that glitters - Wiley Online Library

BRITISH NUTRITION FOUNDATION ANNUAL LECTURE

‘All that glitters’ Alan A. Jackson Institute of Human Nutrition, University of Southampton, Southampton General Hospital, Southampton, UK

‘Not all that tempts your wand’ring eyes And heedless hearts, is lawful prize; Nor all that glisters, gold. (Ode on the death of a favourite cat: Thomas Gray 1748)

Introduction One major aspect of science is to understand the nature of the world in which we live. In biology we seek to understand how the forces of nature combine to enable life. In nutrition our quest is to discover how life imparts structure and function, in a seemingly endless cycle of renewal, by drawing from the environment in which it finds itself. For human nutrition, this biological imperative interacts with the structure and functioning of society which enable the biological processes to take place with the greatest apparent efficiency. When I was examined to become a Member of the Royal College of Physicians, I was in the first group that was able to choose paediatrics. There are many ways that a society may choose to measure its worth and quality, but for some of us, one important characteristic is the quality of care shown to the well-being of its mothers and babies. However, appearances may be deceptive; ‘all that glisters is not gold’ the essence of this lecture. A mother breastfeeding her infant represents an icon of caring and nurturing, and its importance is reflected

Correspondence: Professor AA. Jackson, Professor of Human Nutrition, Institute of Human Nutrition, University of Southampton, Level C (113) West Wing, Southampton General Hospital, Tremona Road, Southampton SO16 6YD, UK. Tel.: + 44 23 80 796317 or + 44 23 80 594302, fax: + 44 03 80 794945 or + 23 80 594383. E-mail: [email protected] This text has been taken from Professor Jackson’s lecture given at the Royal College of Physicians, London, 23 November 1999.

© 2000 British Nutrition Foundation Nutrition Bulletin, 25, 11–24

by the regularity with which it is depicted in some of the greatest works of art. Yet socially, most mothers, when given the choice, elect not to care for their infants in this way, even though nutritionally, biologically and in many other ways it is far superior to any other alternative. This may appear baffling, but being baffled is one of the most entertaining features of life. In one of the rounds of a popular television quiz, teams are shown four images and have to deduce the odd one out. The correct answer is not usually the most obvious, and depends upon a deeper understanding or interpretation of the relationship between the four images. I would like to present four images; a fetus from a normal pregnancy, a healthy breast feeding child, a severely malnourished child, and a malnourished adult in an intensive care unit. You may be tempted to choose the malnourished adult because they are least likely to come under the care and responsibility of a paediatrician, but if the clue was that the answer was to do with protein, the response might be different. A severely malnourished man in intensive care appears to be profoundly depleted in body protein, which might suggest that he would benefit greatly from a generous protein intake. However, a large amount of intravenous albumin would be more likely to produce an adverse outcome (Roberts 1998) and in many ways is similar to the response to treatment of severely malnourished adults in a famine situation (Collins et al. 1998). An awareness of the potential danger in giving large amounts of dietary protein to malnourished individuals, revisits lessons learnt many years ago about the care of severely malnourished children (Landman & Jackson 1981; Waterlow 1992). However, knowing the dangers is not sufficient, and information does not appear to be widely available or acted upon, because high protein feeding is still one of the most common reasons for the very high mortality rates in hospitals throughout the world (Jackson 1990; Schofield & Ashworth 1996). A newborn breastfeeding infant will gain weight at a faster rate than at any time in its life. Because much of the

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weight gained is protein tissue it might be expected that the higher the protein content of the baby’s diet, the more rapidly it would grow. Yet, surprisingly, breast milk contains less protein than will be consumed in the diet at any other stage in life. If the baby was given high protein supplements to make it grow more rapidly, there would be a grave danger of it becoming seriously unwell (Jackson 1989). Thus, in these three conditions, although there appears to be a great need for protein, a high protein diet has adverse effects. In contrast, during pregnancy, the fetus is provided with an abundant supply of amino acids (a very high protein diet). Although most are used for growth, a very large proportion is used as an energy source to drive growth and development (Jackson 1994). Therefore, the fetus is the ‘odd one out’, even though if a pregnant women is given a high protein diet there may be adverse effects on the developing fetus, with the infant having a lower than expected birth weight (Rush 1989; Jackson 1999a). Therefore, appearances are very deceptive. It appears that a diet providing large amounts of high quality protein would be the most desirable for promoting growth or recovery from disease. However, for each of the situations described, large amounts of protein seem to be associated with a poorer outcome. This relationship is counterintuitive, contrary to almost all perceived wisdom in nutrition (Jackson 1999b) and will be used as an example to illustrate some further points.

Why bother eating? We eat because of a fundamental biological need. In order to have food available regularly we have structured a socio-cultural imperative around which life follows a cycle of feasts and festivals that mark the seasons. During the twentieth century enormous advances took place in science and technology, not least in agriculture, food production and processing, and provided commercial opportunities as good as bottling water, or sealing air in tin cans, that cannot be taken for granted. In this sense, food production to satisfy the biological need becomes an economic imperative. The fundamental wealth of a group or country can be directly related to the ease and ability with which it can regularly maintain and secure reliable sources and provisions of food. If sufficient productivity allows time for other social interactions or learning activities, then that group is already on the way to development. Thus, human development at the individual and group levels can be characterised as the ability to reduce the time needed to be spent on activities related to food production

and consumption (Jackson 1990), and leaves sufficient time to acquire new skills, explore the environment and introduce and advance technology. Traditionally, life was ordered around the seasons of planting and reaping, and events determined by the weather and its impact on the harvest. Modern approaches to eating have seen enormous changes. The very idea of ‘fast foods’ reflects the limited time available to prepare food, and the haste with which it is consumed, as much as its convenience. The food industry demonstrates clearly that eating carries a very high economic worth, and even though the social and cultural patterns of consumption are changing, the literal biological drive ‘to consume’ will ensure that we shall continue to eat. Appearances may be baffling and often confusing: what appears to be most desirable actually has the potential for causing most harm. Therefore we have to go behind appearances to obtain genuine understanding. I would like to consider three questions which I believe are burgeoning in the nutritional sciences: Where are we going?; What do we need to do?; Who is going to do it?

Human nutrition: the discipline My job at the Tropical Metabolism Research Unit at the University of the West Indies in Jamaica enabled me to put my newly acquired clinical skills into practice by looking after severely malnourished children. I did not feel particularly limited or unskilled, having managed some very sick preterm babies and I set about the task with earnest. However, after 1 year, despite trying my best, things did not seem to be going well. Although formal audit did not exist, when progress was reviewed it was very sobering to find that, whereas for many years the annual death rate had been falling, since my arrival it had increased to levels nearly twice those expected (Jackson et al. 1979). Although expertly taught, my base of understanding was insufficient to enable effective management of such difficult clinical problems. There appeared to be another set of rules which applied and of which I was not sufficiently aware. There was indeed a great deal of scientific information that should have been available to me (Waterlow 1948; Waterlow et al. 1960; Alleyne et al. 1972; Waterlow & Alleyne 1971). However it could not be readily utilised, partly because it was not formalised into a readily accessible system of care, and because the scientific observations appeared to challenge several cherished beliefs. Although these were the basis of standard approaches to care, in the absence of appropriate clini-


‘All that glitters’

cal trials they failed to adequately address the criticisms of those with more classical perceptions of care. I was not sufficiently aware of the clinical implications of the tremendous scientific discoveries. These included alterations of body composition; fatty liver as a marker for loss of metabolic control; the potentially lethal consequences of accumulated stores of iron in the liver and marrow; the impact on function of depleted intracellular potassium and magnesium; the reductive adaptation in cardiac, renal and circulatory function; the homeostatic cost and loss of metabolic control associated with limited energy availability; and the dynamic nature of body constituents and the functional cost of a reduction in their rate of turnover (Waterlow 1948; Waterlow et al. 1960; Waterlow & Alleyne 1971; Alleyne et al. 1972; Waterlow 1992). None of these findings were easily reduced to a systematised approach. Although a policy statement had been approved for tackling the problems of gastroenteritis and malnutrition in the 1970s (Environmental Child Health 1974), the simple rules of clinical care had not been enunciated (Picou et al. 1975). Nevertheless, by the end of the 1970s understanding had progressed to the extent that in the world’s best centres, the expectation of mortality was about 5%, and guidelines on the treatment of severe malnutrition had been produced by the World Health Organisation (WHO) (World Health Organization 1981; Jackson et al. 1979). It was a hard lesson to learn that publishing a book, even writing a textbook, or talking to people was not enough to change the general practice of those who cared for severely malnourished individuals (Jackson & Golden 1987; Bredow & Jackson 1994). In most parts of the world, case mortality has remained very high (Schofield & Ashworth 1996); a problem which has exercised many agencies and individuals. In 1994 a meeting was held in London, and from a suggestion by David Alnwick was developed the ten-step approach to the care of severe malnutrition (Ashworth et al. 1996). As with all ideas of this kind it has proved to be invaluable in practice. In 1999 WHO published a revised manual on the treatment of severe malnutrition that should have more success (World Health Organization. 1999). Certainly the evidence on the effectiveness of appropriate forms of intervention is incontrovertible (Khanum et al. 1994; Golden et al. 1995; Khanum et al. 1998). What can be drawn from these experiences is that there is a base of knowledge and a range of special skills of direct and immediate relevance to clinical care that are not generally available within the medical profession. This package is best identified as human


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nutrition. There is a special challenge and difficulty in translating from scientific experience to clinical practice or relevant care. The two major hurdles are the need to make the complex sufficiently simple and straightforward for the nonspecialist to grasp effectively, and the inertia towards change. This is especially important where there is no obvious direct economic incentive for the change, and where the advocacy of individuals and organisations becomes particularly important. Government has a special responsibility in facilitating change.

Human nutrition: the big lessons Reductive adaptation For those associated with food production and processing, the emphasis is on the food that is eaten. In dietetics the major emphasis is on the components of the diet as consumed. The other perspective on nutrition derives from a different direction; the nutrients that are required by the body and how these might best be provided. While diet plays its part, cells continue to be nourished even when food has not been taken for long periods. Because the body can be considered as a demand-led system, the processes by which that demand is satisfied are of fundamental interest and importance. The body accommodates to insufficient food through ‘reductive adaptation’, which carries a cost. The same lessons that apply to the care of severely malnourished infants apply to the high technology and sophisticated care of a malnourished individual in an intensive care unit. Our understanding of the nature, implications and physiological cost of reductive adaptation represents a major gift to science and understanding (see Waterlow 1968; Blaxter & Waterlow 1985; Waterlow 1992). The concept of reductive adaptation carries within it two important ideas, the goodness of fit, and capacity to do. Goodness of fit We eat on a regular basis, and for most animals, people included, what they consume appears to be random, and is dictated by their place in the order of things. Amazingly, the material consumed is transmuted into a dog or a snail or a person, and the nature of this process is the stuff of nutritional science. The success with which the various material consumed is converted into a suitable organism seems to be determined by the goodness of fit, and the capacity to do. The idea of the goodness of fit is well illustrated by

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another television programme in which two teams are offered a plentiful supply of broken down household and industrial machinery. They are required to construct a machine and have 16 h to apply their ingenuity and complete the task. Although teams demonstrate great skills and originality, the ability to successfully complete the task is directly related to the quality of the scrap available. The closer this is to the machine they are trying to make, the more likely the success. The goodness of fit of the material available makes a product of better quality, and the process more efficient. Similarly, the sense of a better quality diet is that the closer the composition of the food consumed is to the composition of the body which is being maintained, the more efficient and effective the process. Capacity to do There are other dimensions to goodness of fit. In the television programme, teams can also modify the scrap to make particular parts. Their success is determined by the quality of the machinery available, or its capacity to do the necessary job. There are two dimensions to the ability to do things for oneself; one quantitative, the other qualitative. The former is predominantly an issue of size. Adults have a greater capacity to do things than children, men a greater capacity than women and large people a greater capacity than small people. The qualitative component covers the very broad considerations embraced by metabolic exchange and integration. However, given its fundamental importance, general principles have developed only slowly, especially when compared to other biological sciences. The need for an adequate capacity to make critical metabolic components is best exemplified by the necessity of the body to synthesise large amounts of nonessential amino acids. Much nutritional science has focused on the biological importance of essential amino acids (which have to be taken preformed in the diet). Less attention had been focused on the rates of formation and utilisation of nonessential amino acids. These are required daily in very large amounts, much greater than could ever be achieved through dietary consumption. It is now clear that the ability to protect the pathways through which these compounds are made is of vital importance to health and well-being. The integrity of the pathways depends on an adequate nutritional status, most particularly for the cofactors (usually minerals, vitamins, and trace elements) that enable enzymatic processes. Malnutrition results in a reduced capacity and ‘damaged machinery’, and therefore the body is

less able to do things for itself. The first step in care is to repair the machinery as an absolute prerequisite for a successful outcome.

Fermentation There is another way that dietary components may be modified to improve the fit of available nutrients. Biological waste can be recycled using microbiological processes in the same way that wider nature depends upon the rotting down of material. Humans also carry their own waste-reprocessing plant which depends upon the almost infinite ability of microorganisms to degrade organic material and transform it to another, potentially utilisable, form. Almost all this activity occurs in the colon, where microflora utilise undigested or unabsorbed dietary residues, material secreted into the gut, or produced by the gut itself (for example, mucins or sloughed cells). These compounds are broken down into their components and reformed into a range of products. Those that are potentially available to the host and which are produced in significant amounts include vitamins, free fatty acids and amino acids. The extent of the formation of the latter has been a personal research interest. The potential importance of these processes can be considered in the context of a long running debate on the requirements, for individual amino acids, of people at different ages and in different states. In 1985 an expert consultation was held on protein and energy requirements (FAO/WHO/UNU 1985). With respect to energy requirements, the approach until then had been to assess the energy intakes of individuals and groups, of different ages, engaged in different lifestyles. There were problems and, given the developments in technology, it was agreed that it would be better to use energy expenditure as the basis for assessing requirements – a demand-led approach. In contrast, protein requirements were derived from estimates of nitrogen balance and it is on this basis that the minimum consumption of essential amino acids has been determined. For example, a normal adult male consuming about 12 mg/kg/day of lysine, maintains nitrogen balance. Surprisingly, however, if the body’s demand for lysine is measured, then the amount required to replace that used up is about 30 mg/kg/day in that same adult man (Young et al. 1989). Measurements of demand have lead to the suggestion that if demand is to be satisfied, the intake of proteins, especially those rich in essential amino acids, has to be greatly increased (Marchini et al. 1993). The detailed policy implications of this kind of change have been carefully worked out, and there has been very



vigorous support for them (Pellett 1996; Young & El-Khoury 1996). If serious attention was given to these suggestions, and if they were adopted as the basis for policy and planning, there would be huge implications. It has been estimated that in order to achieve the proposed level of protein consumption by the world’s population, a substantial increase in meat protein consumption and a great increase in the availability of soy beans would be required (Young & Pellett 1990). The environmental and economic implications would be catastrophic, and large regions of the world would find it impossible to have any hope of reaching a situation of food security. This applies not only to current populations, but would also pose a hopeless challenge for the future as populations expand over the next 50 years (Waterlow et al. 1998). This problem is similar to the conundrum posed earlier where there always appears to be the need to consume greater amounts of protein. We may now have a solution to the paradox. It is now well-established that colonic microflora can make their own amino acids by using the end products of mammalian metabolism, including urea, produced by the liver during the breakdown of proteins (Jackson 1993; Jackson 1995; Jackson 1998). There has been some debate as to whether these amino acids might be available to the host, and it is now clear that they are. For example, it has been estimated that a normal adult might obtain about 25 mg/kg/day of lysine from bacterial fermentation, more than enough to satisfy demand (Gibson et al. 1997; Metges et al. 1999; Millward et al. 2000). If this is so, then colonic fermentation plays a very important role in helping to enhance ‘goodness of fit’ of the available material. In a clinical context, because severe malnutrition and diarrhoeal disease go hand in hand, effective treatment of the diarrhoea is very important to successful care. The extent to which the flushing action of diarrhoea impairs the important metabolic functions of the colonic microflora is not yet known.

Summary: Goodness of fit and capacity to do The great nutritional successes of the twentieth century were the identification and management of single deficiency diseases, vitamin deficiencies, single essential amino acids, essential fatty acids and more recently, trace elements. The ability to diagnose and effectively treat a complex specific deficiency is exciting, and can have miraculous results. If a deficiency is identified correctly and an effective treatment begun, the dramatic nature of the response over a short period of time is as powerful as any therapeutic intervention in clinical


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care. The nature of this response has lead to both the search for wonder cures, and the tendency to set fashions in food and nutrition, whereby a single intervention related to a recent discovery has held out hope of straightforward direct responses. Chronologically, the major emphasis has been the importance of vitamins, amino acids and proteins, energy, and trace elements. We are now moving from simple models of disease processes to an understanding of the complexity and the interdependence of the different components. For example, the appreciation of the need to balance free radical- or oxidatively-induced damage, and the processes by which the body protects itself, has been seen as a major process which underlies the risk of disease (Jackson 1986; Golden & Ramdath 1987; Jackson 1990). The body is sophisticated and integration of all its systems is required to maintain its function. This requires the provision of adequate amounts of the components needed to satisfy the overall ongoing metabolic demand. A balance has to be achieved and maintained in the consumption of energy, macronutrients and micronutrients, which best achieves the goodness of fit required at a given stage of development or particular lifestyle. Diet may play a direct part in satisfying this match. However, at least as important is a more subtle indirect involvement of diet in metabolic processes via control and regulation of exchanges that underlie intermediary metabolism, and with colonic fermentation (Fig. 1).

The medical profession and nutrition Across Europe, the media are the main source of information on diet and nutrition for the general population (de Almeida et al. 1997; Flynn 1999). However, whenever public opinion has been sought the consistent response is that doctors and other health professionals are the most trusted and respected sources of advice. Doctors are seen as the custodians of health care, and the most respected source of advice. This is not surprising because the relationships between health, diet and metabolic control are complex and require competent and trained people to provide sound advice and to deliver a high quality service. It is sobering therefore, to find that the training in nutrition given to doctors has been marked by its lack of consistency, its piecemeal and trivial nature. In 1983 the British Nutrition Foundation was amongst the first important bodies to review the training of doctors in nutrition and to call for improvements (BNF 1983).

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Goodness of fit Diet

full support of the medical profession. Representatives of all medical schools came together to commit support for the idea and the process; an important step forward (Department of Health 1996b).

Post-graduate medical training: the Royal Colleges

Capacity to do

Metabolic demand

Colonic microflora Figure 1 Ultimately, for any individual, the metabolic demand has to be satisfied, either directly from dietary components; through a series of metabolic interconversions, the potential extent of which is determined by the metabolic capacity for specific functions; together with the products of fermentation from the colonic microflora.

Undergraduate medical curriculum The response to a call for doctors to be better trained in human nutrition takes time to develop and is likely to have many facets. The creation of my current post, together with the creation of other Chairs in undergraduate medical schools by the Rank Prize Funds, represents part of the response, and there was undoubtedly the expectation that this would contribute to improving doctors’ training. Under the previous Government’s initiative on the Health of the Nation, a Task Force on Nutrition was set up, and amongst its many tasks included the need for properly trained health professionals (Department of Health 1994a, 1996b). A curriculum was developed which covered the basic principles of nutrition, public health nutrition and clinical nutritional care (Department of Health 1994b). The intention was not to create experts in nutrition, but simply to ensure a minimum level of knowledge and understanding, to ensure that a doctor or nurse was safe to practice and provide suitable advice to the public. The publication about the undergraduate training of doctors, Tomorrow’s Doctors, by the General Medical Council, provided an ideal opportunity to integrate nutrition into the undergraduate curriculum (General Medical Council 1993). There was great support for a core curriculum on nutrition training and education from the Chief Medical Officers, but they were quite clear that ultimately this was a matter that required the

Undergraduate medical training inevitably leads to postgraduate and higher specialist training. For undergraduates to be well taught their mentors and teachers should be well equipped with knowledge and understanding. The President of the Royal College of Pathologists invited his counterparts in other Colleges to collaborate to consider the best way to provide high quality postgraduate training in nutrition. The ‘Intercollegiate Group’ thus formed was charged with carrying the matter forward on behalf of all the Colleges (an exceptional development). From this an intercollegiate one-week course evolved. One week is a long time for a busy doctor to be away, but it is only a very short period within which to encapsulate the full experience in clinical nutrition and public health considerations across all the major disciplines for which nutrition has an important relevance. An insistence on the importance of the evidence-base for sound practice has helped to clarify the most suitable approaches, and to reduce controversy.

Models around which to structure training An interesting model with which to approach and best structure understanding has emerged. This recognises that nutritionally, people exist in one of three states, underweight, normal weight and overweight, each with its own health implications. Whilst there may be myriad reasons why an individual or group might be underweight (for example, biological, psychological or sociological), regardless of the underlying cause, there are substantial similarities in the final and common pathways leading to impaired nutritional function. These common features are of interest and relevance to nutritional care, although the principles of care are similar, regardless of the original cause. The prevalence of overweight and obesity is increasing, again the underlying causes may be varied, but they all carry a similar risk of upset metabolic function and wellbeing. Regardless, of the underlying cause, the common pathways which ultimately lead to dysfunction and disease are amenable to similar approaches to care or treatment. For the processes which lead to underweight or overweight there is an increasing need to appreciate



integrated networks of care that reach beyond the traditional approaches and cut across the boundaries between the community and the hospital. With respect to underweight, in 1999 the British Association for Enteral and Parenteral Nutrition, through its Malnutrition Advisory Group, had a parliamentary launch for its plans to address the health, social and economic cost associated with malnutrition in the community. Both nationally and internationally, overweight and obesity are now major agenda items for improved health care. Encouragement to maintain a healthier weight, by individuals and groups making changes in lifestyle will ensure better health (Royal College of Physicians 1998; World Health Organisation 1998). The third state is normal weight and good health, again nutrition is a vital component for maintenance of this state and for ensuring that the normal processes of growth and development occur at an appropriate rate throughout pregnancy, childhood, and with age, to maintain the quality and enjoyment of life. The achievement of health is almost taken for granted in our society. Does any individual or group carry appropriate responsibility for ensuring the provision of suitable care in these areas? Who, if any, are those with the special skills and responsibilities for promoting and protecting well-being? Whilst the provision of sound training in nutrition for all health professionals will undoubtedly provide benefit and improved care, it cannot take on the full societal dimensions of this task. Although it is true that health is more than the absence of disease, doctors are trained to be highly skilled at diagnosing and treating disease, but are less experienced and less skilled in its prevention. In general, doctors have no skills and little direct interest in the active promotion of wellbeing. They do not doubt its importance, but it simply is not their job. Because of this vacuum, there is the need for a very highly skilled, highly motivated class of health professionals who are intellectually on a par with doctors, who have an equivalent standard of training and who can by their practice command the same level of respect across the range of complex health-related issues. Put simply, there is the need for Doctors of Health (see below).

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movement of foodstuffs around the world, and is the economic base for all food-related commercial activities. The ways that different diets might cause disease, and how disease alters the needs for different nutrients, represents the clinical subbranch of nutrition science. The UK is fortunate in having a substantial base of information and interpretation provided by government surveys and reports of many kinds, from the Department of Health; the Ministry of Agriculture, Fisheries and Food; the Health Education Authority, and colleagues. For most of this century different societies have had some form of recommended dietary allowances which have become increasingly complex and sophisticated. This evolution tracks the development of scientific understanding. The most recent document for the UK was published in 1991 (Committee on Medical Aspects of Food Policy 1991) and for me is a very valuable document for many reasons. One important difference when compared with all similar works, is the new nomenclature which it introduced, and most importantly the ideas which were behind the necessary changes. It is always very difficult to reconcile related but different considerations, the need for a single recommendation that represents the requirements of an average person, and the recognition of between and within individual variability. The notional approach used is to identify a single value for intake that is likely to be adequate for the majority of the population; in statistical terms the mean plus two standard deviations. Whilst this approach was used in the report on Dietary Reference Values, the document was much more explicit about upper (Reference Nutrient Intake) and lower (Lower Reference Nutrient Intake) limits of requirements, thus placing greater weight than previous reports on individual variability. For pragmatic reasons this variability is embraced simply within the general advice to eat a varied diet that contains a reasonable balance of the recommended foods. While recognising the value of pragmatism, within nutritional science we have to be careful that we are not lulled into an inappropriate acceptance of the limitations of general approximations of this kind. We also need to continue to accept the responsibility for developing a more profound understanding of the important and complex interrelationships.

The public and normal health: biological requirements

Fetal origins of health

The essence of nutritional science is to understand the energy and nutrient requirements necessary to maintain health in otherwise healthy people. This forms the scientific basis of dietary recommendations and guidelines, and is used for policy decisions about agriculture, the

When I took up my post in Southampton, it was generally considered that chronic noncommunicable adult diseases (for example, heart disease, hypertension, diabetes and cancer), were caused by genetic predispositions interacting with lifestyle factors such as smoking,


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diet and activity. Shortly after my arrival I was invited to consider which nutritional factors might act to increase the risk of death during the first year of life, and might also be associated with an increased risk of heart disease in the same population groups, during later adult life (Jackson 1992). Barker’s group, also in Southampton, had evidence that geographical differences in death from ischaemic heart disease in England and Wales were related to differences in infant mortality 70 years earlier (Barker & Osmond 1986). This suggested that early nutrition and growth might be related to important risk factors for heart disease. Subsequent retrospective cohort studies showed that people with the lowest weight at birth and at 1 year had the highest death rates from heart disease. This work gave rise to the ‘Barker Hypothesis’ or ‘The Fetal Origins of Adult Disease Hypothesis’ (Barker 1994). Work in the last decade has shown clearly that amongst the important factors that relate to chronic disease, the development of metabolic capacity (the capacity to do) during early life is especially important (Jackson 1996). The proposition is that early nutritional exposure programmes future metabolic competence and behaviour by imprinting a change upon gene expression. The general nature of the observations has been replicated in many studies throughout the world, and there is clear evidence that the pace and pattern of early growth represents a major risk factor for the development of disease in adulthood. Although disease or death can be used as a hard end point to characterise the importance of the relationships, the metabolic basis for pathological changes is evident from very early in life. Studies in children have shown that metabolic differences that underlie the risk of disease are evident from as early as 3 or 4 years of age (Barker 1998). Thus, programmed metabolic changes help to determine the capacity for metabolic function during the entire life of an individual. The metabolic function of an adult represents the cumulative experience of their environmental exposure throughout their entire life, and at all ages the memory of past metabolic experience contributes to different extents to current metabolic behaviour. However, the greatest impact appears to be related to prenatal life or infancy, and nutritional exposure plays a central role (O’Brien et al. 1999). One of the most important features of these general observations and which is often ignored or misinterpreted, is that effects operate in a graded fashion, across the range of birth weights which in the past have been considered to be normal. There has been a tendency to interpret the findings as a feature of lower birth weight babies. This in turn has been translated to a special

feature of babies of pathologically low birth weight. The fact that the changes are graded across the normal range of birth weight has major important implications that are often not appreciated.

Nutrition of the fetus The fetus depends on its mother for an adequate supply of energy and nutrients for growth. The availability of nutrients is influenced by the mother’s metabolism and by her own nutrient stores. Maternal fat mass during pregnancy shows a strong relationship with blood pressure of the child at 11 years old (Godfrey et al. 1994), and intergenerational effects can be demonstrated in relation to maternal body composition (Godfrey et al. 1997; O’Brien et al. 1999). In Finland, heart disease was found to be most common in men who had a low birth weight, and especially in those who were thin at birth. The risk was even greater in men with short mothers, especially if they were both short and fat. It was suggested that this was a marker for the demographic transition from poorer to improved social circumstances, with women progressing from being short and thin, to being short and fat, before they become taller (Forsen et al. 1997). Despite the obvious dependence of the fetus on an adequate supply of energy and nutrients for its growth, growth does not necessarily show a simple relationship to maternal dietary intake (O’Brien et al. 1999). The intakes of single macronutrients, or selected micronutrients, show only a modest contribution, explaining about 5–7% of the variability in birth weight (Haste et al. 1991; Mathews et al. 1999), similar to the 12–14% of variation explained by smoking (Haste et al. 1991). In contrast, if measures of maternal metabolic function are used to assess the competence of the mother for carrying a pregnancy, the relationships with growth are much stronger, and therefore more likely to have a direct bearing on the causal chain of events. For example, we have found that 23% of the variability in newborn length is related to maternal protein synthesis, which is dependent upon the size of the mother’s visceral mass (Duggleby & Jackson 2000). The maternal partitioning of amino acids to oxidative or synthetic pathways marks the ‘goodness of fit’ of dietary amino acids to the pattern needed by herself and the fetus. A poor fit (increased oxidation) is associated with poorer fetal growth and explains 34% of the variability in birth weight (Duggleby, unpublished data). These are amongst the most powerful explanatory variables which have been identified for differences in fetal growth. Women who take high protein supplements during



pregnancy have babies of lower weight, especially if the general quality of the diet is poor (O’Brien et al. 1999; Rush 1989). One way to interpret these observations is to compare the pattern of amino acids required for fetal growth with that provided in the mother’s diet. The fetus has a very high requirement for nonessential, compared to essential amino acids (Widdowson et al. 1979; Jackson et al. 1981). This high fetal demand has to be met primarily through endogenous synthesis which requires cofactors (especially folate and other B vitamins) and synthesis is limited if cofactors are in short supply. A high intake of a protein dense supplement provides a relative excess of essential amino acids, which is potentially toxic unless they are degraded and oxidised (Harper et al. 1970). The degradation of essential amino acids consumes more nonessential amino acids, further limiting their availability, and stressing the system for which the available supply is inadequate. Thus it is very clear that the nutritional state in which women enter pregnancy is of very great importance in terms of the future health of the population, and healthier women will undoubtedly reduce the burden of disease for their children at later ages. Over the next five years we will have a much better understanding of the critical metabolic and dietary interactions which give every mother the best chance of having the healthiest baby with the brightest future.

General biology of coping with an increased demand It might be argued that pregnancy represents a special case where the demands for tissue deposition and the exquisite sensitivity of the rapidly growing fetus place an unusually high demand on metabolism. However it is likely that what occurs during pregnancy represents the general metabolic behaviour, whereas the stress of pregnancy simply exposes any limitations in the metabolic capacity of an individual. Using protein as an example, an explanation of what appears to be happening during pregnancy would enable an explanation of the problems and conundrums about protein metabolism posed at the beginning of this paper (Jackson 1999a; Jackson 1999b). Barker has introduced a new way of looking at growth and development. The potential implications are considerable if, as suggested, the development of metabolic capacity during early life has profound implications for function later on. Thus, what in the past has been considered to be normal variability within any population group is now seen as representing variable risk of different responses amongst individuals to a range of similar exposures. For the foreseeable future there will be the need to develop a


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clear understanding of the factors that contribute to this variability and how they impact upon behaviour and function. A clear understanding of the biological basis for variability in health represents a new agenda for the promotion of a healthy lifestyle.

Doctors of health Clean air, potable water and a supply of sufficient food of adequate quality are required for the survival of individuals and groups. Thus, nutrition will always be a major if not central aspect of maintaining and promoting good health. Society needs people who are knowledgeable, skilled and have the requisite understanding to deliver a service that promotes health and optimises opportunity. As discussed, whilst doctors are the source of respected and sound advice, they are not well trained in human nutrition. Our minimum objective for them is to ensure that they all know at least enough nutrition to ensure that they are safe, and will not harm their patients. Doctors have an interest in well people, but it is an intellectual involvement rather than deep fascination. They are really transfixed by working out what is wrong with a broken body, the diagnosis and treatment. In general they are neither skilled in nor interested in health promotion. Doctors of Health need to be trained directly and specifically for the difficult tasks and challenges they face: not as an appendage to medicine, but as a complex discipline and highly respected profession in its own right. This challenge is not an easy one and for there to be any chance of success, important issues relating to the nature of the task, the context within which the tasks are to be carried out, and the professionalism required must all be considered.

Nature of the task Human metabolic variation sets the demand for food, determines the nature of the goodness of fit and the capacity to do. Over the next five years, the human genome project will provide a complete statement of the extent of genetic polymorphisms within groups. We already know that people are different, and increasingly we will have the ability to understand the nature and basis of those differences: an individual’s genes, the extent of metabolic programming, and how these together determine their response to environmental factors. The metabolic capacity of people to cope with new infections, changing lifestyle patterns and the impact of environmental pollution are all potentially modifiable and represent a major programme of future work. This information will enable us to understand

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which aspects of the metabolic demand of an individual have particular relevance in a given situation. The models that need to be created will be multifactorial and multidimensional. They will require very highly trained individuals to understand the components, manage the information, and put the complex models together in a useful way. We have probably gone as far as we can in using simple linear models to understand diet, nutrition and metabolic processes. The approaches which use nonlinear methods to analyse complex networks have to be explored (Rossor 1995; Christ et al. 1997; Bleckert et al. 1998). Certainly we need to be able to manage information systems of increasing complexity, and to know the extent to which the application of chaos theory and fuzzy logic might best serve our purposes (Wirsam et al. 1997; Wirsam & Uthus 1996). Within the broader aspects of the biological sciences many major steps have already been taken towards sophisticated computerised informatics, but we have not yet started to deal seriously with these opportunities (Gedrich et al. 1999). We have to develop the capability of relating dietary intake to the metabolic demand for the variables of relevance, whilst embracing interactions of individual nutrients, and specific combinations (Table 1). Doctors of Health will be faced with a considerable challenge. Most people are ‘normal’ and spend their time in the community, they seldom come into direct contact with doctors or health care professionals. Yet, increasingly theirs represents an unfulfilled need of the general public for help and advice. Much of this responsibility is currently taken on by unskilled, self-trained individuals offering a range of personalised services. One of the important issues therefore is the mechanism

by which access to normal people is managed in the most effective way in order to bring influence to bear on those most in need. This requires greater ingenuity and effort than has been deployed in the past. Perceptions are all important, and the idea that maintaining health is seen as an uninteresting, unrewarding challenge, impedes progress if advice to change is seen as an onerous intrusion, and is not taken up with enthusiasm by those most in need. The most eloquent example of a major failure in this regard is the general lack of enthusiasm for promoting and enhancing breast feeding. Similar comments might apply to the use of folic acid supplements in young women. It is appropriate that very great political concern has been expressed about inequalities in health. It will be interesting to see the extent to which the approach to the problem is managed as a side issue, or taken on as a major task that requires a fundamental shift in cultural values.

Social and political dimensions The availability of adequate amounts of good food, and the utilisation of the food available to maintain good health, have always been issues which have to be managed at all levels of society. However, they are particularly difficult issues because the objectives related to food production, and those related to food consumption are fundamentally different, and apparently antagonistic. The ability to ensure a stable and safe supply of food is the cornerstone of wealth, resource and development for any family, group or society. Those who have abundant food, and guaranteed food security, have the basis for a stable and successful existence. The more time that individuals or groups have to spend in secur-

Table 1 The metabolic demand is determined by a combination of factors, and has to be met by the energy and nutrients provided in the diet or as a result of metabolic transformations Variability in metabolic demand Genetic profile Metabolic programming Lifestyle and behaviour Environmental stresses

Human genome project Fetal development of capacity Activity, smoking Infection, pollution

Quality and quantity of nutrient provision Energy balance Carbohydrate Lipid Protein and amino acids

Simple vs. complex Atherogenicity, pro- and anti-inflammatory Total nitrogen balance, balance of essential and nonessential amino acids

Minerals and micronutrients Minerals Vitamins Trace elements

Substrate provision, pro- and antioxidant status, endogenous de novo formation of critical metabolic intermediates



ing that base, the more vulnerable, and therefore the weaker their existence becomes. All groups need to consume food to maintain health and vitality, but the more that is consumed, the greater the need for production, and the more the threat to security. At the simplest level, within the family, the choice of whether to save or eat seedcorn illustrates the nature of the dilemma (Harrison & Waterlow 1990). As societies become larger and more complex, the direct nature of the relationships may be less obvious, but they are no less real. Thus in all places and at all times a dynamic tension around the nature and the use of food exists between the legitimate demands of the food production sector, and the legitimate demands of the health and welfare sector. Management of this dynamic tension is by its nature difficult, but is achieved more effectively in the most successful societies. All those characterised as developed, industrialised or modern have mechanisms which directly or indirectly manage this tension relatively effectively. The societies which are financially the most successful have learnt how to cope and have the most effective mechanisms. Usually these are not necessarily efficient in the use of the earth’s resources, and tend to be profligate in terms of production, to enable consumption to move ahead without any great constraints. An increasing awareness of the finite nature of available resources, especially the limited availability of water, requires a more considered and ingenious approach than used previously (Waterlow et al. 1998). Increasingly, production will have to be informed more effectively by a better understanding of the nature of the demand that has to be satisfied. I became involved in food policy and planning because the Caribbean region had for many years imported 50% of its food requirements, and the stated political policy objective was to become self-sufficient. At the time it was fashionable for UN agencies to promote some form of intersectoral planning, coordinating group or committee for food and nutrition, at national or regional levels. Similar attempts have been made elsewhere in the world, but success has been modest at best. At the present time consideration is being given to revisiting the same ideas in the European Union. Structures of this kind are not inevitably doomed to failure, but the chances of success are very limited if the nature of the task is not fully or clearly appreciated. We have not yet started to adequately train Doctors of Health who possess the necessary skills to analyse and manage the complex issues involved. Without people who have these skills and abilities, the dynamic tension becomes increasingly antagonistic and eventually implodes.


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Professionalism There is another important difference that marks the success within medicine, and some of the difficulties faced by those who operate within nutrition areas, or the broader health sector. This is perhaps the main reason for identifying a special category; Doctors of Health. The most important feature of the medical profession that commands respect is its professionalism. This encapsulates a range of aspects and values, many of which are not particularly fashionable now, but which I believe to be of critical, fundamental importance if we are to hold out any hope of success. Some of the features I consider to be most important are: • Explicit recognition of standards and values shared by all members of the group which goes to considerable effort to effectively protect them. • Personal aspiration of individuals in the group to achieve and maintain these standards and values. • Active promotion of the desirability and imperative to aspire to and uphold the standards and values, both for the individual and the group as a whole. • An explicit agenda, with a cultural aspiration through which the standards and values might be achieved and maintained. • Recognition of human frailty and the limitation of each individual. The limitations vary amongst individuals, but one collective responsibility of the group is to work within them, to enable each individual to achieve their personal best, and as a group deliver a service of the highest standard and quality. Given the limitations and frailty of individuals; appearances are important. Keep up appearances; there lies the test; The world will give the credit for the rest. Outward be fair, however, foul within; Sin if thou wilt, but then in secret sin. (Night & Churchill 1761) Thus appearances are not used to mask personal and group limitations, but they are used as an external expression of the standards and values to which the individuals and the group aspire to establish and maintain.

Closing comments The progress in nutrition, and in the biological and health sciences over the last hundred years has brought untold benefit to humankind, but in general has operated on the assumption of infinite and unlimited resource. The next 50 years will test our ability to cope when those resources are stretched to the limit. Most wealth is based upon the provision and consumption of

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food, and a very large part of the resource use is related to the provision and consumption of food. We have a wonderful opportunity to manage that resource wisely and well. In every other sphere of life, people are trained with the special skills needed to take on complex tasks. In human nutrition we have not yet started. I believe that the British Nutrition Foundation is critically placed to make a pivotal contribution to this most exciting challenge for nutrition. The opportunity is there for a major impact to be made on all aspects of the values of society. If there is any uncertainty about the starting point, protecting the welfare and happiness of mothers and their young children is the best place to secure any investment in the future.

References Alleyne GAO, Flores H, Picou DIM & Waterlow JC (1972) Metabolic changes in children with protein-calorie malnutrition In: Nutrition and Development (ed M Winick), pp. 201–38. John Wiley & Sons, New York. Ashworth A, Jackson A, Khanum S & Schofield C (1996) Ten steps to recovery. Child Health Dialogue 3/4: 10–2. Barker DJP & Osmond C (1986) Infant mortality, childhood nutrition, and ischaemic heart disease in England and Wales. Lancet; I: 1077–81. Barker DJP (1994) Mothers, Babies and Disease in Later Life. BMJ Publishing Group, London. Barker DJP (1998) Mothers, Babies and Health in Later Life. Churchill Livingstone, Edinburgh. Blaxter K & Waterlow JC (1985) Nutritional Adaptation in Man. John Libbey, London. Bleckert G, Oppel UG & Salzsieder E (1998) Mixed graphical models form simultaneous model identification and control applied to the glucose-insulin metabolism. Computing Methods and Programs in Biomedicine 56: 141–55. British Nutrition Foundation Task Force on Clinical Nutrition (1983) Nutrition in Medical Education BNF, London. Bredow MT & Jackson AA (1994) Community based, effective, low cost approach to the treatment of severe malnutrition in rural Jamaica. Archives of Diseases in Childhood 71: 297–303. Christ F, Abicht JM, Baschnegger H et al. (1997) Cardiovascular monitoring of elective aortic aneurysm repair using methods of chaos analysis. International Journal of Microcirculation: Clinical and Experimental 17: 374–84. Collins S, Myatt M & Golden B (1998) Dietary treatment of severe malnutrition in adults. American Journal of Clinical Nutrition 68: 193–9. Committee on Medical Aspects of Food Policy (1991) Dietary Reference Values for Food Energy and Nutrients for the United Kingdom. Report on Health Social Subjects no 41. The Stationery Office, London. de Almeida MDV, Graca P, Lappalainen R et al. (1997) Sources used and trusted by nationally-representative adults in the European Union for information on healthy eating European. Journal of Clinical Nutrition 51: S16–S22.

Department of Health (1994a) The Health of the Nation Nutrition: Core Curriculum for Nutrition in the Education of Health Professionals. Department of Health, London. Department of Health (1994b) Eat Well! An Action Plan from the Nutrition Task Force to achieve the Health of the Nation targets on diet and nutrition. Department of Health, London. Department of Health (1996a) Eat Well II! A Progress Report from the Nutrition Task Force on the Action Plan to achieve the Health of the Nation targets on Diet and Nutrition. Department of Health, London. Department of Health (1996b) The Health of the Nation Nutrition for Medical Students: Nutrition in the Undergraduate Medical Curriculum. Department of Health, London. Duggleby SL & Jackson AA (2000) Whole body protein turnover during pregnancy, maternal body composition and fetal outcome. Proceedings of the Nutrition Society (in press). Environmental Child Health (1974) Resolution No 7 of the 5th Caribbean Health Ministers Conference Strategy and Plan of Action to Combat Gastro-enteritis and Malnutrition in Children under Two Years of Age. FAO/WHO/UNU (1985) Energy and protein requirements WHO Technical Report Series no 552 WHO, Geneva. Flynn A (1999) Pan EU survey of consumer attitudes to physical activity, body weight and health. Public Health Nutrition 2: 77– 160. Forsen T, Eriksson JG, Tuomilehto J et al. (1997) Mother’s weight in pregnancy and coronary heart disease in a cohort of Finnish men: follow up study. British Medical Journal 315: 837–40. Gedrich K, Hensel A, Binder I & Karg G (1999) How optimal are computer-calculated optimal diets? European Journal of Clinical Nutrition 53: 309–18. General Medical Council (1993) Tomorrow’s Doctors: Recommendations on Undergraduate Medical Education GMC, London. Gibson N, Ah-Sing E, Badalloo A et al. (1997) Transfer of 15N from urea to the circulating dispensable and indispensable amino acid pool in the human infant. Proceedings of the Nutrition Society 56: 79A. Godfrey K, Barker DJP, Robinson S & Osmond C (1997) Maternal birthweight and diet in pregnancy in relation to the infant’s thinness at birth. British Journal of Obstetrics and Gynaecology 104: 663–7. Godfrey KM, Forrester T, Barker DJP et al. (1994) Maternal nutritional status in pregnancy and blood pressure in childhood. British Journal of Obstetrics and Gynaecology 101: 398–403. Golden MHN, Briend A & Grellety Y (1995) Report of a meeting on supplementary fedding programmes with particular reference to refugee populations. European Journal of Clinical Nutrition 49: 137–45. Golden MHN & Ramdath D (1987) Free radicals in the pathogenesis of kwashiorkor. Proceedings of the Nutrition Society 46: 53– 68. Harper AE, Benevenga NJ & Wohlhueter RM (1970) Effects of ingestion of disproportionate amounts of amino acids. Physiological Reviews 50: 428–58. Harrison GA & Waterlow JC (1990) Diet and disease in traditional and developing societies Cambridge University Press, Cambridge. Haste FM, Brooke OG, Anderson HR & Bland JM (1991) The effect of nutritional intake on outcome of pregnancy in smokers and non-smokers. British Journal of Nutrition 65: 347–54.


‘All that glitters’ Jackson AA, Golden MHN & Golden BE (1979) Progress in the manangement of severe infantile malnutrition. American Journal of Clinical Nutrition 32: xxxii. Jackson AA & Golden MHN (1987) Severe malnutrition In: Oxford Textbook of Medicine (eds DJ Weatherall, JGG Ledingham & DA Warrell), pp. 812–28 Oxford Medical Publications; Oxford. Jackson AA, Shaw JCL, Barber A & Golden MHN (1981) Nitrogen metabolism in preterm infants fed human donor breast milk: the possible essentiality of glycine. Pediatric Research 15: 1454–61. Jackson AA (1986) Blood glutathione in severe malnutrition in childhood. Transactions of the Royal Society of Tropical Medicine and Hygiene 80: 911–3. Jackson AA (1993) Chronic malnutrition: protein metabolism. Proceedings of the Nutrition Society 52: 1–10. Jackson AA (1992) How can early diet influence later disease? Nutrition Bulletin 17: 23–30. Jackson AA (1999b) Limits of adaptation to high dietary protein intakes. European Journal of Clinical Nutrition 53: S44–S52. Jackson AA (1999a) Maternal and fetal demands for nutrients: significance of protein metabolism In: (eds PMS O’Brien, T Wheeler & DJP Barker) Fetal Programming: Influences on Development and Disease in Later Life. London: Royal College of Obstetricians and Gynaecologists; 246–70. Jackson AA (1989) Optimizing amino acid and protein supply and utilization in the newborn. Proceedings of the Nutrition Society 48: 293–301. Jackson AA (1996) Perinatal nutrition: the impact on postnatal growth and development In: (eds PD Gluckman & MA Heymann) Pediatrics and Perinatology. London: Arnold; 298–303. Jackson AA (1998) Salvage of urea-nitrogen in the large bowel: functional significance in metabolic control and adaptation. Biochemical Society Transactions 26: 231–7. Jackson AA (1995) Salvage of urea nitrogen and protein requirements. Proceedings of the Nutrition Society 54: 535–47. Jackson AA (1990) The aetiology of kwashiorkor In: (eds Harrison GA, Waterlow JC) Diet and Disease in Traditional and Developing Societies. Cambridge: Cambridge University Press; 76–113. Jackson AA (1994) Urea as a nutrient: bioavailability and role in nitrogen economy. Archives of Diseases in Childhood 70: 3–4. Khanum S, Ashworth A & Huttly SRA (1994) Controlled trial of three approaches to the treatment of severe malnutrition. Lancet 344: 1728–32. Khanum S, Ashworth A & Huttly SRA (1998) Growth, morbidity, and mortality of children in Dhaka after treatment for severe malnutrition: a prospective study. American Journal of Clinical Nutrition 67: 940–5. Landman JP & Jackson AA (1981) The role of protein in the aetiology of kwashiorkor. Wisconsin Medical Journal xxix: 229–38. Marchini JS, Cortiella J, Hiramatsu T, Chapman TE & Young VR (1993) Requirements for indispensable amino acids in adult humans: longer term amino acid kinetic study with support for the adequacy of the Massachusetts Institute of Technology amino acid requirement pattern. American Journal of Clinical Nutrition 58: 670–83. Mathews F, Yudkin P & Neil A (1999) Influence of maternal nutrition on outcome of pregnancy: prospective cohort study. British Medical Journ 319: 339–43. Metges CC, El-Khoury AE, Henneman L et al. (1999) Availability


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of intestinal microbial lysine for whole body lysine homeostasis in human subjects. American Journal of Physiology 277: E597– E607. Millward DJ, Forrester T, Ah-Sing E et al. (2000) The transfer of 15N from urea to lysine in the human infant. British Journal of Nutrition (in press). O’Brien PMS, Wheeler T & Barker DJP (1999) Fetal Programming: Influences on Development and Disease in Later Life. Royal College of Obstetricians and Gynaecologists, London. Pellett PL (1996) World essential amino acid supply with special attention to South-East Asia. Food and Nutrition Bulletin 17: 204–34. Picou D, Alleyne GAO, Kerr DS et al. (1975) Malnutrition and Gastroenteritis in children: a manual for hospital treatment and management Caribbean Food and Nutrition Institute, Jamaica. Roberts I (1998) Human albumin administration in critically ill patients: systematic review of randomised controlled trials. British Medical Journal 317: 235–40. Rossor MN (1995) Catastrophe, chaos and Alzheimer’s disease. Journal of the Royal College of Physicians London 29: 412–8. Royal College of Physicians (1998) Clinical Management of Overweight and Obese Patients with Particular Reference to the Use of Drugs. Royal College of Physicians, London. Rush D (1989) Effects of changes in maternal energy and protein intake during pregnancy, with special reference to fetal growth In: Fetal Growth (eds F Sharp, RB Fraser & RDG Milner). London: Springer-Verlag; 203–29. Schofield C & Ashworth A (1996) Why have mortality rates for severe malnutrition remained so high? Bulletin of the WHO 74: 223–9. Waterlow JC & Alleyne GAO (1971) Protein malnutrition in children: advances in knowledge in the last ten years. Advances in Protein Chemistry 25: 117–241. Waterlow JC, Armstrong DG, Fowden L & Riley R (1998) Feeding a world population of more than eight billion people. A Challenge to Science. Oxford University Press, Oxford. Waterlow JC, Cravioto J & Stephen JML (1960) Protein malnutrition in man. Advances in Protein Chemistry 15: 131–238. Waterlow JC (1948) Fatty liver disease in the British West Indies Special Report Series No 263. Medical Research Council (UK), London. Waterlow JC (1968) Observations on the mechanism of adaptation to low protein intakes. Lancet 2: 1091–7. Waterlow JC Protein-energy malnutrition (1992) Edward Arnold, London. Widdowson EM, Southgate DAT & Hey EM (1979) Body composition of the fetus and infant In: Nutrition and Metabolism of the Fetus and Infant (ed HAK Visser), pp. 169–77. Martinus-Nijhoff, The Hague. Wirsam B & Uthus EO (1996) The use of fuzzy logic in nutrition Journal of Nutrition 126: S2337–S2341. Wirsam B, Hahn A, Uthus EO & Leitzmann C (1997) Fuzzy sets and fuzzy decision making in nutrition. European Journal of Clinical Nutrition 1997 (51): 286–96. World Health Organization (1999) Management of Severe Malnutrition: a Manual for Physicians and Other Senior Health Workers WHO, Geneva. World Health Organization (1998) Obesity: Preventing and Managing the Global Epidemic. WHO, Geneva.

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World Health Organization (1981) The Treatment and Management of Severe Protein-Energy Malnutrition. WHO, Geneva. Young VR, Bier DM & Pellet PL (1989) A theoretical basis for increasing current estimates of the amino acid requirements in adult men, with experimental support. American Journal of Clinical Nutrition 50: 80–92.

Young VR & El-Khoury AE (1996) Human amino acid requirements: a re-evaluation. Food and Nutrition Bulletin 17: 191–203. Young VR & Pellett PL (1990) Current concepts concerning indispensable amino acid needs in adults and their implications for international nutrition planning. Food and Nutrition Bulletin 12: 289–300.
