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1890 In Memoriam. Sir William Gull. [Extracted from "Guy's Hospital Reports." 1890.

p xxv
The late Sir William Gull was born on the last day of the year 1816, at Thorpe-le-Soken, a secluded Essex village near Walton-on-the-Naze.
....He was still a child when his father died, and the family was left in straitened circumstances. He appears to have owed his character and training to his mother and his early education to himself.
The late Mr. Benjamin Harrison, who was for fifty years the despotic Treasurer, the sagacious and beneficent ruler of the Hospital and School, was struck by the appearance and the intelligence of the youth whom he found teaching the village school of Thorpe. He offered to give him work as a clerk in the counting-house at Guy's Hospital, and when he came up to enter on his new duties told him, "if you help yourself, I shall be able to help you." The bargain
p xxvi
was well kept on both sides. Gull's first duty was to copy out in fair hand the catalogue of the Guy's Museum which had been drawn up by that eminent pathologist and excellent man, the late Dr. Thomas Hodgkin. Meantime he worked on at Greek and Latin and mathematics, and in 1838 was able, with this self-tuition, to matriculate at the then new University of London. Mr Harrison, faithful to his promise, thereupon offered to procure him a free entry to the Guy's School of Medicine, and for this purpose, at a meeting of the staff, proposed that William Gull should be made a perpetual student. This was agreed to, and thus his wonderfully successful career in medicine was begun.
p xxviii
....His successful management of the severe attack of enteric fever from which the Prince of Wales suffered in 1871 made him still more widely known. The Queen acknowledged his services by making him a baronet, and appointing him one of the physicians to the Crown, and the Prince always showed a generous and grateful sense of what he owed to his physicians' skill.
Few men have been so successful in practice or have left to large a professional fortune. His striking presence, his searching scrutiny, his minute and deliberate examination of every case, and the few carefully and slowly uttered words in which he delivered his judgement, sometimes with epigrammatic pungency, often with encouragement, and never without sympathy - all combined to give him an almost unequalled ascendency over his patients. His manner was his own, and sprang naturally from the habit of his mind. It was jus the same in a hospital ward as in a palace, and the poorest of his patients leant on his oracular statements, sometimes with hope and sometimes with resignation, but always with comfort ; while the richest were taught to restrain loquacity, to answer truthfully, and to follow out directions implicitly.
p xxx
....In the hospital wards Dr. Gull was admirable both as a physician and a teacher. He was punctual, methodical, and most considerate for his patients. What he most insisted upon and practised was thorough, systematic investigation of every organ. He had a keen and well-practised eye for slight differences of expression, of complexion, and of attitude. No peculiarity in the speech or the gestures of a patient escaped him.
....The merit of Gull, as of Stokes, Oppolzer, Trousseau, and other great physician, was that he added to this methodical investigation of facts the insight and judgement without which a man may be an admirable clinical teacher and yet entirely fail in the diagnosis of really difficult cases, in the estimation of probabilities, and in wise therapeutics. For practical medicine is an art ; and when all the facts which the most elaborate examination of the patient's actual state can supply have been brought in due order before us, and the seat and nature of the anatomical lesion has been accurately determined, there
p xxxi
still remains the due appreciation of its significance in that particular case, of the probabilities of its future progress, and of the most suitable methods of meeting it. Indeed, in many cases the result of physical diagnosis if little more than negative, and we have to depend entirely upon the same half-unconscious use of experience in combination with slight and almost indescribable indications which is depended upon in critical moments by the physician no less than by the engineer, the seaman, the statesman, and the general.

p xxxiii
....He was never tired of exposing the absurdity of much of the traditional polypharmacy. He would show how much harm may be done by the vigorous treating of half-understood diseases, and he once said that if every drug in the world were abolished a physician would still be a useful member of society. To appreciate his position, we must remember something of the unquestioning faith in bleeding and blistering, purging and physicking, which was still held when Gull was a student. The physicians of the first half of the present century seemed to have no conception that many diseased naturally tended to recovery if not interfered with, and that others as naturally tended to death, however treated. Their erroneous notions of physiology and pathology, their not yet exploded remnants of mediaeval superstition, their almost unsuspected ignorance of the processes and even the detection of disease, and their boundless credulity in the action of remedies, led to just criticism in the minds of the more thoughtful of the laity, and to something like negation among a few in the ranks of the profession who were not bound by the fetters of tradition - such as Sir John Forbes and Dr. Hughes Bennett, of Edinburgh. The astonishing fact that under treatment by Hahnemann's
p xxxiv
sect patients did not always die, led thoughtful men to open their eyes. Gull's treatment of fever and of acute rheumatism were valuable contributions to the scientific study of therapeutics ; and he once said to the present writer after his retirement from practice, "One thing I am thankful that Jenner and I have altogether succeeded in doing. We have disabused the public of the belief that doctoring consists in drenching them with nauseous drugs." Nevertheless, those who knew Gull's practice, either in the Hospital or in private, are well aware that his scepticism was perfectly reasonable, and his therapeutical faith all the stronger because it was discriminating. He would give mercury in syphilitic cases with the utmost confidence ; he purged and used steel and quinine and arsenic just as freely as other physicians ; and in cases of cardiac dropsy his belief in "Addison's pill," as he always called it, of digitalis, squills, and mercury, was unbounded. He used opium also with rare sill and judgement.
p xxxv
....The popular belief that he did not believe in medicines did great harm, and did him injustice - injustice which, as usual, was not quite undeserved by the sufferer. But there are not wanting signs of a new era of meddlesome medication and reckless polypharmacy. The generation which is now getting old was brought up under the healthy reaction from the old tyranny of drugs ; but the new generation is familiar with scores of new, much vaunted, but little tested remedies, most of them uncertain, and many dangerous in their effects. The practice of medicine in Germany, and to some extent in America, is with many honorable exceptions rash, meddlesome, and sometimes mischievous, repeating the old blunder of assuming that every disease has its appropriate remedy, and too often treating each symptom as it arises with the self-confidence and ignorance of a homeopathist.
The worst of the almost daily introduction of highly vaunted remedies, to be used, abandoned, and replaced by others destined to live as short a life, is to produce in scientific tempers complete scepticism in therapeutics ; and the worst of the universal scepticism which clever men are apt to feel or to affect is to encourage relapse into pharmaceutical credulity.
p xxxvii
....Also with Dr. Sutton's help , he published the well-known paper in the 'Medico-Chirurgical Transactions,' on the condition of the arteries in chronic Bright's disease, which they called "Arterio-Capillary Fibrosis." The subject is still a difficult one, and much remains to be done before the old problem of the relation between the disease of the kidney and the concomitant vascular changes which puzzled Bright himself can be regarded as settled. But Gull and Sutton made, at all events, this step in advance : they showed that chronic Bright's disease affects the peripheral vascular system generally, and is far from being a mere local affection of the kidney.
....Dr. Gull's last important work was "On a Cretinoid Condition in Adult Women, " a paper also published in the Clinical Society's 'Transactions.' It contains a brief but complete account of a hitherto undescribed condition, which has since attracted great interest under the more distinctive but less accurate name of myxoedema. As in other cases of clinical observation, it is remarkable that a disease which no one had recognised before its existence and characters were established by Gull have since been found to
p xxxviii
exist not only in this country and on the Continent, but in America and Australia. Moreover, he not only caught its characteristic facies and recognised its importance, but in the name under which he described it he indicated its true pathological relations, doubtful and obscure for some time, but by recent investigation established beyond reasonable doubt. ....One of Gull's saying has come true in the experience of many of his pupils. He said to the clinical assistants, "However clever you are, there are three diseases that you are sure to overlook in the course of your practice. They are phthisis and syphilis and itch."
He would say, "Medicines do most good when there is a tendency to recovery without them."
p xxxix
....A hypochondriac, who had been to several doctors of eminence and was dissatisfied with them all, came to 74, Brook Street, and after a brief examination begged to know the result. "Sir," said Dr. Gull, "you are a healthy man who is out of health." "Yes." said the patient, "that's exactly it ; but why didn't the other doctors find it out ? "
.....A favourite remark of his was, "Savages explain, science investigates," which he enforced by remarking that every barbarous nation had a complete explanation of the cause of eclipses and other striking natural phenomena.
p xl
....He was fanciful in his ways of putting things, and sometimes perhaps affected singularity in this particular. A motto which

he invented for himself pleased him so much that during the leisure of his last illness he not only had a seal engraved with the words, but had them printed on a slip of paper as a kind of memento. It was --

Conceptio Dei, Negatio mei, Ratio rei.

This was quoted by one of the newspapers after his death, but running the three phrases into a line their mutual dependence was lost. The true exposition was this : all knowledge begins with materialism, with scepticism, with getting at actual bare objective facts, the thing as it is - the investigation of phenomena, the linking together of necessary cause and effect, that is, the intellectual part of knowledge ; and unless that is the foundation, morals and religion have no true and firm basis.

Next comes ethical knowledge, which consists essentially in self-denial self-restraint, recognition of the overweening importance which we all give to the individual and especially to one individual in comparison with the whole.
Lastly, as the crown of mental development, the fruit of knowledge, and the result of self-discipline, spiritual truth is discerned.

1896 A Collection of the Published Writings of W. W. Gull ... Edited and arranged by T. D. Acland. Medical Papers (Memoirs and Address.). London, 1894, 1896.
p xv

....He had a retentive memory and vast knowledge, - scientific, clinical, and pathological, - acquired by many years' residence at Guy's, and constant study at the bedside of the sick. Added to this he had a peculiar capacity for appreciating each detail of the case before him at its proper worth ; not being led away by symptoms which, though prominent, might be of little importance, and finding not unfrequently the key to the solution of a problem in some circumstance or detail which had attracted but little attention.
"If a case was not clear to him, he did not hesitate to say, "I do not know." He writes : Acquaint yourself with the causes that have led up to the disease. Don't guess at them, but know them through and through if you can ; and if you do not know them, know that you do not, and still inquire. 'Cannot' is a word for the idle,
p xvi
the indifferent, the self-satisfied, but it is not admissible in science. 'I do not know' is manly if it does not stop there." He acted on Newton's words, which he often quoted :"If I do not understand a thing, I keep it before me and I wait." He never wearied of inculcating the principle that it is more important to study than to explain the phenomena of disease. One of his favourite sayings was, "Fools and savages explain ; wise men investigate."
p xvii
....There was no detail which concerned the comfort or well-being of the patient which was too minute for his attention. He knew the relief which might be gained by change of posture, by altering the position of a limb, and not only saw that it was done, but frequently did it himself. His ready tact in dealing with the whims and sufferings of the sick often called forth more admiration, from patients and friends, than even the exercise of his professional skill. In dealing with disease he never lost sight of the personality of the patient ; each case, he would say, should be considered as "the disease, + the person."
p xix
....His influence over his pupils was great, not only from the extent of his knowledge and the originality of his views, but also from his personal character. He seemed to feel instinctively what was the condition of the student mind, - its wants, and its capabilities ; and how its faculties should be nourished and augmented. He presupposed very little knowledge on the part of the students, and he was clear, precise, and suggestive.
He endeavoured to cultivate in them the same painstaking habit of mind, the same care for detail, which so remarkably distinguished the character of his own work. He writes, "The student of medicine can no more hope to advance in the mastery of his subject with a loose and careless mind than the student of mathematics. If the laws of abstract truth require such rigid precision form those who study them, we cannot believe the laws of nature require less. On the contrary, they would seem to require more ; for the facts are obscure, the means of inquiry imperfect, and in every exercise of the mind there are peculiar facilities to err."
At the same time he sought to impress upon them the need of broad views and high ideals : "The scope of Medicine is so wide as to give exercise to all the faculties
p xx
of the mind and it borrows from the stores of almost every form of human knowledge - it is an epitome of science ; its operations are so benevolent, that our Divine Master Himself assumed its offices as a type of His spiritual ministrations ; it has in it the very quality of mercy, and -
'Is twice bless'd;
It blesses him that gives, and him that takes.'
"Medicine holds a foremost rank amongst the natural sciences, and can only reach its full development as they advance to perfection. It is the centre to which some of their brightest rays converge ; for where beside can we look for such illustrations of the highest expression of natural laws as are found in the structure of the living body ? It has been well said : 'Man is one world, and hath
Another to attend him.'

"The first principle for the student to recognise, and one to which in after life he will often have to recur, is that his work lies not in the fluctuating balance of men's opinion, but with the unchangeable facts of nature."
The following passages, although not primarily addressed to students, further illustrate Sir William's views on this point : "The distinction of medicine, as a study, lies in its comprehensiveness. The student of physical science admits that he has to deal with but one half of that truth which is expressed to man. The student of medicine cannot so limit himself. The facts of sensation, whether pleasurable or painful ; the influence of the mental emotions, whether exciting or depressing ; the dominion of the conscience, approving the disapproving, are for him facts due to the operation of laws into which he must inquire. Looked at from the point of view which the student of medicine occupies, these higher facts of man's nature are as essentially parts of one law, and control and modify human existence equally with those lower conditions with which physic alone is concerned. This constitutes the unspeakable difficulty which every student of medicine must feel in the present imperfect state of knowledge. To hold the mind in an equal balance as it passes from the contemplation of the lower facts of our existence to those which characterise the highest claims of our humanity, so as neither to degrade the one nor neglect the other, is one of the highest attainments. What eye is single enough to survey the range of life from the material atoms which build our structures, to those 'mighty hopes which make us men,' without faltering in the vision, or without confusion of the objects ?"

"I believe that, as men occupied with the study and treatment of disease, we cannot have too strong a conviction that the problems presented to us are physical problems, which perhaps we may never solve, but still admitting of solution only in one way, namely, by regarding them as part of an unbroken series, running up from the lowest elementary conditions of mater to the highest composition of organic structure."

At all times he strove to guard those he taught against a narrow specialism ; he would say, "there are no parts in the body, but only different localities," and as is well known he regarded chronic Bright's disease as an affection of the whole arterial system, not one of the kidneys only. Of a specimen of contracted kidneys exhibited by Dr. Bright as a cause of albuminuria he used to say, "Bright observed the heart and kidneys, but he forgot the man between ; the whole man should have been included in the specimen."

p xxv
"He often did not do himself justice. His paper on the treatment of rheumatic fever was headed 'Cases of Acute Rheumatism treated by Mint Water.' But really his treatment of this disorder was most thorough and efficient. He had the patient's bed screened from the rest of the ward, his friends were not allowed to visit him, he was not suffered to be moved, and no examination of the heart was made beyond what could be carried out without disturbing him. He was put on low diet, with plenty of barley water to drink, the inflamed joints were carefully wrapped in cotton wool and protected with cradles, and he always had enough opium at night to secure sleep and prevent painful startings of the limbs."
He never hesitated to prescribe the medicines of which the effects had been proved by facts well observed ; but he
p xxvi
endeavoured, above all things, to study the natural history of disease, uncomplicated by the action of unnecessary drugs, and he resented all useless interference with the course of nature. He would say of meddlesome polypharmacy -
"Fools rush in, where angels fear to tread."
....He held that the highest work of a physician should be rather the prevention than the cure of disease ; and the wide scope of preventive medicine, with all its possibilities for the future, was a subject that profoundly interested him.
He writes :-
"As health is our object, or as near an approach to it as circumstances admit, hygiene and therapeutics claim the last and highest place in our thoughts. Happily, at this day, hygiene has gained strength enough to maintain an independent position as a science. To know and counteract the cause of diseases before they become effective is evidently the triumph of our art ; but it will be long before mankind will be wise enough to accept the aid we could give in this direction., Ignorance of the laws of health and intemperance of all kinds are too powerful for us. Still we shall continue to wage an undying crusade, and truly we may congratulate ourselves that no crusade ever called forth more able and devoted warriors than are thus engaged. "Nothing can stimulate science more to the investigation of therapeutics than the feeling that the diseases calling for treatment prevail in spite of our best efforts to prevent them. Where hygiene fails, properly commences the work of therapeutics ; but it is painful to find ourselves occupied in making feeble and often useless efforts to combat the effects of a poison which might perhaps have been stamped out in its beginnings."
And again, "Medicine yet owes it to society to demonstrate those secondary conditions whereby a healthy mental activity may be secured and advanced ; for of nothing can we be more certain than that the laws of life, in their unimpeded operation, culminate in the advancing perfection of man - corporeally, intellectually, and morally. But the operation of these laws depends upon common things. Whilst the ignorant have recourse to the supernatural, science asserts that everything, if not traced, is yet traceable to its antecedents ; and thus, as the handmaid of religion, proves that what a man soweth, that shall be also reap."
p xxviii
....Special mention should also be made of his paper on "A Cretinoid Condition in Adult Women," almost the last he wrote. It bears evidence of the keenness of his perception and the accuracy of his pathological views, expressed about a not uncommon disease which had hitherto escaped notice. "It is remarkable," writes one of his colleagues, "that a disease which no one had recognised before its existence and characters were established by Gull has since been found to exist not only in this country and on the Continent, but in America and Australia. Moreover, he not only caught its characteristic facies, and recognised its importance, but in the name under which he described it, he indicated its true pathological relations, doubtful

and obscure for some time, but by recent investigation established beyond all reasonable doubt."
p xxxiii
....His admiring wonder of the works of Nature, first excited as he studied the lowest forms of life in the water-butt in his mother's garden, in his wanderings by the sea-shore, or, in the various creatures dredged up, on the many expeditions in his father's boats, continued undiminished throughout his long and active career, and was a constant source of relaxation to him from his professional work. Even the marvel of a tadpole was always fresh, teaching new lessons and opening out new avenues of thought.

In London the sparrows were his teachers and his friends. He would watch their habits and ways with the greatest interest, and would note their respective positions when roosting, deducing from the similarity of these night settlement, the probable fact that each sparrow had its own particular resting place.
For every subject of interest he had a ready quotation, and he would add after contemplation of his little friends, Shakespeare's words:
There's a special providence in the fall of a sparrow."
1899 LE MYXOEDÈME (Myxoedema). Par le Dr. THIBIERGE. Paris : Masson et Cie. 1898. (Royal 8vo, pp. 32. Fr. 1.25). BMJ JUNE 3, 1899 Vol. I p 1339
IN this monograph, which belongs to the medico-chirugical series appearing under the direction of Dr. Critzman, the author divides the subject into : (1) Spontaneous myxoedema of the adult ; (2) infantile myxoedema ; (3) operative myxoedema ; and (4) endemic myxoedema or cretinism. In infantile myxoedema the functions of the thyroid body are suppressed during the period of the development of the individual. Typical cases justify the name of myxoedematous idiocy. Under endemic myxoedema the author observes that mere enlargement of an organ does not necessarily imply increased function, for such enlarged organs may be physiologically inert if the glandular element has been destroyed and replaced by a pathological tissue. After describing the individual forms, Dr. THIBIERGE deals with the diagnosis, pathogeny, and treatment of the affection as a whole. He thinks that iodothyrin is not the only active substance of the thyroid body, although it is the one which has been best studied. The question of the accessory thyroids or parathyroid glands is also discussed. Here the author states that they have not exactly the same significance in man as in animals. Attention is drawn to the untoward symptoms sometimes attending thyroid treatment. Dr. Thibierge's monograph contains an interesting and clear account of a subject of much importance.

1932 EXTRACTS FROM Diagnosis and Treatment of Diseases of Thyroid Gland. By G. Crile and associates ... Edited by Amy F. Rowland, etc. W. B. Saunders Co.: Philadelphia & London, 1932. 8o.
p 96 - 100

There are varying degrees of lack in any deficiency disease, the milder grade producing less definite and more obscure symptoms than those present in the advanced stages. This is particularly true of the milder forms of thyroid deficiency. In its earliest or mildest stages the disease absolutely lacks any pathognomonic signs and symptoms and the diagnosis is further obscured by the tendency of the hypometabolism - as in the type of hypothyroidism last described - to exert a selective action on the various organs and systems of the body, thus producing disturbances which are characteristic of other conditions, such as anemia, constipation, dysmenorrhea, etc. The fact that specific diagnostic methods are lacking and that other diagnoses can be made, which apparently explain the symptoms, results in a failure to recognize the underlying condition in many of these cases. A knowledge of the wide variety of disorders, which may result from mild or incipient hypothyroidism, apprises us of the fact that low metabolism caused by thyroid deficiency must be considered as an etiologic factor much more frequently than is usually supposed. It is true that in the presence of hypothyroidism a mistaken diagnosis does not mean life or death to the patient or, as a rule, even serious disability, but still the fact remains that the well-being of many people could be improved if this condition were more frequently detected in its early stages.
Incipient hypothyroidism occurs at all ages. In children mild deficiency may be the cause of behaviour problems, or of a mild degree of physical or mental inertia, which often is not abnormal enough to be given much consideration. In children of this type startling results occasionally follow the administration of small doses of thyroid extract.
At puberty and in the early teens diminished endurance and a tendency to anemia, nervous disorders, dysmenorrhea, or digestive
disturbances often can be explained as due to a mild degree of hypothyroidism. Extreme physical and nervous exhaustion in young adults, the depressions of middle life, and aggravated symptoms of the menopause may be partially explained on this basis. Late symptoms which simulate senile changes frequently are distinctly improved by the administration of thyroid extract.
If we review the body by systems we find that each may be affected by this disorder which is as protean in its aspects as is hyperthyroidism. Nervous disorders such as headaches, neurasthenia, mild psychic disturbances, especially affective disorders, fears, anxieties, poor memory, and difficult concentration, are frequently seen.
Cases are reported in which disturbances of the special senses, tinnitus, poor hearing, and weakness of the ocular muscles have been benefited by treatment with thyroid extract.

Circulatory symptoms are referred chiefly to the heart and are caused by myocardial degeneration. Mild anginal symptoms occasionally occur. Hypothyroidism is supposed to predispose to premature arteriosclerosis. The associated hypotension and bradycardia often cause vague nervous disturbances which are referred to the circulatory system.
The respiratory system is not frequently affected but the tendency to take deep sighing respirations, often seen in nervous people, is frequently favorably affected by treatment with thyroid extract.

Gastro-intestinal symptoms are extremely common. Anorexia, distress after eating, belching of gas, vomiting, obstinate constipation, and occasionally diarrhea occur.
The genito-urinary system usually escapes any effects of mild thyroid deficiency, albuminuria occurring only in the late stages of myxedema.

The menstrual function is especially susceptible to extremely mild thyroid deficiency and every type of disturbance may be seen from amenorrhea to profuse menorrhagia especially at the menopause. That these disturbances may be due to hypothyroidism is evidenced by the improvement which results from the administration of thyroid extract in small doses. Sterility is a well-recognised result of this condition, and in all cases of sterility both the male and the female partner should be studied to see whether or not hypothyroidism is present in either.

Joint symptoms, muscular aches and pains, skin disorders and many other minor disorders are reported from time to time to be the result of hypothyroidism. The ordinary effects of hypometabolism, asthenia, obesity, subnormal temperature, and susceptibility to cold, dry skin and brittle nails, and tendency to excessive drowsiness are of course frequently seen and one or more of the features usually are present in every case.
The variations which may occur are surprising. Some patients show a very marked degree of nervous energy; some patients instead of being obese, are thin and emaciated and gain weight on thyroid medication; some complain of insomnia. It is obvious, therefore, that there is no definite clinical picture of this incipient type of hypothyroidism. Hypothyroidism should be suspected when such conditions cannot be explained as due to some other cause and if the diagnosis cannot be established, a brief therapeutic trial of thyroid extract will not do any harm provided the patient is kept under careful observation.
The treatment of hypothyroidism of any type consists merely in the substitution of thyroid extract for the deficient secretion. Any form of prepared gland or the active principle, thyroxin, may be used. The gland extracts are satisfactory but the products of the many manufacturing companies vary greatly in their relative potency. One should select one or two extracts and become familiar with the results that may be expected from each and then be sure that the patient uses the one that is prescribed. Only in this way can satisfactory results be obtained. One should also be familiar with the action of thyroxin, for some patients in whom gland extracts are ineffective respond to this, and at times the reverse is true.
No matter how mild or severe the case, I prefer to begin with small doses and to increase the dosage gradually until the replacement is sufficient to bring the metabolism to normal, although many prefer to start immediately with doses sufficient to restore the patient to normal, this dosage being calculated on the basis of the metabolic rate. There are two criticisms of this method. First, the patient will not always tolerate large doses immediately and in consequence becomes frightened for they are often familiar with the warnings in regard to the use of thyroid extract for reducing and any untoward symptoms will often dissuade them from making any further trial of this medication. Patients who have previously had hyperthy-
roidism are also fearful of a return of their former trouble and must be handled cautiously. The second criticism is that any method of calculation is very unreliable. The condition of some patients with a very low metabolism will become normal under dosage with very small amounts of thyroid extract and others whose basal metabolic rate is only slightly below normal will tolerate large doses.
A very important point in the treatment of hypothyroidism, which for some reason is almost universally disregarded, is that the patient should continue to receive adequate doses after the metabolism has reached the normal level. Very frequently I have seen patients, in whom marvelous results have followed thyroid medication, who have been advised discontinue medication completely for a while. It seems to be the opinion that the thyroid function is restored to normal by the thyroid extract while in truth it is only a substitution for a deficiency which will probably continue as long as the patient lives.
I have found that there is seasonal variation in the amount of thyroid extract required, more being necessary in cold weather. Patients who travel should be warned that it may be necessary to vary the dosage with their geographical location. It seems to be especially true that distinctly less amounts are necessary when patients sojourn for any length of time along the seashore. Whether or not it has any beneficial effect, I advise the use of as much fresh sea food as possible, but usually do not prescribe iodine together with thyroid extract. Early in the course of treatment a determination of the basal metabolism should be made every month until the normal level is reached and the proper maintenance dosage determined. A check of the patient's pulse and inquiry concerning the symptoms of palpitation, tremor, and insomnia are made weekly to check overdosage. A very good point to remember is that it is well to administer the thyroid extract early in the day and to avoid giving it late in the afternoon and in the evening. Even when the metabolism is well below normal very unpleasant palpitation is often experienced when the patient assumes the recumbent position at bedtime, if thyroid extract has been taken as recently as five or six hours before. In any case one commonly finds that the subnormal symptoms are more pronounced in the morning and therefore the dose should be given at this time. I do not think it makes much difference whether it is taken on a full or an empty stomach or whether it is given in enteric capsules.

I have mentioned the therapeutic test in doubtful cases, that is, the administration of small doses of thyroid extract for short periods. This can do no harm if the patient is carefully observed and it will often give brilliant results in an otherwise puzzling case. I have never seen any symptoms of overdosage remain permanently after the administration of the thyroid extract was discontinued. Many physicians have a great fear of this drug and hesitate to use it in proper amounts to give the maximum benefit. However, frequent observation and occasional checks of the metabolism take away all dangers which pertain to the use of thyroid extract.

1948 extracts from Diseases of the Endocrine System Zondek (2nd edition reprint)

Chapter XI Graves disease
pg 149 The Peripheral Theory
The peripheral theory (H.Zondek) refers the seat of the primary disturbance to the tissues. The nature of the disturbance may be twofold: (i) either the tissues react abnormally to the thyroid hormone: (ii) or impulses originating in the peripheral tissues stimulate thyroid function.
(i) Normal action of every hormone on the organ which it influences, depends upon the momentary physico-chemical condition of the cell surface in that organ. Among the chief factors influencing the colloid structure of the cell surface are the autonomic nerves and the electrolytes, particularly it's pH. The efficiency of the thyroid hormone on the cells is directed by the same forces. The autonomic nervous system had already in the past been regarded as an important factor in pathogenesis (vide supra), but it was regarded as the sole one.
I has been proved by numerous experiments which cannot be detailed here, that synergistic relations exist between the action of thyroxine and the tonus of the sympathetic nervous system (or the pharmacodynamic action of adrenaline). This has been shown for almost all organs, for the circulation, live, carbohydrate metabolism, et. Hence it is clear that under the influence of raised sympathetic tonus a cell must react more strongly to the same dose of thyroxine. The same holds good for the pH. H. Zondek and "Wislicki found that oxygen consumption of solated muscular tissue at different pH increased with alkalinity. These experiments tend to show the fundamental importance of the cell's environment on all it's functions, particularly metabolism.
Clinical considerations. The role of agents other than thyroid is shown by those cases of Grave's disease where no histological changes are explained by the peripheral theory which postulates that in them there is not an absolute but only a relative hypersecretion of thyroid hormone: the abnormal sensitivity of the cell to the hormone being the determining factor. The same applies to "mixed thyroidism" (H. Zondek), where marked thyrotoxic traits are associated with a tendency to obesity; here too, a local factor may be assumed the inhibit hormonal action at the periphery. In those cases of Grave's disease where localised myxoedema, verified histologically, occurs in the extremities (Sattler, Richl), one must assume the thyroid hormone to be inactivated at the periphery. Lastly, in normal human beings and animals Grave's disease or increased oxidation in the body has not been produced with large doses of thyroid hormone whilst in susceptible subjects it can be caused with much smaller doses. That fact alone shows conclusively the importance of a constitutional factor as an indispensable condition for a pathological hormonal effect. "Not always does hyperthyroidism lead to Grave's disease, nor is every case of Grave's disease primarily hyperthyroid." (H. Zondek).
The hormone alone cannot cause the disturbances which constitute the Graves syndrome. Physiological equilibrium is deranged only if at least two of the regulating factors, viz. hormone and electrolyte equilibrium, are disturbed.
(ii) The peripheral theory further postulates that peripheral influences can stimulate the thyroid, i.e., that changes in the peripheral conditions can cause a secondary increase in thyroid function. If such is the case with a person constitutionally predisposed, even the actual Grave's syndrome may develop. This is shown in animal experiments: e.g. if rabbits are fed exclusively on cabbage, their thyroid grows and shows the histological features of the activated gland. Marine found the reason for this in the high cyanide content of cabbage which inhibits oxidation in the peripheral tissues and thus leads to thyroid hyperplasia.
Clinical evidence. In numerous cases Graves' disease starts acutely after severe physical efforts. In them the disease begins with asthenia and loss of weight, whilst thyroid hyperplasia develops only at a later stage. The inference is obvious that the enormous demand son the performance of oxidative work by the peripheral tissues - demands on the performance of oxidative work by the peripheral tissues - demands far in excess of what they can fulfil - lead to excessive secretion of thyroid hormone (comparable to the rabbit experiment mention previously). Such hyper-secretion will no always exactly correspond to the body's requirements. Now if the patients is abnormally sensitive to the hormone (by means of special conditions in the peripheral tissues), then peripheral metabolism will be greatly enhance, yet more hormone will be called for, and the patient will become the victim of a dangerous vicious cycle.
SUMMARY. The peripheral theory stresses the relativity of the term "hyper-function". The patho-physiological condition of hormonal hyperfunction depends therefore not alone upon the activity of the secreting gland, but also on the susceptibility of the organ influenced. But this theory does not refer the pathogenesis of Graves' disease to peripheral factors alone; rather does it emphasise the close functional connection between all regulative factors, viz., hormonal gland, autonomic nervous system, electrolytes, and perhaps even others. Every theory which explains patho-physiological developments by one single mechanism must be wrong, for each of the factors named can start the disturbance.
pg. 153
Little is known about the influence of severe infectious diseases on the pathogenesis of Graves' disease. Many cases have been recorded where Graves' disease developed during or soon after the onset of acute or chronic infections, e.g. scarlet fever, diptheria, enteric fever, pneumonia, whooping cough, influenza, rheumatic fever. In some cases thyrotoxicosis was

only temporary. In a detailed study, Schereschewsky has shown such combinations to be especially frequent in children. H. Zondek described three cases where typical Graves' disease developed in patients with chronic tuberculosis and subfebrile temperatures. Engel-Heimers noted relations between Graves' disease and syphilis.
The mechanism by which disease arises in such cases may occasionally be that the original illness causes inflammation of the thyroid and thus leads to thyrotoxicosis. In other cases, the fever, through increased oxidation in the peripheral organs, might stimulate the thyroid, as assumed by the peripheral theory. But undoubtedly constitutional predisposition is always involved.

pg. 155 The Comatose Form
In striking contrast to the mild forms discussed hitherto is the severest type, the comatose form. "Coma basedowicum" (H. Zondek). Its chief features are the following: It mostly attacks patients in whom toxic phenomena had been rather pronounced from the outset. Wasting, sweating, tachycardia have predominated: the metabolic rate is usually not much increased, and goitre is usually slight or absent. After some mild infection (e.g. tonsillitis, bronchitis), sometimes even without such preliminary, a grave condition develops which almost unexceptionally ends fatally within a few days.
The catastrophic change occurs almost simultaneously with the onset of fever. The hyperkinesis (tremor, restlessness) characteristic of Graves disease almost suddenly gives place to the other extreme. After a varying period of excitement consciousness gradually grows dimmer: a peculiar form of rigidity develops in which all facial expression is lost, the countenance becomes blank. At first patients are still able to answer questions with some delay, as if their power of association was impeded: later they become completely unconscious. Their condition closely resembles catalepsy, only the limbs are not rigid.
A very marked sign which is seen fairly early is intense asthenia. At the height of the illness not the slightest movement can be performed. Even when consciousness partially returns the patients are hardly able to lift the limbs. The mouth and other mucous membranes are very dry. A very serious feature is the difficulty, or complete incapacity to swallow: this sign might lead to a mistaken diagnosis of bulbar paralysis or sever myasthenia. At an early stage speech is impeded and blurred. When semi-conscious, the patients pass urine and faeces involuntarily.
At the onset of coma the blood supply to the skin is usually adequate, nose and limbs are warm. Circulation is, therefore, not insufficient, although terminally the pulse rate rises to 160 or 180; but even then the pulse remains fairly well filled. The reflexes are normal. Respiration is rapid and regular but not markedly deep. Conforming to the severity of the illness there is leucocytosis with shift to the left. In the urine acetone compounds were only seen in one case. In another case the urine contained numerous casts for several days, but blood pressure and non-protein nitrogen were normal.
Pathogenic bacteria were never found in the blood. Sugar, non-protein nitrogen, calcium, magnesium, and potassium in the blood were always normal. It may be significant that in two of my cases blood iodine, determined by A. Bier, was remarkably low - about 10 μg. per 100c.c. - during the last day or two, but rose to high levels - about 50 μg. - just before death.
These cases cannot reasonable be classified with the ordinary groups of Grave's disease, viz. acute or chronic, pituitary or secondary form, diffuse or nodular goitre. But I am under the impression that is exceedingly rare for the comatose form to develop in cases with well marked typical signs of Grave's disease. In the comatose form goitre is mostly only slight; so far as can be determined by clinical methods, the size of the thyroid and it's resistance to palpation do not change in the beginning or in the course of the coma. Basal metabolism also seems not to be in relation with the development of the comatose condition.
Histologically, no marked change is found in the thyroid which would explain the grave illness. In some of my cases the goitre was chiefly colloid, the epithelial cells and follicles being normal. In others the epithelia were cubical or columnar; there was much branching and marked pleomorphism of the follicles; In some of them the colloid was then or even absent; here and there solid cell clusters lay between the follicles. Thus many cases showed the appearance typical of "struma basedowiana" i.e. goitre with the primary changes of Grave's disease. In some cases the goitre was nodular. In the other organs the findings were completely negative, apart from terminal bronchopneumonia in a few cases.
The name "comatose form" applied to this grave illness is only meant to serve for its classification without implying anything about its origin. Indeed, it is not even possible to determine whether the catastrophic change is brought about by some toxic factor - perhaps flooding of the body with thyroxine, or relative oxygen deficiency in the tissues - or whether a sudden loss of immunity to an infectious agent turns the scales. From the hyperplasia of the thymus observed in some cases it is not possible to infer depression of their antibacterial resistance. But it is known that the transfer of oxygen to the tissues is notably influenced by thyroxine which lowers the oxygen dissociation curve (H. Zondek and Hansi); further, it is probable from the investigation of A. Bier that thyroxine or iodine are deficient during the apparently thyrotoxic state following surgical treatment of Grave's disease. The importance of functional failure in Grave's disease should therefore be considered. Further research will have to determine whether in the comatose form the thyroxine content of the blood is actually diminished. Another possibility is that some acute damage to the liver and muscular tissue might derange glycogen and fat metabolism. Some evidence for this view is given by the result of treating such cases with glucose and liver preparations. The dominant impression is that in the comatose form the morbid process has attacked the cerebral centres (Klien). Riese has described certain forms of Grave's disease originating from the corpus striatum. Older treatises on Grave's disease contain a number of records of anatomical changes in the central nervous system, but the majority were quite negative. In my cases there were neither macroscopical nor (Wuellenweber) microscopical changes in the central nervous system. All the same, there can be no doubt that with the onset of the comatose state cerebral signs appear. It is an object to further study to determine whether they are due to functional or organic changes in the brain.

The treatment of the comatose form is describe on page 173. Since treatment begun early enough may save life, accurate knowledge of the comatose form and careful attention to its early signs are essential. Even if speech has become difficult and indistinct, perception and consciousness slightly disturbed, and the patient can no more raise the head or keep the jaw up, a cure may still be possible. Only in a few cases does the genuine comatose form develop within a few hours and then lead up to the rapid catastrophe.

1966 The Citizen surgeon. A biography of Sir Victor Horsley, F.R.S., F.R.C.S., 1857-1916. Peter Dawnay: London, 1966 John Benignus Lyons
Chapter IV
p 31

....One of those who brought a problem to the Brown Institution was Dr. (later Sir Felix) Semon, a throat specialist, who was studying the action of the vocal cords.
Semon, a German Jew, came to London for post-graduate study intending toe stay a few months and remained a lifetime.
p 32

....Semon's practice included crowned heads and distinguished actors and singers. His spectacular success did not prevent him from doing research and making notable contributions to the literature of his speciality. His most important discovery concerned paralysis of the vocal cords. From observations on patients he came to the conclusion that paralysis of the abductor and aductor muscles are due respectively to organic disease and to hysteria (Semon's Law) Wishing to investigate this further on animals he did several experiments which entailed dividing the nerves to the larynx and stimulating them electrically. To his disappointment his results were confusing and contradictory. At last he realized that his technique was at fault and that his experience of experimental physiology was inadequate. He was delighted when Horsley offered to help him to investigate the relation of the larynx to the nervous system.

.p 33
....Semon, whose training was that of a physician rather than a surgeon, benefited in another way from his association with Horsley. When the former became interested in cancer of the larynx he was at first obliged to seek the assistance of surgical colleagues to operate on his patients. He was not always satisfied with their results and his criticisms were resented. Finally he decided to do the operations himself and was encouraged to do so by Horsley who guided Semon's had when he adopted a role unusual for a Fellow of the Royal College of Physicians.
Horsley, too, owed a debt to the throat specialist whose suggestion led to a new conception of the function of the thyroid gland, a chapter of research in which Victor Horsley played an important part.
A trinity of evils - cretinism, myxoedema, and the condition described as cachexia strumpriva - result from deficiency of the hormone of the thyroid gland. Cretinism, which affects infants, has long been recognized. This tragic condition has never been better outlined than in Sir William Osler's description: No type of human transformation is more distressing to look at than an aggravated case of cretinism. The stunted stature, the semi-bestial aspect, the blubber lips, retroussé nose sunken at the root, the wide-open mouth, the lolling tongue, the small eyes, half-closed into swollen lids, the stolid expressionless face, the squat figure, the muddy dry skin, combine to make the picture of what has been well termed "the pariah of nature".
Gull of Guy's Hospital drew attention in 1875 to a condition particularly affecting females characterized by increasing indolence and a transformation of appearance progressing to a state of
p 34
profound torpor and dementia. A few years later because of the mucinous change in the skin and superficial tissues responsible for the swollen bloated appearance of its victims the condition was named 'myxoedema' by W. M. Ord.
At the same period advances in anaesthetics and in surgical techniques were permitting more extensive operations for goitre and in Switzerland, where large goitres are common, complete removal of the thyroid gland was being practised. Kocher of Berne and the cousins Jacques and Auguste Reverdin of Geneva were the foremost exponents of this operation. Independently, in 1882, they described the ill-effects encountered in a high number of patients who had submitted to complete removal of the thyroid (or stuma as it was also called) and gave the name cachexia stumipriva to the state of weakness and hebetude that ensued.
At a meeting of the London Clinical Society in 1883 Felix Semon declared that cretinism, myxoedema, and cachexia stumipriva were phases of one and the same state - arrest of the function of the thyroid gland. The novelty of the idea is not likely to be grasped unless it is appreciated that at the period there was total ignorance of the function of the thyroid gland and, indeed, of internally-secreting glands in general. Not long before, it had actually been suggested that the thyroid gland was merely a bolster keeping the pressure of the neck muscles off important neighbouring structures. And Kocher and the Reverdins, although in no doubt that their operations had caused mischief, were prepared at first to speculate on the possibility that total removal of the gland had caused damage to the windpipe Later they wondered if the untoward sequelae were due to damage to nerves in the gland rather than to lack of gland tissue.
Semon's remarks were received with polite scepticism but not in the least discouraged the German throat-specialist made the same suggestion in the following year. On the second occasion a committee was set up to consider the matter and Victor Horsley was asked to investigate the relationship of the thyroid gland to myxoedema experimentally.
Horsley lost no opportunity of seeing cases of myxoedema.
p 35
At Wandsworth Road he operated on monkeys, removing their thyroid glands. Subsequently they developed a state akin to myxoedema. Post mortem examinations were done and Horsley reported: 'On turning back the skin in an animal that has

lived for one month after the operation the subcutaneous tissue is found to be notably altered. It is swollen, jelly-like, bright and shining, and excessively sticky; the latter quality is unmistakable. I have many hundreds of post-mortem examinations in man and the lower animals and do not remember having met with this condition before.'
Horsley supplied conclusive proof that myxoedema could be produced by removal of the thyroid gland. He showed that this was quite independent of interference with the nerves and that the thyroid which consists of true secreting gland tissue manufactures from the blood a colloid substance which is again transmitted to the blood. Moritz Schiff of Geneva, who as early as 1856 had demonstrated that removal of this gland in dogs was fatal, resumed this work in 1884 and showed that death could be prevented if prior to removal a gland from another gland was grafted into the abdominal cavity. Anton Von Eiselsberg of Utrecht was engaged in similar experiments which he reported in 1890.

In the intervening years other interests had loomed larger in Horsley's life but throughout he maintained contact with research in myxoedema and had become an accepted authority on the surgery of the thyroid. He published a note on myxoedema and cachexia stumipriva in the British Medical Journal in February 1890:
It seems that these observations of Professor Schiff and Dr. Von Eiselsberg are of special value, as they suggest to my mind that possibly the diseases mentioned .... may be treated with success by transplanting thyroid tissues into the patient. In the first place these diseases are hopelessly incurable with present remedies and consequently anything possibly remedial not endangering life is justifiable.

Speculating on the species from which glands for implantation might be obtained Horsley thought that anthropoid apes might
p 36
be best, but impracticable, and that the sheep's thyroid resembled that of man.

Dr. G. R. Murray of Newcastle wrote to Horsley whom he had known at University College Hospital,, where he had been a house-physician, suggesting that injections of thyroid extract (which Vassale had given to dogs with apparent benefit) might be equally successful. Horsley, with the idea of implantation in his mind, did not at first favour Murray's alternative but he was converted to it. Hector Mackenzie, however, showed that thyroid could be given effectively by mouth and that neither injections nor implantation are necessary.

Thus the modern treatment of myxoedema - one of the most spectacular and successful in the entire field of medicine - was established. The administration of one or two tablets daily can restore and individual who appears to be in the last stage of mental and bodily degeneration to normal health. The flickering embers of cellular life burn brightly again when the miraculous catalyst is supplied.

Horsley's contribution to this achievement was a large one, even though Mackenzie's simpler expedient finally won the day, and his research added impetus to fundamental studies into the physiology of internal-secreting glands. Sir Walter Langdon- Brown who was then a young man wrote of it many years later:
I still well remember, almost as if it were yesterday, the thrill of excitement which went through the Physiological Laboratory at Cambridge when on January 30th, 1892, a paper appeared in the British Medical Journal entitled 'Remarks on the Function of the Thyroid Gland; a critical and historical review'. It was by Victor Horsley, whose name up till then was only known to me by a drawing he made for Schemer's Histology. We eagerly awaited the second part of that paper which appeared a week later. Instinctively we felt that the door was open to a long avenue of discovery. And we were right.

One of the first milestones in that avenue of discovery marked the demonstration on 10 March, 1894, by Schafer and George Oliver of the action of an extract of the adrenal glands, which they named adrenaline. And in 1914, E. C. Kendall isolated thyroxine, the hormone of the thyroid gland, lack of which causes cretinism, myxoedema, and cachexia stumipriva.

1971 FUNDAMENTALS OF INTERNAL MEDICINE A Physiological and Clinical Approach to Disease
ROBERT P. McCOMBS, B.S., M.D., F.A.C.P. Professor of Medicine, Tufts University School of Medicine; Senior Physician, New England Medical Center Hospital FOURTH EDITION, 1971
Myxedema heart disease.- Some cardiac involvement is evident in nearly every case of clinically recognizable myxedema in adults. This is so regularly true that the diagnosis of myxedema should be made only with great caution when the heart is found to be normal. On the other hand, the diagnosis of myxedema may first be suspected by noting a globular configuration of the heart on x-ray examination, or low voltage and flat or inverted T waves on electrocardiography (Fig. 5-11). Contrary to common teaching, blood pressure in myxedema often is elevated; the pulse pressure, however, is usually narrow. Massive edema due to myxedema heart disease is the exception rather than the rule. Atherosclerosis and coronary vascular disease probably are increased because sclerosis and coronary vascular disease probably are increased because of the hypercholesterolemia of myxedema; yet angina pectoris and certain types of chronic congestive heart failure are benefited by the development of hypothyroidism because of the lessened metabolic needs of the body and the lessened work load of the heart.

p 385
Vascular Diseases
Atherosclerosis and arteriosclerosis.- Many animals do not develop atherosclerosis spontaneously; rabbits, chickens, pigs, parrots and monkeys, however, do develop spontaneous atherosclerosis but to a lesser degree than does man. The development of atherosclerosis in experimental animals may be greatly speeded up by cholesterol feeding, depressing

thyroid function, feeding diets low in sulphur amino acids, producing pyridoxin deficiency (monkeys), choline deficiency (rats), and by intravenous infusions of lipoproteins, egg yolk or emulsions of cholesterol. The establishment of renal hypertension in animals augments the development of atherosclerosis.
In humans, the etiology of atherosclerosis is obscure, but hereditary factors are of great importance. The incidence of atherosclerosis is very high at relatively early ages in families with ypercholesterolemia and hyperlipemia. Similarly, it is associated with diabetes, essential hypertension and gout, suggesting that a genetic defect may be at fault (see Hyperlipoproteinemias, p. 252).

Studies on the blood vessels of soldiers killed in the Korean War indicate that atherosclerosis may be present in appreciable amounts before the age of 25 in men. Some degree of atherosclerosis is present in about half the male population by the age of 45, and, of course, there is an increasing incidence with increasing age. Unfortunately, atherosclerosis cannot be recognized clinically until it produces symptoms or signs that are usually due to diminished arterial blood flow to a particular area.

THE HEART.- The anginal syndrome due to atherosclerosis of the coronary arteries is a well-known example of an effect of diminished circulation to a vital area and coronary thrombosis with myocardial infarction a sequel.

The Thyroid
The functions of the thyroid are intimately concerned with the metabolism of iodine. The average normal dietary content of iodine (as iodide) varies between 50 and 200 μg. per day. Iodide is readily absorbed from the intestinal tract and is rapidly removed from the blood, chiefly by the thyroid. The rate of iodide uptake by the thyroid may be accurately measured by the radioactive iodine tracer technique; this is a useful method in studying thyroid physiology and in clinical diagnosis of thyroid dysfunctions.
The accumulated iodide in the thyroid is oxidised to iodine whence it is converted to monoiodo- and diiodotyrosine and to triiodothyronine and thyroxin. The oxidation of iodide to iodine in the thyroid may be blocked by thiouracil and related antithyroid compounds and by the sulfonamides in some species, but not in man. This mechanism forms the basis of the therapy of hyperthyroidism with the antithyroid drugs.
Thyroxin and triiodothyronine are stored in the acini of the thyroid as a colloid, thyroglobulin, but are released into the circulation as needed. The amount of these hormones normally stored in the gland is considerable, a period of several weeks being necessary for its exhaustion following inhibition of formation by antithyroid drugs. Approximately 60 to 80 per cent of the iodine in the body is stored in the thyroid, first as inorganic iodide and later, after conversion, as thyroxin and triiodothyronine.
Thyroxin is released into the circulation at the rate of about 70-125 μg. per day. In thryotoxicosis, the rate of thyroxin production may reach ten times the normal value and in myxedema the production and release of thyroxin is very low.
Both thyroxin and triiodothyronine are active hormones secreted by the thyroid. Eighty per cent of the hormone in the blood is thyroxin, but much of this is bound by an a2 globulin which renders it inactive; some thyroxin also is bound by albumin and prealbumin. Triiodothyronine is less tightly bound by plasma proteins and is more rapid in its action than thyroxin. The metabolic actions of thyroxin and triiodothyronine are similar.
The rate of excretion of iodide from the body under normal conditions equals the intake. Approximately 95 per cent is recoverable in
the urine, the remainder being in the stool. The rate of excretion of radioiodine following the administration of a test dose also is useful as a test of thyroid function. When the uptake of iodide by the thyroid is increased, urinary excretion is reduced.
Actions of thyroid hormones.- Thyroid hormone is essential for normal growth; hypothyroidism in children (cretinism) is associated with stunted growth and retarded skeletal, mental and sexual development. If the condition is recognized in its early months and substitution therapy instituted, permanent damage may be avoided, but if the condition is allowed to go untreated for 2 or 3 years, permanent dwarfism and mental retardation are probably inevitable.
The relationship of thyroxin to the metabolic rate is well known. Following total thyroidectomy, the basal metabolic rate is reduced by 40 per cent. In hyperthyroidism, considerable increases in the metabolic rate are usually noted, and patients are aware of their increased heat production.
Thyroid exerts an important influence upon the heart and circulatory system. It stimulates cardiac rate and stroke volume, apparently by increasing the sensitivity of the muscle to epinephrine. Cardiac output is increased and circulatory rate shortened. The rhythm of the heart may be disturbed. Lack of thyroxin has the opposite effect and a slow heart rate, reduced cardiac output and decreased circulatory rate become evident; conduction defects are noted by electrocardiography.
Protein catabolism is stimulated by thyroxin but probably only to meet the increased metabolic needs. Carbohydrate metabolism is similarly affected. In addition, clinically evident or potential diabetes may be aggravated by thyroxin, and patients with hyperthyroidism may show nondiabetic glycosuria. Cholesterol metabolism is disturbed in hypothyroidism and elevations of serum cholesterol are common in myxedema; the administration of thyroid hormone restores the cholesterol level to normal. In hyperthyroidism, blood cholesterol may be low.
Thyroxin is probably necessary for the normal maturation of red blood cells and a macrocytic anemia may occur in hypothyroidism. In hyperthyroidism, mild hypochronic; microcytic anemia may occur. There is a relationship between

thyroid activity and vitamin A metabolism. Beta carotene is a precursor of vitamin A; in hypothyrodism, carotenemia occurs, producing a yellowish tinge to the skin. In hyperthyroidism, latent vitamin deficiency may become evident as an expression of the increased metabolic needs of the body.
In myxedema, there is some extracellular fluid accumulation and deposition of a collagenous or myxomatous material in the subcutaneous tissues. With fluid retention, sodium is retained. Following the adminis

(612 diagram)
tration of thyroid extract, a moderate diuresis may occur. In hyperthyroidism, calcium and phosphorus excretion is increased.
Emotional instability, hyperactivity, muscle tremor hyperperistalsis, increased sweating and vasomotor instability characterize the effect of excessive amounts of thyroxin upon the nervous system. In myxedema reactions opposite to these are noted. Myasthenia and creatinuria occur in hyperthyroidism, indicating a direct effect of the hormone upon muscle metabolism, and, indeed, focal necrosis of muscles may occur.
There is a relationship between the thyroid and other hormones.
The administration of thyrotropin increases iodide uptake and thyroxin production, and the administration of thyroxin causes pituitary atrophy and cessation of formation of thyrotropin. Epinephrine stimulates thyroid activity. On the other hand, adrenal cortical hormones suppress thyroid activity to some degree, and the administration of thyroid extract causes depletion of the adrenal cortex. The relationship of the thyroid to the gonads is not clear, but goiter develops commonly at puberty and hyperthyroidism at the menopause; menstrual irregularities characteristically occur in hyper- and hypothyroidism. The relationship of thyroid hormones and long-acting thyroid stimulator (LATS) is described on page 571. CLINICAL CONSIDERATIONS
Laboratory aids in diagnosis of thyroid disorders.- BASAL METABOLIC RATE.- This test has been widely used, but as it is generally done in office or hospital practice it is not a reliable guide to the diagnoses of hyperthyroidism or myxedema. In the overt cases, no laboratory confirmation is necessary, but in the doubtful case, treatment should not be instituted solely on the basis of an abnormal BMR.
Basal metabolism, as it is ordinarily determined, is a measure of the heat produced by the body under basal conditions (patients at rest in the fasting state). It is determined by measuring the amount of oxygen consumed in a definite period. Corrections must be made for room temperature and barometric pressure. If the height and weight of the patient are known, the surface area of the body can be calculated from standard tables. The number of calories per square meter of body surface per hour is the common denominator in comparing energy production. Normals have been established for the various age groups. The final determinations are usually expressed as percentages of the mean normal values. The figures usually given as "normal variations" are +10 to -10 per cent. In clinical practice, however, these standards must be taken with considerable latitude. In hospitals, normal values considerably be
low the "accepted" standards will be found to be the rule (+5 to - 15 or -20 per cent). This probably occurs because the "standards" were established from ambulatory healthy individuals, whereas hospitalized patients may be debilitated and have usually rested (often under sedation) for at least 12 hours prior to the test. It must also be remembered that the perfectly normal individuals may have basal metabolic rates moderately above or below the "normal" limits.
There are technical factors that must be taken into consideration. Leaks in the apparatus and gas leaks due to perforation of an ear drum may give falsely high readings. Hysterical hyperventilation and sighing also are apt to increase the apparent oxygen consumption. An inspection of the tracing made during the test, noting the evenness of breathing and any discrepancies in the rate of oxygen utilization, usually will serve to disclose these artifacts.
Elevation of the basal metabolic rate is regularly observed in hyperthyroidism. The rate is also increased by pregnancy, fever, hematologic disorders (anemia, leukemia and polycythemia), diabetes insipidus, malignant disease, pulmonary diseases and heart failure.
Depression of the metabolic rate is found in hypothyroidism. Other causes of abnormal depression of the metabolic rate are: nephrosis, hypopituitarism, Addison's disease, prolonged cachexia from any cause (such as starvation, terminal malignancies and anorexia nervosa).

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2. Yater, W.M., Traum, A.H., Brown, W.G., Fitzgerald, R., Geller, M.A. and Wilcox, B.: Coronary artery disease in men 18- 39 years of age. 866 cases, 450 autopsies. Am Heart J, 36:344-372, 1948
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23. Johnson, K.G., and Kito, H.: Coronary heart disease in Hiroshima, Japan: A report of 6-year period of surveillance. Am J Public Health, 58:1355-1367, 1968.
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25. McNamara, J.J., Molot, M.A., Stremple, J.F., and Cutting, R.T.: Coronary artery disease in combat casualties in Vietnam. JAMA, 216:1185-1187, 1971.
26. Barnes, B.O.: Basal temperature versus basal metabolism. JAMA, 119:1072-1074, 1942.
27. Dawber, T.R; Moore, F.E.; and Mann, G.V.: Coronary Heart Disease in the Framingham Study American Journal Public Health, 47:4-24,1957

28. Smith, C.A.; Oberhelman, H.A.; Storer, E.H.; Woodward, E.R.; and Dragstadt L.R.: Production of Experimental Cretinism in Dogs by the Administration of Radioactive Iodine, Archives Surgery 63: 807, 1951
29. Barnes, Broda O.: The Treatment of Menstrual Disorders in General Practice. Arizona Medicine, 6: 33, 1940 30. Ord, W.M.: On Myxoedema, a Term Proposed to be Applied to an Essential Condition in the Cretinoid Infection Occasionally Observed in Middle-aged Women. Trans Med-Churg Society London, 60-61:57-78, 1877-78

31. Kendall, E.C.: Thyroxine, Chemical Catalog Co., New York, 1929.
32. Gross, J., Pitt-Rivers, R.: The identification of 3:5:3' L- Triodothyronine in human plasma. Lancet, I:439-441, 1952.
33. Gull, W.: A Cretinoid State Supervening in the Adult Life of Women.: London Clinical Society Transactions, 7: 180- 185, 1875
34. Report of a committee of the Clinical Society of London to investigate the subject of myxoedema. Transactions Clinical Society London, Supplement to Vol. 21, 1888
35. Murray, G.R.: Notes on the treatment of myxoedea by hypodermic injections of an extract of the thyroid gland of sheep. Br Med J, II:796-797,1891.
36. Kocher, T.: Letter to the Committee of the Clinical Society of London, reference 34, p.128.
37. Billroth, T.: Letter to the Committee of the Clinical Society of London, reference 34, p.99.
38. von Eiselsberg, A.F.: On Vegetative Disturbances in Growth of Animals after Early Thyroidectomy. Archives Clinick Chirugie, 49:207, 1895.
39. Pick, E.P., and Pineless, F.: Untersuchungen uber die physiologisch wirksame substanz der schilddruse. Exp Path Ther, 7:518, 1910.
40. Virchow, R.: Die Cellullarpathologie in ihrer Begrundung auf physiologische und pathologische Gewebelehre. August Hirshwald, Berlin, 1858.
41. Friedland, I.B.: Untersuchungen uber den einfluss der shilddrusenpraparate auf die experimentelle hypercholesterinamie und atheroskerose. Z Ges Exp Med, 87:683-702, 1933.
42. Leary, T.: Experimental atherosclerosis in the rabbit compared with human (coronary) atherosclerosis. Arch Path, 17:453-492.
43. Leary T: Atherosclerosis: Etiology. Arch Pathol, 21:419-458, 1936.
44. Zondek, H. "The Myxoedema Heart," in Munchen Medical Worchenschrift, 65: 1180, 1918.
45. Christian, H.A.: The Heart and Its Management in Myxedema.: Rhode Island Medical Journal, 8: 109-118, 1925

46. Smyth, C.J.: Angina pectoris and myocardial infarction as complications of myxedema. Am Heart J, 15:652-660, 1938 47. Hurxthal, L.M. Blood Cholesterol and Thyroid Disease.: Archives Internal Medicine, 53: 762, 1934
48. Gildea, E.F., Man, E.B., and Peters, J.P.: Serum lipoids and proteins in hypothyroidism. J. Clin Invest, 18:739-755, 1939. 49. Strisower, B.; Gofman, J.W.; Gaglioni, E.; Ribinger, J.; O'Brien, G.Wp; and Simon, A.: Effects of Long-Term Administration of Desiccated Thyroid on Serum Lipoprotein and Cholesterol Level.: Journal Clinical Endocrinology, 15: 73-80, 1955

50. Moses, C.: Pharmacology of drugs in the control of hypercholesterolemia. Angiology: 13:59-68, 1962.
51. Oliver, M.R., and Boyd, G.S.: Reduction of serum cholesterol by dextro-thyroxine in men with coronary heart disease. Lancet, I:783-785, 1961.
52. Owen, W.R.: Efficacy of drugs in lowering blood cholesterol Med Clin North Am, 48:347-353, 1964.
53. Kountz, W. B. Thyroid Function and Its Possible Role in Vascular Degeneration. Charles C. Thomas, Springfield, Illinois, 1951
54. Israel, M. "An Effective Therapeutic Approach to the Control of Atherosclerosis Illustrating Harmlessness of Prolonged Use of Thyroid Hormone in Coronary Disease," in American Journal Digestive Diseases, 22: 161-168, 1955
55. Wren, J.C. "Thyroid Function and Coronary Atherosclerosis," Journal American Geriatric Society, 16: 696-704, 1968.

1974 Victorian doctor: being the life of Sir William Wilde by T. G. Wilson, Wakefield: EP Publishing, 1974

p 18
....On the whole they were an idle lot, as medical students are apt to be, but they learned much by experience. Wilde tells us that the accident bell rang on an average once every two hours, and then the whole class, idle and industrious apprentices alike, rushed to the reception room. There they saw, in 'all their original freshness', fractures, cut throats, burns, head injuries, poisonings, lacerated wounds, crushed limbs, and all the routine of casualty practice. The Resident Surgeon or the clinical clerk did what was necessary - picked up a bleeding vessel, administered a stimulant, or gave an antidote, and then one of the 'young gentlemen' was given charge of the case. This was an excellent practical supplement to the precepts of their masters and the lectures they received outside the hospital.
The mental and moral upbringing of these young men was mostly in the capable hands of the Resident Surgeon. His position was very different from that of the present-day house surgeon, for instead of his being in a subservient position, he was perhaps the most important man on the staff.
[ 19
....At the beginning of the nineteenth century the curriculum of the medical student was very much more lax than it is to-day. To qualify as a surgeon a man had only to complete his indenture as an apprentice, and pass the examination of the Royal College of Surgeons, for compulsory courses of lectures were unknown. How or where the students acquired their knowledge was left to themselves to decide. In consequence, many private medical schools sprang up in Dublin, as in London, each with its dissecting-room, laboratory and museum. There are records of over thirty of these schools in Dublin between 1800 and 1860.
....No doctor forgets the impressions of his first days in his medical school. The change from boyhood's restrictions to the comparative freedom of the university, the new faces, the dissecting-room with its poor dried-up relics of mortality, the strange sights and the pungent smells, all produce an unforgettable atmosphere.
p 20
....Dissecting the cadaver in those days was not only unpleasant, but often extremely dangerous, for the bodies were often partly decomposed, and the students were sometimes affected by the foetid vapours which arose when the body was opened. A finger prick with the dissecting knife might prove a catastrophe. Sir Henry Marsh originally intended to become a surgeon, but lost the index finger of his right hand as the result of a dissecting wound. Colles was fully alive to the dangers of dissecting, and insisted that every wound should be immediately cauterized and plunged in a cup of oil of turpentine with which every dissecting table was furnished.
Whatever the quality of the bodies dissected, their numbers were never short, for the Dublin resurrectionist had reduced his trade to a fine art. Not only was he able to supply the needs of the Dublin schools, but also to conduct a flourishing export trade, mostly to Scotland via the North of Ireland.
p 22
,,,,The physicians of the eighteenth century, 'the golden age of quackery,' were pompous, periwigged creatures whose ignorance was as extreme as their vanity. Bleeding, blistering, and violent purgation were their principal methods of treatment ; feminine chastity and love-sickness were diagnosed by the inspection of a glass of urine in the sunlight. Some doctors were scholarly enough, others were mere charlatans, but most of them were utterly devoid of scientific conceptions. Son all this was to change, for with the beginning of the nineteenth century medicine began to emerge from the mists of superstitious ignorance which has enshrouded it since primitive ages.
....When he began his medical career, operations were usually limited to amputations, the removal of stones from the bladder, and the tying of arteries for aneurysm. The unhappy patients were bound down with ropes, and the operation was accompanied by screams of terror unless the unfortunate patient fainted.
....During the earlier part of his career, however, the only soporifics known were alcohol and opium. If muscular relaxation was needed to facilitate the reduction of fractures
p 23
or dislocations, an effort might be made to make the patient faint. He might be placed in a hot bath, and when well flushed

removed from it, bled thoroughly, and given tartar emetic to make him vomit. If these measures did not produce the required degree of faintness, the procedure was repeated. Wilde was familiar with another ingenious method which was practised by Colles at Steevens' Hospital. This was the injection of an enema of tobacco smoke into the rectum by means of a long silver tube connected with a large bellows - proceeding which was sometimes attended with disastrous results, but was nevertheless continued until the introduction of ether anaesthesia in 1846.

In those days speed in surgery was essential, and he who could amputate a limb or remove a stone from the bladder in quicker time than his contemporaries was accounted the better operator. The surgeon amputated a thigh by cutting and sawing with his right hand while compressing the main artery with his left. His speed was so great that if the spectator sneezed or tuned his had he missed seeing the operation - it was over. Operating theatres were small, stinking amphitheatres, often crowded to the roof with students. The filth was indescribable. The surgeon came direct to the theatre from the post- mortem room, and neither changed his clothes nor washed his hands. He was proud of his old operating coat,

p 24
the incrustations of blood and pus upon which testified to his experience.


1976 Hypothyroidism: The Unsuspected Illness Broda O. Barnes, Lawrence Galton, Harper & Row

Barnes Basal Temperature:
....Taking the Test
The basal temperature can be taken by a man on any given day. Not so for a woman During the menstrual years, temperature fluctuates during the cycle, as every woman knows. It is highest shortly before the start of the menstrual flow and lowest at the time of ovulation. During a woman's menstrual years, then, the temperature curve is such that basal temperature is best measured on the second and third days of the period after flow starts. Before the menarche or after the menopause, the basal temperature may be taken on any day.

When no other reason can be found, no clear-cut diagnosis made, toe explain the presence of a symptom or a whole complex of symptoms, it is worthwhile taking a thermometer to bed with you. Shake it down well and place it on the night stand. Immediately upon awakening in the morning, place the thermometer snugly in the armpit for ten minutes by the clock. A reading below the normal range of 97.8 to 98.2 strongly suggests low thyroid function. If the reading is above the normal range, one must be suspicious of some infection or an overactive thyroid gland.

For small children who are likely to resist being quiet for ten minutes, more accurate readings often can be obtained by taking the temperature rectally for two minutes. The normal range of rectal temperature is about one degree higher than that of the armpit - 98.8 to 99.2.

1976 Hypothyroidism: The Unsuspected Illness Broda O. Barnes Lawrence Galton Harper & Row p 287

CHAPTER 1 The Many Faces of Thyroid Deficiency
Barnes, BO and Barnes CW Heart Attack Rareness in Thyroid Treated Patients pub. Charles C. Thomas, Springfield Illinois in 1972
Crispell, K. R. Current Concepts in Hypothyroidism The Macmillan Company, New York, 1963
Means, J. H.; DeGroot L. J.; and Stanbury J. B. The Thyroid and Its Diseases 3rd ed., Mc Graw-Hill, New York, 1963 Pitt-Rivers, R., and Trotter, W.R. The Thyroid Gland, Vols. I and II Butterworths, London 1964
Werner, S. C., and Ingbar, S.H. The Thyroid. Harper & Row, New York, 1971
Williams, R. H. Textbook of Endocrinology. W. B. Saunders, Philadelphia, 1968

CHAPTER 2 The Vital - and Errant - Gland
Barnes, BO and Barnes CW Heart Attack Rareness in Thyroid Treated Patients pub. Charles C. Thomas, Springfield Illinois in 1972
Means, J. H.; DeGroot L. J.; and Stanbury J. B. The Thyroid and Its Diseases 3rd ed., Mc Graw-Hill, New York, 1963 pages 321-322
Starr, P., Hypothyroidism. Charles C. Thomas, Springfield, Illinois, 1954, page 46

CHAPTER 3 The Flaw In Diagnosis...and Overcoming It
Barnes, BO and Barnes CW Heart Attack Rareness in Thyroid Treated Patients pub. Charles C. Thomas, Springfield Illinois in 1972
Basinger, H.R. "The Control of Experimental Cretinism," in Archives Internal Medicine, 17:1916, page 260
Jackson, A. S., "Hypothyroidism," in JAMA, 154: 121, 1957
Kimball, O. P., "Clinical Hypothyroidism," in Kentucky Medical Journal, 31: 488, 1933.
Wharton, G.K., "Unrecognized Hypothyroidism, " in Canadian Medical Association Journal, 40: 371, 1930

CHAPTER 4 The Thyroid and Fatigue
Means, J.H. "Circulatory Disturbances in diseases of the Glands of Internal Secretion," in Endocrinology, 9: 192, 1925 Stewart, H.J.; Dietrick, j. E.; and Crane, N. F. "Studies of the circulation in Patients Suffering from Spontaneous Myxedema." in Journal of Clinical Investigation, 1: 237, 1938

CHAPTER 5 Migraine and Other Headaches
Barnes, Broda O, "Headache - Etiology and Treatment." in Federation Proceedings, 6: 73, 1947

CHAPTER 6 The Thyroid in Emotional and Behavioural Problems
Ashner, R. "Myxedematous Madness," in BMJ, 2: 555, 1949
Bruns, Report of a committee of the Clinical Society of London to investigate the subject of myxoedema. Transactions Clinical Society London, Supplement to Vol. 21, 1888, page 105.
Cremer, G. M., et al, Neurology, 19:37
Murray, G. R.; Allbut, C.; Rolleston, A. D. "Myxoedema," in A System of Medicine, Macmillan and Company, London, 1908
Prange, A. J., Jr; Wilson, I.C.; Rabon, A.M; and Lipton, M.A. "Enhancement of Imipramine Activity by Thyroid Hormone, in American Journal Psychiatry, 126:457, 1969
Sanders, V. "Neurologic Manifestations of Myxedema," in New England Journal of Medicine, 226: 599, 1962
Schon, M. "Untreated Thyroid deficiency and Psychological Disorders," Report to American Psychological Association, 72nd annual convention, Los Angeles
Smith, C.A.; Oberhelman, H.A.; Storer, E.H.; Woodward, E.R.; and Dragstadt L.R. "Production of Experimental Cretinism in Dogs by the Administration of Radioactive Iodine," in Archives Surgery 63: 807, 1951
Whybrow, M..B.; Prange, A.J., Jr.; and Treadway, C.R. "Mental Changes Accompanying Thyroid Gland Dysfunction." in Archives General Psychiatry, 20: 48, 1969
Bruns, Report of a committee of the Clinical Society of London to investigate the subject of myxoedema. Transactions Clinical Society London, Supplement to Vol. 21, 1888

CHAPTER 7 Infectious Dseases: Why, For Some, So Many
Barnes, Broda O. "Etiology and Treatment of Lowered Resistance to Upper Respiratory Infection," in Federation Proceeding, 12:10, 1953
White, Paul Dudley. Heart Disease. The Macmillan Company, New York, 1937

CHAPTER 8 The Thyroid and the Skin
Anderson, H.; Asboe-Hansen, G.; and Quaade, F. "Histopathologic Examination of the Skin in the Diagnosis of Myxedema in Children," in Journal Clinical Endocrinology, 15: 459, 1955
Asboe-Hansen, G. "The Variability in the Hyaluronic Acid Content of the Dermal Connective Tissue under the Influence of the Thyroid Hormone." in Acta derm-venerol, 30: 221, 1950
Barnes, Broda O. "Furunculosis - Etiology and Treatment," in Journal Clinical Endocrinology, 3: 243, 1943
---------Thyroid Therapy in Dermatology," in Cutis, December 1971
Bramwell, B. "A clinical Lecture on a Case of Psoriasis Treated by Thyroid Extract," in BMJ, 1, 617, 1894
Gull, W. "A Cretinoid State Supervening in the Adult Life of Women," in London Clinical Society Transactions, 7: 180-185, 1875
Horsley, V. "The Thyroid Gland," in BMJ, 1: 211, 1885
Ord, W.M. "On Myxoedema, a Term Proposed to be Applied to an Essential Condition in the Cretinoid Infection Occasionally Observed in Middle-aged Women." in Trans Med-Churg Society London, 60-61:57-78, 1877-78
Stewart, J.J., and Evans, W.F. "Peripheral Blood Flow in Myxedema." in Archives Internal Medicine, 69: 808, 1942
Sutton, R.I. Diseases of the Skin, C.V. Mosby, St. Louis, 1956

CHAPTER 9 Menstrual Disorders, Fertility Problems, and Avoiding Needless Surgery
Barnes, Broda O. "The Treatment of Menstrual Disorders in General Practice," in Arizona Medicine, 6: 33, 1940
Foster, R.C., and Thornton, M.F. "Thyroid in Treatment of Menstrual Irregularities," in Endocrinology, 24: 383, 1939 Litzenberg, J.C. "The Endocrines in Relation to Sterility and Abortion," in JAMA, 109: 1871, 1937
Means, J.H. The Thyroid and Its Diseases, 2nd ed. Lipincott, Philadelphia, 1948 page 571
Ross, G.T.; Scholz, D.A.; Lambert, E.H; and Geraci, J.E. "Severe Uterine Bleeding and Degenerative Skeletal Muscle Changes in Unrecognized Myxedema," in Journal Clinical Endocrinology and Metabolism, 18: 492, 1958
Scott, J.C. Jr., and Mussey, E. "Menstrual Patterns in Myxedema," in American Journal Obstetrics and Gynecology, 90: 161, 1965
Silenkow, H.R., and Refetoff, S. "Common Tests of Thyroid Function in Serum", in JAMA, 202:135, 1967
Report of a committee of the Clinical Society of London to investigate the subject of myxoedema. Transactions Clinical Society London, Supplement to Vol. 21, 1888
CHAPTER 10 The Hypertension Association

Fishberg, A.M. "Arteriosclerosis in Thyroid Deficiency," in JAMA 82: 463, 1924
Goldblatt, H. "Studies on Experimental Hypertension," in Annals Internal Medicine, 11: 69, 1937
Menof, P. "New Method for Control of Hypertension, " in South African Medical Journal, 24: 172, 1950
Ord, W.M. "On Myxoedema, a Term Proposed to be Applied to an Essential Condition in the Cretinoid Infection Occasionally Observed in Middle-aged Women." in Trans Med-Churg Society London, 60-61:57-78, 1877-78

CHAPTER 11 The Thyroid and Heart Attacks
Heart Attack Rareness in Thyroid Treated Patients by Barnes, BO and Barnes CW pub. Charles C. Thomas, Springfield Illinois in 1972
Barnes, Broda O. Ratzenhofer, M; Gisi, R. "The Role of Natural Consequences in the Changing Death Patterns." in Journal American Geriatrics Society, 22: 176, 1974
Christian, H.A. "The Heart and Its Management in Myxedema," in Rhode Island Medical Journal, 8: 109, 1925
Dawber, T.R; Moore, F.E.; and Mann, G.V. "Coronary Heart Disease in the Framingham Study" in American Journal Public Health, 47:4-24,1957
DeLangen, C.D., "Cholesterol Metabolism and Racial Pathology." (in Dutch, "Gencesk Tijdschr. v. Nederl") Indie, 56, 1, 1916
Falta, W. Endocrine Diseases, 3rd ed., Translated by Milton K. Myers, P. Blakiston's Son and Company, Philadelphia, 1923k Higginson, J. and Pepler, W.J. "Fat Intake, Serum Cholesterol Concentration and Atherosclerosis in the South African Bantu," in Part II, Atherosclerosis and Coronary Artery Disease. Journal Clinical Investigations, 33: 1366, 1954
Hurxthal, L.M. "Blood Cholesterol and Thyroid Disease," in Archives Internal Medicine, 53: 762, 1934
Israel, M. "An Effective Therapeutic Approach to the Control of Atherosclerosis Illustrating Harmlessness of Prolonged Use of Thyroid Hormone in Coronary Disease," in American Journal Digestive Diseases, 22: 161-168, 1955
Kimura, N. "Analysis of 10,000 Postmortem Examinations in Japan." World Trends in Cardiology, Vol. I. Cardiovascular Epidemiology, Hoeber-Harper, New York, 1956, page 159
Kountz, W. B. Thyroid Function and Its Possible Role in Vascular Degeneration. Charles C. Thomas, Springfield, Illinois, 1951
Laurie, W.; Woods, J.D., and Roach, G. "Coronary Heart Disease in the South African Bantu." in American Journal Cardiology, 5: 48-59, 1960
Lerman, J., and White, Paul Dudley, "Metabolic Changes in Young People with Coronary Heart Disease." in Journal Clinical Investigation, 25: 914, 1946 (Proceedings).
Lidsky, A., and Kottman, K. "Influence of the Thyroids on Blood Clotting," in Zeitschrift klin Medicin, 71:344, 1911 Malysheva, L.V. "Tissue Respiration Rate in Certain Organs in Experimental Hypercholesterolemia and Atheroschlerosis." in Federation Proceedings Translation Supplement, 23: T562, 1964
Ord, W.M. "On Myxoedema, a Term Proposed to be Applied to an Essential Condition in the Cretinoid Infection Occasionally Observed in Middle-aged Women." in Trans Med-Churg Society London, 60-61:57-78, 1877-78
Smythe C.J. "Angina Pectoris and Myocardial Infraction as Complication of Myxedema." in American Heart Journal, 15: 652-660, 1938
Strisower, B.; Gofman, J.W.; Gaglioni, E.; Ribinger, J.; O'Brien, G.Wp; and Simon, A. "Effects of Long-Term Administration of Desiccated Thyroid on Serum Lipoprotein and Cholesterol Level." in Journal Clinical Endocrinology, 15: 73-80, 1955
Sturgis, C.C. and Whiting, W.B. "The Treatment and Prognosis in Myxedema." in JAMA, 85: 2013, 1925
Turner, K.B.; Present, C.H.; and Bidwell, E.H. "The Role of Thyroid in the Regulation of the Blood Cholesterol in Rabbits." in Journal Experimental Medicine, 67: 111, 1938
Virchow, Rudolf, "Genaure geschichte der fittmetamorphose," The Cellularpathologic Berlin 185 8 Verlog von August Hirschwald.
von Eiselsberg, A.F. "On Vegetative Disturbances in Growth of Animals after Early Thyroidectomy." in Archives Clinick Chirugie, 49:207, 1895
Wren, J.C. "Thyroid Function and Coronary Atherosclerosis," Journal American Geriatric Society, 16: 696-704, 1968. Zondek, H. "The Myxedema Heart," in Munchen Medical Worchenschrift, 65: 1180, 1918.
Report of a committee of the Clinical Society of London to investigate the subject of myxoedema. Transactions Clinical Society London, Supplement to Vol. 21, 1888

CHAPTER 12 Arthritis
Anderson, H.; Asboe-Hansen, G.; and Quaade, F. "Histopathologic Examination of the Skin in the Diagnosis of Myxedema in Children," in Journal Clinical Endocrinology, 15: 459, 1955
Asboe-Hansen, G. "The Variability in the Hyaluronic Acid Content of the Dermal Connective Tissue under the Influence of the Thyroid Hormone." in Acta Derm-venerol, 30: 221, 1950
Golding, P.N. "Hypothyroidism Presenting with Muscolo-Skeletal Symptoms," in Annals Rheumatic Diseases, 29: 10, 1970 Hill, S.R.; Reiss, R.S.; Forsham, P.H.; and Thorn, G.W. "The Effect of Adrenocorticotropin and Cortisone on Thyroid Function: Thyroid-Adrenocortical Interrelationships." in Journal Clinical Endocrinology, 10: 1375, 1950
Horsley, V. "The Thyroid Gland," in BMJ, 1: 111, 1885
Ord, W.M. "On Myxoedema, a Term Proposed to be Applied to an Essential Condition in the Cretinoid Infection

Occasionally Observed in Middle-aged Women." in Trans Med-Churg Society London, 60-61:57-78, 1877-78 Swain, L.T. "Chronic Arthritis." in JAMA, 93: 259, 1929

CHAPTER 13 The Thyroid, Diabetes, and Hypoglycaemia
Banting, F.G., and Best, Charles. :The Internal secretion of the Pancreas," in Journal Laboratory Clinical Medicine, 7: 25 1, 1922.
Barnes, Broda O., and Regan, J.F. "The Relation of the Anterior Pituitary to Carbohydrate Metabolism." in Endocrinology, 17: 522, 1933.
Eaton, C.D. "Coexistance of Hypothyroidism with Diabetes Mellitus." in Journal Michigan Medical Society, 53: 1101, 1954. Ellenberg, M. "Diabetic Complications Without Manifest Diabetes: Complications as Presenting Clinical Symptoms, " in JAMA, 183: 926, 1963.
Gardiner-Hill, H.; Brett, A.C.; and Smith, J.F. "Carbohydrate Tolerance in myxedema," in Quarterly Journal Medicine, 18:327, 1925
Jackson, W.P.V. "The Expression 'Prediabetes'," in Diabetes, 11;334, 1962
Joslin, E.P. "Arteriosclerosis in Diabetes," in Annals Internal Medicine, 4: 54, 1930.
Lukens, R.D.W., and Franklin, S.N. "Long-Term Diabetes Without Vascular Disease," in Medical Clinics North America 50:1385, 1966.
Moses, C; Danowski, T.S.; and Switkes, H.E. "Alterations in Cholesterol and lipoprotein Partition in Euthyroid Adults by Replacement Doses of Desiccated Thyroid," in Circulation, 18: 761, 1958.
Prout, T.E., and Goldner, M.G. "The University Group Diabetes Program," in Diabetes, 19:(supplement 1) 375, 1970. Schaefer, O. "Glucose Tolerance Testing in Canadian Eskimos: A Preliminary Report and a Hypothesis, " in Canadian Medical Association Journal, 99:252, 1968.

CHAPTER 14 The Thyroid, Lung Cancer, and Emphysema
Barnes, B.O., and Ratzenhofer, M. "One Factor in Increase of Bronchial Carcinoma," in JAMA, 174: 2229, 1960 Campbell, R.E., and Hughes, F.A. "The Development of Bronchiogenic Carcinoma in Patients with Pulmonary Tuberculosis." in Journal Thoracic and Cardiovascular Surgery, 40: 98, 1960.
Duguid, J.B. "The Incidence of Intra-Thoracic Tumours in Manchester," in Lancet, 2: 111, 1927.
Spencer, J.G.C. "The Influence of the Thyroid in Malignant Disease," in British Journal of Cancer, 8:393, 1954 Williams, W.R. "Remarks on the Mortality from Cancer," in Lancet 2: 481, 1898.
Wolf, K. "The Primary Lung Cancer," in Fortschritte d Medicin, 13: 725, 1895

CHAPTER 15 The Thyroid and Obesity: The Real - and Surprising - Connections
Anderson, A.B. "Loss of Weight in Obese Patients on Sub-Maintenance Diets and the Effect of Variation in the Ratio of Carbohydrate to Fat in the Diet," in Quarterly Journal Medicine, 13:27, 1944
Barnes, Broda O. "A Practical Diet for Weight Reduction," in Federation Proceedings, 24: 314, 1965.
Duncan, T.G. "The Burden of Obesity." in Internist Observer, October-November, 1970.
Evans, F.A. and Strang, J.M. "A Departure from the Usual methods in Treating Obesity," in American Journal of Medical Science, 177:339, 1929.
Keckwick, A., and Pawan, G.L.S. "Caloric Intake in Relation to Body-Weight Changes in the Obese," in Lancet 2: 155, 1956.
Lieb, C.W. "The Effects on Human Beings of a Twelve-Month's Exclusive Meat Diet," in JAMA, 93:20, 1929; Journal Biological Chemistry, 87: 651, 1930; Journal Biological Chemistry, 83: 753, 1929.
Pennington, A.W. "The Use of Fat in a Weight-Reducing Diet," in Delaware State Medical Journal, 23: 79, 1951