Werner & Ingbar's The Thyroid: A Fundamental & Clinical Text, 9th Edition

1.The Heritage of the Thyroid: A Brief History

Clark T. Sawin

The occurrence of goiter was no surprise to Europeans 2 millennia ago, especially to those living in the Alps (1). They did not know, however, that goiter was related to the thyroid gland, or that the thyroid gland existed (2). The ancient Greeks called the goitrous swelling in the neck a bronchocele (“tracheal outpouch”); the name was still used in the 19th century, despite the fact that the thyroid gland had been discovered and named 200 years earlier (Fig. 1.1).

FIGURE 1.1. Large goiter in a woman from an area with a high rate of endemic goiter (Bern, Switzerland). The woman was a patient of the Bern surgeon E. Theodor Kocher, a Nobel laureate. (From Kocher T. Zur Pathologic and Therapie des Kropfes. Dtsch Z Chir 1874;4:417, with permission.)

The thyroid gland had not been identified as a discrete entity until the Renaissance and the expansion of inquiry into the human body. Leonardo da Vinci probably found it by about 1500, and Vesalius definitely knew about it in 1543 (although he used the term laryngeal glands for the entire gland we now know as the thyroid gland). By the early 1600s, anatomists definitely identified the thyroid gland in humans and realized that its enlargement caused swelling in the neck, as documented by Fabricius in 1619. The modem name arose in 1656, when Thomas Wharton called it the thyroid gland, after the Greek for “shield-shaped,” not by virtue of its own shape, but because of the shape of the nearby thyroid cartilage (3).

Alpine travelers' observations of cretinism, a thyroid-linked disorder, can be traced to the 13th century, but clinically relevant descriptions appeared only in the 16th century, when Paracelsus (c. 1527) and Platter (in 1562) made the connection between goiter and cretinism (4).

This was the extent of our knowledge of thyroid physiology and disease until the 19th century. Until then, medical theories behind disease causation were humorally based. An imbalance of the four humors (blood, phlegm, bile, and black bile) caused illness. Some thought that goiter was caused by an excess of phlegm. Treatment was empiric, however, and not based on the theoretical cause. Numerous remedies for goiter were proposed; some were complex mixtures of seaweed and marine sponge. These aquatic substances were well known in medieval Europe and had been used to treat goiter a thousand years earlier in China (some historians believe that the Europeans may have learned of these substances from the Chinese indirectly via traders).

Courtois discovered iodine in the residue of burnt seaweed in about 1812 as an indirect consequence of the British blockade of French ports during the Napoleonic wars. Subsequently, Coindet, an Edinburgh-trained physician working among goitrous people in Geneva, Switzerland, considered iodine to be the active ingredient of the empiric therapies for goiter. In 1820, he gave iodine, mostly as the potassium salt, to patients with goiter, after which their goiters shrank remarkably (5). To his chagrin, he also saw major toxic effects in some patients (not his own) who took too much of the astonishing remedy, which consequently fell into disfavor. Still, iodine continued to be given for other disorders (6), such as scrofula, syphilis, and tuberculosis. Coindet had in fact discovered iodine-induced thyrotoxicosis, the cause of the major toxic effects he had seen; this was the earliest description of any form of thyrotoxicosis, although the true nature of the disorder was not recognized for several decades. Despite the controversy over the use of iodine in Geneva, the therapy represented a shift from an empiric, folk medicine to a rational treatment of a defined illness with a specific substance.

The use of iodine as a drug, even though it was effective at shrinking the goiter in many patients, by no means meant that practitioners knew that they were replacing a deficiency. For most of the 19th century, few accepted the idea that disease could be due to the lack of something. Although the use of iodine to prevent goiter was proposed in 1831—based on observations in Colombia, South America (7), and later in 1850 by Chatin, a Parisian pharmacist, botanist, and physician (8)—these suggestions were not in tune with the times, were not accepted by the practitioners of that era, and were put aside. Most believed that goiter must be due to something in the water—a toxin, a bacterium, or a parasite. The issue was not resolved until the early 20th century, when small amounts of iodine were found to prevent goiter in schoolgirls in Akron, Ohio (9). Even then, there was no evidence that these girls were iodine deficient to begin with; the existence of iodine deficiency in certain areas of the United States was not proven for another decade or so.

What has happened since the 1920s is curiously reminiscent of the 19th century: iodine replacement never became widespread and was eventually abandoned because it was seen as toxic or irrational. This attitude resulted in continued goiter and the associated, but less common, cretinism. After the Akron experiment, the notion of deficiency was slowly becoming accepted, but iodine replacement would still not become widespread for decades. The lesson that iodine is a useful prophylaxis against, and therapy for, goiter and cretinism has still not been put into practice universally. Today, an international consortium (the International Council for the Control of Iodine Deficiency Disorders) attempts to ensure that all people receive sufficient amounts of iodine.

The thyroid dysfunctions we know as hypothyroidism and thyrotoxicosis were not thought to be thyroid diseases when described in the 19th century. There was instead a slow accumulation of clinical and physiologic evidence that gradually defined these conditions as we know them today.

Coindet was not the only one to describe thyrotoxicosis without realizing it. Parry, who saw spontaneous thyrotoxicosis before Coindet, but whose observations went unpublished until after his death (10) (and then in an obscure book published by one of his sons, rather than in a journal), saw a few patients with rapid heartbeat, goiter, and sometimes exophthalmos (exophthalmos was not described by Coindet). Parry thought that this constellation of signs represented some form of heart disease. A few years later, Graves described in his Meath Hospital lectures three women who seemed alike (they had goiter and palpitations). His published lectures (11) included a fourth patient who also had exophthalmos. This extra patient had been mentioned to him by his student, friend, and colleague Stokes. Both Graves and Stokes believed that the illness was cardiac. Graves' description was not widely known on the European continent, so when Basedow reported somewhat similar patients in 1840 (12), he was thought to be the first to describe the illness. As a result, many Europeans still use the term Basedow's disease, rather than Graves' disease, for what in fact should probably be called “Parry's disease.” Even after Basedow's report, however, the goiter itself was not considered of much importance. The belief that the syndrome was of cardiac origin faded after about 1860, in part because of Charcot's emphasis on the nervousness of most patients (13); a neurologic hypothesis was then dominant for the rest of the 19th century. The disorder was still not thought to be a thyroid disease.

By the 1880s, surgeons were able to remove the goiters, at least partially, in these nervous, overactive patients without killing many of them, a clear change from 20 years before, when this surgery did in fact kill the majority of patients operated upon. Interestingly, the nervousness often disappeared in the survivors. This fact, plus the observation in the 1890s that too much thyroid extract led to similar nervousness and weight loss, brought a shift in thinking toward the thyroid origin of the syndrome. Only in reference to the 1890s and early 1900s can we really speak of thyrotoxicosis, because only then did the concept of an excessive amount of thyroid hormone come into existence as the cause of the syndrome. The concept was applied to both the spontaneous disease and the disease induced by administration of desiccated thyroid. Note that the term thyrotoxicosis is based on another idea of the 1890s, namely, that the thyroid gland in this syndrome either secretes or fails to inactivate a toxin (i.e., a deleterious substance not found in a normal person). The word is still in common use, but it does not reflect the actual pathophysiology, one cause of which is hyperthyroidism, an excess synthesis and secretion of thyroid hormone. The success of partial thyroidectomy over 100 years ago helped focus attention on the thyroid gland, eventually leading to the now more commonly used treatments, radioiodine (14,15) and antithyroid drugs (16).

Hypothyroidism as a clinical syndrome was recognized even later than hyperthyroidism, and at first its cause was equally obscure. First defined in London in the 1870s (17), what we call hypothyroidism was named myxedema because of the swollen skin (edema) and its excess content of mucin (myx-)(18). It was considered either a neurologic or a skin disease. There was no cure, and its course was inexorably progressive. There was only palliation with drugs such as pilocarpine, to be given in an attempt to reverse the patient's decreased sweating. At about the same time, in the latter part of the 19th century, it became evident that the same surgical skill that allowed thyrotoxic patients to survive thyroidectomy also permitted survival when a goiter was removed from patients who were not nervous or overactive. The ability to remove the entire thyroid gland, however, led to a peculiar and disastrous outcome: the patient lived but became puffy-faced, slow of mind, and socially nonfunctional (19,20). Again, no one knew why, and there was no cure.

The Swiss, writing in German or French, and the English, writing in English, did not read each others' reports of this peculiar syndrome or this disastrous outcome, and so neither were aware of the other's work. That situation changed in 1883, when Felix Semon, an immigrant Prussian practicing laryngology in London, noted to others present at a meeting of the Clinical Society of London that the Swiss patients who had undergone total thyroidectomy seemed quite similar to the English ones with myxedema. Scoffed at, Semon persisted. The Society finally named a committee to investigate his observation. The report was not finished until 1888, 5 years later, and is now considered a classic (21).

The Committee found that cretinism, myxedema, and the Swiss postthyroidectomy changes all were the result of loss of the function of the thyroid body (21). Despite this major step in understanding, the report did not offer an effective therapy. In 1889, however, Brown-Séquard's work in Paris on the supposed rejuvenating effects of testicular extracts of dogs and guinea pigs (22) led to the use of extracts of other tissues as treatments for many disorders. Most extracts eventually proved to be ineffective, but the idea led indirectly to the successful and remarkable cure of myxedema (i.e., Murray's injection of sheep thyroid extract) in 1891 (23). A year later, the treatment was made even easier by simply eating, instead of injecting, ground or fried sheep thyroid, or tablets of dried thyroid tissue. This affirmation that Brown-Séquard's organotherapy was effective in at least one serious illness was the origin of modern endocrinology; this despite the fact that Murray was preceded in his discovery of a successful therapy by two Portuguese, Bettancourt and Serrano, who published, naturally enough, in a local Portuguese journal in Lisbon, but which was completely unknown to Murray. It was another example of simultaneous discovery.

Nevertheless, no one knew just what it was in thyroid extract that made it work, even though the therapy was extended in 1894 to the treatment of goiter (24). [The 15th century Chinese may have used the same therapy for goiter on the basis of “like treating like” (25).] A vigorous search for the “active principle” then took place, but no one found anything helpful until 1895, when Baumann, to his great surprise, found iodine in the thyroid gland (26). Twenty years later, Kendall at the Mayo Clinic, using iodine as a marker for the isolation of the active substance, succeeded in isolating bioactive crystalline material on Christmas Day, 1914 (27). He and his associate, Osterberg, named it thyroxin while waiting for a train. The name was a contraction of thyroxyindole, and stemmed from Kendall's erroneous belief that the compound had an indole nucleus with three iodine atoms per molecule. He never changed his ideas, despite his repeated failure to synthesize an active molecule based on his presumed structure, and was much disappointed when, in 1926, an Englishman, Harington, not only found the correct structure, but found that it had four (not three) iodine atoms per molecule (28). Harington, to Kendall's greater chagrin, then synthesized it (29). Harington also added an e to the name and called it thyroxine to fit the convention at the time for naming amino acid derivatives. Kendall agreed with this change.

Kendall's extracted thyroxine was patented and commercially licensed, but was far more expensive and not as effective as desiccated thyroid. (In the 1920s, no one knew that thyroxine as the free acid is not well absorbed.) Even so, Harington's synthetic product was far too costly. Therefore, until the 1960s, the usual therapy for thyroid deficiency and goiter was the administration of desiccated thyroid. The successful synthesis of thyroxine in high yield in 1949 (30) (in the form of sodium L-thyroxine, which, in contrast to thyroxine itself, is quite well absorbed from the gut) made therapy with this form of thyroxine economically sensible. Thyroxine is used now in almost all treatment with thyroid hormone. Although in 1999, based on one report (31), some have added triiodothyronine to the thyroxine; however, several recent studies have not been able to confirm this report (32,33,34).

Both Kendall and Harington suspected that there might be another thyroid hormone other than thyroxine, but they were never able to find it. Kendall moved on to work with adrenal steroids, which won him a Nobel Prize in 1950, almost 3 decades later. Harington gave up the idea of a second thyroid hormone and became director of London's National Institute for Medical Research. He was much surprised when his associate, Pitt-Rivers, and her postdoctoral fellow, Gross, found and synthesized triiodothyronine and then showed it to be more active than thyroxine in a bioassay (35,36). Harington was elated when, with Gross on a vacation in France, the bioassay was successfully repeated and confirmed the high biologic activity of triiodothyronine. It was found almost simultaneously across the English Channel in Paris by Roche, Lissitsky, and Michel (37,38). There was indeed a second thyroid hormone.

Gaps in our knowledge remain, for example, an identification of the cause of goiter in the absence of iodine deficiency, or an explanation of the initial causes of thyrotoxicosis. The record of the past does suggest a certain optimism; surely some of these gaps will be filled in. Only Kocher, among all those mentioned earlier, won a Nobel Prize for work in the area of thyroid studies, although several others were considered worthy by one or another Nobel committee. No matter; our patients are still the better for it.

REFERENCES

1. Merke F. History and iconography of endemic goitre and cretinism. Lancaster, UK: MTP Press Limited, 1984.

2. Sawin CT. Goiter. In: Kiple KF, ed. Cambridge world history of human disease. Cambridge: Cambridge University Press, 1993:750.

3. Wharton T. Adenographia: sive glandularum totius corporis descriptio. Noviomagi (now Nijmegen): Andreas ab Hoogenhuyse, 1664. (This endocrine classic has been translated into English. See: Freer 5, translator. Thomas Wharton's Adenographia. Oxford: Clarendon Press, 1996.)

4. Cranefield PF. The discovery of cretinism. Bull Hist Med 1962;36:489.

5. Coindet J-F. Découverte d'un nouveau remede contre le goitre. Ann Chim Phys 1820;15:49 (originally published in the Swiss Biblioteque Universelle, 1820, and reprinted in its entirety in J Pharmacie 1820;6:485).

6. Lugol JGA. Mémoire sur 1 'emploi de 1 'iode dans les maladies scrophuleuses. Paris: 1829.

7. Boussingault J-B. Recherches sur la cause qui produit le goitre dans les Cordilieres de la Nouvelle-Grenade. Ann Chim Phys 1831;48:41.

8. Chatin A. Existence de l'iode dans les plarites d'eau douce: consequences de ce fait pour le géognosie, la physiologie végétale, la thérapeutique et peut-etre pour l'industrie. Compt Rend Acad Sci 1850;30:352.

9. Marine D, Kimball OP. Prevention of simple goiter in man. Arch Intern Med 1920;25:661.

10. Parry CH. Collections from the unpublished medical writings. London: Underwoods, 1825:111.

11. Graves RJ. Clinical lectures delivered by Robert J. Graves, M.D., at the Meath Hospital during the Session of 1834–5. Lond Med Surg J 1835;7:516.

12. Basedow CA. Exophthalmos durch hypertrophie des Zeilgewebes in der Augenhohle. WochenschrHeilkd 1840;6:197, 220.

13. Charcot JM. Mémoire sur une affection caractérisée par des palpitations du coeur et des arteres, la tumefaction de la glande thyroide et une double exophthalmie. Compt Rend Soc Biol 1857; 3(2nd series):43.

14. Hertz S, Roberts A. Radioactive iodine in the study of thyroid physiology. vii. The use of radioactive iodine therapy in hyperthyroidism. JAMA 1946;131:81.

15. Chapman E, Evans RD. The treatment of hyperthyroidism with radioactive iodine. JAMA 1946;131:86.

16. Astwood EB. Treatment of hyperthyroidism with thiourea and thiouracil. JAMA 1943;122:78.

17. Gull WW. On a cretinoid state supervening in adult life in women. Trans Clin Soc Lond 1874;7:180.

18. Ord WM. On myxoedema, a term proposed to be applied to an essential condition in the “cretinoid” affection occasionally observed in middle-aged women. Med Chir Trans 1878;61:57.

19. Reverdin JL. Accidents consécutifs a l'ablation totale du goitre. Rev Med Suisse Romande 1882;2:539.

20. Kocher T. Ueber Kropfexstirpation und ihre Folgen. Arch Klin Chir 1883;29:254.

21. Ord WM. Report of a committee of the Clinical Society of London nominated December 14, 1883, to investigate the subject of myxoedema. Trans Clin Soc Lond 1888;21[Suppl].

22. Brown-Séquard CE. Des effets produits chez l'homme par les injections sous-cutanées d'un liquide retire des testicules frais de cobaye et de chien. Compt Rend Soc Biol 1889;41:415.

23. Murray GR. Note on the treatment of myxoedema by hypodermic injections of an extract of the thyroid gland of a sheep. BMJ 1891;2:796.

24. Bruns P. Ueber die Kropfbehandlung mit Schildrusenfutterung. Dtsch Med Wochenschr 1894;41:785.

25. Needham J. Proto-endocrinology in medieval China. In: Needham J, Ling W, Gwei-Djen L, Ping-Yu H, eds. Clerks and craftsmen in China and the West. Cambridge: Cambridge University Press, 1970:294.

26. Baumann E. Ueber das normale Vorkommen von Jod im Thierkorper. Hoppe-Sey/er's Z Physiol Chem 1895;21:319.

27. Kendall EC. The isolation in crystalline form of the compound which occurs in the thyroid: its chemical nature and physiologic activity. JAMA 1915;64:2042.

28. Harington CR. Chemistry of thyroxine. II. Constitution and synthesis of desiodo-thyroxine. Biochem J 1926;20:300.

29. Harington CR, Barger G. Chemistry of thyroxine. III. Constitution and synthesis of thyroxine. Biochem J 1927;21:169.

30. Chalmers JR, Dickson GT, Elks J, et al. The synthesis of thyroxine and related substances. Part V. A synthesis of L-thyroxine from L-tyrosine. J Chem Soc 1949;3424.

31. Bunevicius R, Kazanavicius G, Zalinkevicius R, et al. Effects of thyroxine as compared with thyroxine plus triiodothyronine in patients with hypothyroidism. N Engl J Med 1999;340:424.

32. Sawka AM, Gerstein MJ, Marriott MJ, et al. Does a combination regimen of thyroxine (T4) and 3,5,3′-triiodothyronine improve depressive symptoms better than T4 alone in patients with hypothyroidism? Results of a double-blind, randomized, controlled trial. J Clin Endocrinol Metab 2003;88:4551.

 

33. Walsh JP, Shiels L, Mun Lim EE, et al. Combined thyroxine/liothyronine treatment does not improve well-being, quality of life, or cognitive function compared to thyroxine alone: a randomized controlled trial in patients with primary hypothyroidism. J Clin Endocrinol Metab 2003;88:4543.

34. Clyde PW, Harari AE, Cetka EJ, et al. Combined levothyroxine plus liothyronine compared with levothyroxine alone in primary hypothyroidism: a randomized controlled trial. JAMA 2003;290:2952.

35. Gross J, Pitt-Rivers R. The identification of 3:5:38-L-triiodothyronine in human plasma. Lancet 1952;1:439.

36. Gross J, Pitt-Rivers R. Physiological activity of 3:5:38-L-triiodothyronine. Lancet 1952;1:593.

37. Roche J, Lissitsky S, Michel R. Sur la triiodothyronine, produit intermédiaire de la transformation de la diiodothyronine en thyroxine. Compt Rend Acad Sci 1952;234:997.

38. Roche J, Lissitsky S, Michel R. Sur la presence de triiodothyronine dans la thyroglobuline. Compt Rend Acad Sci 1952;234:1228.

SUGGESTED READINGS

In addition to the references given above, readers will find more historical detail in the following:

Harington CR. The thyroid gland: its chemistry and physiology. London: Oxford University Press, 1933.

Pitt-Rivers R, Vanderlaan WP. The therapy of thyroid disease. In: Pamham MJ, Bruinvels J, eds. Discoveries in pharmacology. Vol 2. Amsterdam: Elsevier, 1984:391.

Rolleston HD. The endocrine organs in health and disease with an historical review. London: Oxford University Press, 1936.

Sawin CT. Defining thyroid hormone: its nature and control. In: McCann SM, ed. Endocrinology: people and ideas. Bethesda, MD: American Physiological Society, 1988:149.

PREFACE TO THE FIRST EDITION

This book is intended for those who must deal with the problems of thyroid function and thyroid disease in man. It is designed for use in the clinic and in the basic science laboratory connected with the clinic. The information made available has been brought together from widely diverse sources, and in some instances is reported here for the first time. Many subjects have been presented both in broad outline and in more comprehensive detail to meet differing requirements. It has been planned to provide sufficient documentation to satisfy most needs and, for more exhaustive requirements, to provide a bibliography adequate enough to initiate a search of the literature.

The introduction of a book into a field of clinical medicine today requires considerable justification. In the thyroid field particularly, there already is a profusion of books including the almost classic works of Means in this country and of Joll in England, recently and capably revised by Rundle. Nevertheless, the recent growth of medical knowledge in general, and about the thyroid in particular, appears to have created need for a new volume constructed on a somewhat different basis from those of previous works.

Barry Wood has compared the growth of medical information to that of bacteria. Bacteria show a lag at the beginning of growth and then multiply at a logarithmic rate. Wood considers the growth of current-day medicine to have reached the logarithmic phase. The accumulation of data about the thyroid provides a good example of this acceleration. One author of a recent review claims to have unearthed 3,000 new references pertaining to the gland and published during the single year before he wrote his article. The Quarterly Cumulative Index Medicus offers about 7,800 references to the thyroid in the past decade. More than this, the thyroid field is permeated by contributions from the cardiologist, neurologist, muscle physiologist, and many others, bringing the highly unique techniques of their particular specialties to bear on the subject.

It is evident that the ability of any one individual to follow progress in all directions at once has all but vanished. As a consequence, marked subspecialization of interest has developed and advances have come to depend upon the interchange of information among many specialist, each providing his own orientation. This trend has suggested that the information in a book about the healthy and diseased thyroid should also be subjected to the process of sifting and appraising through many eyes. The various specialists present material with which they have had direct experience, and the editor functions as the overseer to provide orientation and preserve the inherent orderliness of the entire subject. The total clinical and research experience made available in this way exceeds that of one person alone. Each topic can be subjected to the critique of a man who has worked intensively with the problem. Finally, a book of this sort can be readily kept current, because of the authors' continued contact with investigation and the fact that there are no large sections to be rewritten by any one individual.

Every effort has been made to make available sufficient basic and clinical knowledge to satisfy curiosity about either of these aspects. For example, sections on the fundamental properties of radioiodine that permit the use of the isotope and on the instrumentation that facilitates such use are presented as well as a discussion of the clinical application. Most basic sections are separated from the clinical material, but are incorporated with it where this has seemed reasonable.

The fundamental aspects of thyroid function is man and the mechanisms which control the activity of the gland; the biochemistry of the hormone; and histology and comparative anatomy make up Part I. The mechanisms of action of the antithyroid drugs are included because of the intimate relationship of their effects to the problems of basic physiology.

Part II presents the laboratory methods which supplement the clinical appraisal of thyroid secretory activity. The presentations of the basic principles involved in radioiodine usage and the instrumentation which is employed are included within the laboratory section and are available here for later reference when the therapeutic as well as diagnostic use of the isotope are considered.

The diseases of the thyroid are considered in Part III. The disorders first described are those in which the level of thyroid hormone in the circulation and tissues is within normal limits—euthyroidism. After this come the derangements in which hormone levels are increased—toxic goiter or hyperthyroidism—or decreased—hypothyroidism or myxedema. The effects of hyperthyroidism and of hypothyroidism upon the individual body systems have been subjected to fairly detailed analysis.

The plan to arrange disease by functional categories breaks down in relation to inflammation of the thyroid including the peculiar composite entity, chronic thyroiditis. Inflammations of the thyroid tend to inactivate the gland but chronic thyroiditis is almost as often associated with evidence of hyperthyroidism as with hypothyroidism. The inflammations have been placed under a separate heading on this account.

Before the disease states are presented, several important preliminary subjects are considered in Part III. The normal and abnormal developments of the gland are described, together with the surgical anatomy and a method of physical examination that is an essential procedure because of the accessibility of the thyroid to this approach. The pathology is presented in its entirety in the introductory sections and is not dispersed among the various diseases. A concept of change in thyroid disease emerges in this way which could not otherwise become evident.

A major goal throughout the volume has been to assess the validity of the facts on which current information or procedure is based. Corroborative information is often documented beyond reasonable doubt, but too often is based only on speculation or custom or is wanting altogether. The fact that a critical appraisal has been accomplished is a tribute to the contributors. The world today, as in the past, is threatened by prejudice, of which racial, social, and economic prejudices are but a few. Equally influential, but less well recognized, is the prejudice of “experience,” derived from uncritical or uncontrolled observation, from the word of an “authority,” or from emotional bias.* Fortunately there are those who are willing to give time and effort to seek out and correct such distortions of the truth.

Considerable aid has come to the editor from several sources. Dr. John Stanbury has been particularly helpful. The members of the Thyroid Clinic at the Presbyterian Hospital need recognition for their influence upon the formulation of many of the views presented herein. Credit must be given to the patience and forbearance of the many contributors who tolerated changes in style and length of manuscript in the interest of creating an integrated volume out of a series of individual essays. The editor's wife has acted as guardian of clarity, upon the thesis that even the layman should be able to read and understand a well-written article. Miss Anne Powell, of the librarian staff at P. & S., was extremely generous with her time. Finally, Mrs. R. Levine and Mrs. K. Sorenson were more than patient with the secretarial details.


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