Learning objectives
• To describe the structure of a typical cell and the role of its organelles.
• To discuss how cell differentiation and organization permit physiological function.
• To recognize the features and characteristics of different tissue types that facilitate their function and characteristics.
• To describe the control of provision of oxygen and nutrients to cells and how the waste products of metabolism are excreted.
• To identify key features of physiological control mechanisms.
• To describe the principles and components of a homeostatic system.
• To review the physiological systems involved in maintaining homeostasis.
• To be able to explain basic physiology to women so that they are able to understand how pregnancy alters the way a woman's body functions in order to support her pregnancy and prepare her physiologically for nurturing her newborn infant.
Introduction
Physiology is the biological science which explores how living organisms are able to function in order to survive and reproduce. Physiology investigates the relationship between the structure and function of body systems. The physiological systems are complex structures, which serve a particular function such as blood circulation or respiration. Organs are made up of cells organized into different tissue types such as nerve tissue or muscle tissue. The physiological systems communicate and interact with each other. A key concept of physiology is that life is only possible within some tightly regulated conditions such as temperature and ion concentration. Homeostasis describes an organism's ability to control its internal environment and maintain a stable condition; this allows the organisms to adjust to, and survive in, a broad range of environments. This book focuses on human reproductive function. This chapter aims to provide an illustrated introduction to, and an overview of, some of the basic physiological concepts referred to and developed in subsequent chapters, with specific references to reproduction. (For more details, readers are recommended to look at the list of further reading at the end of the chapter.)
Chapter case study
Zara is a 29-year-old primipara who presents herself at the midwife's clinic, which is held at her GP's surgery, giving a history of a positive pregnancy test.
• If Zara had accessed pre-conceptual care what advice do you think she should have been given in her preparation for pregnancy?
• What information would be available in Zara's medical records that would be useful to the midwife in her initial assessment of Zara's pregnancy?
• How could this information be used by the midwife to inform Zara of the physiological changes that have started to occur in her body?
The cell
The cell is the fundamental unit of structure and function of all living organisms. The evolution of multicellular organisms has led to the differentiation of cells, which means that different cells have evolved to perform specific functions and processes that contribute to the well-being of the organism as a whole. Differentiated cells form tissues, which combine with other tissues to form organs, which are linked together in physiological systems (Fig. 1.1). However, although cells can be highly specialized, they all share common features of the single cellular organisms from which we evolved. A typical human cell is about 10 μm in diameter. The largest human cell is the oocyte (see Chapter 6); it can just be seen with the naked eye. The follicular cells surrounding the oocyte have a more typical human cell size. The sperm cell is one of the smallest human cells. Smaller cells and organelles can be visualized by light and electron microscopy.
Fig. 1.1 Physiological systems: levels of organization of cells, tissues, organs and physiological systems, using breast tissue as an example. |
Cell structure
Most cells contain cytoplasm and are bound by a plasma membrane. Within them are various structures, called organelles (see Table 1.1), and a specialized part of the cell, called the nucleus (Fig. 1.2). The fluid surrounding the organelles is called cytosol.
Table 1.1 Cell components |
||
Cell component |
Structure |
Function |
Cell membrane |
The cell membrane is composed of a phospholipid bilayer embedded with various protein structures such as hormone receptors, ion channels and antigen markers |
The membrane acts as a differential permeable membrane between the cell and its immediate environment |
The nucleus |
The nucleus is bound by a membrane, similar to the plasma membrane of the cell; this contains openings referred to as nuclear pores, which allow the movement of substances in and out of the nucleus |
The nucleus contains deoxyribonucleic acid (DNA), the genetic instruction for the organism. Most of the time, the DNA is organized as chromatin threads; these condense into chromosomes prior to cell division. The nucleus stores and replicates DNA, which is expressed to synthesize proteins via a second type of nucleic acid, ribonucleic acid (RNA). These proteins determine the structure and function of the cell |
Endoplasmic reticulum |
This is a system of membranes, enclosing a space, which is continuous with the nuclear membrane. Endoplasmic reticulum (ER) exists as rough (granular) endoplasmic reticulum (RER) and smooth (agranular) endoplasmic reticulum (SER) |
RER appears rough because of the attached ribosomes. RER is involved in protein packaging. SER is involved in lipid and steroid synthesis and the regulation of intracellular calcium levels |
Mitochondria |
Spherical or elongated rod-like structures surrounded by a folded inner membrane and a smooth outer membrane. There are more mitochondria in cells that are metabolically active and have a high energy requirement |
Chemical processes involved in the formation of adenosine triphosphate (ATP). The cristae (inner membrane folds) are the site of oxidative phosphorylation and the electron transfer chain of aerobic respiration. Krebs (tricarboxylic acid or TCA) cycle and the oxidation of fatty acids take place within the matrix. Mitochondria contain mitochondrial DNA, which is maternally inherited and contains the genes for mitochondrial proteins |
Golgi apparatus (complex) |
A series of flattened curved membranous sacs |
Modifies proteins from the RER and sorts them into secretory vesicles |
Lysosomes |
Spherical or oval organelles enclosed by a single membrane |
Enclose acidic fluid containing digestive enzymes which act as a ‘cellular stomach’ breaking down cellular debris |
Peroxisomes |
Similar structure to lysosomes |
Destroy reactive oxygen species and protect cell |
Cytoskeleton |
Filamentous network |
Involved in maintaining cell shape and motility |
Fig. 1.2 A typical cell. |
Cells and tissues
Although about 200 types of cells with different structures can be identified within the body, cells can be grouped together in functional categories (Table 1.2). The study of the physical characteristics of cells is called histology (see Box 1.1). There are four types of tissue: epithelial tissue, muscle, connective tissue and neural tissue.
Table 1.2 Functional classification of cells |
||||||||
Cell group |
Epithelial cells |
Support cells |
Contractile cells |
Nerve cells |
Germ cells |
Blood cells |
Immune cells |
Hormone-secreting cells |
Example |
Lining gut and blood vessels Covering skin |
Fibrous support tissue, cartilage, bone |
Muscle |
Brain |
Spermatozoa Ova |
Circulating 1. red cells 2. white cells 3. platelets |
Lymphoid tissues, nodes and spleen |
Islets, thyroid adrenal |
Function |
Barrier; absorption; secretion |
Organize and maintain body structure |
Movement |
Direct cell communication |
Reproduction |
1. Oxygen transport 2. Defence |
Defence |
Indirect cell communication |
Special features |
Tightly bound together by cell junctions |
Produce and interact with extracellular matrix material |
Contractile proteins |
Release chemical messengers directly on to other cells |
Haploid (i.e. half-normal chromosome number) |
1. Proteins bind oxygen 2. Proteins destroy bacteria 3. Blood clotting |
Recognize and destroy foreign material |
Secrete chemical messengers into blood |
Box 1.1
Histology
The study of tissue structure is described as histology. The functions of tissues are reflected in the microscopic structure of the cells of which the tissue is composed. For example, cells that are metabolically active contain many mitochondria, whereas cells that produce hormones or enzymes, for instance, will contain a large proportion of ER. Specific tissues and cellular structures are often identified by the application of various chemicals that stain particular tissues. Histology is important in diagnosing cancer, as the cancerous tissue often has histological characteristics different from those of the tissue in which the cancer has developed. Malignant cancerous tumours have highly differentiated cells, which means they often appear different from the normal tissue cells from which they arose; they often have a simpler structure and are usually prolific in their division rate. These cells are less likely to adhere to neighbouring cells as normal cells do, so they are shed into the circulatory system and carried to other parts of the body where they seed more tumours (secondary tumours or metastases). Benign tumours usually have undifferentiated cells, which may closely resemble the cells of the tissue from which they arose and tend only to grow in the one position. Although cancers in pregnancy are rare, many cancerous cells may respond to oestrogen (sometimes referred to as oestrogen dependent); therefore, cancer growth during pregnancy can be quite rapid.
Epithelial tissue
Epithelial cells line the internal and external surfaces of body organs (Fig. 1.3), forming the outer layer of the skin, the mucous membranes, the lining of the lungs, gut, reproductive and urinary tracts, and also the endocrine and exocrine glands. Epithelial cells are often ‘polarized’ and have different characteristics on their apical (top) surface and their basal surface (which is in contact with the basement membrane). Epithelial cells are relatively undifferentiated and tend to undergo frequent mitotic divisions (see Chapter 7). This is because they are often exposed to wear and tear and so replacement epithelial cells are generated from a basal layer where cell division takes place. Epithelial cells form a barrier, which allows secretion and absorption of substances from one compartment to another. The skin is a specialized epithelial layer. The basal layer produces cells that are enriched with the protein keratin. The outer layers of skin cells are dead and so lack cytoplasm; it is these keratinized dead cells that provide the barrier function of the skin. Epithelial cells are classified by shape (cuboidal or columnar) and the number of layers. If there is a single layer of cells, the epithelium is described as simple; if there is more than one layer of cells (such as skin), it is stratified. Pseudostratified cells are a single layer of cells that appear to consist of more than one layer. Glands are derived from epithelial tissue.
Fig. 1.3 Types of epithelial cell: (A) squamous epithelium provides a smooth lining of blood vessels (endothelium, alveoli of lung and glomeruli of kidney); (B) cuboidal epithelium is often found on absorptive surfaces such as in kidney tubules; (C) columnar epithelium is often associated with secretory and absorptive tissues and may have microvilli, as in the gut; it may also be ciliated, as in the upper airways. (Reproduced with permission from Brooker, 1998.) |
Muscle tissue
Muscle cells contain contractile elements, so the cells can generate the mechanical force required for movement of the body or substances within the body (Fig. 1.4) or change shape and size. Muscle tissue is formed from the mesodermal layer of the embryo (see Chapter 9). There are three types of muscle tissue: skeletal, cardiac and smooth muscle. Skeletal muscle may be attached to bones and controls movement of the skeleton. Skeletal muscle can also be attached to the skin, for instance the muscles of the face involved with expression. Contraction of skeletal muscle is usually under voluntary or conscious control. Skeletal muscle is often described as ‘striated’ because of the striped appearance of the sarcomeres of the muscle observed under the light microscope. Skeletal muscle fibres can be subdivided into slow and fast twitch fibres. Fast twitch fibres contract more strongly but they tire easily, whereas slow twitch fibres can contract for prolonged periods.
Fig. 1.4 Muscle: (A) skeletal muscle; (B) smooth muscle; (C) cardiac muscle. (Adapted with permission from Brooker, 1998.) |
Cardiac muscle is only found in the heart; it has some structural similarity with skeletal muscle. Smooth muscle and cardiac muscle are usually under involuntary control (meaning there is no conscious awareness of the control). Smooth muscle surrounds many of the ‘tubes’ in the body, maintaining the function of several body systems. Smooth muscle cells are linked by gap junctions, and muscle contraction is relatively slow. Blood pressure is maintained by the contraction of a smooth muscle layer in the walls of the blood vessels. If the smooth muscle constricts, described as ‘vasoconstriction’, the internal lumen of the vessel will decrease and blood pressure will increase. ‘Vasodilatation’ is the opposite condition: the smooth muscle relaxes and the lumen diameter increases, so blood pressure falls. Organized synchronized waves of smooth muscle contraction, for instance in the gut, renal system and uterine tubes, generate peristaltic waves; these produce unidirectional movement of the contents within the lumen of the tube (Fig. 1.5).
Fig. 1.5 Peristaltic waves: peristalsis is achieved through the interaction of both longitudinal and circular smooth muscle fibres found in vessels with patent lumen. The peristaltic waves are responsible for (usually) unidirectional movement of the contents within the lumen. (Reproduced with permission from Brooker, 1998.) |
Connective tissue
Connective tissue functions to connect, anchor and support body structures (Fig. 1.6). Connective tissue cells often produce an extracellular matrix composed of proteins in a ground substance of sugars, proteins and minerals. Bone is a type of connective tissue, whereas collagen is an example of an extracellular matrix. Adipose tissue is composed of specialized cells that store fat for future energy requirements and have an endocrine role. Adipose tissue also acts as an insulating layer to conserve body heat loss and so contributes to the maintenance of the homeothermic status of the organism. Fibrous tissue is an example of dense connective tissue. It is a tough tissue that forms ligaments, tendons and protective membranes.
Fig. 1.6 Connective tissue: (A) adipose tissue; (B) fibrous tissue; (C) compact bone. (Reproduced with permission from Brooker, 1998.) |
Neural tissue
Neurons are cells that are specialized to initiate and conduct electrical signals (Fig. 1.7). Neurons require the presence of glial cells for nourishment and support; glial cells are also involved in the propagation of the electrical impulses in the neurons. As neurons are so highly specialized, they do not usually undergo further mitotic divisions once developed. Therefore, in the fetal and early neonatal period, the number of neurons produced far exceeds the level required for normal neurological function. To survive and function, neurons need regular stimulation. Throughout life, millions of neurons become dysfunctional and die.
Fig. 1.7 Types of neuron: (A) bipolar; (B) unipolar; (C) multipolar. |
The structural organization of the body
The body's organization can be understood by considering each component organ system separately (see below). However, these systems all work together, as a whole. Together the systems provide nutrients and oxygen for the cells and the excretion of waste products (Fig. 1.8). Movement is controlled and the temperature is maintained. Survival until reproductive function is completed has allowed the species to multiply. Cells are bathed in extracellular fluid, which can be differentiated into the interstitial fluid surrounding the tissue cells and the plasma within the blood vessels.
Fig. 1.8 Organization of the body. |
Homeostasis
Homeostasis is the term used to describe the processes of the various physiological systems that maintain the constancy of the internal environment. Multicellular animals are able to maintain an internal stability that is essential for the optimal functioning of all body systems, whereas simple unicellular organisms tend to inhabit stable environments or have adapted to overcome fluctuations in the environment, for instance by forming spores during dry periods. Unicellular organisms rely on basic nutrients being present in the environment to allow cell growth and reproduction.
The evolution of multicellular organisms and the development of motility meant that these animals were able to move within the environment to seek out the conditions that suited them best and so optimize their ability to reproduce. Mammals have developed homeostasis to a high degree. Motility, together with the homeostatic challenge of counteracting fluctuations in the external environment, places a huge energy burden upon these individuals. This increased energy requirement is above the basal metabolic rate, which is the rate of energy required to maintain essential functioning only.
Homeostasis can be considered to have three main components:
• chemostasis: the maintenance of electrolytes and pH balance
• haemostasis: the maintenance of an adequate circulatory system facilitating the passage of nutrients and oxygen into and waste products out of the organism
• thermostasis: the maintenance of a constant internal temperature.
Homeostasis is regulated by the nervous system, the endocrine system and behavioural factors that are dependent on conscious or subconscious action by the organism. A homeostatic control system requires monitoring a variable, detecting changes and generating responses which will restore the composition of the internal environment (Fig. 1.9). (This type of system, involving a process called negative feedback, is dealt with in more detail under Hormonal regulation in Chapter 3, p. 64.)
Fig. 1.9 The principles of homeostasis. |
Thermoregulation
Temperature regulation is one example of homeostasis (Fig. 1.10). Enzymes regulating biochemical changes, and physiological and metabolic functions, have optimal activity within a narrow temperature range. Outside this physiological temperature range, the protein structure of the enzyme begins to denature, so the configuration (shape) of the enzyme distorts, which affects its functional activity. A warm-blooded (homeothermic) animal is well prepared to react quickly and efficiently to changes within the environment, unlike a cold-blooded (poikilothermic) animal, which depends upon the ambient temperature of the environment.
Fig. 1.10 Temperature regulation: a homeostatic system in operation. |
The nervous system
The nervous system coordinates body functions. It monitors physiological processes by processing input from the senses, integrating them and initiating responses or motor output. The nervous system is an organization of millions of neurons, or nerve cells, and glial cells, which support and regulate the composition of the nervous system. It is composed of the brain, the spinal cord (in the centre of the vertebral column) and the neurons throughout the body. The skull and the vertebral column protect the brain and the spinal cord. The brain and spinal cord form the central nervous system (CNS) and the remainder is the peripheral nervous system (Fig. 1.11). Neurons usually consist of a cell body and dendrites (extensions) and an axon or nerve fibre, which carries information from the cell body to or from the CNS. They are of different sizes; some neurons have axon projections over 1 m in length. A nerve is a collection of axons running alongside each other over the same distance. A ganglion is a collection of cell bodies of neurons within the peripheral nervous system. Ganglions are located in dorsal (back) or ventral (front) branches of the spinal cord. The spinal cord and spinal nerves are organized on a segmental basis; this corresponds to the embryonic origin of the dermatomes (see Chapter 9). Cranial nerves carry information between the brain and regions of the head. Neurons that carry information towards the brain, entering the dorsal roots of the spinal cord, are sensory or afferent neurons. Neurons carrying information from the CNS to the skeletal muscles, and leaving the spinal cord at the ventral roots, are motor or efferent neurons (Fig. 1.12). Neurons that carry information between a sensory neuron and the CNS (or between the CNS and a motor neuron) are known as interneurons.
Fig. 1.11 Organization of the nervous system. |
Fig. 1.12 Afferent and efferent neurons. |
The action potential
Neurons carry information or nerve impulses by changing the electrical charge along their axon length so the transmembrane polarity changes rapidly from negative to positive and back. This change in electrical charge is termed an ‘action potential’. When the impulse reaches the axon, specific channels known as ‘sodium gates’ open, allowing the movement of extracellular sodium ions across the concentration gradient into the axon. As the sodium ions carry a positive charge, the immediate local area around the sodium gate inside of the axon becomes electrically positive compared with the immediate area outside and so the membrane becomes temporarily depolarized. At the height of the action potential (about 1 ms) the sodium channels close and the membrane becomes leaky to potassium ions; these move out of the axon down the electrochemical gradient. The result is restoration of the membrane potential, described as ‘repolarization’. That segment of the axon then enters a refractory period when no further action potential can be produced. However, depolarization in one small segment of the neuron leads to depolarization in the next segment; the rapid movement of the altered electrical activity is therefore propagated along the length of the neuron.
The action potential moves along the axon. The information detected at the periphery triggers activity at the neuron receptor and the action potential travels along the axon to the synapse, a junction with another neuron. There is a gap between two neurons at the synapse. Information transmission across this gap is by chemicals called neurotransmitters. These are released from the first neuron, travel across the synapse and trigger an action potential in the second neuron. The connection between a stimulating neuron and a muscle is called a neuromuscular junction. Action potentials move faster in axons of greater diameter, and if the axon is insulated by a myelin sheath. Myelin sheaths surround the nerve for short lengths punctuated by the nodes of Ranvier. Action potentials in myelinated nerves are not propagated as waves but move by saltatory conduction whereby they ‘hop’ along the nerve in a fast and efficient manner. Multiple sclerosis is due to breakdown of the myelin sheath, limiting the normal conduction of action potentials along nerves.
The somatic and autonomic nervous systems
The somatic nervous system controls muscles that change position. These muscles are called skeletal or voluntary muscles as they are controlled voluntarily, whereas smooth muscle and cardiac muscle are controlled involuntarily by the autonomic nervous system (ANS). The ANS controls the internal functions of the body such as circulation, respiration, digestion and metabolism.
Traditionally, the ANS has been divided into the sympathetic and parasympathetic systems (Table 1.3); these two branches of the ANS are described as working in tandem, either synergistically or antagonistically. The sympathetic nervous system controls the responses and provision of energy required for stressful situations; it is often known as the fear–fight–flight system. Effects of the sympathetic system include increased heart rate and blood pressure, pupillary and bronchial dilation, increased skeletal muscle blood flow (at the expense of blood flow to other tissues), increased glycogenolysis and lipolysis to increase energy provision and other responses that facilitate fight or escape and heightened awareness to threatening situations. The sympathetic system operates in conjunction with the endocrine system, facilitating the release of adrenaline, which augments the manifesting fear–fight–flight reflexes. Conversely, the parasympathetic branch of the ANS is more influential in periods of rest and inactivity and favours rest, increased digestive activity and restoration. Effects of parasympathetic nervous activity include increased blood flow to the gut and skin, stimulated salivary gland secretion and peristalsis, and slowing of the heart rate. In the ANS, two neurons carry information from the CNS to the target organ; these are described as autonomic ganglia. There is a further division of the ANS called the enteric nervous system, which affects smooth muscle and secretion in the gut.
Table 1.3 The autonomic nervous system |
||
Sympathetic division |
Parasympathetic division |
|
Characteristics |
Preganglionic outflow originates in thoracolumbar portion of spinal cord |
Preganglionic outflow originates in midbrain, hindbrain and sacral portions of spinal cord |
Chain of ganglia |
Terminal ganglia near or in effector organs |
|
Postganglionic fibres distributed throughout body |
Postganglionic fibres mainly associated with head and viscera |
|
Divergence of pathways, so system as a whole is usually stimulated. |
Little divergence, so limited parts of the system are stimulated |
|
‘Fear, fight and flight’ |
‘Resting and digesting’ |
|
Examples of effect |
Eye: dilation of pupil |
Eye: constriction of pupil |
Cardiovascular system: increased heart rate and increased strength of myocardial contraction, vasoconstriction of peripheral vessels and increased blood pressure |
Cardiovascular system: decreased heart rate and vasodilation of peripheral vessels and decreased blood pressure |
|
Lungs: dilation of bronchioles |
Lungs: constriction of bronchioles |
|
Bladder: increased muscle tone |
Bladder: increased contraction |
|
Uterus: contraction in pregnant woman; relaxation in non-pregnant woman |
||
Penis: ejaculation |
Penis: vasodilation and erection |
The brain
The brain is the centre of the nervous system; it is the most complex organ and is not fully understood. The vertebrate brain develops from three anterior bulges of the neural tube (see Chapter 9), which are the brain stem, the cerebellum and the cerebrum. The brain stem is formed of the medulla oblongata (which controls autonomic functions), the pons (which relays information to and from the higher centres of the brain) and the midbrain (which integrates sensory information). The brain stem is an evolutionarily older structure which regulates essential automatic and integrative functions; it is often called the ‘lower brain’ and is particularly important in maintaining homeostasis, coordinating movement. The cerebellum coordinates and error-checks motor activities and perceptual and cognitive factors.
The most highly evolved structure of the brain is the cerebrum. The outer layer of the brain is the grey matter of the cerebral cortex, which is divided into the left and right hemisphere (Fig. 1.13). The fibres that connect these hemispheres are the corpus callosum, the largest white matter structure. Different regions of the cortex are associated with different functions; they can be illustrated in a figure known as the ‘sensory homunculus’ (Fig. 1.14). The reticular formation acts as a sensory filter and is concerned with states of waking and alertness. The hypothalamus is involved in motivation and regulation and integration of many metabolic and autonomic processes. The hypothalamus controls body temperature, hunger and thirst, and circadian cycles and links the nervous and endocrine systems. The cerebellum is mainly concerned with coordination of movement and repetitive performance of previously learned tasks.
Fig. 1.13 The brain: an overview of some of the functional areas. |
Fig. 1.14 The ‘homunculus’: a representation of the (A) motor and (B) sensory areas of the brain illustrating the proportion of brain tissue dedicated to these areas. (Reproduced with permission from Brooker, 1998.) |
The digestive system
As animals grew larger, they could not rely upon obtaining nutrients through diffusion and random contact with the environment; they became hunters and grazers. As they evolved, they became able to feed intermittently. They could do this because they had developed the ability to digest (break down) large organic macromolecules into smaller molecules through the action of digestive enzymes. They were able to store and digest food slowly. Mechanisms for food storage, such as the deposition of fat within adipose tissue, enabled periods of food shortage to be overcome. The ability to synthesize new tissue with energy expenditure is termed anabolism. When tissue is broken down there is a reverse process termed catabolism; this usually results in the production of energy and waste products, which require excretion.
The gastrointestinal tract, or gut, is a long tube that runs from mouth to anus (Table 1.4) in which food is digested and absorbed, to extract energy and nutrients; the remaining waste is expelled. Food enters the mouth; here it is masticated (mechanically broken down, thus increasing its surface area) and lubricated and enzymes are added before it is passed through the oesophagus to the stomach. The stomach is a bag-like swollen structure where the first major digestive processes occur. Hydrochloric acid secreted into the stomach maintains a pH of about 2; this has an important role in destroying microorganisms. There is some protein breakdown in the stomach and the food is mixed well. The mixed food, or chyme, then moves into the duodenum where most of the digestion and absorption take place. Digestive enzymes and bicarbonate ions (which neutralize the acidic pH) are produced from the pancreatic exocrine tissue and secreted into the duodenum. Bile salt secretion is important for the digestion of fats. The small intestine is a major site of absorption and has a very large surface area provided by finger-like projections called villi (Fig. 1.15). Tiny projections or microvilli on the surface of the individual epithelial cells further increase the surface area. The net result is a surface area of about 300 m2. The epithelial cells lining the absorptive surfaces of the gastrointestinal system have membrane-bound enzymes, for further digestion of the food molecules, and specific transport mechanisms for absorbing different molecules into the bloodstream.
Table 1.4 The digestive system |
|
Region of gastrointestinal system |
Main digestive events |
Mouth |
• Taste • Mechanical digestion (chewing, mastication) • Food moistened and lubricated, to facilitate passage down oesophagus • Starch digestion (amylase) |
Oesophagus |
• Peristalsis enables transfer of food bolus to stomach • Buccal amylase activity continues |
Stomach |
• Stores, mixes, dissolves, releases food • Hydrochloric acid (HCl) – lowers pH to 2 – kills microbes – denatures proteins – converts pepsinogen to pepsin • Mucus: protects gastric lining • Pepsin: protein digestion |
Pancreas |
• Enzyme production: digestion • Bicarbonate: neutralizes pH |
Liver |
• Bile production |
Gall bladder |
• Bile concentration and coordinated release facilitating emulsification of fats |
Small intestine |
• Digestion and absorption of most nutrients |
Large intestine |
• Passage of undigested matter • Absorption of water and vitamins • Provides environment for commensal symbiotic bacteria |
Rectum |
• Storage of undigested matter • Defecation |
Fig. 1.15 Structure of the small intestinal villi: (A) transverse section through the intestinal wall; (B) a villus; (C) details of the epithelium. (Reproduced with permission from Saffrey and Stewart, 1997.) |
Cells of the mucosa that lines the gut have a very rapid turnover; the entire cell lining is renewed every 4 or 5 days. Therefore, agents that inhibit cell division such as radiation and chemotherapy drugs compromise the epithelium and total surface area. The absorbed nutrients pass from the capillaries of the small intestine into the hepatic portal vein and the liver. The wall of the gut is lined with smooth muscle, which undergoes synchronous contraction, generating waves of peristaltic movement propelling the food along the gut. The control of the smooth muscle is via the enteric nervous system.
The large intestine is important in the maintenance of fluid and iron balance and the absorption of vitamins. It is colonized and inhabited by bacteria, many of which synthesize vitamins, including vitamin B12, vitamin K, thiamin and riboflavin, which can be absorbed across the gut wall. Motility of food through the gut is increased if there are more undigested non-starch polysaccharides (fibre) present. Some breakdown of these polysaccharides occurs by bacterial action, which can produce gas (flatus): nitrogen, carbon dioxide, hydrogen, methane and hydrogen sulphide.
Secretion and motility of the gut are controlled by nervous stimulation (Fig. 1.16). There are three phases or stages of nervous control. The cephalic phase is stimulated by the smell, taste and sight of food, which increase motility and hydrochloric acid secretion. When food reaches the stomach it causes distension, increased acidity and increased peptide formation, which stimulate the gastric phase of control. The hormone gastrin is released, which stimulates secretion of acid and affects the lower regions of the gut. The third phase of control is the intestinal phase, which is stimulated by food within the intestine. The intestinal phase causes the reflex inhibition of gastric secretion.
Fig. 1.16 Phases of hormonal control of the stomach and associated organs. |
The digestive system interacts with the immune system; effectively, the lining of the digestive system is an exterior surface of the body in contact with potentially pathogenic microorganisms. Most of the body's immune cells (about 70%) are located at the digestive system mucosal interface as individual cells and forming the gut-associated lymphoid tissue (GALT) which surveys and protects the digestive system. In addition, the digestive system provides the habitat for trillions of microorganisms (1013–1014 microbes, about 10–100 times the total number of human cells, with a biomass of at least 1 kg). Most of these microorganisms reside in the colon and provide a repository of functional genes that make a significant contribution to host processes such as protecting against pathogens, interacting with the immune system, promoting gut development and synthesizing essential nutrients such as vitamins.
The respiratory system
Respiration is the exchange of gases between the environment and the body. Respiration is essential for the functioning of all living organisms. There are two types: aerobic and anaerobic. In aerobic respiration, organic molecules from ingested food are oxidized to produce energy (Fig. 1.17). Anaerobic respiration is when energy is produced in the absence of oxygen. This form of respiration is relatively inefficient compared with aerobic respiration.
Fig. 1.17 A summary of metabolism: substrate molecules (such as glucose from food) are oxidized (using respiratory oxygen), producing carbon dioxide (expired) and energy in the form of ATP. |
Anaerobic respiration is common among single-celled organisms. Large animals, such as humans, can produce some energy anaerobically, for instance in times of acute stress and rapid muscle activity when oxygen demand exceeds oxygen provision. However, anaerobic respiration results in the rapid accumulation of toxic metabolites. In simple organisms, these may simply diffuse out of the cell into the environment, but for large animals this rapid excretion cannot be achieved and so anaerobic processes are self-limiting. Asphyxia is the term that describes irreversible damage to cells due to the build-up of these toxins (see Box 15.1 for a description of ‘Fetal asphyxia’).
Aerobic respiration is an extension of anaerobic respiration. The metabolites, produced under anaerobic processes such as glycolysis, are further broken down producing carbon dioxide, water and significantly more energy. Aerobic respiration requires the presence of oxygen and mitochondria, the sites of the enzymes involved in these biochemical pathways. Cells require a continuous source of oxygen for metabolism.
The respiratory system consists of the lungs, the branching airways, the gaseous exchange membranes, the rib cage and respiratory muscles. Ventilation is the mechanical activity that moves gases in and out of the lungs; the movements of the intercostal muscles and diaphragm allow filling and emptying of the lungs (Fig. 1.18). An adult at rest will inspire about 250 mL of oxygen and expire about 200 mL of carbon dioxide every minute. The respiratory tract provides a very large surface area that, while optimizing gas exchange, is vulnerable as it is constantly exposed to microorganisms. An important function of the respiratory system is to defend itself and prevent pathogens gaining access to the body.
Fig. 1.18 The respiratory system. |
Gas exchange occurs across the capillary membranes of the alveoli, which are very thin and therefore have a very low diffusion distance. Oxygen from the inspired air diffuses into the capillaries where it binds temporarily to haemoglobin in the red blood cells. The binding of oxygen and haemoglobin can be described by the oxygen–haemoglobin dissociation curve (Fig. 1.19). Haemoglobin has a high affinity for oxygen at higher concentrations and its binding sites are saturated with oxygen in the alveoli. At low concentrations of oxygen, haemoglobin has a low affinity for oxygen so it releases oxygen at the tissues. Binding of oxygen to haemoglobin is altered by carbon dioxide, pH, temperature and the glycolytic intermediate 2,3-bisphosphoglycerate (also known as 2,3-diphosphoglycerate). These alter the shape of the haemoglobin molecule, which affects its oxygen-binding sites. Substances that reduce haemoglobin–oxygen affinity increase the release of oxygen (so the curve is shifted towards the right).
Fig. 1.19 The oxygen–haemoglobin dissociation curve. (Reproduced with permission from Brooker, 1998.) |
Carbon dioxide diffuses from the tissues into the capillaries. It is taken up by the red blood cells where it reacts with water to form carbonic acid. This reaction is catalyzed by the enzyme carbonic anhydrase in the red blood cell. Carbonic acid is unstable and dissociates to bicarbonate and hydrogen ions (Fig. 1.20); the bicarbonate diffuses out of the red blood cell into the plasma.
Fig. 1.20 Carbon dioxide transport. (Reproduced with permission from Brooker, 1998.) |
The respiratory control centre, in the medulla oblongata of the brain stem, affects the activity of the inspiratory and expiratory neurons that control the respiratory muscles, which contract to allow inspiration and expiration. The respiratory centre receives information from stretch receptors in the lungs and from the peripheral and central chemoreceptors that monitor the pH and oxygen content of the blood (Fig. 1.21).
Fig. 1.21 Chemoreceptor control of respiration: the regulation of ventilation is achieved via peripheral and central chemoreceptors, which sample the blood, and then via a neuronal pathway influencing the rate and depth of breathing. CSF, cerebrospinal fluid. |
There is homeostatic regulation of acid–base balance to maintain pH within narrow parameters at around 7.3 (Fig. 1.22). This regulation involves both the respiratory and the renal systems (see Chapter 2).
Fig. 1.22 Acid–base balance. |
The cardiovascular system
The cardiovascular system includes the heart, the blood vessels and the blood. The blood is pumped around a network of blood vessels (Fig. 1.23). Arteries transport blood away from the heart and have thick muscular walls. Veins carry blood towards the heart; they function as a capacitance system. Capillaries link the arterial and venous systems and allow exchange of substances between the blood and the tissues.
Fig. 1.23 Blood vessels: the major role of arteries is in the generation of elastic recoil, which propels the blood around the body. The capillaries are involved in gas exchange and the veins act as capacitance vessels returning blood to the heart. |
The heart functions as a double pump, pumping blood to the tissues of the body and the lungs (Fig. 1.24). Blood from the right side of the heart enters the pulmonary circulation to the capillaries surrounding the alveoli of the lungs where the blood is oxygenated. Oxygenated blood returns to the left side of the heart in the pulmonary veins. The oxygenated blood is then pumped from the left side of the heart around the body. The pulmonary circulation takes blood from the right side of the heart, to the lungs, and back to the left side of the heart. The systemic circulation is the circulation of blood around the body from the left side of the heart to the tissues and back to the right side of the heart. There are two circulatory routes which do not fit the general pattern of double circulation. The portal blood blow from the hypothalamus to the anterior pituitary gland (see Chapter 3) is one of these. The other is associated with the gut. The deoxygenated blood from the digestive system drains into the portal vein which goes to the liver, allowing the liver to take up absorbed nutrients (and neutralize any absorbed toxins). From the liver, blood drains to the hepatic portal veins into the inferior vena cava and from there to the heart.
Fig. 1.24 Interior of the heart to show layers, chambers and valves. (Reproduced with permission from Brooker, 1998.) |
The coronary circulation is the circulation of blood within the vessels of the heart. Blood flow to the brain is via a circular arrangement of vessels (the circle of Willis); this ensures that there will always be sufficient oxygen and nutrients, albeit at the expense of other parts of the body when the circulatory system is under stress. The blood–brain barrier protects the brain against the entry of some harmful substances, such as toxins.
The adult heart beats about 70 times a minute at rest, forcing blood from the ventricles into the pulmonary artery and the aorta. The increased volume of blood entering the blood system causes a fluctuating increase in blood pressure. Blood pressure can be measured using a sphygmomanometer to record pressure within an artery and a stethoscope to hear the turbulence of blood within the blood vessels (Fig. 1.25). The amount of blood that leaves the heart per minute is described as the cardiac output. This is the volume of blood ejected from the ventricles each time the heart beats multiplied by the number of beats per minute (Fig. 1.26). The amount of oxygen that reaches the cells of the tissue depends on the proportion of the cardiac output the tissue receives.
Fig. 1.25 Blood pressure measurement. (Reproduced with permission from Brooker, 1998.) |
Fig. 1.26 Cardiac output. |
The heart's internal pacemaker, the sinoatrial node (SAN), sets the heart rate. The SAN spontaneously depolarizes and triggers a wave of electrical activity, which stimulates the heart muscle to contract (Fig. 1.27). The SAN is innervated by both parasympathetic and sympathetic nerves. Receptors throughout the body respond to changes in blood pressure and respiratory gas level. These baroreceptors and chemoreceptors transmit information to afferent nerves in the medulla of the brain (the brain stem) that control efferent nerves to the heart, lungs and blood vessels (Fig. 1.28).
Fig. 1.27 Sinoatrial node (SAN) depolarization: the conduction pathway of the heart enables the organ's coordinated and rhythmic beating. |
Fig. 1.28 Regulation of blood pressure. |
The total capacity of blood vessels in the body exceeds the volume of the blood. To maintain homeostasis and tissue requirements, the cardiovascular system is carefully regulated to ensure optimal oxygenation of the tissues. The control of blood flow is regulated by alteration of the diameter of the blood vessels, which changes peripheral resistance. The diameter of the blood vessels is altered by the activity of sympathetic nerves that innervate the smooth muscle in the vessel walls. Increased sympathetic activity, or increased adrenergic stimulation, increases vasoconstriction, reducing blood flow and increasing peripheral resistance. Decreased sympathetic activity causes vasodilation, which increases blood flow and reduces peripheral resistance. Blood vessel diameter is also controlled locally by tissue metabolites. This autoregulation increases blood flow to metabolically active tissues.
Blood
Blood is a suspension of cells in plasma (see Table 1.2). Blood cells are all derived from stem cells in the bone marrow. The majority (>99%) of cells are red blood cells (or erythrocytes). Red blood cells contain haemoglobin, which binds to oxygen. Iron, folic acid and vitamin B12 are required for the production of erythrocytes. The kidneys produce a hormone, erythropoietin, in response to low oxygen levels, which stimulates an increase in the production of red blood cells from the bone marrow. Leukocytes, or white blood cells, include polymorphonuclear granulocytes (neutrophils, eosinophils and basophils) and the agranular monocytes and lymphocytes. The role of white blood cells is the defence of the body (see Chapter 10). Platelets are cellular fragments of megakaryocytes, which are an essential component of the blood-clotting mechanism (Fig. 1.29). Plasma contains proteins (albumin, globulins and some clotting factors, such as fibrinogen), nutrients, hormones, waste products and ions.
Fig. 1.29 Haemostasis: the blood coagulation cascade. |
The lymphatic system
The lymphatic system is part of the circulatory system and consists of a network of thin branching vessels, lymph nodes and lymphatic fluid (Fig. 1.30). It collects the interstitial fluid from cells and returns it to the blood. Lymph vessels have one-way valves like veins and depend on the movement of skeletal muscle to propel the fluid which moves slowly under low pressure. The lymphatic system transports lymphocytes and is important in defending the body against microorganisms (see Chapter 10). Lymph nodes in the lymphatic system are lymphocyte-filled and act as collecting filters for viruses and bacteria which are then destroyed. Lymphatic vessels are present in the lining of the digestive tract and transport digested lipids to the thoracic duct and into the venous circulation.
Fig. 1.30 The lymphatic system. |
Metabolism
Energy production and storage
Cells have a continuous requirement for energy and adenosine triphosphate (ATP). The energy from ATP drives virtually all the body processes but there is very little ATP present at any one time, just enough to provide energy requirements for only a few minutes. Every organ requires energy but some, such as muscles, have a very variable energy requirement. Meals provide fuel from food components, which are oxidized to provide ATP and heat. However, the intake of food is irregular and does not coordinate with the requirement for energy. The energy substrates from a meal are usually absorbed within 3 h; as the next meal can be hours away, animals have evolved successful methods of storing energy substrates.
The main storage forms of energy are glycogen in the liver and skeletal muscle and triacylglycerides in adipose tissue. Carbohydrates are the major fuels for the brain and nervous tissue. Oxidation of glucose occurs in several stages (Fig. 1.31). Glycolysis takes place in the cell cytosol and produces a little ATP anaerobically. If oxygen is present, there is further oxidation through the Krebs cycle and oxidative phosphorylation (the electron transfer chain). This increased efficiency of ATP production takes place in cells that have mitochondria and adequate provision of oxygen. In tissues lacking mitochondria, such as red blood cells, or those with insufficient oxygen, such as active muscle, there is a build-up of the key intermediate pyruvate. Pyruvate can be converted into lactate and oxidized by the heart and kidneys or converted to glucose by the liver and kidneys.
Fig. 1.31 Oxidation of glucose. |
About 500 g of the glucose polymer, glycogen, is stored: 100 g in the liver, which can release the glucose when required (by glycogenolysis), and 400 g in the skeletal muscles, which is available for use by the muscle. Triacylglycerides are stored in virtually unlimited amounts, as observed in obesity. As they do not mix with water, the storage form is very calorie dense and efficient. Triacylglycerides are composed of three fatty acids bound to a glycerol backbone. The glycerol can be converted into glucose, thereby providing a substrate for the brain to oxidize for energy. Fatty acids are released with free glycerol from the adipose tissue and can be oxidized by the liver, muscles and kidneys. Fatty acids cannot cross the blood–brain barrier and cannot be converted to glucose so they provide little substrate for the brain. Ketone bodies are water-soluble derivatives of fatty acids formed by the liver during starvation or prolonged severe exercise. When sufficient concentrations of ketone bodies accumulate, the brain and kidney use them to generate ATP. Certain amino acids are also ketogenic, and can be converted into ketone bodies. Overproduction of ketone bodies, as in uncontrolled diabetes, overwhelms the buffering capacity of the body and can cause life-threatening acidosis.
There is no reserve storage form of protein independent of function. Protein can be metabolized to provide energy but at the expense of the breakdown of structural and functional components of the body. The use of protein as a fuel potentially damages the body, so it is used only as a ‘last resort’ when the protein is broken down and the amino acids are converted into components of the glycolytic pathway to produce energy. However, proteins constitute a large proportion of body structure and therefore can provide a substantial source of energy when other supplies have been exhausted. Protein in excess of requirements can be irreversibly converted into glucose or triacylglycerides.
The brain consumes about a quarter of the body's daily energy production when the body is at rest. The brain's requirement for fuel drives energy metabolism. The main fuel storage form of the body is triacylglycerides, but the brain cannot use fatty acids directly. Although the brain can oxidize ketone bodies, derived from fatty acids, for 80% of its energy requirements, 20% must come from glucose. Glucose comes from the diet or from glycogenolysis or gluconeogenesis in the liver. Other cells therefore utilize other substrates in preference to glucose. The hierarchy of fuel use means that the brain utilizes ketone bodies when they are available, or glucose. Muscle has a major reserve of protein and glycogen. Muscle spares brain fuel by preferentially oxidizing fatty acids, thus sparing ketone bodies and glucose for the brain. The glycogen stored in the muscle is specifically available for muscle use.
The external environment is continually fluctuating and energy requirements are constantly changing. However, the body maintains homeostasis or internal stability by ensuring a constant level of amino acids and glucose in the blood, despite intermittent high loads following a meal. The level of ATP within cells is kept relatively constant although the rate of usage is variable; for instance, activity increases energy requirement of a muscle by up to 20 times. Cellular energy requirement is regulated very sensitively; metabolic pathways that predominate after a meal (called the absorptive state) are different from those between meals (the postabsorptive state) (Fig. 1.32). Dominance of the pathways is via changed enzyme activity and altered uptake of substrates, controlled by hormones. Interconversion from one metabolic step to the next is regulated by substrate activation, where the substance stimulates its own use, and product inhibition, where the product prevents the reaction from continuing. Enzymes catalysing the same reaction may exist as isoenzymes in different types of tissue, having different affinities for their substrates. This means that different concentrations of substrate are required for the biochemical pathway to progress.
Fig. 1.32 Absorptive and postabsorptive states. |
Blood sugar regulation
When plasma glucose concentration rises after a meal, secretion of insulin from pancreatic β-cells is stimulated and plasma levels of insulin increase. Insulin triggers the translocation of vesicles containing the insulin-sensitive glucose transporter, GLUT4, from intracellular sites to the cell membrane of the insulin-sensitive tissues, skeletal and cardiac muscle and adipocytes. This increases the uptake of glucose and other substrates into the cell and promotes the anabolic (storage) biochemical pathways (Fig. 1.33). Tissues that have a constant requirement for glucose, such as brain cells, do not have insulin-sensitive glucose transport but do express the high-affinity transporter, GLUT3, as well as GLUT1. Under conditions of low glucose, pancreatic production of glucagon is increased, which acts to mobilize tissue reserves of metabolic fuels. Adrenaline, secreted from the adrenal medulla in response to sympathetic innervation, causes a rapid mobilization of fuels for ‘fight or flight’ (see p. 11). Adrenaline stimulates glucose production from muscle glycogen and increases lipolysis in adipose tissue so that levels of fatty acids increase to provide additional metabolic fuel.
Application to practice
Physiological observations to assess maternal well-being
In order to assess well-being during pregnancy, practitioners must consider how physiological parameters are altered in pregnant women and when these altered parameters become abnormal in relation to pregnancy, but observations to assess well-being cannot be considered in isolation. It is important to monitor respiratory rate as well as blood pressure, pulse and temperature. A rising respiratory rate can be an early indicator of respiratory distress. Ideally respiratory rate should be counted without informing the woman so that she is not conscious of her breathing as being conscious of it is likely to affect the respiratory rate. Tachypnoea (rapid breathing) is a significant clinical feature which should not be dismissed as being caused by anxiety or stress, or related to pain. If tachypnoea is present with a rapid pulse and a fall in blood pressure, then the maternal condition might be deteriorating because of cardiovascular problems, such as haemorrhage or sepsis. It is common for oxygen saturation to be monitored to assess respiratory function; however, oxygen saturation is often maintained in the presence of tachypnoea (98% +) and a fall in oxygen saturation is therefore a late indicator of advanced maternal distress.
A raised temperature is a significant indicator of sepsis; however, if sepsis is severe, body temperature measured orally or in the axilla may be misleadingly low because of peripheral vascular shutdown caused by toxicity. Thus, an abnormally low temperature can also indicate sepsis. In such cases, core temperate should be measured, for example by use of a rectal probe. The greater the difference between core and peripheral temperature, the more likely it is that sepsis is severe.
If the pulse rate is higher (beats per minute) than the systolic blood pressure (measured in millimetres of mercury, mmHg) this also indicates serious deterioration in the well-being of the woman.
Blood pressure is lower and pulse rate is faster in pregnancy, so direct comparisons to non-pregnant values are not valid. Whenever possible, midwives should access pre-pregnancy observations, for example, from well women clinic records, family planning clinics, GP notes, etc., thus providing a reference point when assessing normal physiological changes in pregnancy. As computerized single patient records are developed, access to this information will be easier and faster. Women who do not have lower blood pressure in the first trimester than their pre-pregnant parameter are at greater risk of hypertensive problems in pregnancy and in later life or may have underlying renal problems.
Blood pressure must be measured using a cuff appropriate to the size of the woman's arm. If automated machines are being used to measure blood pressure, blood pressure should be measured manually at least once to confirm that the electronic measurement is valid.
Women should have direct access to midwives as soon as pregnancy is confirmed so that pregnancy care can be planned to meet their individual needs.
Key points
• Cells have different anatomical structures, which are related to their physiological functions.
• Cells are organized together to form tissues, which are organized into organs and the physiological systems of the body.
• The role of the physiological systems is to provide internal stability or homeostasis, which will ensure that the cells' variable but essential requirements for energy are met by an adequate supply of oxygen and nutrients.
• As the enzymes that regulate cellular activity have a protein structure, they are affected by fluctuations in pH and temperature, so homeostasis has to maintain optimum temperature and acid–base balance as well.
Application to practice
The basic physiology described in this chapter relates to the non-pregnant state. During pregnancy there are many physiological changes, which are explored through the rest of the book. A basic knowledge of physiology is essential so that the complexities of the physiological changes in pregnancy can be understood and explained as required. This knowledge is also essential for the midwife to be able to monitor the development of pregnancy effectively.
Fig. 1.33 The effects of insulin. |
Annotated further reading
Alberts, B.; Bray, D.; Lewis, J.; et al., In: Molecular biology of the cell ed 5 (2008) Garland, New York.
A beautifully written and well-illustrated text on molecular and cellular biology which is accessible, easy to read and up to date; the cell biologist's ‘bible’.
Berne, R.M.; Levy, N.M., In: Physiology ed 6 (2008) Mosby, St Louis.
A comprehensive illustrated textbook, which emphasizes physiological concepts and basic principles.
Koeppen, B.M.; Stanton, B., In: Renal physiology ed 4 (2006) Mosby.
Provides a useful reference to the area of renal physiology.
Salway, J., In: Metabolism at a glance ed 3 (2003) Blackwell, Oxford.
A large-format book which provides a comprehensive review of basic human metabolism, including inborn errors of metabolism and clinical aspects of metabolism. Metabolic pathways are summarized as segments with a clear diagrammatic pathway map on one page and an outline of the metabolism on the facing page.
Salway, J., In: Medical biochemistry at a glance ed 2 (2006) Wiley Blackwell, Oxford.
A useful overview of human biochemistry which provides a synopsis using detailed flow-charts and explanatory diagrams.
Tortora, G.J.; Derrickson, B.H., In: Principles of anatomy and physiology ed 13 (2011) Harper Collins, New York.
A clear, illustrated 2-volume textbook (with CD-ROM) providing an in-depth overview of physiology and anatomy. It is targeted at students in health professions and includes clinical applications and study outlines.
Ward, J.P.T.; Linden, R., In: Physiology at a glance ed 2 (2008) Wiley Blackwell, Oxford.
Another of the ‘at-a-glance’ series of books which provides clear illustrated and bullet-point summaries of the role of physiological systems.
Widmaier, E.P.; Raff, H.; Strang, K.T., In: Vander's Human physiology ed 12 (2010) McGraw-Hill, New York.
An updated version of the classical textbook which provides a useful guide to the principles of human physiology using clear diagrams and flow-charts; the new edition includes more clinical applications.
References
Brooker, C.G., In: Human structure and function ed 2 (1998) Mosby, St Louis, p. 15; 30, 32, 33, 88, 207, 211, 228, 277, 279, 296, 372, 383.
In: (Editors: Saffrey, J.; Stewart, M.) Maintaining the whole. SK220 Human biology and health, book 3 (1997) Open University Press, Milton Keynes, p. 65.