On diabetes mellitus and glycosuria

Preface

Among the thousands annually visiting Carlsbad in search of health the diabetics present the greatest clinical interest, and from my first years as a practitioner in the Bohemian Spa I sought some relief from the monotony and many other unsatisfactory aspects of a practice of this kind in a careful study of the gly cos uric dystrophy with its manifold complications.

Early in the nineties I conceived the project of publishing a book upon this subject, hoping thereby to fill a want in the medical literature of the day. Others, however, at about the same time undertook the same assiduous task. A few months after my reading, early in 1895, a paper on "Digestion, Metabolism, and Nutritive Needs in Diabetes " before the Swedish Association of Physicians,* v. Noorden's highly scientific work on diabetes was published, and almost simultaneously with the appearance of my own long-delayed book in the Swedish language, Naunyn's magnificent monograph was welcomed by the profession.

Still, the more than kind reception that has been accorded this book by the physicians of my native country has led me to entertain the hope that the most important part of my clinical, experimental, and literary work of recent years has not been entirely in vain. I resolved to give my book publicity in some more widely used language than the one most familiar to me, and myself, with some few additions and changes, translated my book into English. In doing this I derived considerable assistance from a dear American friend. Finally, Dr. Eshner, of Philadelphia, has revised the manuscript and added his most valuable aid to change my own

* See the " Transactions of the Association " (" Hygiea ") for the same year, and the chapter on Metabolism in this book. In the latter I have added some references to the researches of the last few years.

V

VI PREFACE.

somewhat deficient English into good English, for which work I hereby render my public thanks. For the substance and scientific matter of this book I am myself alone responsible.

I have treated the vast subject of diabetes and glycosuria with as much brevity as is compatible with my purpose of giving as full a viev/ of it as the present time allows, never having out of sight that my chief aim is to facilitate for the general practitioner the acquisition of the knowledge of the glycosuric dystrophy, to which I have devoted considerable time and work.

At the end of the book I give a Hst of names of the chief

authors on the subject of diabetes but no list of their works,

as this alone would fill a small volume, and now that we have the

"Index Medicus " and the "Catalogue," seems to me entirely

superfluous.

Emil Kleen.

Carlsbad, September, 1899.

Contents

Chapter Page

I. Definition and History 9

II. Geographic Distribution and Etiology 15

Chapter I.— Definition And History

Under the name diabetes mellitus are included different pathologic conditions which, however imperfectly understood, undoubtedly in most cases affect the central nervous system, and which are characterized by a faulty metabolism, as a result of which, under ordinary diet, there takes place the excretion in the urine of an abnormally large amount of sugar.

Thus, diabetes mellitus, so far as is at present known, is not a clinical unit, but a syndrome, the chief and most constant symptom of which is glycosuria, and which is represented by very varying clinical types.

There are, however, numerous cases attended with the excretion in the urine of minute yet distinctly pathologic amounts of sugar, which cases differ widely in clinical aspect and in prognosis from the diabetic type, and which generally are not included in the designation diabetes mellitus.

When the power of consuming the ingested and digested carbohydrates is but little or momentarily impaired, and when the pathologic excretion of sugar, under ordinary mixed diet, only slightly exceeds the traces of sugar found in normal urine, or is but transitory, the condition is not called diabetes mellitus, but simple glycosuria.

When the excretion of sugar becomes considerable and more persistent, but disappears when the carbohydrates are decreased or 2 9 lO DIABETES MELLITUS AND GLYCOSURIA.

withdrawn from the food, the condition, which generally is accompanied by other more or less well-defined symptoms, constitutes the mild stage of diabetes.

The severe stage of diabetes is characterized by the occurrence of glycosuria even when the carbohydrates are withdrawn from the food.

We shall find that the limits thus fixed are far more distinct on paper than in the reality of cHnical experience, in which w^e see represented all imaginable intermediate stages between the normal capability of consuming the sugar of the blood and the greatest possible deterioration of this capability.

Our knowledge of diabetes has essentially developed during the nineteenth century, but for many ages previously something was known of it, as is shown in notices occurring here and there in ancient works.

The term diabetes {dia^ij-Tig : 6ia, through ; ^alveiv, to go) is attributed to the Roman, Celsus, who lived in the beginning of the Christian era. The term then probably comprised both diabetes mellitus and diabetes insipidus.

In the Indian Yajur-Vedas we find definite statements upon this subject, and it seems from these ancient documents, discovered about a hundred years ago, that Susruta, whose existence was passed in the native land of the cobra, the Brahman, and the tiger during the seventh century, was familiar with both the clinical picture and the sweet urine of diabetes mellitus, which probably then, as now, was more general among the Hindus than among any other race.

Europe was far behind India in knowledge of diabetes mellitus during those times. As is always the case, single instances occur of correct guesses long before science had acquired the facts. Paracelsus suspected that a change in the blood is the cause of the symptoms of diabetes. It was, however, not until as late as 1674 that the sweet taste of the urine was first noticed by Thomas Willis (1622-1675), and a whole century more elapsed before Dobson showed that this sweetness is due to a variety of sugar. The idea of the presence of sugar in the blood of diabetics then began to gain ground, and we find this opinion general at the commencement of the nineteenth century. Rollo and Cruikshank accepted the existence of blood-sugar in diabetes ; but Nicolas and Gueudeville, Segalas and Vauquelin, as also Sobeiran, tried in vain definitely to demonstrate its presence. Wollaston at first (181 1) denied, but afterward acknowledged, its existence. Maitland and Ambrosiani (1835) believed they had found it. McGregor observed fermentation of diabetic blood, and Simons found in the blood of a diabetic patient after a hearty meal 0.25 per cent, of sugar, although only traces had been present before the meal.

All of these observations, however, concerned diabetes exclusively ; but as early as 1826 Tiedemann and Gmelin deemed sugar a normal ingredient of the blood, and considered that they had proved its presence in dogs, whether

DEFINITION AND HISTORY, I I

the animals were fed with carbohydrates or with meat. Early in the forties this observation was confirmed by Magendie and by Frerichs, and in 1845 Thomson, by fermentation, made (far too low) a determination of the sugar in the blood of fowls.

At the close of the forties Claude Bernard began his all-important investigations, which proved successively the presence of sugar in the normal blood under all dietetic conditions ; its production from glycogen in the liver ; its dependence on nervous influences ; its increase above the normal ratio in cases of diabetes, and many other facts, a knowledge of which is essential for a comprehension of diabetes mellitus, and to which we shall have to return in the chapter on Metabolism.

The enormous amount of work afterward performed in this field by others has, on the whole, simply served to prove the correctness of Bernard's observations and conclusions, and it is only within quite recent times that experimental pathology has provided us with any material additions to what that most admirable physiologist taught us.

In 1848 Traube observed that sugar disappeared from the urine of a diabetic patient when carbohydrates were withdrawn from his food, and that the same individual exhibited glycosuria at a later period, in spite of this withdrawal. He thus discovered the difference between the mild and the severe stage of diabetes, on which others, especially Seegen, afterward attempted to found a division into two different forms of disease.

Toward the close of the fifties Briicke and Bence Jones, independently of each other, found small traces of sugar in normal urinCf an event of importance chiefly because it led to further investigations for small amounts of sugar in urine and brought to light many instances of slight glycosuria, pathologic though often unessential, that present themselves under different conditions. Our knowledge of the simple glycosurias, however, has been chiefly developed during the last two decades, and is still increasing year by year.

Gerhardt, in 1865, discovered that a solution of ferric chlorid causes a winecolored reaction with the urine of patients suffering from severe diabetes. This observation has proved of immense importance, as it greatly facilitated the diagnosis of severe diabetes and promoted the study and the comprehension of certain pathologic metabolic products, and of those acid blood-toxins that essentially invest the severe stage of diabetes with its clinical peculiarities.

Lavoisier had, in the latter part of the eighteenth century, laid down the principles of metabolism, but it was not until the middle of the present century that our knowledge of this most important subject began rapidly to develop through the works of Liebig, G. Lehmann, Bidder and Schmidt, Bischoff, Reignault and Reiset, and others. In 1867 Pettenkofer and Voit — though they themselves at first misinterpreted their own results — taught us that the consumption of oxygen, the excretion of carbonic acid, the production of heat, and the nutritive needs in the diabetic are governed by the usual laws, and that they are not attended with other deviations from the normal than those that arise directly from the loss of sugar through its excretion with the urine. When, later, Rubner (in the middle of the eighties) gave us his calorimetric tables of the nutritive value of different articles of food, the conditions were fulfilled for arranging a rational diet for diabetics, as for others, and we have been enabled more effectually to obviate the mistake of dieting diabetics, with the one view in mind of eliminating hyperglycemia and glycosuria, and with out due regard to dietetic possibilities and to nutritive needs.

In 1886 von Mering discovered phloridzin-glycosuria, which is curiously characterized by the excretion of large amounts of glucose, with a diminished quantity of sugar in the blood. Three years later von Mering and Minkowski, thanks to the great accuracy of their mode of investigation, had the good fortune to discover that severe diabetes can be produced by total extirpation of the pancreas — the one " artificial " method at present known of bringing about with certainty this variety of diabetes. By reason of these two discoveries, and in view of the far-reaching consequences of the latter, von Mering must be considered as the investigator that, next to Claude Bernard, has contributed most effectively to our knowledge of diabetes mellitus.

During the last few decades an extensive literature has accumulated, and many valuable contributions have been made to the knowledge of this dystrophy. In addition to those already mentioned, a great number of authors have distinguished themselves in this connection, among whom I may name Frerichs, Bouchardat, Cantani, Seegen, Pavy, Bouchard, G. A. Hoffmann, Griesinger, E. Kiitz, von Voit, Naunyn, Ebstein, Chauveau and Kaufmann, Lepine, Weintraud and von Noorden — passing over no small number of others who have written more or less important works on the subject.

Diabetes mellitus, being in its "mechanism" a peculiarly mysterious disease, with an undiscovered, or at least not fully explained, pathologic anatomic basis, has been made the subject of many theories, at present amounting to more than thirty. In no other department has medicine made such extended excursions into the domain of purely speculative science, and nowhere has this led to greater liberties with the imagination. It is not my intention in this work, which is designed for the practitioner, to enter upon a consideration of all of these thirty theories ; but in order to show how weak and uncertain our search for truth has been in this field, and how many different theoretic possibilities present themselves, I will cursorily mention the main currents of opinions that have prevailed.

In former times the cause of diabetes was looked for in those organs whose functions show the most manifest abnormity — /. <?., the kidneys. This idea, in all its naivete, has been to a certain degree revived, though with numerous modifications, additions, and limitations by our views on phloridzin-glycosuria, and by the auxiliary influence on the excretion of glucose, attributed on strong grounds by many authors to the kidneys.

DEFINITION AND HISTORY. 1 3

Rollo, the greatest authority on diabetes at the beginning of the present century, supposed the cause of the dystrophy to be a disturbance of the digestive functions, which resulted in an excessive resorption of carbohydrate. Similar opinions, however absurd they may seem at present, have been expressed quite recently by many authors, and, among others, by no less an authority than Bouchardat in his earlier days. The importance in the causation of diabetes of changes in the pancreas was suspected long before Lancereaux wrote his paper on this subject, and before we knew the effect of total extirpation of the pancreas, and could assign to this organ a rational position in the pathogenesis of diabetes. An intuition of such a relation was at the bottom of the views of Bouchardat and others, and later found expression in Popper's idea of faulty digestion, in consequence of a defective secretion of the pancreatic juice as a cause of diabetes mellitus.

Since Bernard's great discoveries and his theory of the formation of the sugar of the blood in the liver from glycogen, and of its consumption in the tissues for the production of vital force, two great schools have arisen, in each of which several divisions are apparent. One of these schools considers the cause of hyperglycemia and glycosuria — i. e., of diabetes — to be a ditninisked consumption of sugar in the tissues. For the sake of brevity, we may be permitted to say that the other school considers the cause to be an increased production of sugar m the liver. According to some views, this excessive production, however, is of an entirely passive kind, and is more correctly expressed as a diminished capability of the organ of transforming into, and storing as, glycogen the sugar conveyed to it through the portal vein, so that a larger part of the sugar reaches the circulation by the hepatic veins than can be stored in the muscles as glycogen, or be consumed by them. A large number of authors consider this view corroborated by the frequency with which sugar appears in the urine in cases of cirrhosis of the liver, A positive participation on the part of the liver may also be conceived. Claude Bernard and his numerous followers believe this to consist in increased activity of a normal function pathologically excited by hyperemia. Pavy and Schiff thought the production of glucose in the liver an entirely pathologic phenomenon. In both views a diastatic ferment and a central nervous influence transmitted through the vasomotor nerves are accepted. The latter influence must be given a place in every general theory of diabetes.

Those that have conceived the idea of defective consumption of the sugar of the blood have either accepted the disappearance from the organism of a ferment that normally should cause decomposition of glucose into glycerin and its aldehyd, and the cessation of which embarrasses further oxidation (Schultzen, Schermetjewski, Nencki and Sieber, Bence Jones), or have thought of defective oxidation in the lungs (Araki), or have placed the fault with the muscles (Zimmer). Since the theory of an " internal secretion " of the various glands of the body was adopted, and the production of diabetes by total extirpation of the pancreas was demonstrated, a large number of scientists have come to consider the cause of diabetes to be the disappearance from, or the diminution in, the blood of a "glycolytic ferment," present normally, and sent into the blood by the pancreas for the combustion of glucose.

There are, moreover, a considerable number of observers who have supposed that there takes place a diminution in, or a retardation of, the entire " internal respiration," which goes on in all of the tissues, — an opinion which at first obtained some support from Pettenkofer and Voit's experiments on metabolism in diabetes by reason of their erroneous interpretation of their results (Cantani, Jaccoud, Bouchard, Lecorche, Naunyn, Huppert).

Diametrically opposed to this opinion is another advocated by Robin, who speaks of an increased metabolism, of a " suractiviie de la nutrition^

In this cursory retrospect I wish to mention also Ebstein's carbonic-acid theory, which, however ingenious, entirely lacks support in facts. Ebstein placed reliance on the incorrect but once wide-spread supposition that a diabetic ceteris paribus always consumes less oxygen and produces less carbonic acid than a healthy individual. The carbonic acid he supposed to act as a check on the diastatic (glucose forming) ferment, and also to render certain proteids — especially globulins — more tenacious. Thus, when the carbonic acid — in consequence of a defect in the protoplasm, with resulting disturbances of the " internal respiration " — is lessened in diabetes, in the first instance and in the milder stage of the dystrophy, the carbohydrate — i. e., glycogen — is attacked by the diastatic ferment more vigorously than under normal conditions. In the severe stage the globulins are also decomposed more readily, and an excessive formation of glucose begins at their expense. After Schierbeck's investigations on the diastatic ferment in alkaline and acid solutions, Ebstein and Schultze, in 1893, came to the conclusion that carbonic acid in alkaline solutions aiigmeftts the diastatic activity, and retards it in neutral solutions, while even a very slight degree of acidity inhibits it altogether. It is rather difficult to understand how these facts, together with the qualities of the blood under normal conditions and in the presence of severe diabetes, could be made to fit in with Ebstein's theory, which, moreover, falls to pieces in the face of the fact, now fully proved, that the diabetic produces as much carbonic acid as a healthy individual. Ebstein's citation, in support of his theory, that Hoesslin found a sojourn at a high altitude, which had been considered as increasing the production of carbonic acid, to be favorable for the diabetic, is an unfortunate one, as Hoesslin's experience in this respect, at the time his treatise was written, was limited to a single case. On such a foundation not even a supposition should be hazarded on the subject of diabetes, and far more reliable facts indicate that residence at great heights does not in any way counteract diabetes. (See the following chapter.) The opinion that a sojourn at a high altitude in rarefied air materially increases the production of carbonic acid (Mermod, Marcet) does not seem to be borne out by facts. U. Mosso came to the conclusion, a few years ago, from investigations conducted on Monte Rosa and in rarefied air, that the quantity of carbonic acid produced in respiration under these conditions at an altitude of 6400 meters differs but slightly from that produced at an altitude of 286 meters (Turin).

Of late years there have been advanced in France — where, since Bernard's time, diabetes mellitus has been the object of constant study — theories concerning its pathogenesis, in which the nervous system, the pancreas, and the liver are all involved. Even if these theories can not as yet be said to be

GEOGRAPHIC DISTRIBUTION ETIOLOGY. I 5

more than hypotheses, they are nevertheless founded on definite observations and are of actual interest. I shall, therefore, return to them in the chapter on Metabolism, when we shall see that the theories of an increased production and of a decreased consumption of sugar both have solid bases, and that they ought not to be pitted against each other as utterly irreconcilable. To the present comprehension of special pathogenetic factors in the dystrophic group, the future will assuredly bring many additions and corrections, and the present generation will, perhaps, in time be forced to confess that " all our wisdom was but folly."

Chapter Ii.— Geographic Distribution— Etiology

Diabetes mellitus is a common phenomenon among civilized humanity,* and is constantly increasing in {x^Q^oncy pari passu with the intensity of cultivated life.

Some time ago I saw it stated — I believe it was by Worms — that among men occupied in intellectual pursuits (statesmen, learned men, professional men, merchants) of an age between forty and sixty no less than ten per cent, are diabetics. Most physicians will be inclined to protest against this figure as far too high, as it is, if by the expression diabetic is meant a person that displays a cUnical type of diabetes. It would be nearer the truth to place the number of diabetics among the classes named at one per cent. On the other hand, if we call every person a diabetic that, taking ordinary food, excretes habitually and daily an inconsiderable though pathologic quantity of sugar in the urine, Worms' figure would be rather too low than too high. If samples of urine be taken an hour after dinner from a hundred brain-workers between the ages of forty and sixty, it will doubtless be found, on testing with Nylander's solution, or with Trommer's test, verified by the fermentation-test, that about fifteen of the hundred samples contain an amount of sugar

* In animals diabetes mellitus — unless designedly caused for experimental purposes — is very rare, but it has been observed in the ape (Leblanc, Beranger-Ferand), the horse (Hiibner), and the dog (Thiermesse, Schindelka). Slight glycosuria has also been noticed in animals.

that attains to hundredths of a per cent. — i. e., are distinctly pathologic. It will, however, also be found that the greater part of the "patients" in question consist of quasi-healthy, or, to use a better expression, very slightly affected, persons, who neither for the moment present, nor are likely in the future to present, decided symptoms of the clinical type that we are accustomed to call diabetes.

Among the European and the American, Aryan, highly civilized races, the difference in the frequency of diabetes, on comparing large areas, will not be found to be very great : not greater than it may be in different parts of the same country. Different conditions of life — altitude, climate, and state of culture, even within very narrow limits — give rise to very considerable variations. Thus we find that diabetes is more common in Malta and Gibraltar than elsewhere on the shores of the Mediterranean, in Tuscany than in the rest of Italy, in Normandy than in the other provinces of France, in Vermont than in the other States of the Union.

The statistical figures that are available are assuredly far too low, as the diabetic type is often not yerY pronounced, and in the milder form does not cause death, except through complications which have no definite relation to diabetes. Moreover, these figures have doubtless been obtained in very different ways in various places, and allow of no absolute comparison. On learning from Saundby that the number of deaths annually from diabetes mellitus per 100,000 inhabitants is in London 5.88, in Berlin 5.04, in Paris 9.6, in Christiania 3.9, in Rome 1.67, in Malta 13.1 (the highest European figure), we can scarcely conclude with certainty that the correct figure for Berlin is higher than the correct figure for Rome, for which latter city the figure cited is assuredly far too low. In Malta, however, diabetes is undoubtedly very common.

In Norway, among 10,000 deaths, 21 are owing to diabetes mellitus (Kiaer).

There is scarcely any doubt that in large communities diabetes mellitus is rapidly increasing. According to Bertillon's statistics (cited from Lepine), diabetes caused the following deaths per annum among 100,000 Parisians :

From 1865 to 1873, a total of 2.3 From 1885 to 1886, a total of 11

" 1878 " 1883, " 9

In Copenhagen the mortality from diabetes has also increased rapidly and constantly during the past few decades. From i860 to 1864, according to Caroe, there was but one death per 62,840 inhabitants, while from 1890 to 1894 there was one per 12,855.

Purdy's statistics for the United States are demonstrative and show :

Purdy, undoubtedly with due cause, ascribes the enormous increase after i860 to the rapid increase of prosperity, the luxurious mode of life, and the more arduous struggle for existence after the Civil War.

Of all races, the Hindu is most susceptible to diabetes. In India and Ceylon diabetes is a very common disease among the upper classes, — so common that, according to the editor of the " Indian Medical Gazette," almost every family in Calcutta belonging to these classes of society has lost one or more members by death from this dystrophy, while another author (Bose) estimates the number of deaths from diabetes in Calcutta at lo per cent, of the entire mortality (! ! !), — a circumstance that must be attributed to the highly nervous constitution of the Hindus, their early marriage, and excessive sexual life in general, the high intellectual culture at present prevalent in India among these classes, their sedentary mode of life, and perhaps also their diet, so rich in sugars and other carbohydrates. The preponderance of male over female patients seems to be at least as great as in Europe. Among the Mohammedan population in India diabetes, though not rare, is not nearly so common as among the Hindus.

Next to the Hindus the Jews — who in many respects occupy the same relative position to Europeans in general as do the Hindus to the Jews — are highest in the scale of diabetic frequency. No specialist in diabetes can avoid noticing the comparatively large percentage of patients among Hebrews, who also are a nervous race, and who for centuries have devoted themselves almost exclusively to intellectual and sedentary pursuits.

It has been of interest to me to form some estimate of the frequency of diabetes among the Chinese, who seemed to me, during the few weeks I spent among a vast number of their race, to be a nation with a highly developed intellectual, but comparatively slightly developed emotional, life, rather difficult of comprehension for any other than a Chinaman. Saundby's statements seem to prove that diabetes is very rare among Chinese laborers. Graham, who at Sumatra practised among 15,000 of them, discovered but a single case during his seven years' sojourn. In the United States, I have myself, from various sources of information, come to the conclusion that the disease is far more uncommon among the lower classes of the Chinese than among the same classes of Americans and Europeans. On the other hand, Dr. Cantlie, who for many years has practised in Hong Kong, has kindly informed me that among the ricJicr Chinese diabetes is not at all uncommon, adding the interesting information that it more especially attacks those that change from the usual Chinese diet, with its preponderance of rice, to a more mixed European diet. I presume this observation to be perfectly correct ; — just as I have repeatedly found that in cases of very slight glycosuria I can cause a larger quantity of sugar to appear in the urine by mixed testmeals than by those that consist exclusively of carbohydrates.

Among the contented Japanese, whose education has hitherto been Spartan in many respects, diabetes is not common. If, as is probable, they ere long provide reliable statistics, it will doubtless be seen that with the nation's wonderful and rapid adoption of European culture, the frequency of diabetes will quickly increase.

Among the Persians diabetes is said to be less general than among Europeans, and the same is stated of the Turks (Tholozan). Among the Arabs of the part of North Africa under French sway the dystrophy is not rare (Calmette and others).

It is interesting to learn that among the laborers on the sugarplantations of the Mauritius and British Guiana, where, relatively speaking, the lower classes consume an enormous amount of cane-sugar, diabetes meUitus is rarely encountered (Blair, Saundby), From Venezuela the same statement has been forwarded to me. Almost all these laborers are " colored " and belong to those races among which diabetes mellitus is uncommon as a general rule. Circumstances, however, seem to indicate that a strongly saccharine diet has per se but little etiologic influence.

Among all people beyond the pale of culture, diabetes is very rare. This I believe to be the correct way of viewing the aforementioned immunity among Africans, and the reason why so little is heard of diabetes among the Indians of America, or among the numerous and various aborigines of AustraUa, or in the English colonies of mixed but predominant colored population. With greater intellectual exertion, keener emotions, higher nervous development, more earnest struggle for existence, more urgent demands, a more intense culture, in fine, we are bound to find more diabetes mellitus.

From what we have already learned we should a priori be inclined to believe diabetes to be far more common among a given number of residents in cities than among the same number of persons in the country. There is, therefore, nothing remarkable in the large number of statements that support such a supposition. On the other hand, it is an interesting fact that statistics point, in some degree, in the opposite direction. In Great Britain there are several counties with a large urban population which are low in the scale of diabetes, while others with a far greater rural population are high in the scale. Purdy has compared the figures in the United States, and has come to the conclusion that in the North diabetes is more general among the rural population, and in the South among the urban population ; and he ascribes this difference to the better protection against cold afforded by the cities as compared with the country, which holds good only for the North. In the South other differences determine the result. These, in my opinion, do not, as Purdy supposes, consist in the better oxidation secured through the country air, but in the mode of hfe of the inhabitants of the country, which, as a general rule, is far more free from nervous influences. Except during the first decades of life, when diabetes mellitus is very rare, and attacks fully as many, or perhaps more, girls than boys, this dystrophy is far more common among males than among females — naturally, in consequence of the severe struggle for existence on the part of men, and their greater proneness to excesses. The difference plainly appears in the second decade, and is manifest in all following decades. Generally, there are three times as many male patients as female. Exclusive of the ages under twenty, Pavy had 928 males and 373 females ; Grube had 137 male and 40 female cases, while my own experience shows nearly three male to every female patient.