SQA CfE Higher Human Biology Unit 2: Physiology and Health

Transcription

1 SCHOLAR Study Guide SQA CfE Higher Human Biology Unit 2: Physiology and Health Authored by: Eoin McIntyre Reviewed by: Sheena Haddow Previously authored by: Mike Cheung Eileen Humphrey Eoin McIntyre Jim McIntyre Heriot-Watt University Edinburgh EH14 4AS, United Kingdom.

2 First published 2014 by Heriot-Watt University. This edition published in 2014 by Heriot-Watt University SCHOLAR. Copyright 2014 Heriot-Watt University. Members of the SCHOLAR Forum may reproduce this publication in whole or in part for educational purposes within their establishment providing that no profit accrues at any stage, Any other use of the materials is governed by the general copyright statement that follows. All rights reserved. No part of this publication may be reproduced, stored in a retrieval system or transmitted in any form or by any means, without written permission from the publisher. Heriot-Watt University accepts no responsibility or liability whatsoever with regard to the information contained in this study guide. Distributed by Heriot-Watt University. SCHOLAR Study Guide Unit 2: SQA CfE Higher Human Biology 1. SQA CfE Higher Human Biology ISBN Printed and bound in Great Britain by Graphic and Printing Services, Heriot-Watt University, Edinburgh.

3 Acknowledgements Thanks are due to the members of Heriot-Watt University's SCHOLAR team who planned and created these materials, and to the many colleagues who reviewed the content. We would like to acknowledge the assistance of the education authorities, colleges, teachers and students who contributed to the SCHOLAR programme and who evaluated these materials. Grateful acknowledgement is made for permission to use the following material in the SCHOLAR programme: The Scottish Qualifications Authority for permission to use Past Papers assessments. The Scottish Government for financial support. All brand names, product names, logos and related devices are used for identification purposes only and are trademarks, registered trademarks or service marks of their respective holders.

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5 i Contents 1 Reproductive organs, gametes and fertilisation Gametes The male reproductive system The female reproductive system Learning points Extended response question End of topic test Hormonal control of reproduction Introduction Onset of puberty Control of sperm production Control of the menstrual cycle Learning points Extended response question End of topic test The biology of controlling fertility Introduction Fertile periods Treatments for infertility Contraception Learning points Extended response question End of topic test Antenatal and postnatal screening and care Introduction Antenatal care Antenatal screening Postnatal screening Learning points Extended response question End of topic test Patterns of inheritance Introduction Genetic terms and their meanings Pattern of inheritance of a pair of alleles - one dominant, one recessive Dominant and incompletely dominant alleles

6 ii CONTENTS 5.5 Sex-linked inheritance Learning points End of topic test Blood vessels Why have a cardiovascular system? Blood vessels Exchange of materials between the blood and the cells Learning points Extended response question End of topic test Structure and function of the heart Introduction The structure of the heart The human circulatory system The control of heart rate The cardiac cycle The cardiac conducting system Blood pressure Learning points Extended response question End of topic test Cholesterol and cardiovascular disease Introduction Cholesterol Atherosclerosis and associated diseases Learning points Extended response question End of topic test Pathology of cardiovascular disease Introduction Regulation of blood glucose levels Blood glucose levels and diabetes Blood glucose levels and vascular disease Obesity Learning points Extended response question End of topic test End of unit test 171 Glossary 179 Answers to questions and activities Reproductive organs, gametes and fertilisation Hormonal control of reproduction The biology of controlling fertility Antenatal and postnatal screening and care

7 CONTENTS iii 5 Patterns of inheritance Blood vessels Structure and function of the heart Cholesterol and cardiovascular disease Pathology of cardiovascular disease End of unit test

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9 1 Topic 1 Reproductive organs, gametes and fertilisation Contents 1.1 Gametes The male reproductive system The female reproductive system After ovulation Learning points Extended response question End of topic test Learning Objectives By the end of this topic, you should be able to: explain the origin of gametes; describe the role of the seminiferous tubules and the interstitial cells; describe the role of the prostate gland and seminal vesicles; describe the development of the ova in the ovary; describe the functions of the follicle in the ovary; describe the process of fertilisation.

10 2 TOPIC 1. REPRODUCTIVE ORGANS, GAMETES AND FERTILISATION As all organisms die, so all organisms must reproduce for their species to survive. Success in evolutionary terms is measured by the numbers of offspring which survive to breed. In animals, the cells which will become the gametes are segregated from the other body cells very early in the development of the embryo, but they only become mature when the body of the individual reaches a stage in growth at which it can support the offspring. We find that in nearly all human societies there is a gap between the age of attainment of sexual maturity and the recognition of that individual as an adult, which we know as adolescence. 1.1 Gametes Learning Objective By the end of this section, you should be able to: describe the production of germline cells; explain how an individual's sex is determined; compare male and female sex cells. In Unit 1 of this course, the two basic types of cell in the body are identified as the germline cells which give rise to the gametes, and the somatic cells which produce all the other cells of the body. A key difference between these types of cell is that while both can undergo mitosis, only germline cells can divide by meiosis. Somatic cells Germline cells In all mammals, the development of the germline cells in the testes or ovaries is determined by the presence or absence of a single gene which is carried on the Y chromosome. You will have learned how the sex of an individual is inherited in your previous course. The male gametes (sperm) are produced in the testes; they are very small and thin (the head being 5 3 microns and the tail 41 microns). They are active swimmers with a compact nucleus, many mitochondria, but no energy stores. The female gametes (ova) are produced in the ovary. In contrast to sperm, they are very large, round cells (200 microns across) with a yolk which are not capable of moving by themselves.

11 TOPIC 1. REPRODUCTIVE ORGANS, GAMETES AND FERTILISATION 3 Gametes: Questions Q1: Why is it necessary for germline cells to divide by meiosis? Q2: Suggest an explanation for the differences in size and structure of the sperm and ovum. 1.2 The male reproductive system Learning Objective By the end of this section, you should be able to: describe that sperm are produced in the testis; describe where testosterone is produced; explain the function of the secretions of the prostate gland and the seminal vesicles. The following diagram shows the male reproductive system.

12 4 TOPIC 1. REPRODUCTIVE ORGANS, GAMETES AND FERTILISATION The male reproductive system The testes are the male reproductive organs. They have two functions: 1. the production of sperm in the seminiferous tubules; 2. the production of testosterone in the interstitial cells, which are found between the seminiferous tubules. Each testis contains several intensely folded seminiferous tubules within which germ cells divide, first by mitosis and then by meiosis, to produce immature sperm. These then undergo differentiation, developing the tail and the thickened mid-piece that contains many mitochondria. The DNA of the (now haploid) nucleus becomes highly condensed and inactive. In this condition, the sperm are further matured under the influence of testosterone, e.g. by the removal of excess cytoplasm, before being transported to the epididymis where they finally become motile and capable of fertilisation.

13 TOPIC 1. REPRODUCTIVE ORGANS, GAMETES AND FERTILISATION 5 Between the seminiferous tubules lie the interstitial cells (also known as Leydig cells after the German anatomist who first discovered them in 1850). These cells release testosterone when they are stimulated by luteinising hormone (LH) released by the pituitary gland. As a result of the action of LH in the male, it is also referred to as Interstitial Cell Stimulating Hormone (ICSH). Also associated with the male reproductive system are two other organs: the prostate gland and the seminal vesicles. These produce fluids which are collectively known as seminal fluid, the role of which is to: maintain the mobility of the sperm by providing a liquid medium at optimum viscosity for the sperm to swim in; supply nutrients (e.g. fructose) for the sperm, which use a lot of energy but carry no energy reserves. The male reproductive system: Questions Q3: Complete the diagram using the labels provided.

14 6 TOPIC 1. REPRODUCTIVE ORGANS, GAMETES AND FERTILISATION Q4: Complete the diagram using the labels provided. Q5: Where are sperm produced? Q6: Where is testosterone produced? Q7: Describe the functions of seminal fluid and suggest why each function is important.

15 TOPIC 1. REPRODUCTIVE ORGANS, GAMETES AND FERTILISATION The female reproductive system Learning Objective At the end of this section, you should be able to: describe the development of ova in the ovaries; state the roles of the follicle and the corpus luteum; describe the possible fates of ova released from the ovary; describe the early development of the zygote after fertilisation. The following diagram shows the female reproductive system. The female reproductive system The ovaries are the female reproductive organs. They have two functions: 1. the production of ova. Each ovary contains on average 300,000 immature follicles at birth. This number is reduced at an accelerating rate towards the menopause when all ovulation ceases (often between the ages of 45-55). Therefore, in each ovary there are many follicles containing immature ova in various stages of development. The follicle both protects the developing ovum and secretes hormones Once a female begins ovulating (at puberty), an ovum matures inside a follicle approximately every 28 days. The ovum is released from the ovary when the follicle ruptures at the surface of the ovary (ovulation). After ovulation, the ovum passes into the oviduct where it may be fertilised. The follicle then develops into a corpus luteum (literally 'yellow body') which also secretes hormones. If fertilisation does not take place, the corpus luteum degenerates after about 14 days and ceases to release progesterone; if an egg is fertilised, the corpus luteum enlarges and continues to secrete progesterone until that function is taken over by the placenta. 2. the production of the female hormones oestrogen (from the follicle) and progesterone (from the corpus luteum). Further discussion of the production, functions and feedback control of these hormones is found in the next section.

16 8 TOPIC 1. REPRODUCTIVE ORGANS, GAMETES AND FERTILISATION Maturation of an ovum: Steps 5 min The following shows the stages in the maturation of an ovum inside its follicle, ovulation, and the development of the follicle into a corpus luteum. If the ovum is not fertilised, the corpus luteum degenerates. 1. In response to increasing levels of FSH, a dormant 'primordial' follicle begins to grow. 2. The follicles matures. 3. At the point of maturation it is known as a Graafian follicle. 4. The Graafian follicle bursts, releasing the ovum from the ovary. This is ovulation. 5. The Graafian follicle develops under the influence of LH into the corpus luteum. 6. If the ovum is not fertilised, the corpus lutem degenerates. 7. In a few days, another follicle will begin to mature and the cycle will start again.

17 TOPIC 1. REPRODUCTIVE ORGANS, GAMETES AND FERTILISATION 9 The female reproductive system: Questions Q8: Complete the diagram using the labels provided. Q9: Match the developments at each of the steps labelled on the diagram to the following descriptions: The Graafian follicle bursts, releasing the ovum from the ovary. This is ovulation. If the ovum is not fertilised, the corpus lutem degenerates. The follicles matures. The Graafian follicle develops under the influence of LH into the corpus luteum. At the point of maturation it is known as a Graafian follicle. In response to increasing levels of FSH, a dormant 'primordial' follicle begins to grow.

18 10 TOPIC 1. REPRODUCTIVE ORGANS, GAMETES AND FERTILISATION After ovulation Once in the oviduct, the ovum is carried down towards the uterus. On this journey it may fuse with a sperm (fertilisation) to form a zygote. This cell divides repeatedly to form the ball of cells known as a blastocyst which will eventually implant itself in the endometrium of the uterus. If the egg is not fertilised by the time it reaches the uterus, it ceases to be receptive to sperm and passes out of the body. During the fertilisation process, only the mitochondria of the sperm do not pass into the ovum; it is the fusion of the sperm nucleus with the ovum nucleus that is technically the moment of fertilisation. Thus, while the inherited information in the nucleus of the zygote is an equal mixture from the male and female parents, the structures in the cytoplasm are all derived from the female parent. In particular, the mitochondria, with their own DNA, come only from the mother. Mitochondrial DNA is always passed down through the female line and is not subject to any of the gene mixing processes of meiosis. Mutations to its genes take place at a slow rate (approximately one every 3,500 years). These have allowed the analysis of the evolutionary relationships between different groups of humans. In the same way, and for the same reasons, the DNA of the Y-chromosome has been used to study such relationships based on inheritance through the male parent. After ovulation: Questions Q10: Suggest an explanation for the fact that the dry mass of the blastocyst when it implants is less than the dry mass of the zygote. Q11: Explain why meiosis does not cause exchange of alleles in: a) mitochondrial DNA; b) Y-chromosome DNA.

19 TOPIC 1. REPRODUCTIVE ORGANS, GAMETES AND FERTILISATION Learning points Summary Sex cells called gametes. Gametes are produced from germline cells. Germline cells first divide by mitosis. Gametes are later produced by meiosis in the testis or ovary. Sperm are produced in the seminiferous tubules of the testis. Testosterone is released from the interstitial cells of the testis. The prostate gland and the seminal vesicles secrete fluids collectively called seminal fluid. Seminal fluids maintains the mobility and viability of the sperm. The ovaries contain many immature ova in various stages of development. The ova are contained within follicles. The follicles protect the ovum and secrete hormones. The release of an ovum from the ovary is called ovulation. From puberty to the menopause, ovulation takes place every 28 days on average. At ovulation, the ovum is released into the oviduct. After ovulation, the follicle develops into the corpus luteum. The corpus luteum secretes hormones. After ovulation, the ovum travels down the oviduct where it may be fertilised to form a zygote. Fertilisation takes place when a single sperm fuses with an ovum and its nuclear material joins with that of the ovum. The zygote undergoes a series of divisions as it passes down the oviduct into the uterus as a blastocyst.

20 12 TOPIC 1. REPRODUCTIVE ORGANS, GAMETES AND FERTILISATION 1.5 Extended response question The activity which follows presents an extended response question similar to the style that you will encounter in the examination. You should have a good understanding of the development of ova before attempting the question. You should give your completed answer to your teacher or tutor for marking, or try to mark it yourself using the suggested marking scheme. Extended response question: Development of ova 15 min Describe: A) the development of ova in the ovary; (6 marks) B) and their possible fates after ovulation. (2 marks) 1.6 End of topic test End of Topic 1 test Q12: Complete the paragraph using the words from the list. (12 marks) Gametes are produced from cells which are found in the testes and ovaries. These cells divide first by and then by meiosis. Sperm are produced in the tubules of the testes and ova within the in the ovaries. Seminal fluid contains secretions from the gland and the vesicles which maintain the motility and of the sperm. Hormones are released from the cells, the follicles and the corpus. takes place approximately every 28 days, releasing an ovum into the oviduct. Fertilisation takes place in the, forming a zygote which then undergoes a series of divisions to form the. Word list: blastocyst, follicles, germline, interstitial, luteum, mitosis, oviduct, ovulation, prostrate, seminal, seminiferous, viability. Q13: Complete the table showing the differences between germline and somatic cells in relation to how they divide and the types of cell into which they can develop. (4 marks) Cell type Difference Germline Somatic Division Develop into Word list: all other cells of the body, gametes, mitosis, mitosis and meiosis.

21 TOPIC 1. REPRODUCTIVE ORGANS, GAMETES AND FERTILISATION 13 The following diagram shows a section through part of a testis. Q14: Which cells on the diagram have been produced by mitosis? (1 mark) Q15: Name the cells labelled A. (1 mark) Q16: State the function of the cells labelled A. (1 mark) The following diagram shows an ovary in cross-section, labelled to identify significant stages in the development of an ovum. Q17: State what is taking place at stages X, Y and Z. (3 marks) Q18: Name structure W. (1 mark)

22 14 TOPIC 1. REPRODUCTIVE ORGANS, GAMETES AND FERTILISATION Q19: State the function of structure W. (1 mark) Q20: State two possible fates of the ovum once it is in the oviduct. (2 marks) Q21: How is a blastocyst formed? (1 mark) Q22: What does a blastocyst do? (1 mark) In fertility clinics, men provide samples of seminal fluid which are tested in various ways. The following table shows the analysis of such samples taken from five men. Man Number of sperm in sample (millions/cm 3 ) Active sperm (%) Abnormal sperm (%) A man is fertile if his seminal fluid contains at least 20 million sperm/cm 3, at least 60% of the sperm are active, and at least 60% of the sperm cells are normal. Q23: Express the lowest number of sperm in a sample as a percentage of the largest. (1 mark) Q24: Express the Active Sperm (%) of man 1 and man 4 as a simple whole number ratio. (1 mark) Q25: How would the clinic ensure that the results for each man were reliable? (1 mark) Q26: Which of the men produced samples containing sufficient sperm to be classed as fertile? (1 mark) Q27: Which men would be classed as infertile on the basis of the whole analysis? (1 mark)

23 15 Topic 2 Hormonal control of reproduction Contents 2.1 Introduction Onset of puberty Control of sperm production Control of the menstrual cycle The menstrual cycle The follicular phase The luteal phase Learning points Extended response question End of topic test Learning Objectives By the end of this topic, you should be able to: explain how hormones cause the onset of puberty; describe the influence of the pituitary hormones (follicle stimulating hormone and luteinising hormone/interstitial cell stimulating hormone) on the testes and the ovaries; describe the influence of testosterone on the testes and the negative feedback control of its production; describe the influence of the ovarian hormones (oestrogen and progesterone) on the uterus and the pituitary gland; explain the changes which take place during the menstrual cycle and the control of these changes through the interaction of various hormones.

24 16 TOPIC 2. HORMONAL CONTROL OF REPRODUCTION 2.1 Introduction Communication between cells in the body is carried out by the production of particular chemicals which act as signals. This communication may be between cells that are: touching, as in the developing embryo; separated by a very small gap, e.g. the synaptic cleft between nerve cells; widely separated, e.g. the adrenal glands on the kidneys and the muscles controlling the opening of the pupil in the eye. The control of reproduction belongs to this third category, in which the signal chemicals are hormones. These chemicals are released into the blood and detected by their target cells through receptors on, or inside, the cell membrane. Hormones control both the initiation of the production of gametes at puberty and their continued production throughout the fertile life of the individual. The production of sperm and eggs are both regulated by a system of negative feedback control, in which the production of a hormone by one organ, or gland, is linked with the production of a second hormone by an another organ. For example, the production of testosterone by the interstitial cells of the testis is stimulated by LH/ICSH released from the pituitary. As the concentration of testosterone in the blood rises, the pituitary reduces its production of ICSH, so the level of testosterone will be reduced in response. By this process, the concentration of testosterone in the blood will be maintained within a narrow range. The same pituitary hormones are involved in both the male and the female, and, in general terms, their effects are similar as well. Thus, FSH (follicle stimulating hormone) stimulates the germline cells to produce gametes and LH/ICSH stimulates the release of hormones from the ovary and testis. The roles of these hormones are examined in more detail in the following sections. 2.2 Onset of puberty Learning Objective By the end of this section, you should be able to: state that the hypothalamus triggers the onset of puberty by passing a releaser hormone to the pituitary gland; describe how the pituitary responds to this releaser hormone by, in turn, releasing follicle stimulating hormone (FSH) and luteinising hormone/interstitial cell stimulating hormone (FSH/ICSH); describe how FSH and LH control the production of gametes throughout the reproductive life of the individual; state that FSH and LH production form part of a negative feedback cycle.

25 TOPIC 2. HORMONAL CONTROL OF REPRODUCTION 17 Puberty is the sequence of physical changes by which the human body develops from that of a child into that of an adult capable of reproduction. The process is initiated by a releaser hormone that is secreted by the hypothalamus, which is a part of the base of the brain. It is located centrally and adjacent to the pituitary gland. Quite what triggers this secretion is still uncertain. The releaser hormone stimulates the pituitary gland to secrete FSH and LH. FSH initiates gamete production by means of the development of follicles in the ovaries, and sperm production in the seminiferous tubules. FSH and LH act together to stimulate the production of oestrogen from the ovarian follicles, although LH prompts the corpus luteum to release progesterone after ovulation. LH in the male stimulates the release of testosterone from the interstitial cells of the testis. It is the oestrogen and testosterone which, when detected by the receptors on the cells of their target organs, trigger the physical and psychological changes that are typical of puberty. These changes principally involve the growth and transformation of bones, muscle, skin, hair, breasts, sexual organs and brain, leading to the development of the secondary sexual characteristics that are typical of men and women. Once gamete production has become established, the various controlling hormones interact in negative feedback cycles, ensuring constant sperm production in the male and regular ovulation in the female. Details of these interactions are given in the following sections. Onset of puberty: Question Q1: Complete the sentences by matching the parts on the left with the parts on the right. 10 min Hypothalamus Pituitary gland FSH acts on the ovaries FSH acts on the testes Follicles release oestrogen After ovulation The corpus luteum LH causes the release of progesterone. releases progesterone. produces releaser hormone. secretes FSH and LH. follicles develop. causing release of testosterone. seminiferous tubules start to produce sperm. LH acts on the interstitial cells under the influence of FSH and LH.

26 18 TOPIC 2. HORMONAL CONTROL OF REPRODUCTION 2.3 Control of sperm production Learning Objective By the end of this section, you should be able to: state that FSH stimulates the cells lining the seminiferous tubules to produce sperm; state that LH stimulates the interstitial cells to release testosterone; state that testosterone stimulates the production of sperm by the seminiferous tubules; state that testosterone activates the prostate gland and the seminal vesicles; describe how high levels of testosterone levels inhibit the production and release of FSH and LH; explain why this is an example of negative feedback control. Sperm production is controlled by the pituitary gland directly, as a result of the secretion of FSH, and indirectly, through the secretion of LH/ICSH. FSH stimulates the cells lining the seminiferous tubules to divide to produce sperm, and LH causes the interstitial cells between the tubules to release testosterone, which then plays a major role in promoting sperm production. High levels of testosterone inhibit the production of both FSH and LH by the pituitary gland. Decreased concentrations of LH lead to a decrease in the secretion of testosterone and, therefore, reduced concentrations reaching the pituitary which increases its production of FSH and LH as a result. The production of testosterone is an example of negative feedback control. Regulation of male hormones As well as promoting the production of sperm, testosterone also activates the prostate gland and the seminal vesicles which produce their secretions that contribute to seminal fluid.

27 TOPIC 2. HORMONAL CONTROL OF REPRODUCTION Control of the menstrual cycle The three sections here describe the menstrual cycle, generally, followed by detailed descriptions of the early follicular phase and the later luteal phase The menstrual cycle Learning Objective By the end of this section, you should be able to: state that the first day of menstruation marks the start of the menstrual cycle; state that a menstrual cycle lasts 28 days on average; describe the part of the menstrual cycle up to the point of ovulation, which is known as the follicular phase; describe the part of the menstrual cycle after ovulation, which is known as the luteal phase. All female mammals have fundamentally the same reproductive system that includes the pituitary gland, which secretes FSH and LH, and ovaries, which release oestrogen and progesterone. There are, of course, significant variations in the manner in which they function, the most basic being timing and frequency of ovulation. Most mammals show an oestrous cycle, ovulating and being sexually receptive only at one time of year which is known as the mating season. Such cycles are timed to ensure that the young are produced when they will have maximum chance of survival, often many months after mating. These species are only sexually active around the time of ovulation and the endometrium is reabsorbed if fertilisation does not take place. Humans (and some other higher primates) show a menstrual cycle in which ovulation takes place at regular intervals; the female may be sexually active at any time during the cycle and the endometrium is shed (menstruation) if fertilisation does not take place. The menstrual cycle in humans lasts approximately 28 days with the first day of menstruation being counted as day 1. Menstruation usually lasts about four days (but anything from 2-7 days is considered normal) and ovulation typically occurs at day 14. The first part of the cycle, from menstruation to ovulation, is known as the follicular phase; the second part, from ovulation to the start of menstruation, is the luteal phase. In the following diagram, the changes taking place during the menstrual cycle are summarised and shown together so that the inter-relationship between the various processes can be more easily appreciated. It is important to remember that this picture is artificial to an extent, in that each cycle does not take place in isolation; therefore, events at the start of the cycle are strongly influenced by what was happening at the end of the previous cycle.

28 20 TOPIC 2. HORMONAL CONTROL OF REPRODUCTION The menstrual cycle: Questions Summary of the menstrual cycle Q2: Suggest some environmental conditions which would maximise the chance of a young mammal, such as a roe deer, surviving its first year. Q3: Suggest why humans do not have a specific breeding season.

29 TOPIC 2. HORMONAL CONTROL OF REPRODUCTION The follicular phase Learning Objective By the end of this section, you should be able to: describe the release of relatively high levels of FSH by the pituitary in the first few days of the menstrual cycle; state that FSH stimulates the development of follicles in the ovary; state that FSH stimulates the release of oestrogen by the follicle; explain that oestrogen stimulates the proliferation of the endometrium in preparation for implantation; state that the high oestrogen levels around the time of ovulation cause the production of cervical mucus, which is more watery so more easily penetrated by sperm; explain that the high oestrogen levels of the late follicular phase causes the pituitary to release a surge of LH into the blood; state that the high level of LH around day 14 triggers ovulation. In the first few days of the menstrual cycle, the influence of the previous cycle is clearly seen. Oestrogen and progesterone levels are low and, as a result of negative feedback control, the pituitary is a releasing a high level of FSH. This prompts the development of a follicle in the ovary; as it grows, it releases increasing quantities of oestrogen, which depress the release of FSH by the pituitary. Oestrogen has other target organs. The endometrium of the uterus proliferates, becoming much thicker and vascularised with a dense system of blood vessels. These changes adapt it to supporting the blastocyst if fertilisation occurs. In addition, the cervix alters the viscosity of its mucus lining, making it more watery and so easier for sperm to swim through. As the concentration of oestrogen in the blood rises, it eventually reaches a critical level at which the pituitary responds by releasing a surge of LH. This sudden increase in LH concentration causes the follicle, which has moved to the surface of the ovary, to rupture and release the ovum into the oviduct. This marks the end of the follicular phase of the menstrual cycle.

30 22 TOPIC 2. HORMONAL CONTROL OF REPRODUCTION The follicular phase: Questions 20 min Q4: Complete the sentences by matching the phrases on the left with the phrases on the right. Low oestrogen and progesterone levels High level of FSH causes Developing follicle releases oestrogen Oestrogen acts on the endometrium increasing oestrogen levels suppress FSH release. under the influence of oestrogen. causing proliferation. development of follicle. Follicles release oestrogen pituitary releases high level of FSH. Q5: Place the following into the correct order of development: pituitary releases surge of LH; oestrogen reaches critical level; oestrogen level rises; follicle releases egg into oviduct; LH acts on mature follicle.

31 TOPIC 2. HORMONAL CONTROL OF REPRODUCTION The luteal phase Learning Objective By the end of this section, you should be able to: state that after ovulation, the high level of LH causes the follicle to develop into the corpus luteum; state that the corpus luteum secretes progesterone and oestrogen; state that progesterone causes further development and vascularisation of the endometrium; explain how this provides an optimum environment for the implantation and growth of the blastocyst; state that during this phase, the secretion of oestrogen and progesterone rise to a maximum and then decline; state that FSH and LH production form part of negative feedback cycle with oestrogen and progesterone; describe how the high levels of oestrogen and progesterone inhibit the pituitary from secreting FSH and LH; state that these low levels of FSH and LH suppress the development of further follicles; explain that the low level of LH causes the corpus luteum to degenerate and progesterone secretion to fall to a minimum; state that the falling level of progesterone at the end of the cycle triggers the start of menstruation; state that the low level of oestrogen at the end of the cycle causes the pituitary to increase secretion of FSH; explain that if fertilisation occurs, a hormone from the implanted embryo causes the corpus luteum to continue producing progesterone for another eight weeks until this function is taken over by the placenta. After ovulation, under the influence of the high level of LH, the follicle develops into the corpus luteum, which then grows and becomes a dense yellow structure up to 5cm in diameter. As it develops, it releases increasing quantities of both progesterone and oestrogen, reaching peak production about halfway through the luteal phase. The progesterone causes the continued development of the endometrium in anticipation of the implantation of a blastocyst, causing the pituitary to gradually release less LH. The oestrogen suppresses the production of FSH by the pituitary so preventing the premature development of further follicles. In the absence of high levels of LH, in the final days of the cycle the corpus luteum begins to degenerate and progesterone production falls. As a consequence, the endometrium is no longer maintained and sloughs off to be lost as the menstrual flow. In the same

32 24 TOPIC 2. HORMONAL CONTROL OF REPRODUCTION way, the low level of oestrogen stimulates the pituitary to increase its secretion of FSH, thus starting the cycle again. If the ovum is fertilised, it develops into the blastocyst as it is carried down the oviduct. About nine days after fertilisation, the blastocyst implants in the endometrium and begins to secrete a hormone which causes the corpus luteum to continue to release progesterone until this function is assumed by the placenta some two months later. The luteal phase: Questions 20 min Q6: Use the statements to complete the diagram showing the events in the order in which they occur after ovulation: progesterone suppresses release of LH by pituitary; follicle becomes corpus luteum; corpus luteum releases progesterone; lack of FSH means no follicles develop; progesterone stimulates continued development of endometrium; oestrogen suppresses release of FSH. Q7: Select the correct organ response to each of the hormone changes described. Hormone changes Low level of LH secreted by pituitary: Progesterone production falls: Low level of oestrogen in blood: Organ responses Organ responses: endometrium breaks down; pituitary increases secretion of FSH; corpus luteum degenerates.

33 TOPIC 2. HORMONAL CONTROL OF REPRODUCTION Learning points Summary Onset of puberty The hypothalamus triggers the onset of puberty by passing a releaser hormone to the pituitary gland. The pituitary responds to this releaser hormone by, in turn, releasing follicle stimulating hormone (FSH) and luteinising hormone / interstitial cell stimulating hormone (LH/ICSH). FSH and LH control the production of gametes throughout the reproductive life of the individual. FSH and LH production form part of a negative feedback cycle. Control of sperm production FSH stimulates the cells lining the seminiferous tubules to produce sperm. LH stimulates the interstitial cells to release testosterone. Testosterone stimulates the production of sperm by the seminiferous tubules. Testosterone activates the prostate gland and the seminal vesicles. High levels of testosterone inhibit the production and release of FSH and LH. This is an example of negative feedback control. Control of the menstrual cycle The first day of menstruation marks the start of the menstrual cycle. Aa menstrual cycle lasts 28 days on average. The part of the menstrual cycle up to the point of ovulation is called the follicular phase. The part of the menstrual cycle after ovulation is called the luteal phase. Follicular phase In the first few days of the cycle, the pituitary releases relatively high levels of FSH. FSH stimulates the development of follicles in the ovary. FSH stimulates the release of oestrogen by the follicle. Oestrogen stimulates the proliferation of the endomentrium in preparation for implantation.

34 26 TOPIC 2. HORMONAL CONTROL OF REPRODUCTION Summary Continued High oestrogen levels around the time of ovulation cause the production of cervical mucus, which is more watery and more easily penetrated by sperm. The high oestrogen levels of the late follicular phase cause the pituitary to release a surge of LH into the blood. The high level of LH around day 14 triggers ovulation. Luteal phase After ovulation, the high level of LH causes the follicle to develop into the corpus luteum. The corpus luteum secretes progesterone and oestrogen. Progesterone causes further development and vascularisation of the endometrium. This provides an optimum environment for the implantation and growth of the blastocyst. During this phase, the secretion of both oestrogen and progesterone rise to a maximum and then decline. FSH and LH production form part of negative feedback cycle with oestrogen and progesterone. The high levels of oestrogen and progesterone inhibit the pituitary from secreting FSH and LH. These low level of FSH suppresses the development of further follicles. The low level of LH causes the corpus luteum to degenerate and progesterone secretion to fall to a minimum. The falling level of progesterone at the end of the cycle triggers the start of menstruation. The low level of oestrogen at the end of the cycle causes the pituitary to increase secretion of FSH. If fertilisation occurs, a hormone from the implanted embryo causes the corpus luteum to continue producing progesterone for another eight weeks until this function is taken over by the placenta.

35 TOPIC 2. HORMONAL CONTROL OF REPRODUCTION Extended response question The activity which follows presents an extended response question similar to the style that you will encounter in the examination. You should have a good understanding of negative feedback control before attempting the question. You should give your completed answer to your teacher or tutor for marking, or try to mark it yourself using the suggested marking scheme. Extended response question: Negative feedback control Give an account of negative feedback control under the headings: A) testosterone production; (3 marks) 15 min B) the luteal phase of the menstrual cycle. (7 marks) 2.7 End of topic test End of Topic 2 test Q8: Complete the sentences by matching the parts on the left with the parts on the right. (10 marks) Hypothalamus: Pituitary: FSH and LH: Negative feedback cycle: FSH: LH/ICSH: Testosterone: Inhibit FSH and LH release: Follicular phase: Luteal phase: menstrual cycle up to ovulation. FSH and LH form part of it. stimulates the cells lining the seminiferous tubules. mestrual cycle after ovulation. high levels of testosterone production. controls the production of gametes. responds to the releaser hormone by releasing other hormones. a releaser hormone released from here triggers puberty. activates the prostate and seminal vesicles. stimulates the interstitial cell.

36 28 TOPIC 2. HORMONAL CONTROL OF REPRODUCTION Q9: Select the option which correctly completes each of the sentences. (10 marks) At the start of the menstrual cycle, the pituitary releases high levels of FSH / LH / oestrogen / progesterone. The hormone which stimulates the development of follicles FSH / LH / oestrogen / progesterone. Proliferation of the endometrium is stimulated by FSH / LH / oestrogen / progesterone. High levels stimulate the surge in the release of LH FSH / LH / oestrogen / progesterone. High levels stimulate the development of the corpus luteum FSH / LH / oestrogen / progesterone. Hormone which causes further vascularistation of the endometrium FSH / LH / oestrogen / progesterone. High levels oestrogen and testosterone inhibit the production FSH and LH / FSH and progestrogen / LH and progesterone. Degeneration of the corpus luteum is caused by low levels of FSH / LH / oestrogen / progesterone. Falling levels trigger the start of menstruation FSH / LH / oestrogen / progesterone. Stimulates the increased production of FSH by the pituitary FSH / LH / oestrogen / progesterone. Puberty marks the start of the fertile period of an individual's life. Q10: How is puberty initiated? (1 mark) Q11: The pituitary gland releases FSH and LH during puberty. Complete the following table to show their first effects in the male and the female. (4 marks) Hormone Effect on male Effect on female FSH LH Phrase list: Follicles release oestrogen; Follicles start to mature in the ovary and release oestrogen; Interstitial cells start to release testosterone; Seminiferous tubules start to produce sperm.

37 TOPIC 2. HORMONAL CONTROL OF REPRODUCTION 29 The diagram represents gamete production in an ovary. Q12: Identify structure B. (1 mark) Q13: Identify structure C. (1 mark) Q14: Name the hormone released by structure B. (1 mark) Q15: State its effect on the pituitary gland. (2 marks) Q16: Describe what happens to structure B after C has been released from it. (1 mark) Q17: During the luteal phase of the menstrual cycle, how is the development of immature follicles suppressed? (2 marks)

38 30 TOPIC 2. HORMONAL CONTROL OF REPRODUCTION The diagram represents a section of part of a testis. Q18: Name the cells labelled D. (1 mark) Q19: Name the structure which contains cells E. (1 mark) Q20: Which cells in the diagram release a hormone? (1 mark) Q21: What is the hormone that is released called? (1 mark) Q22: Explain how the level of this hormone in the blood is controlled. (3 marks)

39 TOPIC 2. HORMONAL CONTROL OF REPRODUCTION 31 The graphs below show the changes in concentration of four hormones in a woman s blood during one menstrual cycle. Q23: Complete the table of hormones A-D. Some of the words may be used more than once. (4 marks) Hormone Name Produced A B C D Word list: Corpus luteum, Follicle, Follicle stimulating hormone, Luteinising hormone, Oestrogen, Pituitary, Progesterone. Q24: On which day would ovulation have taken place? (1 mark) Q25: What causes ovulation? (1 mark)

40 32 TOPIC 2. HORMONAL CONTROL OF REPRODUCTION Q26: Describe and explain the change in concentration of hormone C during the first 12 days of the cycle. (4 marks) Q27: What is the effect of the high level of hormone A between days 18 to 26? (1 mark) Q28: In what way does hormone B contribute to the survival of the blastocyst? (1 mark) Q29: Explain the changes in the concentration of hormone B during the cycle. (3 marks)

41 33 Topic 3 The biology of controlling fertility Contents 3.1 Introduction Fertile periods Treatments for infertility Causes of infertility Artificial insemination (AI) Stimulating ovulation In vitro fertilisation (IVF) Intracytoplasmic sperm injection (ICSI) Contraception Calendar-based methods Barrier methods Intra-uterine devices (IUDs) Sterilisation procedures Chemical contraceptives Learning points Extended response question End of topic test Learning Objectives By the end of this topic, you should be able to: explain the reasons for infertility treatments and contraception; contrast the fertile period of males and females; describe and explain the various treatments for infertility; explain the basis of the different methods of contraception.

42 34 TOPIC 3. THE BIOLOGY OF CONTROLLING FERTILITY 3.1 Introduction Human fertility is a complex subject, attitudes to which vary immensely between different cultures. The perspective of this course is very much that of contemporary 'Western' society where the standard of living for the majority of the population is high, birth rates are low, and infertility is seen as a more important problem than fertility. In less affluent countries where infant mortality is high, advanced medical provision is rarely available, and children represent a much needed addition to the workforce, priorities and practice are very different. It is also important to remember that many of the world's, and humanity's, problems stem from the fact that the human population is growing at such a pace that the resources of the Earth are being exploited as never before. Whether it be the deforestation of the Amazon basin to provide additional farmland, the diversion of major rivers to supply industry, cities and agriculture with water, or the depletion of the fish stocks of all of the oceans, the ultimate driver of these changes is the burgeoning number of human beings. In this topic we will look at the various causes of infertility in men and women, and the ways in which it can be addressed. These techniques provide the possibility of having a child of their own to potential parents, one, or both, of whom are unable to produce sufficient gametes of a quality or quantity necessary for effective fertilisation by normal sexual intercourse. Contraception in our society is seen as an artificial means of preventing a pregnancy, but it should be remembered that natural methods, such as extended suckling to suppress ovulation, have probably been used for thousands of years. 3.2 Fertile periods Learning Objective By the end of this section, you should be able to: Men describe continuous and cyclical fertility; explain why men are continuously fertile; explain why women are cyclically fertile; describe how a woman's cyclical fertility may be used as a contraceptive measure; describe how a woman's cyclical fertility may be used to increase the chances of conception. Men are potentially capable of fathering a child from puberty until they die, although sperm production does decrease with age. Under the influence of the negative feedback between testosterone and ICSH/LH, males produce sperm constantly and so are continuously fertile.

43 TOPIC 3. THE BIOLOGY OF CONTROLLING FERTILITY 35 Women Women only release eggs from puberty until the menopause at age However, as there is only a window of a few days either side of ovulation during which intercourse can result in pregnancy, there is only a brief interval during each menstrual cycle when a female is capable of conception. The regular recurrence of this fertile period means that such fertility is cyclical. The fact that a woman can only conceive for a few days during each cycle can be used to reduce the chance that intercourse will lead to pregnancy. This is often loosely referred to as 'the rhythm method' of contraception; in fact, there are several calendar-based contraceptive methods, some being more reliable than others. A woman's fertile period is determined by noting changes in the consistency of the cervical mucus and her body temperature. Just before ovulation occurs, the cervical mucus becomes thin and watery while body temperature rises slightly (by about 0.5 C). By tracking these changes over the course of several cycles, a woman can predict fairly accurately when she is going to ovulate. Therefore, a couple who do not wish to have a child will not have sexual intercourse during the few days before and after the fertile period. This method is not very reliable if a woman's cycle varies in length from month to month. However, for many people, this is the contraceptive method of choice for either personal or religious reasons. A couple who want the woman to become pregnant would use this method to work out when the woman was fertile and would have intercourse during this period while the chance of fertilisation is at its greatest. Fertile periods: Questions Q1: Use your knowledge from the previous topic to explain the link between ICSH levels and sperm production. Q2: Suggest what triggers the changes to cervical mucus and body temperature. Q3: Suggest some reasons why all calendar-based contraceptive methods have a significant failure rate (at least a 4% chance of pregnancy).

44 36 TOPIC 3. THE BIOLOGY OF CONTROLLING FERTILITY 3.3 Treatments for infertility This introduction gives a summary of the biology of infertility, which will help you understand why the techniques that follow are necessary. This material is not examinable Causes of infertility Learning Objective By the end of this section, you should be able to: state some of the effects on fertility with relation to: age; genetics; disease; lifestyle. Fertility problems affect about one in seven couples in the UK. The cause of this inability to conceive may lie with the male or the female partner, and there are many causes. Men The WHO (World Health Organisation) considers a sperm count (strictly 'sperm concentration') below 15 million per ml to be significantly low (the average being around 60 million per ml). The motility and health of sperm are other factors: do the sperm swim well enough to make good forward movement and do many sperm have an abnormal morphology, such as small or large heads, double heads, or a double tail? Other inherited and environmental factors must also be considered: age - although they usually remain fertile from puberty onwards, men's fertility does gradually decline with age; genetics - including Y chromosome microdeletions, where one or more genes are missing from the Y chromosome, and Klinefelter's syndrome, where nondisjunction in the formation of the egg has resulted in a zygote (and hence a man) with XXY sex chromosomes; disease - mumps is a viral disease that is typically contracted during childhood although when suffered by adult males it can infect the testes and lead to a reduction in size with possible sterility. Sexually transmitted infections, such as chlamydia or gonorrhoea (caused by bacteria), can result in sterility or testicular cancer if left untreated; where the treatment involves the removal of a testis then the associated chemo- or radiotherapy may lead to reduced or complete infertility; lifestyle - smoking tobacco, stress, obesity, drug and alcohol abuse and medications (e.g. anabolic steroids) all significantly reduce fertility.

45 TOPIC 3. THE BIOLOGY OF CONTROLLING FERTILITY 37 Women Infertility in women is generally the result of an interaction of inherited and environmental factors: age - a woman's age is a major determining factor, with a peak in fertility during the early to mid-twenties and an accelerating decline after 35, with cessation of ovulation usually between 45 and 55 at the menopause; genetics - chromosomal abnormalities, such as Turner syndrome (in which one of the X chromosomes is missing or abnormal in some way), and a whole host of genetic mutations may cause a woman to be unable to produce viable ova; disease - as with men, sexually transmitted infections, e.g. gonorrhoea, can result in infertility by causing inflammation and scarring of the Fallopian tubes. Chronic kidney or liver diseases may also cause infertility. Eating disorders, causing a woman to be either under- or over-weight, both tend to disrupt the menstrual cycle by affecting oestrogen production; lifestyle - smoking tobacco reduces the body's ability to produce oestrogen, affecting the development of follicles and also causing the earlier onset of the menopause. Cannabis likewise interferes with fertility by reducing the chances of implantation of the blastocyst. Repeated courses of chemotherapy pose a high risk of infertility. Causes of infertility: Question Q4: Although this material will not be tested in the SQA exam, to help ensure that you have understood the biological basis of infertility, create a table in which you give examples of the factors which can affect the fertility of men and women, under the headings of age, genetics, disease and lifestyle Artificial insemination (AI) Learning Objective By the end of this section, you should be able to: describe what is involved in the process of AI; describe the situations in which AI is appropriate. Artificial insemination, where semen is injected by syringe into the vagina or by catheter (a thin flexible tube) into the uterus, has been widely used in the livestock industry for many years. The procedures were adapted for use in humans where there are problems of a physical or psychological nature which prevent a man from fertilising an ovum by sexual intercourse. In particular, it is useful where the sperm count (concentration) is too low. Sperm samples are usually obtained by masturbation and may be used directly or stored. In the case of low sperm count, repeated samples are collected over a period of days, 'washed' and concentrated by separating them from the bulk of the seminal fluid

46 38 TOPIC 3. THE BIOLOGY OF CONTROLLING FERTILITY (e.g. by centrifugation), and then frozen after being mixed with a chemical to assist the freezing and thawing processes. In the case of the husband or partner being able to provide the sperm, the procedure is known as artificial insemination by the husband (AIH). If another sperm donor is used (e.g. if the husband is sterile), it is known as artificial insemination by a donor (AID). Artificial insemination: Question Q5: Suggest reasons why the use of AI is particularly prevalent in the livestock industry Stimulating ovulation Learning Objective By the end of this section, you should be able to: describe the situations in which ovulation may need to be stimulated; describe the action of drugs that may be used to increase FSH levels in the blood; describe the action of synthetic drugs that mimic the action of FSH and LH; state that these drugs may cause superovulation, providing several ova for IVF; state that superovulation may result in multiple pregnancies. There are two situations in which it is necessary to stimulate ovulation artificially: 1. if a woman is not ovulating or is ovulating irregularly, then the artificial stimulation of ovulation will increase the likelihood of sexual intercourse resulting in conception. Similarly, it makes conception more likely after intrauterine insemination, where sperm from the partner or donor is introduced artificially directly into the uterus; 2. if IVF is to be carried out, ovulation is artificially stimulated so that ova may be collected in order to be fertilised in a culture solution in the laboratory. Ovulation is under the control of the negative feedback loops involving FSH, LH and oestrogen. One way of stimulating ovulation is to block the oestrogen receptors so that secretion of FSH by the pituitary remains high, and the development of follicles continues to be stimulated. Alternatively, synthetic forms of FSH (and to a lesser extent LH) can be used to raise the concentrations of these hormones in the blood, stimulating the development of several follicles during a single menstrual cycle. This is known as superovulation, which is particularly valuable in making ova available for IVF. However, it is not desirable when the intention is to achieve fertilisation through sexual intercourse because the outcome is likely to be a multiple pregnancy, the survival rate in higher order multiple pregnancies being low.

47 TOPIC 3. THE BIOLOGY OF CONTROLLING FERTILITY 39 Stimulating ovulation: Question Q6: Explain why blocking oestrogen receptors, or artificially increasing FSH levels, will stimulate ovulation In vitro fertilisation (IVF) Learning Objective By the end of this section, you should be able to: describe the situations in which IVF is appropriate; describe the process of IVF; state the uses of pre-implantation genetic screening. When is IVF appropriate? The use of IVF is considered when a woman is infertile due to problems with the fallopian tubes, e.g. blockage, or where a man produces healthy sperm but in low numbers. In addition, IVF provides the opportunity to test embryos for a wide range of genetic diseases or chromosomal abnormalities before implantation. The process of IVF After the induction of superovulation, ova are retrieved using an ultrasound-guided needle which is passed through the vaginal wall to reach the ovary. Typically ova are removed and the procedure lasts about 20mins. To promote fertilisation, sperm and ova are incubated together in a culture medium for about 18 hours, with a ratio of about 75,000 sperm per ovum. The sperm are 'washed' and concentrated by centrifugation before being mixed with the ova. The zygotes are then incubated in special culture media until they have divided to form an embryo of 8 or 16 cells, which takes about three days. Some systems continue incubation for another two days so that the blastocyst stage has been reached. The embryo is then transferred to the woman's uterus using a catheter, which is introduced through the vagina and cervix. In most cases, two embryos will be transferred in this way to increase the chance of implantation, but without risking the problems of a multiple pregnancy. Pre-implantation genetic screening Pre-implantation genetic screening (also known as pre-implantation genetic diagnosis - PGD) is used when there is a significant possibility of an embryo inheriting a genetic disorder caused by a single gene or a chromosome abnormality. Following an analysis of the family histories of the parents, the likelihood of such a disorder being present in the offspring can be estimated and, if the expectation is unacceptably high, PGD can be carried out. In the most common screening procedure, two cells are removed from the 8-cell stage of the embryo (at which point all cells are still totipotent, i.e. capable of developing into any cell type), their chromosomes are examined and their DNA analysed. Transfer to the

48 40 TOPIC 3. THE BIOLOGY OF CONTROLLING FERTILITY uterus is delayed until the fifth day, thereby allowing time for the analysis to be completed before the final choice of embryos is made. As well as chromosomal abnormalities, the list of genetic disorders which can be detected is considerable and includes: cystic fibrosis, sickle-cell disease, Huntingdon's disease and Duchenne muscular dystrophy. In vitro fertilisation: Question 10 min Q7: Re-arrange the following steps into the correct order in which they would occur in PGD: blastocyst at eighth day; harvesting of ova; woman given FSH injection; chromosomes and DNA analysed; sperm are washed; superovulation; two cells removed from embryo; embryo transferred into uterus; ova incubated with sperm; eight cell stage at 3 days Intracytoplasmic sperm injection (ICSI) Learning Objective By the end of this section, you should be able to: describe the process of ICSI; state when ICSI is appropriate. ICSI is a form of IVF which differs from the usual procedure in that a single sperm is injected into an ovum. Several ova are collected as a result of superovulation and mature sperm are selected from the donor sample by only using those which have adhered to a microdot that carries some of the chemical which surrounds an ovum. The procedure is normally carried out in a petri dish of culture medium using a microscope and various micromanipulation devices to stabilise the ovum and inject the sperm. A single sperm, which has been immobilised by removal of its tail, is drawn into a micropipette and introduced into a mature ovum. The ovum is then incubated and checked for fertilisation (i.e. the fusion of the nuclei of the sperm and the ovum). ICSI is particularly appropriate where the donor sperm are defective in some way, e.g. they have low motility (i.e. they are not very active) or the sperm count is low.

49 TOPIC 3. THE BIOLOGY OF CONTROLLING FERTILITY 41 Treatments for infertility: Question Q8: Use the phrases below to complete the following table which summarises information about treatments for infertility. 15 min Treatment Full name Appropriate for AI IVF ICSI PGD Phrase list: artificial insemination, blocked fallopian tubes, chromosome abnormality, conception not possible by sexual intercourse, inherited genetic disorder, intracytoplasmic sperm injection, in vitro fertilisation, low sperm count, low sperm motility, pre-implantation genetic diagnosis (some may be used more than once) 3.4 Contraception Learning Objective By the end of this section, you should be able to: explain the principle of calendar-based methods; describe how barrier methods work; explain the how IUDs work; describe sterilisation procedures in men and women; describe the action of the various types of oral contraceptives. Contraception is the prevention of fertilisation and may be achieved by natural or artificial means. Natural methods include extended suckling of infants and calendar-based methods (e.g. 'the rhythm method'). Artificial methods are many, ranging from simple barriers, such as the condom, to the complex control of hormonal interactions by the various contraceptive pills Calendar-based methods The fact that a woman can only conceive for a few days during each cycle can be used to reduce the chance that intercourse will lead to pregnancy. This is often loosely referred to as 'the rhythm method' of contraception; in fact there are several calendar-based contraceptive methods, some being more reliable than others. A woman's fertile period is determined by noting changes in the consistency of the cervical mucus and body temperature. Just before ovulation occurs, the cervical mucus becomes thin and watery

50 42 TOPIC 3. THE BIOLOGY OF CONTROLLING FERTILITY while body temperature rises slightly (by about 0.5 C). By tracking these changes over several cycles, a woman can predict fairly accurately when she is going to ovulate. Therefore, a couple who do not wish to have a child will not have sexual intercourse during the few days before and after the fertile period. This method is not very reliable if a woman's cycle varies in length from month to month. However, for many people, this is the contraceptive method of choice for personal or religious reasons. Calendar-based methods: Question Q9: When would a woman be expected to ovulate (on average) and why is it necessary to abstain from intercourse for days before and after ovulation to minimise the chance of conception? Barrier methods Barrier methods prevent sperm entering the uterus. This may be achieved by means of a male condom placed over the penis or a female condom, cap or diaphragm, all of which prevent sperm reaching the cervix. These methods are made more effective by being used in conjunction with spermicidal jellies. It is a controversial point that the condom is the only form of contraception currently available for use by men. It is also the only form of contraception which also gives a measure of protection against the transfer of sexually transmitted infections Intra-uterine devices (IUDs) IUDs are flexible plastic structures (often T-shaped) which are placed within the uterus. One form contains copper and works by reducing the motility of sperm, stopping their progress towards the ovum. It is also possible that the presence of the IUD in the uterus irritates the endometrium, thus preventing implantation. A side effect is the increased loss of blood at menstruation. The second type of IUD releases a low dose of progesterone, which works more like the contraceptive pills Sterilisation procedures Sterilisation is any medical technique which renders a person unable to reproduce, the most common methods involving the cutting and closing tubes. In women the tubes are the two fallopian tubes down which ova travel from the ovaries to reach the uterus and in which fertilisation must take place. In men the tube is the vas deferens in each testis, which carries sperm from the testis to combine with the secretions of the prostate gland and seminal vesicles to form the semen. The operation for women is called 'tubal ligation' and the operation for men is a 'vasectomy'. In both cases the operation is effectively irreversible.

51 TOPIC 3. THE BIOLOGY OF CONTROLLING FERTILITY Chemical contraceptives Chemical contraceptives are currently only available for use by women. They are usually taken orally as a daily pill. These pills are of various formulations, but all contain synthetic forms of oestrogen and/or progesterone: the pill - the standard contraceptive pill contains a combination of synthetic forms of oestrogen and progesterone which must be matched to the woman's natural level of hormone release. The effect is to adjust the negative feedback mechanism involving FSH and LH which controls the menstrual cycle so that ovulation is suppressed but menstruation still takes place; mini-pill - these contain synthetic progesterone (hence 'progesterone-only pill'), which causes a thickening of the mucus on the cervix that prevents the passage of sperm into the uterus and hence fertilisation; morning-after pill - also known as emergency contraceptive pills (ECPs), these contain high levels of synthetic oestrogen and progesterone and are taken only after sexual intercourse has taken place. They work either by suppressing ovulation or by inhibiting implantation. Despite their popular name, they are effective for two or three days after intercourse, dependent on the formulation of the pill. Contraception: Question Q10: In this exercise you are to complete statements about different forms of contraception by choosing the correct options from the bracketed lists. Sterilisation is available to men / women / men and women and is reversible/irreversible. The mini-pill causes thickening of cervical mucus / failure of implantation/ failure of ovulation and contains oestrogen / progesterone / oestrogen and progesterone. Barrier methods kill sperm / stop ovulation / stop sperm reaching uterus and are available for men / women / men and women. The morning-after pill contains high levels of synthetic oestrogen / progesterone / oestrogen and progesterone and kills sperm / suppresses ovulation / prevents fertilisation. IUDs are placed in the uterus / fallopian tubes / vagina and prevent ovulation / fertilisation / menstruation. The rhythm method requires careful monitoring of temperature / cervical mucus / temperature and cervical mucus and can be totally reliable / used after intercourse / used without medical supervision. The pill contains synthetic oestrogen / progesterone / oestrogen and progesterone and is taken before intercourse / after intercourse / every day. 15 min

52 44 TOPIC 3. THE BIOLOGY OF CONTROLLING FERTILITY 3.5 Learning points Summary Fertile periods A fertile period is when a man is capable of fathering a child or when a woman is capable of conceiving. Men are continuously fertile from puberty to death. Women are cyclically fertile for a few days every month. A woman can calculate her monthly fertile period and use this as a means of contraception. Ovulation can be detected by a small rise in body temperature and change in cervical mucus. Treatments for infertility Causes of infertility Men and women can be made infertile by factors such as age, genetics, disease and lifestyle. Artificial insemination (AI) AI involves the artificial injection of sperm into the vagina or uterus. Several samples of semen are collected over a period of days. AI is particularly used where a man has a low sperm count. If the male partner is infertile, another sperm donor may be used. Stimulating ovulation Ovulation is stimulated if a woman is not ovulating or is ovulating irregularly. Superovulation may result in multiple births. Ovulation is also stimulated to cause superovulation so that several eggs may be collected for IVF. Ovulation is enhanced by stimulating the secretion of FSH or by blocking the oestrogen receptors in the pituitary. Ovulation may also be stimulated by increasing FSH and LH levels by supplementing them with synthetic mimics. In vitro fertilisation (IVF) IVF involves the surgical removal of eggs from the ovaries after superovulation. Ova are incubated in a culture medium along with a much larger number of sperm.

53 TOPIC 3. THE BIOLOGY OF CONTROLLING FERTILITY 45 Summary Continued Embryos are cultured until they reach the 8-16 cell stage before transfer to a uterus for implantation. Embryos at this stage may be tested using pre-implantation genetic screening. Pre-implantation genetic screening identifies genetic disorders and chromosome abnormalities. Intracytoplasmic sperm injection (ICSI) Contraception ICSI is a form of IVF in which a single sperm is injected into an ovum with a needle to achieve fertilisation. ICSI is used where a man has a low sperm count or defective sperm. Calendar-based methods (e.g. 'the rhythm method') are based on the identification of the woman's fertile period. Intercourse must be avoided for a few days before and after ovulation. Barrier methods (e.g. uterus. condom, diaphragm) prevent sperm entering the IUDs are placed in the uterus and reduce the motility of the sperm. Sterilisation involves cutting or closing the fallopian tubes of a woman. Sterilisation involves cutting and closing the vas deferens of each testis of a man. Chemical contraceptives contain synthetic versions of oestrogen and progesterone. The most common chemical contraceptive (the 'pill') contains oestrogen and progesterone. The pill manipulates the negative feedback control of the menstrual cycle to suppress ovulation by preventing the release of FSH and LH. Morning-after pills contain synthetic oestrogen and progesterone. Morning-after pills either suppress ovulation or prevent implantation. The mini-pill causes thickening of the cervical mucus, preventing sperm from reaching the ovum.

54 46 TOPIC 3. THE BIOLOGY OF CONTROLLING FERTILITY 3.6 Extended response question The activity which follows presents an extended response question similar to the style that you will encounter in the examination. You should have a good understanding of fertile periods for men and women before attempting the question. You should give your completed answer to your teacher or tutor for marking, or try to mark it yourself using the suggested marking scheme. Extended response question: Fertile periods 15 min Give an account of fertile periods under the headings: A) men; (4 marks) B) women. (6 marks) 3.7 End of topic test End of Topic 3 test Q11: Complete the sentences by matching the parts on the left with the parts on the right. (9 marks) A woman is capable of conceiving Men are continuously fertile Cyclically fertile means that women are fertile A change in a woman's cervical mucus occurs An example of a barrier method is A method of reducing the motility of sperm is The procedure that involves cutting the vas deferens is The morning after pill contains synthetic oestrogen and The mini-pill causes thickening of progesterone. during ovulation. from puberty to death. cervical mucous. during the fertile period. for a few days a month. the diaphragm. the intra-uterine device. sterilisation.

55 TOPIC 3. THE BIOLOGY OF CONTROLLING FERTILITY 47 Q12: Complete the paragraph using the words from the list. (11 marks) Men and women can both be made infertile by factors such as age, genetics, disease and. Artificial is particularly used when a man has a low sperm count. Ovulation is stimulated when a woman is ovulating. Super-ovulation may result in births. IVF uses as it provides several eggs that may be collected. Ovulation is enhanced by stimulating the secretion of or supplementing hormone levels with mimics. IVF involves removal of after super-ovulation. are transferred when they reach the 8-16 cell stage. Pre-implantation genetic identifies genetic disorders. ICSI differs from IVF in that a single is injected into an ovum. Word list: eggs, embryos, FSH, insemination, irregularly, lifestyle, multiple, screening, sperm, super-ovulation, synthetic. The diagram below represents the negative feedback control of hormone production by the testis in the male. Q13: What is tissue A? (1 mark) Q14: Which stimulating hormone is involved? (1 mark) Q15: Which inhibiting hormone is involved? (1 mark) Q16: Explain how this negative feedback control leads to continuous fertility in males. (3 marks) Q17: Why is the fertility of women described as cyclical? (1 mark)

56 48 TOPIC 3. THE BIOLOGY OF CONTROLLING FERTILITY Q18: State one form of infertility found in men and explain how it arises. (2 marks) Q19: State one form of infertility found in women and explain how it arises. (2 marks) Q20: What is superovulation? (1 mark) Q21: Describe one method of inducing superovulation. (2 marks) Q22: Under what circumstances would artificial insemination be an appropriate treatment for infertility? (1 mark) Q23: State one similarity and one difference between intracytoplasmic sperm injection and in vitro fertilisation. (2 marks) Q24: What is tested in pre-implantation genetic screening? (1 mark) Q25: When is the test carried out? (1 mark) Q26: What can the test identify? (1 mark) Q27: Under what circumstances is the test appropriate? (1 mark)

57 TOPIC 3. THE BIOLOGY OF CONTROLLING FERTILITY 49 The following diagram shows one menstrual cycle. Q28: On which day in the cycle would ovulation be expected to occur? (1 mark) Q29: State two changes to her body that a woman would notice at this time. (2 marks) Q30: Which days would be called the 'fertile period'? (1 mark) Q31: Give an account of the biological basis of the action of the different contraceptive pills. (5 marks)

58 50 TOPIC 3. THE BIOLOGY OF CONTROLLING FERTILITY

59 51 Topic 4 Antenatal and postnatal screening and care Contents 4.1 Introduction Antenatal care Antenatal screening Pre-implantation genetic diagnosis (PGD) Ultrasound imaging Biochemical tests Diagnostic testing Amniocentesis Chorionic villus sampling (CVS) The moral dimension Rhesus antibody testing Postnatal screening Learning points Extended response question End of topic test Learning Objectives By the end of this topic, you should be able to: describe some of the techniques used to monitor the health of a pregnant woman and the developing fetus; describe the background checks which can be made to determine the possibility of an inherited condition in the fetus; describe the tests for inherited conditions which are carried out during IVF treatment; describe routine tests which may be carried out on all pregnant mothers; describe scanning and diagnostic tests which can be carried out at different stages in pregnancy;

60 52 TOPIC 4. ANTENATAL AND POSTNATAL SCREENING AND CARE state the conditions which such tests can suggest or identify; describe the tests carried out after birth and the conditions which they may identify.

61 TOPIC 4. ANTENATAL AND POSTNATAL SCREENING AND CARE Introduction One of the most fascinating features of human development is not that things can go wrong, but that it almost always goes perfectly well despite being an incredibly complex process. With some 23,000 genes in the genome, the processes of mutation and meiosis will inevitably generate some changes to the DNA which controls the biochemistry of the body. Where these changes affect enzymes which form part of a metabolic pathway, the outcome may be very serious; on the other hand, the effect may be of little consequence, e.g. if only the colour of hair is altered. Some problems arise not from genetic change, but from a phenotypic difference between the embryo and the mother, e.g. in Rhesus blood type. Advances in Screening The last half-century has seen a revolution in our ability to detect and address these problems. From the Guthrie blood test, developed in the 1960s (and still used today to test for PKU), we have moved on to the screening of embryos in IVF, the various tests which can be carried out on the fetus, and the battery of analyses which can be used to check the newborn's blood and urine. Other techniques are applied without sampling any tissue from the embryo or fetus, such as ultrasound imaging and blood testing of the mother. These developments have been possible in part because of the advances in technology, e.g. ultrasound imaging and DNA analysis. Of equal importance have been the advances in our knowledge of the underlying biochemistry of the observed medical conditions so that we now understand the significance of particular chemicals appearing in the urine of the mother or the newborn. Advances in Treatment Of course, the identification of a condition is of limited value unless there is some treatment available to cure or ameliorate its effects. The type and success of our responses vary considerably depending on the condition. Here are three examples. 1. The effects of Rhesus incompatibility can in most cases be completely prevented by antenatal injections given to the mother which prevent the sensitisation of her immune system. This condition arises when the mother is Rhesus negative and the fetus Rhesus positive; red blood cells entering the mother's circulation as a result of mixing of the blood during delivery trigger the release of antibodies by the mother, which can cross back into the fetal blood circulation and cause the blood to clot. 2. Phenylketonuria (PKU) is caused by a recessive allele found on one of the autosomes. Thus, the condition occurs only when a child inherits this allele from both parents. If left untreated, it results in severely impaired brain development. Although it cannot be cured, by careful management of diet and suitable medication the effects of the disease can be completely controlled. 3. Huntingdon's Disease results from the dominant mutation of a single autosomal gene. It causes gradual degeneration of the brain, affecting first muscular coordination but leading to eventual dementia. In most cases, symptoms of the disease only become obvious between the ages of 35 and 55 years. There is no cure for the disease, but treatments are available to reduce the severity of the

62 54 TOPIC 4. ANTENATAL AND POSTNATAL SCREENING AND CARE symptoms and allow appropriate care to be given as the disease progresses. If there is a family history of the disease, a couple may opt for IVF treatment so that Pre-implantation Genetic Diagnosis may be carried out to ensure that the embryos chosen for implantation do not carry the mutated allele. 4.2 Antenatal care Learning Objective By the end of this section, you should be able to: state the routine initial tests that are carried out on pregnant woman; state the general purpose of each test. Once a woman has been confirmed as being pregnant, she will be routinely given a physical examination by a doctor and her medical history will be checked for any conditions which might complicate the pregnancy. The examination involves measuring her blood pressure, assessing her general health, and taking blood and urine samples. Height and weight measurements are used to calculate the Body Mass Index (BMI), which will indicate whether a woman is significantly over- or underweight. BMI is calculated as mass (kg) / height 2 (m). A value of BMI = 30 or more is classified as obese. Blood pressure is checked as described in a later topic. Readings of up to 140/90 are considered normal during pregnancy; higher readings indicate hypertension (one of the risk factors for stroke and heart failure) and possible pre-eclampsia (symptoms include protein in the urine) which can lead to a life-threatening conditions such as seizures. Blood tests are used to determine blood group, and check levels of cholesterol (high indicating increased risk of cardiovascular disease) and blood sugar (high indicating diabetes and low indicating hypoglycaemia). Urine tests comprise more than 100 tests which may be carried out on urine. Some are simple, like colour, clarity, ph and smell; others more complex, such as the analysis of ion or cell content. These tests may indicate a wide variety of potential problems, such as infections or renal failure. Medical history questions will be asked in case the woman has any conditions which might complicate her pregnancy, e.g. type 1 diabetes, which can cause early labour or birth defects, or tobacco smoking. Her family history will also be considered in case there are any indications of inherited disorders (e.g. cystic fibrosis). Antenatal care: Question Q1: Complete the table by matching the conditions in the left column with the check or test that may be used to detect them.

63 TOPIC 4. ANTENATAL AND POSTNATAL SCREENING AND CARE 55 Condition Renal failure Obesity Cystic fibrosis Pre-eclampsia Diabetes Check/Test Check/test list: Blood pressure test; Blood sugar test; BMI; Medical history; Urine test. 4.3 Antenatal screening Learning Objective By the end of this section, you should be able to: describe some of the tests which may be carried out on a pregnant woman or her fetus; state the general purpose of each test; state the advantages and disadvantages of each test. Once a woman has been confirmed as pregnant, a range of tests are available to assess the health of both the mother and the fetus as the pregnancy progresses. Some, like the ultrasound scans, are routine and available to all expectant mothers; others, such as Chorionic Villus Sampling, are only carried out when there is good reason to expect some abnormality may be present. These tests may be mainly focussed on: the mother, such as the biochemical tests; both mother and fetus, e.g. ultrasound scans; the embryo/fetus, e.g. amniocentesis. Procedures which do not involve removal of tissue from the fetus (e.g. ultrasound scans, sampling mother's blood) are classed as non-invasive, whereas those that do are invasive (e.g. amniocentesis, PGD) Pre-implantation genetic diagnosis (PGD) If a couple have a family history of a genetic disorder or they have had a previous child who has been born with one, they may opt for in vitro fertilisation (IVF) which will allow embryos to be screened for the presence of the disorder before they are implanted in the mother's uterus.

64 56 TOPIC 4. ANTENATAL AND POSTNATAL SCREENING AND CARE In the most common PGD procedure, two cells are removed from the 8-cell stage of the embryo, their chromosomes are examined, and their DNA analysed. Transfer to the uterus is delayed until the fifth day after fertilisation, thereby allowing time for the analysis to be completed before the final choice of embryos is made. As well as chromosomal abnormalities, the list of genetic disorders which can be detected is considerable and includes: cystic fibrosis, sickle-cell disease, Huntingdon's disease and Duchenne muscular dystrophy Ultrasound imaging This procedure uses very high frequency sound to create an image of the fetus in the uterus. A probe is placed over the area being investigated and pulses of sound are directed into the abdomen. Different densities of tissue reflect different proportions of the sound pulse and these reflections are interpreted electronically to form an image of the uterus and the fetus. The frequencies used are typically between 2 and 18 MHz, which is a thousand times greater than the highest frequencies we can hear. Although this may appear to be quite a drastic treatment, there have been no negative effects reported. The first scan is carried out between 8-14 weeks of the pregnancy and is called a dating scan as it is used to determine the age of the fetus, and hence the expected delivery date (due date). A second scan is also offered at weeks, when the fetus is much larger. This is known as an anomaly scan and is used to identify any aspects of physical development of the limbs and vital organs which are unusual. An example of such an anomaly is a high volume of fluid behind the neck, which in 60% of cases is an indicator of Down's syndrome. If a further check reveals the absence of a particular bone in the nose, the likelihood of the condition being present is increased to 95% Biochemical tests The mother's blood is constantly transporting a whole range of chemicals around her body, from the products of digestion, to her own hormones, and to substances which have crossed the placenta from the fetus. Certain of these show significant changes if there are problems with either the fetus or the mother, and therefore can be used as chemical markers. A blood test can be taken in conjunction with the anomaly scan, and the levels of such marker chemicals in it compared with those expected at that stage in the pregnancy. For example, low levels of certain fetal liver proteins (alpha-fetoprotein) and hormones (estriol) associated with pregnancy are indicative of a fetus with Down's syndrome (although there are other causes). In this case, the marker chemical is not itself part of the disorder but an indicator that the disorder is likely to be present. As the levels of these substances normally increase throughout pregnancy, it is important that the recorded levels be matched to the age of the fetus to avoid incorrectly diagnosing the condition. In the case of Down's syndrome, if the fetus was younger than estimated, the presence of a normal level of estriol would result in it being incorrectly diagnosed as having the condition. This would be a false positive result.

65 TOPIC 4. ANTENATAL AND POSTNATAL SCREENING AND CARE 57 It is also the case that these tests will yield a small proportion of false positives even if correctly applied, i.e. some fetuses which are unaffected will be identified as having the condition. Hence the need for carrying out a variety of tests and for the more precise diagnostic tests which follow. Biochemical tests: Question Q2: State which results of the anomaly scan and the biochemical tests would indicate that a further diagnostic test for Down's syndrome would be appropriate Diagnostic testing The tests mentioned in this topic are classified according to their precision: those that indicate the possible presence of a disorder are screening procedures (e.g. ultrasound scans); those that confirm the presence of a condition are diagnostic procedures (e.g. amniocentesis). Screening procedures highlight symptoms, which may have more than one cause, whereas diagnostic tests identify the causes of these symptoms. All pregnant women are initially offered the screening procedures of ultrasound scans and blood tests. If any of these tests suggest the potential presence of an abnormality, then further diagnostic tests are indicated. At this point, a risk analysis must be carried out because the diagnostic tests are invasive and may, in a few cases, cause damage to the fetus or trigger a miscarriage. Refining the precision of ultrasound imaging, and considering ultrasound together with the biochemical analysis of blood samples, can give a much more certain indication of the presence of a disorder. It is worth noting that all tests, even those based on karyotyping, have a small error rate and that there are no prenatal tests which will detect all disorders or abnormalities. Diagnostic testing: Question Q3: Complete the paragraphs using the words from the list. Soon after her pregnancy is confirmed, a woman is given a range of routine tests to assess the possibility of complications to the pregnancy. These are tests. Examples are, and. These are followed by a scan at weeks which determines. A second scan at weeks seeks to identify physical problems and is called an scan. Both these scans use imaging. All the tests mentioned so far identify the possibility of a disorder being present and are referred to as tests. Tests which identify the presence of a disorder very precisely are called tests. Examples of such tests are and. Word list: amniocentesis; anomaly; blood pressure; blood tests; CVS; dating; diagnostic; due date; screening; screening; ultrasound; urine tests; 8-14;

66 58 TOPIC 4. ANTENATAL AND POSTNATAL SCREENING AND CARE Amniocentesis This procedure involves the insertion (under anaesthetic) of a needle through the abdomen wall, then the uterus wall, and finally (guided by ultrasound) into the amniotic sac at a point away from the fetus. This sac, which is fluid-filled, supports and protects the fetus. A sample of fluid (about 20ml) is extracted and the cells (usually white blood cells) in it are removed and cultured. DNA can be extracted from these cells and analysed. These cells may also be treated to produce a karyotype. They are induced to divide and the process is arrested at metaphase when the chromosomes are at their most prominent. The cells are mounted on a slide, chemically fixed so that they will not alter, and then stained to highlight the chromosome structure. An image of the chromosomes of one cell arranged in homologous pairs, the karyotype, is then analysed to identify any anomalies in terms of the numbers or structure of the chromosomes. This test is carried out after 15 weeks, usually at 18 weeks, with a risk of miscarriage of less than %. In certain cases it may be carried out between weeks, but with increased risk Chorionic villus sampling (CVS) During CVS, a sample of chorionic villi cells will be taken from the pregnant woman's placenta. The villi are the structures in the placenta which contain the blood vessels that are involved in the exchange of materials between the fetus and the mother. Cells are obtaining using either: transabdominal CVS - where a needle is inserted through the abdomen (as in amniocentesis); transcervical CVS - where a catheter is inserted through the cervix (the neck of the womb). In both cases, ultrasound guidance is used to ensure the safe placement of the apparatus. The cell sample is then prepared for karyotyping. The process is quicker than for amniocentesis as the cells are actively dividing. Alternatively, DNA analysis may be carried out. CVS is normally carried out between weeks, giving a much earlier indication of any abnormalities, but has a higher risk of miscarriage of 0.5-1%. Chorionic villus sampling: Question Q4: Using suitable examples, explain the difference between a screening and a diagnostic test.

67 TOPIC 4. ANTENATAL AND POSTNATAL SCREENING AND CARE The moral dimension The screening and diagnostic tests described above provide information about the health of the mother and the fetus. The results may range from indicating that the fetus is perfectly healthy to suggesting that it will live for only a short period after birth and be in constant distress. In the same way, the mother might be found to be in robust health or suffering from some condition such as kidney disease (nephropathy) which would threaten her life as the pregnancy proceeds. Decisions have to be taken by the mother as to whether she will undergo any tests at all, and then, if initial screening or family history point to it, whether she should expose her fetus to diagnostic tests with their associated increased risks (small though they are). If the diagnostic tests indicate that the fetus has a disorder which will seriously reduce the quality of its life after birth or will mean that it will require round-the-clock care, the mother may wish to consider the possibility of terminating the pregnancy. Moral attitudes span the spectrum, from those who believe that the zygote is a human being with an inalienable right to life to those who believe a woman has the right to terminate any pregnancy. Others believe that there should be no medical intervention of any sort during a pregnancy. It is not the purpose of this course to promote any particular moral view, but you should be aware of the different views that people may hold and of the issues that must be considered. The moral dimension: Question Q5: Type A Nieman-Pick Disease is a rare inherited disorder controlled by an autosomal recessive allele which severely disrupts the function of many organs and the nervous system. It is normally fatal by the age of four and there is no cure. A woman has received a positive pregnancy test result from her home test kit. She knows that her aunt had a child suffering from this condition, but her husband was adopted and has no knowledge of his biological parents. What tests would she and her fetus have the opportunity to undergo and what factors might influence her decisions? Rhesus antibody testing Any fetus is genetically different in many respects from its mother and so runs the risk of the mother's immune system being alerted to this foreign invader and taking action against it. One of the many functions of progesterone during pregnancy is to suppress the mother's immune response. However, if cells from the fetus enter the mother's blood circulation, white blood cells will rapidly find them and respond. As you will discover in Unit 4 of the course, the human immune system reacts to the presence of cells which have foreign, or 'non-self', protein markers (antigens) on their cell membranes. The outcome of this reaction is the production of other proteins, called antibodies, by white blood cells. These attach themselves to the antigens on the foreign cells and help destroy them. In the case of the Rhesus factor, problems arise if a mother who is Rhesus negative (does not have the Rhesus antigen) is pregnant with a Rhesus positive fetus. If red blood cells cross from the fetal blood circulation into the mother's blood during the pregnancy,

68 60 TOPIC 4. ANTENATAL AND POSTNATAL SCREENING AND CARE the Rhesus antigens on the fetal cells will be registered as non-self. During a first pregnancy, this is unlikely to cause a problem as the number of fetal cells crossing is insufficient to trigger a response. However, during birth, many cells do cross into the mother's blood and the immune system is sensitised, making white blood cell which 'remember' the antigen. Sensitisation may also result from blood transfusions or damage to the placenta during pregnancy, causing it to leak blood into the mother's system. Should the Rhesus antigen turn up again in the circulation, as it will do if the mother has a second Rhesus positive child, these memory cells trigger a rapid and large production of antibodies. This is not a problem for the mother as the few cells that pass from fetus to mother are quickly removed. However, as the antibody molecules are small enough to pass across the placenta into the fetus, the damage occurs there in the form of the destruction of red blood cells. The effect is to cause jaundice, which only becomes apparent after birth because the breakdown products of the red blood cells are removed across the placenta before birth. The condition can be fatal. When it is known that a woman is Rhesus negative she is given injections of appropriate anti-rhesus antibodies (immunoglobulin proteins) twice; once late in the pregnancy and once shortly after birth. These antibodies bind with any fetal red blood cells which have entered the mother's blood, causing them to be destroyed before the mother's immune system can be sensitised. Rhesus antibody testing: Question Q6: Under what circumstances will a mother's immune system react against a fetus and how may this be avoided?

69 TOPIC 4. ANTENATAL AND POSTNATAL SCREENING AND CARE Postnatal screening Learning Objective By the end of this section, you should be able to: describe how PKU is detected; state how PKU is treated. After the birth, both mother and baby are examined physically and, within three days of birth, the baby is given a blood test. The blood test involves taking a small blood sample by pricking the heel, and analysing the dried blood by a procedure first developed in Scotland by Robert Guthrie in the 1960s. The test is commonly called the 'heel-prick' or Guthrie test. The blood sample is tested for several rare conditions, including Phenylketonuria (PKU). The test is optional, but all of the conditions have very serious effects which can be managed medically if treatment is started immediately. Also, such early warning enables the parents to adapt to the necessary changes in their anticipated lifestyle. Phenylketonuria is an autosomal recessive disorder that involves a mutation to the gene coding for the enzyme which converts the amino acid phenylalanine to the amino acid tyrosine. Without this enzyme, phenylalanine accumulates in the blood and severely retards the development of the brain. Before birth, the excess phenylalanine is transferred across the placenta into the mother's blood and removed by her liver. Thus, the presence of the disorder only becomes apparent after birth. Treatment started soon after birth can result in normal brain development. This can be achieved through the strict control of diet, largely or totally eliminating foods which are high in phenylalanine such as dairy products, meat, fish, nuts, peas and beans. In addition, starchy food intake must also be carefully controlled. Various medications may also be used and the action of some of these permits a more protein-rich diet. Postnatal screening: Question Q7: What is PKU, how is it detected, and how is it treated?

70 62 TOPIC 4. ANTENATAL AND POSTNATAL SCREENING AND CARE 4.5 Learning points Summary Antenatal Care The initial assessments that are carried out once a woman is known to be pregnant are: height and weight, blood pressure, blood tests, urine tests, and medical history. An example of a potential complication that each assessment might reveal is: height and weight - obesity; blood pressure - hypertension; blood tests - diabetes; urine tests - renal failure; medical history - cystic fibrosis. Antenatal Screening Pre-implantation Genetic Diagnosis (PGD) may be carried out as part of the IVF procedure. PGD is used to test the DNA of the embryo for the presence of specific single gene disorders, and for chromosome abnormalities. Ultrasound imaging uses very high frequency sound to create images of the fetus in the uterus. The first ultrasound scan (dating scan) is carried out between weeks to determine the age of the fetus and the date when it is due to be born (due date). A second ultrasound scan (the anomaly scan) is carried out between weeks to detect possible physical problems. A pregnant woman's blood carries a range of chemicals which can be used to check that the pregnancy is progressing normally. The level of these marker chemicals normally varies throughout the pregnancy as the mother's, and the fetus's, physiology change. The timing of these tests must be taken into account in order to avoid false indications about the presence of a disorder. A false positive result would be obtained if the level of a marker chemical indicated the presence of a disorder when in fact the fetus did not have it. Marker chemicals will be present in the mother's blood during a trouble-free pregnancy, but the presence of a disorder may affect the level of a particular marker.

71 TOPIC 4. ANTENATAL AND POSTNATAL SCREENING AND CARE 63 Summary Continued Screening tests, for example ultrasound scans and blood tests, indicate the likelihood of a disorder being present. Diagnostic tests, for example amniocentesis and chorionic villus sampling, confirm whether a condition is present or not. Diagnostic tests, for example amniocentesis and chorionic villus sampling, are invasive and carry a small element of risk of inducing a miscarriage. Amniocentesis samples cells from the amniotic fluid. Cells from amniocentesis samples are multiplied up in culture and used to produce a karyotype. A karyotype is an image of an individual's chromosomes, arranged in homologous pairs. A karyotype is used to identify anomalies in terms of numbers or structure of chromosomes. Chorionic villus sampling (CVS) removes cells from the placenta which can be used immediately to produce a karyotype. CVS can be carried out earlier than amniocentesis but entails a correspondingly higher risk of inducing a miscarriage. Postnatal Screening A Guthrie heel-prick test is used to collect a blood sample from a newborn child. Dried blood from this sample is screened for several inherited disorders. Phenylketonuria (PKU) is an autosomal recessive disorder causing an error of metabolism. PKU results in high levels of phenylalanine which severely restrict brain development. Individuals with PKU are given a restricted diet which lacks phenylalanine.

72 64 TOPIC 4. ANTENATAL AND POSTNATAL SCREENING AND CARE 4.6 Extended response question The activity which follows presents an extended response question similar to the style that you will encounter in the examination. You should have a good understanding of tests which can be carried out during pregnancy before attempting the question. You should give your completed answer to your teacher or tutor for marking, or try to mark it yourself using the suggested marking scheme. Extended response question: Tests which can be carried out during pregnancy 15 min Give an account of the tests which can be carried out once a woman has been confirmed as pregnant, under the headings: A) screening tests; (6 marks) B) diagnostic tests. (4 marks)

73 TOPIC 4. ANTENATAL AND POSTNATAL SCREENING AND CARE End of topic test End of Topic 5 test Q8: Complete the sentences by matching the parts on the left with the parts on the right. (12 marks) Tested as part of a general health check: A procedure that may be involved in IVF: Usually taken 8-14 weeks after pregnancy: Used to detect the possibility of physical problems: Timing of tests taken into account when assessing: Used to indicate the likelihood of a disorder: Used to confirm the presence of a disorder: Screening tests include: Diagnostic tests include: The name for an image of a foetus' chromosomes: Involves removing cells from the amniotic fluid: first ultrasound imaging. blood marker chemicals. chorionic villus sampling. amniocentesis & chorionic villus sampling. amniocentesis. pre-implantation genetic diagnosis. blood pressure. screening tests. ultrasound and blood tests. second ultrasound imaging. diagnostic tests. Involves removing cells from the placenta: karyotype. Q9: Complete the paragraph using the words from the list. (8 marks) A heel-prick test is used to collect a sample from a newborn child, which screens for several disorders. Phenyketonuria is an autosomal disorder causing high levels of which restricts development. Individuals with are given a restricted diet phenylalanine. Word list: blood, brain, Guthrie, inherited, lacking, phenylalanine, PKU, recessive.

74 66 TOPIC 4. ANTENATAL AND POSTNATAL SCREENING AND CARE Once her pregnancy is confirmed, a mother is given an initial examination consisting of a number of screening tests. Q10: What is tested to check for hypertension? (1 mark) Q11: What conditions can be indicated from taking blood tests? (1 mark) Q12: What is checked to test for any indication of cystic fibrosis? (1 mark) Q13: Explain the difference between a screening test and a diagnostic test. (2 marks) Q14: Name one ultrasound scan. (1 mark) Q15: State when the scan is carried out and its purpose. (2 marks) Q16: Describe how a marker chemical might indicate the presence of a fetal disorder. (2 marks) Q17: Explain why a test for a marker chemical might give a false positive result. (2 marks)

75 TOPIC 4. ANTENATAL AND POSTNATAL SCREENING AND CARE 67 The following illustration shows the process of obtaining an amniocentesis sample. Q18: Suggest the purpose of the ultrasound probe. (2 marks) Q19: State two ways in which a diagram of chorionic villus sampling would be different from the above diagram. (2 marks) Q20: State what a karyotype is and what it may reveal about an individual. (2 marks) Q21: What causes PKU? (1 mark) Q22: How does PKU affect development? (1 mark) Q23: How is PKU in infants treated? (1 mark)

76 68 TOPIC 4. ANTENATAL AND POSTNATAL SCREENING AND CARE

77 69 Topic 5 Patterns of inheritance Contents 5.1 Introduction Genetic terms and their meanings Pattern of inheritance of a pair of alleles - one dominant, one recessive Cystic fibrosis Dominant and incompletely dominant alleles Dominance Incomplete dominance Sex-linked inheritance Learning points End of topic test Learning Objectives By the end of this topic, you should be able to: describe the pattern of inheritance of a pair of alleles where one is dominant and one is recessive; describe the effects of alleles exhibiting dominance and incomplete dominance; describe the possible combinations of multiple alleles; describe sex-linked inheritance and the effects of the presence of genes on the X-chromosome but not on the Y-chromosome.

78 70 TOPIC 5. PATTERNS OF INHERITANCE 5.1 Introduction Topics later in this unit are concerned with the various screening and diagnostic procedures which are available to pregnant mothers. These seek to identify conditions that cause aspects of metabolism to malfunction. Many of these conditions are the result of a mutation which affects the action of a single gene. This topic examines the patterns of inheritance of single genes (monohybrid inheritance), considering in particular the behaviour of alleles which are dominant, recessive or incompletely dominant, going on to study sex-linked inheritance and the effects of genes which are present on the X but not on the Y chromosome. This subject, even more than most, has its own specialist language and it is a very good idea to keep a glossary of these words in your notes. 5.2 Genetic terms and their meanings Learning Objective By the end of this section, you should be able to: describe the meaning of various genetic terms. There are many terms used in genetics which, if you understand their meanings, make genetics more easily understood. You should know the meanings of the following terms: haploid - a cell containing one set of chromosomes (gametes); diploid - a cell containing two sets of chromosomes; gene - a discrete region of a chromosome whose DNA codes for the production of a polypeptide or protein; allele - different forms of a gene; homozygous/a homozygote - an individual possessing two identical alleles of a gene; heterozygous/a heterozygote - an individual possessing two different alleles of a gene; genotype - the genetic makeup of an individual with respect to a particular characteristic; phenotype - the expression of a gene in an individual in terms of appearance, behaviour or biochemistry; dominant - an allele that is expressed in the phenotype of the heterozygote; recessive - allele that is not expressed in the phenotype of the heterozygote; incompletely dominant - an allele that is not completely masked by the dominant allele and which therefore has some effect on an individual's phenotype;

79 TOPIC 5. PATTERNS OF INHERITANCE 71 pedigree chart - a diagram that shows the occurrence of the phenotypes of a particular gene from one generation to the next; P generation - the parents at the start of any pedigree chart; F 1 generation - the first generation produced by two parents in a cross; F 2 generation - the generation produced by crossing two individuals from the F 1 generation; sex-chromosome - one of the pair of chromosomes which determine the sex of the individual (XX in the female and XY in the male); autosome - one of the 22 pairs of chromosomes that control the general functioning of the individual, but do not determine the sex; linked genes - genes carried on the same chromosome; sex-linked genes - genes carried on the X-chromosome; carrier - an individual who is heterozygous for a particular characteristic, especially applied to genetic disorders which are caused by a recessive allele carried on an autosome or an X-chromosome; siblings - offspring of the same parents, although the term can also be applied to children who share a single parent (half- as opposed to full-siblings); twins - two individuals produced in the same pregnancy; identical twins - (also called monozygotic twins) two individuals produced by the fertilisation of a single egg and the subsequent splitting of the ball of cells - they are therefore genetically identical; non-identical twins - (also called dizygotic twins) two individuals produced by the fertilisation of two eggs who are no more genetically similar than any other siblings. Dominant alleles are represented by upper case (capital) letters while recessive alleles are represented by lower case letters. The symbol that represents male individuals The symbol that represents female individuals

80 72 TOPIC 5. PATTERNS OF INHERITANCE 5.3 Pattern of inheritance of a pair of alleles - one dominant, one recessive Learning Objective By the end of this section, you should be able to: describe the pattern of inheritance of a pair of alleles where one is dominant and one is recessive. You should remember from a previous course the pattern of inheritance of a pair of alleles that occurs where one is dominant and one is recessive. You should look at the following two activities to revise the pattern of inheritance from the parental generation through to the F 2 generation. The monohybrid cross: F 1 generation 10 min The following illustrates the principle of the monohybrid cross and the inheritance of genetic characteristics by the F 1 generation. The 'bobbit' is a small, roundish mammal. A a brown, male bobbit mates with a white, female bobbit to produce the F 1 generation. There are sixteen offspring, all of which are brown. Q1: The colour of the bobbit is conferred by a single gene. A bobbit with the genotype BB has a brown coat colour whereas a bobbit with the genotype bb is white. The B allele is completely dominant to the b allele. Assuming that the parents in the cross were homozygous, what were their genotypes? Q2: The offspring in the F 1 generation are all brown. Why is this?

81 TOPIC 5. PATTERNS OF INHERITANCE 73 The monohybrid cross: F 2 generation The following illustrates the inheritance of genetic characteristics by the F 2 generation in a monohybrid cross. It is a continuation of the previous activity (The monohybrid cross: F 1 generation) which you should work through before looking at this one. In the previous activity, a brown, male bobbit mated with a white, female bobbit to produce the F 1 generation. In this case, a male and female from the F 1 generation mate to produce the F 2 generation. 10 min In this case there are sixteen offspring, four of which are white and twelve of which are brown. Q3: What is the ratio of brown coloured bobbits to white coloured bobbits in the F 2 generation? Q4: Explain your answer to the previous question, with the aid of a Punnett square. Remember that a bobbit with the genotype BB has a brown coat colour, whereas a bobbit with the genotype bb is white. The B allele is completely dominant to the b allele.) Cystic fibrosis Cystic fibrosis is an inherited condition which causes the production of thick mucus in the respiratory system. This increases an individual's susceptibility to respiratory infections. Thick mucus is also produced in the digestive system and can cause the blockage of ducts (for example in the pancreas) which prevents digestive enzymes reaching the small intestine. Cystic fibrosis is caused by a recessive allele. Individuals possessing only one such allele are perfectly healthy. However, if someone inherits a recessive allele from each parent, they will suffer from the condition. The alleles involved in cystic fibrosis are inherited in the normal manner. The following activity shows the pattern of inheritance of this condition when both parents are heterozygous for this gene.

82 74 TOPIC 5. PATTERNS OF INHERITANCE Cystic fibrosis: Questions 10 min Let N represent the normal allele and n represent the cystic fibrosis allele. Since both parents are heterozygous for this gene, both of their genotypes will be Nn and their phenotypes will be normal mucus production. Both of these individuals will produce gametes, half of which will be N and half n. Q5: Complete the Punnett square to show the possible genotypes of any offspring of these two individuals. N n N n Q6: What is the percentage chance that this couple's first child will have cystic fibrosis? Q7: The couple's first two children are normal and they are expecting their third. What is the percentage chance that this child will have cystic fibrosis? Q8: In another couple, one individual is heterozygous while the other is homozygous for the normal allele. What are the chances of any of their children having cystic fibrosis. 5.4 Dominant and incompletely dominant alleles Learning Objective By the end of this section, you should be able to: describe the effects of alleles which exhibit dominance and incomplete dominance. In this section we will look at the pattern of inheritance involving dominant, co-dominant and incompletely dominant alleles Dominance The disorder Huntington's chorea is a degenerative disorder characterised by slurred speech, uncontrolled movements of the body and a progressive deterioration in mental functions. The first symptoms generally appear between the ages of 35 and 55 and become progressively worse for 10 to 25 years until the patient dies. The allele which causes the condition is dominant to the normal form of the gene. An individual who is

83 TOPIC 5. PATTERNS OF INHERITANCE 75 heterozygous for this gene will eventually develop the condition (as will a homozygous dominant individual). The following shows the inheritance of this condition. Dominance: Question Let H represent the Huntington's chorea allele and h represent the recessive, normal allele. In the following example, one individual is heterozygous for the gene, while the other is homozygous recessive. 10 min Q9: Complete the Punnett square to show the possible offspring genotypes, then answer the questions which follow. H h H h Q10: What is the percentage chance that a child of this couple will develop Huntington's chorea in later life? Q11: If a heterozygous child still had not developed symptoms by the time they were 40, what would be the chances of them being affected later? Q12: Normally such a lethal allele as Huntington's rapidly disappears from a population. This does not happen with Huntington's. The frequency of the gene remains constant. Why do you think this may be? Incomplete dominance Haemoglobin, a protein found in red blood cells and whose function is to carry oxygen, is coded for by genes. Sometimes, a mutation can occur in one of these genes which then codes for another type of haemoglobin called haemoglobin S. Haemoglobin S is much less efficient at carrying oxygen than normal haemoglobin. People who are homozygous for the abnormal allele suffer from the condition sickle cell anaemia. All of their haemoglobin is type S which, apart from not carrying oxygen efficiently, also causes the shape of their red blood cells to be a distorted, sickle (crescent) shape rather than the normal disc shape. Such red blood cells are less flexible than normal cells and tend to stick together. This can cause blockages in small blood vessels. The result is extreme shortage of oxygen to the organs and normally causes the death of the individual at a young age. The anaemia is caused by the relatively short life span of the sickle cells. People who are homozygous for the normal allele produce normal haemoglobin and normal red blood cells.

84 76 TOPIC 5. PATTERNS OF INHERITANCE People who are heterozygous do not suffer from sickle cell anaemia, but from a milder condition known as the sickle cell trait. These individuals can lead relatively normal lives although they are slightly anaemic. Heterozygotes possess a phenotype that is 'in-between' the two homozygous phenotypes because the normal allele does not completely mask the effect of the abnormal one. In other words, the normal allele is incompletely dominant to the sickle cell allele. Since neither allele is completely dominant, each is represented by a different, upper case letter. H is used to represent the normal allele, while S represents the allele for haemoglobin S: HH individuals are normal; SS individuals have sickle cell anaemia - the red blood cells stick together, causing problems in the circulatory system which can lead to severe organ damage and usually death; HS individuals have sickle cell trait - the red blood cells are generally normal, but individuals may show some signs of the disease when carrying out intense physical activity; this occurs because the H allele is not completely dominant to the S allele which means that S is partially expressed. Normally, an allele causing a condition as serious as sickle cell anaemia would quickly disappear from a population and, in fact, in most parts of the world, the frequency of the sickle cell allele is very low. However, the frequency is much higher in certain parts of Africa where malaria is endemic. This is because heterozygotes are more resistant to malaria, as shown in the following table. Genotype Malarial region Non-malarial region HH No protection from infection with malaria - high infection rate Will survive HS SS Protected from infection with malaria - low infection rate Sickle cell anaemia, usually fatal Sickle cell trait - will survive, but are slightly anaemic Sickle cell anaemia, usually fatal Malarial protection conveyed by haemoglobin genotype As a result, the HS genotype is favoured by natural selection in malarial regions. The following graphic shows the correlation between the incidence of malaria and the haemoglobin S allele. The sickle cell mutation provides a selective advantage under certain conditions (where the incidence of malaria is high) but is otherwise a disadvantage.

85 TOPIC 5. PATTERNS OF INHERITANCE 77 Correlation between the distribution of the sickle cell mutation (S allele) and malaria in Africa Incomplete dominance: Questions Q13: Why is there a high frequency of the S allele in regions with a high incidence of malaria? Q14: Why do descendants of Central Africans living in other parts of the world have a far lower incidence of sickle cell trait? 5.5 Sex-linked inheritance Learning Objective By the end of this section, you should be able to: describe sex-linked inheritance, and the effects of the presence of genes on the X-chromosome but not on the Y-chromosome. Human diploid cells contain 46 chromosomes that are composed of 22 pairs of autosomes (chromosomes that are not involved in sex determination) and one pair of sex chromosomes. There are two types of sex chromosomes: X and Y. The Y-chromosome is thought to have evolved from an X-chromosome which suffered an inversion mutation and became unable to pair up with an X at meiosis. Thus, the X and Y-chromosomes are no longer homologous. As a result, the genes on the Y-chromosome have slowly mutated over time without the exchange process of crossing over, and they now do not correspond to any genes found on the X-chromosome. Strictly speaking, genes found on the X-chromosome are X-linked, and those on the Y-chromosome are Y-linked, although the term sex-linked is used generally to refer to genes carried on the X-chromosome. In many animals, including human beings, females have two X-chromosomes whereas

86 78 TOPIC 5. PATTERNS OF INHERITANCE males have one X-chromosome and one Y-chromosome. described genotypically as XX and males as XY. Females are therefore Males produce two types of gametes, each of which contains a full set of autosomes but a different sex chromosome (X or Y). Females only produce one type of gamete, consisting of the autosomes and a copy of the X-chromosome. If a male gamete containing an X-chromosome fertilises a female gamete, then the offspring will be female, but if the male gamete has a Y-chromosome, then the result will be a male. The gender of the offspring is therefore determined by the sex chromosome carried by the male gamete. There is an equal chance of the offspring being male or female. Sex linkage refers to the inheritance of characteristics that are determined by genes located on the sex chromosomes. The Y-chromosome contains almost no functional genes and so most sex-linked characteristics are associated with the X-chromosome. In a male, a sex-linked gene will always be expressed, even if the allele is recessive, because there is no allele for the same gene on the Y-chromosome. Females can be carriers of sex-linked disorders, but very rarely suffer from the conditions themselves. This is because the alleles for these disorders are normally recessive and will be masked by the normal allele on the other X-chromosome. Haemophilia is a human sex-linked condition in which blood clotting factor VIII is defective. Males who suffer from the disease (haemophiliacs) carry a mutated allele of the factor VIII gene which means that their blood fails to clot properly. The smallest wound can be fatal, especially if it is internal and goes undetected. Haemophilia is described as a sex-linked recessive trait. Heterozygous females are carriers: they possess one mutated allele, but do not suffer from haemophilia. There is a 50% chance that the daughter of a female carrier will also be a carrier and a 50% chance that a son will have the disorder (assuming that the father is not a haemophiliac). On the other hand, all of the daughters of a male haemophiliac will be carriers and all of the sons will be normal (because they inherit the X-chromosome from the mother). The genotype of a male haemophiliac is often indicated by X h Y and that of a normal male by X H Y. A female carrier would be genotypically X H X h. Red-green colour blindness in humans is also a sex-linked recessive disorder. Colourblind females are very rare, but carriers have a 50% chance of passing the allele to their sons. Duchenne muscular dystrophy, a very serious inherited disease in human beings which causes muscles to waste away, is another sex-linked recessive disorder. Sex-linked inheritance: Questions 20 min Q15: Complete each of the six boxes with the identity of the sex chromosomes of the parents and the gametes Chromosome Gametes Woman Man

87 TOPIC 5. PATTERNS OF INHERITANCE 79 Q16: Enter the identity of the sex chromosomes of the offspring in the Punnett square. Male gametes Female gametes X X X Y Q17: Why is there an equal chance of human offspring being male or female? Q18: A couple have three children: two boys and a girl. They are about to have a fourth child. What is the chance of that child being a girl? a) 25% b) 50% c) 75% d) 100% Let C represent the normal allele for colour vision and c represent the allele for red-green colour blindness. Q19: The following image shows a cross between a normal female and a colour-blind male. Match the phenotypes on the right with the correct genotypes on the left.

88 80 TOPIC 5. PATTERNS OF INHERITANCE Q20: The following image shows a cross between a carrier female and a normal male. Complete the Punnett squares using the phenotypes on the right hand side. Q21: In the cross between a normal female and a colour-blind male, what are the chances of the couple producing: a normal son; a carrier daughter; a colour-blind son. Q22: In the cross between a carrier female and a normal male, what are the chances of the couple producing: a normal son; a carrier daughter; a colour-blind son; a colour-blind child.

89 TOPIC 5. PATTERNS OF INHERITANCE 81 A gene A is sex-linked. The recessive allele of this gene, a, causes a disorder in males. Q23: Study the family tree and then complete it with the genotype of each individual. Q24: Recessive sex-linked disorders are often said to 'skip a generation'. In other words, an affected male rarely has male children with the disorder, but male grandchildren born to the daughter of an affected male are more likely to be affected. Why is this?

90 82 TOPIC 5. PATTERNS OF INHERITANCE 5.6 Learning points Summary You should know the meanings of the following terms: haploid, diploid, gene, allele, homozygous, heterozygous, genotype, phenotype, dominant, incompletely dominant, F 1 generation, F 2 generation, autosome, sex chromosome, recessive, carrier, pedigree chart, P generation, siblings, twins, identical twins, non-identical twins, linked genes, sex-linked genes. An individual has two alleles for each gene (except for some sex-linked genes). For a pair of alleles where one is dominant and one recessive, the dominant allele is represented by an upper case letter and the recessive allele by the same letter in lower case. Tongue rolling, for example, is controlled by a single gene. An individual who is homozygous dominant (TT) or heterozygous (Tt) will be able to roll their tongue. A homozygous recessive individual (tt) will not be a tongue-roller. Huntington's chorea is a condition caused by the presence of the dominant allele of a gene. HH or Hh individuals will eventually develop the disorder in middle age. hh individuals will not develop it at all. An example of incomplete dominance is sickle cell anaemia. Since both alleles have an effect on the phenotype, each one is represented by a different upper case letter. H represents the normal allele, while S represents the sickle cell allele. HH individuals have normal haemoglobin. SS individuals have sickle shaped red blood cells and suffer from sickle cell anaemia. HS individuals have a mixture of normal and sickle shaped red blood cells and suffer from the milder sickle cell trait. The HS genotype offers a selective advantage over HH in regions where malaria is prevalent. Humans have 46 chromosomes of which one pair, the sex chromosomes, determine sex. Females have two X-chromosomes, which are homologous, whereas males have one X and one Y, which are non-homologous. Homologous chromosomes are of the same size and shape, and carry the same genes (but not necessarily the same alleles) at the same locations. Genes carried on the X-chromosome are said to be sex-linked. Some human sex-linked conditions are red-green colour blindness, haemophilia and Duchenne muscular dystrophy. Males inherit sex-linked conditions from their mother because they receive a Y-chromosome from their father. If their mother is heterozygous for the gene (X C X c for colour vision), then her son has a1in2chance of receiving the abnormal allele. The mother will not be affected since she has a normal allele in addition to the recessive, abnormal one.

91 TOPIC 5. PATTERNS OF INHERITANCE End of topic test End of Topic 4 test Q25: Complete the sentences by matching the parts on the left with the parts on the right. (12 marks) 30 min Diploid: Gamete: Alleles: Genotype: Phenotype: Homozygous: Dominant: Recessive: Incomplete dominance: Autosome: the expression of the alleles of a gene. a chromosome which does not affect gender. a genotype with two identical alleles. a cell containing two of each chromosome. brothers and sisters. a chromosome which carries sex-linked genes. a pair of alleles carried by a gene. a cell containing one of each chromosome. alternative forms of a gene. an allele which is always expressed in the phenotype if present. X: allele which is only expressed by a homozygous person. Siblings: causes three different phenotypes for a gene.

92 84 TOPIC 5. PATTERNS OF INHERITANCE Q26: Select the correct words from the alternatives provided to complete the following sentences. Number of alleles a man has for an autosomal gene on his Y chromosome: 0/1/2 Genotype of a woman heterozygous for tongue-rolling: TT / X T X t / Tt Genotype of a man who will not develop Huntingdons' disease (caused by a dominant autosomal allele): X h Y h / Hh / hh Genotype of a woman who shows sickle cell trait as a result of incomplete dominance: HH / HS / X H X S Number of alleles a man carries for a gene with multiple alleles: 1/2/3 Genotype of a woman with type O blood group: AO / BO / OO Not true of homologous chromosomes: same alleles / same size / same shape Percentage chance of a girl inheriting a sex-linked allele from her father: 25% / 50% / 100% Gametes of the daughter of a father unaffected by recessive condition and a heterozygous mother: X B and X B / B and B / X B and X b Proportion of heterozygotes among the children of parents who are heterozygous for a condition which is lethal in early pregnancy: 1in2/2in3/3in4 Q27: An individual who possesses two identical alleles controlling a characteristic is said to be for that characteristic. (1 mark) Q28: An individual's is their genetic makeup with respect to a particular characteristic. (1 mark) Q29: Characteristics which have three phenotypes are caused by alleles which show. (1 mark)

93 TOPIC 5. PATTERNS OF INHERITANCE 85 A monohybrid cross is performed between an individual with the genotype AA and another individual with the genotype aa. Q30: What percentage of the F 1 offspring would be expected to be heterozygotes? (1 mark) a) 25% b) 50% c) 75% d) 100% Q31: What percentage of the F 2 offspring would be expected to be heterozygotes? (1 mark) a) 25% b) 50% c) 75% d) 100% Q32: What percentage of the F 2 offspring would be expected to be homozygotes? (1 mark) a) 25% b) 50% c) 75% d) 100% A monohybrid cross is performed between an individual with the genotype Aa and another individual with the genotype Aa. Q33: Which of the following phenotypic ratios in the offspring indicates incomplete dominance? (1 mark) a) 3:1 b) 1:2:1 c) 2:1 d) 1:1 Q34: Which of the following phenotypic ratios in the offspring indicates that the genotype aa is lethal to the fetus? (1 mark) a) 3:1 b) 1:2:1 c) 2:1 d) 1:1

94 86 TOPIC 5. PATTERNS OF INHERITANCE Q35: Huntington's disease is an inheritable disorder that leads to the degeneration of nerve cells. Symptoms do not usually appear until after the age of about 35. The disorder is caused by a dominant mutation in a gene on chromosome 4. A couple give birth to a child. The mother is heterozygous for the mutation, but the father is unaffected. What is the percentage chance that the child will inherit the disorder? (1 mark) a) 25% b) 50% c) 75% d) 100% Cystic fibrosis is an inheritable disorder caused by a recessive mutation in a gene on chromosome 7. Symptoms of the disease include very salty sweat and the accumulation of thick mucus in the lungs. A couple give birth to a child. Both parents are heterozygous for the mutation and are described as carriers. Q36: What is the percentage chance that the child will suffer from the disorder? (1 mark) a) 25% b) 50% c) 75% d) 100% Q37: What is the percentage chance that the child will be a carrier of cystic fibrosis? (1 mark) a) 25% b) 50% c) 75% d) 100%

95 TOPIC 5. PATTERNS OF INHERITANCE 87 A man with a dominant sex-linked disorder and a woman who is unaffected have a child. Q38: If the child is a boy, what is the percentage chance that he will suffer from the disorder? (1 mark) a) 0% b) 25% c) 50% d) 100% Q39: If the child is a girl, what is the percentage chance that she will suffer from the disorder? (1 mark) a) 0% b) 25% c) 50% d) 100% Duchenne muscular dystrophy is a recessive, sex-linked disorder in human beings that causes severe muscle wastage. A couple have a child. The mother is heterozygous (a carrier), and the father is unaffected. Q40: If the child is a girl, what is the percentage chance that she will be a carrier? (1 mark) a) 0% b) 25% c) 50% d) 100% Q41: If the child is a girl, what is the percentage chance that she will suffer from the disorder? (1 mark) a) 0% b) 25% c) 50% d) 100% Q42: If the child is a boy, what is the percentage chance that he will suffer from the disorder? (1 mark) a) 0% b) 25% c) 50% d) 100%

96 88 TOPIC 5. PATTERNS OF INHERITANCE Q43: Red-green colour blindness in humans is a sex-linked trait. A man and a woman, neither of whom is colour-blind but who both have colour-blind fathers, decide to have a child. What is the percentage chance of the child being colour-blind? (1 mark) a) 50% b) 25% c) 12.5% d) 0% Q44: Explain why the daughter of a man affected by a recessive sex-linked trait will not be affected, although any son that she herself may have can be affected. Assume the daughter's mother is not a carrier for the condition. (3 marks)

97 89 Topic 6 Blood vessels Contents 6.1 Why have a cardiovascular system? Blood vessels Arteries Capillaries Vasoconstriction and vasodilation Veins Exchange of materials between the blood and the cells The mechanism that causes flow in and out of capillaries Lymph vessels Learning points Extended response question End of topic test Learning Objectives By the end of this topic, you should be able to: describe the structure of the three main types of blood vessel in the blood circulation system; explain how this structure is related to their different functions; describe how the purpose of the circulatory system is achieved by the movement of materials in and out of capillaries.

98 90 TOPIC 6. BLOOD VESSELS 6.1 Why have a cardiovascular system? Life on earth consists of cells, which either live singly (unicellular), or in communities (multicellular) with varying levels of complexity. All cells are bounded by an outer membrane and contain a liquid through which runs a system of membranes where many of the processes of life take place. To carry out these processes, the cell must obtain raw materials to build new cellular material and substrates from which it can release energy. These must come from the surrounding fluid. In addition, the cell must be able to release waste into its surroundings. The human organism consists of some cells (or if gut and other bacteria are included). They may live freely in a liquid, e.g. the cells in the blood, or in tight-knit tissues, e.g cardiac muscle cells. Wherever they are in the body, they must be supplied with oxygen and glucose (or another respiratory substrate) to generate the ATP that drives cell processes, and all of the substances that are necessary for their metabolism, e.g. amino acids. Carbon dioxide and any other products (e.g. hormones) must be taken away. In humans, and all other vertebrate animals, the supply role is carried out by the cardiovascular, or blood circulatory, system, with the heart pumping a liquid tissue, the blood, around the body through vessels. On its route, the blood reaches all parts of the body, allowing not only the transport of the substances that are vital to the cells themselves, but also carrying the hormones which help the body function as a coordinated whole, and the white blood cells which enable the immune system to function. Fluids flow from areas of high pressure to areas of low pressure. By its contraction, the heart creates high pressure which forces the blood to move away from it, while valves prevent any backflow into its chambers. The repeated contractions of the heart cause the blood to flow through the arteries, which are vessels that carry the blood round the body. Close to the heart, these are thick-walled and muscular to absorb the pressure waves, but where they divide to supply the tissues they have much thinner walls (and are known as arterioles). Although the major arteries contract as each wave of blood passes, pressure is gradually lost as the blood moves towards the arterioles. However, there is still a higher pressure in the finest branches of the arterial system than in the tissues. At this point are found the smallest vessels, the capillaries, where fluid is forced out into the tissues and bathes the cells. The tissue fluid then returns to the capillaries, which join to form small veins (venules) and then the veins which return the blood to the heart. About 1% of the tissue fluid goes into the lymphatic system before returning to the blood. The sections which follow in this topic consider in more detail the structure of these blood vessels and the process of exchange of materials with the cells. It should be noted that there are other ways to achieve some of these tasks. Insects, for example, which in terms of diversity of form are the most successful type of animal ever to evolve, supply air almost directly to their cells through a system of air capillaries. The blood of an insect is left to carry out the other less urgent transport functions.

99 TOPIC 6. BLOOD VESSELS 91 Why have a cardiovascular system: Questions Q1: Complete the paragraph about the requirements of living cells by using the words from the list. Living cells need to take in a respiratory to provide to power metabolism. They also require raw materials such as acids and. Waste materials such as and products like must be removed. Word list: ATP, amino, carbon dioxide, fats, hormones, substrate. Q2: Re-arrange the following statements to put them into the correct order to describe the circulation of the blood. Venules join to form veins to carry blood back to heart Cells exchange substances with tissue fluid Arteries divide to form smaller arterioles The heart contracts, increasing the pressure of the blood Blood in arterioles is at higher pressure that fluid in tissues Tissue fluid returns to capillaries Fluid is forced from capillaries into tissues Blood flows through major arteries Capillaries join to form venules Muscular walls contract to maintain blood pressure 6.2 Blood vessels Learning Objective By the end of this section, you should be able to: describe the structure of the main types of blood vessel; state the function of each type of blood vessel. In the simplest terms, arteries carry blood under high pressure from the heart to the tissues, capillaries exchange materials with the tissues, and veins carry blood back to the heart under low pressure. The key features of the structure of each type of vessel relate directly to these functions. Transfer into and out of the tissues only takes place in the beds of capillaries; arteries and veins are the pipe-work through which the blood is transported. All of the vessels are tubes with walls composed of different tissues dependent of the type of vessel. The central space is called the lumen and it is bounded by a layer of cells called the endothelium.

100 92 TOPIC 6. BLOOD VESSELS Arteries Arteries distribute blood from the heart to tissues of the body. To achieve this flow, the heart creates high hydrostatic pressure by contracting and forcing blood into the major arteries which leave each side of the heart. The structure of these arteries must absorb this high pressure, maintain the flow of the blood, and minimise any obstruction to flow. The structure of an artery The elastic fibres in the outer and middle layers allow the artery wall to stretch as each wave of blood arrives, and to contract as the wave passes, so helping to maintain flow. The layer of smooth muscle allows the diameter of the artery to be reduced to control flow through the vessel. The endothelium is not elastic, so when the lumen is reduced by the contraction of the elastic fibres, it becomes folded. As the blood gets further from the heart, the pressure falls because energy has been dissipated during the process of stretching the vessels walls and as a result of friction against the walls. Accordingly, the thickness of the different layers in the walls is reduced. The smallest arteries, the arterioles, supply blood to the capillaries where exchange with the tissues takes place. Arteries: Question Q3: Complete the sentences about artery structure by matching the phrases on the left with the phrases on the right. The centre of all vessels is the All vessels are lined by The outer layer of the artery wall is Smooth muscle and elastic fibres make up the connective tissue with elastic fibres. elastic walls of the arteries. endothelium. lumen. The surge of blood from the heart is middle layer of the artery wall. accommodated by the

101 TOPIC 6. BLOOD VESSELS Capillaries All tissues of the body contain capillaries which radiate out from the arterioles to form a bed, such that no cell is generally more than about 20 microns from a capillary. This is the point at which materials enter or leave the circulation, and so, unlike arteries or veins, capillaries have walls which allow the movement of fluid between the blood and the surrounding tissue. Accordingly, the wall of the capillary consists of only one layer of endothelium cells and a surrounding layer of connective tissue cells. The diameter of the lumen is only wide enough, at 8 microns, to allow the passage of a single red blood cell at a time. The functional length of each capillary, i.e. where transfer can occur, is roughly 20 times its diameter (this is very variable). The structure of a capillary A single arteriole may supply many capillary beds, and the entry of blood to each bed is controlled by smooth muscles in the arteriole walls. Bypass arterioles (vascular shunts) are also present so that when vasoconstriction reduces the flow into the capillary bed, blood passes directly from arteriole to venule. Capillaries: Question Q4: Complete the sentences about capillary structure by matching the phrases on the left with the phrases on the right. A capillary A capillary wall Vasoconstriction Vasodilation allows blood to flow into the capillary bed. exchanges materials with the tissues. consists of two layers of cells: endothelium and connective tissue. involves the contraction of the smooth muscle in artery walls.

102 94 TOPIC 6. BLOOD VESSELS Vasoconstriction and vasodilation The smooth muscle in the walls of the medium and small arteries is also used to control the flow of blood. We probably all remember our fingers and toes being numb with cold when we went sledging or snowballing. That effect is the result of the blood supply being shut down to the extremities to reduce heat loss. In the same way, our faces go white as blood is diverted away from our skin and into our muscles when we are very frightened or angry. These effects are caused by the sustained contraction of the smooth muscle in the walls of the arteries and arterioles involved in the supply of blood to the skin. This is known as vasoconstriction and it is used to close down the flow of blood into the capillary beds supplied by these arteries. When it is required to resupply the tissues with blood, the muscles relax and blood flows again into the capillaries. This is known as vasodilation and can be accompanied by pain, e.g. when it is numb fingers that are involved! If you think about this, you will notice that it means that there must be more space in the blood vessels than there is blood to fill it, otherwise it would be impossible to reduce flow to particular areas. The balancing of this process is primarily carried out by the autonomic nervous system, and so it is not under our voluntary control. Many other factors may be involved, including hormones circulating in the blood (e.g. adrenaline) or changes within the blood vessels themselves (e.g. damage to the vessel walls) Veins The function of the veins is to return blood to the heart from the tissues. However, this is not achieved directly by the contraction of the heart. By the time the blood returns to the venules and veins, it is under very low pressure. The result is that the force of gravity tends to keep the blood in the legs, arms and abdomen in a standing person. Pressure is exerted on the veins by the surrounding muscles, e.g. during walking or by the action of breathing, and the presence of valves in the veins ensures that the resulting flow is back towards the heart. When muscles contract, they get shorter and fatter which causes them to press against the veins; when we breathe out, we increase the pressure in the thorax and abdomen to force the air out of the lungs. The structure of veins

103 TOPIC 6. BLOOD VESSELS 95 Veins have a larger lumen in comparison to arteries at an equivalent point in the circulation. The middle and outer layers of the wall are also thinner and, most obviously, contain valves at regular intervals. The valves work like a one-way door: they allow the blood to flow back towards the heart, shutting to prevent any flow away from the heart. The difference in blood pressure in the arteries and veins is mirrored in the rate of flow, and in the distribution of blood between the different parts of the circulatory system. At any one time, the heart, arteries and capillaries contain about a third of the blood, the other two thirds being in the veins. Veins: Question Q5: Complete the sentences about vein structure by matching the phrases on the left with the phrases on the right. Veins carry the blood Valves cause the blood Veins have a much thinner to flow through veins in only one direction. connective tissue with elastic fibres. back to the heart under low pressure. Veins have an outer layer of muscular wall than arteries. 6.3 Exchange of materials between the blood and the cells Learning Objective By the end of this section, you should be able to: describe the movement of materials in and out of the blood circulation; state the substances which move into and out of the blood and tissues; state how lymph is formed and what happens to it. The capillaries are the only vessels in which movement of materials between the blood and the tissues occurs. The thin wall acts as a filter which allows the liquid fraction of the blood, the plasma, to pass into the surrounding tissue where it forms the tissue fluid (interstitial fluid) that bathes the cells. In most parts of the circulation, the wall acts like a fine sieve, allowing the water from the plasma, carrying glucose, oxygen, and other dissolved substances, to pass out of the capillary. Note that, although the vast majority of the oxygen in the blood is carried by haemoglobin in the red blood cells, to pass into the tissues oxygen must dissociate from the haemoglobin and pass into solution. Large plasma protein molecules and cells are too big and are kept in the blood. A moment's reflection will suggest that this cannot be the whole story for, after all, the blood is full of red blood cells which must be both added to the blood and removed from it. Thus, in the red bone marrow, the capillaries contain much larger pores which allow the

104 96 TOPIC 6. BLOOD VESSELS passage of cells. In other areas, passage out of the capillaries is relatively much more restricted, e.g. in the brain. Here, the capillaries are only permeable to oxygen and ions; larger molecules, e.g. glucose, only pass out of the lumen by active transport. This is the 'blood-brain barrier' which allows very strict regulation of the conditions in the central nervous system. The blood contains water, cells of various types (red blood cells, white blood cells, platelets), and a wide variety of other substances including carbon dioxide, glucose, amino acids, fatty acids, lactic acid, urea, various ions, hormones, and proteins. The proteins carry out a wide variety of functions, e.g. as antibodies (immune system), fibrinogens (blood clotting), enzymes, and hormones. However, the largest proportion (60%) of the blood proteins are the albumins which act as carrier molecules (for some hormones and fatty acids) and, most importantly, maintain the osmotic pressure of the blood The mechanism that causes flow in and out of capillaries The diagram shows the pressure differences which cause the flow of fluid out of and into the capillaries. These are measured in mmhg, the standard unit used in medicine for blood pressure. The flow in and out of a capillary The movement of the fluid is caused by the difference between the hydrostatic pressure in the blood, resulting from the contractions of the heart, and the osmotic pressure, caused by dissolved substances (principally albumins in the blood). On the arterial side of the capillary bed, the hydrostatic pressure exceeds the osmotic pressure in the blood which means that fluid is forced out into the tissues. As the blood passes through the capillary, the loss of fluid causes the hydrostatic pressure to drop until, at the venous end of the bed, the fluid is flowing back into the vessel as the osmotic pressure has remained largely unchanged. This is because the albumin responsible has stayed in the blood. The returning tissue fluid carries with it the carbon dioxide released by the respiration of the cells, any wastes from their metabolism (e.g. lactic acid, urea), and any products (e.g. hormones). The waste products are then carried around the body until they reach the organs which excrete them (e.g. carbon dioxide in the lungs, urea in the kidneys).

105 TOPIC 6. BLOOD VESSELS Lymph vessels Most tissue fluid returns to the capillaries, but up to 10% drains into the lymphatic system through a system of lymph capillaries. Although this is sometimes described as excess tissue fluid, this flow is an essential part of the circulatory system because of its importance in the functioning of the immune system. The fluid in the lymphatic vessels is called lymph, but it is just tissue fluid by another name! There are a few differences: lymph contains more white blood cells, especially when it leaves lymph nodes, and the lymph formed in the small intestine is white with fats (triglycerides). The lymph capillaries join to form lymph vessels which lead to lymph nodes. These are dispersed throughout the body, but are especially frequent in the chest, neck, pelvis, armpit, groin and intestinal regions. These are bean-shaped structures which contain a matrix of connective tissue, enmeshing a variety of white blood cells (especially lymphocytes). The principal locations give a clue to the function of the lymph nodes; they are found where lymph will have been collected from parts of the body which could have been invaded by bacteria. Other lymph vessels carry the processed lymph away from the nodes; it is eventually returned to the blood circulation in veins that are close to the heart (the subclavian veins). The pressure of the lymph is even lower than that of the blood in the veins. Like veins, lymph vessels contain valves and the pressure of muscles contracting in the surrounding tissues forces the lymph to flow. In addition, there is also peristaltic action by the muscle layers in the vessel walls. Lymph vessels: Question Q6: Complete the sentences about capillay bed exchange by matching the phrases on the left with the phrases on the right. Fluids leave capillaries because Fluids re-enter the capillaries because Lymph is formed from Lymph vessels return lymph to The waste and other products of cells return to the Tissue fluid is similar to blood plasma but lacks large protein molecules. capillaries in the tissue fluid. oxygen, glucose and other materials. the pressure is higher than the tissue fluid. tissue fluid, which enters the lymphatic capillaries. veins near the heart. the osmotic pressure exceeds the Tissue fluid supplies cells with hydrostatic pressure.

106 98 TOPIC 6. BLOOD VESSELS 6.4 Learning points Summary General The blood circulation carries blood from the heart, through arteries to the tissues, and back through veins to the heart. Blood pressure decreases with distance from the heart. All blood vessels have a central lumen lined by the endothelium. Arteries Compared to veins, arteries have thicker muscular walls. The outer layer of artery walls is made of connective tissue with elastic fibres. The middle layer of artery walls contains smooth muscle and elastic fibres. The contractions of the heart create surges of blood under high pressure. The elastic fibres in the artery walls allow them to stretch and recoil as these surges of blood pass. Contraction of the smooth muscle in the middle layer of the artery wall reduces the diameter of the lumen of the artery; this is called vasoconstriction. Vasoconstriction reduces the flow of blood into capillary beds. Relaxation of the smooth muscle of the middle layer of the artery wall causes the opposite effect; this is called vasodilation. Vasodilation increases the diameter of the lumen and allows blood to flow into a capillary bed. Capillaries Veins Capillaries allow exchange of substances with the tissues. The wall of the capillary is very thin, consisting of a layer of endothelium cells and a surrounding layer of connective tissue. Compared to arteries, veins have thinner walls with much less smooth muscle. Veins contain valves which ensure blood only flows in one direction, back to the heart. Blood flow in veins is caused by the contraction of muscles in the vicinity of the vein, so squeezing the vein and causing the blood to move through the valves.

107 TOPIC 6. BLOOD VESSELS 99 Summary Continued Exchange of materials The pressure difference between the blood in the capillary and the fluid in the surrounding tissue causes lymph to flow out of the capillary. In most capillaries, the escaping fluid consists of water with a variety of dissolved substances including glucose, oxygen, hormones, amino acids and mineral ions. This escaping fluid becomes tissue fluid. Tissue fluid is similar to blood plasma but does not contain plasma proteins. Tissue fluid returning to the capillaries carries with it carbon dioxide and metabolic wastes for excretion. Lymph vessels Ninety percent of the tissue fluid returns to the capillaries. Ten percent of the tissue fluid enters lymph vessels. Lymph is returned to the veins near the heart. 6.5 Extended response question The activity which follows presents an extended response question similar to the style that you will encounter in the examination. You should have a good understanding of the exchange of materials between the blood and the body tissues before attempting the question. You should give your completed answer to your teacher or tutor for marking, or try to mark it yourself using the suggested marking scheme. Extended response question: The exchange of materials between the blood and the body tissues Give an account of the exchange of materials between the blood and the body tissues under the headings: 15 min A) movement of fluid in and out of the blood; (6 marks) B) substances transferred. (4 marks)

108 100 TOPIC 6. BLOOD VESSELS 6.6 End of topic test End of Topic 6 test Q7: Complete the paragraph using the words from the list. (15 marks) The blood circulation carries blood from the heart through to the tissues and back through to the heart. Blood pressure with distance from the heart. All blood vessels have a central lined by the. Capillaries allow exchange of substances with the tissues. The wall of the capillary is very thin, consisting of a layer of endothelium cells and a surrounding layer of tissue. The difference between the blood in the and the fluid in the surrounding causes to flow out of the capillary. In most capillaries, the escaping fluid consists of water with a variety of dissolved substances including, oxygen,, amino acids and mineral ions. This escaping fluid becomes tissue which is similar to blood plasma but does not contain plasma. Tissue fluid returning to the capillaries carries with it carbon dioxide and wastes for excretion. Word list: arteries, capillary, connective, decreases, endothelium, fluid, glucose, hormones, lumen, metabolic, plasma, pressure, proteins, tissue, veins. Q8: Complete the sentences by matching the parts on the left with the parts on the right. (10 marks) Thick muscular walls are a feature of Arteries are made from an outer layer of connective tissue with The middle layer of artery walls is made from Contraction of the smooth muscle of the artery wall is known as The process that increases the diameter of the artery lumen is Thin walls with little smooth muscle are a feature of Blood flow in only one direction is ensured by The blood flow in veins is caused by the contraction of vasodilation. capillaries. vasoconstriction. arteries. elastic fibres. lymph. veins. smooth muscle. 90% of tissue fluid returns to the valves. A substance that is returned to veins near the heart is surrounding muscle.

109 TOPIC 6. BLOOD VESSELS 101 Q9: Select the correct words from the alternatives provided to complete the following sentences. (4 marks) Blood travels from the heart to the tissues in arteries / capillaries / veins. As blood gets further from the heart, the pressure in the vessels increases / decreases / stays the same. The centre of all blood vessels is lined by the connective tissue / endothelium / lumen. Compared to veins, arteries have similar / thicker / thinner muscular walls. Q10: What is the function of the elastic fibres in the outer layer of the artery walls? (2 marks) Q11: Name the effect caused by the contraction of the muscle cells in the middle layer of the artery wall. (1 mark) Q12: What is the purpose of the contraction of this tissue? (2 marks) Q13: Under what circumstances might this occur? (2 marks) Q14: In which blood vessels does exchange with the tissues take place? (1 mark) Q15: What feature of these vessels allows them to carry out this function? (1 mark) Q16: Explain how blood moves through veins. (3 marks) Q17: What causes fluid to leave the blood and bathe the cells? (2 marks) Q18: What name is given to the fluid that bathes the cells? (1 mark) Q19: How does the composition of this fluid differ from blood plasma? (1 mark) Q20: Name two substances that cells might release into this fluid. (1 mark) Q21: What percentage of tissue fluid is returned directly to the blood? (1 mark)

110 102 TOPIC 6. BLOOD VESSELS Q22: Into which vessels does the excess fluid drain? (1 mark) Q23: Where does this excess fluid return to the blood circulation? (1 mark) Q24: What name is given to this excess fluid? (1 mark)

111 103 Topic 7 Structure and function of the heart Contents 7.1 Introduction The structure of the heart The human circulatory system The control of heart rate Effect of exercise on the body Effect of exercise on cardiac output The cardiac cycle The cardiac conducting system Control of the heartbeat Electrocardiograms (ECGs) Blood pressure Learning points Extended response question End of topic test Learning Objectives By the end of this topic, you should be able to: describe the structure of the heart and the blood circulatory system; explain how blood is pumped through the heart - the cardiac cycle; describe how the function of the heart is controlled; explain how blood pressure is measured.

112 104 TOPIC 7. STRUCTURE AND FUNCTION OF THE HEART 7.1 Introduction The pressure which causes the blood to flow round the body's arteries is provided by the contractions of the heart. This structure is largely composed of a type of muscle, called cardiac muscle, which is unique in the body: it comprises individual cells like smooth muscle, but unlike it the cells are striped in the same way as skeletal muscle; it contracts constantly, at a resting rate of between 60 and 90 beats per minute (bpm); it does not tire, and in the average human lifetime will contract roughly times; the cardiac muscle cells are myogenic, contracting spontaneously to their own internally generated rhythm. 7.2 The structure of the heart Learning Objective By the end of this section, you should be able to: identify the main features of the structure of the heart; name the blood vessels entering and leaving the heart; explain the function of the valves in the heart; explain the difference between the left and right ventricles; state that equal volumes of blood flow through each side of the heart. The heart is a muscular pump which keeps blood flowing continuously in one direction round the body. It starts pumping before we are born and can even continue pumping for a short time after death. The heart is a muscular bag which consists of four chambers through which blood flows. The right and left sides of the heart are completely separated from each other by the septum. The two upper chambers are called atria, while the lower chambers are known as ventricles. The left atrium receives oxygenated blood (bright red in colour) from the lungs via two pulmonary veins. The blood flows into the left ventricle through the bicuspid valve. When the ventricle contracts, the blood is forced out through the semilunar valve into the aorta, the largest artery in the body. The blood is passed around the body, materials are exchanged and deoxygenated blood (blue in colour) flows back to the right atrium via two main veins called the superior and inferior venae cavae (superior means 'above' while inferior means 'below'). The blood flows through the tricuspid valve into the right ventricle, and from there into the pulmonary artery which carries it to the lungs.

113 TOPIC 7. STRUCTURE AND FUNCTION OF THE HEART 105 The bicuspid and tricuspid valves are known as the atrio-ventricular valves. They prevent the backflow of blood into the atria when the ventricles contract. These valves are attached to the ventricle walls by tendons, called chordae tendinae, which prevent the valves inverting (turning inside-out) when the ventricles contract. The semilunar valves (found at the entrance to the aorta and pulmonary artery) prevent blood flowing back into the ventricles when they relax. The walls of the atria are thinner than those of the ventricles because they only have to force blood a very small distance into the ventricles. The walls of the ventricles are thicker because they have to provide enough force to pump the blood further. The wall of the left ventricle is thicker than that of the right since the right ventricle only needs to pump blood to the lungs (which are next to the heart) while the left ventricle has to pump blood all round the body. The volume of blood passing through the two sides of the heart is, of course, the same! The structure of the heart: Questions Q1: Complete the diagram which shows the internal structure of the heart. 30 min

114 106 TOPIC 7. STRUCTURE AND FUNCTION OF THE HEART Hint: when labelling the sides of the heart imagine this is your heart being viewed from the front. Q2: Why are the bicuspid and tricuspid valves also known as atrio-ventricular valves? Q3: What is the function of valves in the heart? Q4: What is the function of the chordae tendinae? 7.3 The human circulatory system Learning Objective By the end of this section, you should be able to: identify the vessels carrying blood to and from the heart, head, kidneys, liver and small intestine. Although a detailed knowledge of the blood supply to the various parts of the body is not specified at this point in the syllabus, this section is included as it provides the background which is essential to the understanding of other parts of the course. Oxygenated blood is pumped out of the left ventricle into the aorta. Almost immediately, the aorta begins to divide into various other arteries including: the coronary arteries suppling the heart muscle itself; the carotid artery carrying blood to the head and brain; the hepatic artery supplying the liver; the renal arteries supplying the kidneys. At the same time, deoxygenated blood is pumped from the right ventricle into the pulmonary artery which carries it to the lungs to be reoxygenated. From here, the oxygenated blood is carried back to the left atrium via the pulmonary veins. As blood passes through the body organs other than the lungs, it loses oxygen and becomes deoxygenated. Various veins, for example the jugular vein from the head, the hepatic vein from the liver, and the renal veins from the kidneys, carry this deoxygenated blood back to the right atrium of the heart. An additional vein is found between the intestines and the liver. Known as the hepatic portal vein, it carries blood containing the products of digestion from the intestine to the liver.

115 TOPIC 7. STRUCTURE AND FUNCTION OF THE HEART 107 The human circulatory system: Questions Q5: Complete the diagram which shows the circulatory system. 20 min

116 108 TOPIC 7. STRUCTURE AND FUNCTION OF THE HEART Q6: Complete the table to show the arteries and veins associated with various parts of the body. Organ/area of body Associated artery Associated vein heart head kidney liver small intestine Artery/vein list: carotid artery, coronary artery, coronary vein, gut arteries, hepatic artery, hepatic portal vein, hepatic vein, jugular vein, renal artery, renal vein. 7.4 The control of heart rate Learning Objective By the end of this section, you should be able to: explain the role of the autonomic nervous system in the control of heart rate; describe the effect of hormones and exercise on heart rate; state what is meant by the terms cardiac output, heart rate and stroke volume; explain the calculation of cardiac output. The heart rate is controlled by nerves from the autonomic nervous system which is controlled by centres in the medulla of the brain and consists of two parts: the sympathetic and the parasympathetic which act antagonistically to each other; that is they produce opposite effects to each other. Nerves from the sympathetic part of the autonomic nervous system increase the rate at which the heart beats by the secretion of noradrenaline (norepinephrine). Nerves from the parasympathetic part of the autonomic nervous system decrease the heart rate by the secretion of acetylcholine. The hormone adrenaline produced by the adrenal glands also increases the heart rate. The following illustration shows the effect that the sympathetic and parasympathetic systems have on the heart rate.

117 TOPIC 7. STRUCTURE AND FUNCTION OF THE HEART 109 The effect of sympathetic and parasympathetic nervous systems on heart rate It can be seen that one heartbeat is longer under the influence of the parasympathetic nervous system. This means that there will be fewer beats per minute, therefore the heart rate is slower when the heart is stimulated by nerve impulses from the parasympathetic system Effect of exercise on the body During exercise, the metabolic rate of skeletal muscles increases sharply, therefore cells need much more glucose and oxygen than they would at rest. Cells also produce more carbon dioxide than they would at rest. These changes interrupt the 'steady state' of the body which brings about changes to the respiratory system and the cardiovascular system. As a result, the body is returned to its 'steady state' Effect of exercise on cardiac output The stroke volume is the volume of blood pumped out of the heart during one heartbeat. The heart rate is the number of heartbeats produced per minute. Cardiac output is the volume of blood pumped out of the heart per minute. Cardiac output = stroke volume heart rate During exercise, the increased levels of carbon dioxide in the blood are detected by the medulla, aorta and carotid arteries. The medulla increases the number of sympathetic nerve impulses being sent to the pacemaker (sino-atrial node) in the heart. These increased sympathetic nerve impulses increase both the heart rate and stroke volume of the heart. This increases the cardiac output so that glucose and oxygen can be transported faster to the skeletal muscles. The sympathetic nerves also stimulate the adrenal glands to secrete adrenaline which further stimulates the sino-atrial node in the heart.

118 110 TOPIC 7. STRUCTURE AND FUNCTION OF THE HEART How exercise affects the body 10 min The following illustrates the immediate effects of exercise on the body. Muscles are working at a higher intensity than normal and require more energy. To provide the extra energy to pump blood around the body more quickly, the breathing becomes deeper and faster to get more air into the lungs. The rate of metabolism also increases in order to metabolise energy stores (carbohydrates and fats) to produce ATP. Sweat is produced to cool the body down. Lactate is produced during anaerobic exercise. Effect of exercise on cardiac output: Question Complete the table by working out the cardiac output for each of the body states. Remember that: Cardiac output (l/min) = (stroke volume (ml) heart rate (bpm)) / 1000 Make sure that you look at the units at the top of each column. Q7: State of body Stroke volume (ml) Heart rate (bpm) at rest during gentle exercise during strenuous exercise Cardiac output (l/min)

119 TOPIC 7. STRUCTURE AND FUNCTION OF THE HEART The cardiac cycle Learning Objective By the end of this section, you should be able to: state the sequence of contraction and relaxation of the muscular walls of the heart during systole and diastole; similarly, state the sequence and cause of the opening and closing of the heart valves; explain the heart sounds heard through a stethoscope. The cardiac cycle refers to the pattern of contraction and relaxation of the heart during one complete heartbeat. Contraction of the heart muscle is known as systole while relaxation is known as diastole; the complete cycle of systole and diastole is one heart beat. If an individual has a heart rate of 75 beats per minute, then the average length of time of one heartbeat is 0.8 seconds. The atria (upper chambers) contract a fraction of a second before the ventricles contract. During atrial systole, the two atria contract simultaneously, the atrio-ventricular valves (bicuspid and tricuspid valves) are open, and blood is forced through into the ventricles. At this point, the ventricles are relaxed (in diastole) and the semilunar valves are closed. Atrial systole is followed about 0.1 seconds later by ventricular systole. The atrioventricular valves are closed and blood is forced out through the semilunar valves into the arteries. It is the opening and closing of the atrioventricular (AV) and semilunar (SL) valves that create the heart sounds which are heard with a stethoscope. This apparatus collects sound waves in a diaphragm-covered bell and carries them through a plastic tube to a pair of earpieces. It has been modified since its invention in the 1850s to enhance the detection of particular frequencies, yet it still remains one of the simplest, but most symbolic, items of medical equipment. With experience, it can be used to provide information about the functioning of not only the heart, but also the lungs, intestines, and the blood flow in the arteries and veins. During atrial and ventricular diastole, blood from the pulmonary veins and the venae cavae fill up the atria. Then the cycle repeats.

120 112 TOPIC 7. STRUCTURE AND FUNCTION OF THE HEART

121 TOPIC 7. STRUCTURE AND FUNCTION OF THE HEART 113 The contraction of the chambers of the heart generates pressure differences in the blood which cause the opening and closing of the various heart valves. During diastole, when the muscle of all the chambers is relaxed, the pressure of blood flowing in from the vena cava and the pulmonary vein opens the AV valves and blood flows into the atria and through into the ventricles. During atrial systole, the muscle of the atrial walls contracts. This closes the veins entering the chambers and increases the pressure in the atria relative to that in the ventricles. As a result, the ventricular walls are stretched as more blood is forced into the ventricles. When ventricular systole begins, the atrial muscle relaxes and the pressure difference is reversed. This forces shut the AV valves, preventing back flow into the atria, and, at the same time, pushes open the semilunar valves, allowing blood to flow into the aorta and the pulmonary artery. When the ventricles relax and the heart enters diastole, the blood pressure in the arteries leaving the heart forces shut the semilunar valves, ensuring that blood flows off to the body and lungs rather than back into the ventricles. The cardiac cycle: Questions Q8: What is meant by the terms systole and diastole? 15 min Q9: During atrial systole, which heart valves are open and which are closed? Q10: During which process, ventricular systole or diastole, is the pressure greater in the ventricles? Give a reason for your answer.

122 114 TOPIC 7. STRUCTURE AND FUNCTION OF THE HEART 7.6 The cardiac conducting system Learning Objective By the end of this section, you should be able to: state that heart muscle is myogenic; explain the role of the pacemaker (SAN) in co-ordinating the contractions of the heart; state that the autonomic nervous system and hormones regulate heart rate; state the role of the atrioventricular node (AVN); describe an electrocardiogram and explain what it shows. The mechanism of controlling the beating of the heat is described first, followed by a description of electrocardiograms and their diagnostic value Control of the heartbeat Cardiac muscle is different from other types of muscle in that it is myogenic. This means that it does not need an electrical impulse in order to contract. However the synchronisation of the heartbeat and the rate at which it beats is controlled by the nervous system. This synchronisation is controlled by an inbuilt pacemaker and the conducting system of nerves in the heart itself. The conducting system of the heart

123 TOPIC 7. STRUCTURE AND FUNCTION OF THE HEART 115 The pacemaker is properly known as the sino-atrial (SA) node and is located in the wall of the right atrium, close to the entrance of the superior vena cava. This SA node generates rhythmical waves of electrical impulses which spread throughout the walls of the atria, making them contract. The cells of the SAN, although modified muscle cells, do not themselves contract. They are autorhythmic, sending out between 60 and 100 impulses per minute without any external stimulation. The effect of the autonomic nervous system is to vary this rate. Between the atria and ventricles there is another node called the atrio-ventricular (AV) node, which passes the electrical impulses on to a network of conducting fibres which spread throughout the walls of the ventricles. The wave of electrical impulses is transmitted very quickly down to the base of the septum (in the 'bundle of His'), then upwards and outwards throughout the ventricle walls (by the Purkinje fibres). This causes the ventricles to contract from the bottom up (the most efficient way of emptying them). This coordination ensures that the atria contract a fraction of a second before the ventricles and enables both the atria and ventricles to fill up with blood before they contract. In this way blood enters and leaves the heart efficiently. Control of the heartbeat: Steps The following shows the steps involved in the process of controlling the heat beat. 10 min

124 116 TOPIC 7. STRUCTURE AND FUNCTION OF THE HEART

125 TOPIC 7. STRUCTURE AND FUNCTION OF THE HEART 117 The cardiac conducting system: Questions Q11: Where is the sino-atrial node found in the heart? Q12: Where do the conducting fibres initiate contraction of the ventricles? Why is this important? Electrocardiograms (ECGs) Learning Objective By the end of this section, you should be able to: state that an electrocardiogram shows the electrical activity in the heart muscle as the wave of excitation spreads first across the atrial walls and then through the walls of the ventricles; state that, in a healthy heart, a single beat is represented by a series of peaks and troughs reflecting first atrial, then ventricular systole, and finally a region of low electrical activity corresponding to diastole. An electrocardiogram (ECG) is a graph showing the electrical activity in the heart muscle. This activity can be detected by electrodes placed on the skin of the chest and shown on a machine called an electrocardiograph.

126 118 TOPIC 7. STRUCTURE AND FUNCTION OF THE HEART Diagram (a) shows an electrocardiogram of a healthy heart. In the diagram, the P wave corresponds to a wave of excitation spreading over the atrial walls, the QRS and T waves correspond to a wave of excitation spreading over the walls of the ventricles. Notice that the pattern repeats at regular intervals. Diagram (b) shows an electrocardiogram of a damaged heart. Notice that there is no obvious regular pattern. This heart is said to be in ventricular fibrillation (VF). What has happened here is that the coordination of the heartbeat has been interrupted. Instead of the electrical impulses from the atrio-ventricular node passing down the Purkinje fibres in an ordered way, they have become chaotic. Rather than there being one coordinated wave of contraction from the bottom up, followed by a coordinated wave of relaxation, some parts of the ventricle walls are contracting while others are relaxing. The effect is called fibrillation and results in little blood being pumped out of the heart. Fibrillation can be fatal unless it is treated immediately by passing a strong electric current through the chest wall to the heart. This usually stops the heart completely for a few seconds, after which it often begins to beat again in a coordinated way.

127 TOPIC 7. STRUCTURE AND FUNCTION OF THE HEART Blood pressure Learning Objective By the end of this section, you should be able to: state that blood pressure changes in the arteries as a result of the cardiac cycle; state that blood pressure is measured by a sphygmomanometer; explain the use of the sphygmomanometer; state a typical blood pressure reading and explain it; state that hypertension is a major risk factor for many diseases including coronary heart disease. Blood flows through the vessels of the circulatory system as a result of the pressure generated when the heart contracts. Blood pressure is measured using a sphygmomanometer. This instrument measures both the systolic pressure (when the heart contracts) and the diastolic pressure (when the heart relaxes). Because the heart pumps blood into arteries, the blood pressure is greatest in arteries. As blood is forced along the arteries there is little decrease in pressure because the arteries have elastic walls which stretch during ventricular systole and recoil during ventricular diastole, continuing to force the blood along them. Blood pressure is measured most accurately just above the elbow on the upper arm, although measurements can also be taken at the wrist or even the finger. The unit is the millimetre of mercury (mmhg), which sounds like a rather archaic unit compared to the pascal or the torr. It stems from the original method of determining pressure by measuring the height of the column of mercury that was supported in the U-tube of a manometer. Measurements are made of the systolic and diastolic pressure, and a person's blood pressure is expressed as systolic/diastolic, e.g. a typical reading for a young adult would be 120/70mmHg. A reading in excess of 140/90mmHg is classified as hypertension, which is a major risk factor for many diseases, including coronary heart disease. However once blood reaches the smaller arterioles the blood pressure decreases as a result of the general increase in surface area provided by the greater number of arterioles. Imagine water in a large pipe being passed into a network of smaller but more numerous pipes; the pressure in each of the smaller pipes would be less than the pressure in the single large pipe as the water is spread out. Also, as a result of the smaller arterioles' inner diameter, the rate at which the blood flows decreases - this further decreases the blood pressure. As the arterioles divide further into capillaries the rate of blood flow and blood pressure continue to decrease. Remember it is here that exchange of materials between the blood and tissues occur, so a slow rate of flow is desirable here. Blood pressure continues to decrease as blood is passed into venules and veins. This is why veins need to have valves present to prevent the backflow of blood.

128 120 TOPIC 7. STRUCTURE AND FUNCTION OF THE HEART Measuring blood pressure: Steps 10 min The following steps show the process of measuring blood pressure.

129 TOPIC 7. STRUCTURE AND FUNCTION OF THE HEART 121

130 122 TOPIC 7. STRUCTURE AND FUNCTION OF THE HEART Blood pressure: Questions 10 min Q13: When is the blood pressure lowest? a) During systole b) During diastole Q14: Margaret has a systolic blood pressure of 130 and a diastolic blood pressure of 85. How should her blood pressure be recorded? a) 85/130 b) 130/85 Q15: Tom's blood pressure is 140/90. What is his systolic blood pressure in mm Hg? Q16: A woman's blood pressure is measured as 165/95. How would you describe her blood pressure? a) Low b) Normal c) High d) Hypertensive Q17: Why do you think the systolic value is higher than the diastolic value?

131 TOPIC 7. STRUCTURE AND FUNCTION OF THE HEART 123 Q18: Complete the graph, which shows how blood pressure varies in arteries, capillaries and veins, using the labels provided. Q19: Can you explain why the blood pressure oscillates (goes up and down) in the arteries? (Hint - think about the heartbeat.)

132 124 TOPIC 7. STRUCTURE AND FUNCTION OF THE HEART 7.8 Learning points Summary The structure of the heart The heart consists of four chambers, two (upper) atria and two ventricles. Blood enters the heart from the body into the right atrium via the (superior and inferior) vena cava. Blood leaves the heart for the lungs from the right ventricle via the pulmonary artery. Blood enters the heart from the lungs into the left atrium via the pulmonary vein. Blood leaves the heart for the body from the left ventricle via the aorta. The atrioventricular valves prevent backflow from the ventricles into the atria. The semilunar valves prevent backflow from the aorta and pulmonary artery into the ventricles. The same volume of blood is pumped through each ventricle. The human circulatory system The heart muscle is served by the coronary artery and vein. The control of heart rate Heart rate is externally regulated by the autonomic nervous system and by hormones. The medulla of the brain raises the heart rate through the sympathetic nervous system. The medulla of the brain lowers the heart rate through the parasympathetic nervous system. The sympathetic and parasympathetic nervous systems act antagonistically. Nerve cells of the sympathetic nervous system accelerate heart rate by secreting noradrenaline (norepinephrine). Nerve cells of the parasympathetic nervous system slow heart rate by secreting acetylcholine. The hormone adrenaline increases heart rate. Exercise increases heart rate.

133 TOPIC 7. STRUCTURE AND FUNCTION OF THE HEART 125 Summary Continued Cardiac output is the volume of blood leaving each ventricle in one minute (ml/min). Heart rate is the number of times the heart beats in one minute (bpm). Stroke volume is the volume of blood pumped from each ventricle during one heartbeat (ml). Cardiac output (l/min) = (stroke volume (ml) heart rate (bpm)) / 1000 The cardiac cycle The cardiac cycle is the pattern of contraction and relaxation of the heart during one complete heartbeat. Systole refers to contraction of the muscle and diastole to its relaxation. Atrial systole starts slightly before ventricular systole, forcing blood through the AV valves into the ventricles. Ventricular systole follows, closing the AV valves and forcing blood through the SL valves into the pulmonary artery and the aorta. During diastole, relaxation of the muscles of the atria and ventricles causes blood to flow into the atria and through into the ventricles. Both atria and ventricles are in diastole for about half of a heartbeat. During ventricular diastole, backflow of blood under high pressure from the arteries is prevented by closure of the SL valves. The opening and closing of the AV and SL valves cause the heart sounds detected with stethoscope. The cardiac conducting system Heart muscle cells are myogenic, i.e. they contract and relax to their own internal rhythm without external stimulation. Heart beating is regulated by the autonomic nervous system and by hormones. The sinoatrial node (SAN), or pacemaker, sets the rate of contraction of the heart muscle. The cells of the SAN are autorhythmic, not contracting themselves but sending out impulses which co-ordinate the contraction of the heart muscle. Impulses from the SAN travel across the atria, causing them to contract simultaneously, and to the atrioventricular node (AVN). The AVN passes the impulses through the ventricles, causing them to contract simultaneously.

134 126 TOPIC 7. STRUCTURE AND FUNCTION OF THE HEART Summary Continued The impulses from the SAN and the AVN generate currents which are detected by electrocardiography and recorded on an electrocardiogram. Electrocardiograms (ECGs) state that an electrocardiogram shows the electrical activity in the heart muscle as the wave of excitation spreads first across the atrial walls and then through the walls of the ventricles; state that, in a healthy heart, a single beat is represented by a series of peaks and troughs reflecting first atrial, then ventricular systole, and finally a region of low electrical activity corresponding to diastole. Blood pressure The contraction and relaxation of the heart muscle during the cardiac cycle cause the variations in blood pressure in the arteries. These variations in pressure are detectable in arteries as the pulse. Blood pressure is measured by a sphygmomanometer. The steps in the use of the sphygmomanometer are: an inflatable cuff stops blood flow and deflates gradually; blood flow restarts as systolic pressure is reached, and the pulse is felt; once blood flows freely, and the pulse is no longer felt, diastolic pressure has been reached. Blood pressure is expressed as systolic pressure/diastolic pressure. A typical reading for a young adult is 120/70mmHg. Hypertension is defined as blood pressure above 140/90mmHg. Hypertension is a major risk factor for many diseases including coronary heart disease.

135 TOPIC 7. STRUCTURE AND FUNCTION OF THE HEART Extended response question The activity which follows presents an extended response question similar to the style that you will encounter in the examination. You should have a good understanding of the cardiac cycle before attempting the question. You should give your completed answer to your teacher or tutor for marking, or try to mark it yourself using the suggested marking scheme. Extended response question: The cardiac cycle Give an account of the cardiac cycle under the following headings: 1. atrial systole; (3 marks) 15 min 2. ventricular systole; (5 marks) 3. diastole. (2 marks) 7.10 End of topic test End of Topic 7 test Q20: Complete the sentences by matching the parts on the left with the parts on the right. (9 marks) 30 min Atria: Ventricles: Right ventricle: Pulmonary artery: Left ventricle: Aorta: Atrioventricular valves: Semilunar valves: Coronary artery: vessel which carries blood from the heart to the lungs. chamber which pumps blood round the body. artery which carries blood from the heart to the body. structures between upper and lower chambers of the heart. vessel which supplies blood to the heart muscle. lower chambers of the heart. chamber which pumps blood to the lungs. upper chambers of the heart. structures which prevent backflow of blood to the heart.

136 128 TOPIC 7. STRUCTURE AND FUNCTION OF THE HEART Q21: Complete the sentences by matching the parts on the left with the parts on the right. (11 marks) Autonomic: Medulla: Sympathetic: Parasympathetic: Antagonistic: Noradrenaline: Acetylcholine: Adrenaline: Stroke volume: Heart rate: Cardiac output: secreted by nerves to decrease heart rate. volume from each ventricle during one heartbeat. secreted by nerves to increase heart rate. part of the nervous system that increases heart rate. part of the nervous system that controls heart rate. hormone that increases heart rate. number of heartbeats per minute. area of the brain that controls heart rate. action of the nervous system that controls heart rate. calculated by multiplying stroke volume by heart rate. part of the nervous system that decreases heart rate. Q22: Complete the sentences by matching the parts on the left with the parts on the right. (10 marks) Cardiac cycle: Atrial systole: Ventricular systole: Diastole: Atrioventricular: Semilunar: Myogenic: Sinoatrial node: Ventricular: Electrocardiogram: contraction of ventricle muscle. valves which open when the atria contract. muscle which can contract without external stimulation. contraction and relaxation of the heart during one complete beat. record of impulses generated by the SAN and AVN. contraction of the muscle of the atrium. co-ordination of the heart muscle contraction. valves which open when the ventricles contract. relaxation of heart muscle. contraction controlled by the atrioventricular node.

137 TOPIC 7. STRUCTURE AND FUNCTION OF THE HEART 129 Q23: Complete the paragraph using the words from the list. (12 marks) The contraction and of the heart muscle during the cycle cause large variations in blood pressure in the which are detectable as the. Blood pressure is measured using a. An inflatable stops blood flow and gradually deflates. As systolic pressure is reached, blood flow and the pulse is felt. Once blood is flowing freely, no pulse is felt and diastolic pressure is measured. Blood pressure is expressed as pressure / pressure, a typical reading being mm Hg. Hypertension, which is indicated by blood pressure reading of over mm Hg, is a major risk factor for heart disease. Word list: 120/70, 140/90, arteries, cardiac, coronary, cuff, diastolic, pulse, relaxation, restarts, sphygmomanometer, systolic. Q24: The volume of blood pumped by the left and right ventricles is. (1 mark) Q25: The cardiac output of a person with a heart rate of 80 bpm and stroke volume of 75 ml is. (1 mark) Q26: During atrial systole, the muscle of the right is. (2 marks) Q27: During diastole, blood flows from the into the right atrium. At this stage, the valves are open and the valves are closed. During ventricular systole, the valves are open and the valves are closed. Blood therefore flows from the left ventricle into the and the right ventricle into the. (7 marks) Q28: Select the correct words from the alternatives provided to complete the following sentences. (5 marks) Cardiac muscle cells are AV node / autorhythmic / electrocardiogram / myogenic / sinoatrial node. The cells of the pacemaker are AV node / autorhythmic / electrocardiogram / myogenic / sinoatrial node. The rate at which cardiac muscles contract is set by the AV node / autorhythmic / electrocardiogram / myogenic / sinoatrial node. The contraction of the ventricles is triggered by the AV node / autorhythmic / electrocardiogram / myogenic / sinoatrial node.

138 130 TOPIC 7. STRUCTURE AND FUNCTION OF THE HEART Impulses in the heart can be recorded on an AV node / autorhythmic / electrocardiogram / myogenic / sinoatrial node. Q29: The two branches of the autonomic nervous system are said to be. They are controlled by the of the brain. The sympathetic nervous system the rate of the SAN by the secretion of. The parasympathetic nervous system the rate of the SAN by the secretion of. (6 marks) Q30: What causes the changes in blood pressure in the aorta? (1 mark) Q31: What instrument is used to measure blood pressure? (1 mark) Q32: Which blood pressure is this instrument measuring when a pulse ceases to be detected? (1 mark) Q33: What is the correct term for high blood pressure? (1 mark) Q34: What unit is used to measure blood pressure? (1 mark) Q35: A blood pressure reading for a middle-aged man was 145/100. Explain what this means. (1 mark) Q36: Suggest a cardiovascular disease that this man would be at increased risk of contracting. (1 mark)

139 131 Topic 8 Cholesterol and cardiovascular disease Contents 8.1 Introduction Cholesterol What is cholesterol? Functions of cholesterol in the body Transport of cholesterol in the body Controlling cholesterol levels Familial hypercholesterolaemia Atherosclerosis and associated diseases Atherosclerosis Thrombosis Peripheral vascular disorders ASSIGN score Learning points Extended response question End of topic test Learning Objectives By the end of this topic, you should be able to: describe the chemical nature of cholesterol, its sources and its roles in the body; explain the factors which affect levels of cholesterol in the body; describe the development and effects of atherosclerosis, thrombosis and peripheral vascular disease.

140 132 TOPIC 8. CHOLESTEROL AND CARDIOVASCULAR DISEASE 8.1 Introduction The diseases covered in this topic (atherosclerosis, thrombosis, peripheral vascular disorders) are all related to the role of cholesterol in the body and its disruption. Despite its being essential to all animal life, cholesterol is often portrayed in the media as a chemical responsible for ill-health. This it certainly can also be when, in association with certain lipoproteins, its concentration in the blood becomes too high, in which case it contributes to the formation of plaques on the artery walls. It is this plaque formation which gives rise to atherosclerosis, leading to high blood pressure, peripheral vascular disorders, angina, cardiac infarction (heart attack) and stroke. 8.2 Cholesterol Learning Objective By the end of this section, you should be able to: describe the chemical nature of cholesterol; state how cholesterol is formed in, and eliminated from, the body; name dietary sources of cholesterol; describe some of the roles of cholesterol in the body; describe the transport of cholesterol in the body; explain how the level of cholesterol may be increased and decreased in the body; explain the cause, effects, detection and treatment of familial hypercholesterolaemia. This section describes the structure, functions, transport and blood concentration of cholesterol What is cholesterol? Cholesterol is a waxy solid which is virtually insoluble in water, but easily dissolved in organic solvents, e.g. acetone and methanol. It is a steroid, a fat, and, like all fats, cholesterol is composed of carbon, hydrogen and oxygen atoms, with the formula C 27 H 46 O. All steroids have a core of twenty carbon atoms, bonded together in the form of four fused rings.

141 TOPIC 8. CHOLESTEROL AND CARDIOVASCULAR DISEASE 133 The structure of cholesterol Although up to 75% of the body's supply of cholesterol comes from the diet, cholesterol is also synthesised within the body. All animal cells make cholesterol, starting with one molecule each of acetyl CoA and the related acetoacetyl CoA. There follows a sequence of enzyme-assisted reactions, one of which is sensitive to cholesterol levels and acts as part of their homeostatic control, which is the point at which statin drugs act. One type of prescription statin The body's daily production of cholesterol is roughly 1g for a 70kg person, up to a quarter of which is produced in the liver. The liver is also responsible for the elimination of cholesterol as a component of bile. Occasionally, this cholesterol develops into crystalline accretions in the gall bladder, which are known as gallstones. These oval structures can be 3cm in length and are the most common type of gallstone. In the diet, the principal source of cholesterol is the animal fat found in cheese, eggs, beef, pork, poultry, fish and shellfish. It is not found in plant foods to any significant extent. Generally, less cholesterol is absorbed from food than is synthesised in the body. Although consumption of saturated fat has been linked to cholesterol levels, there is considerable debate about the nature of the connection between the two. Alternative explanations suggest that lifestyle and consumption of other foods, such as carbohydrates, as causative factors. It should be remembered that excess consumption of any energy foods will lead to the build-up of fat stores in the body.

142 134 TOPIC 8. CHOLESTEROL AND CARDIOVASCULAR DISEASE Cholesterol: Questions 10 min Q1: Complete the paragraph using the words from the list. (some words may be used more than once) Cholesterol is a waxy compound (a fat). It is synthesised in all cells, but the largest producer is the. Dietary sources of cholesterol are foods, such as and products. A diet high in fats may lead to increased cholesterol levels. Cholesterol is eliminated from the body by the in the form of. Word list: animal, bile, dairy, liver, meat, saturated, steroid. Q2: Why is cholesterol only found attached to carrier molecules in the blood and not free in solution? Functions of cholesterol in the body Far from being some alien chemical which causes disease, cholesterol is fundamental to the proper functioning of the body of all animals. Cholesterol is used to build and to maintain the membranes of the cell. As part of membrane structure, it controls the permeability of the plasma membrane to hydrogen and sodium ions as well as other substances. Within the membrane, cholesterol is also involved in the transport of substances into the cell (endocytosis), the processing of cell signals (such as antigens or hormones), and accelerating the conduction of nerve impulses (as part of the myelin sheath). As an important constituent of bile, cholesterol aids the absorption of vitamins A, D, and other fat-soluble vitamins. It is also a precursor for the synthesis of vitamin D (in the skin) and the steroid hormones, e.g. testosterone, oestrogen and progesterone. Functions of cholesterol: Question Q3: Complete the table, which contains information about the functions of cholesterol in the body, using the words from the list. (some words may be used more than once) Function Location Example Control permeability Endocytosis Vitamin D Interstitial cells Word list: hydrogen/sodium ions, plasma membrane, precursor, skin, testosterone, transport into cell.

143 TOPIC 8. CHOLESTEROL AND CARDIOVASCULAR DISEASE Transport of cholesterol in the body Given its near insolubility in water, cholesterol does not circulate freely round the body but is transported attached to carrier molecules. These are lipoproteins which surround and contain insoluble lipid molecules, and enable them to be carried in the blood or across membranes. The most important lipoproteins involved in cholesterol transport are high- and lowdensity lipoproteins (HDLs and LDLs). The difference in density reflects the relative proportion of fat in the molecule, fat having a lower density than protein. HDLs are the smallest of the lipoprotein molecules and have the highest proportion of protein. They are made in the liver and are released into the blood stream, where they pick up excess cholesterol from body cells and transport it back to the liver for elimination. Most significantly, they remove cholesterol from the atheromas, which are part of the plaques formed in atherosclerosis. This cholesterol is sometimes referred to as 'good', but is just the same as that found attached to LDLs or, indeed, in atheromas. As a result, high levels of HDLs can prevent or reduce the accumulation of cholesterol in the artery walls. LDLs are also synthesised in the liver, but have a much larger fat component. They are created in response the presence of the level of fatty acids carried in the blood. Their function is to carry cholesterol to the body cells. These cells, when they require cholesterol, make LDL receptors which are located on the plasma membrane. When attached to a molecule of LDL, they are absorbed into the cell and the cholesterol it carries is released. The concentration of cholesterol in the cell acts in a negative feedback loop to control the transcription of the LDL-receptor gene; a high level of cholesterol will reduce the production of the receptor molecules, and vice versa. Where there is an excess of LDL in the blood beyond that required by the body cells, the LDLs may deposit cholesterol in the endothelium of the artery walls, forming atheromas. LDLs circulate in the blood for a few days and, if not absorbed into other body cells, attach to LDL-receptors on liver cells and are digested. The ratio of HDL/LDL in the blood is important in determining the chances of atherosclerosis. A high ratio will cause the removal of cholesterol from the atheromas in the arterial walls, reducing atherosclerosis. The link between saturated fats and cholesterol levels depends on the observation that, whereas increased intake of all fats increases the concentration of HDLs, only saturated fats increase the level of LDLs (and hence the transport of cholesterol to the body cells).

144 136 TOPIC 8. CHOLESTEROL AND CARDIOVASCULAR DISEASE High density and low density lipoproteins: Question Q4: Select the correct option to complete the sentences about cholesterol transport. 1. Cholesterol is transported by fats / proteins / lipoproteins. 2. Excess cholesterol is carried from body cells to the liver by LDLs / HDLS / lipids. 3. Cholesterol is transported from the liver to the body cells by LDLs / HDLs / lipids. 4. LDL-receptors are found are found on only liver cells / most cells / all cells. 5. When a cell is making cell membranes, LDL-receptor production is unchanged / increased / decreased. 6. Excess LDLs may deposit cholesterol in body cells / atheromas / lipoproteins. 7. Atherosclerosis is reduced by a HDL/LDL ratio which is low / medium / high. 8. LDL levels in the blood are increased by a diet high in fats which are saturated / unsaturated / both.

145 TOPIC 8. CHOLESTEROL AND CARDIOVASCULAR DISEASE Controlling cholesterol levels The concentration of cholesterol in the blood is dependent on the ratio of HDLs to LDLs, which in turn is determined by the balance between the intake of energy and its consumption by the cells of the body. Such changes can be brought about by exercise, which increases energy use, and dietary changes, which alter the intake of energy, especially in the form of fats. Regular physical activity tends to raise HDL levels. However, it does depend on the type and duration of the activity. If the exercise is too gentle, e.g. ambling along with the dog, then respiration can be fuelled by glucose from the blood. Moderate exercise, such as a brisk walk that puts you slightly out of breath, does mobilise the fat reserves and so helps weight loss. Repeated daily for about half an hour, it also raises HDL levels, as does intense exercise, although the latter does not draw on the fat reserves to the same extent as it uses up stored glycogen as a more immediate energy source. Dietary changes can alter both the intake of cholesterol and fats. Reducing the intake of food from animal sources, especially dairy products, meat, poultry, fish and shellfish, directly reduces the quantity of cholesterol taken in, making the body compensate with its own production to supply the needs of the cells. Thus, there will be no excess cholesterol circulating in the blood. In the same way, reducing the intake of fat (saturated fat in particular) will reduce the production of LDLs and hence the cholesterol level in the blood. Drugs may also be used to reduce blood cholesterol levels. Statins act at a critical point in the reaction sequence of the metabolic pathway synthesising cholesterol in the liver. That stage is controlled by negative feedback; statins inhibit the enzyme involved, mimicking the effect of high cholesterol levels and cutting back production. Controlling cholesterol levels: Question Q5: Complete the sentences which relate to controlling cholesterol levels in the blood by matching the phrases on the left with the phrases on the right. Regular physical activity raises The concentration of cholesterol is reduced by lowering Reducing the unsaturated fat in the diet reduces Reducing the content of animal food in the diet reduces Statins are drugs which inhibit the level of LDLs. cholesterol intake. cholesterol production by liver cells. HDL levels. the fat content of the diet. Statins reduce an enzyme in the liver.

146 138 TOPIC 8. CHOLESTEROL AND CARDIOVASCULAR DISEASE Familial hypercholesterolaemia Familial hypercholesterolaemia (FH) is an inherited condition that causes high cholesterol levels in the blood, and in particular very high concentrations of LDLs, which bring about the early onset of cardiovascular disease. It is one of the most common genetic disorders, occurring in 1 in 500 people. Most commonly, people that suffer from the disorder have a mutation in the autosomal gene which encodes the protein of the LDL-receptor. The effect of this is to reduce the number of LDL-receptors on the liver cells (other mutations alter the receptor structure). LDLs circulate for twice as long the blood. This increases the cholesterol concentration in the blood and hence deposition in atheromas in the arterial walls. In the most serious cases, no LDL-receptors are formed. The mutation shows incomplete dominance: heterozygotes develop cardiovascular disease between 30 and 40, whereas homozygotes show the symptoms in childhood. In families with a history of FH, especially if it has developed early in adult life, it is important that children are genetically tested for the presence of the condition. If it is present, a diet should be followed which is low in total and saturated fats. In addition, the condition can be treated with drugs (usually statins), which cause the liver to produce more LDL-receptors, reducing LDL-cholesterol levels in the blood. Familial hypercholesterolaemia: Question Q6: Select the correct option to complete the sentences about FH. i FH is usually caused by a mutation of which gene? LDL-receptor / HDL-receptor ii What inheritance pattern does this mutation show? incomplete dominance / codominance iii What type of chromosome is this gene found on? allosome / autosome iv In FH patients, what is reduced on liver cell membranes? HDL-receptors / LDLreceptors v FH causes the early onset of what disease? cardiovascular / Raynaud's vi This results from increased levels of what in the blood? HDLs / LDLs vii In consequence, what is deposited in artery walls? cholesterol / muscle cells viii What should be reduced in the diet of FH patients? far / sugar ix What drugs may be used to control FH? coumadins / statins

147 TOPIC 8. CHOLESTEROL AND CARDIOVASCULAR DISEASE Atherosclerosis and associated diseases Learning Objective By the end of this section, you should be able to: describe the development of atherosclerosis; name some of the diseases which atherosclerosis causes; describe the development of thrombosis; state the conditions which can be caused by thrombosis; describe the development of peripheral vascular disease; describe the development of deep vein thrombosis. This section considers some of the diseases that are associated with cholesterol Atherosclerosis Atherosclerosis is associated with a thickening of the artery walls that is caused by a build-up of fatty material, especially cholesterol. Although typically associated with older people, this is a progressive, but largely symptomless, condition which begins much earlier in life (20-30 years old). Also known as hardening, or furring, of the arteries, it is not clear what causes the onset of the condition, although a response to the deposition of LDL-cholesterol would seem to be involved. Contributory factors include diabetes mellitus, low HDL/LDL ratio, hypertension, a family history of CVD, and smoking. The thickening of the artery wall is caused by a structure called a plaque, which is composed of plaques of fibrous material, calcified tissue (hardened with calcium salts), and atheromas containing cholesterol. The following diagram shows the development of the plaque beneath the endothelium; the narrowing effect on the lumen of the artery can be clearly seen. The development of plaque beneath the endothelium At the same time as narrowing the lumen of the artery, the plaques also reduce the elasticity of the artery wall, both of which restrict blood flow and increase blood pressure. Atherosclerosis is the root cause of many of the cardiovascular diseases, including angina, heart attack (myocardial infarction), stroke and peripheral vascular disease.

148 140 TOPIC 8. CHOLESTEROL AND CARDIOVASCULAR DISEASE Thrombosis The plaques which develop in atherosclerosis can be divided into two broad groups: stable and unstable plaques. It is the latter group that can rupture and lead to serious complications. The outer cap of an unstable plaque is weak and quite likely to break open, rupturing the endothelium and exposing the fibrous material and cholesterol to the blood plasma. These act as clotting factors, which cause the platelets and blood proteins to trigger the cascade of reactions, resulting in the formation of a blood clot or thrombus. One of the later steps in this extended sequence of reactions involves the conversion of the enzyme precursor prothrombin into its active form thrombin. This enzyme then converts the soluble plasma protein fibrinogen into the insoluble fibres of fibrin, which link together to form a clot. In normal circumstances, the clotting process is initiated when tissue is injured, e.g. by a cut. The clot of fibrin threads forms a meshwork which traps red blood cells and seals the wound. This allows the tissue in the damaged area to be cleaned up by white blood cells. New cells are then produced, creating scar tissue. The formation of a thrombus in an artery is known as thrombosis. If the thrombus occurs in a small artery, it has the potential to block it and cause the death of the cells it serves. A clot which breaks free (called an embolus) travels along in the blood with the potential to block an artery or arteriole. If this happens, the cells served by the blocked vessel die within minutes because of oxygen deprivation, with potentially fatal consequences. If a thrombus forms in a coronary artery, an ensuing embolus causes a heart attack (myocardial infarction). A thrombus in a carotid artery taking blood to the head, or in an artery in the brain, may lead to a stroke Peripheral vascular disorders Peripheral Vascular Disease (PVD) When atherosclerosis or thrombus formation causes the narrowing of arteries other than those serving the heart and brain, it is known as peripheral vascular disease. Most commonly, the arteries serving the legs are affected (although others can be involved) and the effects range from mild pain when walking to extreme difficulty walking, tissue loss because of the onset of gangrene, and amputation. All of these effects stem from the reduced supply of oxygen which is caused by the narrowing of the arterial lumens. Deep Vein Thrombosis (DVT) Whereas all of the preceding conditions have involved atherosclerosis, and by definition arteries, deep vein thrombosis occurs in veins and does not involve plaque development. Although most commonly developing in the legs, these clots may form in many other areas of the body. Unlike emboli in arteries, those arising from DVT pass back first to the heart and then through the pulmonary artery to the lungs where they may lodge, causing a pulmonary embolism. This leads to a variety of possible effects, ranging from breathing difficulties, to collapse or sudden death. Although most people would know of DVT as a risk involved in long-haul air travel, immobilisation in the sitting position for long periods in any situation can cause it. There

149 TOPIC 8. CHOLESTEROL AND CARDIOVASCULAR DISEASE 141 are many other causal factors, some being the same as those of atherosclerosis, like advancing age, obesity and heavy smoking, but there are several others, such as major surgery, cancer, pregnancy, trauma (e.g. a blow to the thigh) and a variety of inherited conditions ASSIGN score Although the ASSIGN Score is not in the syllabus, this section is included to show how a very complex topic like CVD can be approached to allow people who are at risk to be identified. The information has been largely taken from the NHS Scotland website ( Scotland has an exceptionally high level of cardiovascular disease. The preceding section makes clear that CVD has many contributory causes, and so it is possible for a person to be below the critical level on any one factor, but still at high risk because of the combined effect. The ASSIGN Score provides a tool which combines the various factors to calculate a single risk assessment. From a system of predicting a person's risk of CVD, which was produced in the United States (the Framingham Score), the ASSIGN score was developed by Dundee University in conjunction with the Scottish Intercollegiate Guidelines Network. ASSIGN is tailored to the Scottish population in which much cardiovascular disease is associated with social deprivation and family history. The ASSIGN score number is the estimated percent risk of getting cardiovascular disease over ten years. It is based on what happened to 13,000 Scots men and women in the 1980s and 1990s (when risk factors were not being systematically treated). ASSIGN 20 therefore means a 20% risk, but the actual risk is almost certainly now less than that (because overall health has improved). What matters more is what somebody's score is in relation to other people's scores, and therefore how badly they need prevention now to lower their risk. The ASSIGN score is produced by combining the factors which identify people who are at increased risk of cardiovascular disease. These risk factors are: age (being older); sex (being a man); where you live (higher risk in poorer areas); family history (relatives who have or had coronary disease or stroke); diabetes mellitus (a person has sugar diabetes); cigarette smoking; the blood pressure reading (high); the blood total cholesterol reading (high) - mainly 'bad cholesterol'; the blood HDL ('good cholesterol') to cholesterol reading - (low HDL/total reading). The ASSIGN score will lie in the range 1 to 99. The higher the score, the higher the risk of cardiovascular disease.

150 142 TOPIC 8. CHOLESTEROL AND CARDIOVASCULAR DISEASE A score of 20 or more is considered to be high, and is used to identify those people in greatest need of advice and treatment to reduce their risk. In Scotland you would be offered advice, support and treatment. That support might include being invited to join groups to help you with your diet, to stop smoking, or to take exercise suitable for your age and health. Treatment would probably include medication to help reduce the chances of developing cardiovascular disease. These medicines could be: low-dose aspirin to reduce the risk of blood clots (thrombosis); statin tablets to reduce cholesterol levels. If your ASSIGN score was not as high as 20, you might still be given advice about things you could do to improve your own health and lower your risk such as: taking regular exercise; controlling your waistline and your weight; eating healthily; avoiding tobacco.

151 TOPIC 8. CHOLESTEROL AND CARDIOVASCULAR DISEASE Learning points Summary Cholesterol Cholesterol is a waxy solid, a steroid and a fat. It is synthesised in all body cells, but the liver produces most in the body. Cholesterol is present in animal foods, especially dairy products, meat and poultry. A diet high in saturated fats may cause increased cholesterol levels. It is eliminated from the body in the bile produced by the liver. Functions of cholesterol It is a component of cell membranes, where it controls permeability. It is a precursor of vitamin D and steroid hormones. Transport of cholesterol Cholesterol is transported by lipoproteins synthesised in the liver. High density lipoproteins (HDLs) carry excess cholesterol from the body cells to the liver. High levels of HDLs in the blood can reduce the presence of cholesterol in plaques in the artery walls. Low density lipoproteins (LDLs) transport cholesterol from the liver to body cells. LDLs become attached to LDL-receptors, found on the cell membrane of most cells. The LDL-receptors pass into the cell and release the cholesterol. The production of LDL-receptors is controlled by negative feedback. Once a cell has sufficient cholesterol, LDL-receptor production is suppressed. Excess LDL circulates in the blood and can become absorbed into atheromas in plaques in artery walls. A high ratio of HDLs to LDLs lowers the level of cholesterol in the blood, reducing the development of atherosclerosis. Controlling cholesterol levels Regular physical activity raises HDL levels, reducing cholesterol levels. Reducing the content of unsaturated fat in the diet reduces the level of LDLs.

152 144 TOPIC 8. CHOLESTEROL AND CARDIOVASCULAR DISEASE Summary Continued Reducing the content of animal foods rich in cholesterol reduces cholesterol intake. Statins are drugs which reduce cholesterol levels. Statins inhibit an enzyme in the pathway that produces cholesterol in the liver. Familial hypercholesterolaemia FH is caused by an incompletely dominant autosomal mutation of the LDLreceptor gene. The mutant allele results in fewer (or altered) LDL-receptors on liver cells. This causes high levels of LDL-cholesterol in the blood and the early onset of cardiovascular disease. The presence of the FH mutation can be detected by genetic testing. FH can be treated by changes to lifestyle such as following a diet low in total fats and saturated fats. FH can be treated using drugs such a statins which reduce LDL-cholesterol levels in the blood. Atherosclerosis Atherosclerosis is the thickening of artery walls by a build-up of fatty material. The thickening is in the form of plaques beneath the endothelium, consisting of fibrous material, an atheroma of fatty material (mainly cholesterol), and calcified tissue. The growth of the plaque reduces the lumen of the artery. This reduces the blood flow and increases blood pressure. The growth of the plaque also reduces the elasticity of the artery wall which increases blood pressure. Atherosclerosis is the root cause of cardiovascular diseases such as angina, heart attack (myocardial infarction), stroke and peripheral vascular disease. Thrombosis Unstable plaques may rupture, damaging the endothelium, and exposing the fibrous tissue and atheroma cholesterol to the blood plasma. These act as clotting factors, which activate the cascade of reactions of the clotting process. As part of this process, the enzyme precursor prothrombin is converted to the active form thrombin.

153 TOPIC 8. CHOLESTEROL AND CARDIOVASCULAR DISEASE 145 Summary Continued Thrombin catalyses the conversion of the soluble plasma protein fibrinogen to insoluble fibres of fibrin. The fibrin threads form a meshwork which traps red blood cells and forms a clot, sealing the wound and allowing the growth of scar tissue. When such a clot forms in an artery it is called a thrombus. If such a clot breaks loose into the blood stream, it is called an embolus which will travel through the blood circulation and may block a blood vessel. In a coronary artery, this leads to a heart attack (myocardial infarction). In an artery in the brain, it causes a stroke. In these cases, the cells served by the blocked arteries/arterioles die from lack of oxygen. Peripheral vascular disorders Peripheral vascular disease (PVD) is atherosclerosis of arteries other than those serving the heart or the brain. PVD is most common in the arteries of the legs. As elsewhere in the body, the atherosclerosis of PVD deprives cells of oxygen, causing symptoms for mild pain to gangrene leading to amputation. Deep vein thrombosis (DVT) is the formation of a clot in a deep vein, most commonly in the leg. If the clot becomes detached, forming an embolus, it may pass through the heart and lodge in a branch of the pulmonary artery. If the embolus lodges in the pulmonary artery, this is called a pulmonary embolism. 8.5 Extended response question The activity which follows presents an extended response question similar to the style that you will encounter in the examination. You should have a good understanding of cholesterol in the body before attempting the question. You should give your completed answer to your teacher or tutor for marking, or try to mark it yourself using the suggested marking scheme.

154 146 TOPIC 8. CHOLESTEROL AND CARDIOVASCULAR DISEASE Extended response question: Cholesterol in the body 15 min Give an account of cholesterol in the body under the headings: 1. sources and removal of cholesterol; (3 marks) 2. high density lipoproteins and low density lipoproteins. (7 marks) 8.6 End of topic test End of Topic 8 test 30 min Q7: Complete the paragraph using the words from the list. (10 marks) Cholesterol is a waxy which is synthesised in all body cells, although the produces most in the body. It is a component of cell, where it controls. It is also a precursor of and steroid. Cholesterol is eliminated from the body in the produced by the liver. Cholesterol is present in foods, especially dairy products, meat and. A diet high in fats may cause increased cholesterol levels. Word list: animal, bile, hormones, liver, membranes, permeability, poultry, saturated, steroid, vitamin D. Q8: Complete the sentences by matching the parts on the left with the parts on the right. (10 marks) Lipoproteins: High density lipoproteins: Low density lipoproteins: LDL-receptors: Negative feedback: Excess LDLs: High HDL : low LDL: Regular physical activity: Cholesterol intake: Statins: drugs used to reduce cholesterol levels. present on the cell membrane of most cells. reduces the development of atherosclerosis. become incorporated into atheromas. synthesised in the liver and used to transport cholesterol. raises HDL levels. control of LDL-receptor production. reduced by less animal foods in diet. carriers of cholesterol from the liver to the body cells. carriers of cholesterol from the body cells to the liver.

155 TOPIC 8. CHOLESTEROL AND CARDIOVASCULAR DISEASE 147 Q9: Complete the sentences by matching the parts on the left with the parts on the right. (12 marks) Atheroma: Plaque: Increased blood pressure: Atherosclerosis: Fibrin: Thrombus: Embolus: Myocardial infarction: Stroke: Peripheral vascular disease: Deep vein thrombosis: Pulmonary embolism: result of narrower lumen and reduced elasticity of the artery wall. root cause of angina, myocardial infarction, stroke and PVD. caused by an embolus lodged in the pulmonary artery. a clot which breaks loose in the blood stream. caused by a loose clot in an artery in the brain. build-up of fatty material beneath the endothelium. atherosclerosis in arteries other than in brain or heart. formed by a mesh of fibrin threads and red blood cells. thickening consisting of fibrous material, calcified tissue and fat. caused by a loose clot in the coronary artery. formed by the effect of thrombin on fibrinogen. formation of a clot in a deep vein. Q10: Complete the sentences by matching the parts on the left with the parts on the right. (6 marks) Incompletely dominant autosomal: Fewer LDL-receptors on liver cells: High levels of LDL-cholesterol in blood: Genetic screening: A diet low in fat and saturated fat: Statins: a method of detecting FH. the drugs used to treat FH. a type of mutation causing familial FH. the effect of a mutation on the LDL-gene. the result of a mutation to the LDL-gene. the natural method of treating FH.

156 148 TOPIC 8. CHOLESTEROL AND CARDIOVASCULAR DISEASE Q11: Complete the sentences by matching the parts on the left with the parts on the right. (4 marks) Liver: Animal foods: High density lipoproteins/hdls: Cell membrane: transport cholesterol from body cells to the liver. the cell structure that contains the most cholesterol. a type of food which is high in cholesterol. the organ which makes and eliminates cholesterol. Q12: Explain how cholesterol is transported from the organ in which it is produced to body cells. (3 marks) Q13: State one natural and one artificial method of reducing cholesterol levels. (2 marks) Q14: How is the presence of familial hypercholesterolaemia detected? (1 mark) Q15: How may the condition be treated naturally? (1 mark) Q16: Explain how atherosclerosis leads to an increase in blood pressure. (3 marks) Q17: List two cardiovascular diseases resulting from atherosclerosis. (1 mark) Q18: Describe the steps by which an unstable plaque may lead to an embolism. (4 marks) Q19: State the reason that peripheral vascular disease may lead to gangrene. (1 mark) Q20: Explain the link between deep vein thrombosis (DVT) and pulmonary embolism (PE). (2 marks)

157 149 Topic 9 Pathology of cardiovascular disease Contents 9.1 Introduction Regulation of blood glucose levels Blood glucose levels Homeostatic control of blood glucose levels The effect of exercise on blood glucose levels Blood glucose levels and diabetes Blood glucose levels and vascular disease Obesity Measuring obesity Obesity and diet Obesity and exercise Learning points Extended response question End of topic test Learning Objectives By the end of this topic, you should be able to: explain how the concentration of glucose in the blood is maintained within a narrow range; explain the effect of exercise on blood sugar levels; describe the contribution of chronically raised blood sugar levels on cardiovascular disease; describe the different forms of diabetes and their effects; describe the causes and effects of obesity, how it is measured and how it may be reduced.

158 150 TOPIC 9. PATHOLOGY OF CARDIOVASCULAR DISEASE 9.1 Introduction The diseases covered in this topic are all related to the regulation of the level of glucose sugar in the blood, the failure of that regulation which results in diabetes, and the imbalance of diet and exercise which causes obesity. At a number of points, rather more information is included than is required by the syllabus. This has been done to provide a deeper understanding of the biological mechanisms involved, making it easier to comprehend the syllabus topics. The material that will be examined is specified at the start of each section and again in the Learning Points section at the end of the topic. 9.2 Regulation of blood glucose levels Learning Objective By the end of this section, you should be able to: state that blood glucose levels are homeostatically regulated by negative feedback; explain that receptors in the pancreas detect the concentration of glucose in the blood; state that high blood glucose levels stimulate the release of insulin by the pancreas; state that insulin stimulates the liver (and other tissues) to convert glucose to glycogen; state that low blood glucose levels stimulate the release of glucagon by the pancreas; state that glucagon stimulates the liver to convert glycogen to glucose; state that exercise and fight or flight situations stimulate the release of adrenaline from the adrenal glands; state that adrenaline stimulates the liver (and other tissues) to convert glycogen to glucose; state that adrenaline also stimulates the release of glucagon and inhibits the release of insulin by the pancreas. This section considers the role of glucose in the body and the control of its blood concentration.

159 TOPIC 9. PATHOLOGY OF CARDIOVASCULAR DISEASE Blood glucose levels Although fatty acids, and to a lesser extent amino acids, may act as respiratory substrates, glucose is the principal one. Therefore, there is a constant demand for glucose to keep all cells alive. This base level of demand is added to whenever energy must be expended for other functions, such as movement or keeping warm. Glucose is stored in the body as glycogen, a polysaccharide that is very similar to starch, to which it is readily converted (and vice versa). In total, about 125g of glycogen are stored in the average adult, of which about 75% is in the skeletal muscles. However, the intramuscular glycogen cannot be released as glucose into the circulation so only the glycogen held in the liver is able to be mobilised to raise blood glucose levels. Humans cannot convert fat directly to glucose which means that glycogen stores must be replenished either with glucose from food intake (glycogenesis: genesis = making), or derived from other substrates, e.g. lactate, glycerol and some amino acids (gluconeogenesis: neo = new). During fasting or starvation, the latter is the only source of blood glucose. Although much more energy is stored in the form of fat than in the form of glycogen, it is less readily available to the body cells as it must first be split into fatty acids and glycerol in the fat depots (lipolysis), then circulated in the blood to the body cells and the liver respectively. For the average adult at rest, the body uses about 10 grams of glucose per hour, of which more than half goes to supply the brain. It is worth noting that because all of the glucose taken up by the brain is respired and none is stored, the brain is extremely sensitive to reduced blood glucose levels. The structure of glucose In an average adult, about 5g of glucose is circulating in the blood at any one time. Within cells, much more is held in combination with phosphate and other groups, which aids the transport of glucose into the cells by lowering the internal concentration of glucose itself. As there is only sufficient available glucose in the body to fuel metabolism for about 20 minutes, there must be a constant replenishment of the blood glucose to compensate for its absorption into the body cells. The blood glucose level is generally maintained at between 4.5 and 6 mmol/l (81 and 110mg/100mL) and the consequences of allowing the concentration to stray outside this range can be very serious. If it falls below 4mmol/L, hypoglycaemia develops, potentially leading to coma and death. Concentrations above the range do not cause

160 152 TOPIC 9. PATHOLOGY OF CARDIOVASCULAR DISEASE such immediately serious consequences, but if the condition (hyperglycaemia) persists and becomes chronic, then there are many deleterious effects on health. Blood sugar levels are lowest in the morning. The basic measure of blood glucose level is taken after an 8 hour fast. After a meal, a maximum of 10mmol/L might be reached after 90 minutes, rapidly dropping back to 7mmol/L or less. Given that a few minutes of exercise or the eating of a chocolate bar is going to remove or add enough glucose to the blood to push the glucose concentration outside its normal range, it is clear that the body must have a homeostatic mechanism for keeping it within these boundaries. Blood glucose levels: Question 10 min Q1: Complete the paragraph using the words from the list. Glucose is the principal in the body. It circulates in solution in the blood plasma and is stored as an insoluble polysaccharide called. These stores are found in the liver and the, but only the store in the can be mobilised to raise blood sugar levels. Blood glucose levels are kept in a very narrow range, by a process of. If the glucose concentration falls below this range, the condition of sets in with potentially fatal results. If the glucose concentration exceeds the normal range, the condition is known as. Word list: glycogen, homeostasis, hyperglycemia, hypoglycaemia, liver, muscles, respiratory substrate Homeostatic control of blood glucose levels Blood glucose levels are controlled by two types of cells located in groups within the pancreas (called the islets of Langerhans). In response to changing blood glucose levels detected by their receptors, these cells release different hormones which stimulate or inhibit the inter-conversion of glucose and glycogen. When low levels of glucose (less than 4mmol/L) are detected by one type of cell (α-cells), they respond by increasing their production of glucagon. Glucagon is carried in the blood to the liver, where it attaches to glucagon receptors on the cells and stimulates the conversion of glycogen to glucose. This glucose then passes into the blood, increasing the concentration. Muscle cells lack glucagon receptors, which means that they are not influenced by glucagon. Relatively high levels of glucose (more than 5mmol/L) are detected by receptors on the other type of cell (β-cells), which release insulin in response. Insulin attaches to receptors on the liver and muscle cells, stimulating glucose uptake and causing these cells to convert glucose to glycogen. In addition, insulin inhibits the release of glucagon (although glucagon does not inhibit insulin production, for complex reasons). Glucose, insulin and glucagon The following diagram shows how the level of glucose in the blood changes in relation to the consumption of food and the release of insulin and glucagon. The dashed line indicates the average blood glucose concentration, the set point around which the homeostatic process operates.

161 TOPIC 9. PATHOLOGY OF CARDIOVASCULAR DISEASE 153 The action of the pancreatic hormones glucagon and insulin on the liver is a form of negative feedback system, which acts to maintain blood glucose levels within a very narrow range. If blood glucose levels fall below a critical point, glucagon is released, stimulating conversion of glycogen to glucose and a rise in blood glucose levels. Conversely, a rise in blood glucose levels above the normal range triggers the release of insulin, which causes glucose to be removed from the blood and stored as glycogen. This can be summarised as follows: Insulin and glucagon also influence the cells of the fat depots in the same way. Thus, glucagon stimulates the release of fatty acids and glycerol, whereas insulin stimulates the conversion of glucose (via acetyl-coa) to fatty acids and lipids. In this way, excess carbohydrate is converted and stored as fat. Insulin can be seen as the most influential factor of all in homeostasis, i.e. in the maintenance of steady-state conditions within the body. Not only does it play a principal part in the control of carbohydrate, lipid and protein metabolism, it even acts within the brain to improve learning and memory. Together with glucagon, it balances metabolism, with insulin promoting broadly anabolic reactions that store energy and build up protein, and glucagon stimulating catabolic activities such as the release of stored energy.

162 154 TOPIC 9. PATHOLOGY OF CARDIOVASCULAR DISEASE Homeostatic control of blood glucose levels: Question Q2: Complete the sentences concerning the homeostatic control of blood sugar levels by matching the phrases on the left with the phrases on the right. Blood glucose levels are controlled by hormones released from cells in Blood glucose levels are detected on the surface of these cells by The hormone stimulating conversion of glycogen to glucose is The hormone released in response to low blood glucose levels is The hormone stimulating conversion of glucose to glycogen is The hormone released in response to high blood glucose levels is The organ which both releases and stores glucose as glycogen is receptors. glucagon. the pancreas. insulin. glucagon. the liver. insulin The effect of exercise on blood glucose levels Exercise increases the body's energy demand which lowers the blood glucose level. This triggers the release of glucagon, but vigorous exercise also causes the release of growth hormone from the pituitary gland, which promotes glucose formation in the liver, and thyroxine from the thyroid gland, which increases metabolic rate. It should be noted that both of these hormones have a wide variety of other effects. In response to the excitement and stress of exercise, the sympathetic nervous system triggers the release of another hormone, adrenaline, from the adrenal glands which are attached to the top of the kidneys. Adrenaline has a wide variety of effects, all of which prepare the body for physical action; the 'fight or flight' response. These include the inhibition of the release of insulin, stimulation of the release of glucagon, and the promotion of the conversion of glycogen to glucose in the liver and the muscles. The effect of exercise on blood glucose levels: Question Q3: Select the correct option to complete the sentences about blood glucose levels and exercise. 1. Lowering the blood sugar level causes the release of insulin / glucagon / adrenaline. 2. Vigorous exercise stimulates the release from the thyroid gland of growth hormone / thyroxine / adrenaline. 3. Excitement and stress cause the release of glucagon / insulin / adrenaline. 4. Adrenaline inhibits the release of insulin / glucagon / thyroxine. 5. Adrenaline has the same effect on the liver as insulin / glucagon / growth hormone.

163 TOPIC 9. PATHOLOGY OF CARDIOVASCULAR DISEASE Blood glucose levels and diabetes Learning Objective By the end of this section, you should be able to: explain the commonest causes of hypo- and hyperglycemia; state that diabetes is a common cause of hyperglycemia; state that diabetics are unable to control a rise in blood glucose levels; state that chronic vascular disease is a complication of diabetes; state that there are two forms of diabetes called Type 1 and Type 2; explain that Type 1 diabetes typically appears in childhood, resulting from a failure of insulin production, and is treated by regular insulin injections; explain that Type 2 diabetes typically develops in adulthood, resulting from a reduced cellular sensitivity to insulin caused by a decreased number of receptors on the liver cells; state that Type 2 diabetes is frequently associated with obesity and is mainly treated by adjustments to diet and exercise regimes; state that both forms of diabetes cause abnormally high blood glucose levels after meals; explain that, at these high blood glucose concentrations, the kidneys are unable to reabsorb all of the glucose from the glomerular filtrate, and so glucose is excreted in the urine; state that a positive result for glucose in a urine sample test is a strong indicator of diabetes; state that a glucose tolerance test assesses a blood sample taken after an 8 hour fast; state that a glucose tolerance test uses two blood samples, one taken before drinking a solution containing 75g of glucose and a second taken 2 hours later. Blood glucose levels The homeostatic control of blood glucose levels was described in the previous section. If the blood glucose level falls below the normal range, then hypoglycaemia develops (hypo = under). This is most usually a result of excessive insulin levels caused by overproduction or as a complication in the treatment of Type 1 diabetes. If blood glucose levels are consistently (chronically) above the normal range, the condition is known as hyperglycaemia (hyper = over) and various forms of chronic vascular disease result. The most common cause of hyperglycemia is diabetes, which occurs in two main forms, both of which result in the body being unable to control the rise in blood glucose levels after a meal.

164 156 TOPIC 9. PATHOLOGY OF CARDIOVASCULAR DISEASE Type 1 diabetes Type 1 diabetes (also known as 'insulin-dependent diabetes' or 'juvenile diabetes') results from the body's failure to produce insulin, requiring treatment by regular insulin injection. It is an autoimmune disorder, which destroys the insulin-producing β-cells in the pancreas. The condition typically develops in childhood and usually occurs in people who have a family history of the disease, i.e. there is a genetic component. It also appears that there is a need for an environmental trigger, e.g. a viral infection or cold weather. The lack of insulin means that much higher than normal concentrations of glucose are found in the blood for long periods after meals. Type 2 diabetes Type 2 diabetes (also known as 'adult-onset diabetes' or 'non-insulin dependent diabetes') typically develops in adulthood and, although it may be treated with insulin injections, it is usually controlled by adjusting diet, weight and exercise regimes. This is by far the most common form of diabetes, accounting for some 90% of cases, and, like Type 1 diabetes, it has both genetic and environmental causes. Obesity is thought to be the main trigger for the development of the condition in those who are genetically at risk, but it is possible that more complex lifestyle factors are also involved. Usually, this condition results from a decreased sensitivity of the muscle and liver cells to insulin, meaning that they have a reduced response to normal levels of insulin released by the pancreas. Fat cells tend not to lose sensitivity to insulin, continuing to convert glucose into fat, thus contributing to the development of obesity. Type 2 diabetes is typically associated with a 'Western' diet, high in saturated fats and simple carbohydrates, containing more energy than is required to maintain the body's metabolism. Other aspects of the urban lifestyle which may contribute to increased obesity are reduced physical activity, more sedentary occupations, reduced sleep and increased stress. The modern tendency to 'graze' on snacks (often with a high fat and sugar content) will lead to a more continuously elevated blood glucose level, and hence production of insulin, than would result from the traditional two or three meals a day. In such a situation, the pancreas is continuously producing high levels of insulin to combat the intake of glucose from the small intestine. These high levels of insulin eventually inhibit the production of insulin receptors on the key liver and muscle cells, reducing the uptake of insulin, and consequently glucose, into these cells. In other cases, the production of insulin is significantly reduced. The net effect of these changes is to reduce the conversion of glucose to glycogen, leaving a high concentration of glucose circulating in the blood. This excess glucose is then: absorbed into the fat depots, which still retain their insulin receptors and are stimulated by the high level of insulin to store the excess glucose as fat; taken into blood vessel walls, causing damage to them and contributing to vascular disease; excreted by the kidneys in the urine because the cells lining the proximal tubule are no longer able to reabsorb all of the glucose passed out of the blood in the glomerular filtrate by active transport.

165 TOPIC 9. PATHOLOGY OF CARDIOVASCULAR DISEASE 157 Testing for diabetes Both Type 1 and Type 2 diabetes make the blood glucose levels after a meal so high that glucose is lost in the urine. This happens when blood glucose concentrations exceed 11 mmol/l. Urine test: a glucose test-strip is dipped into a urine sample and a positive result is an indication of diabetes. However, the urine test result must be confirmed by blood tests which are much more reliable. Measuring urine glucose levels Blood tests: blood samples can be tested in the following ways: random glucose test: glucose levels are taken at a random time on two occasions - any concentration above 11.1mmol/L indicates diabetes; fasting glucose test: the glucose level is measured after an overnight (8 hour) fast on two different days - concentrations above 7.0mmol/l indicate diabetes. Measuring blood glucose concentration A further glucose tolerance test can be carried out if these tests prove to be inconclusive. It involves taking a standard glucose drink, containing 75g of glucose, after an overnight (8 hour) fast. Blood samples are taken before the drink is given and two hours later; a glucose level above 11.1mmol/L is a diagnosis of diabetes.

166 158 TOPIC 9. PATHOLOGY OF CARDIOVASCULAR DISEASE Diabetes: Question Q4: Complete the paragraph about diabetes using the words from the list. (some words may be used more than once) The condition of blood glucose levels consistently below the normal range is called. Diabetes is the most common cause of. A common complication of diabetes is chronic disease. Type 1 diabetes is also known as known as diabetes. Type 1 diabetes typically develops in and is treated with injections. Type 2 diabetes typically develops in and results from resistance caused by the reduced number of. Typically, Type 2 diabetes is associated with and is treated by altering and increasing. Diabetics excrete glucose in their. The glucose tolerance test is taken before and hours after taking a drink containing g of glucose. Word list: 75, adulthood, childhood, diet, exercise, glucose, hyperglycaemia, hypoglycaemia, insulin, insulin dependent, obesity, receptors, two, urine, vascular. 9.4 Blood glucose levels and vascular disease Learning Objective By the end of this section, you should be able to: state that chronic high blood glucose levels lead to endothelial cells taking in abnormally large quantities of glucose, damaging the lining of the blood vessels; explain that, in larger blood vessels, this may lead to atherosclerosis, cardiovascular disease, stroke or peripheral vascular disease; explain that, in smaller blood vessels, this may lead to haemorrhaging in the retina, renal failure or peripheral nerve dysfunction. The cells of the endothelium, which line the various types of artery, lack insulin receptors and so their uptake of glucose is dependent on the concentration in the blood which they carry. High blood glucose levels will result in high glucose intake. If high blood glucose concentration (above 7 mmol/l) is a chronic condition, as it is in diabetes Types 1 and 2, then the vessel walls become thicker and weaker, slowing the flow of blood and causing hypertension. Eventually, the endothelium begins to break up. This has different outcomes dependent on the size of the vessels involved. In larger arteries, the damage to the endothelium causes the development of atherosclerosis and peripheral vascular disease. The leakage of proteins into the blood can trigger clot formation, with the danger of stroke and myocardial infarction. In smaller arteries and arterioles, certain tissues are particularly at risk. In the eye, a lack of oxygen caused by the reduced blood flow to the retina stimulates the proliferation of more arterioles, which are equally fragile and so also leak blood. As a result, vision becomes blurred and may ultimately be largely lost.

167 TOPIC 9. PATHOLOGY OF CARDIOVASCULAR DISEASE 159 In the kidneys, the result of the endothelial damage is progressive destruction of the glomeruli, ultimately ending in kidney failure. In the peripheral nervous system, the lower blood flow and the associated reduced oxygen supply slow, and ultimately stop, the conduction of nerve impulses in the sensory-motor and autonomic nervous systems. In other words, virtually all body systems and organs may be affected, and the range of effects is exceptionally wide. Blood glucose levels and vascular disease: Question Q5: Complete the paragraph about glucose levels and vascular disease using the words from the list. The cells which line the blood vessels are damaged by high blood glucose concentrations. As a result, the flow of blood is slowed, causing. In small arteries the effects are particularly bad in certain tissues. In the eye, the is affected, causing blurring and eventual loss of vision. In the nervous system, conduction of nerve is slowed or stopped. In the kidney, the damage to the eventually leads to kidney failure. The effects in large arteries are and peripheral disease, which may ultimately lead to and myocardial. Word list: atherosclerosis, chronic, endothelial, glomeruli, hypertension, impulses, infarction, peripheral, retina, stroke, vascula.

168 160 TOPIC 9. PATHOLOGY OF CARDIOVASCULAR DISEASE 9.5 Obesity Learning Objective By the end of this section, you should be able to: describe the origins of obesity; state that obesity is a major risk factor for cardiovascular disease and Type 2 diabetes; explain that BMI (body mass index) is calculated as mass / (height 2 ), where mass is measured in kg and height in metres; state that a BMI in excess of 30 indicates obesity; state that obesity results from an excess of body fat in relation to lean body tissue (muscle); state that, in order to accurately measure body fat, a measurement of body density is needed; state that obesity is linked to high fat diets and reduced physical activity; state that, to counter obesity, the content of fats and free sugars in the diet should be limited; state that dietary fat should be limited because fats contain twice as much energy per gram as proteins or carbohydrates; state that dietary free sugars should be limited because their digestion requires no metabolic energy expenditure; state that exercise increases energy expenditure and preserves lean tissue; state that exercise can reduce the risk of developing cardiovascular disease by helping control weight, reducing stress and hypertension, and raising HDL levels. Why obesity? Obesity is a condition in which fat has accumulated in the body to the extent that it begins to have an adverse effect on health. It is largely a product of our modern 'Western' way of life and is rarely found in the developing world, only appearing when some of the population achieve affluence. Following the increasing incidence of obesity in the population is a whole host of associated diseases, yet storing fat is neither an unnatural nor an intrinsically bad thing. It has been said that although we live in the 21 st century, our bodies remain in the Stone Age. In other words, our social development has taken place at a far faster rate than our physiological evolution. If we assume five generations to the century, and that the Stone Age only finished about 4000 years ago in Britain, then there have only been some 200 generations since its end. More importantly, it is only in the last 200 years (at most) that the majority of the British population have ceased to be dependent on the seasonal availability of food. Not much evolutionary change can occur in 10 generations

169 TOPIC 9. PATHOLOGY OF CARDIOVASCULAR DISEASE 161 except in the face of extreme selection pressure, and selection pressure on the human population in Western society has decreased to zero for all practical purposes over this period. Fat stores represent a means of storing the maximum energy in the minimum mass. Historically, when we had an excess of energy in our food, we stored it as fat against those inevitable times when food would be short. In order to survive the hungry months of winter, a wild mammal like a red deer can lose 30% of its body mass as it draws on the fat stores laid down in the preceding summer. While we have physiological mechanisms to stop us eating when we are satiated, and to prompt us to eat when our bodies require it, we have no such means to stop us laying down fat. Until the very recent past, any excess of food would have naturally come to an end in autumn with the end of the plant growing season. By spring, most of our fat stores would have been gone. In today's Western/developed world, for most people there are no seasonal food shortages. The deepfreeze, supermarket and global air-transport systems mean that most foods are available all year round. If you can afford it, you can eat as much as you can every day. Of course, there is much more to the 'Western' lifestyle than food supply. With increasing affluence comes a dietary shift towards foods of animal origin, an increase in the fat content of the diet, and the increased intake of alcohol and refined foodstuffs (e.g. sugar). In addition, people's occupations tend to be more sedentary and more stressful, while hours of sleep and exercise levels have been reduced. Breakfast! In this complex and biologically unnatural situation, unless we consciously balance our energy intake and energy use, we can easily tend to obesity with its increased risk of cardiovascular disease and Type 2 diabetes.

170 162 TOPIC 9. PATHOLOGY OF CARDIOVASCULAR DISEASE Measuring obesity A person is generally classified as obese if they have an excess of body fat compared to their lean body tissues, such as muscle. The degree of obesity can be estimated by calculating the Body Mass Index (BMI) as: BMI = mass (kg) height (m) 2 BMI values can be used to assign people to body condition categories as shown in the following table. BMI range Category < 18.5 underweight normal overweight 30+ obese These categories are further sub-divided into 'severe', 'moderate' and 'mild', but it would be unwise to go too far with this. For example, the square of a person's height is used, but mass is dependent on volume (and so on the cube power); thus, if two people have the same build, but are of very different heights, the taller one will have a higher BMI. Also, as muscle is much denser than fat, a very muscular person with hardly any fat will be classed as obese, and vice versa. Most modern professional rugby players would be classified as obese, but you may be ill-advised to tell one that! The BMI index was originally developed as a means of comparing groups of people and was not intended for use with specific individuals. In order to accurately measure body fat content, it is necessary to measure body density. This is done in much the same way as Archimedes would have done it over 2,000 years ago. When a person is immersed in water, the volume of water displaced is the same as the volume of the person. After making an adjustment for the air in the lungs, the volume of body tissue is obtained. An accurate measure of mass then allows density to be calculated Obesity and diet Obesity develops insidiously, and countering it requires a change of lifestyle - there are no permanent quick fixes! Within the general mix of features which characterise the 'Western' way of life, two are particularly linked to obesity: a diet high in fats and simple sugars, and a lack of physical activity. After we eat a meal, our blood stream is flooded with nutrients which means that our homeostatic systems have to work very hard to keep the levels of these chemicals within their 'safe' ranges. What isn't immediately used is stored to be slowly drawn upon until the next meal replenishes the stock. If storage exceeds use, then fat will build up. This applies whatever the diet, but some foods create bigger problems than others.

171 TOPIC 9. PATHOLOGY OF CARDIOVASCULAR DISEASE 163 After digestion in the small intestine, fats pass into the lymphatic system and are then circulated in the blood to the cells, which means that little energy is used in their breakdown. In the same way, simple carbohydrates, e.g. sucrose, require little energy to make them available to cells. Proteins require much more 'work' before their energy becomes available to cells. Although sugars and proteins contain much the same energy per gram, sugars yield much more of it to the cells. Fats also contain more than twice as much energy per gram as carbohydrates (hence their use for energy storage by animals). The sensation of hunger is linked to two main factors: blood glucose levels and stomach fullness. Foods which are easily digested, e.g. those rich in sucrose, quickly pass into the blood, emptying the stomach. Equally, they also lead to a sudden rise in blood glucose, which triggers a surge in insulin secretion and a subsequent severe drop in glucose levels. These combined effects will induce the hypothalamus to generate the sensation of hunger. Frequent consumption of sugary or starchy food, or indeed high fat food, will lead to persistently high levels of insulin, leading eventually to insulin resistance Obesity and exercise Taking regular exercise will increase the amount of energy that is used up in metabolism simply because of the increased work that is being done. However, the effects are much more wide-ranging than that. Regular exercise will build up muscle tissue at the same time as reducing fat. As muscle has a higher metabolic rate that fat tissue, the effect is to raise the basal metabolic rate, increasing the body's overall energy use, even when inactive. Also, the increased demand on the heart increases its size, reducing heart rate, increasing stroke volume, and making it more able to cope with sudden physical stress. A girl riding a bicycle