opens the gate 3. Sodium goes down the concentration gradient 4. Sodium entry depolarises the cell – makes the inside more positive 5. If we depolarise it enough, it will generate an action potential

Answer 177

Action potentials are all the same height, all the same width (blue) But the red line (EPSPs) are all looking different In neuroscience, an excitatory postsynaptic potential (EPSP) is a postsynaptic potential that makes the postsynaptic neuron more likely to fire an action potential. This temporary depolarization of postsynaptic membrane potential, caused by the flow of positively charged ions into the postsynaptic cell, is a result of opening ligand-gated ion channels. These are the opposite of inhibitory postsynaptic potentials (IPSPs), which usually result from the flow of negative ions into the cell or positive ions out of the cell.

Answer 178

Here we have a bunch of epsps that are letting sodium into the cell Going from -85 to +20mv = not generating an action potential but becoming more depolarised The more epsps you have, the more depolarised it gets and then maybe when you reach the threshold, you can fire an action potential if you have enough epsps You need enough epsps to reach threshold – then an action potential can be fored

Answer 179

Inhibitory GABAergic synapse Gaba is inhibitory neurotransmitter Action potential happens, calcium increases, Gaba is released into pre synaptic cleft. This time there are 2 different post synaptic receptors, one called Gaba A and one is a gaba B The gaba A lets a NEGATIVE ion down its concentration channel Instead of depolarising, the inside of the cell becomes more negative and so becomes hyperpolarized. The reason it is considered inhibitory is because it uses chloride rather than something positive like sodium

Answer 180

Example: g-aminobuytric acid (GABA) at GABA receptor Cl- entry: hyperpolarizes the postsynaptic membrane causes an inhibitory postsynaptic potential (IPSP) inhibits action potential generation Gaba binds to site, opens the gate and lets chloride in Chloride hyperpolarises instead of depolarises, causes IPSP (not EPSP) and inhibits action potential generation

Answer 181

Inhibitory neurotransmission causes an Inhibitory Post Synaptic Potential (IPSP), which opposes excitability Compared to all-or-nothing action potentials, IPSPs are SMALLER, and are: graded (can vary in amplitude) temporal (decay with distance), and can summate (add to each other) NB : Basically prevents action potentials

Answer 182

A neurone receives both excitatory and inhibitory inputs, a major function is to integrate these inputs and decide whether to signal to the next neurone (or muscle or gland) or not NB : A neurone is probably contacted by 100s of synapses Some are inhibitory, some are excitatory like A and B In this example, the excitatory may win because if you summate them (add them together), if they go above the threshold, it will fire. If it stays below the threshold, it will not fire. If you have more excitatory, then there is more chance of going above the threshold. If you have some inhibitory, there is less chance of it going above the threshold

Answer 183

Synaptic transmission: neurotransmitter released from the presynaptic cell into the synaptic cleft by a Ca2+-dependent process Neurotransmitters bind to postsynaptic receptors to cause a short-lived change to excitability of postsynaptic cell Excitatory neurotransmitters cause EPSPs and activate the postsynaptic cell Inhibitory neurotransmitters cause IPSPs and inhibit the postsynaptic cell Cellular integration: neurones summate EPSPs and IPSPs; the relative balance determines if the neurone will fire or not

Answer 184

1. Parasympathetic nervous system Cranial-sacral output, synapse at ganglia (group of nerve cell bodies) close to innervated tissue 2. Sympathetic nervous system Thoracic-lumbar output, synapse at ganglia either side of vertebral column (sympathetic chain). Ganglia distal to innervated tissue 3. Enteric nervous system Neurones with cell bodies in the wall of the intestine which innervates GI tract, pancreas and gall bladder NB : Pink is the spinal cord For parasympathetic – it is from M,C, S For sympathetic it comes from T and L

Answer 185

The ANS is a visceral (body organs, gut) and largely involuntary motor system. The main processes that the ANS regulates include: cardiac muscle (heart beat) smooth muscle contraction and relaxation exocrine gland function some endocrine secretions some steps in intermediate metabolism In general, the sympathetic system evokes a ‘fight and flight’ response, whilst the parasympathetic system mediates a ‘rest and digest’ state

Answer 186

The ANS is characterised by having 2 neurones outside the CNS **Preganglionic** fibres arising from the CNS synapse onto **postganglionic** nerve in a ganglia. Postganglionic neurones terminate at the effector. 1. Acetylcholine (ACh) is released from all preganglionic neurones of both parasympathetic and sympathetic nerves all postganglionic parasympathetic neurones = cholinergic transmission 2. Noradrenaline (NA) is released from most postganglionic sympathetic neurones = adrenergic (noradrenergic) transmission Noradrenaline important in the sympathetic system Acetylcholine important in the parasympathetic system

Answer 187

1. Sympathetic effects are (largely) due to noradrenaline action all postganglionic sympathetic fibres release noradrenaline to act either on a or b-adrenoceptors 2. Parasympathetic effects are (largely) due to acetylcholine action all postganglionic parasympathetic nerves release ACh to act on muscarinic acetylcholine receptors (mAChRs) 3. Somatic nervous system effects are due to acetylcholine action all motor nerves release ACh which act on nicotinic acetylcholine receptors (nAChRs)

Answer 188

Sympathetic Nervous System

Answer 189

Parasympathetic Nervous system effects

Answer 190

Controls the activity of the gastrointestinal (GI) tract and its associated glands (e.g. pancreas and gall bladder) via two well-defined plexuses (neural networks): 1) myenteric (Auerbach's) plexus (lying between longitudinal and circular muscle layers): controls GI movement 2) submucosal (Meissner's) plexus (lying between circular muscle and submucosa): controls GI secretion and local blood flow The enteric system can function by itself; however, activity is normally regulated by both the parasympathetic (vagal and splanchnic nerves) and sympathetic (mainly via prevertebral ganglia) nervous systems

Answer 191

The ANS is a visceral and largely involuntary motor system. Controls smooth muscle, cardiac muscle and exocrine glands Pathways are bisynaptic: preganglionic neurones located in nuclei of the CNS activate cell bodies of postganglionic neurones in the periphery Postganglionic neurones may be excitatory or inhibitory Sympathetic NS is dominant in emergency situations (‘fight and flight’) increased rate and strength of heart beat, diversion of blood from the digestive tract to skeletal muscles, sweat glands and the skin. Parasympathetic NS mediates 'rest and digest' reactions, reducing cardiac output to resting levels, conserving energy (low muscle and skin blood flow) and reducing basal metabolic rate and ventilation Enteric NS controls the activity of the GI tract and its associated glands

Answer 192

Movement is dictated by the Somatic Nervous System (SNS), which is under hierarchical control of both spinal and central divisions of the CNS: 1) Spinal control Spinal reflexes are unconscious and inherited ‘hard-wired’ systems for fast, survival-orientated effects. In general, function is to maintain posture. 2) Central control Several brain regions involved, but particularly the motor cortex of the cerebral hemispheres, thalamus, cerebellum and the basal ganglia which act via spinal motor neurons. In general, function is to control goal-directed movement.

Answer 193

Simple spinal reflexes represent the basic levels of motor control and they have the following characteristics: do not depend on consciousness or ‘will’ have few synapses and are therefore fast serve protective or survival functions are inherited ‘hardwired’ systems and are not learnt modulated by the CNS (transection of the brain stem leads to continual motor activity due to loss of inhibition)

Answer 194

Vertebrate Nervous System has 2 major divisions: 1. Central Nervous System (CNS) Brain and spinal cord 2. Peripheral Nervous System (PNS) Outside the CNS and divided into: Autonomic Nervous System: largely outside of voluntary control **(ii) Somatic (motor) nervous system: under conscious control**

Answer 195

Peripheral nAChRs are present at i) autonomic ganglia in ANS ii) neuromuscular junctions (NMJs) in somatic nervous system

Answer 196

The SNS dictates movement via motor neuron control of skeletal muscle fibres (neural pathways that affect muscles are called a motor system) SNS is under control of both spinal and central divisions of the CNS: 1) Spinal control Spinal reflexes which are unconscious and inherited ‘hard-wired’ systems for fast, survival-orientated effects 2) Central control Several brain regions involved; in particular, the motor cortex of the cerebral hemispheres, thalamus, cerebellum and the basal ganglia which act via spinal motor neurons

Answer 197

1. Motor neuron cell bodies found in the ventral horn of the spinal cord 2. Motor neuron dendrites receive information from: proprioceptors, recurrent collaterals (supply feedback inhibition) descending fibres from the brain 3. Motor neuron axons exit via the ventral root of the spinal cord

Answer 198

Proprioception is defined as “the perception of self” i.e. where your body is in relation to the surroundings Proprioception is a two-way process: 1. Proprioceptors signal to the spinal cord/CNS (afferent) The two major proprioceptors are: (i) Muscle spindles (within muscle; respond to stretch) (ii) Golgi tendon organs (within tendons; respond to tension) 2. Motor neurons signal to skeletal muscle (efferent)

Answer 199

(i) Muscle spindles (within muscle; respond to stretch) (ii) Golgi tendon organs (within tendons; respond to tension)

Answer 200

1.Skeletal muscle contraction is neurogenic, each muscle fibre receives a single, excitatory a motor neuron terminal, forming one neuromuscular junction (NMJ) per muscle fibre (called the motor unit) at the vast majority (~98%) of fibres. The neurotransmitter at all NMJs is acetylcholine (ACh) which act on postsynaptic nicotinic ACh receptors (nAChRs). 2. Smooth muscle contraction is myogenic (i.e. does not rely on neural input) to display intrinsic, rhythmic contraction. Smooth muscle often receive a dual innervation from the sympathetic and parasympathetic NS divisions of the ANS. 3. Cardiac muscle contraction is also myogenic, but different parts of the heart have different intrinsic frequencies of contraction. The pacemaker region receives a dual innervation from the sympathetic and parasympathetic NS.

Answer 201

The motor unit is the functional element of muscle contraction: = single motor neuron and all the muscle fibers that it activates A single motor unit may have 3-1500 muscle fibres, but individual fibres receive 1 motor neuron input

Answer 202

1. Action potentials from -motor neurons depolarize the terminal 2. Depolarization opens voltage-dependent Ca2+ channels to permit Ca2+ entry and Ca2+-dependent vesicle fusion 3. ACh is released from the nerve terminal = exocytosis 4. ACh diffuses across the synaptic cleft to activate nAChRs, opening the receptor ionophore and causing Na+ influx and depolarizing the membrane 5. Na+ entry triggers an excitatory end-plate potential (EPP). EPPs summate and, if a threshold is attained, trigger a action potential 6. Muscle action potential spreads along the sarcolemma to T-tubules triggering Ca2+ release from terminal cisternae (intracellular stores); this is the final trigger for excitation-contraction coupling 7. Ca2+ ions bind to troponin molecules on the actin fibres permitting cross-bridge formation and muscle contracts according to the sliding filament model which requires ATP 8. ACh is continuously degraded into acetate and choline by the enzyme acetylcholinesterase at the NMJ. Sarcoplasmic Ca2+ concentrations fall and actin-myosin interactions are inhibited i.e. the muscle relaxes

Answer 203

NMJs are blocked by: paralysing poisons such as curare - derived from tree bark and used as an arrow poison by South American Indians, act to block nAChRs agents acting at nAChRs during general anaesthesia to control convulsions/prevent movement during surgery by local injection of botulinum toxin (Botox®), which blocks vesicle fusion with the presynaptic membrane. Used cosmetically and clinically to treat muscle spasms

Answer 204

-motor neurons are the efferent output from the spinal cord and innervate muscle fibres to form a motor unit action potential from the -motor neuron cause exocytosis of ACh ACh binds to postsynaptic nAChRs to generate end-plate potential (EPP) if EPPs attain a threshold a muscle action potential is generated muscle APs promote Ca2+ release from terminal cisternae Ca2+ release couples excitation to contraction

Answer 205

**Skeletal muscle **- voluntary (~40% of body mass) is responsible for movement of bones within the musculoskeletal system consists of skeletal muscle attached to the bony skeleton which provides support, protection, and a movable frame **Cardiac muscle **is specialised to allow heart to pump blood throughout the body **Smooth muscle** is the muscle of internal organs supporting the activities of different systems: cardiovascular (blood flow), respiratory (air flow), GI (gastric motility) and renal systems (bladder and urethra) NB : Striations means lines Control means can we control it or not

Answer 206

In addition to control of movement by contraction, the musculoskeletal system controls respiration (via diaphragm muscle) and has important homeostatic functions (bone is able to store Ca2+ and other ions, skeletal muscle cells store K+). Skeletal muscle also plays a major role in metabolism and in temperature regulation.

Answer 207

1. Supply of energy dictates the activity of muscle. 2. Energy (ATP) can be quickly made without oxygen using glycolysis (but for only short periods). 3. Energy for longer periods of use requires additional processes including oxidative phosphorylation. 4. Muscle function dictates which energy strategy is used. 5. Muscle made of two types of fibres: red or white with distinct properties.

Answer 208

Type I, slow twitch, or "red" muscle fibres, is dense with capillaries and is rich in mitochondria and myoglobin, giving the muscle tissue its characteristic red colour Type II, fast twitch, or “white" muscle fibres, with few capillaries or mitochondria and low myoglobin, giving the muscle tissue its characteristic white colour.

Answer 209

Found in postural muscle, surrounded by adipocytes (fat cells), diameter about half of white fibres. Red due to high myoglobin content. Surrounded by capillaries, with high mitochondrial, but low glycogen content. Red muscles are efficient (produce sustained energy and can maintain contraction for long periods), but contraction rate is slow (as predominantly use oxidative phosphorylation for energy production). **Called slow or oxidative muscle.**

Answer 210

Found in fast muscle, i.e muscle required for quick action and large power production. White (or pale) due to low myoglobin content. Surrounded by few capillaries, with relatively few mitochondrial, but high glycogen content. White muscles rely predominantly on glycolysis (breakdown of stored glycogen) to produce energy (as incapable of using use oxidative phosphorylation for energy production) so are fast, but fatigable. Called fast or glycolytic muscle.

Answer 211

Note: although ‘red’ and ‘white’ are useful distinctions, muscle fibres represent a continuum of which these are the extremes

Answer 212

1. Most skeletal muscles have two ends, usually attached to bones via tendons. 2. Each muscle surrounded by connective tissue- epimysium. 3. Within epimysium tissue organised into fascicles- bundles of muscle cells. 4. Connective tissue (called perimysium) separates individual fascicles. 5.Individual muscle cells (myofibre) in fascicle surrounded by connective tissue - endomysium. 6. Three connective tissues continuous with tendons, bind muscle cells together.

Answer 213

The major two myofibril proteins- are: Actin (thin filaments) Myosin (thick filaments) which give muscle its striated appearance A band- quite dark- length of thick (myosin) filaments I band- very light region with thin (actin) but no thick filaments: length decreases during contraction Z line - bisects I band- protein disc onto which thin filaments attach H zone - length decreases during contraction M line - middle of A band- region where thick filaments attach **Sarcomere- fundamental contractile unit region between two Z lines** NB : Actin is thin – blue Myosin is red - thick

Answer 214

Main take home message is – myofilaments are basic units of muscles – actin and myosin

Answer 215

1. Skeletal muscle is voluntary muscle: requires innervation (nerve input) (neurogenic) 2. Action potential travels from spinal cord to skeletal muscle along one α-motor neuron 3. Each adult myofibre is (typically) innervated by one axon terminal to each myofibre at the neuromuscular junction – becomes clear later on 4. A motor unit is defined as a single motor neuron and all the muscle fibers that it activates 5. Motor unit size varies: (i) Small motor units found in muscles requiring fine control (e.g. eye movement muscles) (ii) Large motor units found in muscle required for strong contraction (e.g. quadriceps) We are interested in the neuromuscular junction – site of action of drugs

Answer 216

The motor unit is the functional element of muscle contraction:

Answer 217

1. Action potential travels from motor end plate along sarcoplasma via T-tubule 2. Two important physically associated proteins: dihydropyridine receptor (DHP) (L-type voltage-gated Ca2+ channel) found at triads on T-tubules and ryanodine receptor (RR) on SR 3. Action potential activates DHP 4.DHP activates RR by changing its conformation 5.Activated RR pumps Ca2+ from SR into cytosol to initiate muscle contraction

Answer 218

Adenosine triphosphate (ATP) Ca2+ Thick filaments Thin filaments Tropomyosin Troponin How to remember the components? Use the mnemonic ACT-4

Answer 219

1. Present at sarcomere I band 2. Major thin filament is actin: two chains composed of actin monomers wound around each other 3. Each actin monomer has a single myosin binding site (MBS) on its external surface 4.Actin MBS is normally covered by the tropomyosin protein 5. Troponin protein is found on thin filaments 6.Ca2+ binds troponin which moves off the actin MBS

Answer 220

1. Chains of actin form thin filaments 2. Actin filaments bound to the Z line 3.Thin filament kept in order by nebulin protein 4.Thick filaments made of myosin 5. Myosin heads face Z line, tails face M line 6.Thick filaments kept linear by titin protein

Answer 221

Myosin heads are in this high energy configuration. Bound to ADP and PI ATP comes in which allows the cross heads to break down and for muscle to contract. ATP then split back into adp and pi again, myosin head is energized into the new configuration where its again available to bind to myosin Take home message – atp comes in, allows cross bridges to break up, allows different filaments to slide over one another

Answer 222

1. Muscle keeps contracting as long as it has ATP and Ca2+ to expose MBS on actin (yellow) 2. Energy is depleted slowly therefore cannot suddenly stop contraction 3.Contraction terminated by Ca2+ being removed from cytosol back into SR 4. Process involves a Ca2+ pump called SERCA (sarcoplasmic/endoplasmic reticulum calcium ATPase) which is a very abundant protein - 90% of SR 5.Ca2+ pumped against [Ca2+] gradient so requires energy (a major use of ATP by muscle). 6.AP stops, no more Ca2+ released but [Ca2+] high. Ca2+ binds SERCA. Induces binding of ATP (blue) to SERCA: ATP hydrolysed, Ca 2+ transported Atp causes cross bridge formation In order to stop muscles contracting, we need another protein called serca to get rid of excess calcium

Answer 223

a) Acquired Inflammatory myopathies e.g polymyositis NMJ disease e.g myasthenia gravis, Lambert-Eaton syndrome Endocrine myopathies e.g Cushing disease: high glucocorticoid induce muscle atrophy b) Genetic Muscular dystrophy e.g Duchenne MD where patients lack dystrophin protein Myotonic dystrophy: genetic defects in protein kinase enzymes Ion channel diseases e.g hypoklaemic periodic paralysis with defects in L-type Ca2+ channel

Answer 224

Skeletal muscle can be broadly divided into red (slow and oxidative) and white (fast and glycolytic) fibres. Muscle consists of cylindrical muscle fibres containing myofibrils made up of repeating sarcomeres, which represent the fundamental contractile unit. Sarcomeres are separated from each other by Z lines, with 2 half I bands (made up of actin) at each end, separated by a central A band (made up of myosin). Myofibrils are surrounded by sarcoplasmic reticulum (SR). Excitation-contraction coupling involves an action potential causing Ca2+ release from SR. Ca2+- and ATP-dependent actin-myosin cross-bridges cause contraction via sliding filament model.

Answer 225

Cardiac muscle (myocardium) is the involuntary muscle that is found only in the heart. Cardiac muscle is controlled by intrinsic factors (e.g., the amount of venous return to the right atrium), hormones, innervation by the autonomic nervous system – has nervous control Cardiac muscle has a number of similarities to skeletal muscle in terms appearance (striated) and contractile process, but is branched and connected by gap junctions (unlike independent skeletal muscle fibres).

Answer 226

Epicarduim: Outer layer of serous pericardium Myocardium: Muscle layer (cardiac myocytes) Endocardium: Inner layer lining chambers (endothelial cells and connective tissue) (also see lectures on cardiovascular physiology) Epi – means outside always Endo – means inner always

Answer 227

Electrical input drives conduction Sino atrial node is the pacemaker – controls heart rate

Answer 228

Branched Multi nuclei Rhymical conduction of the heart IT HAS GAP JUNCTIONS Cardiac muscle contains intercalated disk with gap junctions to allow action potentials to spread across the myocardium. Cardiac muscle cells in the SA node can depolarize spontaneously by a process called automaticity to generate a pacemaker potential. AP passes through heart until reaching ventricular muscle where the characteristic cardiac action potential is generated

Answer 229

The first depolarisation stage is due to sodium ions coming into the cell (Na+ influx), if a positive charge is coming in, then inside negative space of the cell is going to become more positive Potassium is leaving the cell. Potassium is also positive so it repolarises the inside of the cell again to its resting potential – negative inside Take home message – calcium important in the cardiac system The way we keep sodium high outside the cell and potassium high inside the cell is through the protein sodium-potassium ATP-ase. This pumps sodium actively outside the cell and potassium into the cell

Answer 230

Myocardial cells contain actin and myosin and T tubules as in skeletal muscle. Cardiac muscle obtains oxidative energy from aerobic metabolism via numerous mitochondria. At rest, 60% of energy is derived from metabolism of fat, 35% from carbohydrates, and 5% from amino acids and ketones. Excitation – comes from nervous system Contraction comes from the muscle system

Answer 231

1. During phase 2 of the cardiac AP, myocardial depolarization permits Ca2+ entry via L-type Ca2+ channels located in the T-tubules of the sarcolemma. 2. Ca2+ entry is sensed by ryanodine receptors (RyR) to trigger Ca2+ release from sacroplasmic reticulum (Ca2+-induced Ca2+ release, CICR); this is the final trigger for excitation-contraction coupling. 3. Ca2+ interacts with troponin-C (TN-C), causing troponin-I (TN-I) to uncover a myosin binding site on actin to produce the force required for muscle contraction (via sliding filament action) 4. Intracellular Ca2+ is reabsorbed into SR via the sarco-endoplasmic reticulum Ca2+ ATPase (SERCA) pump and removed from the cell via other means such as Na+/Ca2+ exchanger and an ATP-dependent Ca2+ pump. 5. As intracellular Ca2+ decreases, Ca2+ dissociates from TN-C and the binding site on actin is inhibited. ATP is required to unbind myosin from actin and reset the sarcomere to its normal length

Answer 232

During a cardiac AP, the ventricular muscle cell cannot initiate a second action potential = absolute refractory period (ARP). At the end of the AP, there is a relative refractory period (RRP), during which only a subsequent AP can only be initiated by a greater than normal stimulus. Ventricular muscle contraction is completed shortly after the RRP

Answer 233

Smooth muscle is the muscle of internal organs, supports the activities of different systems: cardiovascular (blood flow), respiratory (air flow), GI (gastric motility) and renal systems (bladder and urethra. Smooth muscle is so named because it has no visible striations. Its contraction is involuntary. Smooth muscle fibres are spindle-shaped joined by specialised junctions. Adapted for different functions: single-unit, coupled by gap junctions, (e.g. GI smooth muscle) or multiunit, primarily under neural control (e.g vascular smooth muscle and ciliary muscles and iris of the eye). Innervated by autonomic nervous system.

Answer 234

Smooth muscle also uses actin and myosin for contraction, but these are not arranged as regular sacromeres. Contraction differs from skeletal muscle in that smooth muscle uses tropomyosin but lacks troponin C. Instead, Ca2+ acts through calmodulin to activate myosin light-chain kinase to phosphorylate the myosin heads. This increases myosin ATPase activity to provide energy for myosin to form cross-bridges with actin (via sliding filament action). There is also no T-tubule system. Contraction develops more slowly, but lasts longer than skeletal muscle. ATP usage is much less and slower than for a similar contraction of skeletal muscle.

Answer 235

More complex and diverse than in skeletal and cardiac muscle. Smooth muscle action potentials are longer (10-50 ms) and involves influx of both Na+ and Ca2+ (can differ between locations) Also driven by Ca2+/second messenger pathways: Neurotransmitters stimulate Ca2+ release from SR (e.g. receptors linked to IP3) to allow direct Ca2+ influx Hormones increase cAMP to increase Ca2+ release from SR Ca2+ can be release via second messengers such as nitric oxide

Answer 236

In heart, pacemaker cells in SA node set the rate of cardiac muscle contraction. In smooth muscle, contraction is initiated by membrane events that allow the influx of extracellular Ca2+. Skeletal, cardiac, and smooth muscle all use the motor protein myosin, the structural protein actin, ATP, and Ca2+ for contraction. Muscle types differ in the source of Ca2+, arrangement of actin and myosin, excitation-contraction coupling, and regulation of contraction.

Answer 237

What does it do? Allows nutrients and gasses to exchange/diffuse Diffusion is passive and will reach equilibrium so need to circulate the fluids to maintain diffusion gradients What does a circulatory system need? A pump/driving force A closed loop Large surface area for diffusion and solute exchange

Answer 238

4 chambers Left and right atria Left and right ventricle Oxygenated blood goes all over the body and loses the oxygen Blood returns to the heart Gets pumped to the lungs where it picks up oxygen Goes back to the heart Gets pumped all around the body again

Answer 239

he basis of our heartbeat is an electrical impulse Heartbeat starts with the sinoatrial node which sends electrical impulse through the atria causing them to contract That impulse then reaches atrioventricular node which then sends signals down to the AV bundle which is the split into Purkinje fibres into left and right which then sends the impulse around the ventricles, making them contract, pumping the blood to the lungs (from right ventricle) or around the body (left ventricle) When we have a heart attack, it means some of our electrical system dies, making it less efficient

Answer 240

Parasympathetic nerves dominate at rest e.g vagus nerve Reduce HR and force of contraction Sympathetic nerves increase HR and force of contraction

Answer 241

Artery – thicker wall – maintains pressure, smaller lumen = maintains blood pressure as blood needs to be go all over the body. Arteries also contain more elastic tissue as that also maintains pressure Veins = wider lumen – have less pressure inside them. They are just bringing blood back to the heart Capillaries – very thin – enable diffusion to happen faster – things diffuse across them

Answer 242

Arteries, arterioles and veins = mainly Sympathetic innervation Noradrenaline released constricts blood vessels (see PM2C α1 adrenoceptors) Circulating adrenaline also constricts most blood vessels Dilates those vessels supplying heart lungs and skeletal muscle (PM2C)

Answer 243

Arteries control blood pressure and blood supply to tissues High pressure High velocity Capillaries are site of fluid and solute transfer Low velocity Small, thin, large surface area Veins return blood to the heart hold the largest volume of blood

Answer 244

Elastic (e.g. Aorta) Elastin in wall Muscular (e.g. Brachial artery) Less elastin Resistance (e.g. Mesenteric) Small typically <300 μm Control blood pressure Arteriole Very small <60 μM Control perfusion of capillary beds

Answer 245

Venioles return blood back to the main venous system Larger veins hold largest volumes of blood - elastic Low pressure Contain valves that control direction of flow Valves require skeletal muscle action to return blood to hear

Answer 246

Small 4-6 μm diameter normally <1mm long, Major site of gas and solute diffusion to and from tissues by: Transcellular exchange Also facilitated diffusion Paracellular exchange Vesicular transport Terminal arterioles regulate the number of perfused capillaries Capillary sphincters help to shunt some capillary beds

Answer 247

**Continuous capillaries** Diffusion up to 300 µm Gas and small lipophilic molecules penetrate wall Solute exchange via: Intracellular clefts Caveolae/vesicle mediated transport Facilitated diffusion Most common form found in most tissues/organs **Fenestrated capillaries** Up to 10x more permeable to water and salts small water soluble molecules can also penetrate Fenestrae generally about 50 nM in diameter Closed by fenestral diaphragm (FD) Found in liver exocrine glands kidney glomeruli Discontinuous capillaries (Sinusoids) Gaps up to 100 nM Allows passage of all water soluble molecules Including plasma proteins Found in tissues such as liver, bone marrow and spleen

Answer 248

* Lipophilic chemicals disuse freely along concentration gradients * solutes require transport or move with fluid * **Direction of fluid movement depends on pressure gradients:** 1. Capillary pressure (Pc hydrostatic pressure) 2.Interstitial pressure (Pi fluid surrounding tissue) 3.Oncotic pressure plasma (πp Osmotic pressure from plasma proteins) 4.Oncotic pressure intersitium (πi Osmotic pressure of proteins in interstitial fluid)

Answer 249

In general hydrostatic pressure is greater than interstitial pressure Net filtration Meaning fluid retention unless removed NB : Usually the pressure coming from the capillary is higher than the pressure of fluid around capillary Fluid moves from capillary to the surrounding fluid

Answer 250

Lymphatic system Link between circulation and immune system Lymphatic vessels drain fluid from tissues back to blood Lymphatic fluid similar to interstitial fluid (low oncotic pressure) discontinuous capillaries Semi-lunar valves All fluid must pass a lymph node before fluid returned to the venous circulation

Answer 251

The circulation is responsible for gas, solute and nutrient exchange between blood and tissues The blood vessels consist of the highly specialised arteries, veins, and capillaries. The anatomical features of each type of blood vessels are closely linked to their physiological functions. The capillaries are the major site of fluid and solute exchange and their structure changes in specialised organs Excess interstitial fluid is removed by lymphatic system which also has very important role in immunity.

Answer 252

Epicarduim: Outer layer of serous Pericardium Myocardium: Muscle layer (cardiac myocytes) Endocardium: Inner layer lining chambers (endothelial cells and connective tissue | Heart is a muscle and contains those three layers (epi always mean outs

Answer 253

Right ventricle pumps blood into the lungs. Left ventricle pumps it all around the body Left ventricle is therefore thicker as it needs to generate more stronger pump for it to go all over the body Atria are separated by valves which prevents backflow of the blood back up the atria

Answer 254

There are a series of pacemaker cells that are located in the sino atrial node (located in the right atria) – when a heartbeat is initiated, the signals go over the right atria, depolarisation causes contraction and this spreads all over There are intercalated disks in the gap junctions which are important in spreading the action potential Sinoatrial node – this initates the heartbeat

Answer 255

There are a series of pacemaker cells that are located in the sino atrial node (located in the right atria) – when a heartbeat is initiated, the signals go over the right atria, depolarisation causes contraction and this spreads all over There are intercalated disks in the gap junctions which are important in spreading the action potential Sinoatrial node – this initates the heartbeat

Answer 256

Electrical impulses drive heart beat- termed the cardiac cycle Two Major Components Systole chambers contract and eject blood Diastole chambers are relaxed and filling Atrial Systole occurs before ventricular systole (0.1-0.2s) End diastolic volume The volume of blood in the ventricle just before it contracts (systole) **Stroke volume** The volume of blood ejected by the heart helps determine cardiac output important measurement in heart failure and other cardiovascular diseases (>PM2C) and key determinant of blood

Answer 257

**Stroke volume** The volume of blood ejected by the heart helps determine cardiac output important measurement in heart failure and other cardiovascular diseases (>PM2C) and key determinant of blood

Answer 258

Electrical changes (ECG) precede mechanical events. Electrical happen first Opening and closing of valves due to pressure differences Ventricular diastole- AV valves are open and ventricles fill Aortic and pulmonary valves closed Beginning Ventricular systole pressure exceeds that of atria and AV valves close Peak of ventricular systole aortic and pulmonary valves open Blood ejected from heart to circulation Ventricular relaxation aortic and pulmonary valves close AV open

Answer 259

1. atrial contraction 1. isovolumetric contraction 1. rapid ejection 1. reduced ejection 1. isovolumetric relaxation 1. rapid filling 1. reduced filling

Answer 260

The blood pumped from a ventricle in one minute: Cardiac output= heart rate x stroke volume Cardiac output varies, responding to oxygen requirements of the body Sleep

Answer 261

Sympathetic nervous system release noradrenaline – these act on receptors in the heart called B1 adrenoreceptors – speed up the heart rate Vagus nerves (parasympathetic) release acetylcholine which acts on muscarinic receptors on the heart (slows them down)

Answer 262

Stroke volume= End diastolic volume x Ejection fraction the greater the volume in ventricle the ejected volume will increase therefore force of contraction must also increase……. How? during diastole volume of blood entering the ventricles exerts force on myocardium this tension of the myocardial fibres is termed Preload **Stretched muscle fibres contract more forcefully*** 1. Thus heart automatically adjusts cardiac output to match venous return (Starlings law of the Heart) 2. Frank-Starling mechanism balances output of left and right ventricles Both these are important in cardiovascular disease (PM2C)

Answer 263

Phase 0 Rapid depolarization Phase 1 Initial repolarization Phase 2 Plateaux Phase 3 repolarization Phase 4 Baseline

Answer 264

Everything is due to influx or efflux of ions Sodium goes into the cell via voltage dependent sodium channel Potassium levaes the cell and chloride enters the cell Potassium leaves the cell In phase 4, you see the normal 3 sodiums leaving to every 2 potassiums coming in

Answer 265

Largely dependent on Na+ Channels rapidly inactivate remain inactivated during phase 1, 2. Limits maximum possible contraction rate Repolarization (phase 3) recovery from inactivation Another action potential can only occur when sufficient Na channels can be reactivated giving an absolute and relative refractory period

Answer 266

Complex A mathematical model based on recording currents form different parts of the heart P wave atrial depolarization QRS complex Ventricular muscle depolarization T Wave Ventricular repolarization Duration intraventricular conduction time PR interval Conduction from atrium to ventricle QT interval Duration of ventricular action potential

Answer 267

Physiological Help researchers figure out how exercise and physiological conditions can affect the heart. Clinical Diagnosis Changes in ECG can detect abnormal heart rhythm (arrhythmias; PM2C) ECG can also aid diagnosis of other types of heart disease like coronary heart disease Monitoring Measuring ECG can monitor effect of treatments effect of drugs prescribed for other reasons that may have side effect on heart

Answer 268

The heart is a muscular multichambered organ that is under electrical and mechanical control It is essentially two pumps in series The cardiac cycle must be strictly regulated Differences in stroke volume between Left and right atria are very serious The driving force for the cardiac cycle is the cardiac action potential driven from pacemaker cells in sinoatrial node Pacemaker action potentials (AP) set the rhythm of the heart the AP in cardiac muscle controls contraction The Electrical activity of the heart can be recorded and visualised using ECG

Answer 269

1. atrial contraction 1. isovolumetric contraction 1. rapid ejection 1. reduced ejection 1. isovolumetric relaxation 1. rapid filling 1. reduced filling

Answer 270

**Atrial Contraction ** Initiated by P wave of ECG valves between atria and ventricles open semilunar valves closed

Answer 271

**Isovolumetric contraction** begins with appearance of QRS complex in ECG all valves closed first heart sound (S1) ventricular pressure rises rapidly without volume change

Answer 272

**Rapid Ejection** blood flows rapidly from ventricles into arteries AV valves closed semilunar valves open

Answer 273

**Reduced Ejection ** starts about 200 msec after QRS complex ventricle repolarises tension on ventricle reduces, therefore rate of ejection falls blood flow results mainly from kinetic energy of blood

Answer 274

**Isovolumetric relaxation ** all valves closed ventricular pressure decreases; rate determined by rate of muscle fiber relaxation end-systolic volume ~50 ml in left ventricle stroke volume was ~70 m

Answer 275

**6, Rapid filling** AV valves open semilunar valves closed caused by ventricle relaxation

Answer 276

**7. Reduced filling ** AV valves open semilunar valves closed ventricles are already considerably relaxed at the end of this phase, ventricle is ~90% filled

Answer 277

Systole - atrial contraction isovolumetric contraction rapid ejection reduced ejection Diastole isovolumetric relaxation rapid filling reduced filling

Answer 278

**Ventricular filling ** atrial contraction isovolumetric contraction **Ejection** rapid ejection reduced ejection **Ventricular Filling ** isovolumetric relaxation rapid filling reduced filling

Answer 279

𝒃𝒍𝒐𝒐𝒅 𝒇𝒍𝒐𝒘=(𝑝𝑒𝑟𝑓𝑢𝑠𝑖𝑜𝑛 𝑝𝑟𝑒𝑠𝑠𝑢𝑟𝑒)/(𝑣𝑎𝑠𝑐𝑢𝑙𝑎𝑟 𝑟𝑒𝑠𝑖𝑠𝑡𝑎𝑛𝑐𝑒) Perfusion pressure is the difference in pressure between arteries and veins Increase perfusion pressure - increase in flow The blood vessels themselves offer resistance to flow- this is the vascular resistance Increase vascular resistance and flow will fall For the whole circulation blood flow is dictated by the difference between Arterial (Systolic and Diastolic) and venous pressure Vascular resistance depends upon the radius of vessels and viscosity of blood – Poiseuille’s law

Answer 280

Poiseuille’s law assumes laminar (streamlined flow) Turbulance occurs when blood vessel is distorted e.g. atherosclerosis, branching or clamping of blood vessel Turbulent flow can lead to thrombus formation

Answer 281

Arterial pressure fluctuates Arterial pressure > venous causing flow Pressure wave felt as pulse largest drop in pressure across the arterial system Therefore the vascular resistance in the arterial system controls peripheral resistance and thus blood pressure

Answer 282

1) Direct measurement Cannula directly inserted into blood vessels 2) Auscultation (PM1A blood pressure practical) Turbulent blood flow creates sounds Sphygmomanometer and stethoscope used to listen to turbulent flow (Korotkoff sounds) These sounds can allow us to record the blood pressure The number at which blood starts flowing (120) is the measure of the maximum output pressure of the heart (systolic reading). The doctor continues releasing the pressure on the cuff and listens until there is no sound. That number (80) indicates the pressure in the system when the heart is relaxed (diastolic reading).

Answer 283

Blood Volume Blood viscosity Cardiac output (CO) Total peripheral resistance (TPR

Answer 284

TPR is the total peripheral resistance Sum of all the vascular resistances Small arteries/arterioles control TPR Called “Resistance arteries” They are the site of largest pressure drop Normally partially contracted Resistance dependent on radius4 Small changes in radius > large changes in resistance and TPR TPR and cardiac output affect each other

Answer 285

Contraction ^TPR ^BP Relaxation L TPR L BP Arteries normally partially contracted by the sympathetic nervous system stimulation > contraction stimulation > relaxation Endothelial cells release relaxing factors in response to Increased flow Circulating hormones

Answer 286

There are a number of receptors that detect pressure. These are called baroreceptor. Baroceptors signal to central nervous system Cells in the arterial wall sense blood pressure They send signals to the CNS via the Afferent nerves Cardiovascular centres in brain alter the way in which sympathetic nervous system is regulating our vessels Cardiac output and Total peripheral resistance altered to adjust BP accordingly BP= CO x TPR

Answer 287

Blood volume affects blood pressure. The kidney regulates blood volume Blood volume is affected by fluid levels and levels of electrolytes in the blood (e.g. high Na+ levels leads to fluid retention) Nephron is functional unit of the kidney Renal angiotensin system If we have low sodium in our kidneys, our juxtaglomerular cells detect that They signal that we need to increase renin Renin is an important enzyme because it can convert an angiotensinogen to angiotensin 1. Angiotensin 1 is converted to angiotensin 2 by the angiotensin converting enzyme Angiotensin 2 is important as a mediator of blood pressure as well as having an effect on kidneys – increased secretion of aldosterone which leads to increased sodium reabsorption in the tubule (meaning more of it is reabsorbed into the blood). But the main thing here is its effect on blood vessels. There are angiotensin receptors in blood vessels = increase blood pressure By taking ace inhibitors, we reduce the effect of angiotensin on our blood vessels and therefore reduce blood pressure

Answer 288

Blood flow is determined the perfusion pressure and the resistance to flow Pressure differences between arterial and venous circulations drive blood flow Blood pressure is a measurement of pressure in the circulatory system and is dependent of blood volume, resistance to flow and cardiac output The contractile state of arterial system largely controls peripheral resistance The endothelium largely relaxes arteries whereas nervous system constricts Blood pressure is mainly controlled by the baroceptor reflex and the renin angiotensin system (as well as the renal system in general)

Answer 289

“the chemical processes that occur within a living organism in order to maintain life” Oxford English Dictionary The complex of physical and chemical processes occurring within a living cell or organism that are necessary for the maintenance of life. In metabolism some substances are broken down to yield energy for vital processes while other substances, necessary for life, are synthesized. Dictionary .com Anabolism – The creation of or build up of a substance Catabolism – the Destruction or breakdown of a substance

Answer 290

The liver has many functions include but not limited to: Digestion Energy metabolism Immunity Detoxification – main one Energy and nutrient storage Production of blood components (plasma proteins) – e.g. clotting factors >500 recorded functions all functions of the liver could be considered metabolic processes

Answer 291

Liver is largest organ in the body Able to rapidly regenerate – can fix damaged cells 25% of cardiac output – receives a lot of blood 400ml min hepatic artery 1000 ml min from portal vein Blood from the GI tract passes first via the liver – goes from GI tract straight to liver Portal Vein First pass metabolism – a lot of drug will be broken down by the liver. If drugs have a large first pass metabolism, it means they get broken down a lot by the liver before they get into the blood and have a therapeutic effect During digestion hormones released enhance blood flow The anatomy of the liver contributes to its function……maximises surface area and has independent functional units

Answer 292

Liver has two lobes – left lobe (smaller) 2 and 3 , and right lobe (larger) The liver receives a blood supply from two sources. The first is the hepatic artery which delivers oxygenated blood from the general circulation. The second is the hepatic portal vein delivering deoxygenated blood from the small intestine containing nutrients. Hepatocytes means liver cells

Answer 293

Bile produced by the hepatocytes ~600+ ml per day Continually released into bile ducts stored and concentrated in the gall bladder Contains Bile salts, bile acids, Important for fat digestion Excretion

Answer 294

Bile facilitates the absorption and digestion of dietary fats Bile salts emulsify large fat globules to make fats easier for the body to digest.

Answer 295

Cholesterol is synthesised in the liver By the enzyme HMG-CoA Cholesterol essential in synthesis of bile acids and cell membranes Liver excretes cholesterol in bile salts in combination with lipoproteins LDL carries cholesterol to tissues – some tissues can be arteries – this is bad cholesterol HDL carries cholesterol to liver to be converted into bile salts or excretion – good cholesterol Therefore the liver regulates plasma cholesterol

Answer 296

Breakdown red blood cells recycling or excretion of the by-products: bilirubin (a potentially toxic pigment gives bile its colour) Bilirubin is conjugated in the liver (metabolised), excreted in bile into the small intestine and kidney elimination in the faeces and urine, or re-absorption Iron and globin are recycled (enterohepatic circulation) Some drugs are also eliminated or recycled by the bile Morphine about 20% recycled Rifampicin- antibiotic used in TB

Answer 297

Jaundice: build up of bilirubin in plasma may indicate liver disease Hepatic jaundice when the liver fails to conjugate or sequester bilirubin (breakdown bilirubin) caused by hepatitis or liver cirrhosis Obstructive jaundice Blocked bile duct– normal drainage of bile from liver to small intestine is blocked Haemolytic jaundice Not associated with liver problems When we have increased breakdown of red blood cells = more bilirubin in blood

Answer 298

Carbohydrate metabolism Glycogenesis - increased insulin stimulates storage of glucose as glycogen in the liver = lowers glucose Glycogenolysis – falls in plasma glucose stimulate glucagon – converting glycogen to glucose Gluconeogenisis – formation of glucose from non carbohydrate sources (amino acids, glycerol and lactate) Most plasma protein synthesis including: Albumin responsible for osmotic pressure reduction can cause fluid retention (e.g. Ascities) Globulins for lipid and vitamin transport and antibody generation Most clotting factors

Answer 299

Secretes many hormones into the blood stream Forms and secretes angiotensinogen Precursor to hormones angiotensin I and II (Important for fluid, salt and BP regulation Iron metabolism Iron from metabolized haem returned to plasma (binds to transferrin) Iron stored in liver as ferritin Hepcidin formed in liver secreted into blood to control iron uptake Low levels increase iron absorption from intestine High levels reduce iron absorption from intestine

Answer 300

Metabolism of Hormones e.g. insulin, glucagon, glucocorticoids Metabolism of drugs and poisons (xenobiotics) Biotransformation normally Phase I , enzymes cause oxidation, reduction, hydrolysis Phase II conjugation of functional groups e.g. with glucuronic acid, sulphate, or acetate (adding groups onto the drug Drug metabolism converts hydrophobic compounds into more water soluble compounds, so they can be excreted more easily Although metabolism typically inactivates drugs, some drug metabolites are pharmacologically active—sometimes even more so than the parent compound

Answer 301

Alcohol is oxidized to acetaldehyde then Acetic acid and generate ROS- ALL can lead to tissue damage Rate is limited by rate of action of ADH, only a small amount of alcohol can be cleared over time The liver is resistant to alcohol damage as it regenerates However chronic and repeated heavy drinking damage at a rate exceeding liver regeneratio

Answer 302

Hepatic disease/damage rarely serious due to regenerative capacity of liver However liver disease is on the increase only major disease with increased mortality since the 1970’s High fat/high sugar diets non alcoholic fatty liver disease Alcohol related liver disease change in drinking habits? Viral liver disease (hepatitis) inflammatory damage

Answer 303

Symptoms include: Jaundice Ascites Puritis Hepatic encephalopathy Changes in faeces/urine colour Fat in faeces Failure in blood clotting and many more….. Tests: Blood Urine Imaging Biopsy (Histology

Answer 304

When liver failure occurs often the only solution is a transplant This can be partial or whole liver Occasionally part of the liver can be transplanted from a living donor More rarely recipients liver not removed

Answer 305

Carbon , Oxygen and Hydrogen Carbohydrates are also referred to as saccharides

Answer 306

Monosaccharides - Galactose, Glucose, Fructose Disaccharides - Lactose - Sucrose Lactose + glucose = Galactose Sucrose + glucose = Fructose

Answer 307

1. Storage of energy On-demand ATP production 2. Structural components (cellulose in plants) 3. Components of coenzymes (non-protein compound required for catalysis) e.g., NADH (see ATP production) 4. Required for DNA replication Sugars are components of DNA

Answer 308

Animals - Glycogen: multi-branched polysaccharide of glucose Plants - Starch: multi-branched polysaccharide of glucose Difference? Glycogen is more branched than starch

Answer 309

Two major sites of glycogen storage: liver and skeletal muscle More (in total) stored in muscle, more concentrated in the liver Glycogen can actually been seen using electron microscopy glycogen granules (cytosolic) - contain enzymes of synthesis and degradation

Answer 310

Synthesis and degradation pathways regulate blood glucose levels Synthesis and degradation are regulated by different pathways; underlining a principle of biochemistry Synthesis and degradation pathways are almost always distinct These pathways show the importance of enzymatic control

Answer 311

Glycogen phosphorylase performs phosphorolysis reaction Glucose-1- phosphate cleaved from non-reducing end of glycogen a-1,6-glycosidic bonds cannot be broken by glycogen phophorylase Requires two activities of a single enzyme a transferase activity - glucanotransferase a debranching activity - a-1,6-glucosidase Leads to the release of single glucose molecule

Answer 312

Products: glucose-1- phosphate and glucose glucose-1-phosphate (major product from chains) - phosphoglucomutase glucose-6-phosphate - GLYCOLYSIS hexokinase + glucose-6-phosphatase = glucose (from debranching)

Answer 313

Two major sites of glycogen storage are the skeletal muscle and liver Skeletal muscle glucose-6-phosphate = GLYCOLYSIS Liver - glucose-6-phosphate glucose = blood glucose (brain) Skeletal muscle and brain lack glucose-6-phosphatase

Answer 314

Important: Synthesis is not reversal of the breakdown Excess glucose is converted to glycogen as follows:

Answer 315

Key enzymes: Breakdown = glycogen phosphorylase Synthesis = glycogen synthase The synthesis and breakdown pathways are tightly regulated and do not operate at the same time i.e Breakdown - Active Breakdown - In Synthesis - Inactive Synthesis - Ac Insulin promotes glycogen synthesis in the liver and muscle Glucagon and adrenaline promote glycogen breakdown in the liver and muscle, respectively

Answer 316

Muscle activity (or anticipation) stimulates release of adrenaline Exercise generates adenosine monophosphate (AMP) AMP binds (allosteric site) of inactive (T) glycogen phosphorylase b and promotes formation of the active form (R)

Answer 317

Muscle contractions are caused by an increase in intracellular Ca2+ levels Increased in intracellular Ca2+ levels promote glycogen phosphorylase kinase activity Remember: glycogen phosphorylase kinase phosphorylates glycogen phosphorylase to promote glycogen breakdown

Answer 318

Glucagon is secreted (low insulin) and acts on the liver: 1. Activation of signaling pathways e.g. cAMP, PKA 2. Glycogen breakdown is stimulated in the liver 3. Glycogen synthesis is inhibited in the liver 4. Glucose-6-phosphate converted to glucose 5. Glucose released into the blood stream (and taken up by the muscle and brain)

Answer 319

Glucose levels are high Glucose binds to the catalytic site of glycogen phosphorylase a Catalytic activity of glycogen phosphorylase is inhibited Glycogen breakdown is inhibited Glycogen phosphorylase acts as a glucose sensor Hormones: Glucagon levels are low and insulin levels are high Insulin promotes uptake of glucose from blood stream Insulin promotes activity of glycogen synthase via a phosphorylation cascade

Answer 320

Highly regulated sequence of catalyzed reactions that converts: Glucose > Pyruvate + 2ATP (adenosine triphosphate) ATP is the universal currency of free energy in biological systems

Answer 321

Most important enzyme (a key regulator) in the glycolytic pathway phosphofructokinase Fructose-6-phosphate > Fructose-1,6-bisphosphate Multiple allosteric modulators ATP, AMP, H+, citrate, fructose-2,6-bisphosphate First committed step in the glycolytic pathway

Answer 322

Activity is inhibited by ATP Binding of ATP to an allosteric site lowers the affinity of enzyme for fructose-6-phosphate AMP competes with ATP and reverses inhibition Ratio of ATP:AMP vital in controlling activity H+ also inhibits enzymatic activity Prevents excessive lactate (lactic acid) production and subsequent lowering of blood pH (acidosis) Citrate is an early intermediate product of citric acid cycle Glycolysis and the Citric acid cycle are linked by the oxidative decarboxylation of pyruvate to form acetyl CoA High levels of citrate indicate that biosynthetic carbohydrate precursors are abundant Citrate enhances the inhibitory effect of ATP Frutose-2,6-bisphosphate is a product of the phosphorylation of fructose-6-phosphate Frutose-2,6-bisphosphate is a strong activator of phosphofructokinase Binds to phosphofructokinase at an allosteric site and enhances the affinity of the enzyme for fructose-6-phosphate

Answer 323

Hexokinase I, II and III (low KM) are inhibited by glucose-6-phosphate (feedback inhibition) If phosphofructokinase is inhibited glucose-6 phosphate levels will rise this will feedback into the pathway Thereby preventing unnecessary conversion of glucose to glucose-6-phosphate Muscle – hexokinase I, II and III Liver – hexokinase IV (glucokinase, high KM) Hexokinase IV (liver enzyme) not inhibited by glucose-6-phosphate

Answer 324

Pyruvate kinase catalyzes an irreversible reaction Regulated by allosteric interactions Abundance of energy (high ATP levels)-switches off Fructose-1,6-bisphosphate (previous irreversible step)-switches on (feed-forward stimulation) Reversible covalent modification (liver only): Glucagon stimulates phosphorylation via cAMP leading to inhibition

Answer 325

Conversion of glucose to pyruvate Net generation of 2 ATP molecules and 2 NADH (reduced nicotinamide adenine dinucleotide) molecules NADH important in electron transport chain Enzymes that catalyze irreversible reactions are key points of regulation Phosphofructokinase Hexokinase Pyruvate kinase Prelude to the citric acid cycle and the electron transport chain (most of the energy held by glucose is released)

Answer 326

Made up of C, H, O and sometimes P Hydrophobic molecules (insoluble in water) Functions, Act as energy storage e.g. glucose and then lipids are burnt to fuel us with energy Make up every single cell membranes Provides thermo insulation/regulates heat Synthesis of hormones, messengers and other biologically important molecules (e.g bile acids & some vitamins)

Answer 327

(1) Fatty acids, (2) Triacylglycerols, (3) Glycerophospholipids, (4) Sphingolipids and (5) Steroids

Answer 328

Most lipids are fatty acids Free fatty acids rarely occur in nature. They are often bound to other molecules They are mostly esterified They form monomer-like part in most lipids Fatty acids are made up of a long, hydrocarbon chain ‘tail’ and a corboxyl group (COOH) ‘head Classified into; Saturated & Unsaturated Saturated; no double bonds Solid @ RT (pack well) e.g. butter (mostly animal source) Increases LDL levels & CVD (2) Unsaturated; double bonds liquid @ RT (don’t pack well as the double bond causes crinkling (30 degree angle) e.g. oils (mostly plant source) Mono & Poly US FAs mostly occur as PUFA (several C=C) Good for health

Answer 329

Also known as neutral fats or triglycerides Most fats and oils occur as mixtures of TAG Nonpolar, water-insoluble and triesters of glycerol 1 glycerol + 3 (un)/saturated FAs Energy reservoirs in animals Most abundant form of lipids Because of nonpolar, stored as anhydrous form Glycogen stored as hydrated (twice water) Fats produce 6x more energy (enable to live 2-3 months in starvation) than glycogen (less than a day Specially stored and synthesised in adipocytes These are almost entirely filled with fat droplets Mostly abundant in a subcutaneous layer or abdominal cavity Subcutaneous layer provides thermal insulation Normal fat content in body: 21% Men; 26% Women

Answer 330

Commonly called ‘phospholipids’/phosphoglycerides Forms phospholipid cell membrane (bi layer) Phosphate head + 2 FA tails Amphiphilic nature (nonpolar ‘tail’ and polar ‘head’) X group derives from a polar alcohol

Answer 331

Sphingolipids are also major membrane components Derivatives of C18 amino alcohols, sphingosine or dihydrosphingosine Their N-acyl fatty acid derivatives are called as ‘ceramide’ Ceramide is a parent component for sphingolipids Most abundant sphingolipids are; Sphingomyelins, Cerebrosides and Gangliosides Sphingomyelins Ceramides + phospho choline/phospho ethanolamine Myelin sheath is rich in sphingomyelins Myelin sheath surrounds and electrically insulates many nerve cells Cerebrosides Also called as glycosphingolipids Ceramide + single sugar residue Galactocerebrosides are most prevalent in neuronal cell membrane in brain Glucocerebrosides are in membranes of other tissues Gangliosides Complex sphingolipids Ceramide + oligosaccharides + at least one sialic acid Primary components of cell surface membranes Constitute 6% of brain lipids Act as receptors for hormones and toxins 1 NANA: GM1, GM2, GM3 2 NANA: GD1, GD2, GD3 3 NANA: GT1, GT2 4 NANA: GQ1

Answer 332

No fatty acids; instead C and H rings Mostly function as hormones or signalling molecules E.g. Cholesterol, estrogen, testosterone, etc. Cholesterol acts as a precursor for steroid hormones Weak polar & fused ring system provides greater rigidity It is an important determinant in cell membranes It prevents solidification in cold and movement in warm temperature ~70% of Cholesterol is esterified with FAs (cholesteryl esters) in plasma Plants contain stigmasterol and β-sitosterol (which differ in aliphatic side chains)

Answer 333

Lipids + proteins (noncovalently associated) Transport vehicles for triacylglycerols and cholesterol Classified into 5 broad categories Chylomicrons Transport exogenous TAG & cholesterol from intestines to tissues VLDL, IDL & LDL Transport endogenous TAG & cholesterol from liver to tissues (liver produces TAG from excess CHO) HDL Transport endogenous cholesterol from tissues to liver

Answer 334

Nonpolar core: triacylglycerols and cholesteryl esters Amphiphilic surface: Apoproteins, phospholipid & cholesterol ApoB48: Intestine; Apo B-100: Liver Lipoprotein from intestine is secreted into lymph Lipoprotein from liver is secreted into plasma Apoproteins E, CII & CIII may also come from HDL

Answer 335

Chyme (mixture of gastric juice and partially digested food) enters small intestine (duodenum) It induces the release of bile (from liver) and digestive enzymes (includes lipases) & HCO3 (neutralises pH) (from pancreas) into the duodenum Fat droplets can form aggregates and this prevents the digestion by lipases Bile prevents the formation of lipid aggregates by binding to fat droplets and forming micelles (bile-hydrophilic end at the surface and hydrophobic inside the micelles) Lipase breaks down micelles into FAs and monoglycerides and these pass through the intestinal mucosa and enter epithelial cells These molecules enter ER and resynthesised as TAG Cholesterol is transported through specific channels TAG with cholesterol, phospholipid and proteins forms chylomicrons Proteins on chylomicrons makes them water soluble and facilitate exocytosis So they can leave mucosal cells through exocytosis and transported through lymphatic vessel into the thoracic duct and enters into the subclavian vein

Answer 336

Chylomicrons Intestine – Lymphatic system – Thoracic duct – Circulation Apoprotein C II activates LPL in capillaries and thereby release FAs and glycerol from TAG into muscles and adipose tissues In adipose tissues stored as TAG again VLDL/IDL/LDL VLDL – Liver – Circulation C II activates LPL and release FAs and glycerol from TAG Becomes smaller, IDL HL (hepatic lipase) removes remnant FAs from IDL and forms LDL LDL rich in cholesterol travel back to liver LDLr or LRP (LDL-r related P) binds and take up LDL through endocytosis HDL Reverse cholesterol transport – from peripheral cells to liver

Answer 337

HDL (Reverse cholesterol transport) Synthesised and released as lipid free Apo-A1 (HDL) from intestine & liver Apo-A1 covers around 70% of protein content in HDL In circulation, get contact with foam cells/macrophages/other peripheral cells Hydrolase converts CE into free C and ABCA1 transports free C to the cell membrane from the lipid pool Apo-A1 binds to ABCA1 receptor and acquires cholesterol and become a nascent HDL LCAT (lecithin cholesterol acyltransferase) esterifies the free C on the surface of HDL and then CE moves to the core of HDL (HDL3) Then interacts with ABCG1 & SR-B1 and acquires more cholesterol and becomes mature HDL (HDL2) HDL (Reverse cholesterol transport) HDL also collects C from the cell membranes and caveoli HDL delivers cholesterol to the liver through 2 pathways; direct (via SR-B1) and indirect (via LDL) Through SR-B1 directly delivers cholesterol in to the liver cells Lipid-free HDL returns to circulation and repeat the process Indirect pathway via cholesterol ester transfer protein (CETP) which facilitates direct exchange of CE with TAG between HDL and VLDL/LDL LDL delivers cholesterol to the liver through LDL receptors or LRP Cholesterol is excreted as bile via intestine or formed as TAG HDL can also be degraded in the liver

Answer 338

Fats play major roles in the body as energy source, components of cell membranes, thermo regulators and source for hormone synthesis Fatty acids are normally formed as TAG which act as energy suppliers Phospholipids play a major role in the formation of (bi layer) cell membranes with polar head and inner nonpolar surface Sphingolipids play major roles in neuronal functions Steroids are devoid of fatty acids Cholesterol is involved in several biological pathways Lipoproteins are important cargo molecules for the transport of lipids around the body The functions of lipoproteins are tightly controlled and therefore dysregulation of their functions leads to cardiovascular diseases HDL is an important player involved in reverse cholesterol transport and thereby prevents accumulation of excess fats in peripheral tissues specially in arterial vessel walls

Answer 339

Exchange oxygen and carbon dioxide between the environment and cells of the body Supply cells with O2 for cellular (internal) respiration Dispose of CO2 produced by cellular respiration Regulates blood pH

Answer 340

Processes of respiration: 1.Pulmonary ventilation: exchange of gases between atmosphere and lung 2. Exchange of gases between air in alveoli and blood (external respiration) 3. Transport of gases in the blood between the lungs and tissues 4. Exchange of gases between blood and cells in the tissues (internal respiration NB : In blue: Processes occurring in the respiratory system In red: processes occurring in the circulatory system Respiratory system Internal respiration is the process of diffusing oxygen from the blood, into the interstitial fluid and into the cells.

Answer 341

The lungs are encased by two layers of tissue; the inner (visceral pleura) and outer (parietal pleura) membranes. Both pleurae secrete fluid into the pleural cavity surrounding each lung The diaphragm in the respiratory system is the dome-shaped sheet of muscle that separates the chest from the abdomen

Answer 342

Conducting zone Brings air into and out of the respiratory zone Include also: Nose, Nasal Cavity, Pharynx larynx and trachea Respiratory zone Contains structures involved in gas exchange

Answer 343

Ciliated cells Remove inhaled particles and sweep mucus upward Goblet cells or mucus secreting cells Secrete mucus (that traps particles) Smooth muscle cells Have sympathetic and parasympathetic innervation that regulate airways dilation /constriction Sympathetic, via Beta2 receptors, dilation Parasympathetic, via muscarinic receptors, constriction Club (Clara) cells In terminal bronchioles Exocrine secretory cells: they secrete the primary components of the extracellular substance lining the respiratory bronchioles Regulate content of secretion Progenitor Key role in biotransformation /detoxification/protection

Answer 344

Fibroblasts Elastic fiber Epithelial cells (Type I and II pneuomocytes) Type II: produce surfactant (to reduce surface tension of alveoli) Have regenerative capacity Phagocytic cells (Alveolar macrophages) Keep alveoli free from dust and debris

Answer 345

Alveoli – site of gas exchange Good blood supply Macrophages Has alveolar fluid to keep surface moist Next slide shows what they do Acinus: the functional unit of the lung Deoxygenated blood arrives at the respiratory bronchiole from the heart- pulmonary artery-bronchial arteries (blue). Dense, thin capillaries coat the alveoli Capillaries then join to form vessels, bronchial veins that eventually make the pulmonary vein (red) returning blood with O2 back to the heart

Answer 346

Surface tension The attractive forces between the water molecules in the liquid film that lines the alveolus (air-liquid interface) are responsible for alveolar surface tension. Cohesive intermolecular forces in the liquid mass at liquid-gas interface Physical property that minimizes surface area In alveoli acts to decrease radius (form a sphere) Generate a pressure (Laplace’s Law) p= 2t/r NB : From the standpoint of gas exchange alveoli need to be as small as possible to increase their surface area to volume ratio This is provided by the surface tension generated by cohesive intermolecular forces in the liquid at liquid-gas interface Alveoli are lined with a film of fluid and attractive forces between fluids are stronger then attractive forces between molecules of liquid (water) and gas HOWEVER small alveoli are not ideal for their tendency to collapse. P= collapsing pressure on alveolus T=surface tension R=Radius of the alveolus Large alveolus: low collapsing pressure Small alveolus=high collapsing pressure Fundamental conflict is solved by surfactant as it lowers the surface tension of the lining fluid and reduces collapsing pressure so small alveoli wont collapse

Answer 347

Pulmonary surfactant Surfactant is a mixture of amphipatic complex phospholipids, protein and neutral lipid produced by type II pneumocytes Intermolecular forces between constituent of surfactant reduce attractive forces between liquid molecules It lowers the surface tension of the lining fluid and reduce collapsing pressure Increase alveolar stability It increases lung compliance Reduces breathing effort NB : Amphipatic =having both hydrophilic and hydrophobic parts Intermolecular forces between dipalmitoyl phosphatidylcholine (the major constituent of surfactant) , break up attractive forces between liquid molecules **What if there is no /no enough surfactant? Alveaoli can collapse**

Answer 348

Gas exchange between air and blood occurs in the alveolar air sacs AND the efficiency of gas exchange depends on ventilation Lung function changes in different physiological/pathological conditions Position, age, ethnic group, weight and height can all affect

Answer 349

Static Volumes and Capacities Four standard volumes: tidal, inspiratory reserve, expiratory reserve, and residual volumes Four standard capacities: inspiratory, functional residual, vital and total lung capacities

Answer 350

Dynamic Volumes and Capacities Dependent on the rate of air flow, mostly derived from vital capacity Essential for the diagnosis and follow-up of obstructive lung diseases Forced Vital Capacity (FVC) Maximal amount of air that can be exhaled after a maximal breath Forced Expiratory Volume 1 sec (FEV1) Volume of air exhaled during the first second of the FVC Abnormality in lung function if: FEV1 <80% predicted normal FEV1 /FVC <0.7 FVC <80% predicted normal

Answer 351

Functions of the respiratory system Exchange oxygen and carbon dioxide Regulates blood pH Structure and histology Differ between conducting and respiratory zones Pulmonary surfactant Essential to increase stability and compliance Lung volumes and capacities Parameters to define lung function

Answer 352

Two-steps process where air enters and exits the lungs and involves pressure differences Inspiration: a active process, lung volume increases and lung pressure decreases Expiration: a passive process, lung volume decreases and lung pressure increases

Answer 353

Inspiration Muscles involved in ‘normal quite breathing’: the diaphragm the external intercostal muscles. Additional muscles can be used if a bigger breath is required Inspiration process: Diaphragm contracts Increase in intrathoracic volume Decrease intrathoracic pressure ∆ pressures drives pulmonary ventilation, air can flow into the lung NB : When the diaphragm contracts, it moves toward the abdominal cavity, creating a larger thoracic cavity and more space for the lungs. Contraction of the external intercostal muscles moves the ribs upward and outward, causing the rib cage to expand, which increases the volume of the thoracic cavity. Due to the adhesive force of the pleural fluid, the expansion of the thoracic cavity forces the lungs to stretch and expand as well. This increase in volume leads to a decrease in intra-alveolar pressure creating a pressure lower than atmospheric pressure. Pressure-volume law the volume of a given amount of gas held at constant temperature varies inversely with the applied pressure when the temperature and mass are constant. As a result, a pressure gradient is created that drives air into the lungs.

Answer 354

Expiration Passive process Muscles occasionally involved: Abdominal muscle Internal intercostal muscle Expiration process: thoracic cavity and lungs decrease in volume Increase in intra-alveolar (intrapulmonary) pressure Air driven out by reverse pressure gradient

Answer 355

Pulmonary ventilation depends on: Atmospheric pressure Pressure of the air outside the body Intra-alveolar pressure (intrapulmonary): Pressure inside lungs: it ↓as lung volume increases during inspiration and ↑ during expiration Intrapleural pressure Pressure within the pleural cavity : more negative as chest expand; it returns to initial volume as chest recoils. Created by two opposing elastic forces Inward pull: tendency of lungs to collapse Outward pull: tendency of chest wall to spring out NB : Intrapleural pressure Created by two opposing elastic forces Inward pull: tendency of lungs to collapse): elastic force (elastic tissue) and surface tension of alveolar fluid Outward pull: tendency of chest wall to spring out: elastic force (chest wall) and surface tension within the pleural cavity (pleura fluid) Note: Parietal pleura is the pleura which lines the inside of the chest wall. Visceral pleura is the pleura which covers the surfaces of the lung. Between them there is the intrapleural space: Gap between continuous layers that contains pleura fluid, a lubricant to assist breathing as allows the two layers to slide over one another easily during respiration

Answer 356

Pneumothorax: Collapsed lung, due to the presence of air / gas in the pleural cavity Spontaneous or traumatic rare condition that needs immediate care Symptoms include chest pain and trouble breathing NB : “Pneumothorax” is the medical term for a collapsed lung. Spontaneous Primary Spontaneous Pneumothorax *Pathogenesis is poorly understood Secondary Spontaneous Pneumothorax *Underlying diseases e.g. COPD, asthma, ILD, necrotizing pneumonia, TB, lung cancer Traumatic: Non-iatrogenic. Accidental trauma: Blunt trauma: with fracture ribs. Penetrating trauma: stab wound or gun shot injury. Iatrogenic: relating to illness, caused by medical examination or treatment. Mechanical positive pressure ventilation: with alveolar rupture, interstitial emphysema. Interventional procedures: lung biopsy, thoraco-centesis (removal of fluid or air from the pleural space for diagnostic or therapeutic purposes), central venous line placement, tracheostomy.

Answer 357

Rest State (between cycles) Muscles: diaphragm at equilibrium Intra-alveolar pressure =Patm (=0) Air: no airflow Lung Volume: = FRC Active process Muscles: diaphragm contracts, lung volume ↑, pressure ↓ (Boyle’s low) Intra-alveolar pressure : negative,

Answer 358

Compliance is the measure of the distensibility of a system. It specifies the ease with which matter can be stretched or distorted Elastance is the measure of the ability of a system to oppose stretch or distortion and to return to the original form (recoiling) NB : This means that the more compliant something is, the less elastic it will be, and the more elastic something is, the less compliant it will be. Understanding compliance and elastance is key in understanding lung mechanics because the compliance and elastance of the lungs determine how much they will inflate or deflate with changes in pleural pressure

Answer 359

Lung compliance (ΔV/ΔP) is the volume change that could be achieved in the lungs per unit pressure change. It describes the ability of the lungs to expand under pressure. Lung elastance (ΔP/ΔV) is the pressure change that is required to elicit a unit volume change. It is a measure of the resistance of a system to expand. NB In the lungs: Compliance defines how much the volume will change in response to changes in pressure. Elastance, the reciprocal of compliance, is the pressure required to inflate the lung, a measure of the work that has to be exerted by the muscles of inspiration to expand the lungs

Answer 360

Functional Residual Capacity (FRC) is the volume of air present in the lungs at the end of passive expiration A lowered or elevated FRC is often an indication of some form of respiratory disease. In emphysema, FRC is increased, because the lungs are more compliant and the equilibrium between the inward recoil of the lungs and outward recoil of the chest wall is disturbed

Answer 361

Airflow, Pressure, and Resistance Q = ΔP / R airflow is directly proportional to pressure difference between mouth/nose (atmospheric) and alveoli airflow is inversely proportional to airway resistance (thus proportional to airway diameter) Airway Resistance R = 8ηl / πr4 η = viscosity of inspired air l = length of airway r = radius of airway Changes in Airway Resistance changes in airway diameter provide major mechanism for altering airway resistance and airflow

Answer 362

Parasympathetic stimulation produces constriction of bronchial smooth muscle and thus increase of resistance Muscarinic receptors Sympathetic stimulation produces relaxation of bronchial smooth muscle and thus decrease of resistance Beta 2-adrenergic receptor

Answer 363

Gas exchange of oxygen and carbon dioxide occurs in the lung and in the peripheral tissues to ensure delivery of O2 to tissues and the elimination of CO2 from tissues Ventilation provides air to the alveoli for gas exchange process Gas exchange occurs by simple diffusion : In lungs: exchange of gas with external environment O2 is picked up and CO2 is released at the respiratory membrane (external respiration) At tissues: exchange of gas with the internal environment O2 is released and CO2 is picked up (internal respiration) NB : At two sites in the body: lungs and tissue External: is the exchange of gases with the external environment, and occurs in the alveoli of the lungs. Internal: is the exchange of gases with the internal environment Simple diffusion maximised by anatomical features: Respiratory membrane is highly permeable to gases both respiratory and blood capillary membranes are very thin large surface area of alveoli

Answer 364

Pulmonary circulation is the portion of the cardiovascular system which carries deoxygenated blood away from the heart, to the lungs, and returns oxygenated blood back to the heart.

Answer 365

Pulmonary gas exchange At respiratory membrane Oxygen enters the bloodstream and carbon dioxide exits It allows blood to become oxygenated and carbon dioxide, the waste product of cellular respiration, to be removed from the blood. Systemic gas exchange At tissue level Carbon dioxide enters the bloodstream and oxygen exits It allows: Oxygen to diffuse out of the bloodstream, cross the interstitial space, and enter the tissue Carbon dioxide to diffuse out of the tissue, cross the interstitial fluid, and enter the blood.

Answer 366

Transfer of gases across cell membrane occurs by simple diffusion and diffusion is regulated by the Fick’s low In the lungs: Diffusion of a gas across the alveolar membrane increases with: Increased surface area of the membrane Increased alveolar pressure difference Decreased membrane thickness

Answer 367

Dalton’s Law of partial pressure: in a mixture of non-reacting gases, the total pressure exerted is equal to the sum of the partial pressures of the individual gases Partial pressure is the pressure exerted by each component of a mixture of gases and is directly related to the specific gas concentration. NB : Dalton’s Law of partial pressure: in a mixture of non-reacting gases, the total pressure exerted is equal to the sum of the partial pressures of the individual gases

Answer 368

A pressure gradient for O2 and CO2 is responsible for the simple diffusion of gases across membranes At the respiratory membrane: the partial pressures of gases is different between alveolar air and the blood of the capillary In tissues: the partial pressure gradients are opposite of those present at the respiratory membrane At alveolar level: PO2 in the alveoli is higher than in the blood of the capillary (PCO2 is lower) O2 rapidly cross the respiratory membrane from the alveoli into the blood (CO2 diffuse across the respiratory membrane in the opposite direction) At tissue level PO2 in working cells/tissues is lower than in arterial blood (PCO2 is higher) O2 dissociates from haemoglobin, diffuses out of the blood, crosses the interstitial space, and enters the tissue (CO2 diffuses out of the tissues) NB : In lungs, O2 picked up, CO2 removed into the alveoli. O2 rich blood returns to heart through pulmonary vein. O2 rich blood leaves heart through the aorta into body. At tissues/cells, blood delivers O2 and picks up CO2 and returns to heart (right) through the vena cava At alveolar level: The partial pressure of gases is different between alveolar air and the blood of the capillary. The partial pressure of oxygen in the alveoli is higher (about 104 mm Hg) than its partial pressure in the blood of the capillary (about 40 mm Hg) . This difference creates a very strong pressure gradient that causes oxygen to rapidly cross the respiratory membrane from the alveoli into the blood. Although the solubility of oxygen in blood is not high, there is a drastic difference in the partial pressure of oxygen in the alveoli versus in the blood of the pulmonary capillaries. The partial pressure of carbon dioxide is also different between the alveolar air and the blood of the capillary. The partial pressure of carbon dioxide in the blood of the capillary is about 45 mm Hg, whereas its partial pressure in the alveoli is about 40 mm Hg. Thus, the partial pressure difference is less than that of oxygen, about 5 mm Hg. However, the solubility of carbon dioxide is much greater than that of oxygen—by a factor of about 20—in both blood and alveolar fluids. As a result, the relative concentrations of oxygen and carbon dioxide that diffuse across the respiratory membrane are similar. At tissues level: the partial pressure gradients are opposite of those present at the respiratory membrane. The partial pressure of oxygen in tissues is lower than in arterial blood . The partial pressure of carbon dioxide is lower in the arterial blood than it is in the tissues. The partial pressure of oxygen in tissues is low, less than 40 mm Hg, because oxygen is continuously used for cellular respiration. In contrast, the partial pressure of oxygen in the blood is about 100 mm Hg. This creates a pressure gradient that causes oxygen to dissociate from hemoglobin, diffuse out of the blood, cross the interstitial space, and enter the tissue. Hemoglobin that has little oxygen bound to it loses much of its brightness, so that blood returning to the heart is more burgundy in color. The partial pressure of carbon dioxide is lower in the blood than it is in the tissue, considering that cellular respiration continuously produces carbon dioxide in tissues, causing carbon dioxide to diffuse out of the tissue, cross the interstitial fluid, and enter the blood. By the time blood returns to the heart, the partial pressure of oxygen has returned to about 40 mm Hg, and the partial pressure of carbon dioxide has returned to about 45 mm Hg. The blood is then pumped back to the lungs to be oxygenated once again during external respiration.

Answer 369

Diffusion of a gas across the alveolar membrane increases with: Increased surface area of the membrane Increased alveolar pressure difference Decreased membrane thickness Strenuous exercise, respiratory conditions (fibrosis, pulmonary oedema) or high altitude can interfere with oxygen diffusion processes and seriously alter delivery of O2 to the tissues. NB : The net diffusion rate of a gas across a fluid membrane is proportional to the difference in partial pressure, proportional to the area of the membrane and inversely proportional to the thickness of the membrane. Partial pressure of O2 is reduced at high altitude. Thus partial pressure gradient for O2 reduced. The diffusion of O2 will be reduced and delivery to tissue impaired. In lung fibrosis, thickening of lung tissue increases the alveolar wall thickness, decreasing diffusion capacity of the lung that it is decreased in emphysema also due to the destruction of alveoli, decreasing the area for gas exchange

Answer 370

1.5-2%: dissolved in plasma 98%: reversibly bound to haemoglobin inside erythrocytes Haemoglobin 4 polypeptide chains (globin) + 4 iron groups (heme or haem groups) ONE O2/ ONE heme Cooperative binding NB : Hemoglobin is a quaternary structure protein composed of four subunits arranged in a ring-like fashion, with an iron atom covalently bound to the heme in the center of each subunit it is heme that binds oxygen. One hemoglobin molecule contains FOUR iron-containing heme molecules thus each hemoglobin molecule can carry up to four molecules of oxygen. Binding of the first oxygen molecule causes a conformational change in hemoglobin that allows the second molecule of oxygen to bind more readily. As each molecule of oxygen is bound, it further facilitates the binding of the next molecule, until all four heme sites are occupied by oxygen. When all four heme sites are occupied, the hemoglobin is said to be saturated. Hemoglobin saturation of 100 percent means that every heme units in all of the erythrocytes of the body are bound to oxygen. In a healthy individual with normal hemoglobin levels, hemoglobin saturation generally ranges from 95 percent to 99 percent.

Answer 371

5-7% total: dissolved in plasma 3% total: carbaminohaemoglobin CO2 bounds to Hb at a different site than O2 CO2 binding to Hb reduces the affinity of O2 for Hb >85% total: carried as bicarbonate NB : Carbon dioxide molecules are transported in the blood from body tissues to the lungs by one of three methods: dissolution directly into the blood, binding to hemoglobin in RBC, or carried as a bicarbonate ion. Carbon dioxide can enter the red blood cells and: bind to hemoglobin. To form carbaminohemoglobin . Binding of carbon dioxide to hemoglobin is reversible. Therefore, when it reaches the lungs, the carbon dioxide can freely dissociate from the hemoglobin and be expelled from the body. React with H2O to form the weak carbonic acid (H2CO3). This reaction is catalysed by the enzyme carbonic anhydrase (CA). Carbonic acid is an unstable intermediate molecule that immediately dissociates into bicarbonate ions (HCO3−) and hydrogen (H+) ions. Since carbon dioxide is quickly converted into bicarbonate ions, this reaction allows for the continued uptake of carbon dioxide into the blood down its concentration gradient. It also results in the production of H+ions. If too much H+ is produced, it can alter blood pH. However, hemoglobin binds to the free H+ ions and thus limits shifts in pH. The newly synthesized bicarbonate ion is transported out of the red blood cell into the liquid component of the blood in exchange for a chloride ion (Cl−); this is called the chloride shift. On the lungs, HCo3- is reconverted to CO2 and expired

Answer 372

It describes the relationship of partial pressure to the binding/ dissociation of oxygen to heme The % saturation of haemoglobin is a function of PO2 : PO2 determines the degree of binding of O2 to haemoglobin at the site of the respiratory membrane AND the degree of dissociation at tissues NB : gases travel from an area of higher partial pressure to an area of lower partial pressure. O2 combine reversibly with hemoglobin the affinity of an oxygen molecule for heme increases as more oxygen molecules are bound Each haemoglobin molecule can bind 4 O2, in this configuration saturation is 100% If on average each haemoglobin has THREE O2, saturation is 75% If on average each haemoglobin has TWO of O2, saturation is 50% If on average each haemoglobin has ONE O2, saturation is 25%

Answer 373

Changes in in PCO2 , pH, temperature, 2,3-diphosphoglycerate affect the O2-haemoglobin dissociation curve Shift to right or to the left Reflecting changes in the affinity of haemoglobin for O2 (no in binding capacity)

Answer 374

When there is a DECREASE affinity Caused by: ↑ PCO2 ↓ pH ↑temperature ↑ 2,3-diphosphoglycerate Bohr effect describes the effects of PCO2 and pH on the O2-hemoglobin dissociation curve shifts to the right (>unload of O2 to the tissues) ↑ P50 = partial pressure of oxygen at which Hb is 50% saturated 2,3-Diphosphoglycerate (2,3-DPG) is a intermediate of glycolysis in erythrocytes which is rapidly consumed under conditions of normal oxygen tension. However, when/if hypoxia occurs in peripheral tissues, the concentration of 2,3-DPG can accumulate to significant levels within hours. At these concentrations, 2,3-DPG can bind to hemoglobin and reduce its affinity for oxygen, resulting in a right-ward shift of the Oxygen-Hemoglobin Dissociation Curve. This results in enhanced unloading of oxygen by hemoglobin and thus results in enhanced oxygen transport to tissues encountering long-term hypoxia.

Answer 375

When there is an INCREASE affinity Caused by: ↓PCO2↑ pH ↓temperature ↓ 2,3-diphosphoglycerate ↓ P50 = partial pressure of oxygen at which Hb is 50% saturated ↓ P50 = partial pressure of oxygen at which Hb is 50% saturated Reduction of P50 means that saturation of 50% occurs at lower than normal value of PO2. unloading O2 in the tissue is more difficult i.e. binding of O2 is tighter

Answer 376

Increased metabolic activity in tissues - ↑ CO2 production and ↑ PCO2 → ↑ carbonic acid and H+ → ↓ blood pH Increased metabolic activity in tissues - Increased lactic acid → ↓ blood pH Heat produced by working muscle - ↑ body temperature O2-Hb affinity is reduced and P50 increased More O2 is delivered to hard working muscles!

Answer 377

Increase in blood cells number and increase in hemoglobin Increase in synthesis of 2,3-DPG Hypoxia-inducible factor and angiogenesis At high altitude hypoxia occurs. This stimulates the production of 2,3-DPG in red blood cells. Increased level of 2,3-DPG facilitate the delivery to the tissues as an adaptative mechanism

Answer 378

The foetus has its own circulation and erythrocytes but dependents on the mother for oxygen. Blood supply: maternal vessels-maternal placenta / foetal chorion -umbilical vessels Gas exchange occurs at chorion similar to gas exchange at the respiratory membrane but with reduced diffusion of O2 PO2 in maternal blood =35 -50 mm Hg PO2 foetal blood = 20 mm Hg. Difference not large thus there is not as much diffusion of oxygen into the foetal blood supply. Adaptations are necessary to ensure good O2 supply to foetus

Answer 379

Foetal haemoglobin has a greater affinity for oxygen than does adult haemoglobin Foetal blood has a very high RBC count compared to maternal blood Double Bohr‘ effect When foetal blood loses CO2, its pH rises (increase affinity of foetal haemoglobin for O2 When maternal blood gains CO2, its pH lowers and its affinity for O2 decreases (more O2 is unloaded) NB : Double Bohr effect=As more carbon dioxide passes into the maternal blood, the carbon dioxide will decrease the affinity of adult hemoglobin for oxygen, causing it to unload more oxygen into the fetal blood. At the same time on the fetal side of the placental membrane, there is a decrease in carbon dioxide and this increases the affinity of fetal hemoglobin for oxygen.

Answer 380

Generally involuntary and automatic Four components: 1.Control centers for breathing in brain stem (medulla and pons) 2.Chemoreceptors for O2 and CO2 3.Mechanoreceptors in lungs and joints 4.Respiratory muscles Voluntary control (from cerebral cortex) Major aim: to regulate breathing and maintain O2 and CO2 partial pressure within normal range

Answer 381

Brainstem Controls basic rhythm of breathing Sets the frequency of inspiration and expiration Peripheral chemoreceptors Located in carotid and aortic bodies Detect and relay information about gases and pH to brainstem via cranial nerves IX and X (Vagus) to increase breathing rate Central chemoreceptors Located in short distance from respiratory centers Direct communication Very sensitive to changes in cerebrospinal fluid (CSF) pH Receptors in muscle and joints Mechanoreceptors Detect movements and relay information to inspiration center to increase breathing rate (e.g. during exercise) Lung stretch receptors Mechanoreceptors in smooth muscle Stimulated by lungs and airways distention Decrease breathing rate →prolong expiration Respiratory muscles (effectors) Impulse from respiratory centers travel in the spinal cord (motor neurons) to reach respiratory muscles Inspiratory muscle: diaphragm, external intercostal and accessory muscle Expiratory muscle: abdominal muscle and internal intercostal Cerebral cortex Can temporarily override the automatic brain stem center To voluntarily hyper- or hypo- ventilate Other receptors Irritant receptors Located between airways epithelial cells Detect noxious chemicals and particles Cause reflex constriction of bronchial smooth muscle and increase breathing rate

Answer 382

Function - Digestion Absorption of nutrients FOUR major activities: Motility Secretions Digestion Mechanical Chemical Absorption

Answer 383

The Mucosa Membrane Layer of epithelial cells Protect gut from abrasion Secretes substances into gut Enteroendocrine cells release hormones into lamina propria and capillaries. Absorbs material into capillaries or thin lymph vessel-lacteal

Answer 384

Lamina Propria Connective tissue Contain blood capillaries and lymph vessels Contain lymphoid follicles MUSCULARIS MUCOSA Thin layer of smooth muscle Controls folding of the mucosa

Answer 385

Contains blood and lymph vessels At deep boundary, neurons are organised to form intrinsic or submucosal plexus

Answer 386

The smooth muscle cells of the outer layer run longitudinally The inner layer have a circular arrangement Produce waves of contraction – peristalsis or segmentation Myenteric plexus is located between the thick and thin muscles This network of neurons is connected to the submucosal plexus to form the enteric nervous system (ENS)

Answer 387

Loose connective tissue and membrane that protects the gastrointestinal tract when it moves Forms the visceral (inner) peritoneum and is continuous with the parietal (outer) peritoneum

Answer 388

Parasympathetic - Vagus Nerve / Pelvic nerve Sympathetic - Sympathetic ganglia

Answer 389

Enteric nervous system: the second brain! Millions of neurons Neurotransmitters Receive input from autonomic nervous system but it can work independently (1) from mechano-chemo receptors (sensory information) (2) Send input To smooth muscle, secretory and endocrine cells (3) Between ganglia (interneurons) (4)

Answer 390

Acetylcholine Source: Cholinergic neurons Contraction of smooth muscle in wall Relaxation of sphincters ↑salivary, ↑ gastric ↑ pancreatic secretion Noradrenaline Source: Adrenergic neurons Relaxation of smooth muscle in wall Contraction of sphincters ↑salivary secretion Other neurotransmitters and neuromodulators regulate the enteric nervous system E.g., Vasoactive intestinal peptide, Enkephalins (opiates) Substance P. Source: peptidergic neurons

Answer 391

Mouth Chewing and swallowing Saliva Dilute, buffer and lubricate ingested food Contains > 97% water Highly hypotonic High K+ and bicarbonate HCO3- Low Na+ and Cl- Initial digestion of starches and lipids Amylase Lingual lipase

Answer 392

Conveys bolus to the stomach No absorptive or digestive function Secretes mucus – promote bolus movement The bolus is moved to the stomach by peristalsis - Propulsion of food along the tract and consist of successive waves of contraction and relaxation Peristalsis also occurs in other parts of the gastrointestinal tract

Answer 393

Functions Temporary storage for food Digests food – chemically and mechanically Secretes enzymes and other molecules for digestion and protection Anatomy Four parts Fundus, cardia, body and antrum 3 layers of muscle and varied thickness Oblique muscle layer Thicker where contractions are needed

Answer 394

Receipting relaxation Orad region receives food bolus (temporary storage) Mixing and digestion Caudad region with thick muscular wall Vigorous contraction from body to pylorus area Mixing food and water with gastric secretory products (chyme) Grinding of food to enhance digestion Retropulsion

Answer 395

Secreted by parietal cells (oxyntic cells), predominantly in the fundus and body Function - Acidify gastric content to pH 1-2 Breakdown of connective tissue and muscle fibres of ingested meat Activate pepsinogens Optimal conditions for the activity of pepsins Defense mechanism against microorganisms that may cause infection

Answer 396

REGULATION OF GASTRIC SECRETIONHistamine Released by enterochromaffin-like (ECL) cells Paracrine regulation of parietal cells Activates H2 receptors Increases HCl secretion Acetylcholine From vagus nerve Neurocrine regulation of parietal cells Activates M3 receptors Increases HCl secretion Have also an indirect effect (stimulate release of histamine) Gastrin Secreted by G cells (into circulation) Endocrine regulation of parietal cells Activates CCKB receptors Increases HCl secretion

Answer 397

The regulation of gastric secretion occurs in three phases: 1. Cephalic Phase - Sight, smell, taste, thought , chewing and swolling food - 35% (Stimuli involve the brain ) 2. Gastric phase - Distention of stomach, digestion of protein - 60% ( Stimuli is food or fluid within the stomach 3. Intestinal phase - Protein Digestion products - 5% ( stimulus is food in the small intestine

Answer 398

Stimuli involve the parasympathetic innervation Contributes to 35% of overall gastric secretion response – vagal reflex The sight, smell, taste and thoughts of food kicks off the cephalic phase. Stimulates the vagus nerve that subsequently stimulates the enteric nervous system (ENS) This is followed by the release of ACh and Gastrin-releasing peptide by nerve endings Ach stimulates parietal cells to secrete HCl (and Intrinsic Factor – IF), triggers histamine from ECL (that further stimulates acid secretion), Chief Cells (producing pepsinogen that gets activated by the HCl) and Gastrin-releasing peptide acts on G cells stimulating the release of the hormone gastrin that enters the circulation and stimulate parietal cells to secrete HCl. The vagus nerve also inhibits antral mucosal D cells – reducing somatostatin release (thus reducing somatostatin-mediated reduction of gastrin and histamine release)

Answer 399

Stimuli are distention and breakdown products of proteins. Involves vagal and local reflex. Arrival of food in stomach initiates gastric phase (60% of total gastric secretion) and accelerate gastric secretion in response to chemical stimuli and distention. Vagal and local reflex are involved The food distends the stomach , activates mechanoreceptors/ stretch receptors and thus a ENS reflex (submucosal and myenteric plexus) and stimulation of gastrin release 5) Partially digested proteins (peptones) or amino acids in antrum directly stimulates G cells to release gastrin. Note: intact protein has no effect. 6) Gastrin promotes further secretion by parietal cells (this elevates pH - sudden drop in acidity activates chemoreceptors, chief cells, etc. Gastrin also stimulates contractions (mixing wave) in muscularis externa and intestinal tract (churning like clothing in a washing machine) 7) Gastric acid secretion is self limiting and gastric phase normally lasts for only an hour. Low pH inhibits gastrin via somatostatin release that inhibits HCl secretion by acting directly (direct inhibition of parietal cells) and indirectly (inhibition of ECL and histamine secretion and inhibition of G cells and gastrin secretion thus decrease in H secretion) ) As in cephalic phase there is a direct and indirect stimulation of parietal cell secretion via Ach and GRP and also local reflex triggered by distention that promote gastrin release and a direct effect induced by aminoacid or peprtide on G cells to promote gastrin secretion.

Answer 400

Stimuli involve responses to products of protein digestion (chyme) in duodenum Intestinal phase: When duodenum responds to arriving chyme (5% of total gastric secretion) this is in preparation for the next digestive process in the small intestine As chyme distends the duodenum, it stimulates duodenal stretch and chemoreceptor The enterogastric reflex inhibits the myenteric plexus (slowing the the churning and mixing motion of the stomach). When chyme leaves the stomach, it also reduces the stimulation of the stretch receptors there (around the fundus/body) – this also triggers the enterogastric reflex The presence of lipids and carbohydrates (in chyme) stimulate the production of cholecystokinin (CCK) and gastric inhibitory peptide (GIP aka glucose-dependent insulinotropic peptide ) in the duodenum. The decrease in pH (due to the acidity of the chyme) stimulates the production of secretin (by S cells). Secretin (inhibits gastrin release and thus HCl release) , GIP and CCK will inhibit the secretions of Chief Cells, Parietal cells, G cells and overall peristalsis in the stomach. Note: Secretin and CCK acts on the pancreas and liver as well. Secretin causes the liver to secrete more bile and stimulates the secretion of bicarbonate (in the pancreas). CCK stimulates the contraction of the gallbladder (resulting in the release of bile) and induces the pancreas (acinar cells) to secrete more enzyme-rich pancreatic juice. This is all in preparation of digesting the chyme has arrived in the duodenum.

Answer 401

Secreted by G cells (into circulation) Endocrine regulation of parietal cells Activate CCKB receptors Increase HCl secretion by parietal cells Endocrine regulation of chief cells Increase pepsinogen secretion Stimulates contractions (mixing wave) in muscularis externa and intestinal tract Stimulates growth of the gastric mucosa

Answer 402

Structurally related to gastrin Secreted by enteric-endocrine cells in the small intestine Promotes fat digestion and absorption 5 major actions: contraction of gallbladder and ejection of bile Secretion of pancreatic enzymes Secretion of bicarbonate Trophic effects on exocrine pancreas and gallbladder Inhibition of gastric empting

Answer 403

GIP Glucose-depended insulinotropic peptide Stimulates insulin secretion Inhibits gastric H+ secretion Secretin Secreted by enteric-endocrine (S) cells in the small intestine Stimulates secretion of pancreatic and biliary HCO3- Neutralization of small intestine lumen Inhibits effect of gastrin on acid secretion and parietal cells growth

Answer 404

Secreted by Chief cells and mucus cells Pepsinogen proteolytic proenzyme converted to pepsin at low pH Pepsin starts protein digestion (breaking proteins into peptide fragments)

Answer 405

Region of greatest digestion and absorption. Facilitated by secretions that change pH of chyme to optimal conditions for intestinal juices. Overall macromolecules broken down and absorbed into blood and lymph.

Answer 406

In humans, the small intestine is about 6-7 m long maximum diameter is 4 cm (half the large intestine, 8 cm) Duodenum attached to the stomach ~0.3 m long Jejunum between duodenum and ileum ~ 2.5 m long Ileum terminal part of small intestine ~ 3.6 m long

Answer 407

The absorptive function of the small intestine is enhanced by THREE modifications that increase the surface area Permanent folds called plicae circulares Fold number: Jejunum > Ileum > Duodenum Entire surface of the small intestine is covered by finger like projections of the mucosa called vill Villi length: Jejunum > Duodenum > Ileum Epithelial surface is columnar and its luminal surface has microvilli (brush border)

Answer 408

Covered by columnar epithelial cells – responsible for nutrient and electrolyte absorption Crypt cells primarily participate in secretion The epithelium of the small intestine is self-renewing Secretion of mucin – major component of mucus Secretion of cholecystokinin, gastrin, secretin, glucose-dependent insulinotropic Differentiates into other specialised cells Synthesis and secretion of antimicrobial peptides and proteins (lysozyme) Proliferate to replace lost enterocytes

Answer 409

Mucus - Produced by goblet cells Protects mucosa from action of acids and protease Most needed in duodenal portion WATER - Produced by cells of the crypts Combines with mucus to make it runny (for movement) Functional environment for enzymes BICARBONATE Produced by Brunner’s glands Release mucus-rich, bicarbonate secretions Protection from acidic chyme, alkaline condition for enzymes

Answer 410

Fat → EEC →CCK Pancreas: secretion of digestive enzymes Gallbladder: contraction Sphincter of Oddi: opening The above Digest food and emulsify fat for absorption HCl → EEC →Secretin Pancreas/Liver: secretion of bicarbonate - Acid neutralization

Answer 411

Slow contractions of the circular muscle layer, occlude the lumen and drive contents forward and backward (1-4 cm of intestine at a time) Mix chyme with digestive enzymes Ensure adequate exposure of chyme to mucosal surface of the intestine Ensure ALL absorbable molecules removed from the lumen Strength of contraction is regulated by food content

Answer 412

Rhythmic propulsive movements to move chyme along small intestine to large intestine Mix chyme with digestive enzymes Ensure adequate exposure of chyme to mucosal surface of the intestine Frequency of of contraction varies in the small intestine Duodenum > Jejunum > Ileum

Answer 413

The bacterial load in the small intestine is low and it increases distally Chyme is near sterile – from stomach acids The small intestine employs different ways to keep the bacterial count low: * Motility to sweep bacteria along * Mucus Antibacterial molecules: secreted in the gastric acid, biliary juice or produced by the commensal microflora and intestinal epithelial cells (Paneth cells) Gut-associated lymphoid tissue: contains lymphoid follicles and lymphocytes that secrete immunoglobulins

Answer 414

TWO glands that are intimately mixed together into one organ. Endocrine gland (2%) secreting insulin and glucagon into the bloodstream Accessory digestive (exocrine) organ (90%) Secreting enzyme-rich fluid into the duodenum Rich in bicarbonate (~pH8) – neutralises acidic gastric contents that enter small intestine Complete digestion of ingested carbohydrate, protein and fat Pancreas secretes about 1500 ml fluid each day: the highest rate of protein synthesis and secretion of any organ in the body (> 20 proteins

Answer 415

SMALL ISLANDS CELLS Islets of Langerhans Endocrine cells Release hormones, such as insulin and glucagon, into the blood stream (to control blood glucose levels)

Answer 416

ACINAR CELLS Production and export of large quantities of protein Contain secretory granules at the apical pole – mixture of zymogens and enzymes required for digestion Also secrete isotonic, plasma-like fluid (rich in chlorides) DUCT CELLS The epithelial cells are involved in the secretion of bicarbonate-rich serous fluid

Answer 417

Major functions: digestion and absorption of nutrients FOUR major activities Tightly regulated by neuronal, endocrine and paracrine processes Special structures, different cell types and secretions ensure GI-tract functions

Answer 418

The majority of digestion and absorption of nutrients takes place in the small intestine. Digestion in the small intestine occurs in: Lumen – pancreatic enzymes Brush border membrane – brush border enzymes Cytosolic digestion Digestion in the large intestine occurs by bacterial enzymes Digestion promotes the enzymatic conversion of complex dietary substances to a form that can be absorbed

Answer 419

Requires hydrolysis of oligopeptides before absorption in small intestine Oligopeptides are broken down by gastric and pancreatic protease enzymes Most amino acids are absorbed in the first part of the intestine (duodenum and proximal jejunum) By active transport Amino acids are transported to the liver via the portal vein A few may enter the colon – metabolised by colonic bacteria

Answer 420

Uptake of simple sugars is mediated by active transport and facilitated diffusion [Glucose]cell> [Glucose]lumen therefore simple diffusion cannot promote entry of sugars into cell **Active transport** Na+ transported out at basolateral side of the cell through Na+/K+ ATPase to create Na+ gradient Na+ enters cell from lumen (down [gradient]) with molecule of either Glu or Gal (up[gradient]) through SGLT1 **Facilitated diffusion** Fructose enters cell from lumen (down [gradient]) through GLUT5 transporter Glu, Gal and Fruc transported out of cell (down [gradient]) into blood through GLUT2 transporter

Answer 421

Triglycerides most abundant dietary fat Lipid hydrolysis is carried out by lipases Some fat digestion occurs in the mouth and stomach but most takes place in the small intestine Bile plays an essential role in the digestion and absorption of lipid

Answer 422

Water is the most abundant substance in chyme and 95% of it is absorbed in the small intestine by osmosis. Electrolytes are absorbed along the entire length of the small intestine, except for calcium and iron which are absorbed in the duodenum. The small intestine absorbs dietary vitamins, while the large intestine absorbs biotin and vitamin K produced by intestinal bacteria. Pentose sugars, nitrogenous bases, and phosphate ions are transported actively across the epithelium by special transport carriers in the villus epithelium.

Answer 423

Very little water that enters the gastrointestinal tract (in drink and food) is lost The gastrointestinal tract is very efficient at water retention During digestion process, most water is reabsorbed

Answer 424

Sodium Absorbed by cotransport with glucose and amino acids Diffuses into cells via channels Exported from the cell via pumps Water Diffuses in response to the osmotic gradient established by sodium Diffuses through the tight junctions Water and sodium diffuse into capillary blood within the villus

Answer 425

Final section of the GI tract: shorter (1.5 m in length) and thicker in diameter (6-7 cm) Made out of five regions: Caecum, appendix, colon (ascending, transverse, descending, sigmoid), rectum, anal canal Functions: Absorption of water and vitamins Storage and concentration of faecal matter and conversion of digested food into faeces Excretion of indigestible food, bacteria, inorganic material and cells of the GI tract

Answer 426

The chyme is slowly moved through the four regions of the colon via slow waves of peristalsis Chyme is mixed with bacteria Chyme, enters the large intestine from the small intestine via the ileocecal sphincter Most of the movement of chyme is achieved by slow waves of peristalsis over a period of several hours, but the colon can also be emptied quickly by stronger waves of mass peristalsis following a large meal

Answer 427

single cell that can replicate itself

Answer 428

Example for currently incurable diseases: HIV Parkinson`s disease Alzheimer`s disease Diabetes Mellitus Multiple Sclerosis Cerebral Palsy Asthma

Answer 429

Safety (high genetic stability, no tumour formation) High developmental potential(regeneration of more than one cell type) Potential autologous application (no immunosuppression /personalised regenerative medicine) Easy accessibility (minimally-invasive isolation) Ethical acceptance

Answer 430

Embryonic stem cells: found in the embryo; can form almost any cell type in the human body - High cell division rate Adult stem cells (tissue-specific): in nearly all tissue types - Under physiological circumstances dormant / inactive with highly condensed nucleus; can be activated by injury / regeneration signals Induced pluripotent stem cells: engineered / generated by scientists to act like embryonic stem cells

Answer 431

Derived from (spare) blastocysts after intra-cytoplasmic sperm injection (ICSI) or conventional in vitro fertilisation (IVF) A lot of the embryonic stem cells arise from spare (not needed) blastocytes (egg cells that have been fertilised by a sperm) when women go through IVF treatment etc You can grow these cells very quickly They differentiate really quickly Embryonic stem cells can give rise to nearly all cell types in the body ES cells are pluripotent They can give rise tovirtually any cell type in the body Risk: they need to be differentiated before transplantation! ES cells are immorta

Answer 432

Tumour risks – undifferentiated cells must be removed Ethical issues for embryonic stem cells – when does human life start? Are we killing babies to fix others? Risk of mutation for iPS cells

Answer 433

Present in the adult bone marrow Responsible for replacement of blood cells Highly active: 4-8 weeks to replace all red blood cells in the body

Answer 434

HSCs reside in the bone marrow HSCs generate all types of blood cells!

Answer 435

MSCs reside in bone marrow but also in peripheral blood, dental tissues, and fat Can develop in to chondrocytes Adipocytes Osteocytes But not nerve cells All the things MSC can fix (Refer to pie chart) Transplantation of MSCs is beneficial in many degenerative conditions BUT the level of engraftment and differentiation is negligible Mode of action: bystander effects: they help the patients to regenerate themselves!

Answer 436

Present in all adult fat tissue types Can become bone cells and cartilage cells Plenty of source materials Can mediate bystander effects NB : In skeletal muscle, muscle stem cells are activated immediately after an injury to help replace damaged muscle.

Answer 437

Present in the adult skin (epidermal layer) Responsible for replacement skin cells (epidermis) Highly active: skins regenerates itself every ~27 day

Answer 438

Present at the periphery of skeletal muscles Participate to muscle regeneration / generate new muscle cells Also in charge of muscle mass gain after repeated exercise

Answer 439

Present in young human brain (hippocampus and lateral ventricles) Replace nerve cells and glial cells

Answer 440

Low stress levels Regular exercise Enriching experiences Learning new information Healthy diets: rich in antioxidants Avoid excessive drinking

Answer 441

Present in nearly all tissues and organs No ethical issues Could be used in a personalised setup (autologously) No tumour risk ADULT STEM CELLS: limitations Adult stem cells can only differentiae into cell types of the organ of origin(they are multipotent and NOT pluripotent like ES cells) Thus, any unlicensed clinic claiming that it can cure a disease of an unrelated organ is promising unrealistic and unscientific claims Adult stem cells are not immortal, repeated injection might be required

Answer 442

Anabolism to build up macromolecules using energy Catabolism to break down macromolecules releasing energy There is an high number of different metabolic reactions in our body: Not all of them are needed at the same time. Each complex task (for example the digestion of food) requires a specific set of metabolic reactions to take place timely, so they need to be coordinated-integrated.

Answer 443

To enable the integration of metabolic pathways in order to respond to the body’s needs, we need three main things – sensor, messenger and switch (to on off the pathway)

Answer 444

Do NOT mix up glucagon and glycogen for the exam!!! Glucagon – hormone produced in response to low glucose in blood stream Glycogen = extra glucose is STORED as glycogen in the liver after it is removed from the blood stream

Answer 445

Switch for metabolic reactions = Regulation of enzymes Enzyme: molecule (protein) that catalyzes a chemical reaction Enzymes make possible chemical reactions in a biological context if it is ON the flux the pathway for production of D is more active if it is OFF the pathway for production of D is less active NB : We need enzymes to be either activated or inhibited in metabolic pathways Shown in the diagram is compounds being changed by the enzymes In this example, enzyme 2 has a switch – when it is on, the pathway is more active so you will get lots of compound D being made. If its off, you will have less of compound D

Answer 446

Allosteric regulation Covalent modification Enzyme concentration Enzyme compartmentalization

Answer 447

Allosteric regulators bind non covalently. They bind and release from the enzyme based on their concentration. Nb : The higher the concentration, the more they will bind These allosteric regulators can be inhibitors (top diagram) OR they can be allosteric inhibitors (bottom diagram) If you have more concentration of the inhibitor, you will get more inhibition of the enzyme and vice versa

Answer 448

A chemical group (mainly phosphate) is covalently linked to the enzyme to turn it on or off The binding and the release of the covalent group is catalysed by 2 regulatory enzymes. In case pf phosphate the regulatory enzyme mediating the binding is called kinase the regulatory enzyme mediating the release is called phosphatase.

Answer 449

Although many tissues can also use fats and protein as an energy source, the brain and red blood cells can only use glucose. Glucose is used by the body, but preserved for the brain in case of shortage (i.e. fasting)

Answer 450

3 main steps: 1. Glycolysis (glucose converted to pyruvate) 2. Oxidative decarboxylation of pyruvate (pyruvate converted to acetyl-CoA) 3. Citric Acid Cycle - Krebs Cycle (II) (acetyl-CoA enter the citric acid cycle)

Answer 451

Enzymes are more or less active depending on the energetic level of the cell. NB : We are looking at the allosteric control of glycolysis Enzymes are active depending on the energy level of the cell ATP inhibits phosphofructokinase – a key enzyme and also Pyruvate kinase ADP activates phosphofructokinase This makes sense because if you already have a lot of ATP in the body, you don’t have to make more ATP – you don’t need glycolysis activated. This phosphofructokinase basically sustains a high level of ATP production through glycolysis We don’t need more ATP being produced if ATP is already there On the other hand, if we have lots of ADP, this suggests we don’t have much ATP so the phosphofructokinase will be activated so that more ATP can be produced through glycolysis

Answer 452

Shortage of vitamins causes biochemical reaction not to work properly generating different disorders depending on the biochemical pathway that is impaired. For example, for this reaction we need the coenzyme: Thiamine (B1) – Thiamine pyrophosphate (TPP) Absence of vitamin B1: Not enough in the diet chronic alcoholism (alcohol prevents adsorption of B1 in the gut) Glucose cannot be efficiently converted in energy. The brain uses quite exclusively glucose as source of energy, therefore absence of B1 provokes reduction of energy supply to the brain and brain dysfunctions. Then the circulatory system gets affected with heart dysfunctions and weakening of the capillary walls. Disease called Beriberi. NB : Lack of certain vitamins can make biochemical pathways work not as well Thiamine is needed in the oxidation of pyruvate

Answer 453

Gluconeogenesis is stimulated (process of synthesizing glucose from non-carbohydrate precursors) in liver

Answer 454

When you have insulin and adrenaline both together, you will have high levels of fructose2-6 di-p This activates phospofructokinase (glycolysis) and will inhibit fructose 1-6 bis phosphatase (gluconeogenesis) But, we are talking about when glucose is LOW in the blood. That means, insulin will also be low This means fructose 2-6 di-p will also be low This means we don’t get the glycolysis but we do get gluconeogenesis obviously because the inhibition is gone (as we don’t have insulin) We don’t want glycolysis happening if we have less glucose in the body This will remove glucose even more which we don’t want Glucogeneosis will increase glucose in the blood

Answer 455

Glycolysis is stimulated to use glucose for energy (glycolysis means breakdown of glucose to release energy Diagram below : High glucose = high insulin which means you also have high levels of fructose 2-6 di-P = we are promoting glycolysis (breakdown of glucose) Even in high exercise levels = produce more adrenaline = promotes more glycolysis and the opposite at rest

Answer 456

Stored as glycogen in liver and muscle

Answer 457

Benefits of storing Glycogen Energy is released fast Glucose cannot be store free Glucose for the brain it will increase osmolarity It will increase the energy for other glucose to enter the cell Downsides of storing Glycogen It is hydrophilic so it accumulates water. There is a limit on the amount of glycogen to be stored

Answer 458

Liver and muscle are specialized cells for glycogen storage. skeletal muscles use glycogen during physical activity. The liver uses glycogen to keep glucose level in the blood constant for the brain.

Answer 459

Regulation of glycogen metabolism is complex, regulated allosterically and via hormone-receptor controlled events that result in protein phosphorylation/ dephosphorylation To avoid glycogen synthesis and breakdown occurring simultaneously, cells have a set of controls that ensure only one pathway is primarily active at a time This managed by the enzymes glycogen phosphorylase (breaks glycogen down) and glycogen synthase (creates glycogen)

Answer 460

2 isozymes, in the liver and muscle Isozymes or enzymatic isoforms Slightly different forms of the same enzyme. Glycogen phosphorylase breaks up glycogen into glucose subunits Glycogen phosphorylase (GP) is regulated by both allosteric factors (e. g ATP, AMP, and glucose) and by covalent modification (phosphorylation/dephosphorylation)

Answer 461

Glycogen phosphorylase (GP) is regulated by both allosteric factors (e. g ATP, AMP, and glucose) Its regulation is consistent with the energy needs of the cell High energy substrates (ATP, glucose) allosterically inhibit GP – which inhibits glycogen breakdown, which means no new glucose is produced Low energy substrates (AMP, others) allosterically activate GP – which stimulates glycogen breakdown to glucose as we need glucose

Answer 462

Hormones such as epinephrine, insulin and glucagon regulate GP using second messenger amplification systems linked to G proteins This leads phosphorylation/ dephosphorylation (activation/inactivation) of GP Activation of GP stimulates breakdown of glycogen to glucose Inactivation of GP inhibits breakdown of glycogen

Answer 463

After a meal, blood glucose levels rise and insulin is released. It stimulates uptake of glucose by cells and incorporation of it into glycogen by activation of glycogen synthase and inactivation of GP (phosphorylase) On the other hand, when blood glucose levels fall, GP (phosphorylase) is activated (stimulating glycogen breakdown to raise blood glucose) and glycogen synthase is inactivated (stopping glycogen synthesis)

Answer 464

Type 1 diabetes results from the body's failure to produce enough insulin i.e. problems in controlling the levels of glucose in blood. Muscles and liver - are not stimulated to pick-up glucose therefore after a meal glucose levels stay high in blood – hyperglycemia Management concentrates on keeping blood sugar levels as close to normal as possible, by supplying the blood with insulin taken as a treatment. The dose of insulin to be taken should be carefully evaluated since insulin overdose (miscalculating the carb content of a meal, injecting rapid acting insulin instead of long acting formulation of insulin, missing out or delaying a scheduled meal or snack after having injected, etc) may lead to a fast drop of glucose levels in the blood (hypoglycemia). In case of severe hypoglycemia and prolonged shortage of glucose for the brain, consequences may be coma and seizures

Answer 465

We don’t need all that energy = we are not going to burn it We cannot store too much glycogen

Answer 466

3 Fatty Acids stored after esterification with Glycerol as a Triacylglycerol molecule Stored as lipid drops in the cytosol Adipocytes are specialized cells for triacylglycerol storage Benefits of storing Fatty Acids High energy content Hydrophobic - no need to store hydration water Thermic insulation

Answer 467

Glucagon and adrenaline – will breakdown the triacylglycerol lipase into fatty acids so that they can be used for energy Malonyl CoA inhibits carnitine acyl transferase = this transports fatty acids to the mitochondria Acetyl-coa inhibits fatty acids from releasing energy After lunch – don’t need the fatty acids to be converted to energy. We want less of these three things mentioned so that they DO NOT convery fatty acids to energy The opposite is required in fasting state

Answer 468

He has consumed all the glycogen He is using the fat in his body to generate energy Gluconeogenesis is not keeping up with the glucose demand from the brain He has a lot of Acetyl-CoA from catabolism of fatty acids in the liver .... Acetyl-CoA can be transformed in ketone bodies – emergency source of energy to brain/heart

Answer 469

The most common protein changes: single Amino Acid substitutions (changes the final protein) truncation of the protein (shortened version of protein) change in the expression level (increased or decreased production Protein changes may cause: alteration of protein activity alteration of protein regulation Constitutional mutations alter the activity/regulation of proteins that are important in metabolism = Heritable metabolic disorders

Answer 470

Dominant mutation- 1 mutation on 1 chromosome in the pair is sufficient to give the clinical manifestation of the disease Recessive Mutation - 2 mutations on both 2 chromosomes are required to give the clinical manifestation of the disease

Answer 471

* Classical “inborn errors of metabolism” The mutant enzyme is not functional – not working * Alteration of pathway regulation The pathway cannot be regulated

Answer 472

errors in…. AMINO ACID METABOLISM Albinism Phenylketonuria LIPID METABOLISM Tay-Sachs disease PURINE & PYRIMIDINE METABOLISM Lesch-Nyhan syndrome SUGAR METABOLISM Glucose-6-phosphate dehydrogenase (G6PD) deficiency Lactase deficiency

Answer 473

The pathway cannot be regulated Hypercholesterolemia – second example = compound 2 is being accumulatrd – nothing is being regulated

Answer 474

1. High blood cholesterol levels typically result from a poor life style (diet, exercise, and tobacco smoking) 2. A small percentage of all people with high cholesterol have an inherited form of hypercholesterolemia due to gene mutation (familial hypercholesterolemia)

Answer 475

1 in 20,000 people worldwide 1.None or poor production of the pigment melanin 2.Melanin is synthesized by melanocytes from tyrosine in a membrane-bound intracellular organelle, the melanosome 3. Melanin is important for the colour of the skin, hair, and eyes. Melanin is important for the developed of the retinal pigment epithelium. 4. Types of albinism include: Oculocutaneous albinism (OCA) – affects the skin, hair, and eyes (several different sybtypes) Ocular albinism – affects eyes (reduced colouring in the retina and iris, gene mutation on x chromosome, almost exclusively in males)

Answer 476

in 10,000 people (UK) 1. The enzyme phenylalanine hydroxylase catalyses the conversion of phenylalanine to tyrosine 2.Mutations in the enzyme phenylalanine hydroxylase leading to accumulation of phenylalanine (phenylketonuria - PKU) 3. Excessive amount of phenylalanine causes brain damage. 4. Infants with PKU appear normal until they are a few months old. Without treatment, they develop permanent intellectual disability. Seizures, delayed development, behavioural problems, and psychiatric disorders. 5. Treatment consists in removal of phenylalanine from diet, from birth for the rest of the life

Answer 477

1 in 360,000 people worldwide Tay-Sachs disease is more common in people of Ashkenazi Jewish descent. 1. Mutations in the enzyme beta-hexosaminidase A (HEXA). 2. GM2 ganglioside (complex lipid) is not catabolized. 3. GM2 ganglioside is toxic, particularly in neurons in the brain and spinal cord. 4. Affected infants lose motor skills at 3-6 months, as the disease progresses, children experience seizures, vision and hearing loss, intellectual disability, and paralysis. There is no treatment. 5. Recessive disorder = both copies of the gene have to be mutated to have the clinical manifestation. Both parents have to be carriers of a HEXA mutation to be at risk of having a child with Tay-Sachs disease. 6. Usually fatal by around 3-5 yrs. Death is often due to pneumonia.

Answer 478

1. Mutations in the enzyme hypoxanthine phosphoribosyl transferase 1(HPRT1). 2. When HPRT1 is not active, purines are broken down but not recycled, producing abnormally high levels of uric acid. 3. Uric acid accumulation causes kidney and bladder stones, gouty arthritis 4. For unknown reasons, a deficiency of HPRT1is associated with neurological and behavioural abnormalities like involuntary muscle movements and self-injury behaviour. There is no treatment.

Answer 479

Glucose 6 phosphate dehydrogenase deficiency Lactase deficiency

Answer 480

1. Mutations in the enzyme glucose-6-phosphate dehydrogenase (G6PD) in the pentose phosphate pathway that supplies reducing energy to cells by maintaining the level of NADPH. 2. G6PD deficiency leads to NADPH deficiency, this leads to the destruction of red blood cells (hemolysis) under certain oxidative conditions. 3. Infections, severe stress, certain foods (such as fava beans), and certain drugs, including antimalarial drugs, aspirin, nonsteroidal anti-inflammatory drugs (NSAIDs), mothballs.

Answer 481

1.Primary lactase deficiency is the most common form. Lactase (LCT) production declines over time after infancy. Develops when your lactase production decreases as your diet becomes less reliant on milk/dairy products. 2.Secondary lactase deficiency is a shortage of lactase caused by a problem in the intestine. Can occur at any age and may be the result of medication or intestinal disorders/surgery. Can often be reversed. 3.Congenital lactase deficiency is an extremely rare disorder in which mutations in LCT cause affected infants to have a severely impaired ability to digest lactose in breast milk or formula. 4. For babies with lactose intolerance, lactose-free formula milk is available. 5. Breastfed babies may benefit from lactase substitute drops to help their bodies digest the lactose in breast milk.

Answer 482

1. Some have mild effects that can be cured with ad hoc prescriptions: i.e. Ocular prescription for Albinism 2. Some can be controlled with diet if diagnosed before irreversible damage is done: i.e. Phenylketonuria i.e. Familial Hypercholesterolemia 3. For the more aggressive we do not have a therapy: i.e. Tay-Sachs In these case the most effective action is prevention through genetic counselling. 4. Future – gene therapy – enzyme replacement.

Answer 483

The kidneys are located in the posterior wall of the abdominal cavity They provide a link between the blood stream and the urinary system In broad terms, they act as filter – regulating the content of blood and removing waste products

Answer 484

* Homeostatic regulation of water and inorganic ion balance Maintain the internal environment * Removal of metabolic waste products and foreign chemicals from the blood and their excretion in urine * Essential endocrine secretions (give to the blood stream) including: Erthyroprotein Renin Vitamin D3 Prostaglandins

Answer 485

In a resting individual the kidneys receive 20-25% of the cardiac output (i.e. typically ~ 1.25 l min-1) The kidneys produce on average ~1.5 litre urine per day Containing 50-70 g solid Urine smell affected by food stuffs but bacterial breakdown produces ammonia Colour due to urochrome pigments Colour and smell can help medical diagnosis The primary function of the kidneys is to maintain the constancy of the internal environment i.e. homeostasis

Answer 486

Cortex (outer part) : contains ~ 1 x 106 nephrons which filter blood (glomerulus) and controls secretion/ reabsorption (tubules). Nephrons where filtration takes place Medulla: contains loop of Henle/collecting ducts which are a part of the nephron Renal pelvis: contains renal blood vessels; origin of the ureter Renal calyces: collect urine Renal capsule: tough fibrous cover that restricts volume chang

Answer 487

The nephron is functional unit of the kidney Between 900,000 and a million nephrons per kidney Loops between the cortex and the medulla

Answer 488

1. Vascular The glomerular region: blood under high pressure enters the glomerulus from the renal artery in large afferent arterioles, which recombine to form a smaller, out-going efferent arteriole. The peritubular region: blood under low pressure carries reabsorbed products to renal vein and then vena cava. 2. Tubular The proximal tubule arises from the Bowman’s capsule (also known as Glomerular capsule) Filtrate formed in the BC remains separate from body fluid due to tight junction epithelial cells prevent fluid “leakage” The epithelial lining contains microvilli- form a “brush border” to increase surface area for transport.

Answer 489

The bowmans capsule is where the initial filtration takes place The knot of capillaries is known as the glomerulus Pressure inside them is very high due to all the blood coming in As capillaries have little pores in them, it forces all the small molecules out and the filtrate forms Remember, red blood cells and glucose and proteins wont be able to fit through the pores so none of that should be in the filtrate

Answer 490

Efferent arterioles from outer cortex form peritubular capillaries that drain into stellate veins Efferent arterioles from medulla form the vasa recta (supply medullary regions) and drain into arcuate veins

Answer 491

1. Filtration occurs in the glomerulus Filtration of blood plasma forms the Filtrate which then enters the tubules (now called tubular fluid). This isn’t urine yet 2.reabsorption movement from tubular fluid to blood (as blood vessels are in close proximity to the tubules) (transcellular or paracellular). We need some of these key things in the filtrate so these things will get reabsorbed into the blood as they cannot be excreted in urine – they are needed 3.Secretion movement from blood to tubular fluid

Answer 492

Difference in blood pressure at the afferent arteriole and other tissues (plus oncotic pressure) force blood through the glomerulus. Starling forces Ions, water and small molecules are removed from blood. Big proteins, glucose and red blood cells wont be removed as they are too big The rate at which the kidneys form the ultrafiltrate is measured by glomerular filtration rate (GFR) in ml/min.

Answer 493

Blood enters through the afferent arteriole and leaves the bowmans capsule through the efferent arteriole **Starling forces across the renal corpuscle** There is a lot of pressure in the bowmans capsule- so small ions, water etc will leave the capillaries and enter the capsule. This is the filtrate. This isn’t urine yet because some things that have left the blood will need to be reabsorbed back into the blood as the body will need it

Answer 494

1. Capillary endothelium (walls of capillaries): pores (fenestrations) increase permeability (endothelium is normally a barrier). Molecules can leave capillaries 1. Basement membrane: porous, negatively charged glycoproteins, main site of filtration of proteins 1. Bowman’s capsule epithelium: contains cells called podocytes that extend pedicels to form filtration slits

Answer 495

Extremely important process for conserving electrolytes and regulating osmolality A) Reabsorption Movement of substance from tubular fluid to the blood e.g. K+ , urea B) Secretion Movement of substance from blood into the tubular fluid e.g. hormones

Answer 496

Clearance: the rate at which a compound is removed from the body (i.e. is excreted in the urine) and is equal to the volume of plasma completely cleared of that substance in one minute (ml/min). Clearance = Ux . V ml/min Px where: Ux = urine concentration of substance x V = the rate of urine production in ml/min and Px = plasma concentration of substance x

Answer 497

Example a) urine concentration was 0 as expected clearance was 0 ml/min In example b) some glucose was in the urine why? Clearance was 25 ml/min Filtered glucose is reabsorbed by carrier proteins Glucose cannot cross plasma membrane Glucose was being filtered faster than it could be reabsorbed The carrier systems can Saturate Occurs when plasma glucose levels are high NB : If glucose is FOUND in the urine, that means it has not been reabsorbed = can be indication of diabetes

Answer 498

It is very difficult to work out kidney function In the clinic, medics need to find a way to estimate kidney function Problems with kidney function may lead to: Loss of nutrients from the body Failure to remove toxins Affect drug treatments Affect blood pressure

Answer 499

If the substance being cleared from the blood is: (1) Freely filtered from the blood capillaries into the BC (2) Neither reabsorbed nor secreted by the tubules, and (3) Has no overt effect on renal metabolism Then the renal clearance of that substance must reflect the glomerular filtration rate, i.e. the GFR. These criteria are met by the plant polysaccharide inulin and creatinine (produced at a fairly constant rate in muscle); creatinine is typically used in the clinic to estimate GFR

Answer 500

1. Filtration occurs in the glomerulus Filtration of blood plasma forms the Filtrate which then enters the tubules (now called tubular fluid) 1. reabsorption movement from tubular fluid to blood (transcellular or paracellular) 1. Secretion movement from blood to tubular fluid

Answer 501

Effective renal plasma flow (eRPF) a measure of renal function can be found if a substance is: (1) Freely filtered from the blood capillaries into the BC (2) Secreted, not reabsorbed by the tubules, and (3) Has no overt effect on renal metabolism

Answer 502

These criteria are (largely) met by the organic acid p-amino-hippurate (PAH) which is ~90% cleared directly from plasma eRPF = ClearancePAH = UPAH . V (ml/min) PPAH Where: UPAH = urine concentration of PAH V = the rate of urine production in ml/min and PPAH = plasma concentration of PAH

Answer 503

The fraction of plasma through the kidney that is filtered (Filtration Fraction) Filtration fraction = GFR/Renal plasma flow Normally: FF=125/600= ~20% Plasma volume = ~3 litres GFR = ~125 ml/min = ~180 litres/day So the entire plasma is filtered/processed ~60 times/day generates ~1.5 l of urine

Answer 504

If GFR is not regulated then kidneys may not be able to regulate internal environment Changes in GFR affect Na+ in particular, tubular Na+ is sensed and adjusts GFR Neuronal control from sympathetic nerves also controls GFR (constrict afferent arteries) as do other hormones As we will see next week how Na+ is controlled and how part of this is relies on adjusting GFR

Answer 505

Urinary system consists of: the kidneys, ureters, urinary bladder and urethra The kidney has 3 regions: the renal cortex, renal medulla and the renal pelvis The functional unit of the kidney is the nephron, consisting of tubules and associated blood vessels Unique characteristics of epithelial cells in the tubular portion of the nephron allow each region it to carry out its function (e.g. reabsorption/secretion L/outcomes Learn the structure of the kidney (both macroscopic and microscopic) Understand the organisation of the nephron, and what happens in the different parts of the structure Understand why it is important to have proxy measures for renal function Be able to explain, with examples of how this would be measured, glomerular filtration rate, effective renal plasma flow and filtered fraction

Answer 506

1. The ‘leakiness’ of junctions between tubular epithelial cells Tight junctions less permeable moving from proximal to distal tubule 2. Expression of carriers, channels and pumps on apical and basolateral membrane

Answer 507

Reabsorption (to blood): nearly all is driven by Na+ movement Glucose and amino acid reabsorption into blood occurs by facilitated diffusion Secretion (from blood): organic acids (such as p-amino-hippurate, PAH) and drugs such as penicillin. As Na+ and HCO3- are reabsorbed, there is a slight drop in filtrate osmolarity and an osmotic equivalent amount of water moves into the ISF ‘leaky’ tight junctions allow water and K+ to be reabsorbed paracellularly (between cells) Na+ moves down its concentration gradient; Na+ accumulation prevented by Na+/K+ ATPase (transcelluar) Glucose and amino acids ~100% reabsorbed by (Na+-coupled) facilitated diffusion into ISF bicarbonate moves into ISF by HCO3-/Cl- exchange

Answer 508

2 types = Cortical nephrons (~75%) Juxtamedullary nephrons (25%) Water reabsorbed in descending loop NaCl reabsorbed in ascending limb Tight junctions reduce water permeability Na+ and K+ co-transported with Cl- Together this causes filtrate hypotonicity (~100 mOsm/l) = diluting segment and ISF hypertonicity Transluminal potential caused by K+ back-leak; this drives movement of Ca2+ and Mg2

Answer 509

Absorption and secretion in this region regulated enzymes (e.g. renin) and hormones (aldosterone Principal (P) cells secrete K+ /reabsorb Na+ (due to aldosterone action) K+ movement depends on potential caused by Na+ movement Determines amount of K+ lost in urine (dependent on Aldosterone)

Answer 510

permeable to water and urea regulated by hormones (ADH Anti-diuretic hormone (ADH/ vasopressin) secreted by pituitary gland in response to increased plasma osmolarity. ADH binds to vasopressin II (V2) receptor cAMP causes aquaporin translocation Aquaporins insert into apical membrane to increase water and urea permeability ADH also stimulates urea reabsorption to cause hypertonicity of the IS

Answer 511

Sodium: 99% reabsorbed 66% proximal tubule 20% loop of Henle 12% distal/collecting duct Potassium 99% reabsorbed 66% proximal tubule 33% loop of Henle Urea: 50 % reabsorbed largely in collecting duct Water: 99% reabsorbed Excretion rate: 0.4- 20 ml/min (ADH-dependent)

Answer 512

Renin-angiotensin-aldosterone system activated by low [Na] in the distal tubule Aldosterone functions to: 1. increase Na+ channel insertion into apical membrane 1. Na+/K+ ATPase insertion into basolateral membrane Result: Aldosterone causes Na+ reabsorption and K+ secretion

Answer 513

The renin-angiotensin system is stimulated by: Decreased Na+ ion concentration in the distal tubule Decreased blood pressure Decreased blood volume The renin-angiotensin system is inhibited (negative feedback) by : Increased blood pressure Increased blood volume Constriction of arterioles (due to action of the sympathetic nervous system

Answer 514

K+ excess = hyperkalemia K+ deficiency = hypokalemia 1. Aldosterone Increases the number of K+ channels in the luminal membrane to increase K+ secretion by the principal cells also increases Na+ reabsorption and Na+-K+ ATPase activity. 2. Electrochemical gradient across the luminal membrane Factors that increases the gradient will increase K+ secretion. Factors that decreases the gradient will decrease K+ secretion 3. Dietary K+ 4. Acid-base disturbances Secondary to changes in H+ (due to H+ / K+ exchange). Alkalosis causes hypokalemia (K+ moves out of blood, into cells) Acidosis causes hyperkalemia (K+ moves into blood, out of cells) 5. Diuretics Drugs that increase urine flow rate can inhibit Na+-K+-2Cl- co-transport to produce a profound kaliuresis and blood hypokalemia 6. Luminal anions (-ve charge) The presence of large anions (e.g. sulfate) in the lumen of the distal tubule and collecting duct increases K+ secretio

Answer 515

Variation in water intake results in a range of urine osmolarity: Large water load: can be as low as 50 mOsm/l Dehydration: can be as high as 1400 mOsm/l Water balance is regulated by 3 major, inter-dependent processes: 1. Osmotic gradient across the renal medulla 300 -1200 mOsm/l generated by active Na+, K+ and Cl- transport 2. countercurrent’ multiplication due to flow of fluid in different directions in tubules/vasculature 3. ADH regulation of permeability of collecting duct Collecting duct is selectively permeable to water ADH can determine whether urine is concentrated or dilute

Answer 516

Ascending loop of Henle has little water permeability so active ion transport increases osmolarity of interstitial fluid (ISF)/ decreases osmolarity of tubular fluid

Answer 517

Counter current regulation produces hyperosmotic gradient in the renal medulla ability to form concentrated urine. The ability of the kidney to concentrate urine relative plasma is essential for survival minimizes fluid intake Counter current fluid flow depends on the anatomy and differential properties of the nephron: * Tubular: descending/ascending loop of Henle * Vascular: vasa recta/peritubular capillaries of the renal medulla

Answer 518

1. Tubular fluid osmolarity = ISF osmolarity 1. Active transport of Na+, K+, Cl- produces gradient 1. Water movement out of descending limb by osmosis until gradient is balanced 1. Entry of fluid from proximal tubule ‘pushes’ hyperosmotic fluid into ascending limb 1. Further active transport of Na+, K+, Cl- increases gradient 1. Further water movement out of descending limb by osmosis until gradient is balanced 1. This process continues: results in more solutes in ISF and ‘countercurrent multiplication’ of interstitial osmolarity which can reach 1200-1400 mOsm/l Result: ability to form small volume of concentrated urine

Answer 519

Medullary blood flow is low (< 5% of renal blood flow) to prevent dissipation of the osmotic gradient Cortical nephrons: Peritubular capillaries remove reabsorbed water Juxtamedullary nephrons: Vasa recta carries reabsorbed water into venous blood

Answer 520

* ADH regulates water balance Tubular fluid leaving the loop of Henle has low osmolarity The extent to which water is reabsorbed in the distal tubule/ collecting duct depends on ADH +ADH (high osmolarity) ~1200 mOsm/l no ADH (low osmolarity)~100 mOsm/l * ADH also increases urea reabsorption from the collecting duct to further increase medulla osmolarity Urea then moves down its concentration gradient into the loop of Henle * Also regulates Plasma Volume

Answer 521

Key features: permeable to water and urea regulated by hormones (ADH) Anti-diuretic hormone (ADH) binds to vasopressin II (V2) receptor cAMP causes aquaporin translocation Aquaporins insert into apical membrane to increase water and urea permeability ADH also stimulates urea reabsorption to cause hypertonicity

Answer 522

Caused by the inability of the kidneys to conserve water => frequent urination and extreme thirst Central diabetes insipidus: caused by a lack of ADH; due to damage of hypothalamus or result of surgery Nephrogenic diabetes insipidus: kidneys fail to respond to ADH N.B. Different to diabetes mellitus: Urine contains no sugar

Answer 523

Electrolyte and water balance isregulated by sympathetic nervous system In addition to hormonal control, sympathetic nervous system activity causes: constriction of afferent arterioles to reduce GFR (decreases Na+ and water excretion) Increases renin release/angiotensin II formation to increases Na+ and water reabsorption

Answer 524

The process that regulates the hydrogen ion concentration ([H+]) of the body fluids within normal limits and measured in terms of pH. pH is the negative logarithm to the base 10 of the hydrogen ion concentration: Almost all fluids in the body are strictly regulated to pH7.4 Urine can have a pH as low as ~pH 4.5 PH represents an integrative physiological response, achieved by: Buffering ([H+]) (by proteins, phosphates & bicarbonate) Elimination of acid products by renal and respiratory systems

Answer 525

The major H+ buffering system in the extracellular fluid (ESF) (plasma and ISF) High concentrations of CO2 will drive the equilibrium to the right, increase H+, and hence reduce blood pH and vice versa High concentrations of HCO3- will drive the equilibrium to the left, reduce H+, and hence increase blood pH and vice versa PH Buffering - Depends on: Buffer concentration (higher concentration greater buffering capacity) Buffer pKa = apparent dissociation constant. The closer the buffer pKa is to the blood plasma pH, the more effective a H+ buffer it is for homeostasis

Answer 526

Metabolic System Respiratory System Renal system

Answer 527

Metabolic system Normal metabolic activity generates carbon dioxide. Dietary protein amino acid (produce H+-containing sulphuric, hydrochloric and phosphoric acids) and phospholipids. Dietary organic bases (e.g. citrate) raise the bicarbonate concentration.

Answer 528

Respiratory system Breathing exerts a rapid control as carbon dioxide is reduced by hyperventilation and raised by hypoventilation within seconds. Renal system Powerful, but much slower (hours/days) system, responsible for excreting excess acid/base as appropriate to maintain plasma pH homeostasis

Answer 529

To reabsorb/eliminate the filtered HCO3- To excrete (or retain) H+ * as free H+ - limited by the minimum attainable pH = 4.5 * as ammonia (NH3) or the ammonium ion (NH4+) * with urinary buffers (phosphate, HPO42-/H2PO4-) as titratable phosphoric acid (H3PO4).

Answer 530

Proximal tubules filter HCO3-, 99 % reabsorbed to ensure buffer is not excreted in urine 85% proximal tubule, 15% Distal tubule early collecting duct H+ production from protein and phospholipid ~ 50 mEq/day The kidneys excrete all H+ that is produced by the body: 40% as titratable (mainly phosphoric) acid (20 mEq/day) 60% as NH4+ (30 mEq/day). Overall, the body is in net acid balance and therefore the renal system produces a slightly acidic urine (pH ~ 5)

Answer 531

Low pH (too much [H+]) = Acidosis pH too High (drop in [H+]) = Alkalosis

Answer 532

Metabolic acidosis (↓ pH, ↓ HCO3-) = reduction in [base] in the blood 1. Loss of HCO3- * Diarrhoea * Type 2 renal tubular acidosis (failure to reabsorb HCO3-) 2. Gain of acid (H+ ) * Diabetic ketoacidosis -using sources of energy other than glucose * Accumulation of acid - lactate acid build-up - “hitting the wall” * H+ entering cells causes hyperkalemia (increased K+ in blood) 3. Inability to excrete acid (H+ ) * renal failure Metabolic acidosis compensation: (↑ CO2 loss H2O + CO2  H2CO3  H+ + HCO3- increasing CO2 loss will drive equilibrium to the left this will reduce H+ concentration and prevent acidosi

Answer 533

1. Respiratory acidosis (↓pH, ↑ CO2) = failure to remove CO2 1. Build-up of CO2 (hypoventilation) * Damage to respiratory centre in the brain stem could also be drug-induced * Disorders of respiratory muscles polio, multiple sclerosis Disorders of gas exchange * chronic obstructive pulmonary disease (COPD), pneumonia and emphysema cause ↓ exchange of CO2 between blood and alveoli Renal compensation by↑ H+ excretion as titratable acid and NH4+ and by ↑ HCO3- synthesis and reabsorption Respiratory acidosis compensation: (↑ H+ loss, ↑ HCO3-): H2O + CO2  H2CO3  H+ + HCO3- increasing H+ loss will prevent acidosis increasing HCO3- will buffer H+ and prevent acidosis

Answer 534

1. Metabolic alkalosis (↑ pH, ↑ HCO3-) = increased base in blood * Gain of HCO3- Some antacid drugs Diuretic drugs (enhance HCO3- reabsorption) * Loss of acid (H+ ) Vomiting Excess Aldosterone - increases H+ secretion in distal tubules Diuretic drugs (enhance H+ secretion) Respiratory compensation by ↓ CO2 loss (hypoventilation) Metabolic alkalosis compensation: (↓ CO2 loss): H2O + CO2  H2CO3  H+ + HCO3- decreasing CO2 loss will drive equilbrium to the right this will increase H+ and prevent alkalosis

Answer 535

2. Respiratory alkalosis (↑ pH, ↓ CO2) = increased CO2 removal * Loss of CO2 (hyperventilation) * Stimulation of respiratory centre in the brain stem e.g. neurologic disorders such tumor or stroke; * secondary effects of meningitis or fever * Anxiety/panic attack * Altitude sickness * Renal compensation by↓ H+ excretion as titratable acid and NH4+ and ↓ HCO3- synthesis and reabsorption Recompensation (↓ H+ loss, ↓ HCO3-) H2O + CO2  H2CO3  H+ + HCO3- decreasing H+ loss will prevent alkalosis decreasing HCO3- will increase H+ and prevent alkalosis

Answer 536

Blood pH maintained at 7.4 in spite of the daily production of large amounts of CO2 and fixed acids. pH homeostasis achieved by buffers, respiratory and renal compensation. A buffer is a mixture of a weak acid and its conjugate base. The most effective physiologic buffers have a pKa near 7.4. Extracellular buffers include bicarbonate/carbon dioxide (the most important) and phosphate Intracellular buffers include phosphates and proteins (e.g. heamoglobin) Renal mechanisms include the reabsorption of HCO3- and excretion of H+ as titratable (phosphoric) acid and NH4+. For each H+ excreted, one new HCO3- is synthesized and reabsorbed Acid-base disorders can be metabolic or respiratory in origin. Metabolic disorders involve a primary disturbance of the [HCO3-], caused by gain or loss of fixed H+. Gain of fixed H+ = metabolic acidosis; Loss of fixed H+ = metabolic alkalosis. Respiratory disorders involve a primary disturbance of PCO2, caused by hypoventilation (respiratory acidosis) or hyperventilation (respiratory alkalosis). Compensation for acid-base disorders is either respiratory or renal. When the primary disorder is metabolic, compensation is respiratory. When the primary disorder is respiratory,compensation is renal.

PM1A Spring term Flashcards

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