Towards the Conquest of Vitamin A Difficiency Disorders

TOWARDS THE CONQUEST OF VITAMIN A DEFICIENCY DISORDERS

TOWARDS THE CONQUEST OF VITAMIN A DEFICIENCY DISORDERS Donald S. McLaren

© Task Force SIGHT AND LIFE PO Box 2116 4002 Basel Switzerland Phone +41 61 688 7494 Fax +41 61 688 1910 E-mail: [email protected] http://www.sightandlife.org Layout and cover design: Martin Frigg ISBN 3-906412-02-4

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Foreword We casually and habitually talk about “scientific progress” or refer to the “current state of research” as if the advancement and growth of human knowledge were somehow inevitable. In fact, though, this is not the case. Major breakthroughs invariably depend on individual people being in the right place at the right time and doing the right thing. The present book is a testimonial to the life’s work of Professor Donald S. McLaren, who for over half a century now has persistently been doing the right things in the right places at just the right moments. He made early and decisive contributions to the general recognition of vitamin A deficiency as a public health problem and to our current ability to combat this condition effectively. At first glance, this book appears to be an autobiography. But Donald McLaren’s “personal odyssey” has always led him to areas directly or indirectly involving vitamin A. And so the book can also be read as a kind of history of vitamin A, told from a medical point of view. The value of such a publication lies in the way it reveal-

ingly draws the reader’s attention to the element of time. Those prepared to take a cold hard look at the aberrations and confusions of the past run less of a risk of accepting today’s received wisdom as definitive and absolute. The insight that the current state of our knowledge is also a measure of our current ignorance is a crucial impetus for the improvements and advances of tomorrow. There is no question that Donald McLaren is an irredeemably inquisitive investigator and a man who argues his views elegantly and incisively. Over the years his contacts with the Task Force SIGHT AND LIFE have been many and varied, and this long-standing relationship was intensified further last year when the Task Force published the Manual on Vitamin A Deficiency Disorders. SIGHT AND LIFE feels honoured to have been entrusted by Donald McLaren with the publication of the present work. We are issuing this book, which offers an articulate plea for dedication to research, as a way of saying thank you to an exceptional scientific figure.

Dr Andres F. Leuenberger Chairman, Task Force SIGHT AND LIFE

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Contents Foreword Introduction

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Chapter 1 An outline history Vitamin A deficiency disorders (VADD) Panel 1: Misunderstandings about night blindness Panel 2: The story of cod-liver oil Panel 3: Vitamins and the arrow of time Panel 4: The early neglect of xerophthalmia Discovery of the vitamin Panel 5: Abandoning of the anti-infective vitamin

13 13 15 17 18 20 21 22

Chapter 3

Chapter 2 A personal odyssey Growing up between two world wars (1924–1949) Panel 6: The Edinburgh Medical School and Nutrition Panel 7: Nutrition at the London School Mission in India (1950–1954) Panel 8: William Carey, the Baptist Missionary Society and the Kui people Panel 9: Cicely Delphine Williams (1893–1992) Back in London (1954–1957) Panel 10: The East African Institute for Medical Research Panel 11: The Princeton conference in June 1958

Medical research in Tanganyika (1958–1962) 60 Panel 12: H. A. P. C. Oomen (1902–1986) 61 The Switzerland of the Middle East (1962–1976) 77 Panel 13: The American University of Beirut, Lebanon 78 Panel 14: The Xerophthalmia Club Bulletin 94 Panel 15: Xerophthalmia prevention in Madurai, India 95 Panel 16: The International Vitamin A Consultative Group 102 Return to Edinburgh (1976–1988) 106 Panel 17: Four uneasy bedfellows 107 Retirement in Worthing (1988) 113

25 26 34 38 40

43 47 48 56 58

Update and commentary

117

Chapter 4 Looking to the future Introduction 121 Problems with xerophthalmia No magic bullet for intervention No gold standard for assessment Unanswered questions Unlearned lessons Questionable concepts Future for some “institutions”

121

Epilogue References Index

129 131 141

122 122 123 123 124 126 126

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Introduction This book has rather unusual origins. Dr Martin Frigg of SIGHT AND LIFE and I entered into a collaboration in 1996–97 to produce the SIGHT AND LIFE Manual of Vitamin A Deficiency Disorders (VADD) (1) and the slide set on the same subject. These have been made freely available by SIGHT AND LIFE, and it is gratifying to think that they are making a significant contribution towards the conquest of vitamin A deficiency disorders, which is also the title of this present volume. In the course of undertaking this task I reviewed a great deal of material in the field, both ancient as well as modern. With the help of diary entries and old notes, I then began to write an account of what amounted to “how I got into vitamin A”. Readers of the Xerophthalmia Club Bulletin, which will feature prominently later (Panel 14, page 94), may recall that as its editor I ran a series there on that theme which provided some fascinating accounts of the very diverse backgrounds of those of us working on this problem. Martin read a rough draft of this account, and I am happy to acknowledge that it is entirely due to his encouragement and many helpful suggestions that this work is coming to fruition here. The original concept has been transformed and the value of the final product has, I am sure, been greatly enhanced. It consists of four chapters that are to a considerable extent independent of each other. It will probably be helpful to the reader for something to be said in explanation about the topics covered in each of the chapters. Chapter 1, An outline history of vitamin A deficiency disorders and of the discovery of the vitamin, gives an account of the main events. No attempt is made here to be exhaustive in the treatment of the subject. There are already detailed accounts available elsewhere to which interested readers are referred.

In this chapter I have inserted several “panels”, which present topics that seem to merit separate discussion. This form of presentation, whilst giving some prominence to subjects that might interest the specialist reader, permits the more general reader to pass these panels over readily. Chapter 2, A personal odyssey, forms the main part of the book. It includes my own experiences when I was living and working in many countries while on the trail of VADD. It was a very exciting period to be working on a problem that was gradually revealed to be of enormous public health importance in many parts of the world. I have tried to be as objective as possible, and although I have made every effort to avoid factual errors, I hope that the reader will forgive me if perhaps I have given way to excessive enthusiasm at times. Along with the story of my own experiences I have again included at intervals a series of panels which serve as vignettes of various people, places or institutions that are intertwined with my own story in some way. At first I thought I could write a separate chapter on the work of others in the VADD field at that time. However, as things began to unfold I realised that it was not possible to separate those I needed to mention in connection with my own work and others not so clearly associated. I am sure that for the average reader this unified approach will be more satisfactory. It is probably more important to understand how knowledge in a certain area unfolded over a period of time, than to be told who did what and when. My account is based on the written evidence and the memory I have of what others were contributing during the period of my own active participation. The world of medical research was very different in those days from what it is today. Research was usually car9

Introduction ried on by individuals or very small groups, not like the multidisciplinary forces of today. Projects were on a smaIl scale and funding often both limited and of uncertain duration. It should also be recognised that those of us who were working on nutritional diseases were for the most part living in isolated parts of the world. We had few and uncertain means of communication. Scientific meetings were held much less frequently than today. We only rarely had opportunities to meet face to face. If some who read this feel that I have omitted or diminished their own contribution or that of others they know, then I truly regret this, for any such error was entirely unintentional. Chapter 3 consists of an Update and commentary. It may be said that a new era for VADD began when it was demonstrated in the early 1980s in large-scale field studies for the first time that vitamin A plays an important role in the survival of young children. I have found the unfolding of this major development especially fascinating to follow. Two decades or so previously our group in Beirut had been carrying out clinical (page 82) and field (page 86) studies of a preliminary nature that were pointing in this direction. It so happens that it was about that time when I ceased to make original contributions in the field. However, my continuing participation in such

activities as teaching at the International Centre for Eye Health (ICEH), attendance at meetings of the International Vitamin A Consultative Group (IVACG) (see Panel 16, page 102) and serving as the editor of the Xerophthalmia Club Bulletin since 1985 has meant that I have remained closely in touch with subsequent developments. Achievements in the field over the past 20 years or so have entered the body of scientific knowledge and have been extensively documented, most notably in the book by Sommer and West (2). They have also been recorded in a more general form in the SIGHT AND LIFE manual (1) and elsewhere. This chapter provides the salient information for this period to help the reader to bridge the gap in time between recent history and the final chapter. Chapter 4 is called Looking to the future. It seems appropriate that in a book that looks towards the conquest of a health problem, like VADD, there should be a place for a final section that takes a look into the future and tries to point out some lessons that need to be learned from past experience. Here again the views expressed are bound to be very personal and therefore open to challenge by others. Any such controversy of a constructive nature should be warmly welcomed. It could bring the day of the conquest of VADD nearer than might otherwise be possible. That, indeed, is the primary purpose of this book.

Donald S. McLaren Summer 1999

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Chapter 1

An outline history Vitamin A deficiency disorders (VADD)

enon is clearly described and there are no difficulties over translation then one may be fairly satisfied that VAD is being described. There are other causes of night blindness but these are all quite rare.

This is intentionally a brief introduction to the subject. Wolf has recently written an excellent history of vitamin A and retinoids (3). My main purpose here is to set the scene for the next chapter of personal experiences. I think it is important to view these in perspective. At the time it rather seemed as though very little was known about vitamin A deficiency disorders (VADD). Although this was true the position was that this was because the disease had fallen into a period of neglect. When one comes to review the history it is quite remarkable what a lot of work had gone on.

On the other hand, dryness or xerosis of the conjunctiva or cornea and keratomalacia require close and expert examination of the eye for their identification. Not surprisingly therefore, it is not possible to identify them precisely in ancient literature. Usually no clear distinction is made between various eye diseases that lead to haziness of the cornea and/or the lens.

There are several topics about which there is some controversy or consideration of which may provide a lesson for the present from the past. These would seem to merit separate treatment, and this has been set out within several panels. Most historical accounts of vitamin A deficiency start back in antiquity by reference to what are interpreted as descriptions of the use of liver in various ways for the treatment of night blindness. It is claimed that several medical papyri from Egypt and accounts from India and China convey this kind of information. Recent research casts some new light on the subject and Panel 1 discusses this topic. A good deal of care must be exercised when one is seeking information about the occurrence of VAD in pre-scientific times. True night blindness is a very distinctive symptom and providing that this phenom-

It is quite a surprise to realise that it was as late as 1913, the very year when “fat-soluble A” was discovered by McCollum, that the first connection was made between night blindness, rhodopsin and keratomalacia (4). Ishihara proposed that a fatty substance in the blood was needed for the synthesis of visual purple in the retina and “keratohyalin” in the surface layer of the cornea. Celsus, the most famous Roman author on medicine, sometimes called “the Latin Hippocrates”, is credited as the source of the first description of xerophthalmia (9). His account of the disease and recommended treatment goes as follows: “There is a kind of dry inflammation of the eyes called by the Greeks xerophthalmia. The eyes neither swell nor run, but are nonetheless red and heavy and painful and at night the lids get stuck together by very troublesome rheum; the less violent the onset of this kind of trouble is, the less readily it is terminated. In this lesion there is need for much walking, much exercise, frequent bathing, sitting in the bath and sweating, and much rubbing. The food should not be too flesh13

History making, neither is acid food suitable, but a mean between the two. In the morning when it is plain that all food has been digested, it is not inappropriate to gargle with mustard, then next to rub the hands and face for a considerable time.”

in the treatment of rickets and other bone disorders. How cod-liver oil came to occupy an important role in nutritional medicine in general and VAD in particular and its continuing popularity to the present day is described in Panel 2.

I have given this quotation in full to make it clear that Celsus made no mention at all of liver. This implies that no association was made between xerosis of the eyes and night blindness at that time. Knowledge of the efficacy of liver for the treatment of night blindness persisted through mediaeval times in Europe.

At about the same time the germ theory of disease received a tremendous boost from the discoveries of Pasteur, Koch and colleagues of bacteria as causative agents of major diseases. Also, accepted teaching about nutrition stated that carbohydrates, fats, proteins and some other elements comprised all the components of a complete diet. The scientific community was reluctant, however, to entertain the possibility of an essential role for health of small amounts of organic compounds in the diet, later to be known as vitamins. Possible reasons for this are pursued further in Panel 3.

A book on diseases of the cornea published in 1729 first associated corneal blindness with measles (10), but without any suggestion that a faulty diet was involved. A few years later it was proposed that night blindness could result from either dietary deficiency or excessive exposure to sunlight (11). We now know that bleaching of visual purple (rhodopsin) in the retina can exacerbate the condition. Serendipity is well-known to play a part frequently in medical discovery. An interesting example occurred in the early years of the 19th century when the celebrated French physiologist Magendie was examining food components as nutrients (12). He noted in passing that dogs restricted to wheat gluten, starch, sugar, or olive oil as their sole food developed ulcers of the cornea. This seems to have been the first experimental production of a deficiency disease, i.e., keratomalacia. This chance observation might not have received much attention unless the medical missionary and African explorer David Livingstone years later had not described how the eyes of some of his native carriers who had to subsist on sugarless coffee, manioc, and meal “became affected as in the case of animals fed on experiment on pure gluten or starch” (13). In the middle of the 19th century cod-liver oil was recognised as curative in night blindness and xerosis conjunctivae. This was many years after its first use 14

Throughout the earlier years of the 19th century there were sporadic reports of keratomalacia in severely malnourished patients in Europe. The famous German ophthalmologist von Graefe reported seeing two or three cases a week in his clinic (29). The first report from a tropical country, Brasil, at about the same time (30) spoke of night blindness among plantation workers and keratomalacia in their children. de Hubbenet (31), chief medical officer of the small French force in the Crimean War, gave the first description of conjunctival patches of xerosis and noted their association with night blindness and a poor diet. A few years later Bitot noted the same phenomenon in orphan children in Bordeaux, and his name became associated with the dry spots (32). The relationship of poor general health and infectious disease to xerophthalmia was noted in relation to intestinal disease (33) and liver disease (34) at about that time. Rather later, in 1897, Herbert appears to have been the first to note that other mucous membranes besides the eye were affected (35). These early observations pointed the way to recognition much later on that VAD has important implications beyond the eye for health.

Panel 1

Misunderstandings about night blindness It is generally agreed that liver was recommended for the treatment of an eye complaint that fits with the description of night blindness from very early times. There are reports from Egypt, India and China of animal liver being roasted or fried and fed as a cure. Many writers have seized upon the fact that liver is a rich source of vitamin A and drawn the conclusion that as a consequence it would over the years be found to be effective in night blindness. Against this has to be set the evidence that liver was also recommended for other eye conditions that from their description had no relation to VAD, and even for disease of other organs. More often than not the descriptions of disease were so vague, in our terms, that interpretation into our system is impossible. Moreover, in the magical systems of medicine prevailing in those times in some cultures, study of the liver, hepatoscopy, played an important part. According to an earlier paper by Wolf (5) the earliest sources of a treatment for night blindness in Egypt proposed topical application of an extract from the liver to the eye. He made the suggestion that some of the extract containing vitamin A that was applied to the surface of the eye would have passed down the naso-lacrimal duct and been absorbed into the blood stream. It is not unknown for xerophthalmia to be treated by local application of fish liver oil in this way in some societies in present times. Two sources for this proposed topical use were cited by Wolf (5) – both are Egyptian papyri dating from many centuries BC. Other, much later recommendations in the Greek literature for topical application of liver appear to derive from these Egyptian sources. The less important is known as “The London Medical Papyrus” and dates from about 1400 BC. Recipe number 35 states, “Another recipe. Beef liver placed on a fire of straw of emmer or barley and smoked in their smoke; their (the liver’s) liquid squeezed against the eyes.” The problem is that there is no

An attempt to visualise the problem of night blindness. From the SIGHT AND LIFE poster. specific use of a term that can be translated as night blindness. A similar problem arises with the even more important Papyrus Ebers, dating from about 1520 BC. This is recognised to be the oldest book on medicine (6). It has a large section on eye diseases. While the prescriptions are carefully detailed, the diseases are only mentioned by name. Frequently the latter cannot be positively identified in modern medical terms. It is Ebers 351 that is of special concern to us here. It refers to the treatment of “sharu-disease with roasted ox liver, pressed, applied thereon, really effective”. Sharu was first interpreted as night blindness by Ebbell in 1937 (7). This incorrect interpretation has been accepted by many. However, it is

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now universally agreed by scholars of the subject that Ebbell’s version is full of mistakes, even he (Ebbell) admitted that “most of his attempts at identification were highly conjectural”.

In the Hippocratic collection the word nyktalops occurs five times. The word contains the root nyx, night, and ops, the face – suggesting “somebody who only sees at night”.

Nunn has recently published a very thorough study of ancient Egyptian medicine (8). With regard to Ebers 351 he points out that the word sharu or shau denotes only an eye disease that cannot be specified now. The ideogram for “night” does not appear in the word. Other recent authors cited by Nunn also translate sharu only as “eye disease”. Wolf’s later paper (3) accepts the interpretation by Nunn.

From the descriptions we have it would appear that photophobia is being referred to. This might have resulted from keratitis associated with prolonged exposure to bright sunlight. However, Galen and his successors used nyctalopia in the entirely contrary sense of night blindness. Hirschberg cites many instances of this confusion through the ages. This is how the word is usually used today.

There is another area of confusion that has persisted for hundreds of years over the terminology of night blindness. On the face of it, the symptom of night blindness is clear-cut and can be explained in very simple words. However, as Hirschberg (6) states, the terminology that has been in use since the time of Hippocrates means that “we face a controversy which has continued into our days”. It is primarily the meaning that has been given to the word nyctalopia, and to a lesser extent the use of the term hemeralopia, that have resulted in all the confusion. Hirschberg’s classic (6) is the source for the comments that follow.

It is not clear when the term hemeralopia (hemera, day) was introduced. When used, it is now usually regarded as being synonymous with nyctalopia. This practice persists today especially in the French use of nyctalopie and hemeralopie.

In Britain in 1898 Stephenson (36), in what seems to have been the first extensive field study of VAD, examined more than 6000 children in orphanages and schools and found 1.87% with “epithelial xerosis of the conjunctiva”. Night blindness was usually also present and occasionally contraction of the visual fields was demonstrated.

years later it was suggested that night blindness might be due to retarded regeneration of this visual pigment (38). An accurate description of the histological changes in the conjunctiva and cornea in VAD was given at about the same time (39). These changes could be cured by an adequate diet, using raw cow’s milk (40).

A greater understanding of the nature of VAD began to develop towards the end of the 19th century. The visual pigment, known as visual purple or rhodopsin, was identified in 1878 (37). Three

The first account of truly epidemic proportions was that of the 1400 cases of conjunctival xerosis and keratomalacia in children aged 2–5 years in Japan reported by Mori in 1904 (41). He observed that the

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In conclusion, Hirschberg’s advice to abandon the Greek terms and use only the unequivocable English or German words available, appears eminently sound. He concludes, “It is nonsensical to continue using Greek words which were even to the Greeks 2000 years ago not quite clear”.

Panel 2

The story of cod-liver oil This story is sufficiently important for a book entitled “Cod: A biography of the fish that changed the world” to have been written about it recently (14). Here we are primarily concerned with that part of the story that tells how this oil came to occupy its place as a firm favourite among nutritional supplements in general and as a source of vitamin A in particular. In a crude form, sometimes mixed with mutton tallow, fish oil had been used as a home remedy for as long as can be remembered along the coasts of Northern Europe. It seems to have been first used medicinally in England in the 18th century for “rheumatism” (15). In this connection it is interesting to note that a revival in the use of cod-liver oil in rheumatoid arthritis has been shown to have a scientific basis. Some of the polyunsaturated fatty acids it contains decrease production of leukotrienes involved in the inflammatory process. Cod-liver oil seems to have been first recommended for the treatment of rickets in 1824. The famous French physician Armand Trousseau, who played an important part in the discovery of vitamins (see Panel 3), recommended the liver oils of cod and other fish for the treatment of rickets in the 1830s. This use of the oil tended to overshadow an appreciation of its efficacy in night blindness at about that time. Later on cod-liver oil became standard treatment for all forms of VAD. The first demonstration that cod-liver oil contained vitamin A, or a “fat-soluble complex” as they called it, was made by Osborne and Mendel (16). Zilva and Drummond (17) showed it to be present, sometimes in much higher concentrations, in other fish livers.

Attention has been drawn to the frequent association of VAD with infections. The fascinating story of the era when vitamin A was known as the “anti-infective” vitamin is told in Panel 5. Here it may be noted that in almost all the trials carried out during that time cod-liver oil was given as the source of vitamin A. The pharmaceutical companies were quick to promote the product as a routine preventive measure for young children. The disagreeable taste was sometimes masked in treacle; at others mothers would boast of their “good little boy taking his cod-liver oil” – I remember being such a one! Many years on, cod-liver oil has managed to retain its place as a popular home remedy, but for very different reasons. Now it is generally older people who take it – very often the survivors from the earlier days! This time it is partly for rheumatism, as has been mentioned. Some of the polyunsaturated fatty acids also prevent the aggregation of platelets and the tendency to coronary thrombosis. The oil is also quite a good source of vitamin E, which may also help to prevent heart attacks.

The rich decoration of this cod-liver oil bottle still reflects the value its content once had.

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Panel 3

Vitamins and the arrow of time It is sometimes said that science gives history its time arrow. By this is meant that science is cumulative, with a definite development and progression with time. The arts show this to a much smaller extent and morality would seem to ignore the arrow altogether! Mayer (18) described in a truly thoughtful article how the abandonment of the discovery of the aetiology and treatment of rickets by the great French physician, Armand Trousseau, is an astonishing example of the reversal of the arrow. His association of rickets with a defective diet and its cure by cod-liver oil put forward in the first half of the 19th century were generally forgotten by 1900. It is likely that Trousseau’s contributions, along with other evidence for a defective diet in the aetiology of disease, were, as Mayer says, “swept away in the enthusiasm for Pasteur’s germ theory of disease”. Follis, a nutritional pathologist (19), and Carter, a philosopher (20), have provided convincing evidence for this concept. In their review Ihde and Becker (21) point out that all four of the following diseases – rickets, scurvy, beriberi and pellagra – at about that time were seriously considered by some to be due to infectious organisms. A medical historian, Rosenberg (22), makes the additional point that although physicians of the time were aware of a relation between diet and disease, they found it difficult to believe that a disease might be caused by the absence of a factor in minute amounts. In 1929 F. G. Hopkins of Britain and C. Eijkman of the Netherlands shared a Nobel Prize in physiology and medicine for the discovery of vitamins. In recent years there has been considerable historical research into the lives and work of many scientists over a period of almost 100 years who made contributions in this field. As so often happens when hindsight is

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brought to bear on a matter like this, it is very doubtful if either deserved the special honour they received. In the mid 19th century the ideas of the German chemist, Justus von Liebig (1803–73) dominated scientific and lay thinking alike on nutrition. He taught that foodstuffs contained only “water, mineral matter, proteins, carbohydrates and fats”. The body was like an engine, protein from the diet built up the tissues, carbohydrates and fats provided energy. N. I. Lunin (1853–1937) was probably the first to provide evidence to challenge Liebig (23). He showed that mice cannot survive on purified diets of fat, carbohydrate, protein and salts alone. They could when milk was added. He concluded, “other substances indispensable for nutrition must be present in milk besides casein, fat, lactose and salts”. In Holland in the early years of the 20th century C.A. Pekelharing (24) demonstrated that mice were able to survive on diets to which small amounts of milk were added. W. Stepp (25) extracted the milk with alcohol ether, removing the lipids, and the mice did not live. C. Eijkman was sent to the Dutch East Indies (Indonesia) in 1886 to try to discover the cause of beriberi (vitamin B1 or thiamin deficiency). He returned to Holland convinced the disease was caused by a toxin. It was his successor Grijns who showed it to be a nutritional deficiency; but no Nobel Prize for Grijns! Hopkins, the joint Nobel Prize winner with Eijkman, became a towering figure in the new discipline of biochemistry in the years just before and after World War I. He coined the term “accessory food factors”, which did not last. It is ironic that Casimir Funk’s term “vitamine” did. Funk popularised the subject (26), but made no fundamental contribution. Careful reevaluation of the work of Hopkins on vitamins casts doubt on its quality (27, 28).

SIGHT AND LIFE associated diet was deficient in fat and there was a good response to cod-liver oil. He noted that the children of fishermen were protected. The disease was so common at that time that the Chinese term “hikan” was used to describe it. Wolf has recently written an interesting overview of the work of Mori (3). During the early years of the 20th century evidence grew that fat from certain dietary sources was essential. In a series of experiments Stepp (25) demonstrated that a small amount of lipid in the diet of mice was essential if they were to survive normally. Falta and Noeggerath (42) induced a more severe VAD in rats that led to xerophthalmia. Some years later Holm (43) studied the feeding habits of chickens exposed to different intensities of light and was able to demonstrate the phenomenon of dark adaptation. Holm (44) also showed that deficient animals have a subnormal rate of regeneration of visual purple. The impression may have been given here that considerable attention was being paid to xerophthalmia in the later part of the 19th and the early years of the 20th century. However, this was not in fact the case. With certain notable exceptions VAD was almost always omitted from any discussion of vitamin deficiency diseases. The possible reasons for this are considered in Panel 4. Just before World War I Osborne and Mendel of Yale (48) and McCollum and associates of Wisconsin (49) showed that certain animal fats like butterfat, egg yolk or cod-liver oil contained a substance essential for the growth of rats and which also cured eye disorders. McCollum termed this substance “fat-soluble A” as it was the first of what Hopkins earlier (50) called “accessory food factors” to be identified. McCollum had studied separately under Osborne and also Mendel at Yale before he moved to Wisconsin. It has been suggested (51) that he was rather lucky to have been credited with the discovery of the first vitamin. A paper by Osborne and Mendel (52) appeared in the same journal as McCollum’s paper and

was received for puplication only three weeks later. It is also interesting that Osborne and Mendel paid much more attention than did McCollum to the eye lesions that afflicted their animals (53). At about the same time the paediatrician Bloch (54) in Denmark described 40 cases of xerophthalmia in young children from poor households subsisting on diets of bread, potatoes, and fat-free milk. He extended his work to a children’s home and showed that a group that did not receive whole milk developed xerophthalmia while those who did were protected. Cod-liver oil caused the xerosis to disappear within one week. Bloch thus confirmed for humans the essential nature of dietary vitamin A. Somewhat later Blegvad (55) reviewed over 600 cases of children suffering from xerosis conjunctivae and keratomalacia in Denmark between 1909 and 1920. The peak of the epidemic occurred from 1914 to 1918, the years of World War I, when Bloch was carrying out his studies. During this period butter, a major product of Denmark, attracted such high prices abroad that it was unobtainable at home except by the rich. The poor had to make do with margarine, which was not fortified with vitamins then. Blegvad, for the first time, made a careful study of the outcome of the disease. Of 438 treated cases there was sufficient information available on 391. 93 died despite the treatment. Of the remaining 298, 79 were totally blind, 71 had greatly reduced vision in both eyes, in 105 cases vision was greatly reduced in one eye, and in only 43 both eyes recovered. These early survival figures may be compared with those of later studies (see pages 54, 82). Shortly afterwards interest turned to the suggestion that certain yellow pigments in plants had vitamin A activity. A colleague of McCollum’s at Wisconsin, Steenbock, showed that carotene, but not xanthophylls, induced growth in deficient rats (56). About ten years later Moore (57) demonstrated the conversion of carotene to vitamin A in the body. 19

Panel 4

The early neglect of xerophthalmia The present intention is to try to understand why, in the previtamin era of the 19th and early 20th centuries, xerophthalmia was excluded from the group of diseases considered to be due to dietary deficiency. I call this early neglect because it was to be followed by further periods of neglect (see pages 52, 73, 106). Attention has been drawn (page 14) to the occurrence of eye lesions, almost certainly due to keratomalacia, in dogs fed deficient diets by Magendie in 1816. This chance observation went unnoticed until much later. As we have seen (page 14), sporadic cases were reported in Europe and xerophthalmia was known to occur in the tropics. Nevertheless, when nutritional deficiency diseases began to be considered as a group xerophthalmia was not among them. The only exception of which I know is a series of five articles on “Disorders resulting from defective nutriment” published by a London physician George Budd (1808–82) in 1842 (45). Budd drew on his experience as a physician to the Dreadnought Seaman’s Hospital Ship and visits to prisons and asylums. He grouped three diseases in this category; scurvy, rickets, and “a peculiar ulceration of the cornea”. In recent times Hughes (46) drew attention to this pioneering work, but he made no mention of the fact that Budd was alone in including xerophthalmia in the group of disorders attributable to dietary deficiency. Almost all those writing on the subject mentioned scurvy and rickets and by the beginning of the 20th century the group numbered four members – scurvy, rickets, beriberi and pellagra. Funk (26) adhered to this view and was frequently quoted as a result. As we have seen (Panel 3), at one time or another each of these diseases had been attributed to a causa-

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tive pathogenic organism. Xerophthalmia is not mentioned in this connection, but it is interesting to observe that the eye signs of xerophthalmia in experimental animals were considered at one time to be due primarily to infection (47). It is particularly intriguing that of all the vitamins, and indeed of all micronutrients, it was deficiency of vitamin A that was subsequently shown to be especially associated with infectious diseases. The historical aspects of this subject form the topic of Panel 5. It has been mentioned (page 19) how the final demonstration of the existence of “fat-soluble A” was a closely run thing between McCollum at Wisconsin and his previous associates Osborne and Mendel at Yale. Both groups used rats and while McCollum and his associates relied on growth retardation as evidence of deficiency, the Yale workers frequently commented upon the occurrence of eye lesions which they likened to those of xerophthalmia described in man. Even so, like Stephenson (47) quoted above, they regarded the lesions as being due to infection rather than nutritional deficiency. At this distance in time it is difficult to try to unravel the reasons behind this striking neglect of xerophthalmia. The eyes have always been regarded as special and not to be tampered with by the uninitiated. Even general physicians are quick to refer any eye disease to the specialist ophthalmologist. The belief that the eye lesions in animals and man were infectious in nature would have made it difficult to include xerophthalmia as a nutritional disease. Ihde and Becker (21) in their historical review make an observation which appears to confirm what has already been said. They say that “the nutritional breakthrough came not from medical circles but from

agricultural circles”. They are referring to the contributions made in the United States to the discovery of vitamins that came from Mendel, Osborne, McCollum and others. They later comment on vitamin A in particular – “It is strange that the real breakthrough occurred in connection with vitamin A deficiency, since this deficiency had not been clearly identified with human

The final separation of vitamin A from vitamin D was accomplished by McCollum and colleagues (58) in 1922. At about that time there was intense interest in the possibility that vitamin A might have curative effects in a variety of infectious diseases. It became known as the “anti-infective” vitamin (59). However, despite considerable evidence for this, even in those early years, interest was not sustained. The extent of the interest at the time and the reasons for its disappearance are discussed in Panel 5. Wolbach gave a classic account of the keratinising metaplasia changes throughout the epithelial tissues of the body from his pathological examinations in Boston (60). The Carr Price colour reaction with antimony trichloride (61) made it possible for vitamin A concentrations to be estimated in serum, body tissues and in foodstuffs. From the 1930s George Wald and his colleagues at Harvard studied the visual pigments and elucidated the role of forms of vitamin A in vision (62). In 1967 he was awarded a Nobel Prize. During the years before World War II reports from India (63, 64) and China (65) provided evidence of keratomalacia as a widespread problem among ricedependent populations. Unusual features of the accounts from China were the large numbers of adults affected and the frequent presence of skin changes, known as perifollicular hyperkeratosis, phrynoderma or toad skin, that responded to cod-liver oil (66). In

or animal diseases”. In other words, despite all the prominence given to scurvy, rickets, beriberi and pellagra in this context, it was the factor responsible for maintenance of healthy eyes that was discovered first. There is perhaps a lesson to be learned here. Researchers need to have open as well as enquiring minds if they are to pick up clues from Nature that often come from the least expected sources.

the Dutch East Indies, now Indonesia, de Haas (67) showed that the milk and blood of women with babies with keratomalacia were very deficient in retinol. Most cases of xerophthalmia were associated with the feeding of sweetened condensed and skim milk. A human vitamin A deprivation experiment in volunteers carried out by the Medical Research Council in the UK (68) reproduced the earlier eye changes and determined the approximate daily requirements of βcarotene or vitamin A to treat the deficiency or prevent it occurring.

Discovery of the vitamin Once something termed fat-soluble A and found in certain foods had been shown to have functions as a nutrient, the chemists made rapid progress. Paul Karrer, Professor of Chemistry in Zurich, elucidated the structure of β-carotene (71). This led him to the general building principle of carotenoids and their relationship with vitamin A. The elucidation of the structure of vitamin A itself followed in 1931, and some of its derivatives were then also synthesised. In 1937 Karrer and Walter Haworth received a Nobel Prize. Haworth’s award was for the crystallisation of vitamin C.

21

Panel 5

Abandoning of the anti-infective vitamin Anti-xerophthalmia, fat-soluble vitamin A was the first vitamin to be identified, in 1913. We have followed in the preceeding text and panels the chequered career of disease and vitamin to this point. After only a few years, perhaps not surprisingly, this vitamin was being dubbed “the anti-infective vitamin” and hailed as a cure for a variety of diseases. By about two decades later, round about the outbreak of World War II, it sank into obscurity. Apart from a few isolated instances, noted in Chapter 2, what little attention there was was focussed on xerophthalmia as a cause of blindness. Only in the 1980s (see Chapter 3) did the present-day intense interest in vitamin A and infectious diseases commence. The title of an unsigned editorial for the Lancet (69), which I wrote, “The fall and rise of the anti-infective vitamin” summed up the mood of the time. The extent of the influence of the anti-infective vitamin concept, and the reasons for its sudden demise have only recently come to light. This is the result of the painstaking work of Richard Semba, a brilliant young immunologist-ophthalmologist at Johns Hopkins University (70). His interest in the history of VADD is complimentary to his numerous original contributions to our understanding of the disease itself (see Chapter 3).

22

Semba’s search of the literature for the years 1920 to 1940 reveals about 30 clinical trials of vitamin A therapy, usually in the form of cod-liver oil, for a variety of infectious diseases. These include respiratory disease, measles, puerperal sepsis, and other infections. Most of the studies were carried out in the United States or in the UK. These early studies lacked the strict conditions required now for such trials. Some of the results seem to have been very favourable. Those that do not might have suffered from poor study design or inadequate dosing. In any case the pharmaceutical industry waxed enthusiastic. The public became convinced of the value of regular cod-liver oil for their children. The mid 1930s saw the advent of the sulpha drugs, the first really effective drugs against some common infections, such as puerperal fever and lobar pneumonia. The anti-infective vitamin retreated into the background; not to emerge until the 1980s (see Chapter 3). It is quite ironic to ponder that the second eclipse of vitamin A, like the first, can also be attributed to attention becoming focussed on infections.

SIGHT AND LIFE The synthesis of vitamin A, or retinol, was carried out by two groups in 1936; Fuson and Christ (72) and Kuhn and Morris (73). Kuhn was awarded a Nobel Prize, but was not permitted to accept it by Adolf Hitler. Retinol was isolated by Holmes and Corbett in 1937 (74). In 1945–46 a commercially feasible process for the synthesis of vitamin A was developed by Otto Isler and his team at Roche in Basel from β-ionone (75). The official start of the production of vitamin A at Roche began in 1948. Later on another excellent commercial process was developed by Pommer (76). At the present time in the synthesis of vitamin A very simple compounds like acetone and formaldehyde

are used, making this vitamin available commercially at very low cost. For example, a child’s requirement for vitamin A for one year could be met now at the cost of only 5 US cents. Thus, by about the 1950s, when the author came on the scene, vitamin A had been synthesised and was available commercially. Its relationship to β-carotene had been demonstrated, and the main clinical signs of deficiency in the eye had been recognised. Little, however, was known about the physiology of the vitamin, apart from its role in vision, and nothing about its mode of action. The magnitude of VAD as a public health problem remained to be determined, the underlying causes were not understood and there were no measures for its control.

23

SIGHT AND LIFE

Chapter 2

A personal odyssey “Ophthalmology is to medicine what physics is to astronomy – a model.” A letter of von Helmholtz to his friend von Graefe “It is an old saying, abundantly justified, that where sciences meet, their growth occurs. It is true moreover to say that in scientific borderlands not only are facts gathered that are often new in kind, but it is in these regions that wholly new concepts arise.” Sir F. Gowland Hopkins, Linacre Lecture, 1938

Fifty years ago, when my encounter with VADD began, almost nothing was known about the extent or the underlying causes of this nutritional deficiency disease. Over the intervening years, with the slow but steady increase in scientific knowledge, has come a rising tide of interest and concern. Now there is a constant flow of publications on every aspect of the subject. Scientific meetings addressing various aspects of the subject of VADD are regularly held and are attended by large numbers of experts. Progress in control of the disease has been considered by some to be so promising in recent years that its “virtual elimination” by the year 2000 (now less than one year ahead as I write) has been widely accepted internationally as a part of the “Health for All by the Year 2000” goal (77). However, I have had my reservations on this subject from the start (78). The most appropriate place to discuss this issue is when the way ahead is considered in Chapter 4. I stumbled quite unexpectedly on the problem of VADD in India, but in order to understand how this came about I need to go back to much earlier times.

The author with his parents. 25

Growing up between two world wars (1924–1949) The Prime Minister, David Lloyd George, a few days after the end of World War I in November 1918, boasted that Britain was “a fit country for heroes to live in”. I was born a little later, on 4 February 1924, in London, into an era very different from this; one of depression, unemployment, begging on the streets and civil unrest. I grew up as an only child, my parents having previously lost a baby boy shortly after his birth. We lived in Upper Tooting in south west London. I knew all my four grandparents. In the 1880s my father’s parents had come from different parts of Scotland to “seek their fortune” as many

Wedding of the author’s parents in 1913. 26

young hopefuls did, attracted by the lights of London. My father’s father was a plumber and my mother’s a printer. The two families were brought together through these men being office bearers in the very large Baptist church The Metropolitan Tabernacle, at Newington Butts in south east London. It had been built in the middle of the 19th century to house the thousands who were drawn to hear the famous preacher Charles Haddon Spurgeon. More than a century after his death, volumes of his sermons are still best sellers, especially in the United States.

SIGHT AND LIFE

Christmas card with a nursery rhyme in pidgin English. 27

Growing up Spurgeon played a large part in my early life. My father was Secretary of the Tabernacle from 1929 to 1965, i.e., the senior unpaid official, largely responsible for the administration of the church. He was also superintendent (1932–42) of the orphanage that Spurgeon founded and which in other forms continues to work among needy children in Britain and abroad. I joined the church in 1939 and was made a deacon in 1955, but transferred my membership when we moved abroad. As a child I attended the Sunday School of a small church near our home, and when I was about six it was visited by a Mr Owen Warren working with the China Inland Mission (now the Overseas Missionary Fellowship). He asked us to collect farthings for the work (farthings or “fourth things”, long obsolete, were tiny coins worth less than the one cent US coins that they resembled). I did this, or rather persuaded my mother to do so, with some enthusiasm and was commended some weeks later for having brought along the largest number. I thought that was the end of the matter but, some time later, I received a letter from Hankow in China. It was a thank-you note from Mr Warren and there were two paper bookmarks with scripture texts in Chinese and English and sketches of the countryside. There was also a Christmas card with a well-known nursery rhyme in pidgin English. I have treasured these gifts ever since because of the influence this incident had on my life. From that time onward I decided I wanted to go to China as a missionary.

Scripture book mark from Hangkow.

28

Many years later, during World War II when I was a medical student, I somehow learned that Owen Warren was addressing a meeting in someone’s house nearby. It must have surprised him when I told him how that small act of kindness years before had borne fruit in this remarkable way. Long before the term Public Relations (PR) was invented for this sort of thing, Warren had recognised the importance of the personal touch. It also seems to me to be a good example of what the translators of

SIGHT AND LIFE

“Empire Day” at Fircroft Road Primary School in 1931. An early example of “reverse sex discrimination” – ! – all the girls in the class are in traditional English, Scots, Irish and Welsh dress but only the two top boys were chosen. The author is with a rosette.

the King James’ version of the Bible called “Directions for charity” – Ecclesiastes ch 11 v 1, “Cast thy bread upon the waters: for thou shalt find it after many days”. When I was seven I suffered an attack of acute rheumatic fever that kept me away from school for about nine months. At that time the disease was one of the commonest serious infections of

childhood among the working classes in Europe. It does not seem to have set me back academically or in sports in the long term; even after a three months’ relapse just as I was starting in secondary school at age eleven. These brushes with pain and disease may have made me interested in medicine, although no one else in our family was in the medical profession or had been to university. 29

Growing up

The facade of The Metropolitan Tabernacle, London, after the building was restored in 1959 following destruction by fire bombs during the Battle of Britain in 1940.

On one summer holiday I remember coming across in a second-hand bookshop a very old edition of Price’s Textbook of Medicine, then the leading British textbook on the subject. I paid a shilling or two for it and remember being especially interested in the heart tracings in the cardiology section. In 1932 we moved to Stockwell, a few miles nearer the centre of London, when my father was appointed superintendent of Spurgeon’s Orphan Homes for more than 400 boys and girls. The outbreak of war in 1939 necessitated the evacuation of the orphans from London to what was considered to be a safer place; in this case to Reigate, then a very pleasant small county town about 20 miles south of London. It was not that safe, we had to sleep at the orphanage and have our classes at Reigate Grammar School in underground shelters. During the Battle of Britain in 1940 bombs demolished one wing of our school, fortunately on a Sunday. It meant that the summer holidays had to be extended 30

by three weeks – we boys considered it good coming out of evil! On my entry into the sixth form I had to decide what subjects I was to specialise in. I still wanted to be a missionary and go to China. So I consulted the Headmaster, Mr Clarke, a gruff yet kindly man who served as a lay preacher in the Methodist church and was nearing retirement. He told me that he and his wife had had an only son, also named Donald, who had been a medical student at Guy’s Hospital in London. During a practical bacteriology class he had contracted septicaemia, which had proved fatal in those days before antibiotics had been discovered. He said that I reminded him of his son and he advised me to take up medicine. He lent me a copy of On the Edge of the Primaeval Forest by Albert Schweitzer. This book greatly influenced me, as it has many others (see page 89). At that time Schweitzer was one of the

SIGHT AND LIFE

Balquihiddar, Perthsire, in the highlands of Scotland – the ancestral home of the clan MacLaren. The old churchyard shown here contains the graves of many clansmen.

Ceremony to mark the silver jubilee of the founding of the clan society. Dedication of a cairn on Creag an tuirc (the Boar’s rock in Gaelic). It overlooks Balquihiddar and Loch Voil (seen in the background). In the days of the clan system in Scotland this rock was the rallying point for the clan in time of war. 31

Growing up

Reigate Grammar School.

Author as captain of 1st Eleven cricket team in 1942. 32

SIGHT AND LIFE

Headmaster, Mr A.Clarke, with school prefects in 1941–42. Author on headmaster’s left.

most charismatic figures in the world. He had given up brilliant careers in both music and philosophy to study medicine late in life and then to go and work in a bush hospital at Lambarene in west Africa. I applied to the medical school in Edinburgh and to King’s College in London and was accepted by both. I opted for Edinburgh because I wanted to get back to my Scottish origins (Panel 6). A quite unforseen bonus of this choice came about in the following way. My father wrote to his friend, the minister of a large Baptist church in Edinburgh, asking if he could help with my accommodation. A widowed lady member of his church responded positively to the request by the minister. I arrived in Edinburgh off the Flying Scotsman from King’s Cross railway station in London one cool, misty evening at the beginning of October in 1942. My future wife, Olga, opened the door to me in her mother’s home!

At medical school in war time the men students were obliged to join the Senior Training Corps. After about a year a diastolic murmur was picked up at a medical examination. This was indicative of damage to the aortic valve in the heart as a result of the earlier rheumatic fever infection. It took me some time to get over the unwelcome knowledge that I had a weak heart. At first I kept on listening with my stethoscope to the characteristic diastolic murmur in the left side of my chest. Other students found it useful for increasing their knowledge! I have been very fortunate in that I have never had any trouble with my heart, especially having spent many years abroad, often beyond the reach of proper healthcare. The damaged aortic valve might become infected at any time or it might even rupture suddenly.

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Panel 6

The Edinburgh Medical School and nutrition In the second half of the 18th century Edinburgh became the centre of what has become known as the Scottish Enlightenment. This remarkable movement brought about great advances in all aspects of thought and learning and many famous names are associated with it. The leading medical figure of the time was William Cullen, who became pro-

fessor of medicine in 1766. Cullen’s special interests included dietetics, and his published lectures on the subject were very popular. In addition, more than 2000 of his letters about patients to their doctors have survived. Most of these contain advice on diet that would even today be considered sound (79).

Sir Stanley Davidson (centre, front row), Professor of Medicine in Edinburgh, while the author was a medical student (third from right in the back row).

34

Towards the end of the 19th century Robert Hutchison (later knighted) taught dietetics in Edinburgh before he moved to London, where his lectures on the subject, the most popular of that day, were published in many editions (80). In the latter half of the 20th century history has repeated itself in Edinburgh with the publication of nine editions to date of the best-selling “Human Nutrition and Dietetics” by Davidson and Passmore (81). Stanley Davidson (1894–1981) was my professor of medicine and Reg Passmore (1910–) was my colleague in the Department of Physiology. Both also became close friends when we had to settle back in Edinburgh. Davidson was a haematologist and his interest in nutrition came through his early work on pernicious anaemia in Edinburgh and on iron deficiency anaemia in young women when he moved to Aberdeen as professor of medicine during the economic depression of the 1930s. He returned to Edinburgh in 1938 to occupy the chair of medicine, held all those years previously by Cullen. There he was heavily involved in development and expansion of the teaching hospitals and was a major adviser to the Labour government on the introduction of the National Health Service (NHS) in 1948. Davidson’s medical textbook The Principles and Practice of Medicine was first published in 1952 and more copies of recent editions have been sold worldwide than of any other medical textbook. It is a sad fact that the nutrition section of this book has not been written from Edinburgh for many editions. Reg Passmore is an Oxford graduate and distinguished physiologist. During World War II he was in

Dr Reg Passmore while Deputy Editor of the Proceedings of the Royal College of Physicians of Edinburgh (of which we are both fellows).

the Indian Medical Service and worked at the Nutrition Research Laboratories at Coonoor (now the National Institute of Nutrition in Hyderabad). After the war Passmore came to Edinburgh and over many years until his retirement in 1980 he made important contributions to our knowledge of human nutrition, especially on the energy requirements of man. Although the Edinburgh Medical School has made significant contributions to nutrition over many years that are recognised worldwide, it is disappointing that no lasting impact in that field has been made on the school itself. One is reminded of the proverb quoted by Jesus Christ “A prophet is not without honour, save in his own country” (Matthew 13 v 57).

35

Growing up

Olga when I first met her. In 1945 Olga and I became engaged and as I intended to serve abroad as a missionary doctor she agreed to enter nursing training. I qualified in 1947 with an MB ChB degree and at about that time offered for service in China to the Baptist Missionary Society (BMS). Olga finished her nursing training the following year at the Deaconess Hospital run by the Church of Scotland until it was incorporated into the new National Health Service in 1948. This was just before our marriage on 23 October 1948. Still my eyes were on China and there was an opening at Cheeloo University; but the Communists were taking over. Some years later I met a group of exChina missionaries who said that they had begun to 36

get things ready for our arrival just before they were told to move out. The BMS also had medical work in India and Congo. My recollection is that after a visit to the hot and humid equatorial plant house at Kew Gardens we thought we might stand up to the climate better in the Khond Hills, India, than in Congo! I also had the totally unrealistic idea then that India would be nearer to move on into China when the situation “improved”! After medical and surgical house jobs in Edinburgh and Hull, in February 1949 I enrolled for the 6-month course for the Diploma in Tropical Medicine and Hy-

SIGHT AND LIFE giene at the London School of Hygiene and Tropical Medicine (Panel 7). Almost everbody else on the course was either from a tropical country, mostly from India, or expatriate colonial administrators, tea planters, or missionaries. I had to work hard to keep up with all the information that was new to me. However, it would stand me in good stead in the isolated conditions to which I was going. Of special importance for the future was to be an encounter I had in the field of nutritional deficiency diseases. Nutrition was then, is now, and probably ever will be, a much neglected subject in medical schools (84). The only professorial chair within a medical institution in the UK at that time was that in Human Nutrition at the London School, as it is known. Benjamin Platt was the first occupant and was also Director of the Human Nutrition Research Unit (HNRU) funded by the Medical Research Council (MRC). At that time he was also trying to develop another MRC unit in Gambia, west Africa. He gave us a single lecture and then We were married in Charlotte Chapel in Edinburgh. left for Gambia. His assistant was Dr Dean Smith, who was an extremely good lecturer. We learned he had much to teach us from his personal experiences, a few years previously, in a Japathat the most common nutritional deficiencies were nese prisoner-of-war camp. In 1951 with M. F. A. beriberi (thiamin or vitamin B1 deficiency) and defiWoodruff, who became an eminent surgeon in Edinciency of some other vitamins of the B complex. What burgh, Dean Smith published an MRC report on the is astonishing to me and has never been explained as subject of nutritional deficiencies in prisoner-of-war far as I am aware, is the fact that xerophthalmia was camps (85). Diets in camps in the Far East were based virtually never seen. on rice, usually highly polished. It is not surprising 37

Panel 7

Nutrition at the London School The London School of Hygiene and Tropical Medicine is celebrating its Centenary in 1999. It was founded in 1899 by Sir Patrick Manson, the discoverer of the cause of malaria and often known as the father of tropical medicine. The present building dates back to 1929 and was a gift of the Rockefeller Foundation. It is part of the University of London. The department of nutrition was the first in any medical school in the United Kingdom and only second in the world to that at Harvard in Boston. Its origins can be traced back to Edward Mellanby, who made important contributions after World War I in nutrition, including the role of vitamin A in infectious diseases (59) (see page 21). While he was professor of pharmacology at the medical school in Sheffield he greatly influenced a young doctor, Benjamin Platt. Later Mellanby succeeded to the most powerful position in Britain in medical research, as Secretary of the Medical Research Council (MRC). Platt went to the Lester Institute in Shanghai for five years, where he carried out research on beriberi that was endemic there. Through the years of World War II Platt was involved under Mellanby on work concerning the British diet in wartime. After the war Platt was appointed to the newly created chair and department in nutrition at the London School. He also obtained the directorship of the newly created Human Nutrition Research Unit (HNRU). In the 1950s and 60s many students, including the author, received their PhD degree under Platt for experimental research in animals that related to malnutrition problems in developing coutries. Mention has been made of the indebtedness of the author to Dean Smith and Cicely Williams while they were in Platt’s department, and indeed to the professor himself.

38

Benjamin Platt, the first Professor of Human Nutrition at the London School. John Waterlow succeeded Platt after he died. Waterlow had for many years been director of the MRC Tropical Metabolism Unit in Jamaica and was a leading authority on PEM of the kwashiorkor variety. Other departments of nutrition were springing up around the country and overseas interest was shifting away from clinical and biochemical studies of patients to field surveys and policy making. In more recent years a major research interest in VADD has been developed in the department of population studies, especially by Dr David Ross and Professor Betty Kirkwood. They have carried out an extensive study of the effect of vitamin A supplementation on childhood morbidity and mortality in an area in the north of Ghana (82). The author participated in one aspect of this research (83).

SIGHT AND LIFE Rice is devoid of carotene and prisoners received almost no source of preformed vitamin A. I have heard it said that the prison authorities received instructions for the daily intake of energy, almost entirely from rice, to be restricted to as little as 900 calories per day. This had been carefully calculated to be just enough to keep a person alive, but too weak to try to escape. Dean Smith was to play a key role in the next phase of my career.

50th anniversary reunion of the graduating class of 1947, taken in 1997. Strong evidence for an aging population considering that about 150 graduated originally (the author is in the centre of third row).

39

Mission in India (1950–1954) On 10 December 1949 we sailed from Liverpool to Bombay. Olga was three months pregnant with our son Gavin. We joined colleagues of the Baptist Missionary Society at the Moorshead Memorial Hospital, at Gumsur Udayagiri in the Khond Hills, Orissa (Panel 8). After several years of hospital practice I began to realise that the pattern of disease was sufficiently different in certain respects from that in the UK to warrant it being written up for publication in some form. This was especially so for those diseases that seemed to be related in some way to diet and nutrition. I turned to Dean Smith for help and his replies to my letters were always helpful and inspiring. Without his encouragement I doubt if I would have persisted with this research. I have always tried to model my own behaviour on this experience in more recent years when people have frequently turned to me for help in a similar way. The hospital was always extremely busy and sometimes for long periods there would be only one doctor to do all the work. Even so I set aside any spare time I had to collect all the information I could on the diseases of the area. The most significant research I was able to do originated in the course of routine collection and observation of hospital data over the period of nearly five years that I was working in Udayagiri. I recall reviewing the case records of some of my patients late one night in the little office of the hospital. The night was unbearably oppressive, just before the long-awaited monsoon rains in early June were due to bring relief. The pressure lamp overhead was adding almost as much to the heat as it provided light. I noticed something interesting as I turned over the records of the group of pathetic cases made up mostly of young children, who had been 40

brought to us with their sight almost always irrevocably destroyed by vitamin A deficiency. These were advanced cases of corneal destruction termed keratomalacia. It occurred to me that almost without exception they were of Oriya families from far away on the plains of Orissa, and not from our own local Khond Hills Kui tribes people. In the final account of the work for publication there were 32 Oriyas and only 4 Kui. The difference is all the more striking in view of the fact that in general we saw 5 or 6 times more local Kui children than Oriya. As I have been looking over my notes while writing this I have noticed that each of the 4 Kui cases had some unusual feature. One child of 3 years was described as a “borderline case”, another aged 3 had “leashes of corneal vessels”, suggestive of keratitis due to an infection rather than to VAD. Another 3year old had milder changes of xerophthalmia in one eye and keratomalacia in the other. The fourth case was a 15-year-old male with accompanying skin changes described as perifollicular hyperkeratosis. This was one of only two cases in the whole series in which the age was outside the range of 6 months to 6 years. The second case in an adult was a 26-year-old Oriya woman who was brought to the hospital after the period of one month following delivery during which custom dictated that she could not leave the house. By that time both corneae were undergoing liquefaction from severe VAD. There was no evidence of infection. Unfortunately at that late stage even large doses of vitamin A failed to prevent permanent blindness. Amazingly, the infant was healthy! How its eyes had escaped destruction is a complete mystery, but several similar cases have been reported (88). What was it that made this devastating disease so much more common among the relatively affluent

SIGHT AND LIFE Oriyas? The staple food was rice, devoid of vitamin A, for both groups. I carried out a dietary survey in which the food consumption of fifty individuals was observed for a week. In addition, more than 20 families were questioned about their diet. From these admittedly imprecise observations it was likely that “the diet was deficient in protein and fat, rather than calories and also probably vitamin A and in members of the B group”. These conclusions appeared to apply equally to Oriyas and Khonds, except that the richer Oriyas had rather more food to eat. I then examined the eyes of 100 children of each group aged 6 months to 6 years in their villages. Signs attributable to early VAD were present in both groups at approximately similar levels. Something must be happening to the young Oriya children to make them frequently fall prey to the advanced stages of the disease. At that time my knowledge of both Oriya and Kui languages was good and I began to make a detailed

investigation of the respective customs concerning the upbringing of the young child. The answer came quite unexpectedly one afternoon when I was conducting the usual outpatients clinic. An Oriya woman stood before me holding a young child of about 18 months by the hand. Both eyes had been destroyed by keratomalacia. As I talked to her it was evident that she was pregnant again. On questioning she revealed that as soon as she had realised that she was pregnant again she had weaned the first child because “she knew that her milk would be turned to pus and be bad for the child”. To discourage the child seeking the breasts she had smeared them with the juice of raw peppers. After this, enquiry of several other mothers in similar circumstances confirmed this practice to be general among the Oriyas. When I discussed this finding with my Kui colleagues it became clear that among them it was regarded as a “very shameful thing” if a mother of a young child became pregnant

The Moorshead Memorial Hospital and the mission compound in the 1950s. 41

Mission in India

Our family establishment in Udayagiri in 1954. again soon. It was expected that the customary period of abstention from intercourse until the child had begun to walk at the earliest would be observed. Villagers would poke fun at a woman who had frequent pregnancies, the inference being that her husband was abnormal, having failed to observe social custom. I later discovered that this kind of inbuilt “child-spacing” custom was common among African tribal peoples, especially in polygamous communities (89). There is a sura of the Koran that advises that a woman should be left alone as far as intercourse is concerned by her husband for about two years after a child has been born, in order for it to be nourished properly. As Islam permits polygamy this advice may be realistic and beneficial in practice. However, in my experience among impoverished Moslem communities 42

only the wealthy can afford that luxury. The Oriyas had no such tabu and intercourse was resumed within a month or two of delivery. It occurred to me that this tragic situation paralleled that described by Dr Cicely Williams, the first woman medical officer in the British colonial medical service, in Gold Coast (now Ghana) (Panel 9). She found that among the Ga people there was in use the term “kwashiorkor” for a common disease among young children that meant “the disease that the first child gets when the second child is on the way” (90). She attributed this to malnutrition, a consequence of the sudden weaning of the child onto the family diet of maize, which had poor-quality protein. This “deposed child” situation in each circumstance resulted in malnutrition in the young child; the kind of deficiency disease depending on

Panel 8

William Carey, the Baptist Missionary Society and the Kui people

The Khond Hills countryside.

William Carey (1761–1834), the founder of the modern Protestant missionary movement, was one of the most remarkable men of his time. He received no formal schooling and worked as a shoemaker. At night he taught himself Latin, Greek, Hebrew and Theology. In 1792 the Baptist Missionary Society (BMS) was founded – Carey was its first missionary. He settled at Serampore, near Calcutta. He translated, with Indian scholars, the complete Bible into five Indian languages and smaller portions into 35 other languages and dialects. Other achievements included the founding of the Botanic Gardens in Calcutta, Serampore College (now part of Calcutta University), and the first printing press in India. The Baptist Missionary Society today works with churches in many countries all over the world. Formal responsibility for mission work in Orissa and other parts of India was handed over to the local church

Traditional dress of a young Kui girl.

43

many years ago. The church in the Khond Hills is now part of the Church of North India. Membership of local Kui churches has continued to grow, and in 1998 they were constituted a separate diocese. The population of the province of Orissa is made up of a larger proportion of aboriginal tribal peoples than almost any other part of the subcontinent. They are numbered in the tens of millions. Those that inhabit the hills of the Phulbani and Balliguda districts, the Khond Hills (known to the people as the Kui dina), are two groups, the Khonds and the Pans. They are among the Dravidian peoples, the original inhabitants of India, who in the distant past were

driven into the hills of central and southern India by the Aryan invaders from the north. In their hill fastnesses the Kui people were untouched by Hinduism in the early days and practiced Animism, worshipping gods in hills, streams and stones. Their mother tongue is Kui, which is a minor member of the Dravidian group of south Indian languages of which Tamil is the major member. Outside the home they speak Oriya, the provincial language of the Oriyas. The Khonds have traditionally been the more powerful and conservative people and owners of most of the land. They were notorious in the history of British Rule in the 19th Century for the widespread practices of female infanticide and the meriah or human sacrifice. A young boy was captured from the plains and after prolonged ceremonies he was led to a sacrificial site, hacked to pieces, and the “living flesh” buried in ancestral fields. The purpose was to ensure the success of the rice harvest. This is described in detail as an example of the theme of the “dying king” by the early anthropologist James Frazer in his multivolume work The Golden Bough (86). Several punitive expeditions had to be mounted by the British authorities before these practices were put down towards the end of the 19th century (87). Buffalo sacrifice was substituted. Missionary activity in that part of India, particularly by the Baptist Missionary Society, began at about that time and by the middle of the 20th century scores of thriving village churches had been founded. The Moorshead Memorial Hospital was opened in January 1939. In the 1950s and 60s it drew patients from all parts of the province, but later the work declined, it became the subject of numerous law suits and was closed for many years.

The animistic “priest” of a Khond village. The stone just to the right of the priest’s left arm is the “darni” of the village, the residence of the local spirit which is in his care. The post is for tying the “meriah” sacrifice.

44

The story of keratomalacia among the Oriyas has been described in detail (see page 40). Other diseases of special interest included the frequent occurrence of severe duodenal peptic ulceration leading to pyloric stenosis. This was known to be common throughout the rice-dependent south of India, but very rare in the wheat-eating north. The reason for this difference is still not understood. As far as I

know the occurrence of Helicobacter pylori infection, now known to play an important part in the causation of peptic ulcer, has not been investigated. Cirrhosis of the liver was also very common; almost always in men, and especially in those with a frequent history of heavy indulgence in toddy from the sago palm. Not infrequently imbibing occurred at the top of the tree where the palm was cut for the alcohol and serious and often fatal injuries from falls were common. In the 1950s patients bitten by snakes, or mauled by bears or tigers were often seen. Malaria was endemic and everyone lost many working days from “fever”. The cerebral form was highly fatal in young children. Insecticide spraying brought the disease under control, but after resistance developed malaria once again became endemic, as it has in many other parts of the developing world.

A typical Kui village.

Nowadays even in remote villages there are television sets, mobile phones, motorcycles and four-wheel drive vehicles. It is probable that, as reported from elsewhere in rural India, with increasing affluence and “westernisation” coronary heart disease and other late-onset degenerative diseases are on the increase here too.

The “meriah” sacrifice of the buffalo.

45

Mission in India the particular inadequacy of the diet: protein in west Africa, vitamin A in India. From the present perspective many years later, I regard this piece of amateur research as of great significance. It launched me into this most profitable field of research where in the course of more than 40 years I have been privileged to see a total transformation from neglect to concern. Recognition of the significance of VAD for public health has increased enormously over the years and the problem is gradually being brought under control everywhere. Later on this work was the subject of my first research publication, became a prize-winning essay, formed a major part of a thesis for a higher degree (page 49), and was awarded the status of a classic (page 112). In the SIGHT AND LIFE manual (1) I again compared this work with that of Cicely Williams on the “deposed child” and pointed out that in the intervening decades there has really been no strictly comparable research. It is true to say that in all areas of the world where VADD continue to be a serious problem there is little detailed and intimate understanding of precisely why the problem occurs. We completed our almost five years’ tour in Udayagiri in November 1954 and sailed home on the Pacific & Orient ship “Canton”. I had become fascinated with the opportunities in the Khond Hills area for an innovative programme of primary healthcare (a term coined much later) through the extensive network of the village churches. My senior colleague, Stanley Thomas, was more interested in making the hospital into a large centre of surgical excellence with patients travelling from all over the province. He was not prepared to see me take over some degree of responsibility. I had to make

46

Sailing for home on the P & O liner “Canton” after five years in India.

the difficult choice between committing myself to a lifetime of mission hospital work in India and making a completely fresh start elsewhere. I decided that this was the parting of the ways. We left India with much regret, leaving behind many Kui people who had become our friends, knowing nothing of what the future might hold, and with two small children.

Panel 9

Cicely Delphine Williams (1893–1992) In his obituary notice for Cicely, David Morley wrote that she would always be remembered as a mother figure by those who have worked in tropical child health. This was not only because she initiated the subject, but because of her loving approach whenever she was with young children. Yet she never married. She was born into an old Jamaican family but was educated in England. She graduated BA at Oxford in 1920 on the first day that women were granted the degree. In 1923 she was a member of the first group of women physicians to graduate from Oxford. She was inspired by her great teacher, Sir William Osler, then Professor of Medicine. She lived by his famous dictum: service, training, and research; in that order. Her name will always be linked with the Ga word “kwashiorkor” (see page 42). In 1936 she moved to Malaya and when Singapore was overrun by the Japanese in 1942 she was interned in the notorious Changi Prison and Sime Road Camp for more than

Cicely in retirement in Oxford. three years. She proved to be a tower of strength in many different ways to her fellow prisoners, despite appalling mistreatment. On her final release she was emaciated and had developed beriberi. Williams was well aware of the problem of xerophthalmia and included it in her writings on child malnutrition (91). This was especially so during her years in Malaysia and Singapore. Here she found it associated with the substitution of sweetened condensed milk for breast feeding, particularly common among the Chinese community. Her later contributions were of a more conceptual nature, but no less important. She was among the first to challenge the international milk marketing corporations over the harm they were causing by selling breast milk substitutes to the third world’s poor. Cicely pioneered the concept of primary healthcare in child services, in which curative and preventive care were not artificially partitioned, but combined.

Cicely Williams and Henry Sebrell at an archaeological site in Lebanon while she was Professor of Maternal and Child Health at the American University of Beirut.

Her fascinating life story has been told a number of times (92–95) and should continue to inspire all those who read it, but especially those of us who were so privileged to know her and work with her.

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Back in London (1954–1957) For about one year I was committed to going round the country telling the churches about the mission work which the members were supporting. This meant spending a lot of time away from the family, who had to stay either with my parents in Morden, south London, or with Olga’s mother in Edinburgh. However, it also gave me a vital breathing space to work on the material I had collected in India. The natural place for me to turn to for help was the London School. There I met Cicely Williams, who was a lecturer in Nutrition for a short period (see Panel 9). She was interested in the keratomalacia story and I had helpful discussions with her. Later, in the early 1960s, we were colleagues at The American University of Beirut in Lebanon. Later still, Olga and I often visited her when we were in the UK in London and then when she retired to Oxford. Cicely was a most colourful character and enthusiast in the cause of child care in the tropics. She has a prominent place in the ranks of pioneering medical women of all time. I also received very helpful advice on my MD thesis from Dr Reg Passmore (see Panel 6) in Edinburgh. Years later when we had to leave Beirut in the civil war, he was to become my colleague in the Department of Physiology in Edinburgh (1976–80). Through my visits to the London School I met Professor Platt and he told me that he was looking for a suitable person to work with him for a PhD on the effects of malnutrition in animals on vision. It seemed as though the opportunity and myself had been singularly made for each other! Platt got me a Colonial Research Studentship which amounted to about £600/ year. This would hardly have covered the fees and provided for a wife and two young children.

48

I looked for a general practitioner who wanted help with evening and weekend surgeries. I received a small fee for this work and had to make a special case with the University of London authorities so that I could be considered a bona-fide full-time PhD student. Most importantly, the arrangement provided us with rent-free accommodation situated over the spartan consulting room of the general practitioner, Dr Oscar Stern, a Jewish refugee from Hitler’s Germany, in Tottenham High Road, north London. Night calls to emergencies in the winter after a long day in the laboratories were particularly trying. Once the car had been got going in the cold, the engine had to be cranked with a handle, I had to find my way around a part of London completely strange to me. Most vividly I remember three calls out one night at the height of the last London “pea soup” smog (sulphur dioxide and smoke from domestic coal fires) when several thousand people died of respiratory illnesses. The last patient turned out to have had a heart attack and as he lived in an area quite unknown to me I called in the help of a policeman who guided the car to the door by walking ahead with a torch. Our flat was about six miles from the Human Nutrition Research Unit (HNRU) of the Medical Research Council where I did my research. It was while the HNRU was still at the Medical Research Council Laboratories in Holly Hill, Hampstead, that I met Dick Jelliffe for the first time. In some ways Dick was to become the successor of Cicely Williams. He was another paediatrician who made great contributions to maternal and child health in many developing countries. At that time he had just founded what is still now, several years after his sudden death in 1992, the foremost journal in the field: the Journal of Tropical Pediatrics. I told him

SIGHT AND LIFE

My fellow research student Kalyan Bagchi with Gavin and Jill.

about my work on keratomalacia in India and he invited me to submit it to his journal. It became my first research publication (96). I was putting the finishing touches about this time to the thesis I submitted to the University of Edinburgh entitled rather ambitiously “Health and disease in the Khond Hills, India: a contribution to global epidemiology”. The work on keratomalacia formed a major part of the thesis awarded the degree of MD (Doctor of Medicine) in 1955 (97). I also wrote up the work at the same time for submission to the British Medical Association and received the Oliver Hawthorne prize. Thirty years later it was given classic status (see page 112). I shared a laboratory with Dr Kalyan Bagchi, who started his PhD at about the same time as I did. It transpired that he had also been recruited by Platt to work on the eye! It soon became clear that we could both profit by collaborating. Kalyan concentrated on

the lens and I on the cornea. We were the only medically qualified students or staff in the Unit, apart from the professor. Kalyan and I became great friends; I had just spent five years in his country, he was Associate Professor at the All India Institute of Hygiene and Public Health in Calcutta, and is a Bengali. He had had to leave a wife and two little children behind in India, so he was often in our home and was “uncle” to Gavin and Jill. Kalyan spent most of his subsequent career with the World Health Organization (WHO), in Geneva, and later in Alexandria. We keep in touch but I greatly regret that we have met so infrequently over the subsequent years. Antoinette “Tony” Pirie, head of the Nuffield Laboratory of Ophthalmology in Oxford, was appointed Kalyan’s external examiner and we both went to see her early on in our studies. She later became the first editor of the Xerophthalmia Club Bulletin (Panel 14, page 94) and we both attended early IVACG Meetings. She was a PhD and was the only other British 49

Back in London worker at that time interested in xerophthalmia. Her experience was in experimental animal work rather than deficiency disease in humans. There were no Americans yet on the scene, Oomen was nearing retirement in the Netherlands and some work was going on in India, but that was about all. My adviser for my PhD thesis was Hugh Davson, an eminent research worker supported by the Medical Research Council at University College, London. He made important contributions to our knowledge of vision and wrote several treatises on the physiology of the eye. When the time came for me to defend my thesis Davson seemed to accept the results of my experiments without much comment and spent more time on its grammatical construction. I remember him predicting that I would publish a lot of work and that it was therefore important that I should get the English right! The HNRU was very much a one-man show. Within days of my being appointed in August 1955 Platt was admitted as an emergency to University College Hospital with severe haematemesis (bleeding from a peptic ulcer). He was away for months and when he did return he was not a fully healthy man. We last met in 1967 at a meeting on calorie deficiencies and protein deficiencies held at Sydney Sussex College, Cambridge, and organised by Professor McCance. Platt told me that he was finding the treatment he was receiving for high blood pressure and kidney complications was worse than the disease. He died the following year.

Dr Hugh Davson, external examiner for my PhD in Nutrition from London University. needed to be done, but young PhD candidates straight out of university were left floundering.

More than any other individual Platt had been responsible for giving me the opportunity to make a career in nutrition research in general and in relation to eye disease in particular. He was not an easy person to work for or to get to know. I came to realise, probably too late on, that much of the problem was due to the very poor health from which he suffered for most of the time I knew him.

For nearly three years I carried out animal experiments, mostly on rats, but some on pigs, on the effects of various deficient diets on the eye. Vitamin A deficiency was overshadowed by the overriding interest of the professor, and therefore the Unit as a whole, in protein malnutrition, as it was called then. By that time Platt had fallen out with the authorities in Gambia and the MRC Unit there had to be handed over for research to be done on malaria. Our work in London was greatly hampered by our not having direct access to malnourished patients in developing countries. In retrospect it is perhaps surprising that it did not occur to any of us at HNRU that the general medical and surgical wards of hospitals in the UK were then, as indeed they still are to some extent, full of patients suffering from malnutrition as a secondary effect of various serious illnesses.

Kalyan Bagchi and I were both in our early thirties, with considerable experience and knew what work

In my research I was able to show that protein deficiency did not usually directly damage the eye. In

50

SIGHT AND LIFE fact, if it accompanied vitamin A deficiency the development of xerophthalmia due to the latter was delayed. The reason for this delay appears to be the decreased requirements for vitamin A in the animal failing to grow because of protein deficiency (98) (see also page 80). Just at about the time the Unit was due to move from Hampstead to the National Institute for Medical Research at Mill Hill, north London, I was about half way through my research and became very excited with some results. These were written up fully in my PhD thesis (99) and were summarised in my book Malnutrition and the Eye (88). Two types of lesions occurred in the cornea of a number of the rats on deficient diets. The first was a localised hyperplasia of the endothelium in a few rats

deficient in vitamin A. It was never seen again. The second type of lesion was much more widespread, affecting 28 out of 36 rats deficient in vitamin A. There was a subepithelial infiltration of mononuclear cells that took different forms when the cornea was viewed under the slit lamp microscope. These I described as dendritic, punctate, or granular in appearance. Some of the animals were also restricted in protein or in certain vitamins of the B complex. The lesions remained stationary, appeared several weeks before the usual xerosis changes of xerophthalmia, and underwent no change in a group that was given large doses of vitamin A. After the move to Mill Hill attempts to repeat the changes were entirely unsuccessful. I thought at first I had discovered new, very early changes in the cornea due to nutritional deficiency. I never did discover the cause, but later on I realised that there must have been some environmen-

Kalyan Bagchi (back row 2nd from right) and the author (middle row extreme right) in the class on medical statistics at The London School of Hygiene and Tropical Medicine. Prof. Austin Bradford Hill (front row middle) and Dr Richard Doll (front row 3rd from left). 51

Back in London tal factor responsible, probably a viral infection. I was very near to making a premature announcement in my enthusiasm which I would have regretted later. I wonder how often the inability of research workers to repeat earlier sensational claims may be due to over-zealousness on the part of the former. When unexpected experimental results occur it is rare for those experiments to be repeated in the same laboratory, just to make sure. Kalyan and I took a course in medical statistics at the London School which stood us in good stead later. We had the privilege of being taught by some of the most famous medical statisticians and epidemiologists in the world. I recall an amusing, but acutely embarrassing, experience I had earlier with a group of epidemiologists. Shortly after my return from India I received an invitation to a cocktail party at the London School for former students to meet teaching staff. As I planned to visit the School regularly I thought I would attend. Not surprisingly I found I knew almost nobody. I found myself with a group of strangers and asked one of them what he did. This was met with cries of derisory laughter! I later found out that I had spoken to Dr (now Sir) Richard Doll, who had very recently become famous for his work showing that cigarette smoking causes lung cancer. This brought home to me how out of touch I had become after five years in India. It soon became clear to me that very little attention was being paid to xerophthalmia (the term generally adopted later for all effects of vitamin A deficiency on the eye). Only brief mention had been made of xerophthalmia at several of the early Joint FAO/WHO Expert Committees on Nutrition. Almost nothing was known about its occurrence outside India and Indonesia. While I was seeking support for my work I visited The British Empire (later Commonwealth) Society for the Blind (now Sight Savers International). It had 52

been founded by John (later Sir) Wilson in 1949. Wilson had himself been blinded in an accident while at school and had gone on to study law at Oxford. I found that he appeared indifferent to what I had to say about the severity and likely magnitude of the xerophthalmia problem. I could not get him away from the work the Society was then supporting on “river blindness” – onchocerciasis – in west Africa. Years later, not only in private, but also in public meetings when we have met, Sir John has been very generous in pointing out that he had been slow to realise the importance of xerophthalmia when we had first met, but he has worked hard to set the matter right later on. Sir John, now in his eighties, has turned his boundless enthusiasm to the prevention of disability in general in recent years. At a lecture he gave on this work at the Royal Society of Medicine in London recently I was pleased to be asked to give the vote of thanks. During the summer of 1957, when I had completed my experiments and was writing up my thesis, Platt called me into his office on his return from WHO headquarters in Geneva. He told me that there was an opportunity for someone interested in going to Indonesia for a month for them to report on a serious xerophthalmia problem there. I leaped at the chance, even though it meant postponing my thesis writing, getting a paper ready to present at the 3rd International Congress of Nutrition in Paris ahead of time, and going direct to Paris from Indonesia after my consultancy. Platt’s last words to me were spur enough to succeed – “If you fail, that’s the end of you!”. I had forgotten these remarks over the years, but another quote of his early on in my work I have often repeated as I believe it to carry an important message for young researchers: “There are only two requirements for research – running water, and one idea.” The implication is that there is no lack of “running water” – the hardware for research, but a real dearth of original ideas.

SIGHT AND LIFE These were days before the introduction of commercial jet aircraft. I flew to Geneva for my briefing on the consultancy and then to Rome to catch a Super Constellation to Jakarta, Indonesia, taking most of three days in all. These planes flew at only a few thousand feet and there was plenty to see out of the cabin windows. In those days WHO flew its consultants first class and my travel was made very comfortable. On the way to a stopover in Damascus I caught my first glimpse of Beirut. Little did I know that I was to go to live there 15 years later. In the tiny, shedlike terminal building I also caught my first, and much too intimate for my liking, view of something else – Aleppo (in northern Syria) or Baghdad boil (cutaneous leishmaniasis) on the faces of many pilgrims crowding onto an aircraft to go on the Hajj to Mecca. Many lesions were very active and covered with flies.

trition situation and I was to concentrate on xerophthalmia. All the negotiations with government officials were conducted by Bill Darby. He was an extremely experienced and diplomatic negotiator. Sitting in on these discussions was an invaluable learning experience for me for the future. While our itinerary was being discussed with the Ministry of Health officials in Jakarta we encountered resistance to any suggestion that we might visit Bali. On several occasions officials pointed out that this would not be advisable. Bill had not been there and I had a special reason for wanting to go there. I had made friends at the London School with Dr Jelantic from Bali. He was the son of a chief and

The next day we flew low over Rangoon, the capital of Burma, and the captain said he was going to circle the famous Buddhist pagoda, the Shwedagon, for us all to get a good look at this enormously impressive building with its long tapering upper part covered in gold leaf. I made a mental note to the effect that one day I would try to return to see it from the ground. This happened in 1973 when I was able to obtain a visa to give some lectures at the Medical Research Institute and visit the central hospital, where I saw many cases of xerophthalmia. This was quite valuable information about the occurrence of xerophthalmia, as Oomen had been unable to obtain entry to Burma for his part of our global survey in 1963 (100) (see page 82). In Indonesia I was to work with the man who was probably then the leading international authority on human nutrition problems – William J. Darby, Professor of Biochemistry and Nutrition at Vanderbilt University School of Medicine in Nashville, Tennessee, USA. Bill was to report on the overall nu-

Bill Darby with the author in his historic home outside Nashville, Tennessee, when we last met in 1994. 53

Back in London

At the Central Government General Hospital in Jakarta in 1957 these parents holding their children had all been refused admission towards the end of the morning session in the Paediatric Outpatient Department because both the eyes of these children had already been destroyed by keratomalacia. very influential. He had given me an open invitation to visit. Towards the end of our time in Indonesia we learned the reason for our difficulties. A prominent American physician in the field of nutrition had paid an official visit to Indonesia shortly before ours. After a brief stay in Jakarta he had made straight for Bali with his wife and later left the country without telling anyone. Not surprisingly, this had gone down very badly with the local officials. Bill Darby was too much of a diplomat to press his point, even when he did not know the underlying reason for the opposition. We visited hospitals in several large cities of Java, including Jakarta the capital, Semarang in the north, Jogjakarta in the south, and Surabaya in the east. Everywhere I saw large numbers of severely malnourished children in hospital wards and outpatient clinics. The majority had evidence of xerophthalmia. 54

Many of those seen in paediatric or ophthalmology outpatient departments had their eyes already destroyed by keratomalacia and these were usually turned away. The enormity of the problem was fully appreciated in Java, but our visit for WHO helped to bring it to the attention of the world. In Surabaya the Dutch nun ophthalmologist Ann ten Doesschate was meticulously documenting hundreds of cases of xerophthalmia for a thesis. In this she showed the extent of the mortality over several years after admission to hospital. Within that period about 40% had died (101). This was a considerably higher rate than Blegvad (see page 19) had reported from Denmark many years before. The difference might have something to do with the likelihood of better health and social welfare provision in Europe.

SIGHT AND LIFE The most massive experience of corneal xerophthalmia ever recorded is that of the Yap Eye Hospital in Jogjakarta that we visited. Oomen had recorded the unique experience of more than 6300 cases of xerophthalmia treated there by Drs Yap senior and junior, both ophthalmologists, over less than 20 years (102). The young Dr Yap was a gentle, cultured man and it was a real shock to learn that not long after our visit, in a time of persecution of the Chinese population in Indonesia, he had taken his life. Xerophthalmia of some degree was present in about 75% of all malnourished children in hospital, which confirmed the earlier experiences of the Dutch physicians de Haas (103) and Oomen (104). This is the highest rate ever reported. As I recall, this was the first time massive-dose vitamin A prophylaxis was discussed as a possible emergency measure. It was not tried until the early 1960s – in our WHO-supported study in Jordan (105) (see page 86) and by workers in India (106), where in 1972 the first national vitamin A supplementation programme was initiated (see page 87). I had a memorable departure from the airport in Jakarta. Before we were called to our plane there was a flurry of activity by security officials in the area of a red carpet. The figure of President “Bung” Sokarno with his dark glasses was recognisable. He appeared to be seeing off a white middle-aged elegant couple accompanied by teenage son and daughter. On the plane I found myself the only other occupant of first class besides this group. Once we were airborne the youngsters went to sit in economy with people more of their age. I noticed that the woman was very plainly, but tastefully, dressed, with a simple bangle for ornament. We exchanged a few pleasantries before we soon touched down at Singapore and were all taken to lunch. I had hazarded a guess in Jakarta that the mystery family might be that of the governor of Singapore, but then they would have left the plane. Our passports were taken from us and after lunch we had to wait while our names were called out. Imagine my surprise when Mr and Mrs John D.

Rockefeller III and family were called! Then I remembered that I had read in a local paper that Rockefeller had been on a goodwill mission for the US government. They had no security personnel with them and were most unaffected and self-effacing. It is interesting how breeding shows. The report I wrote with Bill Darby to WHO was rapidly produced and published in November 1957 (107). Nothing really new resulted, but there were three important consequences in my view. WHO finally acknowledged the importance of xerophthalmia as a public health problem. This was the first WHO publication on the subject. The consultancy was considered a success and I was recognised as a budding expert in the field. I got on very well with Darby and through his influence my career greatly benefited. On my return Platt offered me a full-time research position in his department, but I wanted to extend my studies to humans. There were very few opportunities to do this, especially at that time, when Britain was in the process of dismantling its empire. I turned down an offer to work on the eye lesions of onchocerciasis in west Africa; I wanted to stay with nutritional diseases. Eric Holmes, Director of the East African Institute for Medical Research in Mwanza, Tanganyika (now Tanzania), visited Mill Hill to recruit personnel. I explained my interests and he said that although he knew nothing about eye disease he was sure that if I looked sufficiently hard for it I would find it there. When I discussed the appointment with Platt I received a verbal commitment from him that he would try to develop a close link between London and Mwanza. Unfortunately this never materialised. Eric had studied medicine at Cambridge and while doing biochemistry research under Sir Fredrick Gowland Hopkins (see Panel 3) he married the boss’s daughter Barbara, also a biochemist. Eric had remarried by the time I knew him. He had been just the “right” age to serve in both the World Wars, in

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Panel 10

The East African Institute for Medical Research After World War II the British colonial territories in East Africa, Kenya, Uganda and Tanganyika (Tanzania), were administered in a federation by the East Africa High Commission (later the Common Services Organisation). Many public services were jointly administered, and included under this umbrella were numerous research institutes. These specialised in subjects from agriculture, forestry and fisheries to malaria, yellow fever and trypanosomiasis. The institute in Mwanza on the southern shore of Lake Victoria had no clear remit. It was originally known as the East African Survey and in the early years carried out field studies which included nutrition. Eric Holmes changed all this and attempted to turn it into a reputable research institute with its main emphasis on nutritional studies. The name was

View of the shores of Lake Victoria from the bungalows of the staff of the East African Institute for Medical Research in Mwanza.

The semi-nomadic Gogo tribe of Central Province put on a traditional dance for the Governor’s visit. Most of the research on nutritional eye disease was carried out among these people.

56

The East African Institute for Medical Research in the 1950s. changed and new staff, like myself, recruited. The other main interest was schistosomiasis (bilharziasis), which was endemic in the area and caused a great deal of illness. Holmes’ period as director barely spanned the five years of my stay there (1958–62). After his retirement, with funding from the Rockefeller Foundation, the institute concentrated on schistosomiasis. I was fortunate to be leaving at that time for Beirut. In recent years the institute has been the base for research on a malaria vaccine and research on sexually transmitted diseases, including HIV infection and AIDS. The transition to independence in December 1961 took place peacefully. Julius Nyerere, leader of the

Sir Richard Turnbull, the last Governor of Tanganyika visiting the Institute.

predominant political party TANU (Tanganyika African National Union), became president. He introduced throughout the country a Chinese-style commune system that proved to be unworkable and disruptive of the traditional rural way of life. Tanzania is today one of the poorest nations on earth. Despite much activity in the field of prevention of VADD the country is classified as having a serious public health problem (113). As described already most of the research undertaken on VADD took place in Central Province, far from the institute, among the Wagogo people. The terrain consists of cultivation steppe. Wide undulating plains are interspersed with low ridges, hill blocks and ranges. The Gogo are one of 11 tribes of Bantu origin, each with their own language but having Swahili, the lingua franca of much of east and central Africa, in common. Forty years or so ago the Gogo were under considerable Masai influence, imitating them in dress and following a nomadic lifestyle to some extent. Sorghum was the principal crop, growing best, as does maize, in heavy black cotton soil. Cassava and millet predominated in the more hilly, sandy areas. Unlike most other parts of the country, Central Province had experienced numerous periods of food scarcity, sometimes amounting to famine, as in 1953–54. It was to be here then, as the result of following up a chance observation (see page 60) that Holmes’ prediction of “seek and ye shall find” (see page 55) was vindicated, and research funds from a surprising source (see page 63) were justified.

57

Panel 11

The Princeton conference in June 1958

The group outside the Nassau Tavern Hotel. The original historic building dated from 1756. The Yankee Doodle Tap Room, with its famous Mural by Norman Rockwell, has been a favourite meeting place of the Princeton undergraduates for many years. From left, front row: B. S. Platt; V. N. Patwardhan; C. G. Mackenzie; W. J. Darby; W. R. Aykroyd; R. H. Follis, Jr; T. D. Kinney; R. C. Burgess; P. Handler; N. S. Scrimshaw. Middle row: projectionist; S. B. Andrus; D. S. McLaren; E. M. Nadel; E. A. Uehlinger; J. B. Hazard; H. D. Moon; C. Tejada; H. A. P. C. Oomen; A. E. Schaefer; K. E. Mason. Back row: projectionist; V. Ramalingaswami; P. J. Fitzgerald; F. J. Stare; E. Orent-Keiles; R. E. Olson; J. B. Stanbury; J. Matovinovic; J. Higginson; J. M. Hundley.

58

Reference has been made to the author’s participation in this seminal conference. In retrospect it is easy to see that this meeting was just one of many examples of the way in which the United States after World War II was establishing its influence in many fields over the nations of the developing world. They were then in the process of obtaining their independence from the European colonial powers who had been greatly weakened by that war. In the area of nutrition the US National Institutes of Health funded and organised this meeting. Another branch of the government set up the ICNND surveys (see page 65), which much later developed into the periodic nationwide health and nutrition assessments (NHANES) in the USA itself. During this period Bill Darby at Vanderbilt, Henry Sebrell at Columbia, Bob Olson at St Louis, Fred Stare at Harvard, Nevin Scrimshaw at MIT, and many others developed collaborative nutrition research and teaching programmes with centres in the third world.

Of the 29 nutrition scientists in this 40-year-old photograph the fate to date of only about half is known to me. The known survivors include Darby, Burgess (then head of the nutrition unit, WHO, Geneva), Scrimshaw, Stanbury, Olson, Stare, Ramalingaswami (one of India’s foremost medical scientists today). Those of us who made formal presentations at the conference in the section on hypovitaminosis A were: Aykroyd (introduction), Patwardhan (epidemiology), Oomen (clinical), Mason (pathology), Handler (biochemical), McLaren (pathogenesis). Many others contributed during the extensive periods of discussion, all of which was scrupulously recorded in the final proceedings. As an interesting footnote attention might be drawn to the only female participant. This was Dr E. OrentKeiles, who was with the NIH at the time, but previously had been a research collaborator of the great E.V. McCollum (see Chapter 1).

Africa in World War II. He had been drawn back to Africa after the war, partly because of his liking for big-game hunting. He had become director in Mwanza after a spell as Professor of Physiology at Makerere College in Kampala, Uganda.

nent and pensionable” terms, which meant that when Tanganyika gained its independence in 1962, I received quite generous compensation (“compers”) from “loss of career” and a small pension which continues to this day!

Holmes’ research interests were in the rather esoteric area of body composition changes in African adults. In a series of elegant metabolic studies, using radioactive isotopes for the first time in medical research in Africa, his group showed that the values were very different from those for well fed Europeans. However, these results did not lead to any practical recommendations about diet as far as I am aware.

We sailed for Dar es Salaam just before Christmas 1957. Only days before leaving, surrounded by packing cases in my parents’ front room, I had typed three papers from my thesis work and sent them off to the editors (98, 108, 109). I spent much of the time on the voyage writing another paper on the “Involvement of the eye in protein malnutrition”. This showed that in all reported instances deficiency of vitamin A was almost certainly responsible for the eye lesions, and not protein deficiency (110), as was sometimes suggested (111, 112).

I joined Her Majesty’s Overseas Research Service as Medical Research Officer. This was on “perma-

59

Medical research in Tanganyika (1958–1962) Today Tanzania (Tanganyika until independence in 1961) is classified by WHO as being among a number of African countries that have a serious VAD public health problem (113). A nationwide control programme has been in place for a number of years. Forty years ago when I went there it was a complete toss-up as to whether I was wasting my time and others’ money. I was not aware of any reports from anywhere in Africa to suggest that VAD was a problem of public health magnitude. A few isolated reports I collected several years later for Malnutrition and the Eye (88) confirmed this. Mwanza was the capital of Lake Province, situated in the north west of a large and varied country (Panel 10). I made some enquiries and clinical examinations in the large government general hospital and on a few field trips. I came to the conclusion that if I was to find xerophthalmia I would have to start looking in a more impoverished area. I recalled a conversation I had had on the boat coming out with a district officer, which was to prove most helpful. He had mentioned that some years previously, in 1954, in Central Province there had been a severe famine as a result of prolonged drought in which many of the local semi-nomadic Gogo tribe had died. Central Province appeared to be a good place to look for VAD, but first I needed research funds for the project. Application was made to the Tropical Medicine Research Board, our masters in London. The reply came back that the leading authority on eye disease in the UK, Sir Stewart Duke-Elder, Director of the Institute of Ophthalmology in London, had reviewed the request and turned it down. He was quite sure that there was no xerophthalmia in Africa. That appeared to be the end of that; stuck in the middle of Africa on a three-year contract with no research funds. 60

At about that time I received an invitation to present a paper at the “Conference on Beriberi, Endemic Goiter and Hypovitaminosis A”, to be held at Princeton, New Jersey, 1–5 June 1958 (Panel 11). It was organised by the Pathology Study Section, Division of Research Grants, US Public Health Service and supported by WHO, the Food and Agriculture Organization (FAO) and the Pan American Sanitary Bureau (PASB). I suspected that Bill Darby had put my name forward. The meeting brought together top US scientists in the field of nutritional deficiency disease and several of us with experience of the problems from abroad. I got to know many famous scientists, who hitherto had only been names to me, many of them on the train from New York to Princeton as that was the only way to get there then. This was to be one of the most enjoyable meetings I have ever attended. It was organised in a quite informal way, there were only 29 of us. It was held in the intimate and relaxed atmosphere of the historic Nassau Tavern Hotel. I reproduced the group photograph on the front of the July 1988 issue of the Xerophthalmia Club Bulletin to mark the thirtieth anniversary of this, the first international scientific meeting on VAD. The proceedings of the meeting were published in September 1958 (114). When the turn of hypovitaminosis A came on the third day the proceedings were dominated by the presentation by H. A. P. C. Oomen (Panel 12). His pictures of the destructive eye lesions and his impassioned account of his clinical experiences made a powerful impression, especially on the Americans. I had been allotted the rather dry subject of pathogenesis, which I defined as “methods by which lesions are produced by etiological factors”.

Panel 12

H. A. P. C. Oomen (1902–1986) In the era of which I am writing “Janus”, as he was always known to his close friends, was the father figure. After studying botany and zoology at the University of Utrecht he received his medical degree in 1932 and went to work as a Catholic mission doctor to 300,000 patients in north Celebes, now Sulawesi, in Indonesia. He and his family survived internment in World War II. Later he studied the problems of childhood malnutrition on Java, where he was especially impressed by the importance of xerophthalmia. The government of Indonesia appointed him representative for WHO and he served that and other UN organisations on many occasions in the field of child nutrition. Oomen was head of tropical nutrition and director of The Tropical Medicine Institute in Amsterdam after he left Indonesia. He and his wife had five sons – three of whom became

H. A. P. C. Oomen.

doctors, and to my knowledge at least two of these saw mission service in Africa.

I frequently received greetings cards at Christmas from Janus -nearly always they were scenes like this from his beloved Sulawesi.

Oomen served as the first, and only, chairman of the Xerophthalmia Club Bulletin when it was formed at the Jerusalem Seminar on Prevention of Blindness in 1971. At early IVACG Meetings and the two WHO Expert Committees on xerophthalmia Oomen made especially important contributions with his detailed colour photographs of the eye lesions of xerophthalmia and by giving the strongest support to the concept of the importance of dark green leafy vegetables in prevention. One of his medical missionary colleagues, Dr Ann ten Doesschate, wrote a very fitting obituary for Janus after he died at the age of 84 (Xerophthalmia Club Bulletin no. 33, July 1986).

61

None of us who were at the meeting in Princeton in 1958 (see page 58, Panel 11) will forget the impassioned conclusion to his presentation: “Xerophthalmia has been the most bitter pill for me to swallow during 18 years of doctor’s work in Indonesia. The over and over repeated experience of discovering a child, recently blinded, in the arms of the mother; having to tell her that I now could do nothing more to save its eyesight; remembering that I could have done so with a few spoonsful of cod-liver oil some days ago; these things still enter my nightmares. They belong to the most vivid examples of what disprivileged people in underdeveloped regions sometimes miss.

More printing space nowadays is devoted to a few cases of hypervitaminosis A, induced by an irresponsible vitamin racket, than to the thousands of small children who die or get blind every year due to the lack of a handful of vitamin A units. What on earth is nutritional science good for, if, even in the atom age, it is not capable to counteract one of the foulest consequences of bad nutrition?” Oomen contributed other key publications on VADD, not already mentioned in the text (116, 117, 118).

Some of the members of the expert group that advised UNICEF on the fortification of skim milk with vitamin A. From left to right, Bill Darby, “Jim” Burgess (WHO), Glen King (The Nutrition Foundation), and second from right Paul Gyorgy, a prominent American professor of paediatrics. 62

SIGHT AND LIFE Nevertheless, my talk must have made some impression because I was invited to breakfast the next day by two staff members of the Pathology Study Section. It turned out to be the most profitable breakfast I have ever had. They were very polite about my work and went on to point out that it was not possible, of course, for this kind of disease to be studied in the United States. The National Institutes of Health (NIH) were deeply interested in supporting such research and they wondered if I would be so kind as to agree to submit a grant proposal. Nowadays it is very difficult for scientists to get funding from the NIH even for research on diseases that threaten the life and damage the health of the American tax payer, who ultimately puts up the money. Within only a few months my proposal had been accepted in full; US$ 80,000 over three years. This was an awful lot of money in those days, especially with the very low costs of most things in Africa. From this totally unexpected quarter my work had been rescued. I was particularly fortunate in being so successful in view of the fact that at that point I did not have firm evidence that there was really a VAD problem in Tanganyika upon which to work! On this my first of many visits to the United States I was also able to visit a number of leading institutions in New York, Washington D.C., Cincinatti and Nashville. I was invited to the latter by Bill Darby to address a group he had called together to a meeting in his lovely home in the countryside. This was to discuss the need to fortify skim milk going to developing countries with vitamins A and D. I put the case for vitamin A fortification and Cal Woodruff, a young paediatrician at Nashville, who was later to be my colleague for several years in Beirut, spoke for vitamin D fortification. After World War II there were moves in the United States and Europe to gain influence with developing countries by helping to tackle the problem of malnutrition in children which was then being shown to be widespread. At that time childhood malnutrition was (wrongly) considered mainly to take the form of pro-

tein malnutrition. It was pointed out that the dairy industry usually had a large surplus of skim milk, the most commercially desirable part of milk at that time being the cream. Skim milk was rich in highquality protein, so it was proposed that it be shipped to the third world. This appeared to be a good idea as this aid should create a good impression and might help to alleviate the problem. Furthermore, it seemed to solve the problem of what to do with the skim milk. I was told privately by a scientist at the United States Department of Agriculture (USDA) in 1960 that before this idea came along they had been about to make the decision, reluctantly, that there was nothing for it but to bury the stuff in enormous pits somewhere! It was realised that skim milk was devoid of fat-soluble vitamins, and in order to counteract that deficiency cod-liver oil capsules were to be distributed along with the milk. Unfortunately these often went missing or were sold on the black market. Several outbreaks of blindness from xerophthalmia associated with skim milk distribution programmes occurred. The recommendations of the meeting in Nashville were acted upon in due course by the US State Department and the United Nations Children’s Fund (UNICEF). However, it was many years before sources of skim milk from some other countries were fortified. Even today, VAD may present a serious health hazard in emergency feeding situations (115). While in New York I stayed overnight at the home of the eminent Professor of Chemistry at Columbia University, Glen King. At the time Glen was President of the Nutrition Foundation, a body funded by the powerful food industry; Darby was later to succeed him. Glen was noted for his contributions to the discovery of the vitamin C properties of ascorbic acid. Many consider that he should at least have had a share of the Nobel Prize awarded for this work. King was later associated with W. Henry Sebrell Jr at the Institute of Nutrition Sciences at Columbia 63

Tanganyika

The first pictures of keratomalacia from Africa which I took at the CMS Hospital in Mvumi in the late 1950s.

University, New York, with whom I was myself to collaborate for many years when I moved to Beirut in 1962.

into a mobile eye clinic and laboratory and we started to carry out extensive eye surveys in Lake and Central Provinces.

Also in New York, at the Presbyterian Medical Center, it was arranged for me to meet George Smelser, an anatomist who was a world authority on the structure of the cornea. I remember telling him in his laboratory about the way in which thousands of young children were losing their sight from corneal damage and dying as a result of the lack of a few units of vitamin A in the diet. It was evident to me that this news moved him greatly. He asked me to let him know if ever I was to plan an extended visit to the States and he would arrange for me to visit a number of centres of eye research to tell them of my work. Smelser proved to be as good as his word in 1960 (see page 70).

The Church Missionary Society hospital at Mvumi, in Central Province, south of the main town Dodoma, became the base for our work there. A previous medical superintendent of this hospital was an Australian, Paul White, who had written a series of books of stories for children based on his experiences as “The Jungle Doctor” which were extremely popular in missionary and church circles at the time.

Back in Mwanza, with the new funding from NIH I was able to purchase a vehicle that was converted 64

At Mvumi and Dodoma I identified several children in the hospitals with keratomalacia which was being misdiagnosed (119). The doctors were attributing the damage to “muti” or traditional medicine. Decoctions of the bark of a tree known as “mowa” were applied, or “lukaka” or aloe was put in the eye. Even powdered cowrie shell had been applied in one case. The dramatic response when large doses of vitamin A

SIGHT AND LIFE were given soon convinced the mission doctors of the true cause. I have had similar experiences in several countries in Africa and in this way I was able to provide evidence that xerophthalmia was indeed a problem worthy of investigation. However, it took a great deal more work over a number of years to convince most ophthalmologists practising in Africa that VAD, as well as measles, played an important part in childhood blindness resulting from corneal damage. In addition, traditional eye medicine and herpes simplex infection may also be involved. It is of interest to note that much of this story was pieced together at Mvumi, long after I had left for Beirut, by Allen Foster (120). Allen is now a colleague of mine at the International Centre for Eye Health (ICEH) in London and a leading authority on childhood blindness. In Mwanza I interpreted my remit to carry out research on nutrition and the eye in the broadest sense and published papers at this time on other eye problems, including refractive errors, onchocerciasis, leprosy, cataract, and trachoma. I also took the opportunity to study the growth of young children and the composition of depot fat in different races (121–124).

Bill Darby and I with one of the Ethiopian army jeeps on the ICNND Survey.

Not long after the NIH grant came through I received an invitation from Bill Darby to join him in Ethiopia. After World War II the United States set up the Interdepartmental Committee on Nutrition for National Defense (later Development) (ICNND). The purpose of this organisation was to carry out nutrition surveys in developing countries friendly to the United States. These surveys were confined to the military at first, thus their scientific interest was limited. Bill Darby was early on associated with these surveys. The first director of the ICNND surveys was Harold Sandstead, a colleague of Bill’s. Sandstead was on duty with the surveys when he was among the occupants of a plane that was blown up over the United States by a youth who had placed a bomb on it with the intent of collecting the insurance he had taken out on the life of his mother, also on the plane. Harold Sandstead Jr in due course became an associate of Bill’s and is a distinguished worker in public health nutrition. Bill Darby was the director of the ICNND survey in Ethiopia in 1958, in which for the first time the civilian population was studied; the army provided transport. Bill told me that the survey team had been finding many examples in school children of changes in

Typical bilateral non-responsive Bitot’s spots (X1B) in an older Ethiopian school boy. 65

Tanganyika the conjunctiva with the appearance of Bitot’s spots. He wanted me to confirm the nature of these lesions and to investigate whether they were caused by VAD. I soon confirmed that they were indeed typical Bitot’s spots. They were occurring in about 4% of the hundreds of school children being examined. At that time their relationship to vitamin A deficiency was usually considered not to be in doubt. Examination of much younger children in hospitals failed to find any cases of xerophthalmia or keratomalacia, suggesting that in the absence of blinding VAD the Bitot’s spots might not be due to nutritional deficiency. Serum retinol estimated in blood samples from these subjects showed values within the normal range. It was decided that the children with Bitot’s spots should be given vitamin A capsules at regular intervals for six months and blood would be examined again at the end of this period. It was arranged for me to come back again in April 1959 and to repeat the clinical examinations. This time I was joined by Dr David Paton, a recently qualified ophthalmologist from the NIH in the United States. He brought with him a radium plaque US

One of many schools in Ethiopia being used for the ICNND Survey. 66

Navy portable dark adaptometer for measuring night vision. I had brought my portable slit lamp microscope specially made in London for my field work in Africa. Blood retinol after dosing was again normal and no abnormal night vision tests were found in over 200 students. In fact, they tended to see better than the American children upon whom the instrument had been tested by David! The test, dark adaptometry, was carried out in complete darkness with the small dark adaptometer, which was about the size of a portable typewriter. When we set up our equipment in each school we first had to choose a classroom with as few chinks in the doors and windows as possible. We took along great rolls of blackout material and filled every nook and cranny with it. This was not easy, as can be imagined, when it is realised that the schools were made of mud brick walls and corrugated iron roofs. Willing helpers would be seen clambering all over the roof, filling gaps and nail holes on the shouted directions from those incarcerated in the increasing darkness within. When all was ready to start a timer was set going to mark the passage of 30 minutes.

Bill Darby and Bill McGanity (later professor of obstetrics and gynecology at Galveston, Texas) examining subjects.

SIGHT AND LIFE We found that the Bitot’s spots had remained completely unchanged after the vitamin A treatment. Under the slit lamp Paton found that there was more dryness of the conjunctiva than in children of similar age he had previously examined in Washington D.C. The conclusion was that in this group the lesions were definitely not related to active vitamin A deficiency. They might have been residual changes from VAD in the past. On the other hand they might have been related to such local factors as excessive UV exposure at the high altitude of Addis Abeba, chronic conjunctivitis, which was common, or irritation from smoke which filled the huts these children lived in. This research resulted in two publications (125, 126) in the American literature that attracted considerable attention. It is now generally recognised that Bitot’s spots in children older than 6 years are unlikely to respond to vitamin A treatment. Under this age a high proportion respond to vitamin A.

The author examining an eye of a patient with the portable slit lamp microscope. This was the time required to allow the rods of the retina to become adapted as fully as possible to the dark before the actual testing could begin. The testing consisted of spinning on a number of occasions a very faintly illuminated figure in the shape of a cross and asking the subject to indicate the direction in which the long part of the cross pointed. I leave it to the imagination of the reader to picture what it was like to spend this apparent eternity in a room packed full of highly spirited Ethiopian school boys or girls (taken separately!), with no access to light or air from the outside! However, everything always passed off without undue incident.

There is one incident in relation to the work in Ethiopia which I have often used as a salutory lesson in my teaching and writing. The full story is told in the Report of the ICNND Nutrition Survey, Ethiopia, September 1959 (127, pp 67–70). Just prior to the ICNND survey the FAO/WHO nutrition consultant Dr Postmus had examined over 7000 pre-school and school age children and found Bitot’s spots (0.9% in girls and 2.2% in boys – a similar ratio to that which we found in over 6000 school children, both studies showing the usual male preponderance). He had recommended an extended programme of supplementation in schools with capsules containing vitamin A. This was about to be implemented as the ICNND survey started. When our negative findings were reported to the government the expensive and difficult supplementation programme was abandoned. The lesson to be learned is that whilst we confirmed the UN expert’s findings we did not agree with his interpretation that they 67

Tanganyika indicated VAD. From our extensive and thorough studies we were able to prove the point. Observations may concur, but interpretations may not. I have kept a cutting from the Sunday Telegraph of 17 October 1965. It relates how a team from the Westminster Hospital in London under a renowned ophthalmic surgeon from there had flown to Addis Abeba with deep-frozen corneas to carry out grafts on 30 children with blinding corneal opacities. The paper stated, “The project was being so enthusiastically received that the Emperor was meeting him [the surgeon] to convey his appreciation”. The surgeon said, “Our technique of freezing eyes which can be kept indefinitely could mean a breakthrough in the fight against blindness caused by opaque corneas”. This is an example of the popular misconception that the surgeon in shining armour can slay the ugly dragon of disease. More than 30 years later large numbers of children continue to go blind with keratomalacia and many die, in Ethiopia and in many other countries. Corneal grafting under these circumstances remains a futile exercise, as it was well known to us then, and would be considered only by someone seeking cheap publicity. Most of these young children also have internal damage to the eye which makes even successful corneal grafting ineffective in restoring even a vestige of vision. The only ethical approach to the problem of the control of VADD is through public health preventive measures that lack any glamour and require patience and persistence. There is no short cut. In Tanganyika I had been making a study of damage caused to the eyes in leprosy, a subject little investigated previously. I was allowed to borrow the dark adaptometer and I decided to try to use it to investigate whether the Bitot’s spots I had been coming across might be related to VAD. Over the course of several days I examined the eyes of all the inmates, over 400, of the leprosarium at Makutupora, run by the Church Missionary Society of Australia (128). Patients came from several provinces of the country to be treated in this insti68

tution situated in remote bush country on the western slopes of the Great Rift Valley of East Africa. It had an imposing view over the desolate Bahi Swamp, with hardly a rondeval in sight. In quite a number of patients I came across Bitot’s spots. The blackout facilities were none too good; but I chose a moonless and starless night. I shut myself in with a group of patients to wait for our eyes to adapt. It was then that I learned the truth of the saying that you can diagnose leprosy by the characteristic smell! Dark adaptation was normal, as I expected. A year or so later I was one of a team investigating another tropical disease, widespread in parts of Africa – onchocerciasis. As it may be recalled (see page 52), this disease, also called river blindness, had preoccupied John Wilson of the British Empire Society for the Blind several years previously when I had sought his interest for xerophthalmia. A group of scientists had been brought together by Allan Woodruff, for many years Professor of Clinical Tropical Medicine at the London School. After retirement he spent a number of years at the medical school in Juba, helping the people of southern Sudan during their long-running war with the north. He died there a few years ago. The study was carried out among the Mukonjo tribe in the Bugoye region of western Uganda, in the foothills of the Ruwenzori mountains, also called the “mountains of the moon” for their spectacular landscape. My job was to examine the eyes, and as an additional investigation I decided to measure dark adaptation in some subjects. One of the rooms in the dispensary where we had our base was easily made lightproof and I sat down with about a dozen of the rather ferocious-looking tribesmen. They came from huts scattered up the wooded slopes of the foothills. Everything went according to plan for the first 20 minutes or so, but then some of my captive tribes-

SIGHT AND LIFE men began to get restive. All of a sudden there was a stampede for the door with wild shouts and, I presume, gesticulations. I am afraid I do not have the words to describe what it was like to be with a group of hysterical African tribesmen under such circumstances. Needless to say, you will not find in our paper (129) any account of dark adaptation in onchocerciasis. Vitamin A levels in serum were measured in this study and no association was found between these and the presence of onchocerciasis lesions of either the anterior or posterior segment of the eye. This confirmed the view that VAD does not play a part in the disease, as some had supposed. It is evident in retrospect that many of the eye changes we reported in our surveys in Tanganyika (119), such as bulbar conjunctival wrinkling and pigmentation, pinguecula and pterygium, which played a large part in our thinking at the time, turned out later to be unrelated to nutritional status. It was to be the experience gained through the Global Survey (100, page 77) that prepared the way for the resolution of these issues at the first WHO technical meeting on the subject (130, page 96). I see now that it would have been very worthwhile if I had extended the cultural studies I had started in

Udayagiri and if I had in a more thorough way tried to get to understand precisely what were the factors that precipitated xerophthalmia in a relatively small group of any population. The extensive field surveys in the Mwanza and Mvumi areas showed that xerophthalmia was much more common in the latter (119). However, Bitot’s spots in school age children were found equally in both places. This was consistent with the studies in Ethiopia, suggesting again that these lesions are not related to active VAD in this older age group. With the NIH grant I was able to recruit an ophthalmologist, Bill Johnstone, from the United States to assit me in the research. He was some years older than I was and I do not know whether it was cultural shock in the African bush, but he was the only individual whom I have employed with whom I have had serious personal problems. During the early days of my PhD work Ben Platt had directed me to a paper from East London, South Africa, by C. J. Blumenthal, an ophthalmologist in private practice, entitled “Malnutritional Keratitis” (131). Although many of the cases he described seemed to be due to infection there was a small group in which the cornea appeared to melt in one area with a “silent” prolapse of the iris. I saw several cases fitting this description during my years in Mwanza. They were readily distinguishable from keratomalacia. I gave the name Discrete Colliquative Keratopathy (DCK) to the condition and a full acount was given in Malnutrition and the Eye (88) and repeated in Nutritional Ophthalmology (132), when no further accounts had appeared. At the time I gave considerable importance to this condition and went specially to Entebbe to discuss the matter with Blumenthal when he was flying between the UK and South Africa.

An example of what the author termed Discrete Colliquative Keratopathy.

Over time it became evident that DCK, if a true entity, was very rare. In retrospect I suspect that some kind of injury may have been responsible. Even 69

Tanganyika They did some very convenient “baby-sitting” of Gavin and Jill, aged 10 and 6 at the time. This enabled Olga to accompany me when I gave some of the lectures at centres on the eastern seaboard and in the midwest which George Smelser of the Presbyterian Medical Center, New York, had arranged.

Rolling Chair Parade on Atlantic City’s famous Boardwalk which extends several miles south to Ventnor where we stayed. The FASEB Annual Meetings were held in these and other nearby seaside hotels. though this was always enquired about, its occurrence may have been concealed by the patient. In mid 1960 I was due home leave of about six months. For the first month, at the invitation of Nevin Scrimshaw, Director of the Institute of Nutrition for Central America and Panama (INCAP), I was in Guatemala to assess the vitamin A situation there and in El Salvador. Although there was biochemical evidence of deficiency in the former I saw no xerophthalmia. In El Salvador there were many cases. I met the Professor of Ophthalmology and Minister of Health at the time, Humberto Escapini, who was well aware of the problem. Due to some very good fortune as a family we were able to spend much of our remaining leave in the United States. My father knew Malcolm Bradbury, the editor of The Watchman Examiner, a religious newspaper in the United States. He arranged for us to stay at no charge in the “Houses of Fellowship”, a luxurious apartment building in Ventnor, just south of Atlantic City, New Jersey. It provides accommodation for missionary families during furlough. They were generous in their interpretation of eligibility in our case. Olga’s mother and Olga’s sister, Hazel, it so happened were just visiting relatives in Ohio then. 70

One of these lectures was at the Wilmer Institute at Johns Hopkins University in Baltimore. David Paton was on the staff there and made the arrangements. These included Olga and I staying overnight in the house of the widow of a famous former professor of medicine at Hopkins. David drove out to the suburbs in the dark and I followed him in our car. Next morning I had to find my own way back in the rush hour. The most vivid memory of the whole visit is going round a roundabout the wrong way in my confusion. All my previous driving experience had been on the left! On the return journey a car on the road ahead of us in the dark suddenly exploded into flames and two youths leaped out! David Paton went on to become head of the department of Ophthalmology at Baylor School of Medicine in Houston,Texas. His father, Townley Paton, was an eminent eye surgeon in New York. At that time I made one long trip on my own. The end point was to give the guest lecture at the First Congress of the Asia-Pacific Academy of Ophthalmology in Manila, on “Nutritional Blindness” (133). On the way out I stopped in Los Angeles to lecture. In 1960 at the University of California, Los Angeles, (UCLA) ophthalmology was part of the department of Surgery. Not long afterwards a wealthy cataract patient donated money for what became the famous Jules Stein Eye Institute. Two young eye doctors, Christopherson and Stretsma, entertained me and I was surprised that my lecture was to be to the class of chiropractors to whom they taught anatomy! Interestingly, I received my most generous fee of the whole trip – $300! Brad Stretsma has become one of the leading ophthalmologists in the United States and now edits the American Journal of Ophthalmology.

SIGHT AND LIFE I went on to Tokyo, where I stayed in the new 11storey Hotel Nippon run by Japan Air Lines, then the tallest building in the city! The problem of making buildings safe from earthquakes in Japan had not been fully overcome at that time. I was entertained by several professors of ophthalmology. I learnt from them that at that time they had hardly any contact with the outside world and were very eager to meet any visitors. I raised with them the description Mori had given of the epidemic of xerophthalmia at the beginning of the century (see Chapter 1, page 16). I learned from my hosts that there were a few survivors of that epidemic still alive in blind institutions. Otherwise xerophthalmia had virtually been banished from their country in recent years. I wrote the following comments on the incident in 1965 – “Undoubtedly this transformation has resulted from the phenomenal rise in the standard of living, with the economic expansion and spread of education in the post-war period. Japan is the only nation in Asia, or throughout the world for that matter, where

a serious xerophthalmia problem has been conquered. This has been achieved ‘without a shot having been fired’, as it were, in the form of specific measures against the disease itself. The lesson to learn here is that nutritional diseases are symptomatic of a sick society, sick from ignorance and poverty. The problem is too fundamental and basic for superficial tampering measures, but requires a concerted effort such as only the Japanese have in our time demonstrated themselves to be capable of making; to universalise education, control population growth, and promote economic prosperity.” Thirty years later I see no reason to alter anything. Illustrative to me of the remarkable spirit for selfimprovement that animated the Japanese at that time was an incident on my second day in Tokyo. Shortly after breakfast I was informed by the hotel receptionist that a Professor Irinoda wanted to see me. This professor of ophthalmology at a small medical school in the northern part of the main island had published several papers on nutritional eye disease and we had been in correspondence. I had told him I would be in Tokyo. I learned that he had been travelling through-

Professor Irinoda is standing. 71

Tanganyika

In this group at a reception for the 1st Asia-Pacific Academy of Ophthalmology Meeting in Manila in October 1960, besides the author are Dr Gordon Holmes, Secretary-General, and Professor Barraquer of Barcelona, Spain. out the night by train from his home and had brought his assistant with him. Very soon in my hotel bedroom we had the projector he had brought along rigged up and spent the rest of the morning exchanging ideas and comparing our experiences using our slide illustrations. Irinoda described a disease affecting the skin and eyes in patients whose diet was based on highly polished rice (72). My final stop before Manila was Hong Kong and here I had the British government ophthalmologist Dr Dansey-Browning to brief me on the local situation. He was well aware of the problem of xerophthalmia and all children received cod-liver oil in his clinics. Many cases occurred in the children of refugee families from mainland China. He had special access to the old walled city of Kowloon and took me round the opium dens where gambling went on con72

tinuously on the mah-jong games played at a furious pace. I can still hear the hypnotic clatter of the tiles. All this was swept away completely a few years ago. I arrived in Manila in a typhoon, we were drenched leaving the aircraft and on the following day I had to roll my trousers above my knees and wade through flood waters to enter the General Hospital where the meeting was being held. Manila is not my favourite city; on the next visit in 1968 as part of a family travel to the East (see page 92) the four of us were caught in an earthquake that shook Hotel Manila for 40 seconds in the early hours of the morning and cracked some of the walls. Elsewhere in the city an apartment block called “Ruby Towers” completely collapsed, killing about 400 of its occupants, mostly of the Chinese community. On my third visit to Manila, to attend the Third Asian Conference of Nutri-

SIGHT AND LIFE tion in 1973, my hotel caught fire and I had to get out in a hurry. I was very well received by my hosts as guest lecturer coming out of Africa. After my lecture some of the prominent ophthalmologists who were involved in organising the meeting stated during the discussion that xerophthalmia was now no longer a problem in the Philippines. However, several younger eye doctors, from the remote rural areas of this country made up of an archipelago, came up to me afterwards and explained that they were seeing many cases. They were not surprised that their leaders did not see cases now as their patients were exclusively private and rich. Throughout these years I often faced similar experiences when authorities in central offices and hospitals denied the existence of xerophthalmia, even though I was being shown cases in local hospitals and clinics.

I learned from the many leading ophthalmologists whom I met that most of them had seen one or two cases of xerophthalmia in their own clinics in the United States. Some of these had been children of the poorer sections of the black population. Others had arisen through the failure of the general physician to ensure additions of vitamin A to a non-milk formula being fed to a baby who was considered to be allergic to mother’s or cow’s milk. Several instances were reported in the medical literature (88). On a lecture tour of some of the central states of the US Olga and I stayed a few days with Bill and Elva Darby in Nashville and he invited me to join his department. This was a very tempting offer, but I still had both my aged parents in London, my mother being especially unwell at that time, and I felt I still had contributions to make towards resolving some of the problems of malnutrition in young children in developing countries. I declined with great regret.

At the invitation of the Secretary General of the Congress, Dr Gordon Holmes, I stayed over on my way back to the United States at his beautiful mountain home overlooking the city of Honolulu in Hawaii. Also as a result of a contact at the meeting Dr Phillips Thygeson of San Francisco had me stay with him and lecture on xerophthalmia in his department. He was a world authority on trachoma and in charge of the programme to eradicate this disease among American Indians. Everywhere I lectured in the States I met appreciative audiences who were amazed that so little was being done to prevent this tragic disease. Someone got so frustrated that he asked why we could not just spray them with vitamin A from the air! Another common reaction was, “Why can’t every child be injected with vitamin A from birth?” I knew just how they felt. At the 5th International Congress of Nutrition held in Washington D.C. that summer there was not a single paper devoted to vitamin A deficiency and xerophthalmia, although one of the plenary sessions purported to cover “Worldwide problems in human nutrition”.

W. Henry Sebrell, Jr on receiving the Order of the Cedars from the Lebanese Government. 73

Tanganyika Bill Darby turned down the opportunity shortly afterwards to head up nutrition at WHO headquarters in Geneva. Later he declined the invitation to be director of the institute at NIH responsible for nutrition. Overseas he built up a team of researchers at the US Navy Medical Research Unit (NAMRU 3) in Cairo where it was shown that severe zinc deficiency in man could result in dwarfism and hypogonadism (dysfunction of testes and ovaries). On the same visit while in New York I met W. Henry Sebrell Jr for the first time at the Institute of Nutrition Sciences which he was setting up in the Columbia-Presbyterian Medical Center at 163rd Street in upper Manhattan. Henry had just retired after 30 years of service with the US Public Health Service, rising to be Director of the National Institutes of Health for five years. In his view his major achievements then had been to set up the famous Clinical Research Center at NIH and to institute the external research grants system which has been the life blood of innumerable medical researchers, all over the world, until the present. This meeting may have played a part in my being invited a year or so later to head up the Nutrition Research Program Henry was developing at the American University of Beirut. Our time in the United States drew to a close and we made our way to New York and spent Thanksgiving Day there seeing the sights. I was sleeping in the residency of the Eye Hospital at the Presbyterian Medical Center and the others were in a lodging across the street. After a good night’s rest I turned up to find that Olga had been up all night nursing the elderly landlord who had collapsed on returning from a friend’s. The New York police force likewise only arrived when it was all over. We just had time to get down to the docks where I saw the others off on the “Queen Mary”. I had to fly to Edinburgh to give a special lecture in the Royal Infirmary arranged by the Royal Medical Society, of which I had been a president when a student. My old Professor of Medicine, Sir Stanley Davidson (Panel 6, page 34), was in the chair and 74

the familiar old lecture theatre was packed. The audience was very attentive, as was almost everywhere the case, as I had again the privilege of telling the tragic story of children blinded by xerophthalmia. We returned to Africa as a family just after Christmas 1960 and arrived at Nairobi Embakasi airport just in time to see the small DC3 aircraft taking off for Mwanza with Sir Harold Himsworth aboard. As Secretary of the Medical Research Council in London he was making a final tour of British research establishments in east Africa before the imminent programme of independence for the three territories. The next plane was not for another five days. We were put up by the airline we came on, South African Airways, in the New Stanley Hotel at their expense and had a wonderful time over New Year – with the added bonus that I did not get inspected by Himsworth in Mwanza! Instead about a month later I had dinner with him at the Nairobi Club, where he was staying, and talked about my work in that very relaxed atmosphere. At just about the time I was leaving Platt in 1957 he gave me my first opportunity to contribute a chapter to a book (I have done this on more than 50 occasions since). This was for World Review of Nutrition and Dietetics and was to be on “The effects of malnutrition on the eye in experimental animals” (134). This led me to think I might go on to write my first book which would also include nutritional eye disease in man. Bill Darby proved very supportive and was instrumental in having my manuscript accepted by the Academic Press in New York. Bill wrote a Foreword. I was able to do the necessary extensive library research on visits to the United States and the UK. I was keen to have several pictures of the eye lesions of xerophthalmia in colour, but in those days this was very expensive. I mentioned the problem to Henry Sebrell and he suggested I apply to the WilliamsWaterman Fund, of which he was president, for a grant. I was successful in obtaining $ 500 and Academic Press agreed for this amount to have the colour pictures included.

SIGHT AND LIFE The Williams-Waterman Fund was set up by R. R. Williams and his associate to assist research on nutritional diseases. Williams was a chemist working for the Bureau of Science in Manila and while in the Philippines he used his spare time to discover vitamin B1 or thiamin, the lack of which causes beriberi. Williams took a unique approach to the financial aspects of his discovery. He took out a patent on the vitamin and arranged for all the profits to be put into this fund. Williams wrote an account of his work which has the title Towards the conquest of beriberi (135). By the summer of 1961 things had become very difficult in Mwanza. Johnstone and I were hardly talking. My mother’s condition had worsened since our return to Africa and I was wondering whether for family reasons I should accept the offer Platt had made once more for me to join him in London. Independence – uhuru – for the country was due in December 1961 and nobody knew what would happen then. In the midst of this turmoil I received a letter from Henry Sebrell in New York inviting me to become head of an NIH-supported Nutrition Research Program at the American University of Beirut (AUB) in Lebanon, associated with his institute in New York (Panel 13). The university arranged for me to visit Lebanon for ten days in September. I had to catch a connecting flight in Nairobi but none was flying in from South Africa because of severe weather. A second attempt was successful some time later, but on reaching Nairobi on the return trip I found out that the dirt airstrip in Mwanza was flooded and only a three-seater Piper aircraft was able to take off. Olga came up for the ride and for much of the way we had wonderful low-level views over the Serengeti Safari Park. Tribes people and game animals alike had had to congregate on what little high ground there was to avoid the rising floods. My appointment was confirmed with a starting date of 1 May 1962. Just a few days before we left for the UK in March I received two visits which gave me

considerable encouragement. The first was from a friend and colleague over a number of years, Dr V. N. Patwardhan of India, former Director of the Nutrition Research Laboratories in Hyderabad (now the National Institute of Nutrition). He had recently taken up the post as head of the Nutrition Section at WHO, Geneva. Patwardhan had obtained a three-year grant from the NIH to work towards the solution of the problem of xerophthalmia. “Pat” explained that the first year was to be devoted to a world-wide survey of the extent of the problem in countries where it was likely to occur, but from which information was at present lacking. He asked me to undertake travel in North Africa and the Middle East. Oomen was to cover Asia, and Escapini from El Salvador, Latin America. At last WHO was interested in finding out whether xerophthalmia was really as serious a public health problem as some of us had been saying for years. The second visit came about as the result of correspondence I had had with John Wilson of the Royal Commonwealth Society for the Blind (RCSB). I was informed that Dr Cobb, a young eye surgeon from St Thomas’ Hospital in London, was being sent out to investigate the cause of the high rate of blindness among young children in the Luapula Valley area of Northern Rhodesia (now Zambia). By the time Cobb arrived he was lucky to find me still in Mwanza. I met him at the airport in the morning and saw my family off to Dar es Salaam on the train the same evening. I was finishing the packing before leaving by air for Cairo en route to London two days later. As a result of our discussions it was soon clear to both of us that while measles was probably a serious disease among children there, and no doubt some damage was done by indigenous medicines, the real problem was nutritional and the blindness was due to VAD. Subsequently, in his report to the RCSB Cobb provided convincing evidence, both clinical and biochemical, that xerophthalmia is indeed the major 75

Tanganyika cause of childhood blindness in this part of Africa (136). I think this piece of evidence weighed the scales very heavily in favour of xerophthalmia being made subsequently one of the major emphases of the RCSB’s prevention of blindness efforts. I left Tanganyika after nearly five years of full-time research on nutritional eye problems. I felt very privileged to have had the opportunity to work in this important and previously neglected area. My surgical experience in India meant that I was allowed by the district hospital in Mwanza to carry out cataract and other straight-forward eye operations in the absence of an ophthalmic surgeon. This gave me an entree to the hospital to carry out some research projects. Today the old hospital building, erected during German colonial times, is no more. Burgando Medical Centre is a tertiary referral hospital for an incredible population of eight million! The last major operation I ever carried out, about 8 years after the previous one (!), was under very strange circumstances. On one of my visits to Mvumi hospital to carry out nutritional surveys the hospital had been left in the sole charge of a young female doctor only recently qualified in the UK. One evening she sought me out and asked if I could see a woman admitted with severe abdominal pain.

76

We agreed that something had ruptured internally and that emergency surgery was needed. I agreed to assist her, but once we were on either side of the operating table she felt unable to carry on and asked me to take over. There was serious bleeding and it became evident that it was coming from a rupture in the uterus, almost certainly due to a rare type of cancer (choriocarcinoma). The entire mass had to be removed as completely as possible. I tried to recall where the large blood vessels were for ligature, and the two ureters taking urine into the bladder – not to be cut at any cost. It was a relief to learn two or three days later that the patient had passed urine satisfactorily. On my next visit I learned that she had gone home without any complications, but I knew that her ultimate prognosis had to be guarded. My book was finally ready just before we were due to go to Beirut. I well recall the excitement of handing the manuscript in at the London headquarters of Academic Press, at that time in Berkeley Square. There certainly was a nightingale singing just then! I looked forward keenly to the prospect of being on the medical faculty of the finest university in the Middle East situated at the crossroads of Europe, Asia and Africa. There was the added stimulus of the ancient Arabic culture, new to me.

SIGHT AND LIFE

The Switzerland of the Middle East (1962–1976) I realise now that the broadening of my research in Africa to include eye problems other than those related to VAD and to take in more generalised effects of malnutrition paved the way for my translation to the stimulating setting of the School of Medicine at the American University of Beirut (Panel 13). In the early 1960s AUB, and particularly its medical school, was still the academic leader and trend setter in the Middle East. The MD degree was incorporated in the State of New York and most of its professors were Lebanese, former students who had done their speciality training in the States. Throughout my 14 years there, expatriate physicians were in a very small minority. I was appointed as Research Professor of Nutrition, supported by a large programme/project grant from the NIH for “Nutrition Problems in the Middle East”. The programme was linked with Henry Sebrell’s Institute of Nutrition Sciences at Columbia University, New York. I was given several rooms in Van Dyck Hall, the basic medical sciences building, and I set about getting them equipped and hiring staff. Plans were already underway for the building of a large new teaching hospital. Nutrition was included in these plans and in 1968 we moved into a total of 17 laboratories and offices. This later move from the basic to the clinical departments gave us much more influence with the mainstream of clinical medicine. As I was settling in, in the summer of 1962, I was planning at the same time visits to countries in the Middle East and north Africa as part of the global survey of xerophthalmia coordinated by Patwardhan at WHO headquarters. This gave me a very good opportunity to learn about these countries, which were new to me, and also to build up associations with personnel there. Altogether about 50 countries were visited by Oomen, Escapini and myself, and our report appeared in 1964 (100).

We collected impressions rather than hard data and did it on the basis of what has come to be known as a preliminary assessment. In this interviews are held with central and regional government health personnel, hospitals and clinics are visited and attention is especially directed to child-feeding practices and eye diseases. It is interesting to observe that the conclusions reached in our report have stood up very well subsequently to the test of time. The main objective, to determine whether xerophthalmia constituted a public health problem beyond countries like India and Indonesia, was achieved; it certainly did. In the spring of 1963 my book Malnutrition and the Eye was published. It is a 390-page monograph with over 2000 references (88). It underwent a complete revision and updating later and in 1980 appeared as Nutritional Ophthalmology (132). This work remains the standard reference on the subject. The largest sections of the book cover all aspects of vitamin A in relation to the eye, in both man and experimental animals. VADD in various ways have also had a place in other books I have written (Nutrition and its Disorders, 4 editions; Colour Atlas of Nutritional Disorders, 2 editions) or edited (Nutrition in the Community, 2 editions; Textbook of Paediatric Nutrition, 3 editions). It has been my hope that readers of these books will have gained a true impression of the importance of vitamin A in human health and disease. I planned my travel for WHO in 1962–63 to coincide with the peak seasonal incidence of malnutrition in children – in the autumn and early winter. This follows upon the stress of repeated diarrhoeal disease in the hot summer months. Throughout the countries of north Africa, the Near East, and as far east as Iran the clinical pattern of predominantly the marasmic form of protein-energy malnutrition (PEM) was found, with about 5% on average of these cases 77

Panel 13

The American University of Beirut, Lebanon Daniel Bliss, an American missionary to Syria, raised the funds in the United States and the UK to open what was then the Syrian Protestant College in 1866. It was the first western-style, university-level institution in the Ottoman Empire. The school of medicine was opened two years later. By 1920 the college had grown into a true university, Lebanon had become an independent state from Syria, and the institution was secular and American. Thereafter it has been known as the American University of Beirut (AUB).

Beirut in the 1960s. The AUB campus is the area close to the aircraft beacon on the extreme left.

View from the balcony of our apartment over the port to Mt Lebanon (c. 10,000 feet and snow-covered in the winter).

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In 1966–67 AUB entered into a year of centennial celebrations that were planned to contribute hugely to the endowment fund and to culminate at the commencement exercises in early June at the end of the academic year. Many high-ranking officials in nearly all the countries of the region were alumni of AUB, as were many prominent people in all walks of life in the United States. As fate would have it these celebrations were never to take place. At the last minute everything had to be cancelled with the rise in tension between Israel and Egypt and the outbreak of war on 5 June. America and Britain were accused of assisting Israel, and the university closed down and evacuated all its expatriate personnel. Throughout the subsequent years, until civil war broke out in Lebanon in 1975, there was continual unrest in the country, especially among the various groups of students at AUB. Amazingly, the university continued to operate throughout the civil war, but since the closure of the Nutrition Research Program in the School of Medicine there has been no nutrition presence there. The Department of Food Technology and Nutrition in the School of Agriculture has continued throughout. Through Professor Nahla Baba, one of my former students, that department is responsible for training dietitians. On a return visit we paid in March 1998 there were signs that the former link with the institute in New York might be reforged.

The campus with Van Dyck Hall, the Basic Medical Sciences Building (home of the Nutrition Research Laboratories until 1968) on the right.

SIGHT AND LIFE showing accompanying xerophthalmia. This was a much lower incidence than was being reported from south and east Asia, but would still constitute a major cause of blindness in young children. There was probably less known about nutritional status in the region I covered than in those visited by Oomen and Escapini. This provided an opportunity and a challenge to gather new information there. It also meant that it proved very difficult to convince authorities of the importance of VAD in the causation of disease. Not infrequently officials were embarrassed to be confronted with reports of young children going blind and dying in hospitals and for there to be no preparations of vitamin A with which to treat them. The problem of ineffective treatment took a strange form in Tunisia and Morocco. I was told there by several French paediatricians that they were puzzled by the cause of the destructive corneal lesions they were seeing because there was no response to injections of vitamin A. I was able to point out that the oily preparations they were using were quite unsuitable for emergency treatment. The oily solution stayed in the muscle at the site of the injection from where the vitamin was only very slowly released into the circulation. These preparations were originally manufactured for veterinary use, to prevent VAD in cattle. Water-miscible vitamin A disperses readily, but is not always available in hospitals. I was able to advise them to break the ampoule of oily vitamin A and give it by mouth as, even in a severely malnourished child, absorption is quite good. The issue of the formulation of vitamin A for injection loomed large on the agenda at early IVACG Meetings (see page 100). A few individual experiences have stayed with me and they complement what can be gleaned from our official report. In the children’s hospital in Alexandria, Egypt, under the care of Professor Hanafy I saw a little girl aged 18 months. She was one of nine children born to a “felah”, a peasant farmer, who had come into the city ten years previously from Upper

Egypt to try to raise the family as a casual labourer. Of the previous eight children, all except one aged 4 years, had died before the age of 3. The patient seemed to thrive until the age of 8 months while she was being breast-fed. The mother then became ill and upon her admission to a fever hospital the child was weaned onto buffalo milk with starch water and caraway extracts. Sickness of the mother all too frequently results in this way in sudden weaning of the child and leads directly to malnutrition as in this case. After the age of 1 year, bread and some vegetables were introduced into the diet of this little girl. She did not thrive well but things only went seriously wrong when she caught measles two months before I saw her. She had frequent attacks of diarrhoea, and for the treatment of this at home the diet was limited to drinks of caraway tea. Six weeks later it was noticed that she was unable to see, and only three days after this was she brought to the hospital when the sight had already been destroyed in both eyes. In the General Hospital in Tripoli, Libya, I took the picture of two extremely marasmic infants (see page 80). It was this that first set me wondering about the reason why some severely malnourished children,

General state of the child in Alexandria described in the text. The skin changes and oedema of kwashiorkor are evident. There is also noma (cancrum oris) in the cheek area. 79

Middle East such as these, escaped xerophthalmia. Several experiments we carried out on young rats indicated that the amount of vitamin A required by the body is closely dependent upon the rate of growth (98). Later we further investigated the matter in patients in Amman, Jordan, and it was clear that these “skin and bone” babies use up practically no vitamin A while they are suffering from severe growth failure. However, it was evident that once these children begin to recover and put on weight there is a real danger that xerophthalmia can actually be precipitated unless liberal amounts of vitamin A are included in the diet (137). I encountered several instances of skim milk used for recovery in PEM doing just this. This picture of one eye of the patient in Alexandria shows complete keratomalacia with sloughing of the entire cornea. There is no sign of accompanying local infection. The other eye was similarly affected.

In both Morocco and Iraq I was taken around the children’s wards of general hospitals by paediatricians who were obviously interested in the problems of malnutrition as they pointed out cases of kwashiorkor and marasmus. Nevertheless, in each place as I carefully examined the eyes of these children I discovered at least one child who had suffered damage to the cornea. This had developed under the eyes and without the knowledge of the doctors in charge. In Baghdad I saw a gross instance of medical ignorance and neglect. In one of the government maternal and child health centres I saw a young child who had recovered from an attack of measles. The faint evidence of the skin rash could just be seen still. During measles the boy had developed a mysterious eye condition for which he was referred to the eye specialist. He ordered drops to be put in the eyes daily, but did not disclose what the condition was due to. By the time I saw the patient both eyes had been irrevocably destroyed by keratomalacia. I noted at the time that xerophthalmia is so often precipitated by measles in the malnourished child. It was only a number of years later that this important relationship was properly investigated, especially in Africa (see page 118).

Severely marasmic infants in Tripoli, Libya, weighing 3.8 kg at 12 months and 2.25 kg at 4 months, respectively. 80

Another instance of professional ignorance I came across in Damascus, capital city of Syria. On the same

SIGHT AND LIFE for eye cases. He produced statistics which showed that xerophthalmia was the most important cause of corneal disease in his practice. Nearly 100 cases of xerophthalmia at all stages of the condition were seen in the course of a single year. In Lebanon we estimated serum retinol levels in more than 100 severely malnourished infants. Only two had xerophthalmia, but among the vast majority with normal eyes more than 30% had very low retinol levels (<10 µg/dl). We also found breast milk of some of the mothers to be low, compared with values for the United States.

This child in Baghdad had marked photophobia; the eyes were destroyed as described in the text.

day it was arranged for me to visit two ophthalmologists. The first took me round his wards and showed me three young children all of whom were reputedly recovering from injury to the cornea resulting from the application of “kohl” to the eyelids. This consists of a black powder, usually made from antimony and used throughout the Near East to “beautify the eyes”. It has also the reputation of “strengthening the eyes” in children with measles. Like eyeliner this preparation is applied to the edges of the eyelids. I have never heard it suggested elsewhere that “kohl” could cause anything more serious than the rare instance of a sensitivity reaction to antimony. Each of the three children I examined had scarring of the cornea in a healing stage, but with considerable impairment of vision. The scars were in the position typical of those due to xerophthalmia, that is to say in the infero-lateral part of the cornea. When I suggested VAD as a possible cause it was emphatically denied. In the afternoon I talked with the ophthalmologist of the Nouasat Hospital of the University with 54 beds

In retrospect this seems to me to be important evidence for a serious problem of subclinical VAD in some sections of the Lebanese population at that time. However, I did not draw this conclusion then, nor was the work considered to be worth publishing separately. This is a further example of how, at that time, such attention as there was was focussed entirely on the eye problem. I now regard it as another instance of an opportunity I missed.

Bilateral healed scars in the typical position on the cornea almost certainly resulting from previous xerophthalmia (XS) but not so recognised. One of three children in Damascus. 81

Middle East While I was preparing Malnutrition and the Eye (88) for publication I made the first attempt to estimate the global prevalence of blindness due to xerophthalmia, and this appeared in the book (page 215) as about 20,000 annually. On the basis of the notification figures from Jordan (105) (see page 86) I presented a paper at a meeting of the Nutrition Society of the UK (138) which suggested that the previous figure was a considerable underestimate and that it might be nearer to about 100,000 per year. Alfred Sommer (139) after the Indonesian national survey was to propose a figure of about 500,000 annually for corneal xerophthalmia throughout the world, not all of which would cause total blindness. A recent assessment from WHO (140) puts the number of blind children worldwide at about 1.5 million, mainly from xeropthalmia. About 300,000 new cases of corneal xerophthalmia are occurring each year, and about ten times this number (3 million) with non-blinding xerophthalmia – Bitot’s spots and/or night blindness. A very high proportion of preschool age children in developing countries, nearly 250 million, are estimated to be subclinically vitamin A-deficient. After the WHO global survey was completed in 1963 there were still two more years of the research grant to run. The objective for these was to choose a country in which there was a severe problem and carry out detailed studies concerning aetiology and work towards a solution. An ICNND survey in the previous year and my own visits to Jordan had shown that there was a serious problem among both Palestinian refugee and non-refugee Jordanian populations. Patwardhan decided to concentrate the effort there and he took charge of field studies which were located in the most densely populated areas around Amman, the capital, and Jerusalem. Dr Wadie Kamel, an Egyptian physician previously working with the United Nations Relief and Works Agency (UNRWA), providing services for Palestinian refugees in Arab countries, was appointed to carry out the work. 82

I was given responsibility for biochemical and clinical studies which were located at the Sisters of Nazareth Children’s Hospital (later Luzmila Hospital) in Amman. A ten-bed unit was set up for admission of severely malnourished children with preference being given to those with xerophthalmia. This also gave us the opportunity to study PEM, and some of our most significant research on this subject came from Amman, in addition to the work done in and around Beirut. After only two years or so in Beirut I was invited by the editor of the American Journal of Clinical Nutrition to provide original papers from the Nutrition Research Program for a complete issue of the journal. The issue for September 1965 consisted of 12 papers of more than 70 pages. Three related to vitamin A. In the first paper we described the characteristics of severe xerophthalmia (keratomalacia) in Jordan (141). Most of the patients were aged less than 2 years; all also had severe PEM (either marasmus or kwashiorkor). Despite intensive treatment, including large doses of vitamin A, the mortality (64%) was about four times higher than in other severely malnourished children without eye lesions (15%) (see also pages 19, 54). Even this latter group was shown to have low serum retinol levels and severely depleted liver reserves of vitamin A. Serum vitamin E was low in all groups, but lowest in those with very low levels of serum retinol. In a later study (142) in the same ten-bed unit there was the suggestion that the chances of survival over the short term in children with severe PEM was reduced in those with low serum retinol levels. This was another piece in the vitamin A and survival jigsaw that has tended to be overlooked. The second paper was on studies on experimental rats whose dams had been made deficient before birth of the offspring and presented early biochemical changes (143). Once again it was shown that those that had the most rapid growth developed xeroph-

SIGHT AND LIFE firmation of the phenomenon came in 1972 (144), but its possible significance seems not to be appreciated at the present time (Chapter 3, page 119). The third paper described the effects of a very large oral dose of water-miscible vitamin A (600,000 IU) given by our group to 44 parturient women at the time of delivery. Levels in breast milk remained significantly raised until the fourth week after delivery (145). A smaller dose is now part of recommended VAD prophylaxis. An example of keratomalacia from the study in Jordan. Most of the cornea is opaque. There is no sign of infection or inflammation.

Another case from the study in Jordan. The cornea has perforated and the lens is about to be extruded through the softened cornea. thalmia first (see page 51). Coincident with the start of a falling off in growth rate it was found that there was a proportionate rise in haemoglobin and haematocrit, suggesting haemoconcentration. This effect was reversed by treatment with vitamin A. Of considerable interest is the fact that in the human study in paper 1 mentioned above, the group of patients with xerophthalmia had significantly higher haemoglobin and haematocrit levels than those without eye lesions. The opportunity to pursue these interesting haematologic findings further was never taken. Con-

In my 1965 account of the work in Jordan I wrote, “Anyone concerned about a disease that causes blindness in Jordan will very soon be directed to the St John Ophthalmic Hospital situated on a hill overlooking the old part of Jerusalem”. This fine institution, run by the Ancient Order of St John of Jerusalem, was built in its present form as recently as 1960. A previous large hospital served the needs of the people of Palestine for nearly 80 years. The first hospital of the Order goes back to Crusader times. The Hospitaller of the Order at that time was the same Sir Stewart Duke-Elder who had stated that there was no xerophthalmia in Africa! At my first visit to the hospital in 1962 I found little interest in xerophthalmia on the part of the staff. The in-patient record of one malnourished girl, with both corneas affected, showed merely two “squiggles” to represent the eyes and the word “ulcer” indicating the situation of the softened areas of the cornea. There was no more highly concentrated form of vitamin A in the hospital for treatment than cod-liver oil. No attempt in the hospital statistics was made to differentiate xerophthalmia cases from other causes of corneal ulceration and scarring. However, I was pleased to note later that my plea for greater attention to be given to xerophthalmia did not fall on deaf ears and matters did improve. David Paton, with whom I had worked on the ICNND Survey in Ethiopia, had moved on to spend a year at St John’s. He helped to set up there the first eye bank in the Middle East. In an account of his time there 83

Middle East (146) he wrote, “As in all countries of the East, corneal scarring is the major cause of blindness. Keratomalacia is seen with regularity, especially in the winter months. An old local custom of starving children as part of the treatment of measles is undoubtedly a chief cause of nutritional deficiency of the cornea and consequent secondary infections. Corneal ulcers or their scars are the medical hallmark of the population.” Dr Boase, the Warden of St John’s, told me that most of their very young patients with xerophthalmia were seriously ill from general malnutrition and infectious diseases on arrival at the hospital.They had recently made an arrangement with the American Colony Hospital in the old part of the city to transfer such cases there. The renowned founder of the American Colony, Mrs Bertha Spafford Vester, who had spent all her long life in Palestine, showed me round.

Among the 60 children admitted at the time of my visit there were no less than four with keratomalacia. They were three boys aged 7 months, 1 year and 8 months, and 3 years; and a girl of 1 year. The 3year-old boy had been referred from St John’s three weeks previously with a note from one of the British ophthalmologists which I was shown. It was to the effect “Would you kindly take over the care of this child as the visual prognosis is hopeless”. Fortunately for this little boy he was not given up as hopeless by the Arab paediatricians. He was given large doses of vitamin A on admission and when I saw him, although the vision in one eye was destroyed by a total leucoma, in the other it was saved. Subsequently I have often shown this picture to various medical audiences and drawn the lesson that even training at the famous Moorfields Eye Hospital in London, which has special links with St John’s in

The dense and healing leucoma on the left cornea and the clear cornea on the right are evident. The child clutched at my fingers when asked to do so (see text). 84

SIGHT AND LIFE Jerusalem, may not be an adequate preparation for eye work in developing countries. Dr Dajani, the young Baghdad- and US-trained paediatrician, told me that the previous week he had admitted three other children with keratomalacia, all of whom had died. This gave me my first real insight into how fatal severe VAD might be. We were able to document this more fully in the WHO-supported study in Amman over the following two years (141). I used to fly from Beirut once a month on an UNRWA plane which made the circuit of Amman and Jerusalem with supplies for Palestinian refugees. I collected blood and other samples for analysis in our labs at AUB and kept an eye on the research. I often stayed overnight and got to know the director of the hospital, an Armenian AUB graduate, Emmanuael Shirajian. He was a very cultured man, like many of his countrymen, and played viola in a small chamber group in Amman. About one sixth of the population of Lebanon was Armenian, including many of my colleagues in the medical school at AUB. Many were from families who had managed to escape the genocide that had been perpetrated by the Turks just before World War I. The tragic story of some of them was described in the book The Forty Days of Musa Dagh by the famous writer Franz Werfel, author also of The Song of Bernadette. At the American University Hospital (AUH) the Night Nursing Superintendent, a friend of ours, was herself as a little girl the sole survivor in her family. One of the community, a female assistant professor in my department, was murdered under very strange circumstances. The appearance in the country of a former lover raised suspicions, but he was never charged. An integral part of the field research in Jordan was to be the institution by The Ministry of Health of a notification system for xerophthalmia over one year throughout the country. In order to assist its implementation I addressed several meetings of physicians in Amman and Jerusalem to familiarise them with

the disease. In particular, I discussed clinical pictures with them to assist in the recognition of the eye manifestations. The meetings were very well attended, by about half of all the 300 or so physicians in the country of about 1.8 million population at that time. Around one third were AUB graduates. In the subsequent weeks Wadie Kamel toured the headquarters of all the nine districts of the country and repeated the lecture materials. Thus almost all the doctors were briefed. It had been my experience over the years that undue attention was drawn to trachoma as a major cause of preventable blindness. In my surveys in Tanzania and during visits to other countries I had repeatedly observed evidence in children of the spontaneous remission of trachoma without involvement of the cornea and no impairment of vision. Bilateral scarring of the cornea in young children was frequently wrongly attributed to trachoma, rather than to xerophthalmia. A WHO survey in the border area with Israel had reported trachoma to be the most important cause of preventable blindness and a trachoma control programme had been set up. At one of the meetings Dr Schaefel, the Austrian doctor in charge of the trachoma control programme in Hebron, asked to talk with me when the meeting was over. He stated that I had been able to provide the answer to a question that had been troubling him for a long time. He had started work on the assumption that most of the blindness was due to trachoma. However, a preliminary survey he made showed that the great majority of those who were blind had gone blind when very young children. Trachoma would not have behaved like this but would have led to serious visual impairment only in much later life. This served to illustrate the point that Oomen and I had always insisted upon and which should be quite elementary – noting that the age of onset of blindness is crucial information for determining the cause of corneal scarring. The system of notification of xerophthalmia covered 12 months of 1963–64. This was the third year of 85

Middle East drought in the country and this may have contributed to the high number of cases. 472 cases were notified; 276 being in children under 6 years. Most of the cases in older subjects were of night blindness. The notification rate in children under 6 years of age was 7.2 per 10,000. This was a rate three times greater than that for poliomyelitis or diphtheria at the time, and slightly higher than that for pertussis (whooping cough). The xerophthalmia rate was several times higher than the WHO criteria for the presence of a public health problem subsequently recommended (130, 147). The field study, with which I was only indirectly associated, was never published definitively. It was written up as a restricted document (105) and was summarised at a symposium on VAD held at the Massachusetts Institute of Technology (MIT) in the USA (148). In my view Kamel and Patwardhan made an important contribution to our understanding of xerophthalmia at that time. For example, they came across considerable evidence of community awareness of the problem in the villages and among the nomads of Jordan. Vernacular (Arabic) terms discovered to be in common use for night blindness were: el hidbal (stumbling), el asha (blindness after dusk), ama eljaj (chicken blindness) and el wutwat (the bat). Bitot’s spots were termed: kushour beid (egg shells), kushour beida (white scales) or kushour samak (fish scales). That night blindness results from dietary deficiency was recognised by the practice of feeding various fatty foods. Liver (el sawda or el zaida) is widely used for night blindness. It is eaten almost raw; or it is boiled, the vapour directed to the child’s eyes, and then the child is fed with the boiled liver. For topical application the juice is pressed from the liver or oil is added; it is then ground well and the oily juice is dropped into the eyes. This is all very reminiscent of ancient practice in this region (Chapter 1). The belief that the milk of the pregnant mother becomes harmful after the quickening of the fetus is 86

perceived, which we encountered among the Khonds in India (see page 41), is also deep rooted in Jordan. Such milk is called “assassinating milk” (halib al gheil). In the field study households with young children were selected at random. There were 73 households with at least one child with xerophthalmia (Control Positive); 459 with no xerophthalmia (Control Negative); and 122 with xerophthalmia taken from the notification system (Notified Positive). Questionnaires covering social, dietary, and health data were applied to each. Selective biochemical and anthropometric tests were performed. In general, households in the Notified Positive group gave the poorest results, as might be expected. Respiratory infections and to a greater extent diarrhoeal episodes were closely associated with xerophthalmia. This association was shown many years later in Indonesia (see Chapter 3). Of particular interest was that part of the work which consisted of the first-ever vitamin A prophylactic intervention study. A placebo group had 90 children and the vitamin A group also 90, all of them being 35 to 180 days old at the start. The vitamin A group received a single oral dose of 100,000 µg (about 300,000 IU), quite a large dose for such young infants. There was not a single case of adverse reaction, although others have reported that a small percentage of child recipients have had adverse reactions such as vomiting, headache or diarrhoea. Subsequent studies have shown that the slight risk of temporary illness is outweighed by the benefit of vitamin A supplementation where appropriate (149). In the study in Jordan vitamin A levels in blood and growth were not significantly different in the two groups. Infectious disease experience was also similar. There were 9 deaths recorded over a period of more than a year, all from infections. Only 3 of these were in the vitamin A group and 6 in the control group. This difference was not commented upon at the time.

SIGHT AND LIFE If this work had been published at the time it is likely that long-term large-dose vitamin A prophylaxis would have been investigated in larger trials and probably introduced earlier than it was. This occurred in 1972 in India (106), and Kalyan Bagchi, in the Ministry of Health of central government in New Delhi by then, was responsible for the implementation of the nation-wide programme. Even though the numbers of cases found in the field study in Jordan were rather small, if the morbidity and mortality data had been made widely known this would probably have stimulated the funding of more adequate studies in the mid or late 1960s. It was only about 20 years later that Sommer and colleagues carried out the first of many definitive studies (see Chapter 3, page 118). With the advantage of hindsight one may philosophise that in the midst of the hurly-burly of research work it may sometimes be just as difficult to avoid the mistake of erring on the side of remaining silent as of rushing into print. Finally, it is interesting to note an acknowledgement at the end of the report. This was for “the assistance of Messrs Hoffmann-La Roche of Basle, Switzerland. The firm not only made a gift of the vitamin A and the placebo preparations used in the trial but also made available the expert advice of Professor O. Wiss, the Director of Biochemical Research.” After termination of the WHO-supported work in Jordan my association with Luzmila Hospital was lessened. Both there and in Beirut my attention turned more to PEM. There were several reasons for this. Nowhere did xerophthalmia have a prevalence as high as the various degrees and forms of PEM. The severe degrees of xerophthalmia that we were dealing with then invariably occurred against a background of marasmus, kwashiorkor, or marasmickwashiorkor. The reasons for the occurrence of the different forms of severe PEM were not understood and the solution of this problem was considered to be of great importance.

It became increasingly evident to me from our experience in Lebanon and Jordan that the marasmic end of the spectrum of severe PEM was neglected (150) and that the element of protein deficiency in PEM was greatly overemphasised (151). Our work hereafter relating to vitamin A was mostly biochemical in our laboratories (152). We reported a case of a refugee girl aged 9 years consuming a diet lacking any animal source of preformed vitamin A (153). The plasma had high levels of β-carotene and non-provitamin A carotenoids, but hardly any retinol. Large doses of β-carotene failed to raise serum retinol, but dosing with retinyl ester did and cured the deficiency. This was clearly a rare case of absence of the enzyme that converts β-carotene to retinol. When I was writing my book Malnutrition and the Eye (88) in 1960–62 I had not been to west Africa. I copied what other nutrition texts said about the universal consumption of red palm oil (Elaeis guineensis), a very rich source of β-carotene protecting the population of the tropical rain forest area from xerophthalmia, despite the poor quality of their diet in some nutrients. The first inkling I received that matters might not be quite so simple was a conversation I had with Dr Hendrickse, who was then Professor of Paediatrics at Ibadan, Nigeria, when we both attended a conference in Dar es Salaam in 1963. I had read reports that measles was a serious disease in west Africa, frequently precipitating malnutrition. From my experience in the Near East I knew that the eyes could often be affected, leading to blindness. Although measles itself sometimes causes a keratitis we knew that the children were often severely malnourished. Hendrickse confirmed that in his cases the eyes were often seriously affected. In 1964 I had a visit from a young black American paediatrician, Jim Carter from Nashville, who had spent a year in west Africa. He showed me his collection of slides, and among these were several of serious eye lesions which I identified as xerophthal87

Middle East mia. Carter observed that it would not be surprising if severe VAD occurred among the infants of the poorer section of the community as they did not receive the adult diet cooked in red palm oil until they were well into the second year of life. A few weeks later I had a phone call from Bill Darby. He was on his way from Lagos to Cairo but due to a sandstorm there the plane was diverted to Beirut. He had been making preliminary arrangements for an ICNND Nutrition Survey in Nigeria and asked me to meet him for discussion of a mission he had for me. Over lunch I learned that he too had heard of what Carter had found and suggested that there were two contrasting aspects of the vitamin A story that I could investigate. In addition to the possibility of xerophthalmia being missed in infants there was also the possible harmful effects of too much carotene (hypercarotenosis) in the adults habitually consuming diets rich in palm oil. In early February 1965 I was in Rome at the FAO headquarters assisting with the arrangements for an FAO/WHO Expert Group meeting on vitamin requirements when I received the news, from Olga in Beirut, that my mother had died suddenly in London. I quickly completed my part of these talks and flew to London for the funeral. It snowed heavily and our small family was represented by Gavin from school at Eltham College, myself and my father. The next day I flew to Lagos. During two weeks in the country, mostly in Ibadan, I examined a large number of children in outpatients with severe PEM. One had classical keratomalacia. The serum of several others proved to be very low in vitamin A, as was the breast milk of some of the mothers. We were also able to show that much of the carotenoids in serum from adults with hypercarotenosis was composed of non-provitamin carotenoids, like lycopene or lutein (154). At that time the possible beneficial antioxidant effects of carotenoids were not known. 88

As I flew into Beirut after this stressful period I developed a severe pain in my chest. A heart attack was suspected and I was rushed into our hospital. It turned out that I had a lung infection that was probably due to a coxsackievirus. I was on oxygen for eight days and had to have my chest drained of fluid at one point. With my history of valvular disease of the heart it was considered necessary for me to receive twice daily much larger doses of penicillin intramuscularly than normal to try to prevent endocarditis. With devoted care from all I pulled through, being hors de combat for nearly two months. During that period of serious illness I received some very sad news. Dick Jelliffe, whom I had met in London (see page 48), was Professor of Paediatrics at Makerere medical school in Kampala, Uganda. He had invited me to participate in a teaching seminar in nutrition for doctors throughout that part of Africa. I had been looking forward to this, but had to withdraw when I fell ill. Another participant was someone I had come to admire on my visits to Addis Abeba. Dr Edgar Mannheimer was a renowned paediatric cardiologist in Sweden. He had been involved in the medical care of pioneering open-heart surgery in young children. In the late 1950s he had decided to give all this up and to set up the Swedish Nutrition Institute in Addis Abeba. The news came that he had been killed in Uganda. A group he was in had been on a field trip in a minibus when it overturned as a result of reckless driving. Mannheimer was thrown out and was killed instantly. This was a terrible blow for the cause of child nutrition in the tropics. The Unit for International Child Health in Uppsala continues as a memorial to this great paediatrician. When I was well enough to leave hospital my summer home leave was due. We caught a ferry to Venice and viewed that lovely city in the best way there is; sailing up the Grand Canal in the early morning sunlight. We took the train to London and my recuperation was completed through the summer months.

SIGHT AND LIFE My father returned with us to Beirut and spent the last few months of his life very happily with us. He is buried in the Anglo-American cemetery in a part of Beirut that became a constant battle ground during the civil war. I broke my journey back to Beirut by attending the FAO/WHO meeting in Rome. This dealt with requirements for vitamin A, and some of the water-soluble vitamins of the B group (thiamin, riboflavin and niacin). The report of the meeting, published in 1967, made several important new contributions in the vitamin A area (155). These included the introduction of the concept of Retinol Equivalents (RE), which enables the vitamin A activity of a diet to be assessed by allowing for the differences in activity of vitamin A from animal and vegetable sources. In addition, the vitamin A activity of β-carotene was set at one sixth that of vitamin A itself, and the activity of other provitamin A carotenoids was set at one twelfth that of vitamin A. The actual levels of requirements recommended in terms of Retinol Equivalents remain much the same today. However, the experimental evidence upon which the conversion figures for carotenoids were based was sparse. The bioavailability of provitamin A carotenoids has become the subject of intense research in recent years and the recommended values for the conversion figures are currently being actively discussed (see Chapter 3, page 120). Oomen was at the meeting in Rome and I recall that one evening, as we were having a very pleasant evening meal together alfresco, he told me that he also had become a medical missionary through reading Schweitzer’s “On the edge of the primaeval forest”. He gave up his studies in botany, entered medical school in Holland and went to Celebes (now Sulawesi), one of the islands of Indonesia. Xerophthalmia was common among his young patients there. His botanical knowledge stood him in good stead later when he became a strong advocate of dark green leafy vegetables (DGLV) for the prevention of VADD (see also Panel 12).

Over the years I have made many visits to the United States, usually to present research papers at conferences at which VADD often figured prominently. I was admitted to membership of the American Society for Clinical Nutrition and the American Institute of Nutrition in 1965. I was paid the rare honour for a non-American to be elected a Fellow in 1993 of what is now the American Society of Nutritional Sciences. While I was Director of the Nutrition Research Program at AUB I was an Adjunct Professor at the Institute of Nutrition Sciences at Columbia University, New York, and lectured there annually. Henry Sebrell and I consulted on the research supported by NIH and I presented our research at the Federation Meetings held usually in Atlantic City at that time and at other centres. Henry would visit AUB for a week or so each year and discuss their research with the various investigators who were receiving grants through the Nutrition Research Program. He would be involved in the decisions concerning the allocation of grants for the forthcoming year. His experience was of great value in our work and we became very good friends.

Ali Ahmad on admission to our unit in Beirut: age 14 months, weight 6.15 kg. Severe kwashiorkor is evident, the eyelids are swollen and both corneae are destroyed. 89

Middle East One Saturday morning in September 1967 we were holding our usual staff meeting and reviewing our work in the department at AUB when word came from the Outpatients’ Department that there was a 14-month-old boy who should interest us. I found that Ali Ahmad Saloum had very severe kwashiorkor and that both eyes were destroyed with keratomalacia. He was admitted straight away to our metabolic unit. Although we were able to cure the kwashiorkor, the eyes were too far gone despite large doses of vitamin A and Ali Ahmad became permanently blind. This was a unique case in my 14 years in Lebanon. All of the others of our several hundred malnourished child patients in our unit had marasmus and none had xerophthalmia.

Ali Ahmad just before discharge home after about three months’ treatment.

It so happened that at the time of Ali Ahmad’s admission we were carrying out metabolic studies of PEM of the marasmic form using the stable isotope N15, measured by mass spectrometry. Samples from Ali Ahmad provided unique data representative of kwashiorkor in contrast to those from our usual marasmic patients (156).

We delivered Ali Ahmad back to his parents in northern Lebanon. In the mean time a baby sister had arrived. 90

SIGHT AND LIFE

On a visit several years later we gave him a letter for admission to a school for the blind. When Ali Ahmad had recovered we took him back to his village, very near the northern border with Syria. I would visit them once a year and in due course his parents were persuaded to allow him to enter a school for the blind in the hills above Beirut. On a visit there just before the outbreak of the civil war he appeared to be very happy and doing well. Shortly after this, Lebanon was plunged into civil war that lasted until 1991. I often wonder if Ali Ahmad survived the war and what would be the fate now of this man approaching 30. So many questions about friends and colleagues will remain unanswered because of the disruption of normal life that engulfed us all. Some time in the late 1960s I heard from Dr Teng Khoen Hing, an ophthalmologist in Bandung, Indonesia, who had reported a number of cases of the rarely described xerophthalmic fundus (157). Many workers in the field of VADD, including myself, have never seen an example of these lesions. Teng was writing a thesis on the subject and he wondered if I could send him films for his fundus camera to record the changes. This I was able to do and in due course

The last time I saw Ali Ahmad was in about 1975. He was doing very well in the blind school. 91

Middle East

In the village of Kirikuti, in the Khond Hills, where we met Pahano Digal and his mother. I had amputated his leg to save his life from septicaemia. We have corresponded ever since. Now he is near to retirement as a teacher, has seven daughters and a son and the eldest has become a penpal for our granddaughter Hannah.

he very kindly sent me a copy, suitably inscribed, of this most interesting monograph (158). In all Teng reported an astonishing 208 cases of xerophthalmic fundus, in children 5–14 years of age. Most complained of night blindness; Bitot’s spots were frequently present. In a number of cases treated with vitamin A and followed up for many weeks, the lesions “seemed to have become less”, but in no instance did the spots disappear. In the summer of 1968 I was invited by WHO to be a short-term consultant in nutrition in Singapore. This afforded an opportunity for extended holiday travel as a family through Asia. Gavin had just completed his first year at university and Jill was 14. The opportunity was taken to visit colleagues in nutrition in Tehran, Kabul, Delhi, Kathmandu, Bangkok, Chiangmai, Hong Kong and Manila en route. Perhaps the highlights were days on a houseboat called “Miss America” on Dal Lake in Kashmir, and our 92

return visit to Udayagiri, where we were overwhelmed by meeting so many old friends after 14 years. Our children saw the birth place they had been too young to remember. Some of our former colleagues have been there recently, and they tell of the transformation of this once remote tribal area to a place with television, mobile phones and four-wheel drive vehicles! In 1968 Singapore was a rather strictly regimented society with the strongest emphasis by the Ministry of Health being given to hygiene and sanitation. There was no childhood malnutrition and primary healthcare delivery was exemplary. The Chinese quarter still had real character and charm, but was beginning to be pulled down to make way for yet more tower blocks. After a few days Olga and Jill decided they wanted to enjoy the rest of the summer on the beaches at home in Beirut. Gavin stayed on to act as my “secretary” and we moved to the Chinese

SIGHT AND LIFE YMCA, where we enjoyed the culture and sport facilities. An international symposium on the “Metabolic Function of Vitamin A” was held at MIT towards the end of November 1968 (148). This is where Patwardhan presented some of the results of the WHO epidemiologic study of VAD in Jordan (see page 82). I gave a four-page discussion summary in the clinical aspects of VAD section of the meeting. This meeting adjourned on the eve of Thanksgiving Day and a number of us had been invited to attend another meeting in Washington D.C. organised by the Pan American Health Organization (PAHO), the section of WHO for the Americas. I recall leaving the plane on arrival in the capital and several of us making our way through enormous crowds to the baggage hall. Many flights were arriving at about the same time and just as one of our bags would be-

Family group on the balcony of our faculty apartment at AUB.

come visible on the rather limited type of carousel used in those days it would be swamped by newly arriving bags. We were put up in some kind of apartment and as it was the biggest holiday of the year there was no service and it was very difficult to find anywhere open for a meal.

We were members of the Caledonian Society of Lebanon.

On Thanksgiving Day morning itself about 20 of us were in conference when a call came through from Bill Darby in Nashville to say that his associate Bill Pearson had been killed in a car accident in downtown Nashville that morning. Pearson was a very good nutritional biochemist. I had met him first on the ICNND survey in Ethiopia and frequently later. At AUB we adopted his method using trifluoracetic acid for the determination of vitamin A in micro-samples of serum (159). 93

Panel 14

The Xerophthalmia Club Bulletin The so-called Xerophthalmia Club was formed in 1971 in Jerusalem at the Conference on the Prevention of Blindness held there. Oomen was elected president and Pirie became secretary. There has never really been any more to the club idea than the production of a bulletin. The first number appeared in June 1972 with Tony Pirie as editor. A foreword to the first issue was written by John Wilson, who had found the money to get the project off the ground. It goes, “After languishing for too many years as a textbook curiosity and a specialist’s specialism, xerophthalmia has now emerged as a subject of intense international interest, demanding vigorous action on a world scale. We have perhaps reached that critical point in the development of a world movement when scientific, economic, humanitarian and political considerations can fuse into a single coordinated effort which can cover continents and affect multitudes of lives. May this bulletin, written and read by people with varied disciplines in many countries, play its part in generating the knowledge, energy and resources which are now needed to convert world interest into world action.” Pirie produced the first 31 issues and retired in 1984. At the IVACG Meeting in Hyderabad that year I was appointed to succeed her. In the subsequent years I have edited a further 39 issues at regular intervals three times a year until the latest number (no. 70 in March 1999). Both Tony Pirie and I have been responsible single-handed for all the work involved and on an honorary basis. The cost of producing and mailing about 3500 copies three times a year is borne equally by Sight Savers and IVACG. The Xero Bulletin, as it is often known, is quite unlike most of the many newsletters that are distributed free on health topics. The editors have been experts in the field and therefore in a position to make comments that are likely to be well informed, as well as

94

critical. They have also been free to a large extent to choose the contributions without any bias. In recent years the eight pages of the bulletin have followed a standard format. Certain features appear in each issue: these include Notes and News, Literature Digest (abstracts and comments on recent scientifc papers), Reviews (of books, reports, etc.) and Correspondence. From time to time original articles appear, as do notices of meetings and review articles on various topics. Among the latter in recent years have been contributed articles on such subjects as micronutrient surveillance standards, demographic entrapment, the relative dose response (RDR) test; the progress in the accumulation of evidence for the effect of vitamin A supplementation on child health and survival, and an ongoing series pointing out the neglect VADD receive in standard textbooks, especially those written for and by the medical profession. Perhaps the only regret of the present editor is that the readership does not contribute more to the columns of the bulletin. Although knowledge and circumstances have changed enormously since Sir John Wilson’s foreword to the first number quoted above, the need for the bulletin remains as great as ever.

Panel 15

Xerophthalmia prevention in Madurai, India The Nutrition Rehabilitation Centre (NRC) at the Government Erskine Hospital in Madurai, Tamil Nadu, in south India, was opened in 1971. It was, and still is, the only centre of its kind started specifically to help children with xerophthalmia. It was the product of the collaboration of G. Venkataswamy, Professor of Ophthalmology in Madurai, and Dr A. Pirie (see page 49). Funding from the Royal Commonwealth Society for the Blind made this possible. Madurai is one of India’s oldest cities and is a major Hindu pilgrimage site with important temples. The surrounding area is predominantly rural with rice-based agriculture. Poverty is widespread. In the foreword to a popular account of this work (160) Sir John Wilson, founder and former director of Sight Savers (see page 52), described how this idea grew out of the prevailing concept of nutrition rehabilitation promoted at the time for the rehabilitation of children with severe PEM. The underlying concept was for mothers to be admitted to the centre with their malnourished children and for them to receive practical training in every aspect of child nutrition and care. Detailed accounts of the work of the centre and the results achieved have been published (161, 162). The mothers and children stayed in the centre for at least 15 days and often for as long as a month. Regular follow-up visits were paid to the homes, where medical examination and advice were given. In due course the work was extended to villages in three blocks near Madurai. Over the period 1971–87 more than 2500 children with all degrees of xerophthalmia were admitted to the centre. At about the same time one of the most ambitious schemes in the entire history of ophthalmology was hatching in the mind of that most remarkable man, Venkataswamy. From 1976 there grew the concept of the Aravind Eye Hospital under the inspiration of

Professor Venkataswamy of Madurai, the founder and inspiration behind the Aravind Eye Hospitals, including the Xerophthalmia Rehabilitation Centre. Sri Aurobindo (1872–1950), one of the foremost leaders in the early stages of India’s struggle for freedom. Satellite hospitals have been opened as has an institute of community ophthalmology. The Aravind Children’s Hospital in recent years cares for cases of xerophthalmia. A recent report (163) suggests that the number of cases with keratomalacia has diminished greatly in recent years. Young infants seem to be more susceptible now, and this may be due to poorer maternal nutrition and early cessation of breast-feeding. NRCs around the world have not withstood the test of time. The reasons for their closure depend on different circumstances. In general they proved costly in terms of human and financial investment. Some were overwhelmed by international debt or by the AIDS/HIV or other epidemics. Perhaps the spread of the concept of primary healthcare for all was most influential. Good nutrition as part of good health was seen to be the concern of all, and not just of those who had already encountered problems.

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Middle East In August 1971 a Conference on the Prevention of Blindness was held in Jerusalem. Although Beirut was so close it was possible to visit Israel from the Arab world only by transiting Cyprus. One could not return if one’s passport had been stamped in Israel. In any case, it was not considered diplomatic of expatriates like me to try to do so, as it might upset Arab colleagues. Consequently I was not present when at that meeting the Xerophthalmia Club was formed (Panel 14). There is no “club” in reality, but the very informal eight-page newsletter produced three times a year has provided a means of keeping people, especially those in remoter parts, in touch with the latest developments over many years. In 1972 I returned from leave to Beirut inspired by what I had seen of the new nutritional support programmes in hospitals. An Intensive Care Unit had recently been opened at AUH and with the support of the surgeons total parenteral nutrition (TPN) was introduced with considerable success. I have found this to be one of the most effective ways of demonstrating to medical students and doctors the relevance of nutrition in medical practice. I have always believed that the way to increase the knowledge of doctors about nutrition is to work on the problem from within the medical school at the undergraduate level. After my retirement I obtained a research grant from The Wellcome Trust to research the origins of the failure over the years of nutrition to gain its rightful place in the medical school, and this resulted in a paper that has contributed to the progress that is being made in this area, especially in the United States (84). 1973 saw the start of a unique approach to the problem of xerophthalmia (Panel 15). Once again John Wilson of RCSB played a key role in this establishment in south India of a nutrition rehabilitation centre specially for xerophthalmia. In November 1974 an expert group of WHO was convened in Jakarta, Indonesia, on “Vitamin A Deficiency and Xerophthalmia”. This was a milestone in 96

the field. In addition to bringing together all the available information on the nature and extent of the problem the experts agreed finally on a “Xerophthalmia Classification” and also, of great practical importance, recommended “Criteria for Community Diagnosis of Xerophthalmia and Vitamin A Deficiency”. Perhaps of most lasting importance was the resolution of a potential source of conflict. The members of the group gathered to write the report were drawn from just two areas of expertise at that early stage: 1) nutritional biochemistry and 2) ophthalmology. The blinding effects of VAD dominated discussion in those days. Biochemists, like Guillermo Arroyave of INCAP in Guatemala and Barbara Underwood of the US, repeatedly pointed out that subclinical deficiency was much more widespread than clinical. However, at that time there was no proof that it was significant for public health. Oomen and myself had expertise to some extent in both fields and were able to see both points of view. Debate was quite heated at times, but both emphases were brought out in the report, the first draft of which I wrote as rapporteur. This consensus is appropriately reflected in its title – “Vitamin A Deficiency and Xerophthalmia” (130). My colour slides were used to illustrate the eye lesions in the report. At this meeting Alfred Sommer, a young American ophthalmologist-epidemiologist, entered upon the international scene and it was clear that he would take a leading role in the future. With massive US governmental funding and based at The Johns Hopkins University in Baltimore, he and his colleagues there and in many developing countries, especially Indonesia and Nepal, have pioneered the role of vitamin A in young child and latterly maternal mortality and morbidity. In 1997 Al received a Lasker Medical Award and has been honoured by Helen Keller International (HKI) and other bodies. Al has been Dean of the Johns Hopkins School of Hygiene and Public Health for a number of years. Over the many years of our association our relationship has remained close and one of mutual respect and admiration. In the field

SIGHT AND LIFE might have played a part in the apparent reduction in blinding cases. However, general social improvement probably played a major part. Years later (165) data were compiled that showed steady improvement in vitamin A status in Indonesia. As this book is written, it is tragic to see the unravelling of all these achievements with the descent of Indonesia into social and economic chaos. In the early 1970s I became aware of a study being carried out in Bengal, India (166, 167). Dr Bang from Johns Hopkins was principal investigator and dropped by Beirut to discuss the work being carried out in several villages. Dr Sinha moved to the area with his family and made frequent and detailed observations. These documented the marked seasonality of the eye signs of VAD and the lack of response of many Bitot’s spots to treatment with vitamin A. Alfred Sommer MD, MHS in the 1980s.

of VADD Al Sommer has demonstrated a unique ability to unite science with public health action (164). I took with me to Jakarta in 1974 a vacuum flask with dry ice and sample tubes for blood. I left this with the paediatricians on the children’s ward of the Central Hospital where, in 1957, I had seen so many patients with xerophthalmia. I was hoping to be able to take back to my laboratory in Beirut some samples for research. I returned to the hospital when the meeting was over, only to learn that not a single case of xerophthalmia had been admitted during that period of a week or so. Clearly things had improved immensely in the intervening years. In the 1960s red palm oil distribution had been proposed as a public health measure in Indonesia but had not been well accepted. Vitamin A capsule distribution had been started a year or so earlier and

Of greatest interest was the finding that evidence of VAD showed two peaks, in April–June and November–December. This presented a paradox, because from July to September food became scarce, and in November–December green leafy vegetables became abundant. It was suggested that during the food shortage from July to September the poor would forage locally available edible leaves, rich in carotene. During November–December rice is harvested and general food intake, but not that of vitamin A, would increase. This might lead to a growth spurt, stores of vitamin A would be depleted, and overt VAD might be precipitated several months later in April–June. Sinha was also monitoring the growth of the children and this showed an inverse relationship to the signs of VAD. This is some of the strongest human evidence for the concept (see also pages 51 and 80) that growth rate has a strong influence on vitamin A requirements. In the mid 1970s I was approached by representatives of the International Agency for Research on Cancer (IARC) in Lyons, France, about research they were doing in north-east Iran on the aetiology of cancer of the oesophagus. The Turkoman of that area 97

Middle East had one of the highest rates in the world. Nutritional deficiency was suspected as a likely factor. From Beirut and later from Edinburgh I made extended visits, conducting dietary and nutritional surveys. In March 1977 our daughter Jill had completed her RGN (Registered General Nurse) training in Brighton and was due to start her specialised children’s nurse training at Great Ormond Street in London in May. She came as my assistant, and with members of the team from the School of Public Health in Tehran we spent three weeks under canvas outside the village of Korand in the Turkoman Sahro; a basalt desert area within sight of the Soviet border.

Our previous surveys had shown low intake of most nutrients but the only common clinical evidence we had observed was suggestive of riboflavin deficiency – angular stomatitis, cheilosis, and magenta tongue. Overt xerophthalmia was not seen, but there was the possibility of subclinical deficiency. For our study in Korand school children were chosen. Riboflavin deficiency signs were recorded, blood was taken and high doses of riboflavin were given by mouth. The signs cleared rapidly after the treatment. Blood sent for analysis in the laboratories in Tehran showed low levels of glutathione reductase in red blood cells (a reliable test of riboflavin deficiency) before treatment. Levels returned to normal after dosing (168).

Jill giving the vitamin tablets to the school children in the study in Korand. 98

SIGHT AND LIFE

The author in a borrowed Turkoman leather coat and purchased Turkoman headgear, with Jill and two of the local school masters. While on a subsequent, and final, visit for survey work to the Caspian Sea area in 1978 the news was received of the uprising against the Shah in the capital and the work had to be terminated. Several years later IARC shifted its research operations to Linxian in China, where a similar high prevalence of carcinoma of the oesophagus was found. At one stage deficiencies of vitamin A and riboflavin were suspected to be important, but supplementation trials were ineffective. In September 1998 I was very interested to meet Dr Li Jun-Yao, the chief epidemiologist on the project, at a meeting on Nutrition and Cancer in Pavia, Italy, and to learn the latest ideas twenty years later (169). Two very large field intervention trials have been going on there for many years. β-carotene is among many other micronutrients that are being given. Impact on other forms of cancer and on other condi-

tions such as hypertension, stroke and nuclear cataract is also being studied. The First World Conference on Food was held in Rome in November 1974. Henry Kissinger, US Secretary of State, gave the keynote address. He was briefed by the Office of Nutrition at the State Department, the head of which at that time was Martin Forman. Marty suggested that in addition to talking about world famine and widespread childhood malnutrition, Kissinger should stress that there were two specific deficiency diseases that might yield rather readily to intervention. The first of these was VAD and xerophthalmia, the most common cause of blindness in young children in the world and carrying a very high mortality. The second disease was nutritional anaemias, most importantly deficiency of iron. It was argued that both these diseases should respond readily to interventions consisting of supplementation with the single micronutrient. 99

Middle East This advice was followed and as a result in due course two budgets of 10 million US dollars each were voted by Congress to set up the International Vitamin A Consultative Group (IVACG) and the International Nutritional Anemias Consultative Group (INACG). Both organisations continue to the present. IVACG (Panel 16) was formally constituted in 1975 at a small meeting hosted by UNICEF in the United Nations Building in New York and chaired by Les Teply, head of nutrition at UNICEF. I was in New York at the time to help prepare the final version of the WHO report, which appeared the following year. Marty Forman’s idea has certainly paid handsome dividends as far as IVACG is concerned over the years. Its meetings, 19 to date in 1999, and to a less extent the monographs and statements it has produced, have provided a focal point for ever-increasing attention being paid to the need to eliminate VAD – one of the goals of the UN “Health for All by the Year 2000” campaign. On looking back over the proceedings of the earlier meetings I have been surprised to see how often recommendations were made concerning the perceived need for water-miscible preparations of vitamin A for intramuscular injection to be made available by the pharmaceutical industry for the treatment of severe, clinical vitamin A deficiency. For example, the first three recommendations from the second IVACG Meeting in Geneva in May 1977 were on various aspects of this subject. The background to this was mentioned earlier. It became clear later that oily preparations of vitamin A are well absorbed by mouth, even in severely ill children, and that this should be the route of treatment in most cases. Hoffmann-La Roche was represented at IVACG Meetings from the beginning and took a great deal of interest in the problem. They made available water-miscible preparations on request through WHO. Looking back, it is evident that this involvement led eventually to the setting up by Roche of the Task Force SIGHT AND LIFE in 1986. This resulted in a 100

significant increase in their involvement in the control of VADD. Although this issue of parenteral administration of vitamin A in the treatment of active xerophthalmia is no longer discussed, I believe there may still be a problem. We do not know whether oily preparations are still being used intramuscularly in some hospitals. The latest recommendations from WHO (170) have dropped any mention of this route for treatment. I have twice become involved in criticism of studies in the UK in which secondary VAD, due to impaired absorption or utilisation, was treated with oily intramuscular preparations of vitamin A, without effect (171, 172). There is still a tendency to assume that because vitamin A is a fat-soluble vitamin it is bound to be effective by any route, in an oily form. It was mainly through attendance at IVACG Meetings, receipt of the early monographs written by experts for IVACG, and the news and views appearing in the columns of the Xerophthalmia Club Bulletin that one was able to keep up with the increasing number of contributions from around the world. This was long before the internet. Key contributions came from a small, but growing, group of truly international investigators. Guillermo Arroyave at INCAP in Guatemala pioneered the fortification of sugar with vitamin A (173) and was at the forefront of the use of biochemical methods for the assessment of vitamin A status (174). Barbara Underwood developed the relative dose response (RDR) method for assessment of vitamin A status (175) and became a leading figure in the area of prophylactic use of vitamin A, especially in pregnant and lactating women (176). Throughout this period the workers at the National Institute of Nutrition in Hyderabad, India, have contributed many papers on all aspects of VADD (137, 177, 178). In the Philippines Florentino Solon and his coworkers identified the problem of VADD (179) and introduced the fortification of monosodium glutamate (MSG) and other methods of control (180). Jim Olson, of the State

SIGHT AND LIFE University of Iowa, combined an understanding of the human problem gained by periods of living in Thailand and Brasil, with his expertise in biochemistry (181, 182). A fellow countryman of mine, Nick Cohen, spent many years in Asia on the control of VADD and did notable field work with HKI in Bangladesh (183). I am surprised, but very pleased, to realise that all of these colleagues mentioned continue

to be active in various ways in the cause of the control of VADD. I served as rapporteur for the first twelve IVACG Meetings. I missed the next two meetings but attended the subsequent ones in Kathmandu, Nepal; Chiang Rai, Thailand; Guatemala City, Guatemala; and Cairo, Egypt (the XVIIIth in September 1997).

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Panel 16

The International Vitamin A Consultative Group

The first scientific meeting of IVACG held in Port-au-Prince, Hotel Castelhaiti, Haiti, 22 to 26 March 1976. At the table from left to right: D. S. McLaren, H. A. P. C. Oomen, D. Karyadi, E. M. DeMaeyer, W. Fougere (Bureau de Nutrition, Haiti), G. Arroyave, B. A. Underwood. Attendees: E. M. DeMaeyer (Chairman), WHO, Geneva, Switzerland; S. G. Kahn (Secretary), AID, USA; G. Arroyave, INCAP, Guatemala; J. Bauernfeind, Hoffman-La Roche, USA; C. O. Chichester, Nutrition Foundation, USA; J. H. Costello, International Eye Foundation, USA; W. J. Darby, Nutrition Foundation, USA; C. H. Daza, PAHO/WHO, Washington, D.C.; M. J. Forman, AID, Washington, D.C., USA; W. Fougere, Bureau de Nutrition, Haiti; W. W. Kamel, University of Illinois, Chicago, USA; D. Karyadi, Ministry of Health, Indonesia; C. Kupfer, National Eye Institute, NIH, USA; M. A. Lemp, International Eye Foundation, USA; D. S. McLaren, American University of Beirut, Lebanon; J. Olson, Iowa State University, USA; H. A. P. C. Oomen, Royal Tropical Institute

102

of Medicine, Amsterdam, The Netherlands; S. Pettiss, American Foundation for Overseas Blind, USA; A. Pirie, Nuffield Laboratory of Ophthalmology, England; A. Sommer, Johns Hopkins University, USA; B. A. Underwood, Pennsylvania State University, USA; G. Venkataswamy, Madurai Medical College, India. Invitees from Haiti: D. Beaulieu, Public Health Minister; S. Behoteguy, USAID Mission; R. Berret, PRONUDERU; H. Bordes, Div. d’Hygiène Familiale; C. Boulos; G. Deslouches, Public Health; J. C. Desmangles; S. D. Burak; E. Franklin, HACHO; G. Frederique; R. Germain, Public Health; G. Hudicourt; Dr Jeannot Cadet, Hôpital de l’Université d’Etat d’Haiti; Rev. Sister Joan Margaret, St. Vincent School for the Handicapped; M. Mesidor, Nutrition Bureau; A. Pellerin, WHO; V. Rathauser, WHO; S. Toureau, AFOB Vitamin A Program; Dr Charles Weldon, USAID Mission.

Mention has been made of the way in which the idea of IVACG was born and how the organisation came into being in 1975. The mission of IVACG is described as “to guide international activities aimed at reducing vitamin A deficiency in the world. The group offers consultation and guidance to various operating and donor agencies that are seeking to reduce vitamin A deficiency and its accompanying blindness.” More than 20 monographs have been published and these are distributed free of charge in developing countries. Guidelines and recommendations have been prepared on a number of topics. The IVACG has a Secretariat staff of six, with which Laurie Lindsay Aomari, has been associated for a number of years. The IVACG Chair has from the beginning been from a UN agency. Edouard DeMaeyer of WHO was succeeded by Lester (Les) J. Teply of UNICEF and more recently the incumbent has been Abraham Horwitz, emeritus Director of PAHO. IVACG has a ten-member Steering Committee, currently chaired by Alfred Sommer.

Front page of the Cairo meeting 1997 report

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The IVACG group that met in our home in Edinburgh in May 1979 to write their monograph on clinical signs of vitamin A deficiency. The final title was:“The Symptoms and Signs of Vitamin A Deficiency and their Relationship to Applied Nutrition”. From left to right: A. Sommer; E. M. DeMaeyer; J. ten Doesschate; E. J. Ballintine; D. S. McLaren; O. McLaren; V. Beyda; J. McKigney; G. Venkataswamy; Mrs P. Hodges; R. Hodges; C. Chichester. Also member of the group but not on the picture was R. Pararajasegaram.

IVACG has no formal permanent membership as such. As the need may arise, experts are co-opted for certain tasks, such as preparation of monographs or delivery of addresses at meetings. The most highprofile activity of IVACG has been the meetings which it has held at approximately yearly intervals. With the exception of two meetings held at WHO headquarters in Geneva (and the inaugural meet-

104

ing at UNICEF, New York), these have all been held in developing coutries where VADD have been identified to be a public health problem. This has undoubtedly served to give great encouragement to the people of that particular country and those in the region who have been working in this field. Local personnel have been able to attend in considerable numbers, especially on the first day, the pro-

ceedings of which in recent years have been devoted to reports from the host country. The latest IVACG Meeting (no. XIX) was held in March 1999 in Durban, Republic of South Africa. From only 22 members at the first scientific meeting held in Port-au-Prince, Haiti, in March 1976 there has been steady growth in the number of those attending to more than 500. This growth certainly reflects the enormous increase in the interest worldwide in the problem of VADD. This is especially gratifying to those of us who have been involved for many

years. However, it does necessarily bring with it the challenge of trying to make successful the outcomes of such large meetings. Presentations tend to be too short and too formal, discussion time is often curtailed, and resolutions and recommendations for future action are difficult to achieve in a democratic way. IVACG will enter on its Silver Jubilee year with the new millennium and many will be looking to it for continuing leadership and guidance as they have received from it in the past.

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Return to Edinburgh (1976–1988) The civil war in Lebanon is usually dated from Easter 1975 when a bus load of Palestinian militia was massacred by Maronite Christians in Ain-el-Romaneh, a suburb of Beirut where I had our ten-bed Pediatric Metabolic Research Unit at the Solarium du Liban. However, ever since the 5-day-war between Egypt, Jordan and Syria and Israel in May 1967 trouble had been building up with the rise of Palestinian resistance, arming of refugee camps in Lebanon, and the alliance of these with the Lebanese left. Olga and I were on our own. Gavin had completed his Masters degree in history and was in the UK. Jill was in the middle of her nursing training in Brighton, UK. My research was concentrating on field studies of growth failure in children in different parts of Lebanon. All this became impossible to continue. After over a year of living under siege, with sniping from rooftops, shelling from the hills and what amounted to the first occurrence of modern urban guerilla warfare, we came home for Christmas in 1975. Our party was hijacked briefly by militia on the airport road. Through my contact with Reg Passmore in Edinburgh it was arranged for me to join him in the Department of Physiology. In Beirut the seaport was destroyed and the airport closed for long periods. Even so, Olga managed to return there in March, as everything we had was still there. Many of the AUB staff had fled abroad. By a fortunate turn of circumstances I was able to join Olga in April. I paid a visit to the United States earlier in the year, to write a monograph for IVACG in Washington D.C. with Al Sommer and Jim Olson (184). Later in New York I had been able to persuade the authorities in the New York office of AUB that those of us who were over the age of 55 and had considerable length of service should be allowed to retire and receive our pension fund proceeds. 106

As I got dressed in my New York hotel room one morning I turned on the radio and heard the news that two of my friends and colleagues at AUB, Bob Najemi, the Dean of Students, and Ray Ghusan, the Dean of Engineering, had been shot dead by an Arab student on the campus. Several years later during the hostage taking, a number of our colleagues and friends were among those kidnapped and Malcolm Kerr, the son of Stanley Kerr, the professor of Biochemistry and my neighbour at AUB, was gunned down on the campus a few months after he had been appointed President of the AUB. I had been invited to attend a meeting from 29 March to 1 April 1976 in Baghdad. The WHO Interregional Meeting on the Prevention of Blindness was timed to precede the World Health Day whose theme for that year was “Foresight prevents blindness”. When I saw the literature issued to mark this day I was astonished to find that there was not a single mention of xerophthalmia. When I pointed this out to WHO I was told that a professor of ophthalmology in Geneva was responsible for writing the piece. I remember being in Geneva and getting an appointment with him. I explained what a missed opportunity this was. He clearly did not see the importance of my criticism and just made the excuse of not being familiar with the global situation. The following year it so happened that the theme on Child Malnutrition was similarly featured for World Health Day, and again xerophthalmia hardly had a look in. We have noted previously the neglect suffered by xerophthalmia (page 52). Xerophthalmia lies on the indistinct borderland between nutrition and ophthalmology and is neglected from both sides. Once the

Panel 17

Four uneasy bedfellows: A statement presented and circulated at the WHO Interregional Meeting on the Prevention of Blindness in Baghdad, 29 March to 1 April 1976. TRACHOMA

ONCHOCERCIASIS CATARACT

XEROPHTHALMIA

NATURE

Eye infection

Systemic infestation

Metabolic

Vitamin deficiency

PATHOGENS

Flies, Hygiene

Fly

?

Diet

ROLE OF THE EYE

Eye only

General: eye most important

Eye only

General: eye most important

AGE

Mainly adult

Mainly adult

Old age

Very young

Foci in Africa, S. America

Worldwide

Asia, foci in Africa, South America

GLOBAL Drier subOCCURRENCE and tropics

KEY SPECIALIST

Public Entomologist Health Ophthalmologist

Clinical Paediatrician Ophthalmologist

CONCLUSION: These diseases have little in common besides their target organ. There is no more reason for linking them for action programmes than there is for linking such diseases as bronchogenic carcinoma, pulmonary tuberculosis, emphysema, and pneumonia, just because they all affect the lung. Four uneasy bedfellows came to Baghdad Xero, Oncho, Trachoma and Cataract They proved incompatible – too bad All they had in common was to blind Good for jerking tears and raising money For prevention planning, no way to find.

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Return to Edinburgh role of vitamin A in child survival came to prominence in the 1980s, matters in this regard tended to improve. However, even now, especially among the medical fraternity, there is an astonishing degree of ignorance and indifference (Panel 14).

ing there were escorted to the airport by armed guard as hijacking of goods as well as people was commonplace. Everything reached Edinburgh airport safely a day after we did, except for a broken vase and glass in a picture!

At the meeting in Baghdad (185) Sir John Wilson, as President of the International Agency for the Prevention of Blindness, gave the introductory address. In this he identified what he called the “four giants” – blinding infection including trachoma, blinding filaria (onchocerciasis), cataract, and blinding malnutrition (xerophthalmia). Three were preventable and cataract could be cured by surgery. The term “avoidable” encompassed them all.

The Edinburgh University accountant had never seen such a large bill for the transfer of the effects of a new member of staff, but once the circumstances had been explained he did not demur.

This was the first meeting I had been to at which blindness as an entity had been presented. [Years later at a similar meeting (186) held at the Institute of Ophthalmology in London my feelings in Baghdad were to be repeated]. As the meeting progressed I became increasingly uneasy about the concept of making a unified attack on the problem of blindness worldwide. By the last day I had crystallised my thoughts and I prepared a statement under the heading “Four Uneasy Bedfellows” which I had reproduced and circulated to the delegates (Panel 17).

It proved very difficult for both of us to try to make a new life in our mid fifties. Beirut in its good days had seen the happiest period in our family life, as well as provided for me a unique opportunity to carry out research on childhood malnutrition problems. Almost all expatriate staff of AUB and other organisations in Lebanon left the country about the time when we did. Many Lebanese colleagues went abroad too, to work elsewhere in the Middle East or in the United States. My department depended largely on research funding from abroad and this soon ceased. Colleagues and friends with whom one had worked for ten years or more left at just a day’s notice in the prevailing danger and uncertainty.

The very poor standard of composition might be forgiven in the circumstances. The message, at least, is quite clear. I think it came as too much of a shock for most of the delegates. The fighting in Lebanon was intense while the meeting was going on in Baghdad. I had my ear to the radio for the latest news on the BBC World Service even during the presentations! The day I was booked to go to Beirut things quietened down and as we flew over the city before landing, everywhere was deserted. Within a few days Olga and I were able to settle our affairs. I even managed to sell my car and not to have it stolen from me on the road as was usual. The 53 packing cases with our belongings after 14 years liv108

Walter Read and his wife Marie Tchalian working on the mass spectrometer in our labs in Beirut.

SIGHT AND LIFE Walter Read, who had been my chief technician in the laboratory and whom I had brought with me from the institute in Mwanza, went home to England and joined the MRC Clinical Research Centre in north London. He had his name on more than 30 research papers from our department over the years.

Zuheyr Audeh, who had been my first appointment locally, had come from UNRWA. He did his Master of Science with us and then went to the National Institute for Medical Research in London, where I had been, for his PhD. Zuheyr is now an eminent immunologist with Harvard, and I have visited him several times. Abdullah Kanawati, a medical graduate from Damascus, worked closely with me in the field studies, and the last I heard of him is that he is with one of his sons in Saudi Arabia. All of these, and many others, made vital contributions to what I was able to achieve in the field of VADD while in Beirut.

Zuheyr using the technique of isoelectric focussing, which he developed in our labs.

In Edinburgh things did not work out well in Physiology and in 1980 I transferred to the Department of Medicine in the Royal Infirmary (following in the footsteps of Cullen and Davidson), where I remained very happily until retirement in 1988. I had ample opportunity for international work, was representative of the Scottish Office on the influential government Food Advisory Committee for many years, and I published a number of papers and several books. My big disappointment was that despite the influence in the past of Davidson and Passmore I was never able to establish a programme of clinical nutrition as I had done in Beirut. My position was isolated and therefore lacked authority. However, I was able to influence the course of medical education in some ways because of my unique experience which had been in developing and developed countries, in the British and the American systems, and in both preclinical and clinical departments (187).

Dr Kanawati with one of the recovering malnourished infants in our Unit at Christmas time.

By 1980 a number of surveys on the prevalence of VAD had been carried out, following the guidelines laid down in the WHO report of 1976 (130). This had been widely circulated and its recommendations were beginning to be implemented. Most importantly, the first nationwide survey had been carried out in Indonesia under Al Sommer’s direction (Chapter 3).

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Return to Edinburgh

The participants of the WHO Task Force on the Programme of “Research on Control of Vitamin A Deficiency and Xerophthalmia”, Manila, 22–24 November 1979, (left to right ) D. S. McLaren, R. Florentino, N. V. K. Nair, R. Pararajasegaram, A. Sommer, B. A. Underwood, G. Arroyave, E. M. DeMaeyer, D. Karyadi, A. Pradilla.

WHO, UNICEF, HKI, and IVACG jointly sponsored a second technical meeting in October 1980 (see page 111). Again it was in Jakarta, and again I was rapporteur. This meeting was followed by the Third Asian Nutrition Congress which I also attended. An intervening free weekend allowed me to pay a long-delayed visit to Bali (see page 53). I stayed with 110

Gordon Sweatman, a former biologist colleague from AUB, who was doing an assignment for FAO there. There was no obvious evidence of a VAD problem on the island. This was probably due to a relatively low population density, highly structured society and income from increasing tourism. I learned that Jelantic had become chief, but unfortunately he was out of the country at the time.

SIGHT AND LIFE

The Joint WHO/UNICEF/HKI/IVACG meeting on “Control of Vitamin A Deficiency and Xerophthalmia” held in Jakarta, Indonesia, 13–17 October 1980. The second WHO report (147) made relatively minor revisions to the classification and the criteria that had been set in 1976. It was, however, able to provide much more evidence on the worldwide prevalence of VAD and the results of a number of intervention programmes. My last involvement with the production of a report for WHO was with the 1988 report on Vitamin A supplements (188). A second edition was issued in 1997 (170). Most academics manage to take at least one full sabbatical year during their careers. Over the years I had enjoyed several periods of home leave from abroad but have never taken the full year off. The nearest I came to it was in early 1982 when I spent about three months in California at The City of Hope

National Medical Center near Los Angeles. Michael Meguid, a surgeon interested in nutritional support of the hospitalised patient, invited me there with a possible view to joining him on a long-term basis. The clinical and research facilities were excellent, but in the end I felt I was too old to make such a radical move. I had the opportunity there to carry out a piece of research in the vitamin A and carotenoid field (189). At that time the interest in the possible antioxidant effect of carotenoids in cancer and other chronic diseases was just beginning. We submitted a large grant proposal in this area but were unsuccessful – all proposals submitted were turned down. My work would have concerned the activity of non-provitamin A carotenoids, such as lycopene and lutein, not previously investigated. Much research is now going on on this. 111

Return to Edinburgh

Dr Gopa Kothari on my first visit to Dharavi in Mumbai.

Aerial view of part of Dharavi slum in Mumbai.

Michael shortly afterwards moved to the medical centre at Syracuse in upstate New York. In addition to his busy life in general surgery Michael founded and is editor-in-chief of the journal Nutrition. I have been editor of a classics section for some years, and a number of these articles have been in the VAD field. In 1986 my paper on keratomalacia in Orissa was included as a classic, and I was asked to write an overview (190).

ventive Medicine at one of the medical schools in the city. She was carrying out a very effective programme with the support of Sight Savers to combat VADD in Dharavi. This was known as “the largest slum in Asia”, with over 700,000 people living in about one square mile at that time. Over subsequent years we have collaborated in several studies (191, 192), and Gopa has extended her primary healthcare work to other slum areas. She has participated in the teaching at ICEH for a number of years now.

In 1984 an academic link funded by the British Council was established with Dr Sumati Mudambi at SVT College of Home Science in Mumbai (Bombay). There was exchange of staff in both directions over several years. In this way I got to know Dr Gopa Kothari, who was then Professor of Social and Pre112

In 1987 I was invited by Professor Gordon Johnson, head of the Department of Preventive Ophthalmology at the Institute of Ophthalmology in London, attached to Moorfields Eye Hospital, to lecture on nutritional blindness on the course there.

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Retirement in Worthing (1988) We moved to the seaside south of London in June. From October 1988 I again took up the link with ICEH. I worked two days each week at ICEH to develop the component of the programme on nutritional blindness for several years. More recently my participation has been less, but I am still “Honorary Head, Nutritional Blindness Prevention Programme”. I still lecture to students, who are mostly ophthalmologists and ophthalmic nurses from developing countries. I also tutor those who have their MSc thesis work in the area of VADD. Early on I helped to obtain financial support for students from suitable countries from SIGHT AND LIFE, and this has continued to the present. My experience at ICEH exposed me to the dilemma I had faced previously (see page 108) over the rationale underlying prevention of blindness pro-

grammes. A discussion paper I circulated there among my colleagues was politely received, but I sensed that as they were inevitably “part of the system” they could hardly be expected to be enthusiastic. In 1991 the British Medical Journal published an editorial (193) on avoidable blindness from an ophthalmologist working in Africa. It went over the old ground, urging the need for greater awareness and increased resources and personnel to deal with the growing problem of blindness. My response was printed shortly afterwards (194). I suggested that a change of concept was required. I criticised the lumping together for preventive purposes of widely disparate diseases. I pointed out that the misconception was deeply entrenched in international, national, WHO, and NGO (Non-Governmental Organisation) programmes of prevention of blindness worldwide.

Two of the ICEH students from Viet Nam and Zambia in our home. 113

Retirement in Worthing What they have to do if they are to achieve their objectives is to promote total primary healthcare and stop dealing with the eyes in isolation – as Oomen used to say, “as if the eyes were on a silver platter”. In 1994 Karl Kupfer, Director of the National Eye Institute at NIH, whom I knew well through our attendance at many IVACG Meetings, wrote an editorial (195). He strongly supported the traditional approach to blindness prevention. My response (196) and his reply (197) appeared together in February 1995. I thus had opportunities to address those interested through journals on both sides of the Atlantic.

Gavin and family recently (in a friend’s garden). 114

Dr Kupfer agreed that most of the nonclinical community eye care could and should be integrated into the primary healthcare system. On the positive side I do value the support that this concept has received from Gordon Johnson in contributions he has made to a book (198) and at a recent meeting (199). As I see it, most of the preventable blindness in the world could be prevented without an ophthalmologist or ophthalmic nurse within sight! Improved personal hygiene will greatly reduce trachoma (200), adequate diet will banish VADD, onchocerciasis is controlled by a yearly ivermectin

SIGHT AND LIFE

Jill was working for Save the Children Fund in Malawi when we visited her in 1992. At present she is working with Kosovar refugees in Macedonia.

tablet or getting rid of the Simulium fly. Cataract cannot be prevented until we know the cause(s) – much more research should be devoted to this number one cause of blindness in every country. In 1999 I remain in touch with the latest developments in the field of VADD, although not engaged anymore in original research. Postgraduate teaching, editing the Xerophthalmia Club Bulletin, attending scientific meetings continue. The SIGHT AND LIFE manual (2) and the Slide set on VADD are continuing to be distributed widely, without charge, and should be helping to make a significant contribution towards the control of the problem. These may both be taken to a second edition soon.

I have written the section on VADD in The Wellcome History of Tropical Diseases (201). The first book on The Epidemiology of Eye Disease was published early in 1998; it was edited by Gordon Johnson and two colleagues. I contributed the chapter on VADD (202). We have as our immediate family our son Gavin, his wife Hazel and their children Hannah, aged 12, and Alistair, aged 9. This young man is the fifth generation of single male members of the clan to carry on the family name! Our daughter Jill could write an odyssey of her own. She has served as a primary healthcare aid worker for the last twenty years with many organisations, mostly in Africa and Asia.

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Retirement in Worthing As I have been writing this and looking back over a career dominated by VADD I have been pondering on the way in which diseases wax and wane in importance. In Chapter 1 it was pointed out how in the early part of the vitamin era xerophthalmia was almost completely neglected (Panel 4). Scurvy, beriberi, pellagra and rickets were repeatedly grouped together as the then known dietary deficiency diseases. I have tried to describe in these pages how xerophthalmia rose from obscurity and neglect to reach a position of worldwide public health significance. At the same time I think it is of considerable interest and probably importance for the future, to note what was happening to the “big four” nutritional deficiency diseases of an earlier era. In a word, none of these diseases has anywhere reached public health significance in the sense that is used concerning VADD during the years we have

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been concerned with it. Beriberi epidemics, such as those studied by Eijkman in Indonesia, have not recurred. Nor have those of pellagra, for example in the southern United States in the inter-war years when Henry Sebrell assisted Joseph Goldberger in his classic studies that finally proved the disease’s dietary deficiency origin. Sporadic scurvy affects only a few vulnerable infants or elderly, and primary rickets is largely confined to members of some ethnic minorities or to those who from custom or location are rarely exposed to sunlight. My own long experience falls into just that pattern. I have encountered only a handful of patients with beriberi, secondary to alcoholism, only two with pellagra, three with scurvy and several with rickets. However, who is to say that circumstances may not change in the future such that any one or all of these now largely forgotten diseases may once again pose a serious threat to human health?

SIGHT AND LIFE

Chapter 3

Update and commentary The purpose of this section is to bridge the gap between approximately 1980 and the present; a period of almost two decades. Although I have been in touch with the developments in the field during this time, I have not been involved, except peripherally, in making original contributions. It is not my intention here to try to include in detail all of the significant contributions in the field that have been made during this period. I hope I do not make the mistake of omitting any major contribution, but for the definitive account I would draw attention again to Sommer and West (2). For a shorter and simplified account the SIGHT AND LIFE manual is available (1). It so happens that around about 1980 there is a natural watershed in the field of VADD research. Several factors coincided at that time in a way that seems to me to be a good example of the well-known quotation from Shakespeare’s Julius Caesar: “There is a tide in the affairs of men, which, taken at the flood, leads on to fortune.” First of all, medical epidemiology may be said to have come of age at about that time, and as a result well-controlled field studies date from about then. Biostatistics was developing, and strict application of statistical requirements meant that statistical analysis could be applied to the results. The pioneering field studies in VAD in Indonesia of Sommer and his colleagues (203) were probably also among the first of their kind in community nutrition as a whole. Massive funding began to be made available, almost all of it government money in the United States. The formation and funding of IVACG in the mid 1970s played a key role in paving the way for this support.

Without it such large, expensive studies could not have been carried out. In the field of vitamin A deficiency and xerophthalmia Alfred Sommer had what at that time was a unique combination of qualifications and training in ophthalmology and epidemiology. He was thus fully competent in what might be called the old approach, but equally able to lead research into the new era. As a result of the work in Indonesia and other field studies the emphasis in VAD soon shifted away from xerophthalmia and the eye and back to mortality and morbidity. I say “back” because decades earlier the association between VAD and infectious disease had been very strong for a period (Chapter 1, Panel 5) before blindness took centre stage. Our study of xerophthalmia in Jordan (141) in the mid 1960s (see page 82), in which we showed a fourfold increase in mortality if children with severe PEM also had xerophthalmia, and work of ten Doesschate (101) in Surabaya, Indonesia, that showed a very high mortality up to one year after discharge (see page 54) were isolated hospital studies. Neither the methodology nor the funding for massive field prevalence surveys or intervention trials were available at that time. The nationwide study of Sommer and colleagues in Indonesia (203) gave accurate prevalence figures for the first time for an entire country. These were also used to update the rough estimate of global prevalence of xerophthalmia (139). In addition, some outstanding questions were answered about the ocular lesions, such as development of a simple tool for assessing night blindness (204); the complex nature of Bitot’s spots (205); early corneal xerosis (206); and xerophthalmic fundus changes (207). 117

Update and commentary Perhaps of greatest significance for the first time at the field level was that these studies showed the increase in mortality risk that accompanies night blindness and/or Bitot’s spots (208) and went on to report increased rates of diarrhoeal disease (209) and respiratory infections (210) in these same subjects. The next logical step was a vitamin A intervention, the first of its kind also, and which demonstrated to most people’s satisfaction a significant reduction of mortality risk in the treated group, despite some shortcomings in the study design (211). Over several years the group at Hopkins and others carried out similar trials elsewhere in Asia and in Africa. A meta-analysis of eight such studies showed an overall reduction in mortality of 23%, although those in Hyderabad, India, and in Sudan failed to show a significant improvement (212). The precise mechanisms of this dramatic effect have not been fully elucidated. Cell-mediated immunity appears to be impaired (213) but this seems to be far from the whole story (214). Morbidity studies have tended not to produce clear-cut results, unlike those on mortality. In general diarrhoeal diseases respond to vitamin A by a reduction in severity. Acute lower respiratory tract infection (ALRI) tends not to respond to vitamin A (2). On the other hand, studies of very clearly defined infectious diseases such as measles (215) and HIV (216) provide clear evidence of improvement in various ways with vitamin A. To me this is consistent with what one might instinctively expect. The groups of diarrhoeal and respiratory infections are much less well defined. Their symptomatology does not constitute a clear-cut syndrome as do measles and HIV. They have a very mixed aetiology and microbiological tests do not form part of the field studies undertaken so far. Degree of infection and severity of disease probably influence the outcome but are difficult to assess. A recent review has called for such objections to be 118

taken account of in the design of studies in future (217). In 1987 WHO and UNICEF recommended that vitamin A be given to all children with measles in parts of the world where VAD is a recognised problem (218). There is evidence that corneal scarring associated with VAD and measles has been greatly reduced after successful immunisation against measles in the WHO Extended Programme of Immunisation (EPI) (219). Studies have demonstrated the advantage of combining vitamin A dosing with EPI, and this has been recommended by WHO (220). Although there is good evidence of benefit to vitamin A-deficient patients who are HIV positive, especially in the case of women to their offspring, no UN recommendation has been issued on the subject to date. Recent work suggests that there may be some disparity over results reported (221). Considerable advances have been made in the area of methods of assessment of vitamin A status. Along with the passing of the “xerophthalmia era”, in which attention was focussed on the definition and use of the eye signs in the assessment of clinical vitamin A deficiency, there have subsequently been efforts to develop indicators at the subclinical level (222). RDR (175) and MRDR (223) are being used mainly in research studies and more recently isotope dilution (224) has been introduced. However, because of the dangers of transmission of hepatitis, HIV and other infectious diseases by blood these are unlikely to be used on a large scale. They also require sophisticated technology. Breast milk retinol has been introduced as an indicator of vitamin A status fairly recently (222). There are still technologic difficulties to be overcome, but the test is non-invasive and looks promising. Conjunctival impression cytology received enthusiastic support when it was introduced for the detection of VAD at a preclinical stage (225). The early promise has been sustained to a considerable extent

SIGHT AND LIFE and various modifications have tended to produce similar results (226). There are difficulties over reproducibility, especially in marginal cases, and eye infections may interfere (227). The tissue may be readily obtained by experienced workers and the technique is not invasive. The results have tended to correlate well with those of other types of test. Other eye tests for use under field conditions are being developed (e.g. the vision restoration test) (228). In my view there must be some cause for doubt as to whether there is now any need for further development of field tests. Although the signs of xerophthalmia in pre-school age children exceed the criteria for a public health problem in a relatively small proportion of low socio-economic communities it is evident that subclinical deficiency is widespread. General evidence of community disadvantage is virtually a sine qua non for undernutrition, of which subclinical VAD is an integral part. It is estimated that something like half of the pre-school age children in developing countries are subclinically vitamin A-deficient (229). In terms of prophylactic intervention at the community level, all would seem to need it. It has been believed for many years that vitamin A plays some part in haemopoiesis. Recently the subject has received renewed attention (2). The mechanism is still not understood. In communities where subclinical deficiency of both vitamin A and iron are common, and there are many of these, there is a good case for intervention programmes to take account of both nutrients. Added vitamin A or β-carotene may enhance absorption of non-haem iron (230). The effect of VAD on growth is another area that lends support to the concept introduced in the SIGHT AND LIFE manual (1) of the comprehensive term “Vitamin A Deficiency Disorders (VADD)”. Many factors, including a variety of nutrient deficiencies and infections, can adversely affect growth. This makes such a role for a single nutrient like vitamin A very difficult to prove. A few studies, but not all, suggest there is such an effect (2).

In recent years the phenomenon known as the acutephase response (APR) occurring in serious infections and trauma has been investigated. As part of this response the concentration of some nutrients in the plasma, including retinol, falls dramatically (231). It is thought that this results from a combination of factors. These include transient reduction in production in the liver, loss of holo-retinol-binding protein in urine, movement into extra-cellular fluid, and increased uptake by certain tissues (232). This clearly creates difficulty in the interpretation of serum levels of retinol while APR is operating. Recently Rosales (233) has proposed the use of the molar ratio of retinol-binding protein (RBP) to transthyretin (TTR) to overcome this problem. Alvarez and colleagues (234) have provided evidence that during severe infections large amounts of vitamin A may be lost in the urine. This could be a significant cause of VAD under these circumstances that has not been sufficiently considered previously. It might also be at least partly responsible for the marked fall in serum vitamin A noted in APR. Confirmatory evidence from elsewhere would be important. Recently the effects of intervention with retinol/ β-carotene on the morbidity and mortality of women in pregnancy have been studied in Nepal. Weekly doses of 7000 µg RE during pregnancy showed significant reduction in mortality (235). This work opens up the prospect of a whole new area of vitamin A/ β-carotene intervention in relation to maternal mortality from all causes and morbidity. Maternal mortality exceeds 500,000 deaths annually, almost all in developing countries. Experimental studies for a number of years have demonstrated an interrelationship between zinc and vitamin A (236). Deficiency of these two nutrients as well as of others, including protein and energy sources, are likely to occur together. A series of recent studies (237) suggests that effects similar to those found with vitamin A may also occur in undernour119

Update and commentary ished subjects with zinc supplementation. At the same time it has been found that underweight in children, presumed to result from deficiency in protein and energy, is associated with increased risk of mortality. The majority of deaths attributable to underweight are associated with milder degrees of underweight, rather than with severe underweight (238). This is because the milder forms are so much more common. The same is true of subclinical versus clinical VAD. At present it is not at all clear what the relative contributions of different nutrients in these circumstances may be. In recent years WHO has taken over the task of documenting and updating the global prevalence of VAD (113). Although there are gaps in the statistics and also some defects this record is vital if the achievement of goals is to be monitored. There is no doubt that the increasing appreciation of the widespread occurrence of subclinical VAD and its importance in child survival has led to surveys of vitamin A status being carried out in many countries from which previously there were no data.

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The bioavailability of β-carotene and other provitamin carotenoids has been the subject of intensive research recently (239, 240). Many factors in food and in the body influence the availability of these carotenoids. The evidence at present suggests that the factors traditionally used to obtain REs have overestimated, sometimes considerably, the potency of carotenoids. In the area of control of VAD the four traditional types of intervention have been continued and extended. Supplementation using periodic large doses of vitamin A has been in place, with usually diminishing effect, in many countries over long periods. There has sometimes been reluctance to replace it by longerterm measures, such as fortification or dietary modification. Vitamin A fortification of food is undergoing renewed interest, and combinations of nutrients are being employed in some cases. It is being recognised that advice on dietary modification may need to place some emphasis on the need for some animal sources of vitamin A if provitamin bioavailability is less than previously thought.

SIGHT AND LIFE

Chapter 4

Looking to the future Introduction I would like to make it plain at the outset that the views expressed here are entirely personal. They are based on my own experiences and my reading of passed experience of others. It is a sad commentary on human nature that “history teaches us that history teaches us nothing”. We should be aware of this common failing and try to exercise the humility and insight that will help us to learn from the mistakes made in the past. I would suggest that we have no cause for complacency as we take both backward and forward glances from our present position. In a few years’ time it may be that we will be celebrating the centenary of the discovery of vitamins in general and vitamin A in particular (see Chapter 1). We may well ask the question as to why it is that, despite the fact that we have had available the cure for VADD for all those years, the disease continues to take a heavy toll of death, blindness and ill health around the world. I suggest that at least part of the answer may lie in our unwillingness to learn from the past. In addition, I would suggest that the present time, which happens to be at the close of the second millennium, is a time of peculiar uncertainty. A number of things are conspiring to make it so. The present total human population of about 6 billion is far larger than has ever previously been seen. Although the rate of population growth is beginning to slow down for the first time in decades the total number will continue to grow until well into the next century.

are being used up at an increasingly greater rate. This is only partly due to the greater number of humans to feed, clothe and shelter. In addition, there is gross overconsumption on the part of the well-off minority. A combination of these factors – in some communities in particularly acute form – is resulting in what has been called demographic entrapment of some communities (241). All of this has been going on for quite some time and institutions like the Worldwatch Institute in Washington D.C. have been calling attention to the threat of dire effects for years. Of more recent occurrence, dating rather precisely from July 1997 when the currency crisis hit Thailand, bush fires of financial disaster have spread around the world and no one appears to feel entirely safe. When all of this bad news is put together it is difficult not to be pessimistic if one is also to be realistic. I do not think it is right for those of us involved in the control of VADD to turn our backs on these ethical issues and say that we should leave them to others as they are not our concern. In vitamin A supplementation we have one of the most cost-effective of all health interventions (242). If fully implemented, millions of lives each year would be saved (243). Is it ethical to continue to implement vitamin A or even multi-nutrient measures without taking into account also the impact they are having on these other demographic considerations? I would now like to turn from these rather general remarks to make some observations about VADD in particular.

This has to be set alongside the even more disturbing fact that the world’s natural resources of all kinds

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Looking to the future

Problems with xerophthalmia

No magic bullet for intervention

Sommer and West (2) at the beginning of their chapter on xerophthalmia and keratomalacia point out four ways in which concentration on xerophthalmia has had a retarding effect on efforts to control the problem. Briefly stated these are: 1) Its relative infrequency in any population as a whole has been wrongly interpreted as suggesting that VAD at a lesser level does not constitute a significant health problem. 2) Frequent association of corneal xerophthalmia with severe general malnutrition (PEM) has tended to mask the underlying effects of VAD on the rest of the body. 3) High mortality in xerophthalmia has in effect “removed” the problem from attention because of the few survivors. And 4) the dramatic eye lesions have drawn clinical and research attention away from the more prevalent, and less dramatic, systemic consequences of VAD.

There are four main types of intervention for VADD • Supplementation • Fortification • Diet modification • Infection control

I fully agree with all of these points and would only observe here that they are likely to continue to make it more difficult to mobilise efforts to control VADD. I would point out an additional factor that acts in a rather similar way. Blindness has always had a greater emotive influence over the public than other disabilities. Furthermore, the picture of a young child blinded for life through lack of a few basic items of food is among the most moving. The same can be said, in reverse, for the prospect of saving a child’s eyesight with a few US cents’ worth of vitamin A. I have argued (Chapter 2, page 108) that considering the problem as part of primary eye care is not defensible from a conceptual point of view. Here I want to point out that because this is so often the popular approach, it has resulted in a great deal of well-motivated effort that might not otherwise have occurred. VADD looked at in the way Sommer and West are suggesting, and with which, as I said, I entirely agree conceptually, will not have the advantage of this emotive element.

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We used to think that the vast majority of even the poorest people in developing countries managed to avoid VAD. They certainly avoid xerophthalmia, but now we know that this is not the same as avoiding VAD and, moreover, they only need to be subclinically deficient to have a significantly increased risk of disease and death. This changes the whole picture, for it means that perhaps about half of the young children in developing countries have that degree of VAD and run that risk (113). There are also other high-risk groups, such as pregnant and lactating women and school age children. So the task of ensuring an adequate vitamin A intake throughout life becomes that much more difficult to achieve in the future. It is not necessary here to go over in detail why none of the interventions is ideal. These matters have been fully considered in Sommer and West (2) and in lesser detail in the SIGHT AND LIFE manual (1) and elsewhere. Suffice it to say… • Supplementation is really an emergency measure; it does nothing to eradicate the problem, and it has repeatedly proved to be incapable of maintenance at a high level of uptake in routine practice. • Fortification is difficult to initiate and implement and may be costly. Often the vehicle for fortification is not a desirable food item in itself, such as sugar or MSG. However, it does not have to rely on the cooperation of the public for its implementation. Once fortification is established it can bring about a lasting improvement in vitamin A intake of all groups.

SIGHT AND LIFE • Dietary modification requires full cooperation from the public, may not be applicable to the poorest and is difficult to sustain. Increased consumption of dark green leaves and yellow fruits is the usual modification recommended. Serious doubts are now being raised about the much lower bioavailability of carotenoids than we used to think (page 120). On the positive side, however, it brings with it benefits such as income generation and increased intake of other nutrients and fibre. • Infection control. There is no doubt that the synergistic effect of VAD and infections works in both directions often. Ideally vitamin A interventions and measures to control infectious disease, such as immunisation, should go hand in hand. Even when this is not possible, a really effective measure, such as measles immunisation, has been shown to reduce greatly the prevalence of corneal scarring in children.

No gold standard for assessment This statement is generally accepted to be true, and it applies not only to vitamin A status but also to nutritional status in general. This is because existing indices are surrogates for a more basic expression of status. It is bound to be so because nutritional status is a broad concept, incapable of precise definition. In this respect nutritional deficiency is unlike infectious disease, in which not only will a typical clinical syndrome usually be present, but with suitable laboratory facilities it will be possible to isolate, identify and quantitate the causative organism. Nothing so precise is possible in nutrition. Sommer and West (2) in their book have described and discussed the problems associated with each exisiting index of vitamin A status, a subject to which they have made significant original contributions. The group responsible for the WHO document Indicators for assessing vitamin A deficiency and their

application in monitoring and evaluating intervention programmes (222) produced a document which, in my opinion, has a number of weaknesses. As it is being put to the test of practical use in the field it may not prove to be much of a step forward in this difficult field. This is not the place to do more than draw attention to the existence of the problem and the need to continue active research to develop better indicators at the subclinical level of deficiency and perhaps refine those available at present (244). To end this comment on a more optimistic note, it has to be acknowledged that more progress in assessment of nutritional status has been made in the field of vitamin A than for any other nutrient.

Unanswered questions • It has always puzzled me why, in the generally malnourished child (with PEM), clinical evidence of VAD is the most common associated deficiency. When extensive biochemical tests have been carried out levels of almost all nutrients have been found to be subnormal, but apart from vitamin A these have not been accompanied by clinical signs. Vitamin A after all is one of the few nutrients of which the body normally has considerable stores. We know that liver levels of vitamin A are quite low at birth in health and normally increase 60fold during the first 6 months of life. The stress of growth and infectious disease tend to deplete these stores. Furthermore, milk, breast or cow’s milk, normally contains no more vitamin A than serum. We do not fully understand why in a certain community only a few children become clinically deficient. Of course it must not be forgotten that even subclinical deficiency may have serious consequences.

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Looking to the future •

A related question is, “why does the age of peak incidence vary between different places so much?” I am referring to evidence of xerophthalmia, non-corneal and corneal. In my own experience this was particularly evident in the 1960s between our work in Jordan and reports from India. Most of our patients with keratomalacia were infants, many only a few months old. In India and in Indonesia the peak age was more like 2–4 years. Our study from Jordan was met with some surprise in this regard. Many years later another hospital study from Brasil (245) also had most patients young infants.

•

Finally, I do not believe it has ever been explained why in areas where severe PEM is common, accompanying xerophthalmia might be either virtually absent or vary in incidence all the way up to 75% or so, as it was in Indonesia in the 1950s. I used to suspect that the answer lay in the amount of carotene, small though it might be, provided by the respective diets. In particular I suspect that the carotene in the staple food is all-important; rice-dependent populations have always been especially vulnerable.

•

Another question along the same lines: How is it that in famine conditions, such as those all too familiar to us in southern Sudan at the present time, babies dying with extreme wasting show no evidence of xerophthalmia?

Xerophthalmia has by no means been eliminated and I think there is still a need for detailed hospital-based studies in suitable areas to try to provide answers to these and perhaps other outstanding questions of this nature.

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Unlearned lessons More thought and more research will hopefully bring progress in the areas I have outlined above, but how can one deal with those who, for whatever reason, fail to learn and profit from the lessons which have resulted from such dedicated efforts in the past? I do not know the answer – here are some examples which I have found particularly exasperating. •

The misuse of X1A, conjunctival xerosis. The WHO Technical Reports of both 1976 and 1982 (130, 147) gave the reasons why it was unanimously agreed that this sign could not be used in field studies. In essence the changes are highly subjective, cannot be quantified or determined as “present” or “absent” with any certainty in a study population. They are subject to large inter- and intra-observer error. Nevertheless, X1A is continually being reported, often in studies that state that they have been carried out according to the WHO guidelines! Very often “conjunctival xerosis” is by far the most reported sign of xerophthalmia and makes up a high proportion of the total signs. Consequently this “creates” a problem of xerophthalmia where in fact none exists.

•

X1B, Bitot’s spots. Most workers probably know that not all Bitot’s spots are indicators of active VAD. It is perhaps less well appreciated that those that can be related to active VAD are usually confined to pre-school age children. This is one reason why it is recommended that field surveys for VAD in children are confined to those aged 6 years and under. Frequently older children are also included and X1B rates in them are included in an analysis. Again this tends to create a problem or inflate it. However, it should not be forgotten that active Bitot’s spots may occur in older children when they are, of course, an indication for supplementation. Unfortunately, the only practical way to prove the point is by therapeutic test.

SIGHT AND LIFE •

The acute-phase response (APR) and serum retinol. During the 1960s I was fascinated by several reports, one at least from the 1930s, which showed that in acute infections vitamin A seemed to “disappear” from the blood. We also showed, as did Arroyave at about the same time, that serum albumin did the same sort of thing. The acute-phase response had not been invented then, but it did seem clear that this might cast some doubt on the validity of the use of serum retinol, and perhaps other nutrients in the circulation, as indices of nutritional status in the presence of infections, which most undernourished patients have. When this possibility was raised at meetings or in correspondence columns it met with open opposition. As might be expected, this came mainly from the proponents of these tests as 100% reliable indicators of vitamin A status! It is only in recent years when the mechanism has been better understood and its occurrence has been shown to be widespread that views have begun to change.

•

Sample size. This is a very simple general point. Besides meeting other statistical requirements a sample should be sufficiently large to satisfy these requirements. Many surveys of vitamin A status, including some of those considered in the report on worldwide prevalence by WHO (113), are quite inadequate in terms of numbers to be at all representative.

•

Absence of evidence is not evidence of absence. When studies have failed to show a significant effect of a vitamin A intervention it has often been concluded that “vitamin A does not improve growth, reduce morbidity etc.”. All that has been shown is that in the particular instance an absence of a difference between experimental and control groups has been shown. Other trials might just as readily show a significant difference, in which case it would be equally erroneous to say that these have

proved a particular effect to occur. Unfortunately, with such difficult and complex issues the combined results of a number of large, well-designed and well-executed trials are usually required before a consensus can be reached. •

Effectiveness of interventions. A vitamin A intervention, like any other public health measure, occurs in a certain place at a certain time, neither of which can be precisely duplicated elsewhere or at another time. Moreover, in precise detail no two interventions will be identical, however much effort is expended to try to make them so. By their very nature interventions of this kind often need to be implemented, and certainly to be observed, over long periods of time. All possible variables cannot be known at the start, nor can the way in which they may change over the course of the intervention be known either. Great caution should be exercised in coming to conclusions about cause and effect in these circumstances. It is doubtful if any specific public health measure can be as effective as general economic and social development in bringing about improvement in, for example, nutritional status. It might also be added that the reverse is probably equally true; economic collapse or rapid cultural change may be expected to bring about a rapid precipitation of malnutrition. Unfortunately the truth of these words will probably be tested in a number of countries in the near future. On a more optimistic, but speculative, note it is understood that genetic modification of rice is being undertaken in order that it might become a rich source of provitamin A carotenoids. If successful, this might make a major contribution to the control of VADD in many countries.

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Looking to the future

Questionable concepts Four uneasy bedfellows I described in some detail in Chapter 2 (see page 108) how more than twenty years ago I was forced to the conclusion that the prevailing concept, which regarded xerophthalmia merely as a blinding disease and to be prevented by primary eye care, was fundamentally flawed and a major factor in hampering efforts to promote control measures. This is a broader issue than just the nature of xerophthalmia. The concept applies equally to the other “bedfellows” and there may be other instances of illconceived concepts in other areas of medicine. At the present time blindness per se continues to be the focus of efforts at local, national and international level. Looking to the future there is little cause for optimism that a more rational, and I believe effective, approach will prevail. Micronutrient malnutrition In the 1990s this has become a popular concept with agencies and others concerned with nutrition interventions. It has usually been applied to vitamin A, iron, and iodine deficiency, but recently there is a tendency to include also deficiency of zinc and calcium and possibly other micronutrients. This concept seems to have arisen to fill the gap in nutrition policy left by the collapse of the “impending protein crisis” concept in the mid 1970s. For decades PEM had been acknowledged to be the most widespread and serious nutritional deficiency problem. I have told the story (151) of how protein deficiency came to be mistakenly blamed for most of the problem and how this led in the 1960s and 70s to the protein-rich food mixture solution and other similar misconceived attempts that constituted the “great protein fiasco”. Following upon this in the past two decades nothing much has been heard about controlling PEM. However, recently Ramalingaswami, Levinson, and Schuftan have expressed their con-

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cern about the overemphasis on micronutrient malnutrition and the neglect of PEM (246). This trio is greatly experienced in international child nutrition problems and they provide more evidence for the point I have been trying to make here. The micronutrient malnutrition concept seems at a superficial glance to have the attraction of requiring relatively simple measures for the solution of the problem. It is perhaps too early to say, but I have the feeling that this concept has flaws in it not dissimilar to those that are inherent in the “uneasy bedfellows” misconception. The three main micronutrient deficiencies, of vitamin A, iron, and iodine, do not share a common global distribution or vulnerable groups. There are efforts at present to fortify cereals with both iron and vitamin A, which certainly makes sense in view of the interrelationships between these nutrients. However, although fortification of foods has become common practice in industrialised countries, experience to date in developing countries has not been equally successful. Only time will tell whether or not the present measures will prove to be sustainable.

Future for some “institutions” From statements put out in recent years by the UN and other agencies about the “virtual elimination of vitamin A deficiency and all its consequences including blindness by the year 2000” (247) one might reasonably expect that bodies like IVACG, SIGHT AND LIFE, the Xerophthalmia Club Bulletin that are exclusively devoted to the prevention of VADD might not be in existence anymore after that crucial year, i.e. next year! It might also be argued whether giving so much attention to a single vitamin is justifiable. However, my own view is that there will be the need for such institutions to continue into the forseeable future, although they probably will need to undergo considerable change and development in the process.

SIGHT AND LIFE It has to be recognised that no one now takes the goal of “Health for All by the Year 2000”, formulated by WHO in 1978 at Alma-Ata, seriously and in a literal sense with the deadline almost here. Some of us had our doubts at the beginning and said so (69). Even those associated with WHO are now admitting this. Not so long ago all kinds of efforts were being made for the goal’s achievement by the stated deadline. However, we are now expected to forget all that has ever happened. Our attention is now being drawn to the recent publication of a document and a policy, endorsed by the World Health Assembly, the governing body of WHO, in May 1998 entilted “Health for All in the 21st Century”. That part of the “Global health targets to 2020” that applies in the present context reads as follows, “eradicate and eliminate certain diseases” of which VAD is one. Here, in effect, we see a reiteration of the same old goals, but with the “deadline” just pushed back another 20 years to the year 2020! In my view slogan fatigue and a weary sense of déjà vu will rapidly take over. With all this in mind it seems inevitable to me that institutions like IVACG, SIGHT AND LIFE and the Xerophthalmia Club Bulletin are going to be needed even more in the forseeable future. If the deepening economic crisis bites ever harder in years to come these kinds of efforts are going to become even more important. It is equally clear, however, that circumstances will change radically, and this may require serious restructuring in order to face up to the new challenges. At present IVACG is not much more than a cosy chat shop where ideas can be readily aired and exchanged. It has failed so far to tackle really controversial key issues and the recommendations which its meetings pass without comment are not brought up later to see whether they have been implemented. It needs to be given teeth and this is unlikely to happen while its meetings continue to get bigger and more bland.

Despite the representation of UN agencies in IVACG from the beginning it has not led to a really effective collaboration. This is in marked contrast to what has happened in the area of the control of iodine deficiency disorders. In 1985 the International Council for Control of Iodine Deficiency Disorders (ICCIDD) was set up as a nongovernmental organisation to work closely with WHO and UNICEF. It is recognised as the expert group by the United Nations system and reports annually to the Subcommittee on Nutrition. The contribution of SIGHT AND LIFE has grown steadily in recent years and in addition to its regular newsletters there are few studies, meetings or publications in the field in which it does not have some kind of input. In my view these and other novel contributions which it will no doubt continue to make will be needed for years to come. As editor since 1985 I can perhaps speak about the Xerophthalmia Club Bulletin with some authority. I certainly know its weaknesses only too well. In the natural course of events it will need a new editor in the not too distant future and that may be the time for radical change. At present it goes free of charge to about 3500 people all over the world three times a year. Each issue is about 9000 words long. Far too much of it, sometimes almost all, is written by me. Although people usually write something fully acceptable when requested, in my view not nearly enough people bother to write in about issues that concern them. It is not for want of encouragement. It might surprise some to know how much goes on behind the scenes between issues. The internet and e-mail facilites open up a reliable means of communication in the remotest parts of the earth where ordinary postal services cannot be relied upon. Increasingly, we all have less and less excuse for not being up-to-date and on-the-ball in our combat of VADD.

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Epilogue I suppose for all intents and purposes this must be somewhere towards the end of my contributions towards the conquest of VADD. I shall never cease to be interested in and concerned about the problem, but I have to admit that the golf course and my other sporting activities as well as interests like tapestry and the electronic organ and involvement with Christian ecology take up more and more of my time so long as my health lasts. When I started out nearly fifty years ago only the tip of the problem was recognised and we really had no idea how to prevent it. Relatively recently what is probably the full extent of the problem was revealed and we had come to be rather confident that we knew how it could be controlled. At the time of writing this it seems that the clock of progress may be being turned backwards by economic forces that are beyond our control. In these circumstances those who continue to “bear the heat and burden of the day” will need a strong nerve, ingenuity, dedication, patience and perhaps above all insight as they face the difficult times ahead.

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182. Olson JA (1996). Biochemistry of vitamin A and carotenoids. In: Vitamin A Deficiency: Health, Survival, and Vision (eds. Sommer A, West KP Jr) pp 221-250. Oxford University Press, New York 183. Cohen N, Rahman H, Mitra M et al (1987). Impact of massive doses of vitamin A on nutritional blindness in Bangladesh. Am J Clin Nutr 45:970-6 184. Sommer A, McLaren DS, Olson JA (1976). Guidelines for the evaluation of vitamin A deficiency and xerophthalmia. IVACG, Washington, DC 185. WHO (1976). The prevention of blindness. WHO Chron 30:391-7 186. WHO (1992). Prevention of childhood blindness. WHO, Geneva 187. McLaren DS (1980). What to do about basic medical science. Br Med J 281:171-2 188. WHO/UNICEF/IVACG Task Force (1988). Vitamin A supplements. A guide to their use in the treatment and prevention of vitamin A deficiency and xerophthalmia. WHO, Geneva 189. Meguid MM, Landel AM, McLaren DS (1988). Plasma carotenoid profiles in normals and patients with cancer. J Par Ent Nutr 12:147-151 190. McLaren DS (1986). Nutrition/metabolism classic: a study of factors underlying the special incidence of keratomalacia in Oriya children in the Phulbani & Ganjam districts of Orissa, India. Nutr Intern 1:100-7 191. Kothari G, McLaren DS (1993). Keratinization in buccal mucosa – a practical index of vitamin A nutriture. Bombay Hosp J 35:65-70 192. Kothari G, McLaren DS (1995). Assessment of vitamin A nutriture in preschool children – a multi approach. J Trop Pediatr 41:290-4 193. Potter AR (1991). Avoidable blindness. Br Med J 302:922-3 194. McLaren DS (1991). Avoidable blindness. Br Med J 302:1204 137

References 195. Kupfer C (1994). The International Agency for the Prevention of Blindness. Am J Ophthalmol 117:253 196. McLaren DS (1994). The International Agency for the Prevention of Blindness. Am J Ophthalmol 118:405-6 197. Kupfer C (1994). Reply. Am J Ophthalmol 118:407 198. Johnson GJ, Cartwright E (1996). Global Perspectives on the Control of Blindness. International Centre for Eye Health, London 199. Johnson GJ (1999). Prevention of visual impairment. Submitted for publication 200. Dolin PJ, Faal H, Johnson GJ et al (1997). Reduction of trachoma in a sub-Saharan village in absence of a disease control programme. Lancet 349:1511-2 201. McLaren DS (1996). Xerophthalmia and vitamin A. pp 378-385 In:Illustrated History of Tropical Diseases (ed. Cox FEG), Wellcome Trust, London 202. Arthur P (1998). Global situation of vitamin A deficiency. Report of XVIII International Vitamin A Consultative Group Meeting, 22-26 September 1997, Cairo, Egypt 203. Sommer A (1982). Nutritional Blindness: Xerophthalmia and Keratomalacia. Oxford University Press, New York 204. Sommer A, Hussaini G, Muhilal et al (1982). History of night blindness:a simple tool for xerophthalmia screening. Am J Clin Nutr 33:887-891 205. Sommer A, Emran N, Sugana T (1980). Clinical characteristics of vitamin A responsive and nonresponsive Bitot’s spots. Am J Ophthalmol 90:160-171 206. Sommer A, Emran N, Tamba T(1979). Vitamin A-responsive punctate keratopathy in xerophthalmia. Am J Ophthalmol 87:330-3 207. Sommer A, Tjakrasudjatma S, Djunaedi E et al (1978). Vitamin A-responsive panocular xerophthalmia in a healthy adult. Arch Ophthalmol 96:1630-4 138

208. Sommer A, Tarwotjo I, Hussaini G (1983). Increased mortality in children with mild vitamin A deficiency. Lancet ii:585-8 209. Sommer A, Tarwotjo I, Katz J (1987). Increased risk of xerophthalmia following diarrhea and respiratory disease. Am J Clin Nutr 45:977-980 210. Herrera MG, Fawzi WW, Nestel P (1996). Effect of vitamin A supplementation on the incidence of cough, diarrhea, and fever. XVII IVACG Meeting Report, Guatemala City, p 95. The Nutrition Foundation, Washington, DC 211. Sommer A, Tarwotjo I, Djunaedi E et al (1986). Impact of vitamin A supplementation on childhood mortality. A randomised controlled community trial. Lancet i:1169-1173 212. Beaton GH, Martorell R, Aronson KJ et al (1993). Effectiveness of vitamin A supplementation in the control of young child morbidity and mortality in developing countries. ACC/SCN State-of-the-art Series, Nutrition Policy Discussion Paper no 13, United Nations, Geneva 213. Ross AC (1996). The relationship between immunocompetence and vitamin A status.pp 251-273. In: Vitamin A Deficiency: Health, Survival, and Vision. (eds. Sommer A, West KP Jr), Oxford University Press, New York 214. Semba R (1998). The role of vitamin A and related retinoids in immune function. Nutr Rev 56, no 1 (Part II) S38-48 215. Hussey GD, Klein M (1990). A randomized, controlled trial of vitamin A in children with severe measles. N Eng J Med 323:160-4 216. Coutsoudis A, Bobat R, Coovadia HM et al (1994). Vitamin A prophylaxis reduced morbidity in HIV-1 infected infants: a controlled trial. XVI IVACG Meeting Report, Chiang Rai, Thailand. The Nutrition Foundation, Washington DC 217. Wolf L, Keusch GT (1999). Nutrition and infection. In: Modern Nutrition in Health and Disease 9th ed (Shils ME, Olson JA, Shike M, Ross AC eds.) pp 1569-1588, Baltimore, Williams & Wilkins

SIGHT AND LIFE 218. WHO/UNICEF (1987). Joint statement on vitamin A for measles. Wkly Epidemiol Rec 62:133-4 219. Yorston D, Foster A (1992). Corneal ulceration in Tanzanian children: relationship between malaria and herpes simplex keratitis. Trans R Soc Trop Med Hyg 86:456-7 220. WHO/CND Immunisation-Linked Vitamin A Supplementation Study Group (1998). Randomized trial to assess benefits and safety of vitamin A supplementation linked to immunisation in early infancy. Lancet 352:1257-1263 221. Maciaszek J, Talmage DA, Viglianti GA (1994). Synergistic activation of simian immunodeficiency virus and human immunodeficiency virus type I transcription by retinoic acid and phorbol ester through an NF-kappa Bindependent mechanism. J Virol 68:6598-6604 222. WHO (1996). Indicators for assessing vitamin A deficiency and their application in monitoring and evaluating intervention programmes, WHO, Geneva 223. Tanumihardjo SA, Koellner PG, Olson JA (1990). The modified relative-dose response assay as an indicator of vitamin A status in a population of well-nourished American children. Am J Clin Nutr 52:1064-7 224. Haskell MJ, Islam MA, Handelman GJ et al (1998). Plasma kinetics of an oral dose of [2H4] retinyl acetate in human subjects with estimated low or high total body stores of vitamin A. Am J Clin Nutr 68:90-5 225. Wittpenn JR, Tseng SCG, Sommer A (1986). Detection of early xerophthalmia by impression cytology. Arch Ophthalmol 104:237-9 226. Luzeau R, Carlier C, Ellrodt A et al (1988). Impression cytology with transfer: an easy method for detection of vitamin A deficiency. Int J Vitamin Nutr Res 58:166-170 227. Lietman TM, Dhital SP, Dean D (1998). Conjunctival impression cytology for vitamin A deficiency in the presence of infectious trachoma. Br J Ophthalmol 82:1139-1142

228. Congdon N, Sommer A, Severns M et al (1995). Pupillary and visual thresholds in young children as an index of population vitamin A status. Am J Clin Nutr 61:1076-1082 229. McLaren DS (1998). The epidemiology of vitamin A deficiency disorders. In: The Epidemiology of Eye Disease (Johnson GJ, Minassian DC, Weale R eds.) pp 209-225, Chapman & Hall, London 230. Garcia-Casal MU, Layrisse M, Solano L et al (1998). Vitamin A and β-carotene can improve nonheme iron absorption from rice, wheat and corn by humans. J Nutr 128:646-650 231. Blomhoff R, Green MH, Green JB et al (1991). Vitamin A metabolism: new perspectives on absorption, transport, and storage. Physiol Rev 75:951-1027 232. Christian P, Schulze K, Stoltzfus RJ et al (1998). Hyporetinolemia, illness symptoms, and acute phase protein response in pregnant women with and without night blindness. Am J Clin Nutr 67:1237-1243 233. Rosales FJ, Ross AC (1998). A low molar ratio of retinol binding protein to transthyretin indicates vitamin A deficiency during inflammation:studies in rats and a posteriori analysis of vitamin A-supplemented children with measles. J Nutr 128:1681-7 234. Alvarez JO, Salazar-Lindo E, Kohatsu J et al (1995). Urinary excretion of retinol in children with acute diarrhea. Am J Clin Nutr 61:1273-6 235. West KP Jr, Katz J, Khatry SK et al (1999). Double-blind, cluster randomised trial of lowdose supplementation with vitamin A or βcarotene on mortality related to pregnancy in Nepal. Br Med J 318:570-5 236. Baly DL, Golub MS, Gershwin ME et al (1984). Studies on marginal zinc deprivation in rhesus monkeys. III. Effects on vitamin A metabolism. Am J Clin Nutr 40:199-207 237. Shankar AH, Prasad AS (1998). Zinc and immune function: the biological basis of altered resistance to infection. 68 (Suppl 2), 447-463 139

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SIGHT AND LIFE

Index A acute phase response 119, 124 Ali Ahmad Saloum 89-91 American Society of Nutritional Sciences (ASNS) 89 American University of Beirut (AUB) 74-78, 85, 89, 96, 106 Aomari LL 103 Aravind Eye Hospitals 95 Arroyave G 96, 100, 110 Audeh Z 109 B Baba N 78 Bagchi K 49-52, 87 Bang FB 97 Baptist Missionary Society 36, 40, 43-44 Bauernfeind JC 102 beriberi 18, 20-21, 37, 75, 116 Bitot’s spot (X1B) 14, 65-69, 82, 86, 92, 117-118, 124 Bliss D 78 British Empire (Commonwealth) Society for the Blind (see Sight Savers) Burma 53 C cancer of the oesophagus 97, 99 Carey W 43 carotenoids 19, 21, 23, 87-89, 111, 120 cataract 65, 107-108, 115 Chichester CO 102, 104 China 28, 30, 36, 99 cod-liver oil 14, 17, 19-20, 22 Cohen N 101 Columbia University 89 conjunctival impression cytology 118 conjunctival xerosis (X1A) 16, 19, 124

corneal scar (XS) 81, 84 corneal xerosis (X2) 117 Cullen W 34 D Darby WJ 53-54, 58, 59-60, 62-63, 65-66, 73-74, 88, 93 dark adaptation 19, 66, 68 dark green leafy vegetables (DGLV) 89 Davidson Sir LSP 34-35, 74 Davson H 50 DeMaeyer EM 102-104, 110 demographic entrapment 121 diarrhoeal disease 86 discrete colliquative keratopathy (DCK) 69 Doesschate, J ten 61, 104 Doll Sir R 51-52 Duke-Elder Sir S 60, 83 duodenal ulcer 44 E East African Institute for Medical Research 55-57 Ebers papyrus 15 Edinburgh 33-34, 74, 106, 108-109 Escapini H 70, 75, 77, 79 Ethiopia 65 F Florentino R 110 Food and Agriculture Organization (FAO) 88-89 Forman M 99-100, 102 Foster A 65 Frazer Sir J 44 G Ghana 38 Gogo 56-57, 60

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Index H haemoconcentration 83 Helen Keller International (HKI) 110 hemeralopia 16 Hill Sir AB 51 Himsworth Sir H 74 HIV infection 118 Hodges R 104 Holmes E 55-57, 59 Hong Kong 72 Horwitz A 103 Human Nutrition Research Unit (HNRU) 48 Hutchison Sir R 35 I India 36, 40, 46, 97 Indonesia 52-54, 61, 89, 96-97, 109, 117 Interdepartmental Committee on Nutrition for National Defense (Development) (ICNND) 59, 65, 67, 82, 88, 93 International Agency for Research on Cancer (IARC) 97, 99 International Centre for Eye Health (ICEH) 10, 113 International Nutritional Anemias Consultative Group (INACG) 100 International Vitamin A Consultative Group (IVACG) 10, 61, 79, 94, 100, 102-106, 110, 114, 117, 127 Iran 97 Irinoda K 71-72 iron 99 J Jelliffe DB 48, 88 Johnson GJ 112, 114-115 Journal of Tropical Pediatrics 48 K Kamel WW 82, 85-86, 102 Kanawati A 109 Karyadi D 102, 110 keratomalacia 13-14, 16, 19-21, 40-41, 44, 49, 54, 63, 65, 67, 80, 82-84, 88, 90, 95, 112 Khond Hills 36, 40, 43-44, 92

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King G 62-63 Kirkwood B 38 Kissinger H 99 Kothari G 112 Kupfer C 102, 114 kwashiorkor 42, 47, 79, 90 L Lebanon 77, 106, 108 leprosy 65, 68 Liebig J von 18 liver 13-15, 86 liver, cirrhosis of 45 Livingstone D 14 Lloyd George D 26 London 26, 30, 48 London School of Hygiene and Tropical Medicine 37-38, 48, 51-52 Luapula valley 75 M Madurai 95 malaria 45 Manila 70, 72 Mannheimer E 88 Manson Sir P 38 McCance R 50 McKigney J 104 McLaren AS 115 McLaren GS 40, 49, 70, 88, 92, 106, 115 McLaren HJ 92, 115 McLaren JM 49, 70, 92, 98, 106, 115 McLaren OM 33, 36, 40, 70, 73-75, 88, 92, 104, 106, 108 measles 14, 22, 65, 80, 87, 118 Meguid MM 111 Mellanby Sir E 38 meriah 44 Metropolitan Tabernacle 26, 28, 30 Modified relative dose response 118 Morley D 47 Mudambi, S 112 Mvumi 64-65 Mwanza 60, 64-65, 74-76

SIGHT AND LIFE N Nair NVK 110 National Institute for Medical Research 51 National Institute of Nutrition, Hyderabad 100 National Institutes of Health (NIH) 59, 63-64, 74, 114 Nigeria 88 night blindness (XN) 13-16, 82, 86, 117-118 nutrition 34, 37-38, 77 nutrition rehabilitation centre 95 nyctalopia 16 O Olson JA 100, 103, 106 onchocerciasis 52, 65, 68-69, 107-108, 114 Oomen HAPC 50, 55, 58-61, 75, 77, 79, 85, 89, 94, 96, 103, 114 Osler Sir W 47 Overseas Missionary Fellowship 28 P Pan American Health Organization (PAHO) 93 Pararajasegaram R 104, 110 Passmore R 35, 48, 106 Paton D 66-67, 70, 83 Patwardhan VN 58-59, 75, 77, 82, 86, 93 Pearson WN 93 pellagra 18, 20-21, 116 perifollicular hyperkeratosis 21, 40 Pettiss S 103 Pirie A 49, 94-95, 103 Platt BS 37-38, 48, 50, 52, 55, 58, 74 Pradilla A 110 Princeton conference 58, 60 protein-energy malnutrition (PEM) 77, 80, 82, 87-88, 126 puerperal sepsis 22 R Read WWC 108-109 red palm oil 87-88, 97 refractive errors 65 Reigate 30, 32 relative dose response (RDR) 118 respiratory disease 22, 118

retinol (see vitamin A ) retinol equivalent (RE) 89 rheumatic fever 29, 33 rheumatoid arthritis 17 rhodopsin 13, 19 riboflavin 98-99 rickets 14, 18, 20-21, 116 Ross D 38 S schistosomiasis 57 Schweitzer A 30, 89 Scotland 31 Scrimshaw NS 58, 70 scurvy 18, 20-21, 116 Sebrell WH Jr 47, 59, 63, 73-75, 79 sharu 15-16 Shirajian E 85 SIGHT AND LIFE 9-10, 100, 113, 115, 117, 126 Sight Savers 52, 68, 75, 94-96, 112 Singapore 92 skim milk 63, 80 slit lamp microscope 67 Smelser G 64, 70 Smith D 37-40 Solon F 100 Sommer A 96-97, 103-104, 106, 109-110, 117 Spurgeon CH 26, 28 Spurgeon’s Orphan Homes 30 St John Ophthalmic Hospital 83 T Tanganyika (Tanzania) 60 Teng Khoen Hing 91-92 Teply LJ 103 thiamin 75 Tokyo 71 trachoma 65, 85, 107-108, 114 Trousseau A 17-18 Turkoman 97

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Index U Underwood B 96, 100, 103, 110 United Nations Children’s Fund (UNICEF) 63, 100, 104, 110, 118 United Nations Relief and Works Agency (UNRWA) 85 V Venkataswamy G 95, 103-104 Vester BS 84 vision restoration test 119 visual purple ( see rhodopsin) vitamin A 13, 15, 17, 19, 20-21, 23, 40-41, 46, 62, 64, 77, 80, 83-84, 97, 99, 108 and growth 80, 119 and haemopoiesis 119 and zinc 119 anti-infective vitamin 17, 21-22 immunisation and 118 in breast milk 118 in serum 66, 69, 81-82, 86 interventions 118 intramuscular 100 loss in urine 119 meta-analysis 118 prophylaxis 86-87, 121-122 vitamin A deficiency (VAD) 13, 15, 17, 23, 40, 46, 51, 59-60, 63, 65-66, 69, 77, 79, 81, 83, 85-86, 88, 93, 96-97, 99, 111, 117-118, 120 vitamin A deficiency, control of 120 history of 115 mortality and 19, 54, 82, 86-87, 117-119

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prevalence of 82, 109, 117, 120 Vitamin A Deficiency Disorders (VADD) 9-10,13, 25, 38, 46, 57, 67, 77, 89, 94, 105, 112-116, 121 neglect of 73 vitamin C 63 vitamin D 21, 63 vitamin E 17 W Warren O 28 Waterlow JC 38 Williams CD 38, 42, 46-48 Williams RR 75 Wilson Sir J 52, 75, 94, 96, 108 Woodruff A 68 World Health Organization (WHO) 52-53, 55, 61, 69, 75, 77, 82, 85-87, 92-93, 96, 104, 106, 109-111, 118, 120 Worthing 113 X xerophthalmia, 13, 15, 19-20, 22, 37, 40, 50-52, 54-55, 60-63, 65, 70-71, 73-76, 79-83, 87, 89, 95-97, 99, 107-108, 116-117 xerophthalmia, global survey of 69 neglect of 52, 106 notification of 85-86 problems with 122-126 Xerophthalmia Club Bulletin 9-10, 49, 60-61, 94, 96, 100, 115, 126 xerophthalmia rehabilitation centre 95 xerophthalmic fundus 91-92, 117