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

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.

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.

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.

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.

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.

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.

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.

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.

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 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.

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.

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.

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.

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)

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.

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.

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)

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.

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

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.

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.

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.

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.

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.

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.

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.

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.

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

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.