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.

Oral rehydration therapy (ORT) is a fluid replacement strategy used to prevent or treat dehydration. It is less invasive than other strategies for fluid replacement and has successfully lowered the mortality rate of diarrhoea in developing countries. Oral rehydration solutions should be slightly hypo-osmolar (about 250 mmol/litre) to prevent the possible induction of osmotic diarrhoea.
ORT contains glucose (e.g. 90 mmol/L in dioralyte). The addition of glucose improves sodium and water absorption in the bowel and prevents hypoglycaemia. It also contains essential mineral salts.
Current NICE guidance recommends that 50 ml/kg is given over 4 hours for the treatment of mild dehydration.
Once rehydrated, a child should continue with their usual daily fluid intake plus 200 ml ORT after each loose stool. In an infant, give ORT at 1-1.5 x the normal feed volume and in an adult, give 200-400 ml after each loose stool.

Platelets are produced in the bone marrow by fragmentation of the cytoplasm of megakaryocytes, derived from the common myeloid progenitor cell. The time interval from differentiation of the human stem cell to the production of platelets averages 10 days. Thrombopoietin is the major regulator of platelet formation and 95% of this is produced by the liver. The normal platelet count is approximately 150 – 450 x 109/L and the normal platelet lifespan is 10 days. Under normal circumstances, about one-third of the marrow output of platelets may be trapped at any one time in the normal spleen.

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.

The movement of a material against a concentration gradient, i.e. from a low to a high concentration, is known as active transport. Primary active transport is defined as active transport that involves the use of chemical energy, such as adenosine triphosphate (ATP). Secondary active transport occurs when an electrochemical gradient is used.

The sodium-potassium pump, calcium ATPase pump, and proton pump are all key active transport systems that use ATP. An electrochemical gradient is used by the sodium-calcium co-transporter, which is an example of secondary active transport.

The sodium-dependent hexose transporter SGLUT-1 transports glucose and galactose into enterocytes. Secondary active transport is exemplified here.

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.

Cellular respiration is the process by which cells obtain energy in the form of adenosine triphosphate (ATP). ATP transfers chemical energy from the energy rich substances in the cell to the cell’s energy requiring reactions e.g. active transport, DNA replication and muscle contraction.Cellular respiration is essentially a three step process: 1) Glycolysis, 2)The Krebs cycle, 3)The electron transfer system.The main respiratory substrate used by cells is 6-carbon glucose. Fats and proteins can also be used as respiratory substrates. When fats are being used as the primary energy source, in the absence of glucose, an excess amount of acetyl-CoA is produced, and is converted into acetone and ketone bodies. This can occur in starvation, fasting or in diabetic ketoacidosis. Proteins are used as an energy source only if protein intake is very high, or if glucose and fat sources are depleted.

Homeostasis is the property of a system in which variables are regulated so that internal conditions remain relatively constant and stable. Homeostasis is achieved by a negative feedback mechanism.

Negative feedback occurs based upon a set point through receptors, comparators and effectors.

The ‘set point’ is a NARROW range of values within which normal function occurs.

The two body systems that regulate homeostasis are the Nervous system and the Endocrine system.

The smooth muscle of the uterus becomes more active towards the end of pregnancy. This is a POSITIVE feedback.

Cardiac myocytes contract by excitation-contraction coupling, just like skeletal myocytes. Heart myocytes, on the other hand, utilise a calcium-induced calcium release mechanism that is unique to cardiac muscle (CICR). The influx of calcium ions (Ca2+) into the cell causes a ‘calcium spark,’ which causes more ions to be released into the cytoplasm.

An influx of sodium ions induces an initial depolarisation, much as it does in skeletal muscle; however, in cardiac muscle, the inflow of Ca2+ sustains the depolarisation, allowing it to remain longer. Due to potassium ion (K+) inflow, CICR causes a plateau phase in which the cells remain depolarized for a short time before repolarizing. Skeletal muscle, on the other hand, repolarizes almost instantly.

The release of Ca2+ from the sarcoplasmic reticulum is required for calcium-induced calcium release (CICR). This is mostly accomplished by ryanodine receptors (RyR) on the sarcoplasmic reticulum membrane; Ca2+ binds to RyR, causing additional Ca2+ to be released.

Hartmann’s solution (compound sodium lactate) contains: Na+131 mmol/L, K+5 mmol/L, HCO3-29 mmol/L (as lactate), Cl-111 mmol/L, Ca2+2 mmol/L. It can be used instead of isotonic sodium chloride solution during or after surgery, or in the initial management of the injured or wounded; it may reduce the risk of hyperchloraemic acidosis.

Each motor unit contracts in an all or nothing fashion, i.e. if a motor unit is excited, it will stimulate all of its muscle fibres to contract. The force of contraction of a muscle is controlled by varying the motor unit recruitment (spatial summation), and by varying the firing rate of the motor units (temporal summation). During a gradual increase in contraction of a muscle, the first units start to discharge and increase their firing rate, and, as the force needs to increase, new units are recruited and, in turn, also increase their firing rate. For most motor units, the firing rate for a steady contraction is between 5 and 8 Hz. Because the unitary firing rates for each motor unit are different and not synchronised, the overall effect is a smooth force profile from the muscle. Increasing the firing rate of motor units is temporal summation where the tension developed by the first action potential has not completely decayed when the second action potential and twitch is grafted onto the first and so on. If the muscle fibres are stimulated repeatedly at a faster frequency, a sustained contraction results where it is not possible to detect individual twitches. This is called tetanus.

It is very seldom that potassium supplements are required with the small doses of diuretics given to treat hypertension. Potassium-sparing diuretics like spironolactone (rather than potassium supplements), are recommended for hypokalaemia prevention when diuretics are given to eliminate oedema, such as furosemide or the thiazides.

Normal saline (sodium chloride 0.9%) contains:
Na+150 mmol/L
Cl-150 mmol/L

Calcium resonium is an ion-exchange resin that exchanges sodium for potassium as it passes through the intestine, leading to excretion of potassium from the body. Salbutamol and insulin act to increase intracellular uptake of K+ via Na-K ATP pump. Sodium bicarbonate acts to correct acidosis and thus promotes intracellular uptake of K+. Calcium gluconate acts to protect the cardiac membrane and has no effect on serum K+ levels.

One of the major complications of gastroenteritis is dehydration. Choosing the correct fluid replacement therapy is essential according to a patient’s hydration status.

Oral rehydration therapy (ORT) refers to the restitution of water and electrolyte deficits in dehydrated patients using an oral rehydration salt (ORS) solution. It is a fluid replacement strategy that is less invasive than other strategies for fluid replacement and has successfully lowered the mortality rate of diarrhoea in developing countries.

Some characteristics of Oral rehydration solutions are:
– slightly hypo-osmolar (about 250 mmol/litre) to prevent the possible induction of osmotic diarrhoea.
– contain glucose (e.g. 90 mmol/L in dioralyte). The addition of glucose improves sodium and water absorption in the bowel and prevents hypoglycaemia.
– also contains essential mineral salts

Current NICE guidance recommends that 50 ml/kg is given over 4 hours to treat mild dehydration.
Once rehydrated, a child should continue with their usual daily fluid intake plus 200 ml ORT after each loose stool. In an infant, give ORT at 1-1.5 x the normal feed volume and in an adult, give 200-400 ml after each loose stool.

Electrolytes are compounds that may conduct an electrical current and dissociate in solution. Extracellular and intracellular fluids contain these chemicals. The predominant cation in extracellular fluid is sodium, whereas the major anion is chloride. Potassium is the most abundant cation in the intracellular fluid, while phosphate is the most abundant anion. These electrolytes are necessary for homeostasis to be maintained.

Fibrinolysis is a normal haemostatic response to vascular injury. Plasminogen, a proenzyme in blood and tissue fluid, is converted to plasmin by activators either from the vessel wall (intrinsic activation) or from the tissues (extrinsic activation). The most important route follows the release of tissue plasminogen activator (TPA) from endothelial cells.

Typically, granuloma has Langerhan’s cells (large multinucleated cells ) surrounded by epithelioid cell aggregates, T lymphocytes and fibroblasts.

Antigen presenting monocytic cells found in the skin are known as Langerhan’s cells.

The mitochondria is responsible for the production of the cell’s supply of chemical energy. It does this by using molecular oxygen, sugar and small fatty acid molecules to generate adenosine triphosphate (ATP) by a process ss known as oxidative phosphorylation. An enzyme called ATP synthase is required.

Transcription of ribosomal RNA occurs in the nucleolus

Production of messenger RNA occur in the nucleus

Production of lysosome occurs in the Golgi apparatus

The post-translational processing of newly made proteins occurs in the endoplasmic reticulum

Diffusion is the passive movement of ions across a cell membrane down their electrochemical or concentration gradient through ion channels. Ion channels can be voltage-gated (regulated according to the potential difference across the cell membrane) or ligand-gated (regulated by the presence of a specific signal molecule). 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. In secondary active transport there is no direct coupling of ATP but the initial Na+ electrochemical gradient that drives the secondary active transport is set up by a process that requires metabolic energy. Examples include the sodium/calcium exchanger, or the sodium/glucose symporter.

Negative feedback loops, also known as inhibitory loops, play a crucial role in controlling human health. It is a self-regulating mechanism of some sort.

A negative feedback system is made up of three main components: a detector (often neural receptor cells) that measures the variable in question and provides input to the comparator; a comparator (usually a neural assembly in the central nervous system) that receives input from the detector, compares the variable to the variable set point, and determines whether or not a response is required.

The comparator activates an effector (typically muscular or glandular tissue) to conduct the appropriate reaction to return the variable to its set point.

Passive diffusion is a process that describes the movement down a concentration gradient. This process accounts for movement across small distances like within the cytosol or across membranes. Factors that affect the diffusion of a substance across a membrane are the permeability (p) of the membrane, a difference in concentration across the membrane and the membrane area over which diffusion occurs. The membrane thickness and composition, and the diffusion coefficient of the substance also affects the permeability. Fick’s law describes the rate of diffusion of a substance within a solution, which can be modified to describe the rate of diffusion across a membrane.

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.

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.

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.

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.

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.

As part of the investigation of hyponatraemia, serum osmolality is commonly requested in combination with urine osmolality to aid diagnosis.

When:
Serum osmolality is decreased and urine osmolality is decreased with no intake of fluid, the causes are
Hyponatraemia
Overhydration
Adrenocortical insufficiency
Sodium loss (diuretic or a low-salt diet)

Serum osmolality is normal or increased and urine osmolality is increased the causes include:
Dehydration
Hyperkalaemia
Hyperglycaemia
Hyponatremia
Mannitol therapy
Diabetes mellitus
Alcohol ingestion
Congestive heart failure
Renal disease and uraemia

Serum osmolality is normal or increased and urine osmolality is decreased the usual cause is diabetes insipidus

Serum osmolality is decreased and urine osmolality is increased the usual cause is syndrome of inappropriate antidiuresis (SIAD)

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 or
2. ligand-gated – these are regulated by the presence of a specific signal molecule.

The fluid in contact with a tube is dragged by frictional forces at the tube’s sidewalls. This creates a velocity gradient in which the fluid flow is greatest in the tube’s centre.
This is known as laminar flow, and it characterizes the flow in most circulatory and respiratory systems when they are at rest.

The velocity of the fluid flow can fluctuate erratically at high velocities, particularly within big arteries and airways, disrupting laminar flow. As a result, resistance increases significantly.
This is known as turbulent flow, and symptoms include heart murmurs and asthmatic wheeze.

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

Following the action potential, Na+channels remain inactive for a time in a period known as the absolute refractory period where they cannot be opened by any amount of depolarisation. Following this there is a relative refractory period where the temporary hyperpolarisation (due to delayed closure of rectifier K+channels) makes the cell more difficult to depolarise and an action potential can be generated only in response to a larger than normal stimulus. The refractory period limits the frequency at which action potentials can be generated, and ensures that, once initiated, an action potential can travel only in one direction. An action potential is an all or nothing response so the amplitude of the action potential cannot be smaller.

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.

Myosin is the major constituent of the thick filament.

Actin is the major constituent of the THIN filament.

Thin filaments consist of actin, tropomyosin and troponin in the ratio 7:1:1.

At the neuromuscular junction, acetylcholine is released from the prejunctional membrane which acts on cholinergic nicotinic receptors on the postjunctional membrane.

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.

Local currents propagate action potentials down the axons of neurons. Following depolarization, this local current flow depolarizes the next axonal membrane, and when this region crosses the threshold, more action potentials are formed, and so on. Due to the refractory period, portions of the membrane that have recently depolarized will not depolarize again, resulting in the action potential only being able to go in one direction.

The square root of axonal diameter determines the velocity of the action potential; the axons with the biggest diameter have the quickest conduction velocities. When a neuron is myelinated, the speed of the action potential rises as well.

The myelin sheath is an insulating coating that surrounds certain neural axons. By increasing membrane resistance and decreasing membrane capacitance, the myelin coating increases conduction. This enables faster electrical signal transmission via a neuron, making them more energy-efficient than non-myelinated neuronal axons.

Nodes of Ranvier are periodic holes in a myelinate axon when there is no myelin and the axonal membrane is exposed. There are no gated ion channels in the portion of the axon covered by the myelin sheath, but there is a high density of ion channels in the Nodes of Ranvier. Action potentials can only arise at the nodes as a result of this.
Electrical impulses are quickly transmitted from one node to the next, causing depolarization of the membrane above the threshold and triggering another action potential, which is then transmitted to the next node. An action potential is rapidly conducted down a neuron in this manner. Saltatory conduction is the term for this.

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 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.

The extrinsic pathway for initiating the formation of prothrombin activator begins with a traumatized vascular wall or traumatized extravascular tissues that come in contact with the blood. Exposed and activated by vascular injury, with plasma factor VII. The extrinsic tenase complex, factor VIIa-tissue factor complex, activates factor X to factor Xa.

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.

It’s crucial that thrombin’s impact is restricted to the injured site. Tissue factor pathway inhibitor (TFPI), which is produced by endothelial cells and found in plasma and platelets, is the first inhibitor to function. It accumulates near the site of harm induced by local platelet activation. Xa and VIIa, as well as tissue factor, are inhibited by TFPI. Other circulating inhibitors, the most potent of which is antithrombin, can also inactivate thrombin and other protease factors directly. Coagulation cofactors V and VIII are inhibited by protein C and protein S. Tissue plasminogen activator (TPA) from endothelial cells facilitates fibrinolysis by promoting the conversion of plasminogen to plasmin.

The transmural pressure (pressure across the wall of a flexible tube) can be described by Laplace’s law which states that:
Transmural pressure = (Tw) / r
Where:
T = Wall tension
w = Wall thickness
r = The radius
A small bubble with the same wall tension as a larger bubble will contain higher pressure and will collapse into the larger bubble if the two meet and join.

Fick’s law describes the rate of diffusion in a solution

Poiseuille’s law is used to calculate volume of flow rate in laminar flow

Darcy’s law describes the flow of a fluid through a porous medium.

Starling’s law describes cardiac haemodynamics as it relates to myocyte contractility and stretch.

In hypokalaemia, initial potassium replacement therapy should not involve glucose infusions, as glucose may cause a further decrease in the plasma-potassium concentration. Glucose infusions are used for the other indications like diabetic ketoacidosis, hypoglycaemia, routine fluid maintenance in patients who are nil by mouth (very important in children), and in hyperkalaemia.

The resting potential in most neurons has a value of approximately -70 mV.
The threshold potential is generally around -55 mV.
Initial depolarisation when there is Na+influx through ligand-gated Na+channels.
Action potential is an all or nothing response. The size of the action potential is constant and so, the intensity of the stimulus is coded by the frequency of firing of a neuron.
K+efflux is responsible for repolarisation.

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) / R
Resistance 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 fluid
L = The length of the tube
R = The radius of the tube
Therefore, 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.

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.

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.

Cardiac muscle is striated, and the sarcomere is the contractile unit, similar to skeletal muscle. Contracture is mediated by the interaction of calcium, troponins, and myofilaments, much as it occurs in skeletal muscle. Cardiac muscle, on the other hand, differs from skeletal muscle in a number of ways.

In contrast to skeletal muscle cells, cardiac myocytes have a nucleus in the middle of the cell and sometimes two nuclei. The cells are striated because the thick and thin filaments are arranged in an orderly fashion, although the arrangement is less well-organized than in skeletal muscle.

Intercalated discs, which work similarly to the Z band in skeletal muscle in defining where one cardiac muscle cell joins the next, are a very significant component of cardiac muscle.

Adherens junctions and desmosomes, which are specialized structures that hold the cardiac myocytes together, are formed by the transverse sections. The lateral sections produce gap junctions, which join the cytoplasm of two cells directly, allowing for rapid action potential conduction. These critical properties allow the heart to contract in a coordinated manner, allowing for more efficient blood pumping.

Cardiac myocytes have the ability to create their own action potentials, which is referred to as myogenic’. They can depolarize spontaneously to initiate a cardiac action potential. Pacemaker cells, as well as the sino-atrial (SA) and atrioventricular (AV) nodes, control this.

The Purkinje cells and the cells of the bundle of His are likewise capable of spontaneous depolarization. While the bundle of His is made up of specialized myocytes, it’s vital to remember that Purkinje cells are not myocytes and have distinct characteristics. They are larger than myocytes, with fewer filaments and more gap junctions than myocytes. They conduct action potentials more quickly, allowing the ventricles to contract synchronously.
Cardiac myocytes contract by excitation-contraction coupling, just like skeletal myocytes. Heart myocytes, on the other hand, utilise a calcium-induced calcium release mechanism that is unique to cardiac muscle (CICR). The influx of calcium ions (Ca2+) into the cell causes a ‘calcium spark,’ which causes more ions to be released into the cytoplasm.

An influx of sodium ions induces an initial depolarisation, much as it does in skeletal muscle; however, in cardiac muscle, the inflow of Ca2+ sustains the depolarisation, allowing it to remain longer. Due to potassium ion (K+) inflow, CICR causes a plateau phase in which the cells remain depolarized for a short time before repolarizing. Skeletal muscle, on the other hand, repolarizes almost instantly.

Comparison of skeletal and cardiac muscle:
Skeletal muscle
Cardiac muscle
Striation
Striated but arrangement less organised
Multiple nuclei located peripherally
Usually single nucleus (but can be two), located centrally
Discs None
Intercalated discs
No Gap junctions
Gap junctions
No Pacemaker
Pacemaker
Electrical stimulation: Nervous system (excitation)
Pacemaker (excitation)

Calcium gluconate is given to antagonise cardiac cell membrane excitability to reduce the risk of arrhythmias. It has no effect on serum potassium levels unlike the alternative drugs listed above.

Osmolality and osmolarity are measurements of the solute concentration of a solution. Although the two terms are often used interchangeably, there are differences in the definitions, how they are calculated and the units of measurement used.

Osmolarity, expressed as mmol/L, is an estimation of the osmolar concentration of plasma. It is proportional to the number of particles per litre of solution.
Measured Na+, K+, urea and glucose concentrations are used to calculate the value indirectly.
It is unreliable in pseudohyponatremia and hyperproteinaemia.

The equations used to calculate osmolarity are:
Osmolarity = 2 (Na+) + 2 (K+) + Glucose + Urea (all in mmol/L)
OR
Osmolarity = 2 (Na+) + Glucose + Urea (all in mmol/L)

Doubling of sodium accounts for the negative ions associated with sodium, and the exclusion of potassium approximately allows for the incomplete dissociation of sodium chloride.

Local currents propagate action potentials down the axons of neurons. This local current flow following depolarisation results in the depolarisation of the neighbouring axonal membrane, and when this region approaches the threshold, more action potentials are generated and so forth. Due to the refractory period, portions of the membrane that have recently depolarized will not depolarize again, resulting in the action potential only being able to go in one direction.

The square root of axonal diameter determines the velocity of the action potential; the axons with the biggest diameter have the quickest conduction velocities. When a neuron is myelinated, the speed of the action potential rises as well.
The myelin sheath is an insulating coating that surrounds certain neural axons. By increasing membrane resistance and decreasing membrane capacitance, the myelin sheath improves conduction. This enables faster electrical signal transmission via a neuron, making them more energy-efficient than non-myelinated neuronal axons.
Electrical impulses are quickly transmitted from one node to the next, causing depolarization of the membrane above the threshold and triggering another action potential, which is then transmitted to the next node. An action potential is rapidly conducted down a neuron in this manner. Saltatory conduction is the term for this.
Multiple sclerosis is an example of a clinical disorder in which the myelin sheath is affected. It is an immune-mediated disorder in which certain nerve cells in the brain and spinal cord become demyelinated. The ability of some areas of the nervous system to properly transmit action potentials is disrupted by demyelination, resulting in a variety of neurological symptoms and indications.

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.

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.

Myofibrils, which are around 1 m in diameter, make up each myofiber. The cytoplasm separates them and arranges them in a parallel pattern along the cell’s long axis. These myofibrils are made up of actin and myosin filaments that are repeated in sarcomeres, which are the myofiber’s basic functional units.

Myofilaments are the filaments that make up myofibrils, and they’re made mostly of proteins. Myofilaments are divided into three categories:

Myosin filaments are thick filaments made up mostly of the protein myosin.
Actin filaments are thin filaments made up mostly of the protein actin.
Elastic filaments are mostly made up of the protein titin.
The sarcomere is a Z-line segment that connects two adjacent Z-lines.
The I-bands are thin filament zones that run from either side of the Z-lines to the thick filament’s beginning.
Between the I-bands is the A-band, which spans the length of a single thick filament.
The H-zone is a zone of thick filaments that is not overlaid by thin filaments in the sarcomere’s centre. The H-zone keeps the myosin filaments in place by surrounding them with six actin filaments each.
The M-band (or M-line) is a disc of cross-connecting cytoskeleton elements in the centre of the H-zone.
The thick filament is primarily made up of myosin. The thin filament is primarily made up of actin. Actin, tropomyosin, and troponin are found in a 7:1:1 ratio in thin filaments.

There are three types of storage granules contained in platelets. These are dense granules which contain the following:
-ATP
-ADP
-serotonin and calcium alpha granules containing clotting factors
-von Willebrand factor (VWF)
-platelet-derived growth factor (PDGF)
– other proteins lysosomes containing hydrolytic enzymes.

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.

The neurotransmitter in the synaptic cleft is either eliminated or deactivated after the post-synaptic cell responds to the neurotransmitter.

This can be accomplished in a variety of ways:
Re-uptake
Breakdown
Diffusion

Serotonin is an example of a neurotransmitter that is uptake. Serotonin is absorbed back into the presynaptic neuron via the serotonin transporter (SERT), which is found in the presynaptic membrane. Re-uptake neurotransmitters are either recycled by repackaging into vesicles or broken down by enzymes.
Specific enzymes found in the synaptic cleft can also break down neurotransmitters. The following enzymes are examples of these enzymes:
Acetylcholinesterase (AChE) catalyses the acetylcholine breakdown (ACh)
The enzyme catechol-O-methyltransferase (COMT) catalyses the breakdown of catecholamines like adrenaline , dopamine and noradrenaline.

The breakdown of catecholamines, as well as other monoamines like serotonin, tyramine, and tryptamine, is catalysed by monoamine oxidases (MOA).
Diffusion of neurotransmitters into nearby locations can also be used to eliminate them.

Protein and phosphate are the primary intracellular anions, while chloride (Cl-) and bicarbonate are the predominant extracellular anions (HCO3-).

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.

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.

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.

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

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.

Pabrinex is indicated in patients that require rapid therapy for severe depletion or malabsorption of water-soluble vitamins B and C, particularly in alcoholism detoxification.

Pabrinex has the following:
1. Thiamine (vitamin B1)
2. Riboflavin (vitamin B2)
3. Nicotinamide (Vitamin B3, niacin and nicotinic acid)
4. Pyridoxine (vitamin B6)
5. Ascorbic acid (vitamin C)
6. Glucose

Suspected or established Wernicke’s encephalopathy is treated by intravenous infusion of Pabrinex/ The dose is 2-3 pairs three times a day for three to five days, followed by one pair once daily for an additional three to five days or for as long as improvement continues.

Osmosis is the passive movement of water across a semipermeable membrane from a region of low solute concentration to a region of higher solute concentration.
When hypertonic fluid is ingested:
The plasma becomes CONCENTRATED.

The cells lose water and shrink
The intracellular fluid becomes more concentrated.
Water and ions move freely from the plasma into the interstitial fluid and the interstitial fluid becomes more concentrated.
The increased osmotic potential draws water out of the cells.

A refractory period follows each action potential. The absolute refractory time and the relative refractory period are two divisions of refractory periods. Because the sodium channels seal after an AP, they enter an inactive state during which they cannot be reopened regardless of membrane potential, this time occurs.

The sodium channels slowly come out of inactivation during the relative refractory period that follows. During this time, a stronger stimulus than that required to initiate an action potential can excite the cell. The strength of the stimulus required early in the relative refractory period is relatively high, and it steadily decreases as more sodium channels recover from the inactivation of the refractory period.

Nodes of Ranvier are periodic holes in a myelinate axon when there is no myelin and the axonal membrane is exposed. There are no gated ion channels in the portion of the axon covered by the myelin sheath, but there is a high density of ion channels in the Nodes of Ranvier. Action potentials can only occur at the nodes as a result of this.

There are three types of muscle:
Skeletal muscle
Cardiac muscle
Smooth muscle

Individual muscle is enveloped in a layer of dense irregular connective tissue called the epimysium. The epimysium protects the muscles from friction against bones and other muscles.

Skeletal muscle is composed of muscle fibres, referred to as myofibers which is ensheathed by a wispy layer of areolar connective tissue called the endomysium. The endomysium is the smallest and deepest component of muscle connective tissue.

Myofibers grouped together in bundles form fascicles, or fasciculi. These are surrounded by a type of connective tissue called the perimysium.

Beneath the endomysium lies the sarcolemma, an elastic sheath with infoldings that invaginate the interior of the myofibers, particularly at the motor endplate of the neuromuscular junction.

Lysosomes are formed by the Golgi apparatus or the endoplasmic reticulum. Lysosome releases its enzymes and digests the cell when the cell dies.

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.