Facilitated diffusion is the process of spontaneous passive transport of molecules or ions down their concentration gradient across a cell membrane via specific transmembrane transporter (carrier) proteins. The energy required for conformational changes in the transporter protein is provided by the concentration gradient rather than by metabolic activity.

Synthesis of platelets occurs in the bone marrow by fragmentation of megakaryocytes cytoplasm, derived from the common myeloid progenitor cell. The average time for differentiation of the human stem cell to the production of platelets is about 10 days. The major regulator of platelet formation is thrombopoietin and 95% of this is produced by the liver. Normal platelet count is 150 – 450 x 109/L and the normal lifespan of a platelet is about 10 days. Usually about one-third of the marrow output of platelets may be trapped at any one time in the normal spleen.

Mitochondria are membrane-bound organelles that are responsible for the production of the cell’s supply of chemical energy. This is achieved by using molecular oxygen to utilise sugar and small fatty acid molecules to generate adenosine triphosphate (ATP). This process is known as oxidative phosphorylation and requires an enzyme called ATP synthase. ATP acts as an energy-carrying molecule and releases the energy in situations when it is required to fuel cellular processes. Mitochondria are also involved in other cellular processes, including Ca2+homeostasis and signalling. Mitochondria contain a small amount of maternal DNA.Mitochondria have two phospholipid bilayers, an outer membrane and an inner membrane. The inner membrane is intricately folded inwards to form numerous layers called cristae. The cristae contain specialised membrane proteins that enable the mitochondria to synthesise ATP. Between the two membranes lies the intermembrane space, which stores large proteins that are required for cellular respiration. Within the inner membrane is the perimitochondrial space, which contains a jelly-like matrix. This matrix contains a large quantity of ATP synthase.Mitochondrial disease, or mitochondrial disorder, refers to a group of disorders that affect the mitochondria. When the number or function of mitochondria in the cell are disrupted, less energy is produced and organ dysfunction results.

Action potentials are initiated in nerves by activation of ligand-gated Na+channels by neurotransmitters. Opening of these Na+channels results in a small influx of sodium and depolarisation of the negative resting membrane potential (-70 mV). If the stimulus is sufficiently strong, the resting membrane depolarises enough to reach threshold potential (generally around -55 mV), at which point an action potential can occur. Voltage-gated Na+channels open, causing further depolarisation and activating more voltage-gated Na+channels and there is a sudden and massive sodium influx, driving the cell membrane potential to about +40 mV.

Flow through a tube is dependent upon:The pressure difference across the ends of the tube (P1– P2)The resistance to flow provided by the tube (R)This is Darcy’s law, which is analogous to Ohm’s law in electronics:Flow = (P1– P2) / RResistance in the tube is defined by Poiseuille’s law, which is determined by the diameter of the tube and the viscosity of the fluid. Poiseuille’s law is as follows:Resistance = (8VL) / (πR4)Where:V = The viscosity of the fluidL = The length of the tubeR = The radius of the tubeTherefore, in simple terms, resistance is directly proportional to the viscosity of the fluid and the length of the tube and inversely proportional to the radius of the tube. Of these three factors, the most important quantitatively and physiologically is vessel radius.It can be seen that small changes in the radius can have a dramatic effect on the flow of the fluid. For example, the constriction of an artery by 20% will decrease the flow by approximately 60%.Another important and frequently quoted example of this inverse relationship is that of the radius of an intravenous cannula. Doubling the diameter of a cannula increases the flow rate by 16-fold (r4). This is the reason the diameter of an intravenous cannula in resuscitation scenarios is so important.*Please note that knowledge of the detail of Poiseuille’s law is not a requirement of the RCEM Basic Sciences Curriculum.

The electron transfer system is responsible for most of the energy produced during respiration. The is a system of hydrogen carriers located in the inner mitochondrial membrane. Hydrogen is transferred to the electron transfer system via the NADH2molecules produced during glycolysis and the Krebs cycle. As a result, a H+ion gradient is generated across the inner membrane which drives ATP synthase. The final hydrogen acceptor is oxygen and the H+ions and O2 combine to form water.

Frictional forces at the sides of a vessel cause a drag force on the fluid touching them in laminar blood flow, which creates a velocity gradient where the flow is greatest at the centre. Laminar blood flow may become disrupted and flow may become turbulent at high velocities, especially in large arteries or where the velocity increases sharply at points of sudden narrowing in the vessels, or across valves. There is increased tendency for thrombi formation when there is turbulent blood flow. Clinically, turbulence may be heard as a murmur or a bruit. As a result of elevated cardiac output, there may be turbulent blood flow, even when the cardiac valves are anatomically normal, and as a result, a physiological murmur can be heard. One such example is pregnancy.

In most neurones the resting potential has a value of approximately -70 mV. The threshold potential is generally around -55 mV. Initial depolarisation occurs as a result of a Na+influx through ligand-gated Na+channels. Action potential is an all or nothing response; because the size of the action potential is constant, the intensity of the stimulus is coded by the frequency of firing of a neuron. Repolarisation occurs primarily due to K+efflux.

Erythrocytes have a normal lifespan of about 120 days. Mature erythrocytes are biconcave discs with no nucleus, ribosomes or mitochondria but with the ability to generate energy as ATP by the anaerobic glycolytic pathway. The red cell membrane consists of a bipolar lipid layer with a membrane skeleton of penetrating and integral proteins anchoring carbohydrate surface antigens. The shape and flexibility of red cells allows them to deform easily and pass through capillaries.

The vast majority of systems within the body work by negative feedback mechanisms. This negative feedback refers to the way that effectors act to move the variable in the opposite direction to the change that was originally detected. Because there is an inherent time delay between detecting a change in a variable and effecting a response, the negative feedback mechanisms cause oscillations in the variable they control. There is a narrow range of values within which a normal physiological function occurs and this is called the ‘set point’. The release of oxytocin in childbirth is an example of positive feedback.

Darcy’s law states that flow through a tube is dependent on the pressure differences across the ends of the tube (P1 – P2) and the resistance to flow provided by the tube (R). Resistance is due to frictional forces and is determined by the length of the tube (L), the radius of the tube (r) and the viscosity of the fluid flowing down that tube (V). The radius of the tube has the largest effect on resistance and therefore flow – this explains why smaller gauge cannulas with larger diameters have a faster rate of flow. Increased viscosity, as seen in polycythemia, will slow the rate of blood flow through a vessel.

Potassium (K+) is the principal intracellular ion; approximately 4 mmol/L is extracellular (3%) and 140 mmol/L intracellular (97%).

An action potential is a self-propagating response, successive depolarisation moving along each segment of an unmyelinated nerve until it reaches the end. It is all-or-nothing and does not decrease in size. Conduction in myelinated fibres is much faster, up to 50 times that of the fastest unmyelinated nerve. Myelinated fibres are insulated except at areas devoid of myelin called nodes of Ranvier. The depolarisation jumps from one node of Ranvier to another by a process called saltatory conduction. Saltatory conduction not only increases the velocity of impulse transmission but also conserves energy for the axon because depolarisation only occurs at the nodes and not along the whole length of the nerve fibre. Larger diameter myelinated nerve fibres conduct nerve impulses faster than small unmyelinated nerve fibres.

Ion channels are pore-forming protein complexes that facilitate the flow of ions across the hydrophobic core of cell membranes. They are present in the plasma membrane and membranes of intracellular organelles of all cells, and perform essential physiological functions. They provide a charged, hydrophilic pore through which ions can move across the lipid bilayer. They are selective for particular ions and their pores may be opened or closed. Because of this ability to open and close, ion channels allow the cell to have the ability to closely control the movement of ions across the membrane. Gating refers to the transition between an open and closed ion channel state, and is brought about by a conformationational change in the protein subunits that open or close the ion-permeable pore. Ion channels can be:1. voltage-gated these are regulated according to the potential difference across the cell membrane or2. ligand-gated – these are regulated by the presence of a specific signal molecule.

The first place that haematopoiesis occurs in the foetus is in the yolk sac. Later on, it occurs in the liver and spleen, which are the major hematopoietic organs from about 6 weeks until 6 – 7 months gestation. At this point, the bone marrow becomes the most important site. Haemopoiesis is restricted to the bone marrow in normal childhood and adult life.

Mitochondria are membrane-bound organelles that are responsible for the production of the cell’s supply of chemical energy. This is achieved by using molecular oxygen to utilise sugar and small fatty acid molecules to generate adenosine triphosphate (ATP). This process is known as oxidative phosphorylation and requires an enzyme called ATP synthase. ATP acts as an energy-carrying molecule and releases the energy in situations when it is required to fuel cellular processes. Mitochondria are also involved in other cellular processes, including Ca2+homeostasis and signalling. Mitochondria contain a small amount of maternal DNA.Mitochondria have two phospholipid bilayers, an outer membrane and an inner membrane. The inner membrane is intricately folded inwards to form numerous layers called cristae. The cristae contain specialised membrane proteins that enable the mitochondria to synthesise ATP. Between the two membranes lies the intermembrane space, which stores large proteins that are required for cellular respiration. Within the inner membrane is the perimitochondrial space, which contains a jelly-like matrix. This matrix contains a large quantity of ATP synthase.Mitochondrial disease, or mitochondrial disorder, refers to a group of disorders that affect the mitochondria. When the number or function of mitochondria in the cell are disrupted, less energy is produced and organ dysfunction results.

Haemoglobin is a 64.4 kd tetramer consisting of two pairs of globin polypeptide chains: one pair of alpha-like chains, and one pair of non-alpha chains. The chains are designated by Greek letters, which are used to describe the particular haemoglobin (e.g., Hb A is alpha2/beta2).Two copies of the alpha-globin gene (HBA2, HBA1) are located on chromosome 16 along with the embryonic zeta genes (HBZ). There is no substitute for alpha globin in the formation of any of the normal haemoglobins (Hb) following birth (e.g., Hb A, Hb A2, and Hb F). Thus, absence any alpha globin, as seen when all 4 alpha-globin genes are inactive or deleted is incompatible with extrauterine life, except when extraordinary measures are taken. A homotetramer of only alpha-globin chains is not thought to occur, but in the absence of alpha chains, beta and gamma homotetramers (HbH and Bart’s haemoglobin, respectively) can be found, although they lack cooperativity and function poorly in oxygen transport. The single beta-globin gene (HBB) resides on chromosome 11, within a gene cluster consisting of an embryonic beta-like gene, the epsilon gene (HBE1), the duplicated and nearly identical fetal, or gamma globin genes (HBG2, HBG1), and the poorly expressed delta-globin gene (HBD). A heme group, consisting of a single molecule of protoporphyrin IX co-ordinately bound to a single ferrous (Fe2+) ion, is linked covalently at a specific site to each globin chain. If the iron is oxidized to the ferric state (Fe3+), the protein is called methaemoglobin.Alpha globin chains contain 141 amino acids (residues) while the beta-like chains contain 146 amino acids. Approximately 75 percent of haemoglobin is in the form of an alpha helix. The non helical stretches permit folding of the polypeptide upon itself. Individual residues can be assigned to one of eight helices (A-H) or to adjacent non helical stretches.Heme iron is linked covalently to a histidine at the eighth residue of the F helix (His F8), at residue 87 of the alpha chain and residue 92 of the beta chain. Residues that have charged side groups, such as lysine, arginine, and glutamic acid, lie on the surface of the molecule in contact with the surrounding water solvent. Exposure of the hydrophilic (charged) amino acids to the aqueous milieu is an important determinant of the solubility of haemoglobin within the red blood cell and of the prevention of precipitation.The haemoglobin tetramer is a globular molecule (5.0 x 5.4 x 6.4 nm) with a single axis of symmetry. The polypeptide chains are folded such that the four heme groups lie in clefts on the surface of the molecule equidistant from one another.

Total adult haemoglobin comprises about 96 – 98 % of normal adult haemoglobin (HbA). It consists of two alpha (α) and two beta (β) globin chains.

Haemoglobin is composed of four polypeptide globin chains each with its own iron containing haem molecule. Haem synthesis occurs largely in the mitochondria by a series of biochemical reactions commencing with the condensation of glycine and succinyl coenzyme A under the action of the key rate-limiting enzyme delta-aminolevulinic acid (ALA) synthase. The globin chains are synthesised by ribosomes in the cytosol. Haemoglobin synthesis only occurs in immature red blood cells.There are three types of haemoglobin in normal adult blood: haemoglobin A, A2 and F:- Normal adult haemoglobin (HbA) makes up about 96 – 98 % of total adult haemoglobin, and consists of two alpha (α) and two beta (β) globin chains. – Haemoglobin A2 (HbA2), a normal variant of adult haemoglobin, makes up about 1.5 – 3.5 % of total adult haemoglobin and consists of two α and two delta (δ) globin chains.- Foetal haemoglobin is the main Hb in the later two-thirds of foetal life and in the newborn until approximately 12 weeks of age. Foetal haemoglobin has a higher affinity for oxygen than adult haemoglobin. Red cells are destroyed by macrophages in the liver and spleen after , 120 days. The haem group is split from the haemoglobin and converted to biliverdin and then bilirubin. The iron is conserved and recycled to plasma via transferrin or stored in macrophages as ferritin and haemosiderin. An increased rate of haemoglobin breakdown results in excess bilirubin and jaundice.

An ‘average’ person (70 kg male) contains about 40 litres of water in total, separated into different fluid compartments by biological semipermeable membranes; plasma cell membranes between extracellular and intracellular fluid, and capillary walls between interstitial and intravascular fluid. Around two-thirds of the total fluid (27 L) is intracellular fluid (ICF) and one-third of this (13 L) is extracellular fluid (ECF). The ECF can be further divided into intravascular fluid (3.5 L) and interstitial fluid (9.5 L). Transcellular fluid refers to any fluid that does not contribute to any of the main compartments but which are derived from them e.g. gastrointestinal secretions and cerebrospinal fluid, and has a collective volume of approximately 2 L.Osmosis is the passive movement of water across a semipermeable membrane from regions of low solute concentration to those of higher solute concentration.

Haemoglobin is composed of four polypeptide globin chains each with its own iron containing haem molecule. Haem synthesis occurs largely in the mitochondria by a series of biochemical reactions commencing with the condensation of glycine and succinyl coenzyme A under the action of the key rate-limiting enzyme delta-aminolevulinic acid (ALA) synthase. The globin chains are synthesised by ribosomes in the cytosol. Haemoglobin synthesis only occurs in immature red blood cells.There are three types of haemoglobin in normal adult blood: haemoglobin A, A2 and F:- Normal adult haemoglobin (HbA) makes up about 96 – 98 % of total adult haemoglobin, and consists of two alpha (α) and two beta (β) globin chains. – Haemoglobin A2 (HbA2), a normal variant of adult haemoglobin, makes up about 1.5 – 3.5 % of total adult haemoglobin and consists of two α and two delta (δ) globin chains.- Foetal haemoglobin is the main Hb in the later two-thirds of foetal life and in the newborn until approximately 12 weeks of age. Foetal haemoglobin has a higher affinity for oxygen than adult haemoglobin. Red cells are destroyed by macrophages in the liver and spleen after , 120 days. The haem group is split from the haemoglobin and converted to biliverdin and then bilirubin. The iron is conserved and recycled to plasma via transferrin or stored in macrophages as ferritin and haemosiderin. An increased rate of haemoglobin breakdown results in excess bilirubin and jaundice.

In order for primary active transport to pump ions against their electrochemical gradient, chemical energy is used in the form of ATP. This is facilitated by the Na+/K+-ATPase antiporter pump, which uses metabolic energy to move 3 Na+ions out of the cell for every 2 K+ions that come in, against their respective electrochemical gradients. As a result, the cell the maintains a high intracellular concentration of K+ions and a low concentration of Na+ions.

Parasympathetic preganglionic neurones originate in the brainstem from which they run in cranial nerves III, VII, IX and X and also from the second and third sacral segments of the spinal cord. Parasympathetic preganglionic neurones release acetylcholine into the synapse, which acts on cholinergic nicotinic receptors on the postganglionic fibre. Parasympathetic peripheral ganglia are generally found close to or within their target, whereas sympathetic peripheral ganglia are located largely in two sympathetic chains on either side of the vertebral column (paravertebral ganglia), or in diffuse prevertebral ganglia of the visceral plexuses of the abdomen and pelvis. Parasympathetic postganglionic neurones release acetylcholine, which acts on cholinergic muscarinic receptors.

For an action potential to occur, the membrane must become more permeable to Na+and the Na+influx must be greater than the K+efflux. An action potential occurs when depolarisation of the membrane reaches threshold potential. The membrane must be out of the absolute refractory period, however an action potential can still occur in a relative refractory period but only in response to a larger than normal stimulus.

When the concentration of intracellular Ca2+rises, muscle contraction occurs. The pathway of an action potential is down tube-shaped invaginations of the sarcolemma called T-tubules (transverse tubules). These penetrate throughout the muscle fibre and lie adjacent to the terminal cisternae of the sarcoplasmic reticulum. The voltage changes in the T-tubules result in the opening of sarcoplasmic reticulum Ca2+channels and there is there is release of stored Ca2+into the sarcoplasm. Thus muscle contraction occurs via excitation-contraction coupling (ECC) mechanism.

The electron transfer system is responsible for most of the energy produced during respiration. The is a system of hydrogen carriers located in the inner mitochondrial membrane. Hydrogen is transferred to the electron transfer system via the NADH2 molecules produced during glycolysis and the Krebs cycle. As a result, a H+ion gradient is generated across the inner membrane which drives ATP synthase. The final hydrogen acceptor is oxygen and the H+ions and O2 combine to form water.

Each muscle fibre is divided at regular intervals along its length into sarcomeres separated by Z-lines. The sarcomere is the functional unit of the muscle.

A membrane potential is a property of all cell membranes, but the ability to generate an action potential is only a property of excitable tissues. The resting membrane is more permeable to K+and Cl-than to other ions (and relatively impermeable to Na+); therefore the resting membrane potential is primarily determined by the K+equilibrium potential. At rest the inside of the cell is negative relative to the outside. In most neurones the resting potential has a value of approximately -70 mV.

In order for primary active transport to pump ions against their electrochemical gradient, chemical energy is used in the form of ATP. The Na+/K+-ATPase antiporter pump uses metabolic energy to move 3 Na+ions out of the cell for every 2 K+ions in, against their respective electrochemical gradients. As a result, the cell the maintains a high intracellular concentration of K+ions and a low concentration of Na+ions.

Foetal haemoglobin (HbF) makes up about 0.5 – 0.8 % of total adult haemoglobin and consists of two α and two gamma (γ) globin chains.