mtmam ■^ >fl rr^ ""^^ i'K:. r-1"-?' /-t /f^ ''i i^]s'-^ -, •) r *' i [i I 1^ :H » V;.'.*' /4-7 Cornell University Library RB 147.H141903 Uric acid as a factor in the causation o 3 1924 000 230 783 CORNEL L UNIV ERSITY THE amzt Hct^nnaty Kihtata FOUNDED BY ROSWELL P. FLOWER for the use of the STATE VETERINARY COLLEGE 1897 N. Y. Cornell University Library The original of tiiis book is in tine Cornell University Library. There are no known copyright restrictions in the United States on the use of the text. http://www.archive.org/details/cu31924000230783 URIC ACID FACTOR IN THE CAUSATION OF DISEASE. First Edition Publishkd February, 1892. Second Edition Published ApriLj 1894. Third Edition" Published February, 1896. Fourth Emtion Published December, 1897. FXFTH Edition Published August, 1900. Sixth Edition Published May, 1003. URIC ACID A FACTOK IN THE CAUSATION OF BISEASE A OONTEIBTTTION TO THE PATHOLOGY of HIGH BLOOD PEBSSUEE, HEADACHE, EPILEPSY, NEEVOUSNBSS, MENTAL DISEASES, ASTHMA, HAY FBVBE, PAEOXYSMAL H^MOGLOBINDEIA, ANEMIA, BEIGHT'S DISEASE, DIABETES, GOUT, EHBUMATISM, BEONOHITIS, AND OTHER DISORDERS BY ALBXANDEE HAIG, M.A., M.D.Oxon., F.E.C.P. PHYSICIAN TO THE METROPOLITAN HOSPITAt., AND THE ROTAL HOSPITAL FOR CHILDREN AND WOMEN ; LATE CASUALTY PHYSICIAN TO ST. BARTHOLOMEW'S HOSPITAL Sijtb Edition WITH SEVENTY-FIVE ILLUSTRATIONS PHILADELPHIA P. BLAKISTON'S SON & 00. 1012 WALNUT STREET 1903 [AU Rights Reserved] 1^^ / 1 03 (\/,, it^Ti LONDON JOHN Bale, sons and danielsson, ltd. OHEAT TITOHFIELD STREET, W. PEEFACE TO THE SIXTH EDITION. Among additions to this volume I may mention : — -the classification of uric acid diseases fp. 135), a reference to which, will, I hope, render the relationships of the processes more easy to understand (my readers must bear in mind that any classification in a progressing research is necessarily imperfect, but still, such as it is, I hope it will be useful) ; the record of some of my work with the uric acid filter throwing much Hght both on pathology and the action of drugs ; some fresh work on the circulation, and some records of interesting cases to illustrate it. The chapter on treatment has also been largely re- written, and contains my more recent practical points with regard to diet in circulation troubles, some of which are of great importance. What eleven years ago in the First Edition was httle more than possibihty or probability is now absolute certainty, and a certainty which can be made visible to the untrained andunaided eye in a few moments. A friend recently brought into my room two people of whom one was a taker of meat and tea, and the other an abstainer from them, and he said to me, " Now you must teU me which is which without asking any questions." The circulation test enabled me to do this correctly in a few moments. The abstainer had a quick circulation and a good colour, the self-poisoner had neither. I have several times offered people £5 for every meat eater they could produce whose colour and circulation would equal my own ; I might have made it £50 or £500, for no one has made any money at it, or is ever likely to do so ; there are practically no such meat eaters, with possibly a few exceptions in the highest nutrition periods of hfe. Such exceptions are not to be found among the boys of our meat-loving pubhc schools ; I saw two of them only the other day, and their circulation was twice as slow as mine and their colour oaly about half of mine, and I have often had to treat school boys for anaemia, a minor degree of the chlorosis from which their meat-eating sisters suffer so severely. It is now also obvious that most of those troubles which I began by calling diseases are not diseases at all, but mere results of food poisoning, and that very numerous other troubles, though not directly caused by the poisons, are in many and important ways greatly aggra- vated by them. viii. Preface to the Sixth Edition It is still impossible to compute accurately the real amount of either direct or indirect poisoning ; this wiU only be possible when large numbers of people have lived on a correct diet for several generations. As these visible and tangible facts become more generally known and understood, and as large numbers of people see for themselves the results of abstaining from the poisons, a great change of habits will result, and those who do not change or even go, as some are at present going, ever further and further in the fatal direction of poisons and stimulants, will leave a vacant place, for Nature makes no bargains and favours no compromises, she simply eliminates. The records made by such champions as E. H. Miles, Karl Mann, G. A. OUey and others within the last few years bear eloquent testimony to the splendid results which may be produced in athletics by abstaining from the friction-causing poisons ; and the condition of these record makers can be tested in a moment by the rapidity of their capillary circulation, as that is the record of' the friction in the machine, and other things equal, that machine which has least friction will win. Those who consider that sluggish circulation, poor blood, defective cerebration, mental and bodily lethargy and a life of almost constant pain and disease terminating in the forties or the fifties, represent the summum bonum of human existence, can no doubt get the little they ask for ; but it will soon be no longer possible for them to say that nothing better was known or obtainable. A stronger, more active and more noble life lived for a hundred rather than for fifty years, and ending in a natural death which will be painless and unconscious as birth, is what knowledge of the truth promises to-day to all who dare to follow it ; and to make this more quickly, certainly and generally attainable is, and has always been, the purpose of this volume, and it gives me much pleasure to see that it is fulfilling its object. Now, as before, I have to thank an ever-increasing number of fellow workers, and many who, having experienced the benefits of the change of habits in themselves, are most anxious to spread the knowledge of these facts by every means in their power ; for theSe and more there is room. fpS, wBble races and continents have to be influenced, and- numerous as are the workers the harvest is still too large ^^thefflgi^ut hope in these and. all directions is now, I am glad €5 know, changing into certainty. 7, Brooh Street, London, W. May, 1903. PREFACE. This is practically a r&sum& of the facts and arguments in some twenty-five papers, on the subjects which form the headings of the chapters, which have appeared in various journals, transactions and reports from the year 1884 to the present time, together with such alterations and additions as further experience has suggested. As my investigations tend to show that the functional and organic disorders of which I speak are in many cases entirely due to an excess of uric acid in the body and blood, this is practically a work on the causation of disease by uric acid, of the process by which it comes to be present in excess in the body and of the means of preventing such excess. I nevertheless- regard the investigation at which I have been working during these years as only in its very first stages, and this volume as a mere preliminary communication, and one which was only undertaken because I felt that papers thus scattered about in various journals did not do the subject justice; and it is certainly not with any feeling that the matter is ripe for final judgment that I now put it forward. Considerations of space have compelled me to give in mere out- line much of the results of my work during the last six years, but any portions which the future may show to be of value can easily be recorded at greater length. It would also have been almost impossible to carry through tlie thread of my argument if greater details had been given here. My most hearty thanks are due to Dr. Lauder Brunton for much kind assistance, advice and encouragement, and my readers will doubtless see that the investigation has not been by any means devoid of difficulties and doubts, though some of these now seem to have been happily surmounted. I am also under considerable obligation to Sir Dyce Duckworth for allowing me to investigate certain interesting cases and for much kindly notice and instructive criticism of my researches in his work on " Gout " ; also to Dr. Norman Moore and Dr. Ormerod for X. Preface permission to work in the departments under their charge at St. Bartholomew's Hospital, and to my colleague, Dr. H. H. Tooth, for permission to quote some cases, and for much assistance in studying epilepsy from my point of view. I have also to thank Mr. J. B. Saul, F.I.C., for kind help in several places in regard to points in chemistry where I should otherwise have been at fault ; and to many others who, as appears in the text, have helped me by permission to study their cases, copy their notes, or profit by their experiences, I must here also return my grateful thanks. 7, Brook Street, London, W. February, 1892. CONTENTS. CHAPTER I. HiSTOBY • . . 1 CHAPTEB 11. FOEMATION AND EXCBETION OP UBIC AoID 16 CHAPTEB III. PoBMATiON AUD BxcBETioN OF Ubio Acid {Continued) 66 CHAPTEB IV. Ubio Aoid ajstd Metabolism- 131 CHAPTER V. XJbic Aoid and the Cibculation 167 CHAPTEB VI. Headaohe 250 CHAPTER VII. Epilepsy, Convulsions, and Hystebia 277 CHAPTER VIII. Mental Disease, Fatigue and Syncope . . . . . . . . . . 320 CHAPTEB IX. Asthma and Bbonohitis . . . . 410 CHAPTEB X. Dyspepsia and Gout op the Intestines i47 CHAPTEB XI. Raynaud's Disease 476 CHAPTEB XII. Paboxysmal H^moqloeinubia and An^imia . . . . . . . . . . 513 xii. Contents PAOE CHAPTER XIII. Albuminubia and Bbiqht's Disease . . . . . . . . . . . . 575 CHAPTER XIV. Gltcosubia and Diabetes Mellitds 6i9 CHAPTER XV. GoTJT 692 CHAPTER XVI. Rhedmatism and Morbus Coedis . . . . . . . . . . . . 741 CHAPTER XVII. Teeatment . . . . . . ..■■■..•.. . . . . . . . . 825- CHAPTER XVIII. Instruments and Methods • 893- LIST OF FIGUEBS. Pig. I. Natural Plus Excbetion op Ubic Acid in the Alkaline Tide 22 „ II. Daily Excbetion of Ubic Aqid in Epitome . . . . 23 I) III. Daily Excbetion op Ubic Acid ebom Houe to Houb . . 25 „ IV. Ye ABLY Excbetion oe Ubic Acid ebom Month to Month 32 „ V. CuBVES of Tempkeatube in Mouth and Bectuk to show theie Relation to the Excretion of Ubic Acid . . 85 ,, VI. Plus Excbetion of Ubic Acid pboducbd by Alkalies.. 40 „ VII. Plus Excbetion of Ubic Acid peoduoed by Phosphate OF Sodium . . . . . . . . . . . . . . d2 „ VIII. Plus Excbetion of Ubic Acid pboduced by Salicylate OF Sodium . . . . . . . . . . . . . . 44 „ IX. Plus Excbetion of Ubic Acid peoduced by Belladonna 46 ,, X. Plus Excbetion of Ubic Acid produced by Quinine . . 48 „ XI. Eetention of Uric Acid produced by Acids . . . . 50 „ XII. Eetention of Ubic Acid peoduoed by Ieon . . . . 53 „ xin. Retention of Ubic Acid peoduced by Lead . . . . 54 „ XIV. Retention of Ubic Acid produced by Lithia . . . . 57 „ XV. Betehtion of Ubic Acid produced by Morphine . . . . 60 „ XVI. Retention of Ubic Acid produced by Cocaine . . . . 62 „ XVII. Retention of Uric Acid produced by Mercury . . . . 67 „ XVIII. Retention op Ubic Acid peoduced by Antipybin . . . . 68 „ xrx. Effects of Niteo-Glycebine on the Acidity of the Ueine 70 „ XX. Effect op Niteite of Am yd on the Acidity of the Urine 71 „ XXI. Curves showing the Relation of the Number of Geanules in the Blood to the Excbetion of Ubic Acid in the Ueine, Hour by Houb . . . . . . 96 „ XXII. Retention of Ubk Acid produced by an Iodide . . . . 100 List of Figures xiv. Fig. XXIII. Effects of Balsam of Copaiba on the Excretion of Ubic Acid and Wateb . . . . . . ' . . . . . . 102 „ XXIV. Effect on the Excbetion of Uric Acid of Swallowing Urate of Sodium . . . . . . 108 „ XXV. Effect on the Exceetion of Uric Acid of Sodp, Pish, and Meat 109 „ XXVI. Effect on the Excretion of Uric Acid of Liebig's Extract OF Meat. . .. .. .. .. .. .. Ill ,, xxvn. Effect on the Excretion of Ubic Acid of Swallowing Hypoxanthine . . . . . . . . . . . . . . lis „ xxviii. Effect on the Excretion of Ubic Acid of Swallowing Xanthine . . . . . . . . . . . . ... 114 „ XXIX. Effect on the Excretion of Uric Acid of Swallowing Citrate of Caffeine . . . . . . . . . . . . 115 „ XXX. Effect ON the Excretion of Ubic Acid of Swallowing A Sheep's Thyroid . . . . . . . . . . . . lie „ xxxL Excretion of Ubic Acid dubing Menstbuation. . . . 140 ,, xxxn. Effects of Menstruation on Pulse and Temperature . . 157 „ xxxiii. Curves showing the Effect of EHTTHROPHL.ffi!UM upon the Blood Pressure and Secretion of Urine . . . . 171 „ XXXIV. Pulse Tracings showing the Blood Pressure (A) before AND (B) during the ACTION OF Meroury . . . . . . 194 „ XXXV. Pulse Tracings of Opium Bebound, of Opium Well-being AND OP Antipybin Well-bbing . . . . . . . . 195 Pulse Tracings of High Blood Pressure in Bright's Disease and of the Effects of Drugs upon it. . . . 202 Pulse Tracings op High Blood Pbessube ; (A) Faltering, (B) Intermittent . . . . . . . . . . . . 213 Normal Curves of After-image Blood Pressure and Capillary Reflux. Normal Mobning and Evening . . 235 CuBVEs OF Afteb-image Blood Pressure and Capillary Eeflux. Showing Effects op Diet . . . . . . 236 Curves of Apteb-image Blood Pressure and Capillary Eeflux. Showing Effects of Weathbe . . . . 239 OuEVES OF After-image Arteriombtbr and Capillary Kbplux, showing the Flattening Out that follows on taking Salicylates, and the Fluctuation of a Headache . . . . . . 340 „ xLii. Curves of After-image AND Capillary Reflux. Showing Effects op Rise of Temperature . . , , . . . . 242 „ XXXVI. „ XXXVII. „ XXXVIII. „ XXXIX. „ XL. „ XLI. List of Figures XV. Fia. XLHi. O0RVBS OF Blood Pressure and Gapidlaey Reflux in Eelation to the Excretion op Uric Acid over a Series of Days ,, XLiv. Pulse Tracinq of High Blood Pressure in a Uric Acid Headache . . . . . . . . „ XLV. Curves showing the Excretion of Uric Acid before, during and after a Headache . . „ XLVi. Effects op Exercise on the ExoRiijaoN op Uric Acid AND Urea (Morning) . . „ XLVii. Effects of Exercise on the Excretion of Uric Acid AND Ueea (Afternoon) „ xLViii. Eppbcts op Exercise on the Excretion op Uric Acid and Urea AFTER Calomel .. „ xLix. Effects op Exercise on the Excretion op Uric Acid AND Urea after a Course of Salicylates „ L. Curves op Uric Acid Excretion and the Blood Decimal „ LI. Curves of Uric Acid Excretion and the Blood Decimal from Day to Day „ Lii. Curves op Uric Acid Excretion and the Blood Decimal prom Hour to Hour . . . . „ Liii. The Blood Decimal Curve, showing the Ordinary Diurnal Variations, their Relation to the Excretion OF Uric Acid, and their Reversal by Reversing the Excretion of Uric Acid ,, Liv. Curve op Blood Decimal IN Chlorosis, showing Effects of Iron, Beep Tea and Alkalies ij Lv. Curve op Blood Decimal in Chlorosis, showing Effects OF Iron, Beep Tea and Caffeine Lvi. Curve op Blood Decimal in Chlorosis, showing Effects OF Uric Acid Lvn. Curve OP Blood Decimal IN Chlorosis, showing Effects OP Iodide of Mercury LViii. Curve op Blood Decimal in Myxgsdbma, showing the Effect op Thyroid Feeding Lix. Curves showing Development in Boys and Girls and its Effect on the Excretion of Uric Acid . . Lx. Curve of Blood Decimal in Chlorosis showing the Effect of a Uric Acid Free Diet LXi. Cdrves of Excretion op Uric Acid and Sugar in a Case op Glycosuria 244 251 252 360 362 364 365 533 535 537 539 541 543 545 546 549 553 570 xvi. List of Figtires PAOE Fig. lxii. Curves of thb Excretion op Ubic Aoid in Gout as PUBLISHED IN St. BARTHOLOMEW'S HOSPITAL KbEORTS IN 1888 696 „ Lxiii. Curve of Urinary Acidity, showing the Effects of 2 Oz. OP Sherry . . . . . . • • • • • • • ■ '^^'^ „ LXiv. Curve op Urinary Acidity and Water, showing the Effects of 20 Grains op Citric Acid 718 „ Lxv. Curve of Urinary Acidity and Water, Control Ex- periment TO Pig. 64 719 „ Lxvi. Curve op Urinary Acidity showing the Effects op Stewed Ehubahb . . . . . . . . . . ■ • 721 ,, Lxvii. Curve OF Urinary Acidity showing THE Effect op Taking Brandy Undiluted . . . . . . . . . . . . 723 „ Lxviii. Curve op Excretion op Uric Acid in Acute Rheumatism under Salicylate op Sodium 768 „ Lxix. Temperature Chart op Rheumatic Endocarditis showing the Cause and Cure 786 ,, Lxx. Temperature Chart of Rheumatic Endocarditis. An- other Case . . . . . . . . . . . . . . 7go ,, Lxxi. Effects on Excretion of Uric Acid of giving Bicar- bonate op Sodium with Salicylate of Sodium . . . . 793 „ Lxxii. Effects of a Turkish Bath on the Acidity op the Urine prom Hour to Hour 802 „ Lxxiii. Uric Acid, "Urea, and Acidity Excretion Month to Month, showing Effects of Diet over Years . . . . 832 „ Lkxiv. Uric Acid and Urea Excretions and the Blood Decimal FROM Day to Day ; showing the Effects of Diet in the Production of an Attack op Gout and its Cure by Salicylates 842 „ Lxxv. Excretion of Uric Acid after 4 Oz. op Lentils. Effects on the Curves op Blood Pressure and Capillary Reflux op its Passage through the Blood 858 ITRIC ACID AS A FACTOR IN THE CAUSATION OF DISEASE. CHAPTER I. History. It is now more than twenty years since I began the research of which I propose to give an account in the following pages. It seemed to rae then a small and simple matter to investigate the causation and treatment of the headache from which I suffered ; but gradually through these years the horizon has expanded, and I now see that a very large portion of the field of medicine may be modified by my results. As time has gone on the matter has gradually become more and more simple till it is to-day clear that " uric acid disease " is only uric acid toxaemia ; the poison is swallowed, and poisoning and its signs and symptoms result as a matter of course. It is also clear that uric acid is a poison for all, and though some suffer in one way and some in another, all who swallow it have sooner or later reason to regret that they did so. Having been all my life a sufferer from migraine it was in the autumn of 1882 that in despair of obtaining any complete relief from drugs, and not without some fear that I was really suffering from organic disease, I gave up all butcher's meat and replaced it by milk and fish, the latter in decreasing quantities till milk and cheese formed, as they do now, my only animal foods. I had previously tried a great variety of alterations in diet, including an increased allowance of meat and various alterations in quantity and quality of less important constituents, such as sugar, tea, coffee, 1 a UEIO ACID — CHAl'TEK I and tobacco, without any noticeable result. But on the non-meat diet a change was at once apparent ; my headaches diminished both in frequency and severity, and from an average of one in a week they fell steadily, as the diet was persevered in, down to one in a month, one in three, six, eight, or twelve months, and eventually eighteen months elapsed without an attack of notable severity. Since that I have never gone back to butcher's meat, and I never intend to, because by avoiding it I obtain what is practically immunity from a disorder which, at one time, bid fair to cripple me and prevent completely all mental and sedentary work ; not that the headache was confined to periods of sedentary work, for I have often had to give up portions of a day's shooting because my head was too bad to stand the noise and concussion of firing, and yet this was in the open air of the country, and when a book had probably not been opened for weeks, and under conditions which were infinitely more favourable to health than those in which I now exist and have immunity. But if I at any time forget my lesson of the past and presume on niy apparent security from attack, if I, dine with two or three friends in the same week, and especially if I take both meat and wine, of the action of which I shall speak presently, I am practically certain to have a more or less severe headache in two or three days' time ; though, as will appear further on, I can generally prevent the intense pain from which I used to suffer in former days, as more correct knowledge of causation gives more complete power of coatrol. Having arrived, then, at the conclusion that leaving off butcher's meat had practically relieved me of headache, I began to ask why this was so, and at first {Practitioner, 1884) I was inclined to attribute it to the formation of some poison, possibly of the nature of a ptomaine, in the intestines during the digestion of the butcher's meat. But a further study of the clinical history of migraine brought out such a strong relationship to gout, that (Practitioner, 1886) I began to suspect that uric acid might be the poison of which I was, in search, and I therefore proceeded to estimate the excretion of uric acid and urea. At first I estimated only the excretion of twenty-four hours, and as many of my headaches lasted only a portion of a day, I got indefinite or contradictory results ; but when I separated the urine excreted during the headache from that both before and after it, a definite and distinct relation between the headache and the excretion of uric acid at once became aipparent — a relation which I have since found both in myself and others, in very numerous instances, quite sufficient to- remove the result out of the chapter of accidental coincidences. But. HISTOEY the headache in question, as described by Liveing and others, has other important concomitant symptoms — as slow high tension pulse, cold surface and extremities, mental depression, and disinclination for exertion, mental or bodily, and the urine during the headache is scanty and of high colour and specific gravity. But once having noticed the relation of this headache to the excre- tion of uric acid, I soon noticed that each of its concomitant symp- toms bore exactly the same relation to uric acid, that when the pulse was slow and of high tension there was always a greater excretion of uric acid than when it presented the opposite character, and the same with the mental depression and scanty urine. After this a little further experimentation brought out the fact that the excretion of uric acid was completely within my control, and that I could alter it from day to day or hour to hour in either direction at pleasure (Journal of Physiology, vol. viii.). I now soon found out that in altering the uric acid I could alter the symptoms related to it ; that when I produced an increased excre- tion with alkah, I produced the headache, mental depression, cold surface, slow pulse and scanty urine, and that when I stopped the plus excretion with an acid I removed all these symptoms ; so that not only had I acquired the power to produce or remove the headache, but I had also the power to free or obstruct the capillaries, to affect the tension of the pulse, the rate of the heart's action, and thus to influence the circulation in the brain, skin, kidneys, and probably the whole body. Then I also soon noticed that in curing a headache by giving an acid to diminish the excretion of uric acid, I always produced a certain amount of pricking and shooting pain in my joints (generally in those which had been most used on the day in question), and it naturally occurred to me that the uric acid was held back in these joints and produced the pains. The uric acid which failed to appear in the urine must have gone somewhere. What more natural than to suppose that it had been retained in the joints (where in gout it is found), and that the pricldng pains were the evidence of its presence ? Then on turning to Sir A. Garrod, I found that he had described precisely similar joint pains as occurring in gouty subjects imme- diately after the ingestion of beer or wine, and a very little investi- gation sufficed to prove that all beers and wines are strongly acid, so that a very simple explanation could be given of the facts. Since that I have found not only that an attack of gout or rheu- matism can be produced by giving acid, but that what I had observed was only a single instance of a general law, and that all substances 4 UEIC ACID — CHAPTER I which increase the solubility of uric acid increase its excretion in the urine and do good in those joint troubles which are due to its irritating presence ; while conversely all substances which diminish the solubility of uric acid, diminish its excretion in the urine, and also increase those irritations in joints and other fibrous structures which are due to its presence. And the capillary circulation now tells us in a moment where the uric acid is, whether in the blood, in which case the circulation will be slow, or in the fibrous tissues outside the vessels, in which case the circulation will be quick, just in proportion as the blood contains little uric acid. Uric acid can now be seen as it passes through the circulation. On such comparatively simple facts and observations the whole of my writings have been based, and as side issues I have been led to reason on the pathology of epilepsy, in some cases of which I found exactly similar fluctuations in the excretion of uric acid to those met with in migraine, thus explaining a clinical relationship between these two diseases which had long been known and written about — also on the pathologj- of rheumatism and rheumatoid disease, the causation ■of Bright's disease, and diabetes, Raynaud's disease, and paroxysmal haemoglobinuria and ansemia. But if uric aoid affects the capillaries in the way and to the extent which I claim that it does, it will easily be understood that it must influence for good or evil the function, nutrition and structure of every organ and tissue of the body, from the skin outside to the most central fibres of the spinal cord and brain within. And when they have looked carefully into the effects which uric acid produces in the causation of fatigue, and the way in which it brings about a rise or fall in the formation and excretion of urea, I think that no one will have any difiiculty in admitting its enormous power over the metabolism of the whole body (see also " Diet and Food," chapters i. and ii.). And besides, any one can see in a moment that the capillary circulation of a taker of flesh and tea is always much slower than that of one who abstains from these poisons. Naturally the subject is not so simple as might appear from this outline, but that will be sufficiently evident when we come to deal with the points in detail, and I shall endeavour as far as possible to conduct my reader through the same course of reasoning that I myself followed, so that I may escape the omission of any important points. Before going on to do this I shall just mention shortly some passages in the writings of Sir A. Garrod, Dr. Liveing and others, which have had important influence in shaping the course of my investigations. Sir Alfred Garrod says (" Gout and Rheumatic Gout," ed. iii., p. 6) : ■' Galen, who lived about the latter half of the second century, was HISTOEY 5 of opinion that gout was caused by some unnatural accumulation of matters in the part afiected. These matters were supposed to con- sist of phlegm, bile, blood, or a mixture of these fluids, and chalk-stones were considered to be formed by their concretion or solidification." Our knowledge now in the twentieth century, might be expressed in almost the same words if we substitute " uric acid " for " phlegm, bile and blood." On a previous page Sir A. Garrod says (p. 2, prev. ref.) : " It is by no means rare to hear of inflammation of a joint by one practi- tioner called gout, by another rheumatism, and by a third rheumatic gout," and if it should appear in the following pages that my work tends to show that these more or less distinct clinical conditions may all be due to accumulation of uric acid, I hope this will not be regarded as a step backward, but rather as an advance, in that, with greater knowledge of the chemical and physical properties of uric acid, we are now able to understand how it may produce very different clinical pictures according to the time during which it acts, according to the quantity in which it is present, and according also to the metabolic activity as well as the structure, vascularity and general anatomical arrangement of the tissue on which it acts. And' we may think rather that the discrepancies of opinion which Sir A. Garrod mentions reflect credit on our profession, who failed to detect essential differences where nature had placed none. Further on Sir A. Garrod says (p. 275), " The causes which predispose to gout independently of individual peculiarity are either such as produce an increased formation of uric acid in the system, or lead to its retention in the blood." And in the Lumleian Lectures {British Medical Journal, January, 1883, p. 549), he says, " May it not be the case that when uric acid exists in the blood it is attracted differently by different organs, and thus the spleen and liver more frequently contain appreciable quan- tities than other tissues ? Or, again, may it not be that in some organs, as the spleen, the substance of which, if not acid during Ufe rapidly becomes so after death, while the blood remains strongly alkaline, the uric acid becomes less soluble and more easily retained." I shall presently show how I was led by my results, and without any knowledge of Sir A. Garrod's remarks, to believe that excess of uric acid in the blood and body are almost never due to increased formation, but generally to failure of excretion (or retention) ; and that then, having observed that I was always able with alkalies to increase and with acids to diminish the excretion, I adopted {Journal of Physiology, vol. viii.) Sir A. Garrod's above-quoted suggestion to explain my results, and have continued to use it ever since. 6 UEIC ACID— CHAPTER I With regard to lead Sir A. Garrod says (p. 243), " It would appear, therefore, that in individuals impregnated with lead the blood becomes loaded with uric acid, not from its increased formation, but from its imperfect excretion." My researches seem to me to show that the blood never becomes loaded with uric acid except as the result of excessive introduction (flesh, tea, &c.), followed by or acting in conjunction with imperfect excretion, and such imperfect excretion (or retention) is sufficient to account for the largest quantities I have ever seen in the human body, so that there is no need of excessive formation as an explanation. I do not assert that excessive formation never occurs, but only that I have not met with any conclusive proof of its occurrence, while all the phenomena of disease can be completely explained by the ordinary formation of uric acid, plus a certain quantity of it introduced ready formed in food, without postulating the excessive formation of a single grain (see fig. 73). It is now also evident that if my own sufferings had been due to formation they would have remained incurable, as I should have gone on forming excess of uric acid on any diet. But the above-mentioned figure shows that this has not been so, and I have been cured mainly by stopping all avoidable introduction. The late Sir W. Roberts says (" Urinary and Renal Diseases," ed. iv., p. 73) : " It may be regarded as probable that the defective power of the kidneys to eliminate uric acid in gout arises from a diminished alkalescence of the blood." From my point of view it has nothing whatever to do with the kidneys ; the urates are not in solution in the blood, and are not brought to them ; when they have been got into solution by an alkali and come to the kidneys they are excreted fast enough. But neither Sir A. Garrod nor Sir W. Roberts knew what I found out, that the excretion of uric acid can be made to vary at any time and in any direction — a discovery which not only enabled me to explain all the symptoms of the uric acid headache, but also showed me the way in which, by the gradual accumulation of small quantities, very large amounts of urate come eventually to be stored or retained in the body without any excessive formation having taken place. It also showed me that the daily physiological fluctuations in the excre- tion of uric acid are due to the same cause, and depend on the amount of solvent alkali in the circulation, the- greatest excretion of the dav occurring in what Sir W. Roberts has called the " alkaline tide," and the smallest excretion in the high acidity period of the night. And not only is this so, but it is easy to demonstrate that this well- HISTOEY 7 known large excretion in the " alkaline tide " is not due to formation ; for if a dose of alkali is taken at bedtime for several nights, there is an increased excretion of uric acid during the night, and then the " alkaline tide " excretion is correspondingly diminished till after a few days the hourly excretion is almost equal all through the day and night. I would like to add here one word to express my great respect for the magnificent work of Sir A Garrod, which, founded as it is on experimental research of the most accurate kind, must for a long time to come remain a landmark for all those who work at uric acid. And if in a few points I have ventured to give other explanations of the facts than those he suggests, or to think that in some few of his results he may have been misled by the working of a less perfect process than that I have used, that has never prevented me from seeing how greatly I am indebted to the careful records of his experimental work, and to his valuable suggestions founded upon it. To Dr. Liveing's very interesting work on headache I am indebted, not only for a knowledge of the relationship of migraine to gout, but also for that of the relationship of migraine to epilepsy and of both to gout, and it was his quotation from du Bois Reymond and others that led me to look for a uric acid reaction in epilepsy similar to that I had found in migraine. Since the first edition of this book appeared (1892) I have made two discoveries with regard to the causation of disease by uric acid ; first of all I found that uric acid taken by the mouth passes into the blood, and that if this fluid is kept in a condition to hold it in solution, it will remain in the blood till the kidney has time to pass the whole of it into the urine ; so that of 12 grs. taken by the mouth some 10 or 11 grs. can be obtained from the urine within three or four days after it has been swallowed. (See Journal of Physiology, vol. xv., p. 167.) Now this brings to the front two important points : (1) That the uric acid excreted normally in the urine comes from two sources, (a) the uric acid formed in the body out of nitrogenous food and {fi) the uric acid introduced into the body in meat, meat extracts, soup, tea, coffee, &c., all of which contain it in considerable quantity. (2) That in so far as the morbid processes of which I shall speak in the following pages are due to an excess of uric acid in the blood, they can be produced at pleasure simply by taking that substance by the mouth, and thus any one who wishes to do so can repeat my experi- ments and satisfy himself as to their truth. As regards the quantity of uric acid in meat, meat extracts, soup, &c., it is necessary to bear in mind the following points : — Not to go deeply into theoretical chemistry, it may be said that UBIC ACID — CHAPTER I Haycraft's process for the estimation of uric acid in urine, wkich I have used throughout my researches, estimates as uric acid not only the uric acid present in that fluid, but also a certain amount of xanthin, hypoxanthin, or other members of the xanthin group. This process, therefore, estimates the amount of uric acid too high in proportion to the amount of these xanthin bodies present ; but inasmuch as urine contains only very small quantities of these xanthins the error from this source, so long as the process is applied to urine, is not great. Some writers on these subjects speak of uric acid and the xanthin bodies not as the xanthin group but as the alloxur group or as the purin group, according to the name of a certain chemical combination which is supposed to form the basis of the whole group. I mention this merely that those who are not following the literature of the subject should not be confused by new names which carry no new discoveries or changes in chemical formulae. As met with in human urine, uric acid contributes from four-fifths to five-sixths of the whole group, and the remaining one-fifth or one- sixth is made xip of the xanthin bodies. I am therefore calling the whole group by the name of its chief constituent, the other writers have one name for the whole group, in which the well-known chief constituent is merged. When, however, the process is applied to extracts of muscle, blood and other tissues, which contain considerable quantities of these xanthin bodies in addition to a little uric acid, the error may obviously be very large indeed, and what is reckoned as uric acid may not, chemically speaking, be that substance at all. If this was a work on Physiological Chemistry, the error thus introduced would no doubt be a very serious one. I shudder to think of the number of atoms of oxygen that I have inadvertently added on to the xanthins contained in muscle by reckoning them as uric acid. But as we are dealing with physiology and pathology alone, it is easy to show that the chemical inaccuracy above-mentioned is a matter of no consequence, indeed it has probably been an advantage, for as I have pointed out it makes absolutely no difEerence to physio- logical and pathological results whether a man swallows two grains of hypoxanthin, xanthin, caffeine, theobromine, or uric acid itself ; all these substances alike produce obstructed capillaries, high blood pressure, headache, mental depression, scanty secretions, and a large excretion of a substance estimated as uric acid in the urine by Hay- craft's process. On the other hand, if I had estimated only the true uric acid in mxiscle, I should have quite missed the explanation of its physiological HISTORY and pathological efEect, and we must not forget the points mentioned at the beginning of the chapter, that my whole research originated with my observation that a certain form of headache is made worse by eating meat, meat soup, or meat extracts, and is cured or prevented by abstaining from them. If physiological chemistry is correct, muscle contains only a very small quantity of true uric acid, but a considerable quantity of xan- thins which are physiologically and patholQgically identical with it, and differ from it chemically merely in the absence of one or more atoms of oxygen. The explanation is therefore complete ; meat produces the head- ache by introducing into the body and blood uric acid plus substances of the xanthin group, and the same headache and visible slowing of the capillary circulation can be produced at will by swallowing any one of these substances in a state of comparative chemical purity. I have all along felt that in applying Haycraft's process to extracts of tissues I was walking on dangerous ground as regards theoretical chemistry, and I have, therefore, been careful to point out (ed. ii., p. 355) that, while I gave figures of the amount of uric acid found in various animal foods by this process, the only satisfactory test of the amounts of these uric acid compounds contained in them is the phy- siological one of eating a known quantity of the substance in ques- tion and watching the effects on excretion in the urine (see figures in chapter iii. and elsewhere.) And this can -be done without any fear even of theoretical chemistry, for as xanthin, hypoxanthin, &c., have only been found as mere traces in urine, it follows that the relatively considerable quantities of these substances contained in meat food must be largely converted into uric acid by the addition of oxygen in their passage through the body. My second discovery, which was to a large extent a result of the fiist, was that uric acid when present in excess in the blood affects its quality in an important manner, producing the changes met with in anaemia, paroxysmal hsemoglobinuria and other diseases, and also counteracting the effects of iron and preventing it from building up the blood and curing these diseases, if indeed iron has any such action, which, as we shall see later on is more than doubtful. Thus I found not only that by administering uric acid I could con- trol the value of the blood decimal (haemoglobin divided by red cells) in myself and others, but that my own blood decimal actually varies from day to day, and even from hour to hour (see fig. 52) in accordance with the quantity of uric acid passing through it into the urine. Now it has been pointed out by other observers that the blood decimal 10 UEIC ACID — CHAPTER 1 is commonly high in the morning and low in the evening, and this is not due to the explanation they give, but simply to thefact that but little urio acid passes through the blood at night and a good deal by day ; and this can be proved by making the uric acid excretion of the night large and that of the day small, and then the blood decimal is found to be low in the morning and high in the evening, just the reverse of its usual movement (see fig. 53). We shall also see in the following chapters that uric acid aSects not only the blood, but in- fluences in a similar way the function, nutrition, and eventually the structure of every organ and tissue in the body, and as regards infec- tious diseases has in some cases a more important influence than the microbes themselves. As regards the. tissues, it controls not only their nutrition but also their great physiological functions, the production of energy and the production of heat, to an extent which, acting as it does from hour to hour throughout the whole of life, cannot but be of enormous importance. But more recent advances have carried us far beyond this, and we can now say, with absolute certainty, that uric acid controls and condi- tions the capillary circulation of the whole body (and this control can be demonstrated in less than a minute, and by any one without instru- ments), and thus regulates the blood pressure, the heart's action, the nutrition of the heart and vessels, the nutrition of the tissues, and all the metabolic phenomena which constitute the life of the body to its minutest cells. For the granules precipitated in the blood by chloride of ammonium and first mentioned in the fourth edition, prove, on further investiga- tion, to be an absolutely certain guide to the quantity of uric acid in the blood and urine ; corresponding absolutely with this in pathology, drug action and physiology, and under all times and conditions. So that with drugs it is possible to change the number of granules in the blood from a relation to the red cells of say 1 to 30 or 1 — 40 up to a relation of 1 to 5, 1 to 3, or even 1 — 1, and to do this at any time and at pleasure. (See chapter iii.) But with this change in the number of granules in the blood, goes also and always a corresponding change in the quantity of uric acid in the urine, and a change in the capillary circulation of the whole body. And the capillary circulation conditions the blood pressure and the rate of the heart's action, and many other phenomena both circulatory and metabolic dependent on these. With a small number of granules in the blood 1 — 30 the capillary circulation is quick, so that C. R. (^ Capillary Reflux, see chapter v.) is only 3 — 4 half seconds, the blood pressure is low, 100 mm. of mercury, and the heart's action is quick, above 72. HISTORY 1 1 With a large number of granules in the blood, whether produced by drugs or due to physiological changes, diet or other natural causes, the capillary circulation is slow, so that C. R. is 8 — 10 or 12 half seconds, and blood pressure is high, 120 — 140 or above, and the heart's action is slow, 60 or below. With the small number of granules in the blood and quick capillary circulation, low blood pressure and quick pulse, goes the pathological condition — fever. And with a large number of granules in the blood, slow capillary circulation, high blood pressure and slow pulse, goes the pathological condition — Bright's disease. And the one pathological condition can be distinguished from the other with absolute certainty, and in less than half a minute, by gauging C. R. with the tip of the finger. And the whole of these phenomena, uric acid in blood and urine, blood granules, capillary circulation, blood pressure, and numerous conditions of nutrition dependent on capillary circulation and blood pressure, not only always alter together and correspond, but can be made to alter at pleasure, and in any direction by drugs which have long been known to control the amount of uric acid in the urine. Thus, any accurate measurement of capiUary circulation or blood pressure and their results is a measure of the uric acid in the urine and blood, because the uric acid controls the circulation. Thus, we can not only say that meat produced the uric acid head- ache by introducing uric acid and xanthin into the body, but we can demonstrate with ease and certainty that every symptom that accom- panied that headache was the effect of the excess of uric acid on the capillary circulation, and the blood pressure and the phenomena these control. We can demonstrate also, that the headache and aU its symptoms can be produced by swallowing either uric acid or any one of half a dozen forms of xanthin in known quantity, and that the headache and all its symptoms disappear and remain absent if the blood is kept in a state of physiological purity and freedom from uric acid (absolute freedom is of course impossible). That this relative freedom can be produced either by diet which leaves out the poisonous xanthins of flesh and tea and similar sub- stances (which is far the best way of producing it), or by drugs which directly clear the blood by forming insoluble compounds with uric acid while not aiding its eHmination from the body, or by those other drugs which clear the blood by effecting elimination through the kidneys. But with this relative freedom, however produced, will go free 12 UBIC ACID— CHAPTER I capillary circulation and quick C. E., and its efiect normal blood pressure ; and the headache and all its phenomena will depart and remain absent so long as the freedom of blood from excess of uric acid andjgranules is maintained. I know of no proof of the reaUty of any knowledge save the power of control which it gives in action ; and I may say that my power over the uric acid headache and the circulation conditions which determine it, is now little if anything short of absolute : but those who read the following chapters must form their own judgment on this matter. Then, as the uric acid headache is a functional disturbance of circu- lation, and the epitome of a wide iield in pathology, the power over it extends in various directions into that field, more especially to the diseases connected with the circulation, and here again power, if not absolute, is certainly advancing in that direction. Then again, as several figures will demonstrate, power over the quality of the blood and its changes, both physiological and patho- logical, is to say the least very considerable ; but those who will study previous editions will see that these powers have been slowly and gradually enlarging for years, and those who have applied these state- ments to practice have also, like myself, found that they possessed powers of control previously jinknown. To make these general statements as definite and clear as possible, I will now give in tabular form an epitome of the changes in circulation phenomena and their results, that can be produced at will. Let us take, say, a case of acute rheumatism before treatment by salicylates and after it {i.e., 10 — 12 or 15 — 24 hours later). Acute Rheumatism. Before Treatment. Later after 60 — 90 or 120 grains of salicylate of soda. Temperature 102°. Temperature 99°. Pulse 110. Pulse 70. C. E. 3—4 half seconds. C. E. 8—10 half seconds. Blood pressure 80 — ^90. Blood pressure 110—120. Urine per hour 50 — 70 co. Urine per hour 30 — 40 cc. Uric acid to urea 1 — 40 to 1—50. Uric acid to urea 1 — 15 to 1 — 12, even 1—10. Uric acid per hour 0-3 — 0"4 grain. Uric acid per hour 0-8 — 1-0 grain. Blood granules to red cells 1 — 30. Blood granules to red cells 1- 3 to 1—5, or even 1 — 1. Blood decimal -55. Blood decimal -53. Water from lungs, above normal. Water from lungs, below normal. Difference between temperatures in DifEerence between temperatures in mouth and rectum 05° or less. mouth and rectum I'O — 2'0° or more. HISTORY 13 And these changes are not due to the change of temperature and relief of the acute pain, for salicylate produces identical though less marked changes in a few hours in physiological conditions. None of these changes are accidental or fortuitous, they all follow each other in definite order ; if one is absent those dependent on it are also absent. Thus the central factor is the uric acid in the blood as shown by the blood granules and the excretion in the urine. The secondary phenomena dependent on it are the capillary circu- lation, the blood pressure,, the pulse rate, the quantity of water passed from the kidneys and lungs per hour, and the relation of surface to deep temperatures ; and these are mere results of the free or blocked capillary circulation in various parts of the body to which they each bear witness. The circulation in the retina tells the same tale (see fig. .38). If any condition such as will be mentioned later prevents the salicylate from producing excess of granules in the blood, and of uric acid in the urine, then all the secondary phenomena will be absent along with them. The quantity of uric acid in the blood can therefore be measured by the C. R., with the point of the finger and the power of counting half seconds, or by The blood pressure ; The pulse rate ; The water from the kidneys or the lungs, and doubtless also that from the skin and other glands ; The difEerence between surface and deep temperatures, as well as by the blood granules and the absolute and relative excretion' of uric acid in the urine. This is either knowledge and power or it is not ; but the question is not one of abstractions to be debated away from the facts ; but of demonstration or failure to demonstrate the facts themselves, and of power or failure of power to prevent and control disease by their means. And that I myself am alive and well to-day is for me an absolutely convincing and ever present demonstration of power, to which similar experiences with other people are being constantly added. Eighteen years ago my blood pressure was at least 20 — 30 higher than at present, and headaches were severe and frequent, my blood decimal also was quite 20 per cent, lower than it is now. These facts can be demonstrated in twelve to eighteen months on any sufEerer from these forms of headache, by anyone who will take the trouble to record the conditions, before, during, and after treatment. 14 UEIC AOID — CHAPTEB I The point is that some one who is suffering from uric acid " disease " is found to be excreting in the urine 16 to 18 grs. per day. By altering diet so as to put a stop to introduction, the uric acid excretion will, in eighteen to twenty-four months, be found to have sunk to 10 or 11 grs. per day, and with this all the signs of excess of uric acid in the circulation and fibrous tissues (collsemia and arthritis) will be found to have disappeared. It is impossible to reduce the uric acid below 10 or 11 grs. per day becautjfi this quantity is formed in the body in the relation to urea of ] to 34, and varies up and down with the urea from day to day. But as a rule this small quantity of uric acid (10 to 11 grs.) is all excreted from the body day by day and does no harm ; it is only the extra 6 to 8 grs. a day which is introduced with the food which does harm ; and as we are able to control this introduction we are also able to control or prevent " disease," and if it has not gone too far, to cure it. The C. E., the urinary water per hour, and the surface and deep temperatures, can be recorded by anyone. The blood pressure and the blood decimal are not difficult once the instruments are obtained (see chapter xviii.). The blood granules are easy and the uric acid in the urine only wants a little practice to become easy. The uric acid in the urine can be estimated by any reliable process and is not dependent on any one process ; and in the following chapters it will be evident that many of my results have been corroborated by other workers with different processes. I still believe that that of Professor Haycraft combines facility with sufficient accuracy to an extent which no other process does ; indeed, I should go farther and make Haycraft's the standard process for accuracy also ; as I think that if it over-estimates the uric acid, other processes under-estimate it to a still greater extent ; and those who will look into the literature of the subject will find that practical chemists are not all of one opinion (see chapter xviii.). For daily work C. R. and blood pressure with an occasional examina- of the blood granules and the blood decimal are amply sufficient, and even with C. R. alone it is possible to tell with great accuracy what the uric acid is doing either from hour to hour or from day to day (see figs. 38 to 43 and 75), in fact to see it passing through the blood. The final conclusion is. Do not swallow unnecessary uric acid, and the " diseases " (really signs and symptoms of poisoning by it) will gradually clear up and disappear ; and here is an answer to all ques- HtSTOKY 15 tions of causation, for exclusion of uric acid will either relieve, or fail to relieve. Let those who have a taste for insoluble problems worry and be worried over these ; but those whose object is the relief of suffering can get an answer which is for ever sibove and beyond all theories, in eighteen to twenty-four months or sooner. 16 CHAPTER II. Formation and Excretion of Uric Acid. One of my early observations on the ^excretion of uric acid and its relation to a headache showed that while there might be a bad head- ache one day, with, say, an excretion of 16 grs. of uric acid in the twenty- four hours, there might also be an exactly similar excretion on another day without any headache whatever, and viewing only the absolute excretion of uric acid these observations appear to be contradictory and prove nothing. It was always necessary, however, to view something besides the absolute excretion of uric acid, viz., its relation to urea, and when this was done a difference between these two days at once came out. On the day when 16 grs. were excreted without a headache, the relation of uric acid to urea was 1 — 33 (one of uric acid to 33 of urea), but on the day when, with a similar absolute excretion of uric acid there was a severe headache, its relation to urea was 1 — 18 or 1 — 20. The uric acid excretion in the uric acid headache is not only abso- lutely large, but it is greatly in excess of its normal relation to urea. Before going further we may try to determine what is the normal rela- tion of uric acid to urea in excretion, and also if possible in formation. My researches have extended over a large part of the last seventeen or eighteen years, but taking only the figures of the longer periods of my estimation of my own excretion, we get a total of 3,161 days in which 38,029 grs. of uric acid, 1,104,730 grs. of urea, and 158,723 grs. of acid (reckoned as oxalic acid) were excreted ; giving a relation of uric acid to urea of about 1 — 29, and a relation of acid to urea of 1 — 6'9. These figures divided by the number of days give uric acid 12 grs., urea 349 grs., and acidity 50 grs. per day. I must explain that my urea at the present time runs at from 360 to 420 grs. per day, or from 3 to 3-J grs. per pound, and that the low urea in the totals just given is in part the result of my having attempted to diminish my nitrogen during several years, which are included in the above totals (see fig. 73). FORMATION AND EXCEBTION OP URIC ACID 17 Now however that I know that the uric acid which caused my troubles was to a large extent due to direct introduction, I can easily keep my urea about the physiological level by eating substances which contain sufficient nitrogen, but which introduce into the body Httle - or no uric acid or xanthin (see chapter xvii.). But the total uric acid is increased probably by about 200 grs. swallowed intentionally for experimental purposes, and, say, some 300 grs. which were stored in the body before the estimation of the excretion began : (thus I have calculated, from the percentage of urate found in the various organs and tissues after death, multipHed by the weight of these tissues in the body, that a man of 12 stone would probably have 300 grs. in his various organs and tissues. And as this is probably not an over-estimate I have put down 300 grs. as the quantity in my own tissues, but it must be understood that the calculations I am now making are provisional merely and subject to revision as our knowledge becomes more accurate). Subtracting the 500 grs. thus accounted for from the total of 38,029 grs., we get 37,529 grs. as representing the excretion of uric acid in the above 3,161 days, apart from the urate which was intentionally intro- duced, and apart from that which was already present in the body when the experiment began. This gives a daily excretion of nearly ir2 grs. of uric acid and a relation of uric acid to urea of about 1 — 31'1. But the daily excretion equals the daily formation plus the daily introduction of urate ready formed in the food ; and though my food is probably much poorer in urate than that of persons on ordinary diet with an ordinary allowance of butcher's meat, soups and meat extracts, still there seems to be little doubt that my food does con- tain some uric acid or other members of the xanthin group equivalent to it. Let us say, for the sake of getting even figures, that I introduce or did introduce during some periods of my research with my food 1-2 grs. of .uric acid per day, and subtracting this from the 11-2 grs. of daily excretion we get 10 grs. of uric acid as the actual quantity of the substance daily produced in my body out of nitrogen introduced into it in other forms, the remainder of this nitrogen furnishing about 349 grs. of urea, giving a relation of uric acid to urea of 1 — 34. Now that pulses have been found out and removed from the diet (see chapter xvii. and fig. 75), daily introduction is probably a mere fraction of a grain ; but as we can only say that formation is about 1 to 34 we can only estimate introduction roughly by the difference between 1 to 34 and the actual excretion we get from day to day ; nor are we quite certain that some of that difierence may not be due to solution of some previous storage in the body. 9 18 UKIC AOID — CHAPTEE 11 Let US now try and work out the formation and excretion of a man of 150 lbs. from these data. Let us say that he forms 3-5 grs. per lb. of urea = 525 grs. a day, and uric acid in relation of 1 — 35 = 15 grs. per day. Then he will introduce in his food perhaps 1 gr. of uric acid per 100 grs. of urea = 5-25 grs. Therefore the total uric acid formed and introduced will be 20-25 grs. a day, and if he excretes the whole of this uric acid it will hold the relation to urea of 1 — 26. Bat this man with higher introduction of uric acid will have diminished alkalinity of blood, and with this, and depending upon it, lessened solubility and excretion of uric acid, that is to say, he will not excrete all the uric acid introduced in his food or formed in his body, but will retain a portion of it in his body. So that while I, in 3,161 days, have probably washed out of my tissues and excreted some 300 grs. of uric acid because my acidity has been low, this man with higher acidity may have retained in his tissues in the same or a shorter period some .300—400 grs. Such a man, instead of excreting the full 20'25 grs. of uric acid which is formed and introduced into his body each day, will only ex- crete, say, 19'5 — 20'0 grs., retaining in his tissues the remaining '2 — "7 of a grain, which in the course of years will amount to many hundreds of grains, and the higher the acidity the greater the proportionate retention will be. I consider, therefore, that every man who eats what is called ordinary diet with butcher's meat twice a day, and also drinks acid wines or beer, will, by the time he is 35 or 40, and certainly by the time he is 50, have accumulated 300 — 400 grs. of uric acid in his tissues, and possibly much more : and about this time, owing to the large amount of uric acid in his body, he will probably be subject to attacks of some form of gout or chronic rheumatism, and he will have defective capillary circulation and a low blood decimal. If such a man is killed by accident at this time, a quantity of uric acid, more or less equivalent to the above-mentioned amounts, will be found in his tissues. If,' on the other hand, he dies slowly after several years of wasting disease very much less will be found, for during his wasting there will be a marked fall of urea and acidity, his blood will become more alkaline and will take up uric acid from his tissues and pass it in excess in his urine. This is the reason we find erosions with but little urate deposit in the joints of patients who have died of wasting disease ; before these patients began to waste all the erosions were no doubt full of it. If the blood of such a patient suffering from wasting disease is examined every few weeks a steady and continuous fall of the blood POEMATION AND EXCEETION OF UEIC ACID 19 decimal (see chapter xii.) will be found corresponding to the amount of uric aeid passing through the circulation, and this is no doubt the secret of the causation of much of the ansemia of old age and wasting In most cases of wasting disease the plus excretion of uric acid and the excess passing through the blood produces symptoms which it is generally easy to recognise, such as slow capillary reflux (see chapter v.), slow high tension pulse, with some headache and mental depression, and I doubt not that in the more or less physiological conditions of mere old age an excess of uric acid in the blood having a similar causation plays an important part. With regard to the relation of uric acid to urea in excretion, namely, 1 — 33 or 1 — 35,^other investigators, Messrs. Yvon and Berlioz {Rev. de Med., September, 1888), found as the result of one series of experi- ments the relation 1 — 30, and of another series 1 — 40 ; while Lecanu (quoted by Sir Dyce Duckworth, " A Treatise on Gout," p. 120) found much the same relation that I have, viz., 1 — 33. There is thus a considerable collection of figures tending to show that the normal relation of uric acid to urea in excretion is 1 — 30 or thereabouts, and I have ventured to suggest that where this has been found over a very long period of time, it may represent something near the real relative formation of these two substances. It is probable, however, that these results, as found by myself and others, all include a considerable quantity of uric acid which is introduced with the food and not formed in the body, so that the real ratio of formation in man may be nearer 1 of uric acid for 35 of urea (see also Pulses and Researches on them in chapter xvii. and fig. 75). As already mentioned (chapter i.) I have adopted the theory of Sir A. Garrod, that the final stage in the formation of uric acid is the production of urate of ammonium in the kidney.* According to this theory a large part of the urate so formed passes at once down the ureter and is excreted ; but a small residue lingers in the kidney or the blood circulating in it, and is eventually carried over by the renal vein into the general circulation ; when there it is, according to the same authority, attracted differently by difEerent organs, and tends to be rendered less soluble, and so to be held back and accumulate in certain organs, as the liver, spleen, and certain * Sir A. Garrod also read a paper before the Boyal Society, in 1893, in whioh he shows that there is urea in the blood of birds though their urine contains none. He concludes, I believe, that in birds, just as in man, uric acid is formed in the kidney out of urea and other nitrogenous antecedents which come to it in the blood. 20 UEIC ACID — CHAPTEE II fibrous tissues, especially those of joints, probably because these tissues are less alkaline than the rest of the tissues and fluids of the body. Now, it has long appeared to me that these theories of Sir A. Garrod would enable me to explain completely all my results regarding the excretion of uric acid ; not to mention a whole string of disease pro- cesses of which, as we shall see presently, they afford an equally simple explanation. We are now, however, in a position to return to our original question — why there is a headache one day with an excretion of 16 grs. of uric acid, and little or no headache another day, when an identical quantity is excreted. Taking it that uric acid is never formed in greater relative propor- tion to urea than 1 — 33 (1 gr. uric acid for 33 grs. of urea), how comes it that on any given day uric acid can be excreted in the relation to urea of 1—18 or 1--20 ? Obviously Sir A. Garrod's theories supply an explanation ready to hand. If 16 grs. of uric acid are excreted to-day, while judging from the urea excreted only 12 grs. of uric acid were formed, then 4 grs. of uric acid must have come from some other source than the formation of this day, i.e., must have been formed on some previous day, when, however, they were not excreted, but were held back and retained in the body — in the liver, spleen, joints, or fibrous tissues elsewhere. And the curves which I have shown to illustrate various papers exactly bear this out. In my paper on " Headache " in the Trans- actions of the Royal Medical and Ghirurgical Society, I mentioned that the excess of uric acid on the day of headache was almost exactly made up and accounted for by the amount retained, as shown by the curve on the four or five preceding days (see fig. 45). So that in so far as the headache was due to uric acid it was due to a fluctuation in its excretion, no alteration in formation having necessarily taken place, and we shall see presently that the action of various drugs exactly bears out this supposition. When 16 grs. of uric acid were excreted with 528 grs. of urea {i.e., in the nearly natural relation of formation 1 — 33) there was no great excess of uric acid in the blood, the whole 16 grs. of uric acid were formed that day in the kidney, and there was no headache because there was no great excess of uric acid in the blood. When, however, 16 grs. of uric acid were excreted with only 396- grs. of urea, a relation of 1—24-7, the whole of the uric acid was not formed in the kidney on this day, and some 4 grs. of it must have come from other parts of the body, as the liver, spleen, joints, in which we. are supposing it to have been previously retained. FORMATION AND EXCRETION OP URIC ACID 21 This uric acid, however, would pass through the blood in addition to that usually overflowing from the kidney ; it would be for some hours in excess in the blood, and would give rise to headache and other signs of its presence, and this is, I think, a good and sufficient answer to our question. Similarly any uric acid' introduced into the body with the food will pass through the blood on its way to the kidneys, and one has to judge from other concomitant conditions which source (introduction or retention) the excessive excretion comes from. In accordance with this reasoning I have always insisted that the relation of uric acid to urea in excretion is of very great importance, as it shows on any given day whether there has or has not been an excess of uric acid in the blood, and the condition of the blood itself, its haemoglobin value or its circulation, either from hour to hour or day to day, can now be freely used as a further index of the same thing. I would here just remind my readers that if one grain of uric acid is held back in the body every day, nearly one ounce could be so pro- vided in a year, and though in nature such a thing would rarely happen, the balance of retention and excretion over a series of years may tend either to increase the stores or to gradually diminish them. Fig. 1 shows the natural plus excretion of uric acid which occurs in everyone every day during certain hours. The exact hours in which it will fall depends upon their habits as to food, exercise, sleep, &o., because these control the daily fluctua- tions in acidity, and the acidity controls the excretion of uric acid. By altering completely the acidity of the whole day we can alter com- pletely the excretion of uric acid also throughout the whole day. In this figure we see that the curve of acidity is low at 8.45 a.m., and rises from this gradually up to 2.45 p.m. ; after this it falls again, more or less decidedly, producing what I have called the second or afternoon alkaline tide. As a result of this low acidity in the a.m. and early p.m. hours, uric acid is above urea, and comes below it for the first time at 3.45 p.m. We must bear in mind, however, that this high uric acid is dependent upon two factors — (1) the low acidity of the urine corresponding to high alkalinity of the blood and rendering that fluid a good solvent of uric acid, and (2) the presence somewhere in the body of a quantity of uric acid available for solution when the condition of the blood becomes favourable to this solution. If we have cleared out all the available uric acid by means of sol- vents, the acidity may fall much lower than it does in this figure without there being any plus excretion of uric acid (see fig. 73). 22 UEIC ACID — CHAPTEK II We shall see presently how there comes to be a store of uric acid in the body in the ordinary daily excretion ; but it is of the first im- portance to bear the above-mentioned factors in mind, if we are to avoid misunderstanding and error in watching the daily and hourly excretion of uric acid. We see also in this figure that the urinary water is low all through the morning hours and rises for the first time at 3.45 p.m., when also for the first tioie uric acid is below urea. So that this figure, like many others in this volume, serves to illustrate that relation between uric acid and water in excretion which ^-Houf. ending. ■70 23 « 120 55 16 3 SO URIC AC ■40 13 2 60 URINARY WATIR - •25 B I 30 ^ ACIOI, Fia. 1. — Natural Plus Exceetion oe Ubic Acid in the Alkaluu! Tide. Breakfast ended 9.50 A.M. Lunch ended 2.10 p.m. Two and a half miles sharp walking 3.0 to 3.45 p.m. ; perspiration, and low tension pulse after walk. Total urinary water 527 cubic centimetres. Total urea 118 grains. Total uric acid 5'0 grains. Relation of uric acid to urea 1 to 23-6. I have ventured to formulate as a law — that the urinary water varies from hour to hour and day to day, inversely with the excretion of uric acid or inversely with the height of the uric acid above the urea. We shall see later that other secretions and excretions bear an exactly similar relation to the amount of uric acid in the urine and blood, and that this law is of the utmost importance in enabling us to prove the power of uric acid over the circulation of the whole body and that the capillary circulation and blood pressure bear a similar relation to uric acid excretion. So that a touch with the point of the finger wiH show in the slow or quick capillary reflux whether we have FOEMATION AND EXCRETION OF UEIC AOID 23 to deal with scanty urine or diuresis, with free excretion of watec or dropsical retention; for dropsy, as we shall appreciate later on, is nothing but a result of retention of water in the body due to coUsemia, generally acting in association with more or less heart failure, and cutting off all excretions. Figure 2 shows the daily excretion of uric acid, urea, water and acidity in epitome. The total excretions of the hours placed at the top of each column are divided by the number of hours, so that the curves represent the average hourly excretion in each period. ; \ 7^i \e/0 TY ^ t Fig. 2.— Daily Excbbtion of Ueic Acid in Epitome. We see, then, that in the hours 7 a.m. to 11 p.m. (i.e., the usual woridng day hours) uric acid is above urea, and water is low. Acidity is also low, and this is the cause of the high uric acid. In the hours 11 p.m. to 4 a.m. acidity and urea have risen con- siderably, as a result of the high acidity uric acid has fallen considerably below urea, and as a result of this low uric acid, which means absence or relative absence of uric acid from the blood, the capillaries through- out the body have been freed, and as a result of these freed vessels in the kidneys there has been a free elimination of water from the blood and a diuresis, hence the urinary water is, as we see, very high. The free capillaries all over the body produced everywhere quite 24 DEIC ACID — CHAFTEE II definite and distinct efEects, with some of which we shall have to deal at length in other chapters, and it will then appear that part of the rise of urea is due to the fall of uric acid, and to the free capillaries and increased metabolism throughout the body which are the results of this fall. In the hours 4 a.m. to 7 a.m. we see that acidity falls to its lowest point, that urea falls very greatly, that water comes down, also to its lowest point, and that uric acid rises. The rise of uric acid is due to the fall of acidity, but it is also due to the retention of uric acid in the previous night hours. When uric acid was low in the night there was no alteration in its formation relative to urea, it was being formed then as always in the relation to urea of about 1 to 35 ; but the condition of the blood was unfavourable to its solubility, and a certain quantity of it was being held back and retained in some of the organs and tissues instead of being excreted in the urine, and the consequence of this was that the moment the acidity fell in the early morning hours there was some uric acid available for solution in the blood, and this passing into the blood and urine raised the excretion of uric acid above urea, there being again no alteration in formation (relative to urea) whatever. And this fact is susceptible of most simple demonstration, for if you administer sufficient alkali to prevent the rise of acidity in the night hours, you will find that there is then no excess of uric acid passed in the urine of the early morning hours. But if the large excretion in the morning hours was due to new formation of uric acid, it is difiicult to see how the previous administra- tion of an alkali could possibly prevent this formation. Further, if you gave an alkali so that there was no rise of acidity and fall of uric acid in the night hours, you would have also no diuresis in those hours ; but the water would remain in the blood and body and pass out the next day whenever the uric acid was exhausted and fell below urea from this cause. I would ask my readers to give this matter their careful attention and to bear this small figure constantly in mind, as it is the key to nearly everything that follows. They will find also as a matter of experiment, that by controlhng the acidity or the uric acid and pro- ducing changes in these such as are shown in the figure, they are able to control to a large extent the urea and to a still greater extent the urinary water, and that these are the signs and results of similar but more important control over the capillaries, the blood pressure, the action of the heart, and the physiology of the whole body. Now the acidity can be controlled by the administration of acids FOKMATION AND BXCBBTION OF URIC ACIB 2-5 and alkalies, by increase or diminution of activity and perspiration, (as in fig. 1), or by altered formation of urea (as in fig. 2), and by many things which indirectly affect these factors. Uric acid can be controlled by the administration of many sub- stances which increase or diminish its solubility in the blood ; it can ■8.0 90 /o.o //.o 120 to 20 3.0 o-.o su> S.0 7.0 eo S.0 100 110 /.« 7.0 24- ZIO 200 \ 1 ISO .1 % . * 170 leo i! 5 * ■ 1 ■ i ^? lid 130 120 110 100 so ■8 ■7 ■e 227 ZIO I9Z .A \ p. ^t mic ACID y / \ i I I 4 \ \ N (\ ¥, \ 1 t 1 \ / \ /' \ ^ ■^ j « *«0 1 \ / A \ \ \ .^ / \ i 5 6 1 \ ! ^ \ r/^ i \/ / ! ■s V ' ■^ \ 1 i r. \ V / '\ 1 ■ \' y,' 1 \ \ \ i i. 70 4- IS7 \ t / \ '^ 1 i }j L \ % ■■« y ft \ J /»- X- '^S '^ ^ >»- ^ "*' V \ 1 1 SO to 3d tj 1 ? 5* 1 ■3 ft u 1 12 2 lO-S B8 i V -^ ^ IS' s( ^ \ vP/ *• Jfct^ f alls at the end of it, just as the uric acid retained in the evening and night when the acidity is high passes out next morning when the acidity is low. And the diurnal variations in blood pressure, as also those which FOEMATION AND EXCEBTION OF URIC ACID 29 correspond to fever and convalescence, are as we shall see absolutely dependent on the uric acid. Chronic Bright's disease gives us another illustration of the same thing. Here during the day hours there is excess of uric acid in the blood as shown by numerous, granules (see chapter iii.) with obstructed capillaries and high blood pressure, and in spite of the ingestion of, it may be, large quantities of water, the urine is scanty but the blood is dilute. Such urine may have quite a good sp. gr., and the fact that it is the product of chronic Bright's disease may thus be overlooked. In the night, however, this is reversed, there is a rise of acidity with lessened quantity of uric acid in the blood and comparatively free capil- laries, and with this goes so great a diuresis that the urine of the whole twenty-four hours is rendered profuse and of low specific gravity, and under these conditions the hourly excretion of water at night is often twice as large, or more than twice as large, as that in the day. Before leaving fig. 3 I will just point out one of the ways in which it may be misread and give rise to misunderstanding. Taking the law that urinary water is inversely as the height of the uric acid above urea. Suppose we take three hours, such as 7, 8, and 9 p.m., and mix the urines together, and suppose that the uric acid as at 8 and 9 was not only above urea but was rather higher above urea than in this figure, the mixing of these urines together might give a result showing a considerable excretion of water more than in several of the morning hours, and yet uric acid might come out above urea. Now anyone coming upon such a result would at once say " here is an exception to your law," but when you separate the hours carefully you see that the diuresis really occurred when uric acid was below urea, and in the following hours when it was above it the water was scanty, but the diuresis of the first hour was so great that it made the urine of the whole three hours seem profuse. There is no exception to my law, on the contrary, the more carefully it is investigated the more clearly does its truth stand out. Conversely when there is -no water there can be no diuresis however much the uric acid is brought down, and the capillaries freed ; if the water has been run ofi by perspiration, vomiting, or diarrhoea there will be no diuresis till fresh supplies hav-e been introduced. I do not claim that fig. 3 represents an absolutely typical day, it is one of many days taken more or less at random out of my researches, and many details do vary greatly from day to day with diet, clothing, temperature, exercise, and other things ; but the main points, that uric acid is above urea in certain hours and below it in certain others, that acidity is high in certain hours and low in others, and that the 30 DEIC ACID — CHAPTEB II water varies inversely as the height of uric acid above urea, are practi- cally constant both for my excretions and those of everyone living under similar conditions ; and they are constant not only in physiology but for the most part also in pathology, and dominate, as we shall see, the circulation, and consequently the nutrition and function of the whole body, and govern these probably from development and intra-uterine life up to the hour of death. There is one further point of interest I will just mention in connec- tion with fig. 3, and that is that when, as here, the urinary water is scanty in the morning hours from obstructed capillaries and not from want of water in the blood, there is an absolute distaste for fluids of all kinds, so that it is quite difficult to get them down ; on the other hand, after a diuresis when the blood is poor in water there is thirst and a strong desire for fluids, so that by careful observation it is possible to tell whether in any given case the scanty urine is due to coUsemia* and obstructed capillaries, or to want of water in the blood. In the morning hours the drinking of a very considerable amount of water will not produce a diuresis, it is kept in the blood by the obstructed capillaries ; in the evening and night it tends to pass very soon after it is swallowed, and .precisely the same will occur in the morn- ing hours if you bring down the uric acid and free the capillaries. No doubt water is required for digestion, and while it is active a certain amount of water will be retained for its purposes, but digestion takes place both in the morning and in the evening, and yet the water is profuse in the one and scanty in the other, and if you have removed the uric acid so that there is no plus excretion in the morning, the water will be passed freely then just as at other times, and under these cir- cumstances there will be no great diuresis the following evening or night, because water has not been retained during the day. It will have been noted that the afternoon alkaline tide is but poorly represented in fig. 3 by a small fall of acidity at 5 p.m., but this is one of the things that varies with exercise, food and other factors, and I believe that the fall is commonly due to the fall of urea as the albumens of lunch are coming to an end and to the alkaline bases intro- duced with lunch, aided by a certain amount of exercise commonly taken after lunch which tends to reduce the acidity by loss of acids in perspiration (see 3.45 and 4.45 in fig. 1) ; but in the day represented * CoUsemia means excess of -uric acid in the blood, the uric acid being in some colloid form which obstructs more or less the capillary circulation all over the body. High blood pressure is almost always due to coUsemia, and the slowness of the capillary reflux and the height of the blood pressure are, other things ec^ual, a measure of the extent of the coUsemia. (See chapters v. and xvii.) FORMATION AND EXCRETION OP URIC ACID 31 in fig. 3 there was no exercise after lunch, because it was a pouring wet day and I did not go out. The diurnal variations in the excretion of uric acid explain abso- lutely the times of incidence of the diseases which are due to it. Thus of the diseases which are due to excess of uric acid in the blood, headache, epilepsy, mental depression, or melancholia and suicide, vertigo, high blood pressure, angina, asthma, Raynaud's disease, all tend to come on or to be at their worst in the morning hours, though once there is any severe disturbance of digestion there may be collsemia right through the day. because the natural curve of acidity is upset. On the other hand those diseases which are due to the presence of uric acid outside the blood, as gout and rheumatism, and inflamma- tions of fibrous tissues, affect especially those hours in which the blood is generally cleared of uric acid, i.e., the evening and night, and illus- trations of all these points will be found in the chapters that treat of each disease. The common diurnal fluctuations in the blood decimal correspond very well with those of acidity and uric acid in fig. 3 ; thus it falls in the morning with low acidity and high uric acid and rises towards 1 or 2 p.m. as acidity rises and uric acid comes down ; then it falls more or less decidedly with the fall of acidity in the afternoon alkaUne tide, varying with the distribution of meals and other factors, and rises very decidedly in the evening and early night hours. It will be noted that the curves in fig. 52 only illustrate some of these points, but this is a somewhat exceptional curve both as to uric acid and the blood decimal, and it is given for reasons which appear in its description. Fig. 4 is an attempt to show the annual fluctuations in the excre- tion of uric acid. I have no curves which show them well, because in the course of each year over which my investigation has extended, I have taken so many drugs that the natural fluctuations have always been more or less clouded over by their effects, and I have selected the year shown in the figure simply because it seemed to be less obscured by drugs than the others. What we see I think in this figure is that, spealcing generally, the warm months of the year correspond to the morning hours of the day and show a relatively large excretion of uric acid, and it follows from our first principles that they should do this, for acidity is diminished in them all by an increased loss of acids from the skin in perspiration ; conversely the cold months of the year correspond to the evening and night hours, as in them the acidity is raised by a diminished loss of acids from the skin, and with this we see a diminished excretion of uric acid. 32 UEIC ACID — CHAPTEE II Now in the cold months, October, November, December, January, and February, uric acid is nearer urea than any other time, with the exception of June, of which I shall speak again. With the fall of acidity in March uric acid rises. The high acidity in April, May, June, July and August is due to /8S3 JAN. FEB MAR APR. MAY. JUHS JULY AUG SEPT OCT HOV. D^C \ I s 1: imo 14:000 13,000 I2.00G 11.000 10.001 iooo $.000 7000 efioD y i «; 39S 370 34-2 313 2SS zse 228 5 t ism 1700 1600 ISOO 1 — 9 Sup si i sis h J Si . s 51; ^?: Il; A i?3 ^1 J5 J«5 «5v ? S ;" SSS fi^ /\ l? = 'S §■ .. . §■? §-s §■% 1 + + + ■\- Aom ITY \ \ Ij A \ / \ . ^ S \ A s \ % \u. \ / \ \ ■? V \ 1 1 1300 IIOO 1100 1 ^'u ?/C> CIO \ f\ r ^ \ \ 1 \ 1 \ 4 tEA \ \ R \ \\ \ \ /^ \ a ©^ / .A fe V / '\ \ / \ \ \ \ Fig. 4. — Yearly Excebtion of Uric Acid from Month to Month. the drugs taken, and the numbers opposite these indicate the number of days on which they were taken. May, June, July and August marked + were not estimated through- out, but the excretion for the month was estimated from the days that were worked out. In many months a considerable quantity of phosphate of soda was FORMATION AND EXCEBTION OF UEIC ACID 33 taken, and sometimes salicylate of soda also, and these would both tend to raise the acidity and also the excretion of uric acid, because they are solvents of uric acid. In fact this year is selected not because few drugs are used but rather because they are used so constantly throughout the year that their effects may to some extent be neglected. But whether we pay much attention to this figure or not, the fact, I think, remains, that the acidity tends to be high in the cold months and low in the warm, and the uric acid in its inverse relation to this tends to be low in the cold months and high in the warm. It follows also from our diurnal experiences that uric acid will tend to be highest in the early warm months, March, April and May (and this may account for jfart of its fall in June, unless, indeed, June was a very cold month in 1888, which my notes do not enable me to say), and lowest at the first onset of cold as in October. The fall of urea from March to May was due to my leaving off meat, of which I had previously taken a small quantity, and the further fall May to August was due to my making milk my only animal food without taking care to take sufficient milk and bread stuffs to replace the nitrogen left out, and this is an experiment which I do not advise any one to repeat, and if I had known then what I know now about the direct introduction of uric acid, it would never have been necessary for me to do it ; but I then believed that my only way of reducing uric acid was to reduce the total nitrogen. Taking it that these are the natural annual variations in the excre- tion of uric acid, and the whole of my researches and observations are in favour of this, as I found out long ago that I got a relatively increased excretion of uric acid 1 to 29, or 1 to 30 in the spring and summer months, as compared with 1 to 33 in the winter, it follows that the greatness of the uric acid excretion in the warm months will, just as in the corresponding diurnal variations, depend partly on the greatness of the fall in acidity and partly on the quantity of uric acid which has been stored in the body in the previous cold months ; and it is obvious that a man who has been introducing all through the winter some 6 grs. of uric acid per day, ought to suffer much more severely from such spring and summer diseases as are due to excess of uric acid in the blood than the man who only introduces from 1 to 2 grs. per day, and evidence will, I think, not be wanting that this is the case ; for the man who introduces 6 grs. a day not only intro- duces it, but the uric acid so taken interferes with its own excretion by tending to keep up the acidity of the urine and diminish the alka- linity of the blood, though it is true that if he goes on introducing it 3 34 UEIC ACID — CHAPTEE II in summer it will tend to keep up the acidity then also ; this, however, will have little effect compared to the external temperature, and when- ever the acidity is reduced he will have a correspondingly great rush oi urates into his blood. We shall see also that all the diseases which in the diurnal varia- tion of excretion tend to have their greatest incidence and severity in the morning hours, tend also to have their greatest annual incidence in the spring and summer months, while those which are most promi- nent in the evening and night will also be seen to be most prominent in autumn and winter, and I must add on to the diseases which are worse in the morning hours, some others, such as phthisis, some skin diseases, and pneumonia, because they are not of such a nature as to show well their relation to the diurnal fluctuations of uric acid, but yet as we shall see, some of them do show very well a distinct relation to its annual fluctuations. For the same reasons the blood decimal of the flesh and tea taker is higher in the winter months, as • 5 to ' 55, and lower in the summer months, as " 45 to • 5 : but under no circumstances and at no time of the year are the blood decimal or the capillary reflux of the flesh eater equal to those of the abstainer, and consequently at no season of the year is the flesh eater equal in endurance and athletic power to the abstainer. It will no doubt be a surprise to some to see such diseases as phthisis and pneumonia included in the list ; but we shall see in chapter iv. and elsewhere, that uric acid, by controlling the metabolism and com- bustion of the body, does in very many instances absolutely determine whether microbes should be burnt up and destroyed, or obtain a footing and live within it, and in this way does practically determine both the incidence and course of microbic diseases. Moreover, we shall also see (chapters ix. and xvii.) that uric acid by affecting the fibrous tissues of the trachea and bronchi not only produces acute inflammation of these structures, but also brings about pneumonia of neighbouring portions of the lungs, and that in any of the lesions so produced^ bacilli and other microbes may find a nidus. In these cases the uric acid is the important factor, the removal of which prevents or cures the disease ; the microbe merely fiourishes in the conditions which uric acid produces, and is in itself quite unimportant (see cases under Catarrh, Pneumonia, Malaria, &c.). Fig. 5 shows, I think, that the diurnal variations in the excretion of uric acid have a not unimportant effect on the temperature of the body. This figure is one of a large number which I have, and which all FOEMATION AND EXCRETION OF UEIC ACID 35 show much the same thing, and I give it here while the diurnal varia- tions in the excietion of uric acid are fresh in our minds, though I shall have to return to its points in connection with other subjects later on. The upper curve gives the temperature in the rectum, the lower curve that in the mouth. And what we cannot help noticing at first sight, is that between the h^urs of 7 a.m. and 6 p.m. these tempesatures are further apart than at other times of the day. 100 33 S6 a? A-rf. fl« KM HH ^ ■» -rtf, 7.0 IZJS /^ e.O 8.0 10. 2Q if i !a 1 1 S ■A 5 *0 1 § e .i ^' & % tj ■^ / "^=H- -■^ ,> A \ -^ _y \ Pig. 5.^C0BVes op Tempbraiurb vs Mquth: and Ebcium to show their Rblation to the Excretion op Uric Acid. I was led to investigate this mattei- by some statements I found in Marey's work on the circulation of the blood (" Circulation du Sang," pp. 588 to 596). As he points out that by observing the temperature simultaneously in the rectum and mouth we can tell whether a low temperature in the mouth is due (1) to contraction of surface vessels, or (2) to dimin- ished production of temperature. If it is due to contraction of surface vessels, the rectal temperature rises as the mouth temperature falls, and the temperatures of the two places are far apart ; on the other hand, if it is due to diminished production of heat, the temperatures in the two places will be close together. 36 DEIC ACID — CHAPTEE II Again, suppose we find a raised temperature in tlie rectum, if the temperature in the mouth is nearly the same there is an increased formation of heat, but if they are far apart, the mouth being lower, there is contraction (obstruction) of skin vessels. Marey also points out that in cholera algide the rectal temperature is high in proportion as the surface temperature is low, and in the re- action the rectal temperature falls as the surface temperature rises. In cholera algide the surface vessels are contracted (? obstructed), and tartarate of antimony and emetine both produce similar results. Alcohol, on the other hand, dilates the surface vessels and reduces the temperature in the rectum. Inanition lowers the temperature both of surface and rectum, hence the diagnosis between this and contracted arterioles, or rather obstructed capillaries (see chapter v.). In ursemia he points out that you may get a fall of the central temperature as well as that of the surface, i.e., I suppose that the obstruction of vessels is so great and general that the production of heat is affected as well as its distribution. During fever the two curves come together as the vessels are free, and the temperature equalised everywhere. In oases of intermittent fever the curves are close together at the times of high fever, but the surface temperature is considerably the lower in the intervals, and this corresponds, as I know, pretty abso- lutely with the amount of uric acid in the blood, as it is absent during the fever, being stored up in the enlarging spleen, in the Uver and else- where, and present in more or less considerable quantity during the intervals. These observations couJd not but suggest to my mind that if the difference between the temperature of the mouth and rectum is a measure of the obstruction of the skin vessels, it might also be a measure of the amount of uric acid in the blood, for uric acid in the blood obstructs the skin- vessels ; and on carefully investigating the point I found, as fig. 5 shows, that this is the case ; and that the greatest divergence of these temperatures corresponds exactly with those hours of the day in which there is naturally the largest amount of uric acid passing through the blood. In this figure we see that at 7 a.m. the two curves are pretty close together, and this temperature was taken in bed, so that any effect that uric acid might have on the skin vessels was counteracted by the equable temperature of the bed clothes, and this is practically a con- stant feature day alter day. The next observation is at 12.]. 5 p.m., and here we see that the FOKMATION AND EXCEETION OF UEIO ACID 37 mouth temperature has fallen, while the rectal temperature has risen, so that they are considerably further apart than at 7 a.m., and the skin vessels are therefore obstructed. At 1.30 p.m. the mouth temperature has risen very slightly, but the rectal temperature has risen considerably, and they are now 2J degrees apart. An hour and a quarter of walking exercise has been taken, and has, as is usually the case, raised the temperature, but it has afEeoted the rectal temperature much more than that in the mouth, as the surface vessels are still obstructed. At 6 p.m. the mouth temperature has risen very decidedly and reached its highest point, the rectal temperature has fallen and come to meet it, and they are now only separated by about ^^ of a degree, the surface vessels are therefore but little obstructed, and the alkaline tide, with the colleemia that accompanied it, has come to an end. At 8 p.m the rectal temperature remains he same as at 6, while the mouth temperature has fallen. They are about IJ degrees apart, and the surface vessels are again a httle obstructed ; possibly there was again a slight excess of uric acid passing through the blood, as there was at 8 and 9 p.m. in fig. 3, but at 10.30 p.m. this has come to an end, the mouth temperature has fallen to its lowest point, but the rectal temperature has fallen still more and is now again pretty close to it ; the skin vessels are but little obstructed, and the blood, as we know, is probably pretty clear of uric acid, and this fall of tempera- ture is therefore due to diminished formation of heat. I have many curves showing almost exactly the same thing, and when there is no exercise to cause fluctuations the greatest divergence of temperature always occurs about 1 p.m., and they come together again early in the afternoon, and remain more or less close together in the evening and night. The efEect of exercise is very interesting, for it causes divergence of the two curves most in the morning, but to a considerable extent also in the afternoon, and as we shall see further on, exercise increases the excretion of uric acid and causes an increased quantity of it to pass through the blood ; we shall also see that in accordance with its effects on uric acid, exercise controls the formation and excretion of urea ; these temperature curves show that uric acid controls the distribution of heat, and we shall see reason to beUeve later on that it also controls the formation of heat. In the same way coUsemia will account for the algide stage of cholera, as collsemia is the natural and constant result of every severe gastro- 38 URIC ACID — CHAPTER II intestinal disturbance. Tartarate of antimony or emetine act in the same way and produce the same result, and sea-sickness as I know, also does the same. Alcohol, on the other hand, or the acids so often mixed with it, cures or prevents collaemia, and consequently frees the skin vessels and the temperature curves come together, and I believe that every drug which has the same effect on uric acid has also the same effect on the curves. In urfiemia, which I have long been pointing out is merely severe coUsemia, the obstruction of vessels may be so great that there is dimin- ished production of heat, just as we shall see that in severe fatigue there is diminished production of urea. If the effect of uric acid is so great in the physiological conditions which obtain in fig. 5, its effects in pathological conditions must often be much greater, and so far as my observations go this is certainly the case. It is obvious also, that in observing in this way the superficial and deep temperatures and their relations to each other, we have at hand a ready means of estimating the amount of uric acid that is passing through the blood, at a time when it might be quite impossible to esti- mate directly the quantity either in the blood or the urine, and we can control our results by the use of drugs which are known to influence the solubiUty of uric acid, and which will therefore affect the tempera- tures ; and the capillary reflux or the blood pressure will tell us the same thing more quickly. I may mention also that a uric acid headache always affects the relations of these temperatures : thus in fig. 5 at 10.30 p.m. they are less than a degree apart, but if there is a headache, even a slight head- ache at this hour, they will be a full degree apart or more, and at the corresponding hour next night perhaps only • 4 of a degree apart. Similarly in the low excretion of uric acid which follows for a day or two after a course of salicylates they wiU be nearer together in the a.m. hours and at 1.30, and I have records of only '2 to "d of a degree of difference at 12.30 or 1.0 p.m. under these circumstances. We are now in a position to consider the action of drugs. So far as we have gone, we see that the hourly, daily, monthly, and yearly excretion of uric acid has to do with the variations produced by intro- duction, on the one hand, and the effects of various factors on solubilitv on the other, while there is no proof whatever that the formation of uric acid relatively to urea ever alters at all. In the same way with drugs we shall see that they act merely by increasing or diminishing solubility, and influence excretion accord- FORMATION AND EXCRETION OP URIC AOID 39 ingly, but there is ao evidence that any of them can' produce an in- creased formation of uric acid ; and what has been said by others to be due to increased formation of uric acid has, I believe, always been due, either to increased introduction in food substances, or to increased elimination by the action of solvents. I myself found out very early in my investigations that by influenc- ing the solubility of uric acid I could do almost anything I Uked with its excretion ; and more recently, that by controlling the amount intro- duced into the body, I could exercise still further and more decided control over the amount that could pass into and through the blood (see fig. 73). And when we once fully recognise the enormous power which uric acid has in controlling the circulation, we shall see that this knowledge gives us a lever of the utmost importance in guiding both the physiology and pathology of the human body, and a power of explaining almost numberless facts and sequences in both regions which are otherwise inexplicable. And now in speaking of the action of drugs I shall divide them into (1) those that increase, and (2) those that decrease excretion, and having first enumerated those in each class, shall say a few words as to the action of the individual drugs in turn. The chief substances which increase the excretion of uric acid are alkalies, salicyhc acid and its compounds, salicin, salol, &c., phosphate of soda, piperazidin, quinine and belladonna. I place alkalies first because they are found in action every day in nature, and hence have far greater importance than any substances which are not in every-day action. The curves in fig. 6 show the effects of giving the alkaline salts of potash and soda. We see that they produce a decided fall in the acidity curve in day 2, and keep it more or less low on days 3 and 4. The result of this is that uric acid which is close to urea on day 1, rises considerably above it op. day 2, remains high on day 3, and is still fully half a grain above it on day 4. The rise of urea on day 2 is not the result of taking potash, but of some alteration in diet or exercise ; other things equal, a fall of apidity and a rise of uric acid tend to depress urea. Speaking generally, and apart from the action of other solvents, it seems, as I have said, that the excretion of uric acid from day to day and hour to hour is inversely as the acidity of the urine. And I think there is evidence to show that speaking generally, the fluctuations in the acidity of the urine correspond both in directioji and extent with fluctuations in the alkalinity of the blood ; thus it has been shown by Peiper {Virchow's Archives, June, 1889, p. 337) 40 UEIC ACID — CHAPTER I[ and others, that the alkalinity of the blood is diminished in all fevers except such as are complicated by dyspnoea and cyanosis, and the acidity of the urine is increased in all fevers ; a good instance of this fact being recorded in Sir W. Roberts' work " On Urinary and Renal Diseases," fourth edition (p. 59), where a patient with alkaline urine got erysipelas, and the urine became acid and remained so during the fever, becoming alkaline again at the end of it (see previous remarks on fig. 5). uci re IS Il- to g s 3 1 4 3 4 i 5 1 \ i \ \ ia *23 Acn 10 nr\ j \ I A \ 12 396 30 1 1 >\\ T 1 V ^ \ v^ \ » II 10 363 330 ;i37 URIC A 20 u 10 cioU sa v_ REA. i Si "1 ^ i4 5 1 ? g5 1^1 Fig. 6. — Plus Excretion of Ukic Acid peoduced by Alkalies. Conversely a vegetarian diet is known to diminish the acidity of the urine, and I believe that it also increases the alkalinity of the blood. There is, however, one exception to the above statement about the rela- tion of the excretion of uric acid to the acidity of the urine looked upon as an index of the alkalinity of the blood ; and that is where, as in the fits of epilepsy (see cases in chapter vii.), there is a huge excretion of uric acid relatively to urea ; for here the acidity of the urine is ex- tremely high, and the greater the amount of uric acid present the higher the acidity. It thus appears that when a very large amount of uric acid is being excreted the acidity of the urine may be no safe index of FOKMATION AND EXCRETION OF UEIC ACID 41 the alkalinity of the blood, because the acidity of the excretion is to some extent afiected by the amount of uric acid it contains. But it is usually easy to distinguish this pathological exception to the rule, for the usual relation between acidity and urea no longer holds good. In the urine excreted after a fit acidity rises, but urea is steady or even falls a little (see chapter vii.) ; the rise of acidity is therefore not due to the ordinary urea metabolism, but it corre- sponds with a very marked rise in uric acid, and may, I think, be due to this ; the alkalinity of the blood on the other hand varies inversely with the metabolism of urea, and is therefore high and rising. A similar rise of acidity, not accompanied by any rise of urea, is seen in several of the figures, showing the efiects of taking uric acid or xanthin compounds (figs. 25 and 26). I am indebted to Dr. G. C. Garratt for pointing out to me that a rise of acidity such as that we are speaking of after a fit of epilepsy is in part due to a rise of the phosphates excreted in the urine (see also his paper in the Journal of Physiology, vol xxiii.. No. 3). But he also shows in his paper that phosphates always follow very closely the acidity curve of the urine, and this is just what we should expect from the observed relation between the curves of urea and acidity ; for the phosphates probably represent the final metabolism of the phosphorus in the albumen molecule, just as urea represents the final metabolism of its nitrogen. No doubt there may be some increased excretion of phosphates after an epileptic fit as the result of increased metabolism in the tissues of the nerve centres rich in phosphorus,* and this may account for part of the observed rise of acidity. In this case part of the increased excretion of uric acid after an epileptic fit is a result, not a cause, and there is no exception to my law of solubilities, as phosphates in the blood are solvents of uric acid ; but uric acid in combining with phosphates diminishes their alkalinity and must thus raise the acidity of the urine. Sir A. Garrod has shown that the alkahes soda and potash form extremely soluble compounds with uric acid, and phosphate of soda is also well known as a solvent of uric acid. Fig. 7 shows its effects ; here in day 1 uric acid was far below urea owing to the high acidity, which again was due to the taking of acids and antipyrin. A drachm of phosphate of soda is taken three times on day 2, and uric acid rises and gets just above urea, which has fallen. Now this high urea on day 1 was probably partly due to the low uric * Zuelzer, " Semiologie des Hams," p. 89 (see also chapter lii.). 42 URIC ACID — CHAPTER II acid, because, as we shall see in chapter viii. and elsewhere, everything that brings down uric acid tends to raise urea, or in other words, everjrthing'fthat "clears the blood of uric acid quickens the metabolism throughout the body, and stimulates the formation a;nd excretion of urea ; but this only lasts for a short time, therefore urea does not remain up on day 2. On day 3 a'similar dose of phosphate is taken, and uric acid rises more decidedly above urea, and on day 4, when the drug is left off, but no other change is made, it falls a long way below it. . URIC ACID. UREA. 1 2 3 * II aoo 10 330 SO % ^ 1 \ 9 297 10 7""^ V a 26* 7 23/ 6 /sa 5 I6S u 30 20 10 '"\ / /{ / \ i ^ ? I «0 t o 1 1 to 1 to 1 Pig. 7. — Plus Excretion of Ubic Acid PRODncED by Phosphate op Sodium. We see then, that phosphate of soda causes a distinctly increased excretion of uric acid, which, just as in the case of some other solvents, is followed by a fall when the drug is left off ; proving, I think, that we are dealing with excretion merely, and not with any new formation of uric acid. As to salicylic acid and its compounds, I have shown that they increase the excretion of uric acid, and I have pointed out that what is known about the compound (salicyluric acid) which they form, seems to show that it is not only more soluble in water than the salts of uric FOEMATION AND EXOEETION OF UEIC ACID 43 acid, but also much more soluble in sligbtly acid fluids— a very im- portant point to which I shall often have to refer again. I should perhaps explain with regard to salicyluric acid that, it is not a com- pound of uric acid and salicylic acid, but of glycoeoU, one of the ■ constituents of uric acid, and salicylic acid ; just as hippuric acid is a compound of glycocoU and benzoic acid. And what I say with regard to the solubility of salicyluric acid applies to its presence in the blood only, for where it is present in the urine it does not give any reaction with Haycraft's process, and is therefore, so far as my results are concerned, not estimated as uiic acid. So that in so far as a salicylate increases the excretion of uric acid, the compound salicyluric acid, which it may form with it in the blood, is probably largely reconverted into uric acid and salicylic acid as it passes the kidney (see my experiments with regard to these points in the Transactions of the Royal Medical and Ghirurgical Society, vol. Ixxi., p. 137). I regret also that the statements regarding the solubility of sali- cyluric acid to be found in standard works of reference on chemistry are not sufficiently definite for our purpose, so that we have to be satis- fied with probability rather than with certainty. But if this somewhat hypothetical chemistry serves in the meanwhile to remind us of the clinical fact, that salicylates are not good solvents of uric acid when the alkalinity of the blood is high and the acidity of the urine low, and that for the same reason it is a mistake to give alka- line salts of sodium or potassium along with them (see fig. 71 and cases narrated in chapters ix. and xvi.), it will not be entirely useless (see also uric acid filter experimeats further on). Fig. 8 shows the efiect of a salicylate on excretion, and I need hardly describe it at great length. It shows a great plus excretion on day 2, the first under the salicylate salt, followed by a fall next day, the same dose being continued ; and a second rise on days 4 and 5, a fall on day 6, and a great fall on day 7, when the drug had been left ofi. The last is a constant feature of the exhibition of a salicylate, and as will be seen further on, I have made use of it for studying the effects of absence of uric acid from the blood, both in physiology and pathology (chapters viii. and xii.). I think that most of the avail- able uric acid was cleared out by the solvent on day 2, hence the fall on day 3, and that the rise on days 4 and 5 was due to some fresh introduction of uric acid with the food. This figuje unfortunately does not give the water, which would have been low on day -2, followed by more or less diuresis on day 3, for here as elsewhere the water is inversely as the uric acid, and this explains the observation made by 44 UEIO ACID — CHAPTBK II Others that the diuresis produced by salicylates does not come till the second or third day of their action, and this depends on the amount of available uric acid, when this is large uric acid will remain high for several days and the diuresis will not come till it falls. This figure, and all the curves of excretion under salicylates show, I think, that we have to do with excretion and not with formation of uric acid ; if salicylates cause new formation of uric acid, why does the curve Ofi Y / 2 3 « 5 6 7 §^ § S IS <^9S 60 /* 462 SO ACID 13 429 W 12 396 30 II 363 20 URIC Ai 10 330 10 URi a 297 / 1 ,■? / i _, ^ 2 s C3 Si. to to to 5 Or to u ? -..1 S 1 A / / 5: ID I 1 /\ \ \ 1 / r ^ '* 9 236 W If. 1300 VRIC f / ;/i)9 / \ \ I \ \ 3 264 30 1100 1 \\ j \ \i 7 23/ 20 WA. 900 £11 -k fe. \ -\« '■-^ 6 133 10 100 0; u Q « o s Fi0. 17. — Retention op Ubic Aoid produced by Mebcuby. ' Note that on day 2 uric acid falls in spite of a marked fall in acidity, which apart from the action of mercury, would have made it rise. From this we see that there is good reason to believe that the urates of mercury are insoluble in water, in neutral solutions, in alkalies, or in solution of borax, and as the blood may be practically re- garded as an alkaline solution, they are probably insoluble in the blood. Therefore, mercury diminshes the excretion of uric acid in the urine, clears it out of the blood, and retains it in the body, because it forms 68 UEIC ACID — CHAPTER III with it an insoluble compound, and it is therefore a single instance of my law of solubilities. And the well-known action of mercury on the pulse-rate and blood pressure, and the flow of urine, are also single instances of the laws I have formulated with regard to the re- lation of these to uric acid. Some have objected to this that the amount of uric acid held back by the mercury is much more than could possibly be combined with it as an urate ; but, as I shall have to point out in chapter iv., the mercury, if it clears the blood of uric acid for quite a short time, e.g., one or two hours, starts an upward metabolism Pig. 18. — Retention of Ubio Acid produced by Antipyein. with a rise of urea and urinary acidity and a fall in the alkalinity of the blood, and this latter causes a further retention of uric acid, which may continue for six or eight hours more. This effect of mer- cury is better seen in hour to hour curves rather than in day curves, as in fig. 17, but it is also seen to some extent in fig. 48. I think it is extremely probable that the urates of other metals, such as zinc and silver, are also insoluble, and indeed Haycraft's process for the estimation of uric acid depends upon the insolubility of the urate of silver ; and I believe that the so-called tonic action of these drugs, and of iron and manganese, and indeed of acids, is reallv FOEMATION AND EXCEBTION OP UEIC ACID 69 due to their clearing the blood of uric acid, and so improving the circulation in the brain and other portions of the nervous system. It is interesting to remember that zinc, hke mercury and lead, may produce colic (Ringer, " Handbook of Therapeutics," ed. xii., p. 254). I have suggested that antipyrin cures headache by acting as an acid, and its administration is always followed by a rise in the acidity of the urine. Fig. 18 shows the efiects of antipyrin on the acidity, which on days 1 and 2 rises and remains high, and with this on day 2 uric acid falls below urea (probably the antipyrin came too late to afiect the alkaline tide of day 1, so that the greater part of the urate excretion had already taken place). On day 3 no drug is taken, and acidity falls decidedly, in spite of the fact that urea has risen, and in normal con- ditions acidity would have risen also ; but the antipyrin had raised it so much on the previous days that the moment the drug was with- drawn down it fell. On day 4 antipyrin was again given, acidity rose in spite of falling urea, and uric acid was brought down much nearer urea. We can now see how antipyrin cures a uric acid headache by rais- ing acidity and clearing the blood of uric acid, all the signs of which, mental well-being, low tension, quick pulse (fig. 35), joint pains and diuresis, it also produces ; it therefore acts just as an acid, and I for one should prefer to give an acid in its place. Strychnine causes a marked rise in urinary acidity and cures headache. I have suggested that the rise of acidity is due to its improving the condition of the stomach and promoting digestion and absorption of food, which in headache with nausea is often at a standstill ; like other things that raise acidity, it often causes pricking and shooting pains in the joints. The administration of hyposulphite of soda produces a very marked rise in acidity of the urine, possibly by the formation of sulphurous acid or the further oxidation of sulphur, and it produces all the symptoms and effects of the administration of a strong dose of acid (see fig. 11). And it has appeared to me to be very probably that nitrites may act in much the same way, and by the formation of nitrous acid may diminish the alkalinity of the blood and raise the acidity of the urine, which it is easy to demonstrate that they do (see figs. 19 and 20). This being granted, it appears to me that the well-known efEects of nitrites on the pulse rate and tension may be explained by their acting as acids on the solubility of uric acid. And in favour of this supposition is the fact that an acid injected 70 UEIC ACID — CHAPTEE III into a. vein produces, I believe, much the same effect on the pulse as a nitrite does. So far as my observations go, nitro-glycerine taken by the mouth does not exert its maximum effect on blood pressure for some seven or eight minutes, and in the case of a volatile sub- stance rapidly difiused throughout the body this is a considerable time ; and as regards uric acid, I take it that the action of an acid or anything that interferes with its solubility in the blood is as rapid as that of precipitation in a test tube, and is practically instantaneous. I do not suppose that the uric acid is precipitated in crystals, but it MAr.2. SOpm. 60 70 60 9 10 110 Shr^. e 3 t 3 2 1 i > -•f* to to 5 Q —J a: Is A 5 Sou, to 1 'O 2 '\ / ^ \ / ^ \^ Be-2lS mi— 15 132—25 ^4-3 5 5/— 6 .5 55-5 SS-3Z5 ^ZO-^li Pig. 19. — Effects of Nitro-Glycebine on the Acidity of the Ubine. is rapidly rendered less soluble in the fluids, and is held back in certain organs and tissues in accordance with the theories of Sir A. Garrod ; I shall presently have to bring forward evidence that anything which clears the blood of uric acid frees the capillaries all over the body, and thus rapidly reduces blood-pressure, the rapidity of the fall of pressure depending on the rapidity and the completeness with which the uric acid is driven out. In the Lancet (vol. i., 1891, p. 1323), it is pointed out that the admin- istration of sulphurous acid, and even its inhalation, will reduce the FORMATION AND EXCRETION OF URIC ACID 71 alkalinity of the blood, whicli is greatly in favour of my argument as to the action of nitrites, and my results as regards the acidity of the urine when hyposulphites or sulphur in other forms are taken. The same article shows that sulphurous acid is largely used in the preserva- tion of wine and vegetables — a fact of considerable importance for gouty subjects. It is certainly remarkable what very small quantities of these acids APKIL 21. 1066 46-70 IOZIg.m. 4 3 2 / o Q ^ a:' li ~ 5 5S *■ 6- A *3 a: H'OAlBnm jimPAini / / ^ N ST Ht . BEFORC APACHE y 3 2lpw 73-1-25 4 2/pjTj. 6/ — 4^ 5 21 p m 31-2-5 isa-MS 721pm es-si B-ZI pf. SI-12S iO-M Fig. 20. — Effect of Niteitb of Amyl on the Acidity op the Ubinb. (nitrous, sulphurous, &c.) wUl produce marked effects on the excretion of uric acid, and in this they do not stand alone, for quite small quan- tities of salts of the mineral acids will produce similar effects, of which I have had experience in very numerous instances. And thinking over this matter, it has occurred to me that the solvent power of phosphate of soda for uric acid and urates may help us to explain this apparent difi&culty, just as they helped us to explain the difficulty in the case of lithia. If a little lithia produces marked retention of uric acid by throwing out of action a quantity of its natural solvent, phosphate 72 URIC ACID — CHAPTER III of soda, a minute quantity of acid may possibly have the same effect on the phosphate, and may change a large quantity of it from NajHPOj to NaHgPO^ ; then the efEect on the solubility of the urate will be proportional to the amount of phosphate which is thus thrown out of action, and not to the relatively minute amount of acid which caused the change. Hence the stimulant action of aU kinds of acids is dependent upon the conditions present in the blood and fluids of the body ; if these are favourable to diminished alkalinity they may produce a large efEect, if unfavourable, little or none ; and so the action of a given dose will vary considerably not only in difierent individuals, but in the same individual at different times. ' With regard to the action of the nitrites, the researches of the late Professor Leech (Croonian Lectures, 1893) seem to show that these substances undoubtedly exercise a direct depressant action on muscular tissue. They also show, however, that these compounds are decom- posed in the stomach, giving off nitrous acid, which is absorbed into the blood and importantly afiects its composition and reaction ; thus Professor Leech says (Lancet, vol. i., 1893, p. 1502), " When absorbed it (nitrous acid) is no doubt at once converted into an alkahne nitrite, for it can replace carbonic acid in its sodium compounds and convert normal sodium phosphate into acid phosphate, sodium nitrite being at the same time formed." Now, the result of this conversion of normal phosphates into acid phosphates, is a rise in the acidity of the urine, which I have just pointed out that the nitrites produce ; and as the normal phosphate of sodium is a good solvent of uric acid while the acid phosphate is not a solvent at all (see Medico-CMrurgical Transactions, vol. Ixxii., p. 399), the blood becomes, as a result of this action of the nitrites, a bad solvent of uric acid, and ceases to hold it in solution, and as a result of this the capUlaries wiU be freed and blood pressure reduced. It seems probable, then, that the action of nitrites on blood pressure is the resultant- of two forces ; first of all, of the muscular depressant action weakening the muscle fibre in the heart and the vessel walls generally, an action similar to that of tobacco, lobelia, and other depresso-motors (see Brain, Spring and Summer number, 1893, p. 245) ; and second, of the general freeing of capillaries which all substances produce which clear the blood of uric acid. In this connection I was much interested to hear from my friend Captain Newland, R.A.M.C., that a friend of his. Dr. Saunders had been using nitrites in ague to shorten the cold stage and bring on the sweating stage, apparently with good results. FOEMATION AND BXCEBTION OF UEIC ACID 73 Sir A. Garrod tells us* how lie found uric acid in normal blood, and an excess of it in that fluid, and in the serum of a blister in gout, and also in lead poisoning ;•[■ and he there shows that lead given medicinally diminishes the excretion of uric acid in the urine ; and he remarksj— " It would appear, therefore, that in individuals Im- pregnated with lead the blood becomes loaded with uric acid, not from its increased formation, but from its imperfect excretion." This is in absolute and complete accord with my results, § and T should apply the same reasoning not to lead only, but to all sub- stances that diminish the excretion of uric acid in the urine ; ,and for my part I have not met with any evidence that there is, or ever has been, an excess of uric acid in the blood due to increased formation, i.e., above the relation to urea of 1 to 35. I believe that for every 35 grs. of urea that are formed in the body, 1 gr. of uric acid is also regularly and punctually formed, but no more. The 35 grs. of soluble urea are excreted with practically absolute certainty ; but the insoluble uric acid, though in much smaller quantity, is very apt indeed, from " various causes, to lag behind and be retained in the body. We shall see also later on, with reference to the above quotation from Sir A. Garrod, that the uric acid is probably not in excess in the blood at the time when under the influence of lead it is diminished in the urine, but it subsequently appears in excess in the blood when that which has been held back by the lead is got into solution by alka- lies or other solvents in the blood, as soon, however, as it is in excess in the blood it begins also to pass in excess in the urine. My investigations, I beheve, prove absolutely that an excess of uric acid in the urine above the relation to urea of 1 to 35 comes from an excess in the blood, and that when the uric acid in the urine is diminished below that relation (say 1 to 45) there is little or none in the blood, because every particle that gets into it from the kidney by the renal vein is at once caught up, so to speak, and stored in the liver, spleen, and other tissues, j According to Sir A. Garrod's theory, the antecedent elements of uric acid come probably from the liver to the kidney, and are there formed into urate of ammonium. By far the largest part of the urate thus formed (say for the sake of a^definite quantity nine- tenths) passes at once down the ureter ^and leaves the body ; but the remaining one-tenth may, under certain * " Gout and Eheumatio Gout," 3rd edit., p. 84, et seq. t Ibid., p. 240. t Ibid., p. 243. § See Med. Chir. Trans. , vol. Ixxi. , p. 284 74 UBIC ACID CHAPTEB III conditions, pass, according to Sir' A. Garrod, into the general circula- tion through the renal vein ; and when there it is attracted differently by different organs, being liable to retention in certain organs which are less alkaUne than the blood, and therefore less able to hold it in soliition. It is this residue of uric acid, plus that which is directly introduced ready-formed in food which, according to my interpretation of my results by the light of Sir A. Garrod's hypothesis, furnishes all the uric acid of pathology. If the whole of the urate formed in the body had passed down the ureter as soon as formed, there would have been much less trouble, and to bring about the complete excretion of aU that is formed, as well as to keep down the quantity introduced, must be the aim of all treatment. It seems extremely probable that the alkalinity of the kidney struc- ture determines to some extent how much of the urate formed in it shall be at once excreted, and how much shall be temporarily kept back with a chance of eventual passage into the general circulation. Possibly the pathological urate deposits found in the kidney after death are mere exaggerations of the normal retention which constantly occurs to some extent during life. When urea is high and especially when it is above the physio- logical relation to body weight, 3 or 3 " 5 grs. per pound per day, it seems probable that the alkahnity of such organs as the Uver, spleen and kidneys wUl be diminished, just as the acidity of the urine is in- creased ; so that when urea is too high we shall get increased retention of uric acid in these organs (see fig. 74). To render my meaning clearer, I shall now speak of definite quan- tities. If a man forms, as my results render it probable that he does, 1 gr. of uric acid for 35 grs. of urea, let us suppose that he forms in twenty-four hours 12 grs. of uric acid and 420 grs. of urea. The whole of the urea and 10 grs. of uric acid are excreted, giving a relation in the urine of 1 of uric acid to 42 of urea ; and 2 ■ grs. of uric acid are held back in the kidney, passing gradually into the general circulation. Once in the general circulation the urate is rendered insoluble and kept back in certain tissues (according to Sir A. Garrod, the Uver, the spleen, the joints and the fibrous tissues), because of their rela- tively diminished alkalinity and consequent deficient power of holding urates in solution. Next day let us suppose that again 420 grs. of urea are formed and excreted, but this time uric acid is in excess of its normal relation to urea, say 1 to 30, i.e., ]4'0 grs. are excreted. FORMATION AND EXOEETION OF UKIC ACID 75 But according to our hypothesis only 1 2 grs. were formed, and there- fore 2-0 grs. must have come from somewhere else, even supposing that all the uric acid formed in the kidney on this day passed direct down the ureter. It is now, of course, evident that the amount of uric acid held back and retained on the previous day furnishes just what is required for the excess in excretion of this day, and thus the excre- tion of uric acid, but not its formation, fluctuates from day to day. We can now explain completely why the excretion of uric acid is large during the " alkaline tide " of the morning, and small during the acid tide of the night hours. It is a simple question of solubility in the blood (see remarks on fig. 3). Further, by giving alkalies the excretion can(as I have long pointed out)* be at any time increased, or by giving acids diminished. But if the stores in the liver, spleen, and joints have been swept out by the repeated administration of solvents, then there is no drug which wiU cause a plus excretion of uric acid till there has been again some retention and accumulation in these structures (see figs. 7 and 8). These facts account completely for all the conditions in which an excess of uric acid is met with in the body, and failure of excretion will soon keep back as much as is ever found in the body before or after death. On the other hand, the theories of excessive formation {i.e., forma- tion of uric acid in excess of the normal relation to urea, about i — 35) or of deficient oxidation are at once incompatible with the facts 1 have brought forward, and unnecessary for the explanation of the pheno- mena of disease ; and as we shall see further on the whole of the diseases treated of in this book may be prevented or cured without the least reference to them, and we should be much nearer the truth if we attri- buted them to poisoning by meat and tea, which can be both demon- strated and prevented, rather than to the above-mentioned theories, which are wholly devoid of foundation on fact. Sir A. Garrod has also pointed outf that there is little or no uric acid in the blood in acute rheumatism, and he proceeds to draw the conclusion that this disease is not due to uric acid. I have given else- wherej my reasons for thinking that this conclusion may require some revision, and I shall have something to say about it further on. My facts are in complete accord with those of Sir A. Garrod ; it is only * See Journal of Physiology, vol. viii., p. 216; and Biit. Hied. Jour., 1890, vol. xii., p. 124. t Reynold's " System of Medicine," 1st edit., vol. i. p. 897. J Med. Chir. Trans., vol. Ixxiii., " Salicin compared with Salicylate of Soda," &o. 76 URIC ACID — CHAPTER III regarding the conclusion to be drawn from them that I venture to differ from him. One further fact about uric acid is, I believe, mentioned in all text- books of physiology, viz., that it is found as a practically constant constituent of the spleen pulp after death. It is interesting to note that uric acid is nearly always present in great excess in the urine in cases of enlarged spleen, as in splenic leucocythsemia, and it has been shown by others to be in excess in the blood in this condition.* In several cases of this kind I examined the urine for eight or ten consecutive days, the whole excretion being saved ; and in these, over the whole period, the average relation of uric acid to urea in the urine was 1 — 12 or 1 — 14. It is little wonder then that under these condi- tions an excess of uric acid should have been found in the blood, the excess in the urine being, as I have said, the index of this ; and in such cases one finds now a great excess of the granules precipitated in the blood by chloride of ammonium, 1 to 2 and even 1 to 1 being common (see later on). It may be remembered also that I have shown that there is gener- ally an excess of uric acid in the blood excreted during an epileptic fit (see cases in chapter vii.). Sir A. Garrod found excess of uric acid in blood drawn during an epileptic fit, and has pointed out the alter- nation between gout and epilepsy — a fact which my results and con- clusions completely explain. And if the liver, spleen and joints are less alkaline, as Sir A. Garrod has pointed out, than other tissues, any uric acid coming to them in the blood stream is rendered, as Sir A. Garrod puts it, " less soluble and more easily retained ; " and we can thus at once explain why these tissues are frequently found after death to contain considerable quantities of uric acid. In order to estimate the amount of uric asid in the blood and tissues I first of all made a water-extract of them by a process described by Salkowski and Leube,t and then having evaporated and cleared my solution, I applied Haycraft's process to it, just as in the case of urine (see chapter xviii., also my remarks as to my results with this process on p. 8). In specimens of human blood obtained during life, I found quanti- ties of uric acid ranging from • 03 per cent, in a case of cerebral haemor- rhage to ■ 0006 per cent, in a case of cellulitis, the blood flowing from incisions made into the inflamed tissue. In the blood of a fatal hmmop- • See Salkowski und Leube, Die Lehre vom Sam, p. t Prev. ref., p. 94. FOKMATION AND EXCEETION OF UEIC ACID 77 tysis in a case of fibroid phthisis, the patient being at the time on sali- cylate of soda, I found • 0065 per cent, of uric acid, and having plenty of blood to work on in this case, I was able to estimate the quantity more accurately than is generally possible with small samples. With regard to the very small quantity of urate in the blood from incisions in an arm afiected with cellulitis, Sir A. Garrod, it may be remembered, has pointed out (" Gout and Eheumatic Gout," pp. 187 and 274), that there is no urate in the fluid of a blister or in blood drawn directly over the inflamed joiat in gout, and suggests as an explanation that inflammation destroys uric acid. My facts are in complete accord with his ; but I think the explana- tion is that local inflammation means local reduction of alkalinity, so that all urate coming to that part is rendered insoluble and retained, and the blood or serum which has passed through the inflamed part is practically cleared of uric acid. It is interesting to remember that in this condition the capillaries are very free, and the capillary reflux (C.E., see chapter v.), very quick, being only one half second, or like a flash, and we see the explanation of this in the above-mentioned very small quantity of uric acid in the blood from an inflamed tissue. We may also recall that in many inflammations of fibrous tissue throughout the body, those drugs do good which just reverse these conditions, bring uric acid back into the blood and slow the C. R., e.g., alkalies and salicylates. A surgeon would say that the above cellulitis was due to a microbe ; but it is also in a sense due to uric acid, for removal of uric acid would relieve or cure. Possibly as I suggest further on with regard to catarrh, tubercle, and other troubles, the microbe and the uric acid are partners, the former fails to grow and fructify without the latter ; hence catarrh, pneumonia, cellulitis, &c., are so much more virulent in those who have gout, collsemia, or Bright's disease. Hence in acute rheumatism the urate is all in the joints and the blood is cleared of it ; but in gout (a more local disease) only that part of the blood which has passed through the inflamed area is cleared of urate. Here also we have a complete explanation of the well-attested facts as to the alternation of gout or rheumatism with headache, epilepsy, and mental depression, for uric acid, as we know, attracts uric acid, and where accumulations are going on in certain joints or fibrous tissues these urate deposits tend to take up all the urate that comes past them in the blood, and hence perhaps for weeks, months, or even years, the blood is kept relatively clear of uric acid, and headache, epilepsy, and depression are remarkable by their absence. We have also a complete explanation of the fact that inflammation 78 UKIC ACID — CHAPTER III increases combustion (everything that clears the blood of uric acid does so), and inflammation clears the blood of uric acid locally very completely as we have just seen, and to some extent also generally ; and this clearing up of collaemia, this quickened circulation and in- creased combustion diminishes, as we shall see later on, albuminuria and glycosuria, the products of imperfect combustion, and increases in their place the products of more complete combustion ; for the same reason that, as we have already seen, and shall see more clearly in chapters viii., xiii. and xiv., every fall of uric acid causes a rise of urea. In specimens of human blood obtained after death from the heart cavities, it seemed to me that when the joints contained urates there was more in the blood than when they contained none — thus eleven cases with urate deposits gave "03184 per cent, of uric acid in the blood, and eleven cases in which there were no urates gave an average of •02255 per cent. Then I noticed that in the blood of cases dying of pneumonia there was generally a great excess of uric acid, and five cases of this kind gave an average of ' 03742 per cent. ; but in a case of pneumonia and delirium tremens the blood obtained by venesection, while the tempera- ture was 102°, only contained '0006 per cent., and this fact enables us at once to explain the great excess met with in the blood of these cases after death. During the acute onset and high fever of the first two or three days of a pneumonia, there is a great rise of acidity, or what amounts to the same thing, a fall in thelilkalinity of the blood and tissue fluids, and this drives all the uric acid out of the blood, and retains it in consider- able quantity, for the reasons previously given, in the kidney, liver, spleen, and possibly the joints and other tissues. There it goes, and there it remains so long as the fever is able to keep down the alkalinity of the blood and tissue fluids ; but when the dyspnoea increases or the temperature falls, the alkalinity of these fluids quickly rises, aild the retained uric acid is soon got again into solution, thus coming to be in excess in the blood, and passing from it in excess in the urine ; the excess of uric acid in the blood accounting for the headache and mental depression and suicide, with slow pulse, high blood pressure and sub- normal temperature, which are so common in convalescence from acute febrile diseases. If, however, the patient dies, precisely the same thing occurs. For some hours before death there is a great failure of nutritive processes • and even if the temperature keeps up, the alkalinity of the blood and fluids will rise, owing to the failure of nutrition and of respiration. FOBMATION AND EXCEBTION OF URIC ACID 79 Hence uric acid is dissolved out from its places of deposit, and is in excess in the blood at the time of death, this excess being, as wiU now be understood, the direct result of its expulsion from the blood ~ and retention in certain organs during the diminished alkalinity of the early stages of the acute fever. Then again cases, in which at the time of death the temperature was high and rising, as in meningitis, yield generally only a small amount of uric acid in the blood ; but there are several exceptions to this rule, -due probably to the fact above mentioned, that in spite of high temperature the alkalinity of the blood and fluids may be rising just before death, owing to general failure of nutrition ; and in one case of pyaemia with embolic hemiplegia I got quite a large amount (•05426 per cent.) in the blood, in spite of a temperature rising to 104° at the time of death ; and in another case of cerebral lesion about the same amount. With reference to cases of this kind, I would suggest that the cerebral changes (softening) in connection with the hemiplegia would cause the passage through the blood of a large amount of phos- phates ;* and that, as I have pointed out,f certain phosphates of soda, potash, and ammonia are powerful solvents of uric acid, and greatly increase its excretion, and no doubt its quantity in the blood for the time being. Two cases, in which the blood contained ■01243 and '0588 per cent., had '06384 and "08668 per cent. = 4'5 to 6'1 grs. per lb. in the spleen respectively, the relative excess in the spleen being in accord, as pre- viously mentioned, with all that is already known on the subject. Nine cases of morbus cordis gave an average of '0335 per cent, in the blood after death. For the rest my results show that the blood after death generally contains some little uric acid, though the amount is subject to consider- able variation, the largest quantity met with being '0744 per cent, in a case of pneumonia, and the smallest 'OlOOS per cent, in a case of meningitis. Eight specimens of liver yielded an average of '05928 per cent., = 4'2 grs. per lb., and the liver of a six months' foetus that did not survive its birth yielded "003 per cent. := "2 grs. per lb. Five specimens of spleen yielded an average of '06412 per cent. =z 4'5 grs. per lb., or slightly more than the liver. Nine specimens of kidney yielded an average of '0513 per cent. ^ 3'6 grs. per pound, that is, less than either the liver or spleen. One * Zuelzer, " Semiologie des Hams," p. 89; aud Brain, vol. ix., p. 364. t Pig. 7, and Med. Chir. Trans., vol. Ixxii. 80 UEIC ACID — CHAPTEE III kidney (not included in the above) from a child thirteen days old, which contained well-marked uric acid infarcts, yielded the very large quantity of "23 per cent. = 16'4 grs. per pound, or more than four times as much as the above specimens. My best thanks are due to my colleague. Dr. S. W. Wheaton, who kindly placed this most inter- esting specimen at my disposal. He informs me that the uric acid of these infarcts, which were plainly visible in the medulla of the kidney, was seen under the microscope to be both in the tubules and in the connective tissue round them, which, according to authorities on the subject, is generally the case (see Zeigler, Pathologische Anatomic, vol. ii., p. 333). The kidney of the above-mentioned six months' foetus contained "002 per cent. = '14 grs. to the pound. A piece of human psoas muscle contained apparently '028 per cent. =: 2 grs. to the pound. It may also be interesting to mention here that half a pound of beef-steak yielded '019 per cent. = 1'3 grs. to the pound, and that I found the equivalent of '697 per cent. = 49 grs. to the pound, in some meat juice, and of '883 per cent. = 63 grs. to the pound, in some meat extract (see also chapter xvii. and remarks on these quantities there). In'a case in which the blood from the heart had '06904 per cent, (a very large quantity), the xirine drawn from the bladder gave a relation of uric acid to urea of 1 to 9"4, a very great excess also. In a case with "02384 per cent, in blood, the relation in the urine was 1 to 27, i.e., much less in both. In another case there was -03024 per cent, in blood, and relation in urine I to 29. And in another, -03914 per cent, in blood, and urine relation 1 to 10, i.e., a considerably greater excess in the urine than in the blood. And in another case -06888 per cent, in the blood, and a relation of iiric acid to urea in the urine found in the bladder of 1 to 18, and the percentage of uric acid in the urine was -03696. The liver in this case contained -088 per cent. = 6-3 grs. per pound. The amount in the spleen was not estimated, but no doubt, as in other cases, it contained nearly as large an amount as the liver. I would remark, in passing, that these facts seem to me to be strongly in favour of my argument that the excess in the urine is an overflow from an excess in the blood, and that the excess in the blood again is due to its dis- solving out and taking up some of the stores in the liver and spleen. For some interesting facts with regard to the origin and experi- mental production of uric acid infarcts, see Dr. E. Schreiber Zeitschr. fur Klin. Med., 38 Bd., H. 4, 5, 6, where it appears that two factors are necessary (1) excess of uric acid, and (2) some irritation in the FORMATION AND EXCRETION OF UEIC ACID 81 kidney, tlie latter, no doubt, diminisking its alkalinity and rendering its tissue fluids bad solvents of uric acid (see chapter xiii.). A similar explanation can be given of tbe greater quantity of uric acid in tbe blood of cases which have urates in their joints ; here the blood has obviously an additional storehouse from which supplies of uric acid can be drawn. And in cases of chronic wasting disease it is easy to demonstrate that it does draw on it ; that for weeks together there is, as I have observed, an excessive excretion of uric acid in the uiine, and after death erosion of joints is found, but all or nearly all the urate has been dissolved out of them. These results show that when there is excess in the blood there is also excess in the urine, but we must not, I think, press the matter more closely than this, or we shall get into difficulty and error. We must remember that the urine found in the bladder after death is the excretion possibly of several hours during which the amount of uric acid in the blood fluctuated considerably, so that nothing more than a general rough relation between the two can be expected. It is not a httle remarkable that in upwards of sixty specimens of post-mortem blood examined by me, it should have been possible to throw into groups the diseases which caused death, in accordance with the amount of uric acid or xanthin found. Thus a specimen containing a very large quantity might come from a case of pneu- monia or cerebral haemorrhage, one with moderate quantity from a case of any wasting disease, especially if there are urates in the joints while one with a very small quantity would probably come from a case of meningitis or other disease accompanied by acute fever right up to the time of death. I would also point out that in thus fluctuat- ing with the presence or absence of fever in the hours preceding death, this substance (uric acid or xanthin) in the blood follows exactly the laws that govern the excretion of uric acid in the urine during life. It also corresponds quite definitely with the excretion of uric acid in the urine just before death, and this may be linked with what 1 shall have to point out further on that the swallowing of any xanthin compound increases the excretion of uric acid in the urine. The granules precipitated in the blood by chloride of ammonium, which I shall have to mention further on, tell the same tale, for they are scanty in fever and more numerous in conditions of debility and wasting disease, and after a fever has passed off. I may mention also that having had my attention drawn io the matter by my friend Captain E. Eoberts, E.A.M.C., [ examined a collection of cataractous lenses kindly furnished me by my colleague, Mr. Holmes Spicer, by the same process as was used in the case of the 6 82 UEIC ACID — CHAPTER III above organs and tissues, but was unable to satisfy myself that they contained any trace of uric acid. Captain Roberts tells me that it has been found by some observers, but it seems to me that the catar- acts we see in this country associated with feeble old age are much more hkely to be connected with the circulation changes of coUsemia, the other signs of which are often so marked in the aged, rather than with the uratic arthritis which comes at an earlier and more vigorous period of life ; whereas in feeble old age the urates are being removed from the joints rather than deposited, as the blood is then a good solvent. I have also made a few examinations of the blood and organs of animals. Dog killed after operation under chloroform :. blood contained ■00168 per cent. That of another dog '00336 per cent., and the urine of this dog obtained at the time of death gave a relation of uric acid to urea 1 to 85, which is a large amount of uric acid for a dog. The urine of a cat gave a uric acid urea relation of 1 to 110. The blood of several other dogs contained very small traces, about •00126 per cent. ; their livers from '04: to '02 per cent., and their urine at the time of death gave uric acid urea relations of 1 to 136 to 1 to 144. I then tried to work on the urine of a single animal (dog) to collect it day after day, and to try and alter the uric acid urea relations by diet and drugs. A bitch, weighing 11 lbs., was kept in the ordinary form of cage for collecting the urine, and was fed on 6"6 oz. boiled horse, 5 oz. milk, and 5 oz. of water. The urine was passed at very irregular intervals, but the aric acid urea relation was 1 to 87 on the first day, and 1 to 165 on the fifth and last day of the above meat diet ; urea being 25 grs. per lb. So that it rather appeared that the meat diet in the dog, as in man, diminishes the excretion of uric acid at first. The animal was then put on a diet of porridge one pint and milk one and a half pints, which, however, it took very badly ; on this urea fell very greatly down to 13, and eventually even to 5 and 6 grs. to the lb., and uric acid increased relatively, being 1 to 146, 1 to 110 and 1 to 98. On the last day of this experiment I gave hyposulphite oE soda in the milk with the object of diminishing the uric acid, and appar- ently with some success, as the relation altered to 143. The animal, which now weighed 13 lbs. (an increase of 2 lbs.), was killed, and the blood, liver and kidneys examined. FORMATION AND EXCRETION OF URIC ACID 83 The blood contained '0003 per cent. „ liver „ -0287 „ kidneys „ -0460 The Tery small quantity in the blood was in accordance with the diminution in the urine, which again was probably due to the drug given, and this further corroborates what I have said above as to the general correspondence between the quantities in the blood and urine. I would point out also in reference to the question of formation V. introduction, that this bitch probably formed absolutely no uric acid, for as she excreted 25 grs. of urea per pound, or 275 grs. a day, and uric acid in about the average relation to it of 1 to 120 or 2'2 grs., the whole of this uric acid might have come direct from the meat eaten, for if there is as much uric acid in horse as in beef (see chapter xvii.), 6'6 oz. of horse-flesh would supply 2-4 gj:s. of uric acid, and it thus seems to me that the whole of the uric acid in the urine of these carnivora may be due to introduction, while their formation is nii. In other dogs I attempted to increase the uric acid in the blood,, and urine by giving salicylate of soda, but this failed completely. There was practically no uric acid in the, blood of either of the two animals thus treated, nor was there any increase of uric acid in the urine, the relation being ia this latter fluid 1 to 140 to 1 to 150. Both urines gave a strong salicin reaction with perchloride of iron, so that the drug was plentifully absorbed and excreted. Now this I think is a very interesting fact, that salicylate of soda, which has such a great power over the excretion of uric acid in man, should produce absolutely no effect on it in dogs. I think, however, that I can see my way to some explanation of the fact, as in all that I have written about the action of saHoylate of soda in man, I have always been careful to point out that acids aid, and alkalies hinder, its solvent action on urates (see p. 42 and fig. 71). Now, strange as it may seem, the acidity of dogs is very low indeed ; and the bitch that I fed on horse-flesh, though excreting 25 grs. of urea per lb., only excreted acid to the equivalent of 1 gr. of oxahc acid for 16 to 17, or even 18 grs. of urea, the acidity urea relation being 1 to 18 ; but in man, as I have shown in my own case, it is 1 to 6-8 ; so that this dog (a carnivore) excreted only one-third of the acid per grain of urea that man does ; probably, therefore, its blood was far more alkaline than that of a man on the same diet, and hence the salicylate failed to affect the uric acid as it does in man (see also cases in chapter xvi.). With regard to the above relation of acidity to urea. Dr. A. Auer- 84 UEIC ACID — CHAPTER III bach has pointed out {Virchow's Archiv., vol. xcviii., p. 512) that no amount of acid that can be given will render the blood of carnivora acid, as they form ammonia to neutralise the acid, and no doubt something of the sort accounts for the very low acidity in the dog above mentioned. I think, also, that the fact that man has not this power of forming ammonia to neutralise acids (or has it only to a very slight extent as compared with the carnivora) is a further proof that he is physio- logically a frugivore and not a carnivore (for further differences between men and carnivora see " Diet and Food," ed. iv., p. 84). In two monkeys, the organs of which were very kindly placed at my disposal by my colleague, Dr. H. H. Tooth, I found in the blood about •00441 per cent. = '3 grs. per lb., in the liver -060 per cent. = 4'2 grs. per lb., in-the kidneys '050 per cent. i= 3'5 grs. per lb., and in the muscles of the back '017 per cent. = 1^2 grs. per lb. of uric acid or xanthins (here, just as in man, the kidneys contain less than the liver). Alongside of my results it may be interesting to mention those of a well-known author. Professor E. v. Jaksch, of Prague, who in a paper " Ueber uricacidsemie " {Deutsch. Med. Wochenschrift, Aug., 1890, p. 741), gives his results of the investigations into the uric acid in the blood, together with an explanation of the causes that tend to increase its quantity. His facts in the main are in accord with my own ; but his conclu- sions from them are based on what I believe to be a completely erro- neous theory, that all increase of uric acid in the blood is due to deficient oxidation, and not, as I have for some years been endeavouring to show, to a retention of it in the body, together with daily introduction, leading to subsequent increased excretion, the increase passing through the blood on its way to the kidneys. Now Professor v. Jaksch relates that he found no demonstrable uric acid in the blood of nine healthy individuals, and the same in cases of tabes, multiple sclerosis, polyneuritis, and cerebral tumour. I should have expected that if there was any wasting in the diseases mentioned there would have been some uric acid in the blood, but as all the facts are not given, it is impossible to draw any definite conclusion. To reason from the results in healthy subjects, it would be neces- sary to state the time of day at which the blood was drawn ; for my researches make it extremely probable that there is some appreciable amount of uric acid in the blood of every one for an hour or two during the " alkaline tide " of the morning (fig. 3, also 52 and remarks on it), FOKMATION AND EXCRETION OF UBIC ACID 85 and tliat the excess in the urine commonly met with, at this time is an overflow from some excess in the blood ; and, as I have elsewhere pointed out, the mental condition, the capillary reflux, the blood pressure and the rate of the pulse, the temperature and other things, often point to excess of uric acid in the blood during the " alkaline tide." Again in nine cases of, typhus Professor v. Jaksoh found no uric acid in the blood ; but it was present in one case alter the fever had gone. Similarly in intermittent fever there was no uric acid during the fever ; but when the temperature fell uricacidsemia or coUsemia supervened, just as my researches on blood granules, to be mentioned presently, show that it does. This, it will be noticed, is in complete accord with my results and reasoning. When there was fever the alkaUnity of the blood was diminished, the uric acid became less soluble in it, and was retained in the liver, spleen, joints, &c. (see previous remarks about fig. 5). The enlargement of the spleen in malarial fevers has an interesting relation, as I shall have to point out at some future time, to the amount of uric acid that can be retained in the body in this disease, and in other diseases in which the organ is enlarged. I have found the spleen, as above shown, to contain about i'S grs. per lb. ; so that obviously a spleen weighing 6 to 8 lbs. would contain 27 — 36 grs., and if this organ is alternately filled up and emptied in the alternations of fever and remissions, we shall be able to account for all the uric acid which is so often found in excess in some part of the body in these cases. Again, if we reflect that the holding back or retention of little more than 1 gr. a day, that is to say, if the formation plus the intro- duction of the 24 hours exceed the excretion of the same period by one grain (and it is easy on any given day to produce a retention to this extent with drugs), will furnish 1 oz. of uric acid in a year, we shall be at no loss to account for all that is ever met with in the body after death, whether in the joints, viscera, and tissues, or in the urinary passages in the form of calculi. On the fall of temperature the alkahnity of the blood was increased, and it dissolved out and removed the uric acid from its places of deposit ; if the urine had been examined at the same time, corresponding changes in the quantity of uric acid excreted would have been observed, and as I have already pointed out the amount of urinary water and the rate and tension of the pulse would show concomitant alterations corresponding to the effects of uric acid on the capillaries (see fig. 42). In diseases of the liver, intestines and "stomach, there was only collsemia when they went along with ansemia. I should be inchaed to 86 URIC AOID — CHAPTBE HI read for anaemia wasting and debility, with their result a fall in the excretion of urea and acid, and a consequent fall in the acidity of the urine and increase in the alkalinity of the blood. Among heart diseases he observed that those in whom the disease caused most cyanosis, had most uric acid in the blood. Again, he often found uric acid in the blood in diseases of the lungs and pleurse, emphysema and exudations. He found it constantly present and in considerable quantity in five cases of pneumonia even during the febrile stage. The explanation of these results in pneumonia which appear to be in opposition to my result will be gone into presently. The blood, in the single case of this disease I was able to examine, was drawn early in the acute stage of the disease, and it must be remembered that in my results with fost-mortem blood I found an extremely large amount of uric acid in the blood of pneumonia cases. None in six cases of rheumatic fever. A very considerable quantity in kidney diseases of different forms, ton cases. From these results he deduces the general statement that the blood contains much uric acid in all cases of primary and secondary anaemia. That uric acid is present in the blood in considerable quantities in other diseases besides gout ; That uric acid does not take part in the acid intoxication of fevers, since fever is unfavourable to the presence of uric acid in the blood ; That in dyspncea and cyanosis the more the blood is overloaded with carbonic acid the more uric acid it contains. Hence in pneu- monia you may get coUsemia in spite of the fever. And lastly, he concludes that it is plus in nephritis and anemia, because the red cells are unable to further oxidise the uric acid, and hence everything that interferes with the oxygen-carrying power of the red cells causes excess of uric acid in the blood. This sounds on the face of it a very plausible conclusion, but my researches on the excretion of uric acid throw, I think, considerable doubt on its validity, and we shall, I think, see eventually that all excess of uric acid in the blood is the cause of defective interchange between the blood and the tissues, and so of defective nutrition and combus- tion in general : and that the cause being removed the efiects remain absent. It has long been known that the excretion of uric acid is large in the morning when the acidity of the urine is low, in what the late Sir W. Roberts has named the " alkahns tide." This has, I think, been generally regarded as due to a plus forma- FORMATION AND EXOEBTION OF UEIC AOIQ ■ 87 tion of uric acid during these hours ; but I have shown that the excre- tion of uric acid, both in these hours and at other times of the day, can be altered in either direction. The natural plus excretion of the " alkaline tide " can either be increased very considerably, or dimin- ished to a corresponding extent. If it is required to increase it, this can be done by first retaining a little uric acid in the body by acids given on the previous day, and then increasing the alkalinity next morning with a dose of alkali. If it is required to diminish it, this can be done directly by giving an acid to counteract the alkali of the " alkaline tide " ; or more powerfully still, by removing all the most easily available uric acid stores on the previous day, i.e., by giving a powerful solvent, as salicylate of soda, when the " alkaline tide " next morning will have nothing to act upon, and there will be no plus excretion of uric acid. I have given instances of all these results before, and anyone who will take the trouble to give a few drugs and watch the results, may easily convince himself that the excretion of uric acid can be varied at pleasure in either direction (see also blood pressure and circulation curves in chap. v.). It may be of interest il, in illustration of what I have been saying, I refer again to fig. 8. From this it may be seen that a dose of 15 grs. of the salicylate, taken three times a day for five days, produced on the first day it was taken a very large excretion of uric acid. Next day, the drug being continued as before, it fell down close to the urea again ; then on the two following days (4 and 5 in the figure) it rose a little, but to nothing approaching the height of its rise on the first day under salicylate (day 2 of figure). On day 6, the last day of salicylate, it came stiU nearer the urea ; and on day 7, when salicylate was left off, it fell very far below the urea, and remained there, as my curves (not given in the figure) show, for the three following days. AH curves of uric acid excretion under salicylate show practically the same thing, and the same is seen in the excretion curve of acute rheumatism treated by this drug (see fig. 68), only that the quantities are greater. In all the excretion reaches its highest point on the first or second day, and the same height is never again attained, however long the drug is continued. On the contrary, the excretion shows a tendency, with a few oscillations, to come down to the level of the urea and remain there ; and, if the drug is now stopped it at once falls far below the urea, and remains there for several days. My explanation of these results is, that on the first day it is given the salicylate meets with a considerable amount of uric acid in the joints, liver, spleen, &c., on which it is easily able to act; that as it gets this into solution and passes the greater part into the urine, 88 • UBIC ACID — CHAPTER III it never on any subsequent day meets with so much uric acid on which it can act, hence the curve never rises so high again. On subsequent days a Uttle is introduced, or here and there comes within its range of action, but each day there is less and less left, so that the curve approaches the urea curve which is the level of formation. As soon as the drug is withdrawn there is at once a retention of uric acid (day 7), replacing to some extent what has been removed from the organs and tissues by the solvent. If on day 2 an alkali had been given in place of the salicylate, it would have produced a plus excretion of uric acid ; but the same dose of alkali given on day 7 would have quite failed to raise the >irio acid above the urea ; the more powerful solvent salicylate has now removed so much uric acid that the alkali has nothing to act upon. It will now be understood that by giving drugs in this manner, and watching their effects from day to day, or, if need be, from hour to hour, it is no very difficult [matter to alter the excretion of uric acid in any required direction. The plus excretion of the " alkaline tide " is thus seen to be a single instance of a general rule which may be thus stated : — -\11 substances which increase the solubility of uric acid increase its excretion (pro- vided there is some uric acid in the body for them to act upon ; in myself, for instance, a solvent will produce a much smaller excretion than if given to a man who is saturated with uric acid), and, conversely, all substances which diminish the solubility of uric acid diminish its excre- tion and cause it to be kept back and retained in the body. If the normal plus excretion of uric acid in the " alkaline tide " was due to plus formation, why should the previous removal of uric acid diminish it, or why should the previous storing up of uric acid increase it ? I have given above my reasons for believing that every plus excre- tion of uric acid in the urine is simply the overflow from an excess of this substance in the blood, and that when there is a diminished excre- tion in the urine there is none, or almost none, in the blood. In other words, that the amount of uric acid in the urine in relation to the urea is the index of the amount in the blood, and that in altering the amount in the excretion we of necessity alter at the same time the amount in the circulating fluid. The results published by Professor v. Jaksch will presently be seen to be simple instances of the action of the law of solubilities above stated. From my point of view I can show that alkalies, phosphate of soda, and compounds of salicylic acid, increase the excretion of uric acid in the urine, and for a time also increase the amount of it in the FORMATION AND EXCEBTION OP UKIC ACID 89 blood. Conversely, acids, lead, and other substances mentioned before, diminish the solubility of uric acid, diminish its excretion in the urine and the amount of it in the blood. That acids, iron, and lead interfere with the solubility of uric acid is well known, and lithia, as I have pointed out elsewhere,* though said to be a beautiful solvent of uric acid in a test tube, yet when given to the human sub- ject by the mouth never reaches the uric acid at all, because it at once forms an insoluble compound with the phosphate of soda in the blood, thus removing from that fluid one of the natural solvents of uric acid, and diminishing its power of holding uric acid in solution ; and in accordance with this, as I have pointed out, it diminishes the excre- tion of uric acid in the urine and the amount contained in the blood ; as a result of this it has the same effect, on the rate and tension of the pulse, the flow of urine, and the circulation of the brain (as evi- denced by the mental condition), that acids, iron, and lead have, though acids raise the acidity of the urine and diminish the alkalinity of the blood, while lithia lowers the acidity of the urine and increases the alkalinity of the blood ; thus clearly showing that the pulse rate and tension of the circulation in the various organs mentioned are not , directly affected by the drugs used, but only indirectly through their effects on the solubility of uric acid and the amount of this substance which the blood can hold in solution. Under ordinary circumstances a dose of potash or soda will increase the excretion of uric acid in the urine, and will also increase the amount of uric acid in the blood ; as a result of this it will slow the pulse, raise the tension, and produce mental depression and scanty urine from its effect on the circulation of the brain and kidney respectively ; but if aU the available uric acid has been cleared out of the body by giving a salicylate for two or three days beforehand (see fig. 8), then a dose of soda or potash wUl produce no plus excretion of uric acid in the urine and no excess of it in the blood ; and in accordance with this none of the above-mentioned vascular phenomena will make their appearance, and the circulation in the brain and kidney will go on unhindered ; thus proving beyond all doubt, that these vascular phe- nomena are due, as I have previously pointed out, not to the direct action of the drugs used, not to the greater or less alkalinity of the blood fer se, but to the larger or smaller amount of uric acid which it is able to hold in solution. We have now also got the blood granules to teU us the quantity in the blood stream, and the capillary reflux to tell its effects on the circulation, so that the quantity of uric acid * Med. Chir. Trans., vol. Ixxi., p. 287. 90 UEIC ACID — CHAPTER III in tte blood can be told approximately in half a minute. We shall see also in chapter viii. that the larger or smaller amount of uric acid in the blood determines the presence or absence of fatigue, and the rise or fall of 'urea as the result of exercise ; and we have already seen (fig. 5) that it afiects both the distribution and the production of heat. I think, therefore, that the connection traced by Professor v. Jaksch between deficient oxidation and excess of uric acid in the blood is quite correct as regards the facts, only the explanation is probably a little different from that which he has given. Dr. Peiper, whom v. Jaksch quotes, points out that the alkalinity of the blood is diminished in all fevers, except when they are compli- cated by dyspncea and cyanosis.* Now this is a most important exception, and on further investi- gation it will, I think, be seen that it furnishes us with an easy explanation of most of Professor v. Jaksch's facts. It may -be worth while to stop for a moment and enquire why dyspncea and cyanosis, that is, deficient oxidation, should prevent the diminution of the alkalinity of the blood which commonly takes place in fever. We have not very far to look for an explanation, for the word oxygen itself supplies one to hand, as its derivation, given in every work on chemistry, o^is acid, and y^yvda I produce, at once furnishes a clue. It is extremely probable, one may almost say certain, that oxygen in the human body acts just as in the chemical laboratory, and when it oxidises certain substances it produces certain compounds of an acid nature, and that form of energy which we call heat. I know as a fact that when certain compounds of sulphur are given by the mouth, they themselves having a neutral reaction, there is soon seen a very marked rise in the acidity of the urine, as if a very strong dose of acid had been given, and this rise goes on for some little time (see fig. 11). Now, it seems to me that there can be scarcely any room for doubt that this is due to the oxidation of the sulphur with the formation of some acid. And it is extremely probable that in the ordinary metabolism of the human body exactly the same thing occurs, that is to say oxygen combines with certain elements in the food or tissues, e.g., the phosphorus or sulphur of the albumen molecule, to form, as in the laboratory, heat and acids ; in fever the same processes are carried to excess, and we have as their result a rise of body temperature and an increased forma- * Virchow's Archiv., June, 1889, p. 337. FORMATION AND EXCEETION OF URIC ACID 91 tion of acids causing a rise in the acidity of the urine and a fall in the alkalinity of the blood (see also chapter iv.). But if oxygen is deficient, as in dyspnoea or cyanosis, the chemical changes are interfered with and the temperature does not rise so high, and there is a lessened formation of acid ; hence, as pointed out by Dr. Peiper, the alkalinity of the blood is not diminished. If, then, with regard to the amount of uric acid found in the blood by Professor v. Jaksch, we read for deficient oxidation, deficient forma- tion of acids, we are at once iu a position to explain all his results ; as the excess of uric acid which he finds in the blood in all conditions of diminished oxidation can at once be accounted for by my law of solubihties previously stated. In ordinary fevers the increase of oxidation diminishes the alka- linity of the blood and reduces almost to nil the amount of uric acid it can hold in solution ; here we have a complete explanation of the results of Sir A. Garrod in acute rheumatism and the concordant results of Professor v. Jaksch and myself in fever and inflammation ; and the blood granules and the capillary reflux agree in confirming these. But if there is a deficiency of oxygen the acids are not formed, the alkahnity of the blood is nt diminished — it may even be increased ; and its solvent power for uric acid being thus undiminished or increased, it at once takes up a large amount in solution, and there is a corre- sponding increase in the amount passed in the urine. Hence also, in conditions of dyspnoea the blood granules are numerous, the capillary reflux slow and the blood pressure high, in spits of some fever. Ad I have also poiuted out, precisely the same changes in the amounts of uric acid in the urine and in the blood can be produced at will by giving alkalies and acids respectively. There is, as I have said before, no reason to believe in the existence of an excessive formation of uric acid, and all fluctuations in excretion can be explained by its simple retention, so that what Sir A. Garrod said about lead (previous quotation) is probably true of all substances that affect the excretion of uric acid in the same way. Practically, in the human body uiic acid is always formed in a definite proportion to urea, about one grain of uric acid for 30 or 35 grains of urea ; and I have given above some reasons for this statement. Sir A. Garrod* noted this fact, and sought to explain it by suggesting that certain cells in the kidney Jormed urea, and certain other cells, having a definite numerical relation to them, formed uric acid ; but • Brit. Med. Journ., vol. i., 1883, p. 547. 92 UEIC ACID — CHAl'TEE III I am inclined to believe that a satisfactory chemical explanation of the relative formation of these two substances may yet be forth- coming. So that the whole of Professor v. Jaksch's results refer to excretion of uric acid, and have nothing to do with formation ; and his extremely interesting observation on the relation between ansemia and excess of uric acid in the blood, which agrees so completely with my own as regards the facts, is also made the foundation for an absolutely erro- neous inference, for my researches further on show pretty clearly that he has exactly inverted the truth, and that, instead of the anaemia being, through deficient oxidation, the cause of the excess of uric acid, the excess of uric acid is the cause of the anaemia. As regards the presence of uric acid in the blood, Mr. Barker Smith has pointed out {Medical Times and Hospital Gazette, September, 1896), that using chloride of ammonium as a precipitant he was able to obtain microscopic evidence of the presence of uric acid or urates in urine diluted so as to contain about one per forty thousand of these substances, and this led him to examine the blood for similar micro- scopic evidence of urates, and he points out that he apparently got positive results. The following are the directions he gives : " Prick the finger with a needle and obtain a droplet of blood, touch it with the cover glass, then with the needle add a minute portion of carbonate of soda solu- tion, and then a similar portion of sal ammoniac. Mix together and examine under a fourth or fifth object glass after half-an-hour." The solutions used appear to be sodii oarb., 10 per cent., and ammon. chlor., 20 per cent. He further says, " Granular urates may be seen distinct from micro- cocci and from albooytes ; some appear in the blood corpuscles." In some subsequent writings on these points he acknowledges that the granular urates have to be distinguished from granules thrown down by the solutions used, as well as from micrococci and albocytes. Thinking over this matter it soon occurred to me that having as I believe almost absolute power over the quantities of uric acid in the arine and also in the blood, it would not be very difficult to put these statements to such tests as would very promptly settle the question of their value one way or the other. What I had to distinguish these possible urates from were (1) micro- cocci, (2) albocytes, and (3) granules from the solutions used. With regard to the last it appears probable that by using as far as possible constant and small quantities of the solutions, they may be averaged and neglected, and as regards albooytes and micrococci FOBMATION AND EXCBBTION OP UEIC ACID 93 there is no reason to suppose that they will vary constantly with the uric acid present ; then if the granules are found to vary constantly with the amount of uric acid in the urine in health, and with what is known as to its presence in the blood in disease, we may similarly neglect albocytes and micrococci. Now, as we know, uric acid is present in the urine in large amount during certain hours of the day, and in very small amount during certain hours of the evening and night, and it can be made to vary in the urine at- any time by very numerous drugs ; I have also given my reasons for believing that every such artificial or natural variation in the excretion in the urine is the index of a similar variation in the quantity present in the blood. Now, if this is true, and if the granules pointed out under the micro- scope by Mr. Barker Smith are urates, or xanthins (for xanthin also appears to be precipitate by chloride of ammonium), they ought to vary in quantity, with the normal urinary excretion of uric acid in physiological conditions, with the artificial alterations in excretion produced by drugs or feeding with uric acid or xanthins, and with the best known and attested pathological variations in the amounts of uric acid in the urine and blood. I. accordingly began to examine my own blood night and morning, taking it in the morning at some hour between 6 a.m. and 9 a.m. when uric acid is above urea, and comparing this with 10.30 or 11 p.m., when uric acid is below urea (fig. 3). And I soon found that there were always many more of these granules present in the morning hours than in the evening hours. Thus, in the morning it was no uncommon thing to find granules present in the relation of one to every eight, ten, or twelve red cells, while in the evening the relation was one to fifteen, twenty, or twenty-five. Then one morning, when I had all the signs of coUsemia and high blood pressure after a late and rather indigestible supper the previous night, I examined the blood, and finding more granules than usual, I took a dose of calomel and watched the urine half hour by half hour, and when a diuresis came (the urine rising from about 35-40 cc. in an hour up to 70 cc. in the same time) I examined the blood again and found a much smaller number of granules. And it seems to me very unlikely that either alboctyes or micro- cocci could present such constant variations with the time of day, and as to the solutions, they were used in the same way each timCj. and it is hardly likely that any granules from them could account for such constant variations. Besides, any natural blood elements would be more numerous after a diuresis than before it, but it was just the reverse with these granules. 94 UEIC ACID— CHAPTBE III I then began to examine into the possibilities of pathology, and I put the matter here to the most severe test I could devise. I think there is no fact more generally agreed upon by workers on uric acid than this, that if you are ever likely to find excess of uric acid in any blood, it is in that of a patient who suffers from chronic gout, more especially if it is conjoined with chronic Bright's disease, and I happened to have such a case binder my care ; and I think it would be further agreed that if you wish to find a blood almost com- pletely free from uric acid you had better examine that of a patient suffering from acute fever, as both Sir A. Garrod and Professor v. Jaksch have pointed out that uric acid is absent from the blood under these conditions. I accordingly took the blood of a patient suffering from acute pulmonary disease with a temperature above 102° F., and I prepared for comparison with it a similar specimen^f blood from my case of chronic gout and chronic Bright's disease. And the result was absolutely conclusive ; a single glance down the microscope sufficed to tell which was which, for the blood of the febrile patient contained comparatively few granules less than my own blood usually contains ; while that of the gouty patient contained an eno'r- mous number, three or four times as many as I had ever seen in my -own blood ; and I believe the relation of granules to blood cells in this gouty blood was practically one to one. I repeated my examina- tion several times and always found more in this patient's blood than in any I had examined. I then produced an artificial increase of the uric acid and xanthin in my blood by swallowing some small quantities of theobromine, and again the granules seemed to increase or diminish with the uric acid found in the urine. Thus, one day when the uric acid urea relation in the urine was one to twenty-six, and when 3| grs. of uric acid passed through the blood, I examined it at 4.50 p.m., when there was some fairly marked mental depression, and found granules in the relation to red cells of one to four ; and on this afternoon my blood could not at once be told from that of the gouty man above mentioned, and it was only on carefully counting with a micrometer eye-piece that his blood was found to give a relation one to three or even one to two. On the following day at the same hour I again examined my blood, there being no mental depression, and the relation of the uric acid to urea in the urine of the day being one to thirty-six, and in this blood I found relations of one to sixteen and one to eighteen, and this blood could as on other occasions have been easily distinguished from that of the gouty man. FORMATION AND EXCRETION OP URIC ACID 95 Further experience has led me to modify Mr. Barker Smith's process to some extent. Thus I take a very small drop of blood on a microscope slide and mix with three or four times its volume of each of the solutions, so as to considerably dilute it, which facilitates counting. After mixing well I put on a cover glass and place the slide in a box or under a glass, with some moist blotting paper or cotton wool to prevent evaporation, so that there shall be little or no increase of granules from the solutions. At the end of half an hour I examine under the microscope, choosing a field as near the centre of the cover glass as possible, that is as far from the effects of evaporation as possible. I then count all the granules in a field and then all the red cells in the same field, and then repeat this three or four times, adding the results together ; and then the total of the granules divided into the total of red cells gives me the average relation of granules to cells. To facilitate counting the red cells I use a micrometer eye-piece, and count the red cells only in a fraction of the field and multiply. By this process I soon found, as I have said, that I got absolutely constant results, and that there could be no question as to albocytes or micrococci, for it was impossible to believe that either of these could vary as I found these granules to do in constant relation to the excretion of uric acid in the urine, whether in its daily physiological fluctuations or in those of drug action or pathology. It was soon evident that as I had practically absolute power over the excretion of uric acid in the urine, so I had also absolute power over the number of granules in the blood. As the matter is so simple and my results can be reproduced easily bv anyone, I shall not devote space to giving an account of the whole of my research, but shall content myself with mentioning a few typical instances of the relations of granules to red cells in physiology, drug action and pathology. Indeed, since I found that the results were absolutely constant and reliable I have ceased to collect and tabulate them. After watching the morning and evening results in physiology in my own person for some time, I came to the conclusion that I should probably get definite and distinct results by examining both blood and urine from hour to hour, and fig. 21 shows one of the results I obtained in this way. The broken line shows the total hourly excretion of uric acid in the urine in fractions of a grain, the continuous line shows the relation of the granules to red cells in the blood at one moment in the hour 10.15 to 11.15, and so on, the blood being drawn just after the urine had been passed, and the blood results were worked out and tabulated before the uric acid was estimated in any of the samples of urine. 96 UEIC ACID — CHAPTBK III Now in this figure we see that at 10.15 a.m. the hourly excretion of uric acid was 0-49 grs., while the relation of granules to red cells was 1 to 8. At 11.15 the uric acid excreted in the hour was 0%34 grs., and the blood granules 1 to 17. At 12.15 the uric acid was 0-29 grs., but the granules had risen to 1 to 10. At 1.15 the uric acid had risen to 0-44 grs., but the granules had fallen to 1—15. At 2.15 the uric acid had fallen to 0"35 grs., but the granules were not examined. Looking at the whole figure one cannot help being struck by the similarity of the two curves, and if we could move the granules' curve about an hour to the right they would be almost absolutely parallel. In other words the changes in the granules in the blood preceded by about an hour the corresponding changes in the excretion of uric acid in the urine. Thus the lowest point in the granules is at 11.15, the lowest in the excretion curve is at 12.15 ; the granules show a rise A.M. P.M. j 9§ 50 0-4 0-30 id" oio; nolo 11020 101 5 1 11 5 1215 115 215 \ \ \ \ 1 t\ y. V HOUf A ■- C ACID II STIQN' URIH£ -di Pig. 21. — Cubves showing the Relation of the number oi' Granules in THE Blood to the Bxorbtion of Ubic Acid in the Urine hour by hour. at 12.15, the excretion shows a rise at 1.15 ; the grd,nules show a fall at 1.15, the excretion shows a fall at 2.15. Now this is a fairly constant characteristic, so that I have said from my other similar results that the changes in the blood granules precede the corresponding changes in the excretion by from 30 to 90 minutes. The larger the change in the granules the more marked will be the corresponding fluctuation in the excretion, but we must expect a certain small amount of variation where the changes are less marked, for the excretion is the total result of a whole hour, while the granules represent the condition of the blood only at one moment in that hour. The blood of children generally contains more granules than that of adults (say, for instance, 1 to 6 in the morning and 1 to 12 in the evening, just as their urine generally contains more uric acid, and as they excrete POEMATION AND EXCEETION OP UEIC ACID 97 more per day or per hour for eacli pound of body weight than adults do (see " Causation of Rheumatism," chapter xvi.). ^ In coming to drug action, salicylates were among the first things that I used on account of the very great fluctuations they produce in the excretion of uric acid in the urine, and here again the granules were found to parallel the urine changes to an extent of which at first I had no expectation. ■Thus on a day when I took 50 grs. of salicylate of soda and excreted 19"5 grs. of uric acid in the urine the blood granules at 10.30 a.m. were 1 to 5. On the following day no drugs being taken the excretion of uric acid in the urine was only 12 grs. and the blood granules at the same hour in the morning were 1 to 36. On the following day no drug being taken uric acid had further fallen to 7'6 grs. in the day, and the granules at 10.30 a.m. were 1 to 75. This, of course, is a very severe test of the granules to examine them at one moment of the 24 hours and compare them with the urine excretion of the whole 24 hours. Nevertheless, even apart from the large fluctuations caused by the salicylates, an examination of the blood about 10 a.m. in what is nearly the middle of the large alkaline tide excretion of uric acid, will very often give a good index of a larger or smaller excretion of uric acid in the corresponding 24 hours. On another occasion with upwards of 20 grs. of uric acid excreted in the urine as the result of taking salicylates, the granules in the morning were 1 to 4. On the following day with no drugs uric acid in the urine had fallen to 10*7 grs. and the granules were 1 to 34. On the following day uric acid had risen to 13'4 grs. and the granules were 1 to 10, both the granules and the excretion being here about the normal average. On another occasion the blood was examined at 9 p.m., no drug having been taken, and the granules were found to be 1 to 22, about the average for the time of day. Twenty grains of salicylate of soda were swallowed just after drawing the blood, and at 10.15 p.m. the blood granules had altered to 1 to 8, and at 11 p.m. were 1 to 6. Similarly the granules can be increased in a few hours by a dose of alkali, or they can be diminished to a corresponding extent by a dose of iron or mercury, or by anything that diminishes the excretion of uric acid in the urine. Coming to patients and pathology, Thomas J., age 10 years, on salicylates for erythema had granules to red cells 1 to 1. The same boy on the first day after leaving off the salicylates was 1 to 9. Emily S., age 19, salicylates beginning to reheve the pains of acute rheumatism, temperature 102°. Granules to red cells 1 to 2. 7 98 UEIC ACID — CHAPTBE III Rose 0., age 7, last day on salicylates for rheumatic fever . . 1—6 „ ,, first d«^ on no drugs .. .. •• •• ■• 1 1' Emily B., aged 21, sixth day of sub-acute rheumatism, no drugs, temperature 101° . . . . ■ ■ • • • • 1 — 1° „ „ two days later pains relieved by salicylate, tempera- ture normal . . . . . . • • • • ■ • 1 — ^ „ „ no drugs for three, days . . .. .. ■• •■ 1 — 12 William W., age 12, on salicylates for acute rheumatism . . 1 — 3 „ „ first day on no drugs . . . . . . . • ■ ■ 1 — 12 Several of these cases illustrate the large number of granules met with in children. In these cases the urine was not examined, and the blood was simply taken in reference to the probable action of the drug. In Bright's disease there is always a fairly marked excess of granules, thus : — Julia A., age 24, chronic Bright's disease, large pale kidney, blood granules 1 to 3. Bhza S., age 21, similar disease to last patient ; granules 1 — 1 to 1 — 6, as the result of a large number of examinations. I also examined the urine of Eliza S., and found a great excess of uric acid, on one occasion as much as 1 to 12 {i.e., 1 of uric acid to 12 of urea), a relation never met with in physiology. And this is very interesting because it has been suggested by some that kidney disease prevents the excretion of uric acid; yet in this patient, whose kidneys had probably not a single normal cell in any part, and in whose urine the microscope shows an immense number of casts with extensive fatty and degenerative changes, the excretion of uric acid is much larger than anything met with in physiology. It is easy, however, to explain it, for we have here advanced disease with great debility, cardiac failure, general anasarca and sub-normal temperature ; as a result, the alkaUnity of the whole body is increased, and the blood is flooded with uric acid which passes freely through the kidney into the urine, and the most advanced degeneration of kidney structure will not, under these conditions, prevent its passing. In early and acute cases of Bright's disease, on the other hand, the excretion of uric acid is often, I believe, decidedly diminished, in spite of far less destruction of kidney structure than we had to deal with in the above case ; but in the more acute condition there ma,y be some diminution of the alkalinity of the blood, and possibly stilL more marked diminution of the alkalinity of the kidney, and the uric acid is either not in solution in the blood or fails to pass the less alka- line kidney. In both cases it is a matter of solubility and not of FOEMATION AND BXCEETION OF UEIC ACID 99 minute structural integrity, and over and over again I have seen kidneys, which were found 'post-mortem to be practically^destroyed, passing excess of uric acid as in the case of Eliza S. Among cases which were probably granular kidney I may mention : — John W., aged 63, granules 1 — 3 Caroline E., aged 43 „ 1—3 Abraham W., age 60 „ 1 — 4 Joseph H., age 38 ,, 1 — 4 As to chronic gout, I have already mentioned one case, and another is that of Samuel H., age 35, gout for fourteen years and numerous tophi visible on the surface of his body and much general joint change, 1 to 2 ; and D. M. M., age 52, chronic arthritis with depression, 1 — 6. Then in fever one gets more or less marked diminution of granules, as — William D., age 20, 9th day of enteric fever, granules 1 — 30 Lucella T., age 13 mouths, meningitis, temp. 101° „ 1 — 14 (a relatively small number for a child) Alice W., age 10, 5th day of pneumonia, temp. 103° „ 1 — 22 We see, then, that the granules are scanty in fever, are numerous in gout, Bright' s disease, and I may say also in diabetes, in those cases I have been able to examine. In physiology they precede all the well-marked fluctuations in the excretion of uric acid. And in drug action it is possible to make them vary in almost any direction and at any time. We have then in these granules, I believe, a perfectly reliable guide to the quantity of uric acid in the blood, for though it is not possible to get any chemical reaction from them as they exist in the blood, it is inipossible to believe that any substance, which follows so accurately the excretion of uric acid in physiology and drug action, and corresponds so closely with what is known of uric acid in path- ology, can be anything except uric acid itself or a form of xanthin capable of immediate conversion into it; and we know that xanthin is so converted in its passage through the body. But other considerations which we shall deal with later make it probable that it is uric acid itseK, and that this Constantly exists in the blood in very similar colloidal granules, only a trifle smaller and less visible than those produced by the action of chloride of ammonium. Though I thus quite believe that these granules are a rehable index of the amount of uric acid in the blood, I do not very often use them for that purpose, because as will be seen in the chapter on the circulation, the uric acid in the blood furnishes its own index 100 UEIC ACID — CHAPTEE III by its effects on the capillary circulation, and as these can be meas- ured with considerable accuracy in less than one minute, it is only necessary to appeal to the granules when some special confirmation of the circulation evidence is required. The granules, then, show that there is always some uric acid in the blood, more in the morning and less in the evening, correspond- ing with the excretion of uric acid in the urine, and that many of my previous results with the blood of venesection, and even with " i i ■ / 2 3 i 5 6 7 s H ■ Mil 2/00 70 14 4S2 mo so IS 4-23 '.TOO so' 12 336 ISQQ 40 It 3t3 1300 30 10 -we IIQO 20 a i$7 300 10 B 264 700 7 231 G>-- ■-■aUJ fC AC fi A «f "A \ A V ,' \ / \.c iDirr 50^ V 43^05 h \ 'A' SS3Z^ '^i' WATCh \ - h V V ; / 1 !? v^ "^" I REA 5 1 s fe 1 3 ^ «S i <3 1 S § 4 ; Pig. 22.— Ebtention of Ueic Acid pboduoed by an Iodide. post-mortem blood, accord fairly well with our greater and more accurate knowledge now obtaiaable. Thus I found little in the blood in fever and inflammation, much in the blood in gout, uraemia and in death from pneumonia.' As wiU appear also in the chapter dealing with anemia I can control absolutely the condition of the blood by controlHng the amount of uric acid that passes through it, and with increasing know- ledge in all these directions we have obtained a great corresponding increase in power. Fig. 22 shows the effect of an iodide on the excretion of uric FORMATION AND EXCRETION OP DEIO ACID 101 acid. On day 1 uric acid is high, and on day 2 it rises still further. On day 3 gr. x. of iodide of sodium are taken three times, and uric acid falls and comes close to urea ; and on day i, though no more of the iodide is taken, it falls further and remains close to the urea. On the remaining days of the figure no drugs are taken, but on day 5, the effect of the iodide having now passed off, uric acid rises very high. This constitutes what I have spoken of as the rebound, and makes it probable that the low excretion of urate on days 3 and 4 was not due to its destruction or elimination in other forms, but to its retention in the body, the iodide making the blood for the time being a bad solvent of urates, so that they are retained in the liver, spleen, kidneys, and fibrous tissues ; and when the effect of the iodide passes off they are again taken up by the blood from these organs and tissues and excreted 'in excess in the urine. A similar plus excre- tion due to the rebound is seen after the administration of all substances which, like iodine, cause retention of uric acid. Those substances on the other hand which cause a plus excretion of uric acid, as alkahes, salicylates, &c., are followed by a great fall in urate excretion the day after they are left off (see figs. 7 and 8). On days- 6 and 7 in this figure uric acid remains high and a long way above urea. Note also that the usual relation of uric acid to acidity is broken through, for urate falls and remains low on the fourth, though acidity has fallen decidedly. On the fifth, however, the effect of the iodide passes ofi, and the fall of acidity allows of a plus excretion of urate ; on the sixth acidity rises and urate falls somewhat, so that it has regained its normal relation to acidity. See. also the excretion of water, how it rises to 1,500 cc. on the third, when the urate falls down clo3fe to urea. On day 2 uric acid exceeds the relation to urea of 1 — 33 by nearly 3^ grs. (that is to say, on this day about 3J grs. of uric acid passed through the blood), the capillaries of the kidney and of the whole body were obstructed by the urate, hence the urinary water was scanty, only 1,100 cc. On day 3 the iodide produces its well-known diuresis, and this diuresis, lilce that of many other drugs which cause retention of uric acid, is due to its clearing uric acid out of the blood. On day 3 uric acid was above urea by only J of a gr., and so only i gr. passed through the blood, therefore the capillaries were everywhere free, the circulation through the kidneys was free, and the urinary water ran up to 1,500 cc. In a paper on " The Iodides and their ESects on Arterial Tension and the Excretion of Urates " {Transactions of the. Royal Medical and 102 €BIC ACID — CHAFTBK III Chirurgical Society, vol. Ixxvi., p. 113), I have pointed out that the relaxation of aiterioles and the diuresis which the iodides produce are contemporaneous with a diminished excretion of uric acid in the uiine, and I have further said that a large number of drugs and disease processes which similarly diminish the excretion of uric acid and clear it out of the blood, produce also a relaxation of arterioles, or as I should now prefer to say, a freeing of capillaries, and a diuresis ; and I have asserted that arterial tension is influenced, not by the drugs, but by their effects on the solubility of uric acid and the amount of this substance present in the blood. AueusT 7* «■* 3'" /o* 2/00 70 /* ■ISO '^\ ^ y/ iCAt 10 14, 9 1900 60 /J •— -% Ac orrv V "Ff \, rs'^p 1700 so {2 ■m / . fK TEn 1 r A i tSQO ISOO 4-0 30 ft 3BS 310 1 A / / J 1100 20 S 3/S 1 i I 5 i 1 I i 1 1 1 g 1 Fig. 23. — Effects of Balsam op Copaiba on the Excretion op Ubic Acid and Watbe. Copaiba is another drug whose power of causing diuresis is well known, and 1 would point to fig. 23 as showing that just as with iodides, of which we have been speaking, the increased excretion of water is contemporaneous with a fall in the excretion of uric acid, and we are bound therefore to consider whether its action is not due to its effects on the solubiUty and excretion of uric acid. In this figure we see that on August 7 uric acid exceeded the rela- tion to urea of 1 to 35 by nearly 4| grs., that is to say 4f grs. passed through the blood. On this day the urine was rather scanty in the day hours, but this was made up by an excretion of exactly double POEMATION AND EXCEETION OF URIC ACID 103 the amount m the night hours. On the 8th on which the copaiba was taken uric acid fell, and urea rose so that only 3J grs. passed through the blood, and with this we see that the water rises decidedly, being nearly twice as much in the day hours as on the 7th. On the 9th, uric acid falls still further, and urea continues to rise so that only IJ grs. of uric acid passed through the blood, and with this the urinary water remains high, but the hourly excretion at night is again larger than that in the day hours. On the 10th urea is stationary, while uric acid rises so that 2 grs. pass through the blood, and with this the water falls and the hourly excretion at night is nearly double that in the day. We see, then, that on the 8th and 9th urinary water is high, and that this corresponds with a well-marked fall in the quantity of uric acid passing through the blood on these days. The diuresis produced by copaiba is therefore merely another illus- tration of the action of my law of excretions, that the urinary water varies from hour to hour and day to day inversely as the height of the uric acid above urea, that is, inversely with the amount of uric acid passing through the blood (see descriptions of figs. 1, 2, and 3). We are less concerned with the manner in which copaiba interferes with the solubility and excretion of uric acid than with the fact that it does so ; but on looking at its composition one cannot help being struck with the large amount of acid (copaibio acid) it contains. The rise of acidity on August 8 is small, especially as there is a pretty marked rise of urea ; but it looks as if there must have been something to raise the acidity on the 8th, because it falls on the 9th in spite of a further and more marked rise of urea. It is interesting also to note that several substances which produce similar effects, as tar, turpentine, cannabis indica, and guaiacum, contain also very similar acids or acid resins ; and I believe that a very large part of the physiological and therapeutic effects of the drugs just named can be completely explained by their action on the solubihty and excretion of uric acid which controls the circulation throughout the body. With reference to guaiacum I would refer to my remarks in the debate on Sir A. Garrod's paper on this drug, at the Koyal Medical and Chirurgioal Society (see Proceedings, 26th May, 1896, also Lancet, 1896, vol. i., p. 1494) ; and in the above debate Dr. Norman Moore mentioned the interesting fact that in the 17th century guaiacum was considered as the best remedy for tertiary syphilis ; it would certainly tend to clear the blood of uric acid, and free the capillary circulation just as do the iodides used in these days. We now come to uric acid itself, and a large group of substances which are almost chemicallv identical with it. 104 UEIC ACID — CHAPTEE III Uric acid and all these related substances have several important effects which are common to them all, and the chief o£ these is that they all interfere with their own solubility in the blood ; they not only do not remain in solution in the blood themselves, but they prevent any other similar compounds that may be otherwise present in the blood stream from remaining in solution. And they probably produce this effect by acting like acids or acid salts, such as the nitrites, sulphates, salts of the mineral and other acids of which we have spoken, so that when they get into the blood they take alkali from the norfnal phosphates of the blood and convert them into acid phosphates, which, as we have seen, are not solvents of uric acid. The solvent powers of the blood for uric acid are thus diminished by these substances, with the result that the blood stream is at once more or less cleared of uric acid, and the whole of the physiological and pathological effects of these substances depend upon this action. The substances which thus at once clear themselves and their rela- tives out of the blood stream, pass, as we have seen reason to believe, into the parenchyma of the Uver, spleen, kidneys, and many fibrous tissues throughout the body ; but in the natural course of events, perhaps introduced in food, a fresh supply of alkali gets into the blood, the acid phosphates again become normal phosphates, and the solvent powers ofthe blood for uric acid and its congeners are restored.'*,- The blood now acts on the uric acid previously driven out of it into the above-named tissues and organs, gets a certain quantity of it into solution, and keeps it in solution till it is all excreted by the kidney, or till a fresh introduction of acids in some form drives it agaia out of the circulation into the tissues. The urine is thus an absolute index of what is going on in the blood, and we can now completely understand why the excretion of uric acid varies from hour to hour and day to day inversely with the acidity of the urine. I notice that Dr. J. Fawcett in " Guy's Hospital Reports " (1896, vol. lii., p. 140), objects to my saying that uiic acid varies inversely as the acidity of the urine, and also that the acidity of the urine ia sometimes and in part due to uric acid, and he thinks this last is an unfair deduction. But I must explain that the inverse relation between the excre- tions of uric acid and of acid in the urine is only strictly true in physio- logical conditions and where the daily introduction of uric acid is moderate and does not vary much ; thus, if 10 grs. are taken in to-day POEMATION AND EXCRETION OP URIC ACID 105 15 to-morrow, and onJy 5 tke next day, there will be large variations both in acidity and in excretion, and they will not always vary in the rule. Again, if we consider for a moment that the excretion of uric acid in the urine is the resultant of two factors: — (]) The amount avail- able ; and (2) its solubility in the blood ; we see at once that as the acidity of the urine varies for the most part with only one of these factors [i.e., the alkalinity of the blood and its solvent power for uric acid), unless the other factor (the amount available or the introduc- tion) is kept fairly constant, there will be exceptions to the rule. Thus I could increase my excretion of uric acid to-morrow by taking an alkali, but if I also swallowed some extra uric acid along with the alkali I should have a still larger excretion than if I only took the alkali alone. My own physiological results were obtained on a practically constant diet, with a fairly constant and very small daily introduc- tion of uric acid, and so the amount available tor solution varied but little ; but even here the results are occasionally put out by intro- ' duction, especially in the curves obtained some years ago, before I knew all I have since learned about introduction in various sub- stances. In pathology the same rule holds for the most part, but there are one or two exceptions such as gout and rheumatism, when the uric acid has, so to speak, an additional outlet, being taken up and deposited in the fibrous tissues which have become the seat of chronic irritation. Here any uric acid in solution in the blood is apt to be attracted to and caught up by the urates already in the seat of gouty irritation (just as uric acid on a filter soon clears all the uric acid out of the urine that is poured over it), hence in gout it is not brought to or excreted by the kidneys to such an extent as one might expect from any given fall in the acidity of the urine. Hence the well-known alternation of gout with melancholia, and of migraine with rheumatism ; when urates are being retained in the firbous tissues and joints the blood contains relatively little, so that high blood pressure and its effects are absent. During the continuance of the gouty condition the tophus in the big toe is being daily increased by the addition of all the uric acid that is brought to it in the blood ; but the rest of the blood is thus kept poorer in uric acid, so that the excretion from the kidneys is less than the acidity of the urine might lead us to expect, and there is no high blood pressure and no melancholia. Again, clinically, nothing is more common than to hear a patient 106 UEIO ACID — CHAPTBB III say that she sufEered much from rheumatism a year or so ago, but that lately the rheumatism has been better and the headaches much worse. This means that an increase of dyspepsia and debility or other cause of a rise in the alkalinity of the blood has reversed the above process, and urates are now being taken up from the fibrous tissues, in place of being deposited in them. We can now understand why Dr. Fawcett could not imitate my physiological results with alkalies when working on cases of gout ; and he also further complicated matters by giving foods (eggs, fish, and tea, and occasionally full diet) which varied somewhat from day to day, and introduced various amounts of xanthins, to which apparently he paid no attention. With salicylate of soda, however, he was able to get results much more nearly resembling mine, for the salicylate was at once able to dissolve the uric acid out of the gouty joints and fibrous tissues, and bring it in a steady stream to the kidneys for excretion (see action of salicylates, chap. ii.). While speaking of Dr. Fawcett's results, 1 may mention that he was unable to see that colchicum lowered the acidity of the urine ; but tlien I notice that he used the vinum, and in rather small doses ; and sherry, as we shall see in fig. 63, distinctly raises the acidity of the urine, and would therefore tend to counteract the efiects of the colchicum. In my experiments with colchicum I used tr. colch. sem., the alcohol in which would at least do nothing to counteract the effects of the colchicum on the acidity of the uriae. Dr. Fawcett also thought he saw some exceptions to my rule as to the inverse relation between water and uric acid in excretion, but his remarks raised in my mind a doubt whether he had read carefully my remarks on this subject with reference to fig. 3 ; and in any case, with the very complex excretions he would get when dealing at one and the same time with pathology, drug action, and varying food and intro- duction of urate, I should not expect the rule to come out clearly. But to return once more to uric acid and the xanthins : the primary efiect of taking any one of these substances is to clear the blood of uric acid, and all other immediate effects are the results of the circulatory changes which this clearance produces ; on the other hand, its secondary effect is to flood the blood with uric acid, and this flooding again accounts for all the other effects. Fig. 24 shows both these series of effects very well. 1 shall now mention the chief substances in this group with their chemical composition, and then pass on to describe in detail the physiological effects of a few of the most important ones. FOBMATION AND EXCEBTION OF URIO AOID 107 Uric acid = CsH.N.Oj. Xanthine = C^H.N.O,. Hypoxanthine = CSH4N4O. Purine =C5H4N4. Guanine = CsH^NjO. Kreatine = C.H^NjO,. Kreatinine C^H.NjO. GlycocoU = aHsN.O. Theme or Cafieine = CgH^N^O,. Theobromine =--. C.HgN.O,. Other vegetable alkaloids of similar composition. Ptomaines. I shall have to point out that as regards physiology and pathology it makes absolutely no difference whether we swallow a grain of uric acid, xanthine, hypoxanthine, theine, cafieine, or theobromine ; all alike produce as a primary effect clearance of uric acid from the blood with free capillaries and general stimulation of metabolism and nutrition ; all alike have also a secondary action or rebound when the uric acid again passes into solution in the blood with obstructed capillaries and general depression of nutrition and metabolism. What we know of several other vegetable alkaloids and their physio- logical effects points strongly to their acting in exactly the same way, and what we know about ptomaines makes it worth while to bear in mind the possibility that such part of their action, as resembles that of the above substances may be produced in exactly the same -way. Guanine is a very similar substance, and glycocoll I have previously spoken of as uniting with benzoic acid to form hippuric acid, and with salicylic acid to form salicyluric acid (see salicyluric acid, p. 42) ; it also under certain conditions unites with ten parts of urea to form uric acid (see also p. 8). The whole of these substances thus stand together in a natural group which from my point of view is of enormous importance. Now fig. 24 shows the effect of taking urate of sodium (grs. 9) by the mouth, and it apparently produces a rise in the excretion of uric acid, not on the day it was taken, but in the 'first, secoiid ^d third day after the dose. Its first effect is to clear the blood of uric acid, and with this clearance the excretion of uric acid falls below urea on day 2. The rise of acidity on day 3 is partly the result of the action of the urate on the phosphates of the blood before mentioned, and partly also due to the increased metabolism which is the result of clearing^the blood of uric acid, and this again accounts for the rise of 108 UEIC ACID — OHAPTBB III urea on days 2 and 3. But tte increased metabolism comes to an end, the urea falls and the acidity with it, and now the uric acid which was stored up on day 2 is got into solution in the blood and passed out in some excess in the urine during the rest of the figure. Precisely the same thing occurs if uric acid is taken in place of a urate, but here again, on one of the following days, acidity falls, and uric acid rises and remains high for several days more or less in pro- portion to the dose taken. h ■ Mis ISOO BO 13 423 1700 SO IZ 336 ISOO 40 II 3S3 1300 30 10 330 -" 1100 20 3 237 900 10 8 254 700 7 231 y 1 2 3 4 5 e 7 A V' V •-^ ^AC wmr ' ^^" \ \ —0-- -<5 A 43^76 mnn '"b" SS^*2 -A 1 i \ \ \ •ICACI tEA JffvJ/ / s V / s>L 1 1 1 i « ^ Pig. 24. — Effect on the Excebtion of Ubic Acid of Swallowing Ubate of Sodium. If, however, acidity runs at a very high level, as in a person who- eats much meat and drinks wine, taking uric acid or urates by the- mouth may appjarently produce no effect whatever on the excretioiL of uric acid ; for the excretion of uric acid is dependent on its solu- biUty in the blood, and where the conditions are unfavourable for this solubility it remains in the body instead of passing through the blood into the urine. In this figure it was the fall of acidity on day 4 that made the plus excretion of urate on this and the following FOEMATION AND BXCBETION OP UEIC ACID 109 day possible, but bad tbere been no urate introduced this fall la acidity migbt not have been followed by a rise in its excretion. If, on the other hand, the blood is kept in a condition to hold uric acid in solution by supplying it with alkalies or salicylates beforehand, the uric acid or urates taken by the mouth pass almost at once through the blood into the urine, and by repeating and varying the dose, it (0 s i • • //'* Z^* 13* >^* 15" I6f ilOO taoo 5 fc 1 70 eo g s IS 5 *30 4-S5 ?>-- / < \ ACIDI\ "•^ I ^^ I \ IV AT. -m\, \ URIC AC .os'\ s. 1700 so IZ 420 \ '> \ \ '^ UR ■A\ \ ISOO *0 II 3SS \ \ \ ^/ A \ // \ V 1300 1100 30 20 10 a 3Sa SIS \/ / \ \ ft: 5 5 \ « 4 1 1 ^ «0 s Pig. 25. — Effect on the Excretion of Uric Acid of Soup, Pish and Meat. is easy to show that the excretion is proportional to the amount ingested. Thus in the Journal of Physiology (vol. xv., p. 167) to which I must refer for farther figures and details, I have shown that, while a given dose of salicylate of soda produced in five days, under ordinary circumstances, an excretion of uric acid which exceeded the relation to urea of 1 to 33 by llj grs., a similar course of salicylate taken on other five days along with 12 grs. of uric acid produced an excretion of 2/01 S^^- above the relation to urea of 1 — 33. 110 UEIO ACID — CHAPTER III It does not seem to me that there is any reason to doubt that the extra 9 grs. excreted on the latter occasion came from the quantity ingested, and that if the experiment had been continued a day or two longer the whole of the 12 grs. would have been excreted. Fig. 25 shows the effect on the excretion of Tiric acid of two dinners consisting of soup, fish and meat, taken on two consecutive days. On the 11th uric acid exceeded the relation to urea of 1 — 35 by about 1 gr. ; on the 12th, the day of the first dinner, it exceeded it by 2i grs. ; on the 13th, the day of the second dinner, by 4| grs. ; on the 14th by 4 grs. ; on the 15th by 2| grs. ; and on the 16th, the last day of the figure, by li grs. It appears then, that the effect of these two dinners was to intro- duce into the body and pass through the blood some 15 grs. of uric acid, or if we take ofE 1 gr. for each of the last five days in the figure on the supposition that as uric acid was above urea by 1 gr. on the 11th, it might have exceeded urea by this amoimt on the following days even if no soup, fish or meat had been taken, we still get 10 grs. as the introduction of the two dinners, or 5 grs. for each. In a paper in the British Medical Journal, 1894, vol. ii., on the " Direct Introduction of Uric Acid into the Body, its Bearing on the Prevention and Treatment of Disease," I have pointed out that, judging from the quantities of various substances taken, and the quantities of uric acid or xanthins they contain, a man may easily introduce nearly 2 grs. of uric acid with an ordinary dinner, and as we shall see further in chapter xvii., the percentages of uric acid from which this is calculated are probably decidedly under the truth, so that the introduction of 4-5 grs. with a flesheater's dinner Ls by no means extraordinary. It appears, then, from this figure that uric acid passed almost directly into the blood and urine, and that there was no first stage of stimulation due to the blood being cleared of uric acid. And this illustrates a very important point, namely, that uric acid will produce one or other of two opposice effects, according as it is introduced with conditions which are favourable to its solubility in the blood, or the reverse. Now in fig. 25 tlie conditions were distinctly favourable to its solubility in the blood, because as I generally take neither meat nor wine the alkalinity of my blood rules high, and uric acid was already in some excess in that fluid on the day before the first dinner. The first dinner, therefore, failed to stimulate, it failed to overcome the depressing effect of the uric acid abeady in the blood, it failed, there- fore, to raise either urea or acidity, and the uric acid it introduced FOEMATION AND EXCBBTION OF UEIC ACID 111 passed almost at once into the blood and added its depressing effects on circulation, nutrition and metabolism to those of the uric acid previously there. On the 13th almost the same thing occurred ; there was again a failure of stimulation and a further fall of urea, and again the uric acid introduced passed abnost at once into the blood and added to the general depression. The rise of acidity in this figure is very slight, and was very probably due to the rise of urinary acidity which excess of uric acid produces (see p. 40 and also chapter vii.), rather than to any real fall in the alkalinity of the blood. But those who eat meat two or three times a day must not expect that they will be able to introduce uric acid into their blood in the direct manner shown in the figure ; with higher acidity which they are certain to have so long as they keep well, the uric acid introduced will pass much more slowly into solution and be much more gradually excreted ; a dinner of this kind will act as a stimulant, they wiU feel better and stronger and happier for it, and nothing will persuade them that they are doing themselves any harm by taking it. And so long as they keep well, they have decidedly the best of it, and can point triamphantly to very good results ; it is true that they are continually introducing considerable quantities of uric acid, which remain in the body and may produce now and again more or less decided reminders of their presence in the shape of gout or rheumatism ; but so long as the blood is kept clear or moderately clear of uric acid by continued stimulation, there is no great harm done, and they may suffer neither from gout on the one hand nor high blood pressure on the other. Unfortunately, however, in the natural course of events, as old age comes on, nutrition begins to fail, and further stimulation becomes more and more difficult, then alcohol, morphine, and cocaine are perhaps called in one after another to help to keep the fires going brightly ; at first they succeed ; later, like everything else, and even in large doses, they fail, and then comes the final disaster. Urea and acidity fall down and down for the last time, and with this the long pent up store of urates breaks its dams and rushes into the circulation with an overwhelming flood. Circulation, nutrition, and function are soon rendered nearly impossible, and the physio- logical wreck has a chance of destruction by some of the most terrible efiects of the most severe coUaemia, as we shall see in the following chapters. If it escapes the ever threatening rocks of cerebral haemorrhage, it may drift onward through some years of the discom- fort and misery of high blood-pressure and chronic Bright's disease, to end in uraemia on the one hand or heart failure on the other. 112 UKIO ACID — CHAPTEK III Long before this stage has been reached, however, it will be quite obvious to onlookers that the meat- eater has got far the worst of the » argument, and will presently have to pay a terrible price for his stimulants. Figs. 25 and 26 show what his meat does for him, and how it does it. In the chapters that foUow we shall see, how uric acid in the blood blocks the capillaries, overworks the heart, prevents circulation, nutrition and combustion, and produces anaemia, and how the effect (J \ I 5 I 1 1 4* s'!' el- r!" a'!' .^^ 1700 so n 336 ^V^ ^, AC 101 '/ { \ S^ ^ 5^,_^^ ka: SX \ i ^ ISOO 1300 1100 to 30 2ar II 10 3 3C3 330 2S7 \ N \ ■<^^ y ^ / \ / \ Ul .A^ \^ URIt Acia N. <■ /\, ^. V s s. « ■>< \, s \ V V" 5 •5 1 (4 1 5 1 Fig. 26. — Effect on the Excbetion of Ukic Acid of Liebig's Extbact OF Meat. of such meals as those recorded in fig. 25 can be observed by anyone who has the means of estimating either the quality of the blood, or its rate of circulation through the capillaries, or the effect of the capillary circulation on the blood pressure. Fig. 26 shows in the same way as the previous figures the effects of taking meat extracts. On the 4th uric acid is below urea, urinary water is consequently high, and acidity stands about 55 grs. ; on the 5th 3 drachms of Liebig's Extract are taken in the course of the FOEMATION AND EXCRETION OF UEIC ACID 113 day, and the effect is that urea remains steady, uric acid rises quickly and decidedly, and water comes down equally decidedly, while acidity rises a little above 60 grs. Here, again, just as in fig.' 25, the rise of acidity wasjprobably due to the increased quantity of uric acid in the urine, and does not show any diminished alkalinity of the blood, or the uric acid would not have been so freelv excreted. li • 12 3 4 ^ s 1 ■ g 1 S 3 ^ 1 1 1 mo eo a 423 1700 so 12 336 ISOO .40 il 3a laao 30 10 330 1100 20 9 237 300 10 a 264- 700 7 231 ^ -> f' ^j, •wirr «„« ! V WATSf, K ,' & 1 RICAC a I' v« ! \ / \ . \ 1 ^ — " i REA '~~ ^. 1 * 5 S 1 ^ s Fig. 27. — Effect on the Excretion of Ueic Acid op Swallowing Hypoxanthinb. The rest of the figure merely shows that uric acid comes gradu- ally down, there being no further introduction, that acidity falls more or less in parallel with it, and that urea falls also, part of its fall being, no doubt, due to the diminished metabolism which excess of uric acid in the blood produces (see chapter viii.), and last, but not least, the water falls and remains low the whole time the uric acid is high, thus again proving in the most absolute manner the obstruction of the capillaries of the kidney by the excess of uric acid in the blood. 114 UEIC ACID — CHAPTBE III Will anyone, after looking at ttese figures, venture to tell me that I cannot control from hour to hour or day to day the excretion of water from the kidney, or for that matter the circulation, function and nutrition of every organ and tissue of the body ? We shall see further on that what controls the flow of water from the kidney controls also its exhalation from the lungs, and controls also digestion and all digestive secretions. Fig. 27 shows the effect of 8 grs. of hypoxanthine taken on day 2, /*(*. ZTT" 2«r» 231' SO'* 31" 1^ 16 IS / \ ' k ^ 70 14- 13 \ 4^5 ^1/ VCA to N" r£4 ACIi ITY •,; /•^ V ^ '\F tJOQ ISlfO SO 11 *20 vJ i. ''^', ATSi ,/ '\ / 1100 1 30 I s 10 1 360 1 * / V % x Ts^e? 1 1 1 *9 § S ? <0 Pig. 28. — Effect on the Excbetion of Ueic Acid of Swallowing Xakthihb. and it appears to increase very markedly the excretion of uric acid which rises on days 2 and 3 in spite of a slight rise of acidity, and falls again on day 4 in spite of a fall of acidity. Note also the inverse relation of the urinary water which falls on days 2 and 3 with high uric acid, and rises again on day 4 as uric acid comes down. What I have just said about the previous figures will apply almost word for word here ; the hypoxanthine does not appear to increase the urea, and the small rise of acidity which we see is here again probably due merely to the excess of uric acid in the urine, and not to any change in the reaction of the blood. FOEMATION AND EXCBBTION OF URIC ACID 115 It thus appears probable that the metabolism of the human hcdj makes short work of the slight chemical difierences between members of the xanthine group, and passes the greater part of them through the blood and into the urine as uric acid.* And one very important consideration forces itself in here, though I shall have to return to it again later on, namely, that if members of the xanthine group are thus converted into and must practically be reckoned as uric acid. 1. 1 2 3 4 S S 5 ? s § 1 ? I s ? s s ZWO 7(7 « ISOff SO 13 4ZS ma ii/ u JS£ 1500 40 II 3S3 1300 30 10 330 1100 ZO $ Z37 300 lu a Z£l 700 Q t 2SI ?" "^ h ^ ; / f \>. ■iDirr - ^ V ir- \ '■^' _-(,■■ ku •IC AC ^ ^^ ^ \ s i 5 * IS WATEl Pig. 29. — Effect on the Excbetion of Ubic Acid of Swallowing. CiTEATE OF Caffeine. the estimation of the uric acid present in any food substance gives only an imperfect record of the amount of uric acid it may introduce into the body ; for the xanthine and hypoxanthine remain unestimated to a considerable extent. The table, therefore, which I give of the amount of uric acid found in various food substances must be taken only as showing a part of the uric acid which these substances may See also Lea, " Chemical Basis of the Animal Body," p. 182. 116 UEIC ACID — CHAPTER III introduce into the body, and important substances should be put to the more valuable physiological test of taking known quantities by the mouth, and estimating the increased excretion of uric acid produced as in the figures I am now describing (see chapters i. and xvii.). With' regard to xanthine, I note that Bunge says (in " Physio- logical andPathological Chemistry," Wooldridge's Translation, 1890, << i % .1 \ 2 ISOO eo a 42a 1700 50 12 3S6 ISOO w 11' b63 aoo 30 10 330 1100 20 3 237 Fig. 30. — Effect on the Exceetion of Ubic Acid of SwAiiLOwiNO A Sheep's Thyroid. p. 348), " xanthine occurs in too large quantity in the tissues and too small quantity in the urine to be eliminated unchanged," and fig. 28 shows that it is changed into uric acid. Acidity is below 60 grs. a day, and the conditions are favourable to the solubility of uric acid in the blood, it is consequently nearly half a grai u above urea on the 27th. On the 28th 6 grs. of xanthine are taken and uric acid rises sharply to about 4 grs. above urea and comes down rapidly on the 29th, and more gradually on the following FOKMATION AND EXOBBTION OF URIC ACID 117 days. Urea falls from the beginning to the end of the figure very much as it does in fig. 26, and probably for the same reasons. Fig. 29 shows the effect of a dose of 10 grs. of citrate of cafieine takdn on day 2, namely, a marked and immediate rise in the excre- tion of uric acid, which remains high above urea on all subsequent days of the figure. On day 1 uric acid exceeds urea by about 1| grs. ; on day 2 it exceeds it by more than i grs. ; on day 3 by more than 5 ; on day i by 3 grs., and so on. Here then we have another member of the xanthine group (for cafieine is, chemically, trimethyl xanthine — Lea, prev. ref., p. 175) • which taken by the mouth markedly increases the excretion of uric acid, and the amount of that substance passing through the blood. And this result is, I believe, absolutely constant, for as will appear presently I have been able, by administering cafieine, to produce pathological changes in the blood similar to those produced by uric acid when taken in other forms. An important corollary follows from this figare also, namely, that all vegatable alkaloids similar to cafiein, which are chemically ureids or xanthines, must be regarded as possible introducers of uric acid into the body, and I have already mentioned this in chapter ii. in reference to the effect of quinine and strychnia. Fig. 30 shows the effect of eating a sheep's thyroid gland, and this also apparently produces on the second and third days after its ingestion some plus excretion of uric acid. The first effect of taking the thyroid was a very marked diuresis ; the first dose of the gland was taken at 1.30 p.m., and it did not greatly affect the urine of the day, which was 44 cc. per hour, but in the night it ran up to 138 cc. per hour. Note that with this big diuresis there was a rise of acidity and urea, and that the uric acid exceeded the urea by almost nothing, that is to say, there was no uric acid passing through the blood. Here we have shown in a very marked manner the primary stimu- lating effect of thyroid gland or extract ; the secondary depressing effect was evident on day 4, and would have been still more evident on day 5, but for the drugs which had to be taken to make it possible for me to work. Bear in mind, also, that acids, mercury, iodides, iron, lead, and a host of other drugs which clear uric acid out of the blood, will produce a similar rise of urea and a similar diuresis. The sequence of causation in the case of this figure was probably somewhat as follows : eating the thyroid gland introduced certain 118 DBIC AOID — CHAPTER III nitrogenous substances and certain acids or acid salts ; tliese pro- duced a rise of uiea and acidity ; this latter cleared uric acid out of the blood and freed the capillaries. With this freedom of capillaries went a general quickening of metabolism, and a further rise of urea and acidity, and the relaxation of the kidney capillaries allowed of a profuse diuresis because the water had been scanty on day 1, and fluid had been accumulating in the body. On day 3 uric acid exceeded urea by J gr., and on day 4 by more than 4 grs., and it would no doubt also have exceeded it on day 5, but on the morning of this day there was considerable headache, and drugs which brought down the uric acid had to be taken to cure it. Note the large excretion of water on day 2 when uric acid is close to urea, and none passed through the blood, and its steady fall on subsequent days when uric acid rose, and also the extremely scanty water in the day hours of day 5, when there was a headache, and no doubt an excess of uric acid in the blood, though the mixius excre- tion produced by the drugs brought down the level for the whole twenty-four hours : but here the water tells us in which hours the uric acid was scanty and in which profuse. I notice also in a paper in the British Medical Journal (1897, vol. i., p. 196) it is stated that the most active constituent of thyroid gland is a compound of iodine (iodo-thyrin or thyro-iodin) contained in the thyroid material, and this is most interesting, as I have just mentioned the iodides a few lines above as resembling it in their action. If this is so then the action of thyroid gland may be retention of uric acid, as shown in day 2 of fig. 30, followed by a rebound and plus excretion on days 3, 4 and 5, which exactly resembles the action of any one of the group of drugs mentioned. But I should also have very little doubt that at least part of its efiects are due to the nitrogenous extractives, which probably directly increased the excretion of uric acid on days 3, 4 and 5, and in which it is well known that these glands are rich (see Professor Foster's " Text-book of Physiology," ed. v., p. 762). And as we shall see presently in patients treated with these glands or their extracts, we soon get strong symptomatic evidence of the passage of an, excess of uric acid through the blood, exactly as we do when uric acid is taken in other forms (see chap, xii.) ; and in my experience after patients have been taking thyroid for a long time, they often suffer from periods of depression both of mind and body, these being, no doubt, contem- poraneous with the passage through the blood of some of the excess of uric acid they have been introducing, but partly also due to a rebound after the action of the above iodine compound. We shall FOBMATION AND BXCEBTION OF URIC ACID 119 also see that the administration of thyroid extract affects the com- position of the blood and precipitates attacks of angina or epilepsy, just as in fig. 30 it produced uric acid headache (migraine) in myself, and that it acts in all these cases to a considerable extent in the same way as uric acid or any member of the xanthine group would do. For a case in which apathy followed the taking of thyro-iodin, see British Medical Journal, 1900, vol. ii., p. 582. I may mention also here that others have noted a large excretion of uric acid in the urine dtuing thyroid treatment, and have also seen some tendency to syncope while taldng it,* which facts bear on what I shall have to say presently on this subject in chapter viii. Mordhorst also refers, in his paper in Zeitsch. fiir Klin. Med., to be mentioned in chapter v., to the fact that eating calf's thymus greatly increases the excretion of uric acid both in the gouty and in the healthy, and thymus is very similar both to the thyroid and to the spleen as regards the extractives it contains. I may also mention that Dr. W. J. S. Jerome has, like the above- named experimenter, found an increased excretion of uric acid as the result of thymus feeding, and concludes that at least some part of the daily output of uric acid is due to the alloxur-holding bodies (i.e., xanthines) in the food (Journal of Physiology, vol. xxii., p. 146). The same observer (same Journal, vol. xxv., p. 98) also found a distinct increase in the output of uric acid from feeding on Liebig's Extract, thus confirming my previous results. He also considers that Minkowskie has conclusively established that one at least of the alloxur bases (viz., Hypoxanthine) can yield uric acid in both dogs and men, which again confirms my results. He also says that nuclein from spleen and yeast increases uric acid ; butj would remark that both spleen and yeast contain xanthine (and as regards the latter, see Watt's " Dictionaryj'of Chemistry," 1892, Art. Xanthine). Dr. Jerome also quotes from Kossel the quantity of alloxur bases found in fresh beef ; of which, calculated as uric acid, the percentage is •0841, or about 5'7 grs. to the pound, while the largest quantity I have found in beef is about 7'0 grs. per pound (see chap. xvii.). A point of interest in this connection is mentioned in a review of the fourth edition of this book in the Edinburgh Medical Journal, August, 1898, p. 173, namely, that " milk and cheese contain much nuclein." And if this is so it must be pretty clear by this time that nuclein * Lancet, 1896, vol. i., p. 144G. 120 URIC ACID — CHAPTBE III is not a source of uric acid, for I can take every day for months and years as much mUk and cheese as will produce from 300 to 400 grs. of urea without getting any excess of aric acid or the troubles of cir- culation and nutrition it produces ; while the same urea value in flesh, fish, or egg would produce all those troubles in a few days, together with a great increase in the excretion of uric acid. Again, Messrs. Hopkins and Hope point out {Journal of Physi- ology, vol. xxiii., p. 283) that thymus extract when freed from nuclein causes a rise in the excretion of uric acid : probably it was not also freed from the alloxur bases. On the other hand, milk and cheese contain much nuclein, but being free from alloxur bases do not increase the excretion of uric acid (see also my remarks in the Journal of Physiology, vol. xxiv., p. 156). The conclusion seems obvious, as I have already suggested, that nuclein itself does not give rise to uric acid when ingested, while the xanthine which is associated with it in certain tissues does so. Giajinis (as mentioned in the Epitome of the British Medical Journal, September 10, 1898), found that liver increased the uric acid more than a corresponding qiiantity of muscle tissue, which, of course, is just what we should expect because, as I have pointed out in the preceding pages, it contains considerably more uric acid or xanthine. Several of the drugs of which I have been speaking, and the effects of which I have attributed to their action on uric acid, are supposed to have some direct action on the heart or vessels, or both, or to influence certain centres in the brain and cord. But a large part of this is admittedly mere hypothesis, and we must beware of taking it as representing a proved fact. I by no means wish to assert that they have not these actions on the vessels and nerve centres, my facts will not carry me nearly so far as that, and I have no intention of going beyond them, even by the fraction of an inch. But the fact that we do not know everything is no reason why we should not observe carefully and argue logically as to the results of our observations. To say, for instance, that small doses of opium in producing mental stimulation and well-being act directly on the vessels or nerve tissues is, I think, to talk nonsense and make two causes for one effect when one will suffice. Opium, as I have shown, clears the blood of uric acid, thus freeing the capillaries all over the body, and altering the circulation from the crown of the head to the sole of the foot. FOBMATION AND EXCEETION OF UKIC ACID 121 Tlie altered cerebral function is either due to the altered circula- tion or it is not. If it is not, then why does every one of the long list of drugs mentioned above as clearing the blood of uric acid, and lowering the blood pressure, produce the same or similar effects on the cerebral function ? Do such drugs as copper, zinc, mercury, sUver, lithia, acids and opium all affect the vessels or the nerve substance in the same way, or is their action due to that which is alone common to them all — their effect on the solubility of uric acid in the blood, and so on the circulation ? When any of these drugs produce results which differ absolutely from those produced by all the drugs .which have a common action with them on uric acid, then some other explanation of their action must be found, but I am at present only concerned with their common action. As regards opium, I have shown that if it is given when there is diarrhoea, or when the alkalinity of the blood is -very high, it will have difficulty in reducing the alkalinity of the blood and affecting the solubility of uric acid, and under these circumstances its usual effects upon cerebral function, as also upon muscle function, and the fatigue it gives rise to, will be remarkable by their more or less complete absence ; but when opium has thus failed, a drug such as mercury, which clears the blood of uric acid by the direct formation of an insoluble compound with it, and is therefore independent of alkaKnity and acidity, will succeed (see Fatigue, chap. viii.). All the drugs just mentioned, and many more that clear the blood of uric acid and alter the circulation of the whole body, afiect not the cerebral function merely but the action of every gland and tissue in the body, thus increasing the formation and excretion of urea ; but if their action on uric acid is prevented, their other effects fail to appear. Thus sahcylates cause diuresis, but not while uric acid is high, only when it is coming down on the second or third day of their action ; while uiic acid is high urinary water is scanty. On the other hand, drugs which clear the blood of uric acid at once, produce diuresis in a few hours. It is again, I think, a*bsurd to say that any of the drugs I have spoken of produce diuresis by acting on the renal epithelium. If it is said that they act on the renal vessels, and not only on the renal vessels, but on all the other vessels of the body at the same time, I should offer no objection. -, « But to sav that the substances belonging to this large group (only 122 UEIC ACID — CHAPTBE III a few of which I have mentioned and given figures of) which have the power of diminishing the excretion of uric acid in the urine and clear- ing the blood of it, produce diuresis by acting on the renal epithelium, mental brilliancy and well-being by acting on the nerve centres, increased flow both of saliva by acting on the salivary epithelium, and of other excretions by acting on the cells of the stomach, intestines, liver and skin, increase of urea by acting on the muscle fibre, and increase of expired water by acting on the pulmonary epithelium, and to ignore while we say this that the whole of these substances free the capillaries, lower the blood pressure, and so afEect the circula- tion from end to end of the body and through all its tissues, is to talk the most absolute nonsense, to make the straight crooked, and the simple complex. In the case of any single one of these substances which has the power of diminishing the excretion of uric acid and as a result of this (for it occurs constantly in physiology) increasing the excretion of water, it is easy to show that it increases not only the urine, but also the sweat, saliva, and all digestive secretions and functions, increases the water given off from the lungs, raises the temperature of the skin and extremities, and increases the formation of urea, thus dominating the phenomena of fatigue ; and that all this is contemporaneous with a general freeing of capillaries and a fall of blood pressure, and that everything that produces these two last will also produce all the other effects. In fig. 23 we see the rise of water and also the rise of urea, and similarly in fig. 22 there is a rise of urea as well as a rise of water when uric acid is brought down by iodides ; a similar rise of water, contemporaneous with the clearance of the blood of uric acid and the rapid improvement of the blood decimal, is seen in the case- of the patient who took iodide of mercury for chlorosis (fig. 57). We shall see also in many other places that this same iodide of mercury is perhaps the most powerful drug we have, and the one on which we can most depend to clear the blood of uric acid, and counteract most of its effects in the causation of disease. But even this drug will fail, and may fail ignominiously, if it causes salivation and gastro-intestinal irritation and diarrhoea, for these troubles always depress urea and acidity, and increase the alkalinity of the blood, and they will also diminish the absorption of the iodide, and under these circumstances the coUaemia and its effects will continue in spite of the drug, and you must now get the stomach and intestines nto proper order before you will have any power to diminish the excretion of uric acid with drugs. FOEMA.TION AND EXCRETION OF URIC ACID 123 The primary stimulant action of uric acid and its congeners being thus in evidence, and it being also clearly proved that this is due to their interfering for a time with the solubility of uric acid in the blood, we are in a position to explain completely the primary stimulating effects of tea, coffee, cocoa, guarana, beef-tea, meat extracts, soups and thyroid extract, also the use of such things as pigeon's dung in ancient prescriptions, and a draught of child's urine as a stimulant by some nations at the present day. It is a point of no little interest that these stimulating efiects are in all cases due to one and the same chemical substance and are produced in exactly the same way, and that this is also followed later on by depression, which requires further stimulation to remove it. I am indebted to my friend, Mr. H. B. Meakin, formerly house surgeon and house physician at the Metropolitan Hospital, for the interesting information that in Morocco the popular remedy for severe fright in a child is a drink of urine, preferably that of a virgin. I will merely remark that if by a virgin is meant a young girl recently arrived at puberty, her urine would probably contain more uric acid then than at any other period of her hfe (see fig. 59). I am also indebted to Dr. Eushton Parker for a reference to a paper by Dr. R. Neale in " Food and Sanitation," June, 1894, p. 195, in which he says, " In South America the urine of little boys is spoken of highly as a stimulant in malignant small-pox. " Among the Chinese and Malays of Batavia urine is very freely used. One of the worst cases of epistaxis ceased after a pint of fresh urine was drunk, although it had for 36 hours or more resisted every form of European medicine. This was by no means an unusual result of the use of urine, as I was told by many of the natives. As a stimu- lant and general pick-up I have often seen a glass of child's or young girl's urine tossed off with great gusto, and apparent benefit. Dr. Hastings' report of the value of the excreta of reptiles in 1862, in the treatment of phthisis, will also be fresh in the recollection of the older members of the profession." As regards the epistaxis, the urine had no doubt exactly the same eifect as the iodide of mercury, of the value of which in other forms of hsemorrhage I shall have to speak presently, i.e., it cleared the blood of uric acid, and lowered the blood pressure ; and reptiles' excreta in phthisis act in the same way as meat diet and other things of which I shall have to speak in chapter ix. I would also remark in passing, that fright is a powerful depressant, and generally upsets digestion and metabolism, producing colleemia (hence its common connection with the onset of chorea, see chapter 124 UKIC ACID — CHAPTEE III xvi.), and, a draught of urine or a dose of uric acid would, as some of the preceding figures show, be a very good way of clearing the blood of uric acid and putting an end to the depressing efEects of fright ; alnaost any of the above-mentioned stimulants in daily use would do as well, but possibly in Morocco urine is more easy to obtain than most of the others. I have also heard from my friend, Mr. G. S. Haynes, of an inter- esting case which he saw while resident at Addenbrooke's Hospital, Cambridge. It was that of a blacksmith of middle age, sufEering from aneurism of the aorta, who gave a history of having sufiered from severe re- current sore throat, " which frequently went on to quinsy." As this occurred verjr frequently, he was prepared to do anything to be free from it, and he was advised by a friend to apply to a gipsy who said she knew a certain cure. On asking her she directed him " to make his own water and drink it." The blacksmith did this, and both drank his urine and gargled his throat with it with such benefit that he was always able to check the disease at its onset on future occasions. The quantity of urine taken was two or three tumblers. This is also very interesting, for the relation of recurrent tonsiHitis to fatigue in gouty and rheumatic subjects is v/ell known, and fatigue is accompanied by.coUsemia, and the draught of urine would clear up this coUeemia, just as do the iron, mercury, &c., we more commonly use for this trouble. Hence, prob- ably, the value of feeding up, beef-tea and meat extracts, &c., in such cases. These figures (24 to 30), then, practically show : — that uric acid and many substances chemically related to it, as the xanthines, alkaloids and ptomaines, when taken by the mouth, whether in food or as an ad- dition to food, pass into the blood, and, when the conditions in that fluid are favourable to their solubility, remain there till they are excreted in the urine ; that they are not to any appreciable extent converted (as was supposed) into urea ; that the rise of urea which these sub- stances produce is secondary to the rise of acidity, which they also produce ; and that other acids which introduce no nitrogen into the body produce a similar rise in the excretion of urea. From these facts I think we may draw a few general conclusions. First, that the amount of uric acid in the blood of man, and pro- bably of animals also, is not a mere matter of chance, but is always subject to certain definite rules, which to my mind can be summed up by saying that the amount of uric acid in the blood is propor- tional to the solvent power of that fluid for uric acid and its salts. FOEMA.TION AND EXCRETION OP UEIC ACID 125 Increase of solvent power means increase of urate in the blood, so long as .there is urate anywhere in the body to be dissolved ; and by influencing the solvent power of the blood we can influence within limits the amount of uric acid it contains ; we can also influence it indirectly by the amount of iiric acid we introduce ready formed in the food. Second, excess of uric acid in the blood means contemporaneous excess of uric acid over urea in the urine : but, since the urine in the bladder may be a mixture of urines excreted under several difierent conditions of blood, it must not be expected that the amount in the two fluids wiU correspond too closely. , This rule probably holds in all cases in physiology, but in path- ology there is at least one well-marked exception to it, namely, nephritis ; for in this condition the alkalinity of the kidney is prob- ably diminished by the irritative processes going on in it, so that there may be (and according to Professor v. Jaksch there is) excess of uric acid in the blood, and yet it may be unable to pass the kidney into the urine. Hence we may get in nephritis chronic retention of urates and chronic coUsemia (of which the signs are well-marked) without excess of urates in the urine. Probably the kidney is one of the places in which acids at once cause a retention of uric acid, and we perhaps see an instance of this in the relatively large amount of uric acid in the kidneys of the dog to which I administered hyposulphite of soda (p. 83), the small amounts in its blood and urine being results of this retention. Third, the quantity of urate in the various organs and tissues seems to stand in a certain order of proportion : thus, the Hver and spleen have most, the kidneys decidedly less, and the muscles least ; the quantity in the blood varies considerably, but it always contains less, often much less, than the liver or spleen from the same body. The quantities found after death in the blood again bear fairly definite relations to certain diseases ; in pneumonia cases there is almost sure to be a large quantity ; but in meningitis and other cases in whicd the temperature is high, and rising at death, there will be very little ; again, in death from chronic wasting disease there will be a good deal, especially if there are urate deposits in the joints. In the case in which the kidney contained so-called uric acid infarcts the temperature was high and rising at death, which was due to marasmus ; we should, therefore, expect very little urate in the blood, because it had been driven out of it, and the infarcts in the kidney probably show us one of the places into which it had been driven, there being, in fact, a gout of the kidney, this possibly being secondary to the irritation of previous coUsemia. 126 UiJIC ACID — CHAPTER III It thus seems to me to be practically certain that, wten uric acid is found in excess in the blood after death, it was in excess in that fluid at the time of death, and was passing from it in excess in the urine ; and the excess in both fluids is due to the action of the same causes which determine excess in them during life. I have shown that I can alter the amount of uric acid in the urine at any time, and that in addition to the above argument I have good clinical reasons for believing that I alter at the same time the amount in the blood ; that when I increase the amount in the blood by giving an alkali, I at once bring about obstruction of the capillaries through- out the body, thus raising the blood pressure and slowing the heart, and causing deficient circulation in numerous organs, the efEect of which is soon visible in cold surface and extremities, mental depres- sion or headache, and scanty urine containing a relative excess of uric acid. If I now reverse the process by giving an acid I at once free all the capillaries, and the uric acid is driven out of the blood into the liver, spleen, joints, &c., and if much of it is sent into the latter it generally renders its presence clinically evident by a certain amount of shooting and pricking pain, or more severe irritation up to distinct arthritis ; the free capillaries allow a lowering of the blood pressure and the heart quickens its pace, the surface and extremities become warm, the mind is clear and tranquil, the urine increases in quantity and shows diminished uric acid. The alterations in the amount of uric acid in the urine so produced are alterations of excretion merely, and the quantity to be found in the blood at any time depends on its solvent power for uric acid, the amount daily introduced in the food, and. the amount previously stored in the liver, spleen, joints and other tissues on which the solvent can act. When the alkaUnity of the blood, (i.e. its solvent power for uric acid) is reduced it contains little or none ; but when its alkalinity is increased it may contain a very large quantity. As I have previously pointed out, all fluctuations in excretion taken over a long period of time practically balance each other, giving a result near what I believe to represent the real formation of uric acid, viz., 1 of uric acid to 30 or 35 of urea. Though the large excretion of uric acid in splenic leucocythsemia, for instance, looks for a time like excessive formation, it is probably merely the passage out of the body of large amounts of uric acid, which were retained in the early febrile stages of the disease. Thus in a case of this kind which I was able to examine after death FORMATION AND BXCEETION OF UEIC ACID 127 I found in the blood '06 per cent., a very large liver and spleen contained between them 100 grs. of it, there were urate calculi in one kidney and erosion in the great toe-joint, but no deposits of urates there (see " St. Bartholomew's Hospital Post-mortem Book," case of N. T., age 32, April 25, 1892). Here the urates were being dissolved and passed out, and some of them unfortunately got deposited in the kidney on the way, and probably the liver and spleen contained much more uric acid earlier in the disease ; for in these cases we know that there are often intercurrent pyrexial attacks during which the spleen enlarges (see Lancet, vol. i., 1892, p. 965), and during which, I would add, the store of urates in the liver, spleen and joints, and the body generally is increased. So that while I do not deny that a process of which I have no knowledge, viz., excessive formation of uric acid, may nevertheless occur (in excess that is of the usual relation to urea), I am in a position to assert that I beHeve all my results, as well as those of Professor v. Jaksch, can be explained by fluctuations in excretion, aided, as is generally the case, by more or less constant introduction, and further, that all the results which can be produced by drugs are in favour of this explanation, but are quite inexphcable on any theory of excessive formation or deficient oxidation. If, for instance, the plus excretion of uric acid under alkalies or salicylates (figs. 6 and 8) is due to a plus formation, why does it, except under pathological conditions, not continue for more than two or three days ? And even in pathological conditions it does not continue long, for in the case of splenic leucocythaemia, of which I give notes in chapter xii., a course of salicylate of soda sensibly diminished the .excretion ; while at the first administration of the drug I got excre- tions of 1 of uric acid for 12 of urea, it gradually diminished as the drug was continued down to 1 to 24 or less ; in other words, the stores of urate in the body were slowly being reduced. The facts pointed out above, namely, that the liver, spleen, and joints contain large amounts of uric acid, are in accord with Sir A. Garrod's theory, and with my explanation of my results ; and in accordance with these the amount in all these organs and tissues can be increased or diminished at pleasure. That this explanation satisfactorily accounts on the one hand for the well-known physiological fluctuations in the excretion of uric acid, and on the other for the previously recorded relations of a whole series of diseases, as, for instance, the alternation of gouty arthritis (i.e., retention of uric acid going on in the joints and its absence from the blood), with such diseases as headache, epilepsy, mental depres- sion, and glycosuria, with excess of uric acid in- the blood and urine. 128 UEIC ACID — CHAPTEE III The arthritis corresponds with free capillaries and low tension pulse due to absence of uric acid from the blood, and the latter diseases correspond with obstructed capillaries and high tension pulse due to the excess of uric acid in the blood. In all these cases the excretion of uric acid in the urine cor- responds with the amount in the blood, and the facts about these diseases have been recorded by others who had no knowledge of their real relation to uric acid. It seems to me that it is impossible to explain these facts either on the theory of excessive formation or on that of deficient oxida- tion, while Sir A. Garrod's dictum in the case of lead, " the blood becomes loaded with uric acid, not from its increased formation but from its imperfect excretion," serves, with the help of our more recent knowledge about introduction, to explain the whole situation. It is now, I hope, obvious that we can not only explain aU the physiological fluctuations in the excretion of urates and most of the pathological alterations as well ; but that in accordance with my law of solubilities we can imitate Nature and demonstrate the effects of collsemia on the function, nutrition, and structure of the tissues of the human body to any required extent ; and where the urates already in the body are insufficient for our purpose, we can increase them by the simple process of taking them by the mouth in one form or another (see also chapter xii.). It is, I know, believed by some of my fellow-workers that Horbaczewski has demonstrated that uric acid is formed from the nuclein of cells, especially that of white blood cells. And supposing for a moment that we take this as a proved fact, I will merely point out that it afiects in no way either the facts I am now bringing forward or the conclusions I found upon them. For if it be true that the nuclein of certain cells is converted into uric acid, the rest of the cell may be similarly converted into urea, and the relative formation of these two substances may not be one bit affected thereby. This would be quite on all fours with the suggestion of Sir A. Garrod previously referred to, that certain cells in the kidney form urea, and certain other cells less in number form uric acid. Horbaczewski's observations that feeding on nuclein increases the excretion of uric acid is probably quite correct, but to my mind this by no means amounts to proof that there is any new formation of uric acid ; for in the first place is it quite certain that the nuclein or the spleen pulp from which it is obtained does not contain xanthine, hypo- xanthine, &c., which is merely introduced into the body as the previous POBMATION AND EXCRETION OF UEIC ACID 129 figures show that it can be, and in the second place, is it not a fact that spleen pulp and nuclein contain phosphates,, and that these phosphates may increase the excretion of uric acid by acting as sol- vents (see fig. 7) ? If this is the case, the administration of nuclein after a course of salicylates would produce less increase in the excretion of uric acid than the same quantity of nuclein administered before it. But as I have said, HorbaczewsH's conclusions affect me but little ; if they prove to be true we shall merely have to add nuclein on to the list of substances above given, which are either uric acid or so closely related to it that human physiology makes short work of the small difierence between them. It really matters nothing to me whether uric acid is present in animal tissues as nuclein, as xanthine, hypoxanthine, or as urates visible to the naked eye, I am only concerned with the fact that when taken as food they produce disease by introducing this uric acid into the body of man ; and this is the answer to the question which originated my research. If it was true that uric acid when swallowed was at once converted into urea, as used to be supposed, then Horbaczewski's conclusions would stand on much stronger ground, for any increase of uric acid, he observes, must be due to new formation ; but my results show that uric acid in foods is not converted into urea, on the contrary, it is absorbed unchanged into the blood, and passes gradually into the urine in quantity directly proportional to the amount introduced. In reference to my question as to the connection between the ingestion of animal tissues, their products, uric acid in other forms, and the causation of the uric acid headache (migraine), my researches return me this answer, that these substances not only introduce a considerable quantity of uric acid into the body, but this uric acid in process of introduction interferes with the solubility in the blood of uric acid previously formed in, or introduced into, the body ; and in both ways these substances tend to form a store of uric acid in certain organs and tissues of the body. It has long been known that it was possible to give large amounts of albumen in the form of white of egg, cheese, &c., without any great increase in the excretion of uric acid ; but if a similar quantity of albumen were given in the form of meat, there was a great increase, and if in the form of liver, spleen, and other glands there was a very great increase in the excretion of uric acid. The explanation of these facts is now quite simple, for the one set of foods contain uric acid ready formed and the other set of foods 9 130 UEIC ACID — CHAPTER III does not ; and the great final conclusion from my research is that we should take the one class of foods and avoid the other. Swallowing uric acid pure and simple will produce a similar rise in the excretion, and, when the conditions aSecting solubility in the blood are attended to, the rise in excretion is very rapid ; this rapidity furnishing a further proof that we have to do with excretion and not with formation. As the result of more or less natural changes in the alkalinity of the blood, the urates thus introduced and stored up tend from time to time to pass into solution, and uric acid may then for a time be present in the blood in considerable excess; and this excess of uric acid produces such changes in the circulation as are amply sufficient to account for the pain in the head. Lastly, they show that this headache can be completely pre- vented by stopping this needless introduction of uric acid, and that this can be done without reducing urea below the physiological level of 3^ grs. per lb. per day, if care is taken to get the required nitrogen from substances which contain little or no uric acid or xanthine com- pounds. So that we should probably not be very far wrong as regards this country if we put down the uric acid headache and most of its concomitant symptoms to poisoning by the flesh of animals, more or less aided by theine and similar vegetable alkaloids ; thus " the uric acid diathesis," to which these troubles were said to be due, is seen to be nothing but a myth.* If this was the only result of my research I should have no reason to be sorry that my sufierings induced me to undertake it ; but in the course of this research it has gradually become evident that an enormous number of the diseases of the human body own a causation which is practically identical with that of the uric acid headache, and farther, that uric acid in controlling the circulation, exercises a directing power over the physiology of the human body to an extent which was quite undreamed of at the beginning of this research. In the chapters which foUow I hope we shall see that the know- ledge thus obtained has the best hall mark of truth, in that it gives us a remarkable increase of power both to prevent and cure disease. * See article on " 'The Uric Acid Diathesis,' Are we to continue to believe in it ? " — Edinburgh Medical Journal, July, 1897. 131 CHAPTER IV. U»ic Acid and Metabolism. At this point I propose, in order to give my readers a grasp of the subject which may be of some practical utUity, to state in a few words what we have already learned, and in equally few words what we seem likely to learn in the chapters that follow ; leaving them to judge when they have read these chapters whether my statements are sufficiently supported. And I would before doing so remind them again that I am presenting to them no finished picture, but a prehminary communication on a progressive research, on a subject which is still plastic in all directions, and with regard to which much stiU remains to be learned. We see then as the result of the researches mentioned in previous chapters, that the uric acid daily excreted in the urine comes, or may come, from three sources : (1) the uric acid or urate formed out of nitrogenous substances along with a certain amount of urea, probably in the proportion of 1 of uric acid to 30 or 35 of urea. (2) Uric acid, urates, or other members of the xanthine group, as cafieine and other vegetable alkaloids, introduced with the food. (3) Uric acid or urates previously stored in the body which pass into the blood whenever the alkahnity of that fluid favours their solution in it. I may here state that uric acid in the title of this book and gener- ally throughout the book itself, unless otherwise specified, is used as an inclusive term, comprehending uric acid and its salts. When in the urine of 24 hours uiA acid is present in the relation to urea of 1 to 35, we conclude that this uric acid was formed along with urea of that day, and passed directly down the ureter into the urine, and that there was no uric acid furnished direct from the food or from the stores in the body. If any uric acid was introduced in the food this was not allowed to remain in the blood, because the condi- tions of that fluid were unfavourable to its solubility, and for the same reason no uric acid was taken up from the stores in the body. 132 UEIC ACID— CHAPTER IV If, however, uric acid was excreted in the relation of 1 — 20 or 25 of urea, we conclude that the excess over formation (1 — 35) is made up from uric acid introduced with the food or taken up from the deposits in the body, or both. Under these conditions it is quite easy to understand why all substances which form soluble compounds with uric acid, or increase its solubihty in the blood, should increase its excretion ; and why all substances which form insoluble compounds with it, or diminish its solubility in the blood, should diminish its excretion. If, on the other hand, the excretion of uric acid is very low, having the relation to urea of 1 — 43 or 1 — 50, we must conclude that some of the uric acid formed on this day met with conditions in the kidney, the liver or other organs and tissues, which were unfavourable to its solubility, and was retained there instead of passing at once down the ureter ; and we know that the kidneys may contain an amount which varies from a small percentage up to a quantity which is plainly visible to the eye (see p. 80). I thus regard the formation of uric acid in the body as practically constant in relation to urea ; while excretion varies partly with the conditions afiecting its solubUity in the blood and partly with the quantities available for solution, i.e., those introduced in the food, or previously retained in the body. I absolutely disbelieve in the formation of uric acid as a cause of disease ; nor do I see any proof that the gouty man forms any more than the non-gouty in relation to his urea ; but the gouty inan often indulges largely in animal food, and, as a result, forms more urea per pound of body weight than the physiologists would allow him, and some extra uric acid in normal proportion to the urea ; and he also absorbs directly from his food a considerable quantity of uric acid or xanthine compounds. I take, therefore, a hopeful view in regard to these diseases, because these errors of diet can be eUminated : but if there really was an excessive formation of uric acid, due, as used to be supposed, to a fault in the metabohsm of the gouty man, this might be beyond our control. It is obviously then in our p^er to control the excretion of uric acid by controlUng (1) the conditions afEecting its solubUity, (2) the quantities directly introduced in the food, and (3) the quantitv of nitrogen in the food, from which uric acid can be formed in the relation to urea of 1 to 35. From the clinical history of the uric acid headache we learn that at the time of the attack, when there is an excess of uric acid in the blood and in the urine, the pulse is generally slow, and of high tension., URIC ACID AND METABOLISM 133 And it will appear in the next chapter that this is due to obstruc- tion of the capillaries, of which there is abundant evidence in the cold skin and extremities that accompany the headache. And a very little experimentation will, I believe, suffice to convince anyone that obstruc- tion of the capillaries varies directly with the uric acid that is circu- lating in the blood, even if fig. 5 does not of itself suffice to prove it. And this obstruction of capillaries will produce two results : (1) a rise of blood pressure in the heart and great vessels on the proximal side of the obstructed vessels — high arterial tension, or high blood pressure ; and (2) a deficient circulation and interchange between the blood and the tissues in, and on the distal side of, the obstructed vessels. It follows from this that all drugs and disease processes which diminish the excretion of uric acid and clear it out of the blood, will lower blood pressure and improve the circulation through all the organs and tissues of the body. The drugs have already been mentioned, and the most important disease process which has this effect is fever, which diminishes the alkalinity of the blood, and thus prevents its holding much urate in solution. Conversely, drugs and disease processes which increase the excre- tion of uric acid and bring it through the blood in increased quan- tity will raise blood pressure, and diminish or hinder the circulation through all the organs and tissues of the body. The most important disease processes which produce this effect are Bright's disease, post-febrile conditions, dyspepsia, splenic leucocy- theemia, marasmus, and the cachexia of new growths, &c., for in all these conditions of low or failing nutrition there is commonly some increase of the alkalinity of the blood rendering it a more than usually good solvent of uric acid ; and in post-febrile conditions not only does the blood thus become a good solvent of uric acid, but a large supply of uric acid is present ready to be dissolved, namely, that which was held back and retained during the low alkalinity of the acute febrile period. Now, other things being equal, a freeing of the capillaries of the kidneys means a free flow of urinary water, and their obstruction means scanty water ; for this reason the urine is scanty (30 cc. per hour) during the uric acid headache (migraine), and profuse (60 — 160 cc. per hour), during the minus excretion of urates which precedes and follows it. And not only is this true in pathology, but so constant is the relation of obstructed capillaries to uric acid, that in physiology also, in every one from hour to hour and day to day, the urinary water varies inversely 134 UBIC ACID — CHAPTBE IV as the uric acid excreted along with it ; or to state it as accurately as possible, other things being equal, the more the excretion of uric, acid exceeds the relation to urea of 1 to 35 the more scanty will be the corresponding hourly or daUy excretion of ^ater, and vice versd, because as we have seen from previous arguments the uric acid which is excreted in excess of formation (1 — 35) probably passes through the blood on its way to the kidneys. It follows from this that all drugs and disease processes which diminish the excretion of uric acid and clear it out of the blood must increase the flow of urinary water, and this I believe represents in its simplest terms the modus operandi of the great majority of so-called diuretic drugs. And drugs and disease processes which produce or are accom- panied by an increased excretion of uric acid will also be accompanied by a scanty excretion of urinary water ; so that the hourly excretion of urinary water being known, the greater or less excretion of uric acid can be calculated from it with sufficient accuracy for many clinical purposes. This relation between uric acid and water can be seen in nearly every figure in this book, and during the years I have been estimating my own excreta I have not met with anything that could really be called an exception to the rule, if one bears in mind that the excre- tion of water is dependent partly on the freedom or obstruction of capillaries and partly on the supply of water available for excretion ^ for obviously no amount of freedom of capillaries wUl bring about a diuresis when all fluids have been drained from the blood and tissues by vomiting, diarrhoea or perspiration ; but conversely slight and imperfect freeing of capillaries may produce a marked diuresis when there is an excess of water in the blood and tissues (dropsy). One to 33 is the old relation of uric acid to urea in excretion, which I arrived at after a few months' work, and it forms the basis of all the older curves of excretion in the book. Further investigation now seems to show that while the relative formation of uric acid to urea is about 1 — 35, or 1 — 30, as in the more recent curves, excretion varies greatly from this with the amount of urate (previously stored in the body) available for solution, and with the amount daily intro- duced in the food. Now for the purpose of getting a bird's eye view of the field we may roughly classify uric acid diseases in two groups as follows : — A. The local or precipitation* group due to the irritating pres- * Called also the uric acid filter group, for each local precipitation aets the part of a uric acid filter to the Hood and tissue fluids of the rest of the body (see experiments mentioned further on). UEIC ACID AND METABOLISM 135 ence of uric acid in a fibrous tissue either in solution or suspension (colloid form) as in gout.' Gout. Rheumatism. Morbus cordis (inflammatory). Local inflammations of all fibrous tissues, some of which are to be found in the — Brain and meninges. Nose, pharynx, larynx, trachea, bronchi, lungs and pleura. Stomach (gastralgia, gastritis, gastric ulcer), liver (jaundice, cirrhosis, and liver abscess) and peritoneum. Ovaries, uterus and pelvic fasciae, uterine fibroma and other fibromata, epididymis, &c. Fasciae and fibrous tissues in neck, back, spinal cord and lumbo- sacral region, hands, &c. Other fibrous tissues in the body, as of skin (eczema and psoriasis fibromata). Intestines, caecum, and appendix (flatulence, colic, enteritis, colitis and appendicitis). Muscles (myalgia). Nerves (neuralgia). Teeth coverings (periostitis). Uric Acid plus microbes acting together as in— Catarrh, influenza, phthisis, pneumonia and malaria (its fever and sequelae). Glands, irritation and fibrosis of (not pyaemic). B. The circulation or solvent group, due to excess of uric acid in the blood (collaemia), and its efiects on the circulation, blood pressure and nutrition, as — Headache, epilepsy, convulsions, chorea, hysteria, neurasthenia, nervousness. Mental depression, excitement, mania, insanity. Bodily depression, fatigue, lethargy. Vertigo, syncope, insomnia. Periodic paralysis, chronic paralysis. ■■-■•- Asthma. Dyspepsia — dilated stomach. Congestion of Hver, glycosuria, diabetes. Bright's disease, albuminuria, haemoglobinuria, dead hands, cerebral haemorrhage, cramps, dropsy, uraemia. Gravel and calculus. Neuritis. Retinitis. 136 UEIC ACID — CHAPTEE IV Cerebral degenerations. Spinal degenerations. Skin diseases as — Atrophy, ulcerations. Eaynaud's disease. Diseases of vessels — Purpura, thrombosis. Degeneration, atheroma, calcification. Aneurysm, morbus cordis (coUsemia acting with strain and resulting in dilatation), 'angina pectoris. Diseases of blood — Anaemia, chlorosis. Haemoglobinaemia. Leucocythsemia. Pernicious anaemia. Graves' disease. Menorrhagia and uterine congestion, dysmenorrhcea. PUes, pruritus ani et vulvae. It thus appears that man's ignorance has inflicted on him a terrible plague of words almost a disease in itself, and of course ignorance is the underlying cause of all disease. Once the cause is known we can express all the above in two words — A. Group = Gout. B. Group = CoUaemia. Gout is relieved by solvents ; coUaBmia by retentives. Both are prevented, relieved, or wiped ofi the record, by a uric acid free diet. Gout is accompanied by quick circulation, raised temperature and few granules in the blood. CoUaemia is accompanied by slow circulation, sub-noTmal tempera- ture, and many granules in the blood. Here we have the whole of " Uric Acid " in epitome, and but for the plague of words it would be unnecessary to write more about it. Will this now be accepted and acted on that man may be relieved from the plague of words, as well as from gout and coUaemia ? In myself and the few hundreds who have " dared " to foUow me these things are represented by old scars and memories only ; will the rest of the race now follow ? No ! I fear not ! for history shows that things of this kind have been discovered and forgotten, rediscovered and reforgotten, and no doubt the process wUl be repeated yet many times ; still I do think that possibly the representatives of homo sapiens (not of this race. UEIC ACID AND METABOLISM 137 for it will be mostly wiped out), in the SOth or 40th century may be a little more unanimous than they are to-day in believing that their natural food is after all that which is also best for them. I am also inclined to think that once they have come to a unani- mous appreciation of this important point, it is probable that their evolution will proceed in the future at a somewhat more rapid rate than it has achieved up to the present time ; if only for the reason that nature is stiU, and may be so even in the 40th century, a trifle more powerful than man. Homo safiens — how that last word always raises in my mind shouts of derisive laughter ; it is so fortunate that he had the classifi- cation of himself ; look at the ant-like pigmy dancing a can-can on his rubbish heap, look at the cradled infant waving a feeble arm in the air, yet calling the universe his own. How that gift of speech, in the use of which he has not yet found his balance, has led him into a maze of words and self-glorification bordering on the insane ; but young animals are always prone to carry to extremes the use of new powers. With the exception of gout and rheumatism (A. Group), all the diseases connected with uric acid are due to its efEects on blood pressure and the interstitial circulation in the organs and tissues throughout the body. Thus headache, fits, mental depression, and bad temper, as also vertigo and a host of minor functional disturbances, represent the efEects direct and indirect of high blood pressure on the intra-cranial circulation. In saying this, as in all I shall have to say, I wish it to be under- stood that while I consider uric acid to be a cause, often the most important cause of these disturbances, I should never go so far as to put it down as the only cause ; and in the chapters which treat of the cerebral circulation, it will, I hope, be quite evident that other causes may produce similar alterations in the cerebral circulation, and, therefore, similar symptoms. The well-known symptoms of high blood pressure represent the efiects of uric acid in obstructing the capillaries and raising the pressure in the arterial system behind them. Asthma and chronic bronchitis (in part) again probably represent some of the efiects of high blood pressure and obstructed capillaries on the bronchial and j)ulmonary circulation, and this probably explains the relation so often seen between these diseases on the one hand, and gout and chronic Bright's disease on the other. Dyspepsia may undoubtedly be produced by obstructed capillaries 138 UEIC ACID — CHAPTBE IV in the stomach and intestines, which inhibit gastro-intestinal diges- tion and allow putrefactive processes to take their place ; and this again will explain at least part of the relationship between dyspepsia and such troubles as headache, epilepsy, and mental depression, or between dyspepsia, Eaynaud's disease, paroxysmal hsemo-globinuria, and anaemia. In the hver again, just as in the stomach or intestines, we may obviously get more or less stasis or congestion as a direct or indirect result of the circulatory changes produced by uric acid. Precisely the same thing applies word for word to the kidney, and here we have a very obvious and tangible result of the changes so produced in its circulation, i.e., the fluctuations of the urinary water previously referred to. Now, any excess of water in the blood and tissue fluids is promptly excreted so long as the circulation through the renal arterioles and capillaries is free. But the circulation through the renal capillaries, which we must remember are doubled or reduplicated, may fail for two reasons ; (1) that the capillaries are obstructed so that a normal heart cannot drive blood through them (as in coUssmia), or (2) that the capillaries are normally free, but the heart is weak (strain, debility, morbus cordis) and is unable to drive blood through them. In either case there is retention of fluids in the blood and tissues, and in both cases the heart is not up to its work either absolutely or relatively. In (1) we must treat the collasmia, in (2) the heart, taking eare at the same time that there is no collsemia, for practically (1) and (2) often act together. The same thing is seen in the salivary and probably in all other glands ; and, in accordance with this, when a uric acid headache is present and the urinary water is scanty, the mouth also tends to be dry or sticky, and the saliva is scanty ; and when the headache has been cured by acids, opium, mercury, iodides, or any of the drugs which clear uric acid out of the blood — not only is there a diuresis, but the saliva also becomes relatively profuse. And we shall see also in chapter ix. that exactly the same thing applies to the excretion of water from the lungs, which rises and falls with the urinary water and other secretions, and inversely with the uric acid. » In the muscles also there can be little doubt that collsemia pro- duces deficient circulation and deficient removal of waste products, though probably the disinclination for muscular exertion, which is UBIC ACID AND METABOLISM 139 SO marked a feature in attacks of migraine or mental depression, is due partly to the condition of the nerve centres ; still, I think that cramps and other slight disturbances of muscle function are not im- probably sometimes due to the deficient circulation of coUsjemia (see also the Causation of Fatigue in chapter viii.). The skin also has its circulation and nutrition very markedly influenced by uric acid, both in physiology (fig. 5) and in pathology, as witness the very pale and cold surface commonly seen in attacks of migraine. Then in conditions in which there is for some time a con- tinual excess of uric acid in the blood (as in post-febrile conditions, marasmus, and chronic dyspepsia) the nutrition of the skin may be interfered with to an extent which may account for not a few eruptions, especially ulcerative eruptions, slow healing of wounds and other troubles ; and in these conditions I am' in the habit of ordering drugs that clear the blood of uric acid, in full confidence that, if there is no organic disease, I shall be able to improve the nutrition of the skin and facilitate the healing of wounds and the clearing up of rashes. Such a consideration explains the frequent time connection between skin eruptions and menstruation in women, for menstruation is nearly always accompanied by a certain amount of dyspepsia and lowered nutrition, and the collsemia which results from it (see chapter xii.). But the efEeot of menstruation on the excretion of uric acid has a much wider bearing on the causation of disease than the production of a few skin eruptions would imply, and I will now therefore give a figure to illustrate the fluctuations it may produce. Fig. 31 shows the efiect on the excretions of normal menstruation in a woman aged 36 in ordinary health. On November 13, the first day of menstruation, uric acid is fairly close to urea, and urinary water is fairly high. On the two following days uric acid rises and remains very high, and on the second of these days urea and water fall very decidedly. Acidity follows the uric acid much more closely than the urea, and its rise is probably much more the result of the excess of uric acid in the urine than of any change in the alkalinity of the blood, and indeed with the fall of urea on the 15th, the blood probably became more alkaline. On the 16th uric acid falls, but rises again on the 17th, which is the last day of the menstrual flux. On the 18th and 19th it rises still further, but falls very decidedly on the 20th. Urea and water rise aU the way from the 15th to the 18th, and then fall again sharply on the 19th and 20th, this fall being very pro- bably in part due to the high uric acid on the 18th and 19th. On the 15th, along with the high uric acid and falling urea, there uo URIC ACID — CHAPTER IV was some decided headaclie, and on the 16th there was headache and increased irritability ; on the 17th she felt rather better, but on the 18th there were some distinct rheumatic pains, and I think it is possible that the rise of urea and of water on this day were due to some slight febrile movement accompanying the rheumatic pams. On the 19th she felt fairly well, but was taking some soda mint tabloids W*. f/o.e«a,i, ^^,„ ^^„ ^^„ ^^, ^^, ,^. ^^, Fig. 31. — Bxcbetion of Uric Acid dubing Menstruation. for the relief of dyspepsia and other minor troubles, and on the 20th there was some depression due to the falling urea and the still rather high uric acid. We see then, so far as this figure goes, that menstruation at its onset may be accompanied by a fairly normal excretion of uric acid, but this is 'quickly followed by a very marked rise in excretion which UEIC ACID AND METABOLISM 141 continues with some fluctuation right through menstruation, and even lasts for 2 to 3 or more days after the flow has ceased; that these rises of uric acid are accompanied by headache, irritability and depression, with some dyspepsia and a very marked fall of urea ; in a word by the usual signs of coUaemia by impeded circulation and diminished metabolism which it produces. Thanks to the kind help of my friend, Mr. A. G. Ewbank, formerly house physician to the Metropolitan Hospital, I was able to get the excretions in several other cases during menstruation, and though they vary somewhat, and in some cases are complicated by the presence of active disease, they all agree in showing that menstruation is generally accompanied by a plus excretion of uric acid, especially towards the end of the period, or just after it was over ; and in cases where I got the excretion a few days before the period began, it rather appeared as if its onset was accompanied by a diminished excretion of uric acid and a period of stimulation. Unfortunately I was unable to get this in fig. 31, but the uric acid was in fairly normal position on November 13, the first day of the period. It thus appears probable that menstruation merely causes a fluctuation in the excretion of uric acid, a diminished excretion or retention just before or at the beginning of the period, followed by a corresponding plus excretion during the period and just after its termination. These facts enable us to explain very completely the connection between menstruation on the one hand, and such troubles as head- ache, epilepsy, mental depression, dyspepsia, skin eruptions, rheu- matism and catarrh on the other ; in a word, we have here an epitome of the caifeation of disease by uric acid. Menstruation causes a fluctuation in the excretion of uric acid and in the amount passing through the blood ; and the uric acid in the blood, by controlling the circulation, dominates the function, nutrition and metabolism of the whole body. So that just before and at the beginning of menstruation we have a diminished excretion or retention of uric acid, with which goes a free circulation, a rise of urea and acidity, and a general stimulation of function, nutrition and metabolism throughout the body; with this there goes increased activity of mind and body, and a sense of well being ; neither headache, fits, depression, dyspepsia or catarrh come at this time, but rheumatism if present may be slightly increased. On this there follows an excessive excretion of uric acid, with the passage of its excess through the blood, and as a result the circula- tion is everywhere hindered and obstructed, nutrition and metabolism 142 UEIC ACID — CHAPTEE IV diminish, and there is a more or less marked fall of urea ; in a word coUsemia and its results. With this there comes increasing headache, irritability and mental depression, with fits if the patient is subject to them ; dyspepsia begins or is increased, and skin eruptions appear or are distinctly aggravated, or if anyone in the house has a cold, she is liable to take it just at this time ; on the other hand, rheu- matism if previously present, is often distinctly better, because rheumatism is always better with a plus excretion of uric acid ; hence the alternation between rheumatism and migraine which has been observed in so many cases ; what cures the one aggravates the other. It is interesting in this connection to remember that Dr. Oliver has noted, by means of the arteriometer, the high blood pressure of menstruation and the absence of postural variation in this physio- logical condition, which resembles the similar absence of postural variation met with in the gouty and in migraine (see British Medical Journal, 1896, vol. i., p. 1375). In the case of fig. 31 after the first onset of coUaemia and depression there follows a rise of urea and acidity from November 15 to 18, and with this the headache and dyspepsia get better, but some rheumatic pains become prominent. Later on the coUsemia again causes diminished metabolism, and the rheumatic pains again give place to dyspepsia and mental depres- sion. • And there is still one more physiological connection of menstrua- tion which may I think be eventually found to explain a corresponding pathological section. I refer to the well-known fact that the menstrual period in many women is accompanied by enlargement of the thyroid gland. Here then we have three things together, which are perhaps of some importance, a fluctuation in the excretion of uric acid with its temporary excess in the urine and the blood ; as the result of this a temporary period of high blood pressure, and with this, possibly in connection with it, enlargement of the thyroid. Here we have a side light on the causation of Graves' disease and its frequent occurrence in women, for the chief signs of this disease are but exaggerations of those which occur in physiology, and the quick action of the heart may be but the ordinary effect of high blood pressure when the heart fails because of it ; in a word Graves' disease may be a result of high blood pressure originating in the recurrent high blood pressure and coUasmia of each menstrual period. And while considering this subject we must not lose sight of the UBIC ACID AND METABOLISM 143 fact that at least one drug (chloride of calcium), which has ob- tained some reputation for curing or relieving Graves' disease, has as I have pointed out a very distinct and decided efEect in lowering blood pressure, which it does by clearing the blood of uric acid. Then a case or two I saw brought this again into my mind, and made me decide to give the treatment of Graves' disease a thorough trial from this point of view. The most interesting of these cases was that of a young man, aged 22, sent to me by Dr. Maclaren, of Harley Street, and his history showed that a few years ago, after much sedentary work and rather excessive smoking, he suddenly took a good deal of violent exertion, and then began to sufier from attacks of palpitation and threatenings of syncope. He was carefully treated for heart weakness or strain, and after a course of Schott treatment the condition of the heart improved, and he then began to suffer from severe headaches, apparently ordinary migraine (uric acid headache), from which he had suffered periodically for some years, since puberty. This continued for some time, and he was able to go back to his professional work again, and then again after hard work and exposure his heart got weak, and he got the palpitation attacks again and the headaches went off. Again he was treated with the Schott method and very numerous tonics, and was also fed up on raw beef juice, beef jelly, and a great excess of nitrogenous food. The condition of the heart again improved, and again the head- aches returned, having been absent while it was weak. When I saw him a little after this, my notes were as follows : — " He is decidedly pale, but fairly nourished. Eyes slightly promi- nent, and there is distinct fulness of the lower part of neck, over the thyroid region. Patient volunteered the statement that he now had to wear collars |-inch larger than a year ago. " Pulse rate 96. Apex beat shghtly outside the left nipple line. First sound reduplicated over the septum of the ventricles, and second sound loud both at apex and base. " At present he is fairly well, and only had one slight headache about a week ago, which was cured by tea." Such is a short outline of what I think is the most interesting medical case I have ever seen ; for it is interesting not only for what it tells us certainly, but in what it merely suggests. I think it may be rsad as follows in summary, cardiac strain from 144 UEIC ACID— CHAPTEE IV exertion following much sedentary work, and the muscular depressant action of excess of tobacco. Relief of cardiac condition and return of the old headaches due to high blood pressure. Relapse of the heart and disappearance of the headaches. Relief of the cardiac condition, and excess of nitrogenous food taken . Present condition : some little failure and dilatation of the heart, headaches comparatively slight, pulse quick. And with these signs there is slight prominence of the eyeballs and distinct enlargement of the neck (? early Graves' disease). This case leaves in my mind no doubt that he suffered all along' from high blood pressure, as shown by the old migraine. That after the strain the heart first failed and then recovered under treatment,' only to fail again because the cause of the high blood pressure was never removed ; hence the headaches due to the high blood pressure came with the ability of the heart to keep up the blood pressure, and went when the heart was unable to keep it up. The condition when seen by me was one more or less half way between severe c rdiac failure on the one hand, and high blood pressure with severe headaches on the other ; the pulse was quick, there was some dilatation of the heart and the headaches were comparatively slight in accordance with this ; and there were now associated with these what might be the signs of early Graves' disease. But be this as it may there is no room for doubt in my mind that if the blood pressure had been treated and reduced by putting him on a uric acid free diet from the time of his first cardiac strain, he would have recovered both more quickly and more permanently, and would not have had the alternating signs of heart failure on the one hand or headache on the other, and might in all probability have also escaped the more threatening signs of Graves' disease. It is now difiicult to say what may be the result and how far quickened heart's action, dilated heart, enlarged thyroid, and pro- minent eyeballs, point to organic and incurable disease. The case is incomplete, but I give it here for its great interest and suggestive- nsss, and because it gives an absolutely convincing demonstration of the pathology of the uric acid headache, which may be taken along with what I shall have to say of the action of antipyrin in this head- ache in chapter vi. With regard to prognosis, I may mention that before I saw the above case, the idea that Graves' disease might be a result of high blood pressure, occurring most frequently in women, because of their monthly fluctuation in blood pressure, had led me to put a hospital UEIC ACID AND METABOLISM 145 patient of mine upon a uric acid free diet, and that this even in a few weeks apparently gave some relief, as her pulse rate fell from 120 to 92, and her face became less congested. This case had been under observation for several years, and had been given all the drugs supposed to be useful in the condition, though ice to the thyroid seemed to do more than anything else, and she had had the right lobe of the thyroid removed by my colleague, Mr. W. H. A. Jacobson, with the apparent result of lessening the prominence of the right eyeball. Still, in spite of all treatment, up to the time of altering diet she had all the signs of progressive dilatation of the heart. I see that Sir T. Lauder Brunton points out in St. Bartholomew's Hosfital Journal, December, 1897, p. .35, that Graves' disease is gene- rally the result of shock or injury, and shock or injury, I remark, produces collaemia, which may become chronic. There is also a rather interesting parallel between Graves' disease and chorea (of the pathology of which I shall be speaking farther on), as both bear the same relation apparently to shock or injury and to the coUsemia it produces, only in the Graves' disease the collaemia produces high blood pressure, enlargement of thyroid, prominent eye- balls, and eventually heart failure ; in the chorea the collaemia pro- duces obstruction in the circulation of some important nerve centres in the brain, intensified by more or less heart failure. It is said, I believe, that some have found a history of acute rheu- matism in about 11 per cent, of cases of Graves' disease, and this is very interesting, for if Graves' disease is, as I am suggesting, a result of collaemia, it probably bears just the same relation to acute rheu- matism that migraine, another collaemic disease, does ; and chorea, of which we have just spoken, is similarly related to collaemia and acute rheumatism. Thus we see three diseases, migraine, chorea. Graves' disease, all due to collaemia and all more or less similarly related to the acute arthritis which is produced when a coUaemia is terminated by a retention. I also note that Professor Murray points out in the Lancet, vol. i., 1899, p. 752, that while little or nothing is really known of the path- ology of Graves' disease, most cases that are improved by treatment generally get mercury in some form, and mercury, as we have seen, is one of the drugs which has most power in putting an end to collaemia and lowering the blood pressure. And now that I have, as will appear in the next chapter, almost absolute power over blood pressure, I have considerable confidence that I can do a great deal for Graves' disease either by drugs or diet. 10 146 UEIC ACID — CHAPTER IV But I have now come to consider that while the full picture of Graves' disease. is somewhat rare, the prominent eye or some degree of this condition is rather common, especially among the uric acid feeding upper classes, and is to be seen perhaps in one or two out of almost any ten people we meet. The underlying cause common to Graves' disease and minor con- ditions of the prominent eye is high blood pressure. I now look upon the prominent eye as a valuable and readily observed symptom of high blood pressure, and with the exception of certain alterations in the eyeball itself, such as those of myopia, which can easily be identified, or certain new growths or tumours either in the eye or neighbouring structures, blood pressure is the chief determining factor in the prominence or retraction of the eyes. To take extreme cases, we have the prominent eye of Graves' disease with blood pressure say 150 mm. of mercury or above, on the one hand, and on the other the sunken eye of the young child dying of diarrhcBa and collapse with blood pressure probably 50 mm. of mercury and below, and here we have also the cold extremities, the shrunken skin and perhaps the deeply concave fontanelle to tell the same tale of diminished blood pressure. Between these great extremes we get all varieties of intermediate conditions, so that the position of the eye is a ready guide in clinical medicine to the vascular condition of the patient, and its value is increased by measuring even roughly the extent of the prominence or retraction, and noting the other signs of the vascular condition to be seen in the face with each position of the eyeball. As I have just pointed out. Graves' disease may, if taken in time, be relieved or even cured by removal of the high pressure, or its cause, uric acid coUeemia. I will merely say further that of the three cardinal symptoms of Graves' disease, the prominent eye is met with very frequently in the high blood pressure headache (migraine or uric acid headache), that enlargement of the thyroid occurs in most women during menstruation when the blood pressure is raised, and when those of them who suffer from migraine or epilepsy have their attacks, and that the quick pulse is met with in all similar high blood pressure conditions, as the heart begins to fail before the high pressure. Graves' disease is, in a word, as I have already suggested, but an exaggeration of some of the common signs of high blood pressure. Thus I know several sufferers from uric acid headaches who have attacks with each menstrual period, and with each of these attacks their neck enlarges so that for a day or two their ordinary clothing cannot be used ; and no doubt it is this monthly fluctuation in coUsemia UEIC ACID AND METABOLISM 147 and its resultant blood pressure that accounts for the fact that ex- ophthalmic goitre is chiefly seen in women ; and those that are weak or nearing the period of life at which the heart tends to fail may have more or less palpitation and quick pulse with each such periodical attack, just as in the patient whose case I have described above. I will merely add that in all these conditions of Graves' disease, or developing or partial Graves' disease, where the prominence of the eyes is well marked, blood pressures of 150 mm. of mercury and above are the rule. Now if a normal eye is closed and a card is held vertically over its centre, its edge will rest firmly over the supra-orbital ridge above and the malar and superior maxillary bones below ; but it will touch the eyeball so Ughtly as to cause no discomfort. On removing the card a pale line is seen where it has pressed the blood out of the skin over the bones ; but it has hardly affected the skin of the eyelid at all. And this is no doubt the natural position for the human eye, for the bony boundaries of the orbit now afford it eificieat protection from pressure and injury ; and this is its position when the blood pressure is normal. When, however, the card is applied in the same way to an eye which is too prominent it rests on the front of the ball and rocks up and down over it, only touching one of the edges of the orbit, it makes a pale mark on the eyelid and causes painful pressure on the eyeball, without touching both the upper and lower borders of the orbit at the same time. Then when one looks at a face in which the eyes are markedly prominent one sees the whole side of the face forming a cone of which the apex is the front of the eyeball. In a normal face there is an upward and forward slope to the lower margin of the orbit, then there is a crateriform depression, and the ball of the eye projects more or less from the centre of this. But in the face with the very prominent eye the depression above the margin of the orbit is done away with, and the cone is continued up without a break to its apex at the front of the eyeball. The eye is so prominent that the lids stretch forward over it, obliterating the normal depression at the margin of the orbit. And there is here I think a point of difference between the eye of exophthalmic goitre and the prominent eye I am now seeking to describe, for the eye in Graves' disease becomes prominent more or less suddenly, so that the eyeball leaves the lids behind, so to speak, and they fail to cover it to anything like the normal extent ; but in the prominent eye of chronic high blood pressure there has been more time. 148 UEIC ACID — CHAPTEB IV the ckange and increase of prominence has been gradual over years, and the lids have been able to follow the eyeball and cover it to a greater extent than in Graves' disease. Among concomitant signs of the prominent eye the most impor- tant is a distended condition of the skin, whether it be with fat, blood, or serum, or all three more or less mingled ; the wrinkles tend to disappear or get smoothed out, and the whole sMn of the face gives the idea of distension and puffiness. This is well seen in a woman of say 45, the stout body gives an idea of distension, the skin of the face is pufiy and tense, the eyes stand out and the side of the face slopes up to them with hardly any indications of the whereabouts of the orbital margin ; with such signs at such an age it is pretty safe to say that the blood pressure is not below 150 mm. of mercury. Some minor conditions which may be seen with some stages of the prominent eye are a distended condition of capillary vessels, giving a dark streaking of colour very different from the delicate flush of health, in which no vessels are visible. Then as time goes on the tense skin and prominent eye gradually give place to a more wrinkled skin and an eye which, though stiU pro- minent, shows now the margin of the orbit surrounded by more or less large folds of eyelid as the previous stretching is relaxed, and this probably comes at an age when the hair is becoming markedly grey or even white. Later still we get an eye hardly prominent at all, a skin still puffy, but in wrinkles and folds, the colour in the distended skin vessels becomes dusky and irregular, almost blotchy, as heart weakness and venous congestion increase. And last near the final stages of heart failure, of which the above are intermediate stages, we get the face becoming pale and the blood even falling out of the distended and degenerate vessels, which gave the face for so many years what was often thought by the man in the street to be its hue of ruddy health, but which was in reality its stamp of vascular degeneration and decay. With wrinkled but still puffy skin, a sunken eye, an orbital margin surrounded by loose folds, with a paling surface and a shrunken appear- ance, we get a quick irregular or intermittent pulse and a blood pressure but little over 100 mm. of mercury. Thus a woman in front of us has eyes that are distinctly prominent, a skin which is pufiy, a face and figure which are decidedly stout and give an idea of distension. An older woman with grey hair who sits beside her, probably her mother, has a pufiy skin but her eyes are retracted rather than UEIC ACID AND METABOLISM 149 prominent, and her pale face, wrinkled skin and wasting figure tell a tale of heart failure and falling blood pressure ; a single glance at these two teUs us which has the lower blood pressure, and why. Or again, one sees a woman who is obviously too excitable, and in her face the eyes are somewhat prominent and the skin pufiy, but round and below the eyes are large loose folds of skin, and here we can see the whole history of cause and effect ; her blood pressure is high and it has been high for a long time, and has been higher also than it is now ; as her hair has grown grey her heart has failed, the eye has become less prominent and hence is surrounded by a large loose fold of skin, and we already know that heart failure and faU of blood pressure is a cause of mental excitement, even of mania (see chapters v. and viii.). Or again, one sees a man with exactly the above facial signs, and he tells us that for years he has sufiered from periodical headache, but that of late he has had less headache but some palpitation ; his face tells us what his palpitation tells us, that his heart is failing and that blood pressure not being maintained headaches due to it are not so severe. Prominent eye is most common and most marked about 45 and 50 years of age, for then the heart attains its greatest hypertrophy together with good nutrition ; but it may be seen in early age, and I recently had among my out-patients a child of 9 or 10 with this sign fairly marked, and its mother had it still more developed, for both were sufierers from high blood pressure headaches. Thus those who have high blood pressure tend to have prominent eyes from the time they are full grown, from the time, that is, when the heart attains its full power ; and here we have no doubt one reason why the headache and epilepsy of high blood pressure start into prominence at puberty. And this continues onward through life, the eyes attain their greatest prominence in middle life just when the heart is strongest, and gradually become less and less prominent as the heart fails with advancing years. Then if in two cases the obstruction to the circulation is equal the eyes wiU be most prominent in that which has the stronger heart, and indeed it is in many cases possible to gauge approximately the thickness of the left ventricle simply from the greater or less promi- nence of the eye. Then naturally conditions which hinder the circulation through the lungs, as bronchitis, asthma and emphysema, will make the pro- minent eye more prominent, for such conditions not only directly obstruct the circulation, but defective oxygenation of the blood is 150 UBIO ACID— CHAPTEB IV a cause of collaemia, and it is also a cause both direct and indirect of obesity. In the same way coughing, straining and heavy exertion as lifting, raise the blood pressure and increase the prominence of the eye; on the other hand deep breathing lowers blood pressure and diminishes the prominence of the eye; hence breathing exercises frequently practised when unrestrained by clothing are good for all those who sufier from high blood pressure and obesity ; while those who suffer from obesity and insist on keeping their clothing tight are only increasing their trouble. Mental excitement also raises blood pressure and will therefore increase the prominence of the eyes. On the other hand absence of the above troubles and the presence of good respiratory power may to some extent mask the effects of blood pressure on the eye and render it less prominent than it other- wise might be ; but good respiratory power also tends to prevent very high blood pressure, and to diminish the tendency to obesity. Then a tendency to stoutness will no doubt increase the prominence of the eye and the distension of the whole face and body ; but high blood pressure is a wonderfully constant concomitant of obesity, so that I have long regarded obesity as a sign of high blood pressure, or rather as one of the results of the defective circulation which causes the high blood pressure, hence we so often find obesity accompanied by glycosuria or albuminuria ; these are all merely forms of defective combustion due to defeotiva capillary circulation, and they tend to occur together because they are results of one common cause ; and the prominent eye is the facial sign of the first efiect of this cause — high blood pressure. Then in estimating the actual prominence of an eye we must remember that folds of puffy skin round the orbital margins may make it appear less prominent than it really is, and in such cases we must take care to feel the margin of the orbit and gauge the position of the eyeball in reference to this ; but allowing for these things and for diSerences of face and form and of size and prominence of bony ridges, there is no doubt that the position of the eye is often a most valuable guide to the blood pressure of its possessor ; and the prominent eye with some of its associated facial conditions is a very constant sign of the coUsemic circulation. It is not everyone who, having high blood pressure from coUsemia, will sufier from headache ; it is only those who have a certain size and arrangement of vessels at the base of the brain ; and again among those who ^do sufier there are all variations' as to the height of blood pressure at which they begin to sufier ; thus some sufier at anything UEIC AGIO AND METABOLISM 151 over 130 mm. of mercury, others only at 160, and others again will have little or no headache, even with the highest blood pressures we know of. Again not everyone that has coUsemic high blood pressure will suffer from asthma, or glycosuria or albuminuria ; these may only be present when some concomitant condition precipitates the chief stress of the altered circulation on the lungs and bronchi, the liver, or the skin respectively ; but the one underlying condition common to all is coUsemia and the high blood pressure it produces, and more or less prominence of the eye is a wonderfully good and constant index of this condition. The prominent eye tells us not only whether there is high blood pressure, it will often tell us how long it has been there, and whether the heart has slowly and steadily hypertrophied under it, or has failed early before much hypertrophy was possible, or only later after it had for years kept up a very high blood pressure. And when we observe not only the prominent eye, but the condition of the skin round it, whether it is tense and smooth over an organ almost starting from its socket, or hanging in folds round a less pro- minent organ, or again wrinkled and atrophied but still unduly lax over an eye scarcely prominent at all, I think we can often read in the patient's face, not merely more or less high blood pressure or low blood pressure, but no unimportant part of the life history of his vascular system. In marked contrast with the previously mentioned effects of menstruation note the efiects of normal pregnancy. Here we have a steady upward progression of nutrition and metabolism ; urea and acidity rise steadUy, and the blood is consequently cleared and kept clear of uric acid. For this reason in normal pregnancy all diseases due to an excess of uric acid in the blood, such as headache, fits, mental depression, dyspepsia, asthma, &c., are remarkable by their absence, while Sir A. Garrod (prev. ref., p. 212) tells us, just as we should expect, that women occasionally suffer from gout during pregnancy, and not only so, but there is a common idea among the people which is mentioned by Sir W. F. Wade {British Medical Journal, 1872, vol. ii.) and which I believe to be well founded, that pregnant women do not readily take diseases, such as colds, fevers, &c., ta which they may be exposed. We shall see further on that opium,, by giving its habitues temporary freedom from collsemia, gives, them also similar relative immunity from disease, and that braoing^ mountain climates and training for athletics also do the same to 152 UEIC ACID — CHAPTER IV a certain extent. Normal pregnancy, therefore, corresponds to the first or stimulation stage of menstruation, and the diseases of the one to the diseases of the other. But if pregnancy is not normal, or if metabolism is upset by such a disturbance as vomiting, the picture is completely reversed ; there is no rise of urea and acidity, on the ■ contrary they fall, and the blood instead of being kept clear of uric acid is flooded with it, and the diseases which are due to this — headache, fits, depression, dyspepsia, asthma — in place of being diminished are present or increased, and the patient, instead of being proof against colds and fevers, is liable to take them ; and indeed, if the upset of metabolism is at all severe, that last and worst stage of defective combustion, Bright's disease itself, may appear on the scene. And in chapter xiii. we shall see a case in which such disturbance of pregnancy, perhaps aided by the altered pressure relations in the abdomen and some failure of the heart, did apparently bring on this disease. With regard to infection, the point may be expressed shortly thus : in normal conditions, and still more in conditions of stimu- lated nutrition, when the blood is free from uric acid and the circula- tion is, in consequence, free and perfect in all the tissues, when digestion is perfect and metabolism complete, when, in a word, the fires of life burn strong and bright, the microbes of disease are burnt up and destroyed, and have no chance of taking root anywhere. On the other hand, when under the reverse conditions the draught is bad, combustion is incomplete and the fires run low, the microbes get a firm hold, and are able to multiply and produce the disease. From this point of view the causation of fever is of extreme interest, for fever is accompanied by a general increase of combustion and metabohsm, and, indeed, it looks very much as if it was a protec- tive effort on the part of nature to stimulate the fires of life and burn out the invader ; and it is interesting to note that Loewy and Richter (Berl. Klin. Woch., March 1, 1897) found that artificially produced fever protected animals to some extent against microbe inoculation. I shall have more to say on these points in treating of the causa- tion of catarrh and phthisis in chapter ix., and, indeed, I am here merely giving an outHne of the part played by uric acid in the causa- tion of disease, and each individual disease will be treated of separately in the chapters which follow. To put these points in a nutshell, we may say that the effect of excess of uric acid in the blood is deficient and incomplete combus- tion, while the result of keeping the blood clear of it, no matter by UEIC ACID AND METABOLISM 153 wtich of the numerous means at our disposal this is accomplished, is satisfactory and complete combustion. Previous writers have very often told us, and some are saying so still, that the excess of uric acid found in the urine in these conditions is the result of deficient combustion ; my researches, however, show, and indeed make, the demonstration almost absolute, that the truth is the exact reverse of this, and that uric acid is the cause of the deficient combustion. When pregnancy comes to an end, however, especially if labour is tedious and fatigue is great (see Fatigue, chapter viQ.), the fires of life run low, and then the wet blanket in the shape of the uric acid stored during pregnancy gets on top of them and keeps them down, and lactation may further add to the depression. Under these conditions all or any of the diseases which were re- markable by their absence during normal pregnancy return in an aggravated form. Before I leave fig. 31 I will just point out that it serves to explain certain observations made by others as to the effects of menstruation on metabohsm ; thus in an article on " Stoiiwechsel Wahrend der Menstruation," by T. Schrader (in von Noorden's Beitrage zur Lehre vom Stoffwechsel, 1894, Heft, ii., S. 132), it is pointed out that men- struation is accompaniedr by a constant fall in the output of nitrogen by the faeces and urine, which is not the result of any alteration in diet, as this was purposely kept constant, but which Schrader thinks is due to a diminished formation of urea. He proceeds to give an explanation which seems to be lacking in completeness, and for which I must refer my readers to the original article, but I think this diminished production of urea is sufiiciently evident in fig. 30, and its causation, by the deficient combustion and metabolism which excess of uric acid in the blood always produces, is sufficiently clear. It is, I believe, a universal law dominating both physiology and pathology, that high uric acid means low and falling urea, and low uric acid means rising and high urea, and this law, as we shall see, lies at the very root of such conditions as fatigue in physiology, and of many blood changes up to Bright' s disease itself in pathology. Lastly, I wiU just point out that the stimulation which accom- panies the sexual act in men has an effect on nutrition and the excretion of uric acid almost identical with that of menstruation in women. The sexual act is no doubt a powerful stimulus to circulation, and is accompanied by muscular activity, but this is not pushed to 154 UBIC ACID — CHAPTEE IV the fatigue point, and consequently it produces a rise of urea and acidity, wtich, as we shall see in chapter viii., is the first efiect of all exercise, and continues till the acidity is brought down by perspiration. This rise of urea and acidity clears the blood of uric acid and pro- duces a stimulation of nutrition and metabolism just as occurs apparently at the beginning of menstruation, but just as in men- struation and in the action of a long list of drugs, this primary retention of uric acid, the result of the stimulation, is followed by a secondary plus excretion of uric acid or a rebound ; and during this stage of the fluctuation a man will sufEer from similar troubles to those which affect women during or at the end of menstruation, and this is the reason that many men who sufier from the uric acid headache (migraine) have noticed that they often have an attack on the day following sexual intercourse (see chapter vi.). It seems to me also to be a fact of some interest that the sexual appetite appears to increase with high and rising blood pressure, and to be slight and in corhplete abeyance with low or falling blood pressure, and as the sexual act itself tends, as above shown, to produce low and falling blood pressure, it tends to remove the desire for repetition of the act. Further, I think that as the sexual act produces low and falling blood pressure, it will of necessity reheve conditions which are due to high and rising blood pressure, such for instance as mental depres- sion and bad temper ; and unless my observation deceives me, we have here a connection between conditions of high blood pressure with mental and bodily depression and the act of masturbation, for this act will relieve those conditions, and will tend to be practised for this purpose. I think, therefore, we must bear this in mind in such cases, and where these are obviously associated with high blood pressure, we would do better to assist Nature in lowering this pressure, rather than by attempting to fight against her with such feeble weapons as mental and moral suasion ; that, in a word, we should treat the morbid conditions present in the circulation, and leave morality to right itself when a satisfactory cerebral circulation has been restored by the use of suitable diet or drugs. I have been much interested to see that the connection between sexual appetite and blood pressure, or what is the same thing, the mental conditions its chamges produce, has been noticed by opium- eaters in whom these changes of blood pressure are seen to perfec- tion, in whom also they are due, as elsewhere, to changes in the amount UEIO ACID AND METABOLISM 165 of uric acid present in the blood, and can be completely controlled by controlling the uric acid.^as, for[^instance, by means of salicylate (see fig. 15, and remarks on it). Thus in " L'Encephale," 1887, p. 306, we are told by an opium hahitui that during the stage of opium well-being, in which, as we know, the capillaries are free and the blood pressure low (see fig. 35b), there is no desire for women, and that the difference of sexes ceases to exist ; but that later on in the stage of rebound, misery, high blood pressure (see fig. 35a) and craving for a fresh dose of the drug, desire for women is great, and that contact brings calm with it, though the act can be repeated many times. These effects of the sexual act on the blood pressure account, no doubt, for the calm and good temper which follows the act, and also probably for the terrible storms of passion which may follow in either sex if the desire is not obtained, and when consequently the high blood pressure is not relieved, and these in turn may account for not a few of the murders and suicides of every-day life (see chapter viii.) which are often so obviously connected with the sexual relations. Here again my remarks about masturbation will apply, for the poor wretch under the dominion of coUsBmia and high blood pressure is in no way accountable for his or her acts, and is, as the jury truly put it, temporarily insane ; and it is useless to appeal to the mens insana which is the result, while leaving untreated the corpus insanmn which is the cause. I would strongly recommend all those who are interested in the causation of disease by uric acid to read the article just referred to,* as it gives a most able summary of the evil effects of excess of this substance in the blood, as well as of the opposite effects of its more or less complete absence ; it shows also quite clearly, I think, that the necessary increase of dose is due to the storing up of more and more uric acid, which is always ready to pass back into the blood the moment the acidity is allowed to fall, and as opium diminishes appetite, and produces wasting as a result, more and more help from outside is continually required to keep the acidity from falHng. It demonstrates also that the action of opium in saving its habitue from diseases which others take is the exact parallel of that of normal pregnancy and the exact reverse of the second stage of menstruation, and is due to its preventing coUsemia and keeping the fires of life at white heat. I note also, with interest, in this connection that Mr. Havelock BUis* considers that sexual climaxes may fairly be regarded as ulti- * " Studies in the Psychology of Sex," vol. ii., p. 121. 156 UEIC ACID — CHAPTBE IV mately a physiological reaction to cosmic influences, among which influences he reckons the annual fluctuations in the excretion of uric acid. And the annual curve of the conception rate in Europe, with its- most marked rise in April, May, and June (prev. ref., p. 297) must correspond very closely indeed with the maximum excretion of uric acid in early summer, and is a very remarkable confirmation of what I have just been saying. In a later chapter, I shall have to refer to some other curves showing the maximum incidence of suicide and insanity in London, and of general paralysis in Paris in the same month. From my point of view they are all efiects of one and the same cause and hence their time association ; a point we shall better understand after the circulation problems of uric acid have been dealt with in the next chapter. That coUsemia afiects the nutrition of the extremities as well as the skin is seen in the pale, cold hands and feet which are so marked a symptom in migraine, in the " dead hands " of Bright's disease, and the still more marked alterations in nutrition met with in Raynaud's disease. Last, but not least, an excess of uric acid seems to produce changes in the nutrition and structure of the blood itself, so that just as it is possible to cure anssmia by giving iron, it is also possible to produce ansemia by giving uric acid, and where the two are given together the uric acid overpowers the iron, and the blood either remains in statu quo or deteriorates, and in my own person not only does my blood fraction — '"^°d°cl'ii'»'"pe''r°cen''t"'' vary in value from hour to hour and day to day with the quantity of uric acid passing through my blood, but it is possible to make it vary up and down at pleasure by giving uric acid or iron as required. While speaking of the efiects of uric acid on the blood, and while we have still not forgotten the efiects of menstruation on uric acid as shown in fig. 31, I will pass on to fig. 32, which is a temperature chart of Mary H., aged 18, who was under my care in the Royal Hos- pital for Children and Women, sufiering from chlorosis, in October, 1894. Up to October 12 her temperature was slightly raised, as is com- mon in such cases, and varied between 98-2^ and 99-6°. She was at first put on bismuth and Carlsbad salts for some dyspepsia, and on the 7th these were stopped, and she was put on pulv. ferri. carb. gr. X. three times a day. On the 13th the temperature became more irregular, with an evening rise and morning fall, and this continued on the 14th and 15th. On the llth menstruation began and lasted URIC ACID AND METABOLISM 157 three days, till the evening of the 16th. On the 16th temperature was exactly normal both morning and evening. On the 17th it passed below normal, and remained there till the evening of. the 21st, when it rose to 99'6°, and on the following nights it did much the same, only falling below normal once on the morning of the 24th. The pulse during the first thirteen days ranged from 72 to 102 ; during menstruation it was 108 on one day and 102 on another ; during the subnormal temperature which followed on the 17th, 18th, 19th and 20th its highest rate was 96, and pulses of 66 were recorded on two mornings, and it once again fell to 66, with the subnormal temperature on the morning of the 24th'. I examined her blood on the 10th, 17th and 24th. On the 10th 10 n 12 13 It- IS IB 17 IS la 20 21 22 23 24- ? g ^ t C li I s a a. l« a, s ? » K g 1 ? 1 5 5 J- 1 J 0: . ii ^ If S « ff i 5 X s b. * too % , s 5 S ^ !i 33 08 —3 ^ ^ t "^ h«-«. / V* V* ^*^ ^ t ^ f ^ a ^ ^ m^ f ^ ^ / \i PUISE ^ ^ y" / V / \ \ / / ^ ^ \ / \ / ^ S / / \ \ . _ Fie. 33. — OtFBVES SHOWING THE EFFECT OF EbtHROPHLSIUM UPON THE Blood Pressube and Seceetion of Urine. (Prom Sir T. Lauder Brunton's paper in Fhil. Trans., vol. olxvii.) result. I have been much interested, and in several of my papers have quoted from Sir T. Lauder Brunton's researches, which show that this is the case with these drugs. Thus he says (" Pharma- cology and Therapeutics," ed. iii., p. 430) : " Thus Mr. Power and I found that on injecting digitalis into the circulation of a dog the blood pressure rose, but the secretion of urine was either greatly diminished or ceased altogether. Here it is evident that the renal vessels had contracted so much as to prevent the circu- lation through the kidney, notwithstanding the rise that had taken place in the blood pressure. After a while the blood pressure began to fall, and then the secretion of urine rose much 172 " UBIO ACID — CHAPTER V above its normal, showing that the general blood pressure was then able again to drive blood into the kidneys." And Sir T. L. Bmnton's figure of the excretion of urine during the action of erythrophlseum, which he has most kindly allowed me to reproduce here, shows exactly the same thing (see fig. 33). It seems that in the case of digitahs, and other drugs of similar action, the diuresis has been wrongly credited to the rise of pressure, which Sir T. L. Brunton's figure and facts show that it does not completely correspond to. The first efiect of these drugs is to hold back and retain in the body some water, and then, as the arterioles are relaxed and the blood pressure falls, this passes out, producing a marked temporary diuresis. Digitalis and erythrophlseum thus exactly parallel what occurs in the uric acid headache, in epilepsy, hysteria, and other condi- tions accompanied by high tension pulse and obstructed capillaries. While the capillaries are obstructed and the pressure high, the water is held back and retained in the blood and tissues, but later on when the capillaries are freed and the pressure falls, it passes out in a more or less copious diuresis, and urinary water is thus inversely as the uric acid excretion, and inversely as the obstruction of the capillaries. Then again in chapter ix. we shall see that the capillaries of the lungs own to heing obstructed in exactly the same way and in exactly the same relation to the excretion of uric acid that those of the skin and kidneys have already owned to, and what has been said about the excretion of water from the kidneys might apply almost word for word to that from the lungs, for both of these vary together, both in physiological and pathological conditions, inversely with the height of the uric acid above urea in the urine. These facts alone, to say nothing of the evidence from other tissues and organs which is also, as we shall see in other chapters, often very striking, suffice, I think, to prove that high arterial tension or high blood pressure in man, occurring either in physio- logical or pathological conditions, is due to obstruction of capil- laries throughout the body, and that the most important cause of this obstruction is the presence of a relative excess of uric acid in the blood stream. See also figs. 64 and 66, with the changes in the pulse rate and blood pressure there shown. There are absolutely no facts against such an explanation of what has been observed, and there are hundreds of facts in its favour ; for not only does it explain an almost numberless sequence UEIC ACID AND THE CIECULATION 173 of events in physiology and a still larger number in pathology, but it gives us a power to which we were previously complete strangers, to vary and control these events and sequences. Having arrived, then, at the conclusion that excess of uric acid in the blood stream produces obstruction of capillaries throughout the body, we may spend a few moments in considering the way in which it may produce this efiect. I have nothing definite to say on the matter, but think that we shall gain by keeping the more probable ways in our mind's eye, so that if we meet with anything pointing to one road rather than the other, it may not escape us. (1) To make a beginning, uric acid may act hke digitalis, or erythrophleeum just mentioned, and these we learn from Sir T. Lauder Brunton (previous reference, pp. 996 and 273), act locally on the vessels of an artificial circulation, and in the case of ery- throphlaeum, after division of the cord, so that all question of any action on the vaso-motor centre is removed. (2) Then again it may act directly on and through the vaso- motor centre. • (3) And lastly, I think there is a third possibility, though so far as I know, this has never been suggested by anyone except myself, and should it eventually work out, it might come to very much the same thing as the local action theory No. 1. It was suggested to me by watching day after day, as I have done for years, the extremely slow and tedious filtration of the gelatinous urate of silver through the asbestos fibre filter as used in Haycraft's process for the estimation of uric acid (see chapter xviii.). It occurred to me that if the capillaries of the body resembled in any way the interstices of that asbestos filter, and if the uric acid were present in the blood stream in some similar gelatinous form, and if the heart had to shove it through these capillaries, it might have great difficulties in doing so, and might occasionally, as we know occurs sometimes in pathological conditions, get the worst of the encounter. In a word, it occurred to me that the obstruction produced by uric acid in the capillaries of the body might be mechanical and not vital. To test the possibility of such a thing, I got some kidneys and tied a cannula into the renal artery and measured the quantity of water or salt solution that poured out of the renal vein in a given time and under a given hydrostatic pressure. 174 URIC ACID — CHAPTBE V I then added on to this solution small quantities of finely divided oatmeal, flour, mud and other things, and watched their effect on the flow from the renal vein. And lastly, I got some gelatinous urate of silver, washed it free from chemicals, and added it to the solution passing through the kidney, and found that it had a far more powerful effect on the circulation than the other substances, as comparatively small quan- tities sufficed to stop almost completely the flow from the renal vein. As regards the quantity of uric acid in the blood, if we have say '035 per cent, urea in the blood, or 30 to 35 grs. in the whole quantity (10 pints), and uric acid, as in the urine, in the relation to. it of 1 to 35, then there may be normally in the blood about 001 per cecLt. of uric acid or 1 grain in the whole quantity. Then this quantity of uric acid in the blood might correspond with an average number of granules, say 1 to 15 red cells (see p. 92), and when the granules are to red cells as 1 to l' we should have '015 per cent, of uric acid in the blood, and i,t appears from the figures givea on p. 76 that we may have about twice this quantity in some pathological conditions (cerebral hsemorrhage). Now in the urine you may get 18 grs. in say 50 ozs. of water, or about 7 grs. to a pint, which is 1 in 1,250, and this, even when diluted with three volumes of water (1 of urine in 4 or 1 of uric acid in 5,000) greatly blocks the asbestos filter. I think then that it is not greatly to be wondered at that uric acid in the blood in the proportion of 1 in 87,400, or 1 granule to 20 or 25 red cells, considerably blocks the capillary blood paths, and given a strong heart, causes a blood pressure of say 100 mm. of mercury ; whilst 1 granule to 1 red cell, or uric acid in the blood in the proportion of 1 to 5,823, causes a blood pressure of 150 mm. of mercury. The condition in which uric acid causes obstruction of capil- laries in the human body is one in which probably it is in solu- tion in the normal phosphates of the blood stream, in which there are also probably present some alkaUne salts of potash or soda • and we know that uric acid or urates, when in solution with phosphate of soda in a test tube, will, when cooled or treated with other chemicals, deposit in a similar coUoid or gelatinous form ; and it is quite possible that in the blood something of the same kind may occur just when there is a change of solubiUties or a balance, as it were, between alkalies on the one hand and UEIC ACID AND THE OIECULATION 175' acids on the other ; and the action of salts of lithia, for instance, makes it practically certain that it is upon the neutral phosphates of the blood that the solubility of uric acid in that and probably other fluids of the body, chiefly depends. This condition of the blood, to which I propose for the sake of convenience in writing to give the provisional name coUcBtnia, which will henceforward be used as equivalent to uricacidsemia, especially when I want to bring out the possible powers of urates in obstructing the capillaries, may be represented to the mind as much resembling a snow shower in the atmosphere ; there the crystals come either one or two at a time or in groups and batches, now numerous, now scanty, or finally in a blinding storm, shutting out the landscape and promptly obstructing the roads and paths. Such floating masses of colloid passing through the tiny blood- paths must, even when not very numerous, by mere constant con- tact, hke floating ice in a river, very greatly hinder the capillary circulation, and there is no difficulty in believing that they may adequately account for all the phenomena of obstruction on the one hand, as seen for instance in the skin in migraine, and of high blood pressure as measured in the radial artery on the other ; and, as we shall see presently, they will account for several points in the connection of disease with the excretion of uric acid in the urine which are otherwise inexphoable. Mr. J. E. Saul, F.I.C., who has very kindly at my request undertaken from time to time to examine the conditions affecting the solubUity of this colloid uric acid, has brought out some points which, if not entirely new, are well worth bearing in mind while we consider the question. Thus it appears that uric acid or urates, in solution with phos- phate of soda, win quickly throw down a bulky colloid precipitate if rapidly cooled, or if the solution is rencjlered faintly acid ; a similar solution of alkahne urates does not give an immediate precipitate on coohng, but on addition of a little acid a colloid precipitate is at once thrown down. And this colloid precipitate is said to consist of a combination of acid urate of sodium and uric acid, the so-caUed quadriurate of Sir W. Roberts. We see then that, speaking broadly, there are two things which will bring down coUoid uric acid in the test tube, one is cold and the other is shght acidification. Now it appears probable that the acidification acts in the tube just as I have pointed out that acids act in the human body, i.e., 176 UEIC ACID — CHAPTER V they convert a certain amount of the neutral phosphate of soda, which is a solvent of uric acid, into acid phosphate of soda, which is not a solvent, so that some of the uric acid is precipitated ; and' if this is so the effect of a given dose of acid will depend on the- amount of neutral phosphate of soda it meets with in the blood, just as I have also shown (again with Mr. Saul's help, see chapter ii.) that the effect of a given dose of lithia depends on the amount of phosphate it meets with. It seems then as if there is a certain point at which there is a balance between acid on the one hand and alkah on the other, depending also somewhat on the quantity of phosphates present, when colloid uric acid tends to be thrown out in the blood stream just as in the glass test tube (collcemic point) ; but it, when this condition is present in the human test tube, you give an acid you get such a further and decided precipitation of uric acid that it is all caught up in the hver, spleen and fibrous tissues (gout), and the blood in general promptly becomes clear of uric acid, just as we know that it is generally relatively clear in acute gout, or still more markedly so in acute rheumatism ; and the urine now con- tains less than normal, and the blood pressure falls because the' capillaries are free. If, on the other hand, when there is coUsemia from a balance of alkalies and acids in presence of phosphate of soda, we give an alkali, the blood pressure remains high and the urine scanty and full of uric acid, and this continue.^ as long as alkah is given, and as long as there is any uric acid to be dis- solved in it ; but if the uric acid comes to an end, the alkali being continued, then there is eventually a fall of blood pressure and a diuresis. This seems on the face of it as if the solubility in the blood formed an exception to that in the test tube, in that alkalies prevent the precipitation of colloid uric acid in the glass, and yet alkali in the blood do^s not lower the blood pressure ; but I think that this exception is apparent rather than real ; for if in a con- dition of collsemia we give an alkali, this may indeed dissolve up some of the precipitate in the blood, but as the action of the alkah is also to bring fresh uric acid into the blood from the liver, spleen and fibrous tissues (the reverse of the action of acids in driving it out of the blood into the tissues), the condition of coUsemia may remain much as before until the supply of uric acid runs short, and then, as we know, the capillary reflux quickens and the blood pressure falls even though the alkah is continued as before. UEIC ACID AND THE CIKOUIiATION 177 As soon as the supply of uric acid runs sliort there is a diuresis in spite of the alkali being continued, just as there is a diuresis under salicylates when the excretion of uric acid is coming down. The above-mentioned storing up of uric acid in the Hver and spleen (retention) has exactly the same mechanism as its retention in any other fibrous tissue of the body in gout or rheumatism. In both these the blood is relatively clear of uric acid and the granules are few in number. When the fibrous tissues of the liver are less alkaUne than the blood, uric acid tends to be collected upon and around them just as it is in the fibrous tissues of the great toe ; in these and all fibrous tissues throughout the body there is constantly going on throughout life a retention of uric acid when the alkahnity is diminishing, and a corresponding solution and throwing ofi of uric acid when the alkalinity is increasing, this accounting for the hourly, almost momentary, fluctuations in the excretion of uric acid in the urine, and the correspondingly frequent fluctuations in capillary reflux and blood granules. Some* have been much exercised to understand the exact way in which this comes about ; but it appears to me that it is simple enough, for uric acid is always present in solution round the colloid granules and the dissolved uric acid tends to pass in one direction or the other through the membranes of the body accord- ing to the ordinary laws of the diffusion of crystalloids. But in the case of uric acid this law is conditioned by the fact well known to physiologists that uric acid attracts uric acid ; for instance, a little powdered uric acid thrown on a filter will almost completely clear a urine of uric acid, even if it is only poured quickly through it once or twice. Now this attraction is dependent on the amount of alkaK present in the urine in question, and I have taken some trouble and made some experiments to ascertain this point, the results of which I may now mention. The fact that uric acid thus attracts uric acid has been demon- strated for us for years in every waterless urinal ; for the moment a urine falls on a crust of uric acid or urates it leaves behind as an addition to the crust from one half to two-thirds of the uric acid it contains, according to its acidity. But an alkahne urine on the other .hand deposits no uric acid ; * Dr. A. B. Conklin, Milwaukee Medical Journal, July, 1902, p. 192. ' 12 178 UBIC ACID — CHAPTEB V it on the contrary takes up some from the deposits over which it is passing ; but as urines are generally acid the deposits on the urinal go on increasing. Now probably precisely the same thing occurs in the living body in all the fibrous tissues as well as in those we are now specially considering in the liver and spleen. When there are accumulations or deposits in the fibrous tissues of the liver, and the blood and tissue fluids round them are slightly alkaline, the accumulated uric acid attracts more from the blood and fluids ; on the other hand, when the blood and fluids are highly alkaline they take up and carry away uric acid from the deposits. Hence gout and rheumatism occur just in those special fibrous tissues which, from the action of acids, cold or local injuries, are least alkaline at a time when the blood contains much uric acid. All the uric acid coming past the slightly alkaUne part is caught up and retained, hence Sir A. Garrod's old observation, confirmed by my own (see p. 77), that blood drawn off from an inflamed area contains little or no uric acid. This can be demonstrated in the case of the hver and spleen and is demonstrated in all my flgures of the results of swallowing uric acid ; when uric acid is swallowed and the blood is not well supplied with solvents there is no rise in the excretion in the urine, for all the uric acid swallowed has of course to pass through the liver and it there meets with other uric acid and is retained ; hence there is no increase of uric acid in the blood, no slowing of capillary reflux, no increase of granules ; but if solvents are sup- plied (saHcylates or alkahes) then the uric acid swallowed arrives in the urine grain for grain as swallowed ; the capillary reflux is also slowed and the granules in the blood are increased. In further illustration of this I will now mention a few facts about the uric acid filter, but I have unfortunately only room for a few. A morning urine, full amber, clear, sp. gr. 1024, and only shghtly acid, contains -QSi per cent, of uric acid ; the same passed through the uric acid filter is found to contain •06048 per cent., only a slight loss because it is only shghtly acid. The same urine with 10 per cent, of dilute acetic acid added to]jit and passed through the filter yields only -03024 per cent, of uric acid, a great loss by retention being produced by the increase of acidity. Again the same urine, made alkaUne to the point of precipitation of the phosphates by means of a little solid caustic potash and UEIC AOID AND THE CIBCULATION 179 passed through the filter, takes up an enormous amount of uric acid from the filter (about five times its original quantity) and is found to contain "5376 per cent, of uric acid. Another morning urine, sp. gr. 1026, is found to contain ■08736 per cent, of uric acid, and after passing the filter "0672. The same urine made alkaUne with hq. ammoniee and passed through the filter gives "06048 per cent, of uric acid, which shows that ammonia has not acted as a solvent but the- reverse, and we know that ammonium and its salts do not make gout and rheu- matism better but worse. Again, the same urine with as much phosphate of soda added as it will dissolve in the cold, when passed through the filter jdelds •10752 per cent, of uric acid, which demonstrates that the phosphate has acted as a solvent. Then an evening and night urine (amber, clear, sp. gr. 1017, acidity neutralised by 4'3 cc. of decinormal soda solution to 10 cc. of urine) yielded "05376 per cent, of uric acid and after passing the uric acid filter "02633 per cent. Note the smaller original quan- tity in the night urine and the greater proportional retention on the filter on account of higher acidity. The above morning urine gave up only J of its uric acid to the filter, the night urine gave up almost exactly | of what it contained, and here we have the exact parallel of what occurs in the body : the night serum is apt to throw out a little uric acid, leaving it in the joints and fibrous tissues of the body ; the day serum and especially that of the morning is apt to take up a little uric acid from the same joints and fibrous tissues and pass it in excess in the urine ; so that the behaviour of the urine in relation to the uric acid filter is a good and rehable index of the behaviour of the blood serum during the hours in which it was excreted. The same urine after the addition of a little bicarbonate of potash took up a little from the uric acid filter and yielded "0672 per cent., and after the addition of a similar quantity of bicar- bonate of soda "07056 per cent. The small difierence between these two was due, I think, to difference in rate of filtration through the uric acid filter, for though one does one's best to keep the filter the same and the rate of filtration the same for each specimen, absolute identity in this matter is scarcely possible, and a slightly thicker filter paper may cause slower filtration, and then a solvent wUl take up more, or a precipitant throw out more uric acid on to the filter. But in no case are these little difierences in rate of filtration 180 UBIC ACID — OHAPTBE V sufficient to account for the enormous difierences between the effects of acids on the one hand and alkalies on the other ; it is only in the case of salts, which have but a small action either way, that these shght causes of variation have to be considered. The same urine with the addition of a little citrate of potash (gr. XV.) yielded after filtration -02016 per cent., and the same urine after the addition of a similar amount of acid tartrate of potash yielded '02352 per cent. But the same urine after the addition of a small quantity of decinormal soda solution stopping short of complete neutrality, at once took up a large quantity from the uric acid on the filter and yielded '10752 per cent. Another night urine (sp. gr. 1012, acidity neutralised by 2 cc. of decinormal soda solution to 10 cc. urine) before passing the uric acid filter contained '03024 per cent, of uric acid,' after the uric acid filter '02352 per cent., a relatively sUght loss, probably owing to lower sp. gr. and greater dilution as compared with the previous specimens. The addition of grs. iii. of sodii carb. to 25 cc. of urine gave after passing the uric acid filter '18816 per cent, of uric acid — a great increase. And the use of a similar quantity of magnesii carb. yielded '14784 per cent, of uric acid. The addition of grs. iii. of urea caused a yield of '03024 per cent., i.e., it appeared to prevent retention by the uric acid filter to some extent. The addition of salicylate of soda almost up to saturation yielded '09408 per cent. And the same experiment repeated with somewhat quicker filtration yielded '06048 per cent. ; but in both the salicylate clearly acted as a solvent. The same urine with sodii salicyl. almost to saturation and with 8 per cent, of dilute acetic acid yielded '0672 per cent, of uric acid, that is, the acid slightly increased rather than diminished the solvent effect of salicylate. And this is very interesting as it is the exact parallel of what occurs in the body, where acids, as we have seen, rather increase the excretion of uric acid under salicylates. Salicylates also act best in acute conditions with fever, when the alkaUnity of the blood is low, and act feebly and inefficiently in chronic conditions with debility, when the alkalinity of the blood is high. UEIC ACID AND THE CIECULATION 181 And for the same reason they act well in cold seasons and in cold climates, badly or not at all in hot seasons and in warm climates. Again, an evening urine, full amber, sp. gr. 1030, acidity neutral- ised by 9 cc. of decinormal soda solution to 10 cc. of urine. Uric acid before filtration, '08064 per cent. Uric acid after filtration, "04704 per cent. 25 cc. of the same urine with 2 cc. acid acet. dil. gives after filtration '02688 per cent. The same urine with acetic acid added, also salicylate of soda nearly to saturation, yields after uric acid filtration "1008 per cent. The same urine with 11 cc. of decinormal soda solution yields ■1512 per cent, after filtration. The same urine with soda solution as above and salicylate of soda almost to saturation yields "24192 per cent. The above experiment shows very well the great efiect of a salicylate in overcoming the retentive action of an acid ; for the acidulated urine yielded | of its uric acid to that on the filter, while the same acidulated urine with salicylate of soda added, yielded nothing to the filter, but on the contrary took up from it extra uric acid to the extent of J of the original quantity. So that the total • solvent power of the salicylate was here equal to "07392 per cent. There seems to be no interference between alkalies and salicylates here in strong solutions, as the above result of their combined action is if anything more than the sum of their separate effects ; but we 'shall see further on that this does not hold for more dilute solutions of these solvents, as their combined efiect is then very decidedly less than the sum of their separate effects. Then the same urine with addition of 5 to 6 per cent, of borax yields "1344 per cent, of uric acid. An evening and night urine, amber clear, sp. gr. 1017, acidity equal to 3 cc. of decinormal soda solution to 10 cc. of urine, yields "04704 per cent, of uric acid. The same urine plus salicylate of soda in the proportion of 1 to 46 by weight yielded after passing the uric acid filter "04032 per cent., i.e., there was no solvent efiect, and I had previously found that small quantities of salicylate had no efiect. I also found that if I diminished the acidity of this urine to I of the original quantity, it became almost neutral to the uric acid filter and yielded "04032 per cent. I then prepared a urine containing a mixture in equal parts of the two urines above-mentioned, so that it contained half the amount of salicylate and half the amount of alkali of the above 182 URIC ACID — CHAPTEE V urines, and tke result one would have expected to be equal to ■04032, but I only got tbe result -02688. I then, using the same urine, doubled the amount of salicylate that produced -04032 and got after the uric acid filter -05376. I also doubled the alkali and got -0504. I then doubled both alkali and the salicylate in a specimen of the same urine, and one would naturally have expected the result to be about "05376, but it was on the contrary only -03024. These results seem to show that in these small quantities when the solvents are present in such small amounts that there is only a shght solvent action, the result is not equal to their united action but to something less ; instead of causing a slight solution, the effect of mixing the two solvents (salicylates and alkalies) is to diminish their action and cause a shght retention. And this again is pretty much what we see in the living body, namely, that if salicylates are losing power and alkalies are gaining, then there is what I have called " a dead point" between the two, a decided retention of uric acid producing now and then a somewhat disastrous relapse in the arthritis of gout or rheumatism. We can now understand why salicylates act well in conditions of fever and high acidity of urine, for acids do not diminish, but if • anything rather increase their solvent powers ; also why they act feebly- in conditions of debiUty in the absence of fever and with slightly acid or alkaline urine, for alkalies diminish their solvent powers. These solvents cannot be present in the blood except in somewhat dilute solutions, so that the above experiments furnish a complete explanation of their observed action. We also see why it is wrong to let the patients parspire, or to wrap the joints in cotton wool while we are giving salicylates. Alkalies and heat pull together, salicylates with fever or with cold and acids go together ; but to mix salicylates with alkalies and heat is a fatal mistake, and often accounts not only for the failure of salicylates to do good, but also for their doing much harm (see cases in chapters ix. , xvi. and elsewhere). Then we can range the substances above mentioned in the order of solvent power somewhat as follows : First come the alkalies potash and soda, and next their carbonates, and behind them their bicarbonates, solvent power obviously falling as the amount of alkali diminishes ; next come the salicylates in strong solutions, and lastly borax and phosphate of soda. Among the notable things assisting retention are acids, liq. UEIC ACID AND THE CIBCULATION 183 ammoniae, citrate of potash and acid tartrate of potask; these two last no doubt act as solvents in the body, but that is only after their conversion into carbonates, which as we have seen are powerful solvents. The action of Uq. ammoniee is very interesting, as its effect in clearing the blood of uric acid and relieving migraine and depres- sion has long been known ; and even the inhalation of diluted ammonia fumes will produce quite a marked improvement in some of these conditions. Some evidence that alkalies seem to have a solvent action in collaemia is that kindly given me by Dr. T. Wilson, of Wallsend- on-Tyne, who reports that his headaches have been cured by my diet, and that his own remedy for them was bicarbonate of soda when the attack was coming on, and this always gave relief in from five to ten minutes. Acting on what he told me, I did try some bicarbonate of soda in a sHght headache, and it undoubtedly relieved me, but as I, without thinking, took it in a tumbler of warm water, I am stOl in some doubt whether it was the hot water or the alkali that did good, as both the heat and the alkali would, as we can now see, tend to prevent collaemia. I can, however, contribute an experience which, I think, throws some light on these points, for one day when I was taking an alkali and had got my urine almost continually alkahne, and feeUng very well, as I thought, because I had little or no uric acid to get into solution with it in the blood, I chanced to take some rhubarb for lunch, and very soon after the meal was over I was surprised to be taken with a shght but quite distinct head- ache. I can only suppose that when on an alkali I was well, not because I had no uric acid in the blood, but because with plenty of alkaK I was on the alkaline side of the coUsemic point, and that then the rise of acidity after lunch, reinforced by the acid of the rhubarb (see fig. 66), brought the blood to the neutral or coUsemic point, causing a rise of blood pressure and headache. And Dr. Wilson, it is interesting to note, regards acids as poisons, and records several instances in which the taking of vinegar, or some food mixed with vinegar, or an acid wine such as sherry seemed very distinctly to bring on an attack of headache. And it is quite possible that if the alkalinity of the blood is high, or he had been taking an alkali, the subsequent taking of such an acid would bring his blood to the collsemic point and produce a headache just as the acid of the rhubarb appeared to do in my 184 UEIC ACID — CHAPTEE V case. And such a headache might be cured either by taking more acid to clear the blood of uric acid completely, or by taking an alkali to get away from the coUsemic point in that direction. Speaking of this reminds me that I have seen from time to time quite a number of patients who have asserted that a dose of an ordinary acid mixture brought on a headache, though a very much larger number have had their headaches prevented or cured by a similar mixture," and we can now see that the report of the minority may have been just as true as that of the majority. I have also notes of several cases in which an attack of asthma was relieved by a dose of sodii bicarb., which is diifi- cult to explain unless the above considerations explain it (see chapter ix.). In old times, when I had frequent headaches and much uiic acid, alkalies used to produce headaches or make them worse, but it is possible that in those days I did not take enough alkali to combine with all the uric acid present and carry it beyond the coUsemic point. Further, if this is correct, we can at once see that the cause of the onset of headache or depression, with very high blood pressure, in the early a.m. hours is the gradual change of reaction from the acid tide of the night, through the collsemic point to the alkaline tide of the morning, which may coincide with plus alkalinity of the blood and very low acidity of the urine. And I am decidedly of opinion that the pulse is often slower and the blood-pressure higher about 5.0 or 6.0 a.m. (time of collsemic point) in spite of being warm in bed, than it is an hour or two later, though the lowest acidity of the urine may not be reached till about 8.0 or 9.0 a.m. (see fig. 3). At the time of the lowest acidity of the urine and the greatest alkaUnity of the blood (9.0 a.m.) there may be more uric acid in the blood than at the time of the coUeemic point (6.0 a.m.) : but as some of that uric acid is held in better solution owing to the larger amount of alkah available, there may be less coUsemia and less blocking of capillaries at 9.0 a.m. than at 6.0 a.m. We can now see why there may be less high blood pressure, head- ache and depression at 9.0 a.m. than at 6.0 a.m., though the amount of uric acid in the blood is greater at the former hour than at the latter. And this is one of the conditions under which colleemia is not co-extensive with uricacidsemia. UEIO ACID AND THE CIECULATION 185 Again we can see that the low blood pressure and soft pulse which result from continued muscular exercise may be due to the colleemia being dissolved by the plus alkali and increased tempera- ture, as well as to the lowered pressure produced by the increased area of circulation in the muscular tissues ; and then when the exercise has ceased, and the acidity of the urine is rising and the alkahnity of the blood is falling, we again get it passing through the coUsemic point, and get the headache, depression, and high blood pressure of fatigue in those cases where there is enough uric acid available to produce severe coUsemia. Another point which it may explain is the value of getting the urine alkaline (with citrate of potash, for instance) in acute Bright's disease, as pointed out by the late Sir W. Roberts (" Urinary and Renal Diseases," ed. iv., p. 436) for this will not only lower blood pressure by getting some of the colloid in solu- tion, but it will also render the substance of the kidney alkaline, and so prevent the retention and aid the excretion of uric acid from it. To test some of these points I gave, in a case of chronic Bright's disease with high blood pressure and slow pulse, enough citrate of potash to render the urine alkaline almost throughout the twenty-four hours ; but this, even though continued for more than a week, neither increased the urine, lowered the blood pressure, or quickened the pulse, at least to any marked extent ; while iodide of mercury subsequently given very distinctly quickened the pulse. Most of these points require much further investigation, but there are now very many things which seem to show that col- leemia is the cause of high blood pressure, and as we shall see, this already serves to explain more or -less completely several facts otherwise inexplicable.' Thus there is no doubt that the uric acid headache is greatly relieved by warmth, such as sitting in front of a good fire or plunging the hands and feet in hot water and keeping them there, and it seems probable that the real explana- tion of this is the effect of the warmth in preventing the col- laemia, just as in the case of the drink of hot water I have men- tioned, and this also is just the reverse of the efiect of washing the hands in cold water in Raynaud's disease. Some evidence that an alkali may possibly help to dissolve collsemia so long as there is not more uric acid present than it can hold in solution is, I think, to be seen in the record of the cases of epilepsy in chapter vii. treated with an alkah by Dr. C. Mordhorst, of Wiesbaden, as well as in the case, also there re- 186 UEIC ACID — CHAPTBE V corded, in whicli an alkali given to a gouty patient apparently produced epilepsy (see also remarks on these cases and on tne paper of Dr. Ackermann in the same chapter). Again, I have seen a patient who came from South America, and who said that while out there he was able to eat a large quantity of meat without harm ; but that if he attempted to do the same in this cold country he sufiered terribly from depression, and he had thus been obUged to take less meat in this country. Now, I think that as he ate a large amount of meat in South America he would certainly have a large amount of uric acid through his blood, but the warm climate might do a good deal to prevent coUsemia ; while in this cold climate, even if he got less uri,c acid passing through his blood, there might be more severe coUsemia owing to the precipitating action of the cold. And I believe also that when there is much uric acid in the blood exposure to cold causes severe coUsemia, and this causes such a paralysing effect on circulation and nutrition that the result is a depression of nutrition and metaboUsm all round. Hence, as. I know, some cases of mental depression are much worse in the very cold weather. On the other hand, when there is but little uric acid available, cold acts as a stimulant, it raises the acidity of the urine and lowers the alkalinity of the blood, clearing it of uric acid in the way that acids do, thus stimulating nutrition and metabolism, and causing the fires to burn up brightly ; and this is probably the explanation of the now very generally recognised fact that those who live on a fleshless or uric-acid-free diet, feel the cold less and require less clothing in winter than those who take flesh constantly. Cold is a stimulant to the former, but as it helps to cause severe coUeemia in the latter, the fires are put out by it rather than stimulated. These considerations also help us to understand completely the great efEects of cold on the nutrition of the skin and the important part attributed to this agent in the production of Bright' s disease by the late Professor Semmola. To understand these points we must always bear in mind that cold has a double action in precipitating uric acid in the blood, (1) the direct action of cold as in the test-tube, alkaUnity being unaltered, and (2) cold, by diminishing the excretion of acids in perspiration, diminishes the alkalinity of the blood. To overcome the effects of cold alkaU must always be very plentiful, for it has not only to counteract the retention of acids in perspiration, but also the direct precipitating effect of cold. UEIO ACID AND THE CIECULATION 187 Hence in cold weather we must not only avoid acids but supply plenty of alkali, and I often carry alkali in my pocket to supply the place of the absent sun or an extra great-coat. This treatment would not do for a meat-eater because his supplies of uric acid are almost unlimited ; but mine are small and easily kept in complete solution by a little alkali, and then I am accustomed to say that I have " summer " in my pocket. And the circulation curves at once tell where " summer " has been absent, as cold then causes retention, followed by a rebound quite visible in the curves of capillary reflux and blood pressure (see fig. 40). For these reasons I never advise those on diet to keep them- selves cool, on the contrary, I advise them to keep warm and avoid retention ; and warmth will not depress and fatigue them as it does the collaemic meat-eater (see " Physiology and Pathology of Fatigue," chapter ii. of " Diet and Food."). Then I notice that Herz (Wiener Klinik, June and July, 1896) in an article (an abstract of which appeared in the British Medical Journal, epitome, November 28, 1896) points out that the smallest vessels, whose walls are not muscular, pulsate more vigorously the greater the rigidity of the tubes connecting them with the heart, and argues from this that the degenerative processes cannot, as supposed by Gull and Sutton, begin in the smallest vessels, but must in them be secondary to changes in the arterioles and larger vessels. These points are entirely favourable to the possibility of mechanical obstruction in these smallest vessels that have no muscles, and the obstruction thus produced reacts on the larger muscular vessels behind and gives rise to pressure and strain and eventual degenerative change ; but I shall have to refer to some of these points again. Some most interesting points with regard to the solubility of uric acid in the blood have been brought out by Dr. C. Mord- horst, of Wiesbaden, in some researches published in an article, " Die Entstehung und Auflosung der Harnsaureverbindungen ausser- halb und innerhalb des Menschlichen Korpers," ZeitscJir. fur Klin. Med., 32 Bd., H. 1, u. 2. Thus he divides the urates with which we have to deal into two : (1) The spherical urate, which probably corresponds to the colloid urate, investigated by Mr. Saul, which has a spheroidal structure under the microscope, and (2) the needle urate — the biurate or acid urate of sodium. 188 XJBrC ACID — CHAPTER V The spherical urate differs from the needle urate chiefly in containing more alkali, and it does not appear to be a definite combination, but contains more or less alkali according to the quantity available in the fluid in which it is dissolved or suspended. The more alkali and the less uric acid it contains the more soluble it is ; but if with any given alkalinity the saturation point is exceeded, the urate is thrown out in spheres, which are so minute as to be invisible at first, but which gradually combine into visible masses. The spherical urate is thus suspended not dissolved ; but the addition of a solution of sodium will cause it to pass again into solution, or on the other hand the addition of an acid or acid salt will cause it to be still further thrown out of solution. The longer the spherical urate has been in suspension the more difiicult it is to redissolve it, and after it has been in existence for some time it begins to decompose into sodium and acid urate of sodium (needle urate). If a solution of sodium is added to crystals of uric acid, spherical urate is formed, and becomes visible in suspension round the uric acid crystals ; with excess of alkali the spherical urate then passes into complete solution. The spherical urate in solution or suspension is that which we have to deal with in the blood and tissue fluids of the body ; and Mordhorst does not find in the blood any urate having less sodium than the biurate (needle urate), such as the quadri- urate of the late Sir W. Koberts, though he thinks that such a quadriurate may form a temporary stage in the change from acid urate to uric acid\ We thus get a perfect gradation by addition of alkah from uric acid, through quadriurate and acid urate up to spherical urate, and a corresponding change in the reverse direction from spherical urate to uric acid by the action of acids or acid salts taking alkah away. Hence everything that increases alkahnity increases the solu- bility of uric acid, and everything that removes alkali or diminishes alkahnity diminishes its solubility, which is in absolute and com- plete accord with all my physiological results in the human body, as well as with the uric acid filter results given above. These results have been obtained by Mordhorst by placing uric acid or urates under the microscope, and acting on them with solutions of caustic alkali, salts, or acids, as the case may be. When we have the spherical urate in solution its precipitation UKIC ACID AND THE CIRCULATION 189 is brought about by over-saturation of the containing fluid, and this may be produced either by addition of uric acid, taking away of alkali, evaporation or cooling. Owing to the defective circulation, the fluids in the slightly vascular fibrous tissues and cartilages of joints tend (as Sir A. Grarrod has already pointed out) to be less alkaline than other tissue fluids, but they will contain the same quantity of spherical urate as the blood. The spherical urate in the fluids of these tissues will therefore tend to be thrown out, partly on account of their diminished alkahnity and partly because in sedentary conditions the fluids are not moving much between and through the tissues. This spherical urate is first thrown out in extremely minute particles, which, however, may unite and congregate into larger and larger masses many times the size of a white corpuscle. These increasing masses' of spherical urate eventually get large enough to block the lymphatic vessels of the part and to give rise to stasis, pressure and pain, and this is, according to Mord- horst, the causation of an attack of rheumatism, and accounts for the local swelling and tension. If the spherical urate is left for some time in situ the needle urate is eventually thrown out ; but, as in rheumatism, there comes very soon a general rise of alkahnity, the spherical urate is redissolved again without, it may be, leaving any needle urate behind it ; the needle urate can also take up alkali and pass back again into the spherical form. In gout, on the other hand, the spherical urates remaining longer in suspension become more difB.cult to dissolve, and hence the needle urate is more likely to be thrown out ; but it is the spherical urate which causes the local irritation and the tissue changes, and when the needle urate is thrown out the irritation ceases. Mordhorst also believes in opposition to Ebstein that necrosis of tissue is entirely secondary to the throwing out of the spherical urate, and this subject he has treated of in another paper, " Zur Entstehung der Uratablagerungen bei Gicht," Virchow's Archiv, 148, B., 1897. It is only possible to give here quite a short outline of these interesting results obtained with the microscope, ajid it is obvious how very favourable they are to the explanation I have given of my physiological results. Dr. Mordhorst says in a letter I received from him : "I am convinced of the correctness of your 190 UEIC ACID — CHAPTBK V opinion, that the uric acid is retained in the tissues of the difierent organs through an abnormally low alkalescence " ; and further on he says : " I am of opinion that Sir William Eoberts has made the mistake to believe the fluid parts of the body to be a simple solution of alkaline and neutral salts, whereas it is a solution the alkalescence of which is considerably reduced through the presence of acid salts (mono-natrium phosphate), a thing still more the case in the cartilage and tissue." And it follows from Mordhorst's results above stated that the more alkali the phosphates of the blood and tissue fluids contain, the better will they hold the spherical urate (colloid urate) in solution ; and this is in complete accord with what I pointed out some years ago in the Medico-GMrurgical Transactions (prev. ref.) that binatrium phosphate given with sodii carb. increases the excretion of uric acid, while if the same salt is given with dilute phosphoric acid, or even with a salt such as sulphate of sodium, it will cause no plus excretion of uric acid, perhaps even a diminished excretion. It is also of the greatest possible interest to me that Dr. Mordhorst should have seen reason to suggest that the spherical (or colloid) urate could block the lymphatics, and thus give rise to some of the phenomena of rheumatism, as this is very close to my own suggestion first made in the third edition, that the same substance may mechanically obstruct the blood capillaries, and thus account for the phenomena of defective circulation and high blood pressure. Among points of minor interest, Dr. Mordhorst lays stress on the influence of cold in throwing the spherical urate out of solu- tion, and its bearing upon the causation of rheumatism locally in certain exposed tissues, and this also bears on the explanation I have for some years been giving of the limitation of Raynaud's disease to the skin and superficial structures of the thicker parts of limbs. Dr. Mordhorst is a believer in the presence of uric acid in healthy blood, and thinks that von Jaksch and Klemperer, who found none, worked on too small quantities of blood (prev. ref., p. 21 of reprint). He thinks also that blood can at times dissolve more uric acid than it can continue to hold in solution, and this is in favour of. what I have said (that uric acid interferes with its own solubility in the blood) and is interesting in reference to the effects of alkalies previously mentioned, as they may, as I have suggested UBIC ACID AND THE CIRCULATION 191 bring mucli uric acid into the blood, and when there may fail to hold it in complete solution and so produce coUaemia and high blood pressure, while some increase of alkali may dissolve up the colloid or spherical, urate once more. Dr. Mordhorst also points out that the effect of deficient circulation in the skin, whether produced by cold or other causes, is to make its fluids less alkaline, so that they become super- saturated with urates, and contain the spherical urate in sus- pension, and if this is so the defective circulation produced by collaemia will tend to keep up the coUsemia, and hence in Ray- naud's disease washing the hands in cold water may start a local collaemia, which tends to progress and requires a great change of general alkalinity to dissolve it up again. I wiU now give a few more facts bearing on the relationship of urinary water to uric acid in excretion. Thus, in my notes of May 8, 1891, uric acid was high, having a relation to urea for the whole twenty-four hours of 1 to 22. This means that there was a large excretion of uric acid, some 4J grs. of it being washed out from deposits in the organs and tissues, and passing through the blood on its way to the kidney. Now, practically, a large excretion of uric acid on any day means a large excretion in the alkahne tide periods of that day. And now look at the urinary water on this day ; with a large excretion of uric acid the water of seventeen hours of the day equalled only 600 cc, or 35 cc. per hour, a very low excretion ; and during the seven hours of the night it was 570 cc, or 81 cc. per hour ; the water held back during the day was, to a large extent, passed out as soon as the high acidity of the night period cleared the blood of uric acid (the exact parallel of digitalis, see remarks on fig. 33). Then take another day, as May 11, when the uric acid bears nearly its normal relation to urea, namely, 1 to 32 ; there would be but a slight excretion in the alkaline tide, and, in accordance with our premisses, httle or none passing through the blood ; and, under these conditions, the water for seventeen hours of the day was 1370 cc, or 80 cc. in the hour ; while the excretion in seven hours of the night was 630 cc, or 90 cc. per hour ; on May 8 the urine per hour at night rose to two or three times its amount per hour in the day. On the 11th the night urine was only one eighth ■ more per hour than that of the day ; on the 8th water was held back in the day and passed out at night ; and on the 11th it was passed freely in both periods ; hence, as I have said. 192 UBIC ACID — CHAPTEE V the urinary water is inversely as the uric acid excreted along with it, and inversely as the amount of it in the blood, because the greater the amount of uric acid in the blood the more obstructed are the capilla,ries of the kidney. It will thus be seen that my assertion, that arterial tension (blood pressure) varies directly as the uric acid in the blood, has other foundations besides observations of the pulse rate and ten- sion, though, as we shall see presently, these are conclusive enough ; and the same thing is seen when followed from hour to hour ; the urinary water is inversely as the uric acid, and if the uric acid is intentionally increased or diminished the water alters in the opposite direction. This brings me to the action of drugs and the experimental aspect of the question, but the same laws hold good : — (1) All substances which increase the solubility of uric acid increase its excretion and vice versd. (2) Substances which increase its solubility bring it into the blood in large quantities, obstruct the capillaries, slow the heart, and diminish the urinary water. I have already gone into the action of drugs on uric acid : I shall here merely mention their effects as regards the pulse rate and tension, and the secretion of urine. First of all, drugs which increase the excretion of uric acid : — alkaUes, as soda asid potash, increase the excretion of uric acid and diminish the urinary water ; but as their effect on uric acid is coming to an end (possibly because all the immediately available uric acid is cleared out) there is more or less diuresis, the water passing out which they at first held back. This is illustrated in the figures of May 8 just mentioned. This was a natural excre- tion (or fluctuation in excretion) apart from drugs, but precisely the same thing would have occurred if I had given alkalies to increase the uric acid. Salicylates again bring excess of uric acid into the blood, and while the excess of uric acid is being passed in the urine, the water is not very copious, but tends to be high-coloured and scanty ; hence, as has been noted by several observers (Huber in Deutsch. Archiv. fur Klin. Med., xii., p. 129, and Stiller, British Medical Journal, 1890, vol. i., p. 808), as well as myself, the great diuresis with salicylates comes on the second day of their admin- istration, when the excretion of uric acid and the amount of it in the blood is beginning to diminish from want of supplies. Diuretin -= Salicylate of sodium and theobromine (= dimethyl- UEIC ACID AND THE CIECDLATION 193 xanthine) appears to me to produce diuresis in much the same way that salicylate of soda produces it, namely, by clearing the Uood of uric acid. I made some experiments with tabloids of this sub- stance, kindly sent me by Messrs. Burroughs, Wellcome and Co. and my results show that just as with salicylate of soda there is no diuresis on the first day of taking the drug, on the contrary, the uric acid rises and the water falls, but there is a diuresis on the second or third day, when the excretion of uric acid comes down again. I have no doubt, therefore, that the diuresis is due to the salicylate element, or rather to the action of this element on the excretion of urates, and this explains the fact, noted by some observers, that the diuretic efiects of diuretin may continue after ceasing to take the drug (Massalongo and Silvestri, " Re- forma Medica," March, 1893). On the other hand, if the diuresis were due to the dimethyl-xanthine it would occur soon after the drug was administered, as is the case with uric acid, hypoxanthine, caffeine, &c. (see previous remarks on these substances). It is interesting to note that diuretin has been said to diminish the area of cardiac dulness by exerting a tonic action on the cardiac muscle, and it is therefore proposed to give it in uraemia in place of digitalis, when there is a slow pulse (Zeitsch. filr Klin. Med., 1894, vol. xxii.). As will be seen in chapter xiii., I have given salicylates in uraemic conditions with considerable benefit ; but I should doubt very much whether dimethyl-xanthine has any tonic action on the cardiac muscle, and I believe that it reduces the area of cardiac dulness in the same way that iodides or mer- cury and other metals reduce it, by clearing the blood of uric acid, freeing the capillaries and thus allowing of a fall of blood pressure, which reduces the resistance to its action, and, therefore, the work the heart has to do. Probably caffeine, a near relative of theo- bromine, which is now a good deal spoken of as a cardiac stimu- lant and tonic, acts in exactly the same way. With phosphate of soda again the water fluctuates in accordance with the excretion of uric acid, and independently of the amount of the drug ; when the drug markedly increases the excretion of acid, the water tends to be low. A large excretion under the phosphate or salicylate is not, as I have remarked before, accompanied by any headache, but the excess of uric acid in the blood keeps the capillaries moderately obstructed and blood pressure somewhat high, though to nothing like the same extent as would be the case if the same amount of uric acid was being excreted under an alkah ; so that I have sup- 13 194 UEIC ACID — CHAPTEE V posed that the compound formed by uric acid with salicylates and aUcal^ue phosphates has less efEect on the capillaries than the com- bination with a simple alkali; but probably even when salicylates or phosphates are in circulation there is always some urate combined with an alkali, and this may account for the efEect on the capillaries in all cases. Of drugs which diminish the excretion of uric acid, opium is perhaps the most important ; I believe that it acts as an acid, which in nature, apart from drugs, is the most important factor. The pulse of opium well being and of the rebound next day are to be found in fig. 35. The efiects of morphine in raising the acidity and causing retention of uric acid are shown in fig. 15, and along with these go the quick low tension pulse, B in fig. 35, which again is the Pig. 3i. — Pulsb Tbacings showing the blood pebssube, A bbfobe and B DURING, THE ACTION OP MeBCURY. sign of a free capillary circulation throughout the body ; its efiects and further signs are mental well-being, bodily strength, power of endurance, and a free excretion of urinary water. Here, again, all these efiects are due to the action of the drug on uric acid, and correspond with it. Thus, one morning before breakfast when my pulse was slow and of high tension (rate 58), I measured the urine in the hour ending 8.15 a.m., and found it 53 cc, I then took TTL vi. of tincture of opium, in tabloids and without fluid, the pulse at 8.15 being 62, and I collected the urine of the next hour ending 9.15, no food or drink having meanwhile been taken since the previous evening. At 9.15 a.m. the pulse was 72, markedly softer, and with a larger dicrotic wave than the pulse trace at 8.15, and the urine passed in the hour was 234 cc. Obviously then the comparatively scanty urine at 8.15 a.m. was not due to want of URIC ACID AND THE CIRCULATION 195 water in the body, but to obstruction of the capillaries with which it corresponded ; and the ordinary morning collsemia was here brought to an end by the action of the opium as an acid. Mercury I have also written about, and as to the facts that it reduces arterial tension, and produces diuresis, the wntings of Broadbent and Jandrassick sufficiently testify. I believe, as I have said, that these effects are simply and solely due to its action on uric acid, furnishing in this respect but a single instance of my general laws above stated. Fig. 34 shows the pulse tracing, A Pig. 35. — Pulse Tracings of Opium Ebbound, of Opium well-being, AND 01" AnTIPYBIN WELL-BEING. before and B during the action of mercury, the latter correspond- ing with a minus excretion of uiic acid and a diuresis (see fig. 17, p. 67). Fig. 35 shows, B the pulse of opium well-being, the first stage action of opium ; note the quick fall, and the smaU first wave and the relatively large dicrotic wave. The capillaries are obviously free, and the pulse soft and quick ; and with this the urine is pro- fuse, as in the instance mentioned above, where a dose caused such marked diuresis in myself, and there is well-being and increased mental activity. D shows a very similar pulse, produced by taking antipyrin, and both opium and antipyrin relieve the uric acid headache. 196 UBIO ACID — CHAPTBE V A is the opium rebound, the second stage action of opium, the pulse of the morning hours after a dose of opium overnight. Note the slow fall, the large first wave ,and relatively small second wave. With this there goes headache, mental depression, malaise, disinclination for exertion, and the urine is scanty and contains excess ot uric acid, and the contrast between this pulse tracing and B and D is very marked. Fig. 34 shows that mercury produces a pulse Uke B or D, because it also clears the blood of uric acid, and it also cures migraine. Lithia is one of the most interesting of the other drugs which produce the same results. I have given above, with reference to fig. 14, my explanation of the fact that it reduces the excretion of uric acid. Lithia markedly diminishes the acidity of the urine, and yet, unlike the alkalies which produce this result, it reduces blood pressure, quickens the pulse, and produces diuresis. Here again we see that the efEects on the blood pressure and flow of urine depend on the uric acid and not on the acidity, alkalinity, or other power of the drug. Soda and potash raise the blood pres- sure, diminish the urine, and make it more alkaline. Lithia diminishes blood pressure, increases the urine, and also makes it more alkaline, but soda and potash increase the excretion of uric acid, lithia diminishes it. Again, as before remarked, if all uric acid has been removed by a course of salicylates, soda or potash will fail to increase the excretion of uric acid, and in this case they will also fail to raise the blood pressure and diminish the flow of urine. The facts about hthia are very interesting, and I find on a reference to my old notes and curves that on a day when no drugs were taken the urinary water was 1280 cc, and there was a plus excretion of uric acid (1 — 24). On the following day 25 grs. of the citrate of lithia were taken, and with this there was, as is usual with hthia, a great fall in acidity of the urine, viz. to 38 grs. from 62 grs. on the previous day, but in spite of this, uric acid was diminished greatly, having a relation to urea of 1—44. And now mark the result; i£ an alkali had been given, as potash or soda, to produce such a fall of acidity, a plus excre- tion of uric acid would have been the result, the blood pressure would have been high and the urine scanty, but lithia, for the reasons previously given in chapter ii., produced retention of uric acid, cleared it out of the blood, and in spite of the rising alka- UBIC ACID AND THE OIEOOLATION 197 linity there were free capillaries and a very marked diuresis. The day before the Uthia, the uriae containing a plus excretion of uric acid was 1280 cc, that of the Hthia day with a minus excretion of uric acid was 1790 cc. Here again we see that the freedom of the capillaries and the diuresis resulting depends not on the greater or less alkalinity, but on the greater or less amount of uric acid in the circulation, and lithia apparently prevents col- laemia just as acids do by throwing a certain amount of phosphate of aoda out of action ; and possibly the non-appearance of these phosphates in the urine may account for the fall in its acidity. It may be of interest also to remark that a somewhat similar fall in the acidity of the urine accompanies the diminished excre- tion of uric acid produced by iodides, and this suggests that the retention they produce which remains unexplained, may be the result of some effect on the phosphates of the blood, but so far as I can learn there are no known chemical facts to support this. In contrast to lithia see the effect of other alkalies. On March 16, 1888, no drugs, urine 1410 cc. ; on March 17, pot. bicarb, gr. xxx., urine 1400 cc. ; on the 18th, pot. bicarb, gr. XX., sodii bicarb, gr. xx., urine 1170 cc, and with this fall in urinary water there was a plus excretion of uric acid. Again, on May 19, 1887, with no drugs urinary water was 1670 cc, and uric acid to urea 1 — 32. On 20th, with 70 grs. of bicarbonate of potash urine was only 1260 cc, and uric acid to urea 1 — 26, i.e., with a plus excretion of uric acid as the result of the alkali, the urinary water was reduced, which corresponds with the fact, that in the natural plus excretion of uric acid in migraine the urine is scanty, and bears out what I have said previously, that the urinary water is inversely as the uric acid excreted along with it. The action of iron and lead is precisely the same ; so long as they diminish the excretion of uric acid they free the capillaries and produce diuresis, but when their first action comes to an end uric acid is excreted in excess, and there are then high blood pressure, slow pulse, and scanty urine, just as in the opium rebound. All other drugs which diminish the excretion of uric acid pro- duce just the same results ; as cocaine, antipyrin, the nitrites and various salts of the mineral acids, especially sulphates. Strychnia also (possibly indirectly) raises acidity and affects uric acid, the pulse and urine, like other members of the group. Fig. 23 shows us the effect of copaiba, the diuretic action of 198 UEIC ACID — CHAPTBE V which is so well known, and we see that the diuresis it produced corresponds with a marked fall in the excretion of uric acid, so that no doubt the capillaries were freed. I believe that this may- be taken as a type of a number of resinous substances which produce diuresis, and all of which probably act in the same way. Thus copaiba introduces a considerable quantity of copaivic acid in its resin which forms glycuronic acid in the "system, and one or both of these acids may no doubt afiect the neutral phosphates of the blood and prevent their being good solvents of uric acid. Tar, again, contains several acids. Ehubarb contains chrysophanic acid, and cannabis indica contains a resinoid substance, cannabin, which, like the resin of copaiba, may consist of acids. All these substances act as stimulants, causing free capillaries, well-being, and more or less diuresis, and all these effects correspond in time with a diminished excretion of uric acid in the urine. Tar is a stimulant, and in the form of a patent medicine which I have used, it undoubtedly causes marked weU-being and freedom of capillaries. It is interesting to remember its value in lung troubles, as bronchitis and phthisis, and if it acts on uric acid it wiU no doubt free the capillaries all over the body, and be of use in lung troubles in the same way that the iodides are ; and tar water is, I believe, one of the constituents of Hair's Asthma Cure, in addition to an iodide, the action of which it wiU no doubt increase. Liquorice is another substance which has been used for many years in bronchitis and catarrh, and its action as a stimulant is referred to by Dr. Keith ("Fads of an Old Physician," p. 77), though I cannot quite agree with his pathology of headaches, sleeplessness, and low spirits ; but liquorice, I have very little doubt, contains some resin or acid similar to that of tar or copaiba, and its solution in distilled water distinctly reddens litmus, and this no doubt accounts for its stimulant effects. Ehubarb, again, has a remarkable stimulating efiect, causing freedom of capillaries and weU-being, and its valuable stimulant action in gouty dyspepsia is, I think, probably due to its efiect on uric acid. Cannabis indica is a stiU more marked instance of the same thing, and its stimulation is very clearly contemporaneous with a diminished excretion of uric acid. Its stimulating powers are great, and it is well known to cure or prevent migraine, the uric acid headache ; in the same way, also, it is very useful in melancholia URIC ACID AND THE CIECULATION 199 mental depression and bad temper; like tar, it is useful in asthma and phthisis. Another drug with a similar action, the American spirit weed (Lachnanthes) has also been strongly recommended for phthisis, and it also appears to raise the acidity and clear the blood of uric acid, causing very marked well-being. Cannabis indica has also been strongly recommended as a haemostatic in menorrhagia, and this is extremely interesting, as we shall see later on that drugs such as mercury and iodides, which have the same effect that cannabis indica has on uric acid, are often very useful in haemoptysis, when they probably act by lowering the blood pressure ; but about this I shall have more to say presently. If we only bear in mind the fact that clearing the blood of uric acid means freeing the circulation and quickening combustion and metabolism throughout the body, we shall have no difficulty in understanding how many of the drugs mentioned above afEect at one and the same time such different organs and tissues as the skin, the brain, the lungs, the stomach, the kidneys, and the uterus. This shows up also very clearly the nonsense that is often talked about diuretic drugs and their action on the renal epi- thelium, it is easy to demonstrate that they have a similar and contemporaneous action on the epithelium and cells of every gland and tissue of the body, and this is due to the fact that they clear up collaemia and allow of a free capUIary circulation through- out the body, hence the corresponding fall in blood pressure and the lessened diameter of the radial artery. If now we turn to pathology, we again find a whole series of facts which our knowledge of the effects of uric acid on the capillaries will enable us to explain completely. It is a well known clinical fact that having to rise one or more times in the night to pass urine is a very common symptom in Bright's disease, but it will, I think, presently appear that this is not so much a symptom of Bright's disease as of a condition (high blood pressure) which is very commonly present in Bright's disease. When a patient tells me that he has to rise one or more times in the night to pass water, I feel sure that he has high blood pressure (provided, of course, there is no local irritation in the urinary passages), but this may or may not be due to Bright's disease. The excretion in my own person on May 8, previously men- 200 UBIO ACID — CHAPTBE V tioned, will very weU illustrate what I mean. On this day th«re was marked collsemia in the alkaline tide, and the urine during the day was only 35 cc. per hour, but at night the acidity rose, the collsemia came to an end, and the excretion of water rose to 81 cc. per hour. Now, something of this kind happens in the high blood pressure of Bright's disease every day ; there is chronic coUeemia, but this is most marked in the alkaUne tide of the morning, when the slow pulse is at its slowest, and the hourly excretion of water is at its lowest, and the temperatures in the mouth and rectum are at their furthest distance apart. It is least marked in the acid tide of the night, when the pulse is at its quickest and the hourly excretion of water at its highest ; hence the patient with high blood pressure, whether he has Bright's disease or not, has to rise in the night because he ex- cretes much more water per hour at that time ; and in my own case I have, under conditions similar to those of May 8, been roused up in the early hours of the morning by a distended bladder. Under the opposite conditions eight or nine hours may easily pass without micturition being necessary. For a case in which the hourly excretion of urinary water was much greater in the night than in the day in association with slow high tension pulse, see article on " Obesity Treated by an exclu- sively Nitrogenous Diet and copious Libations of Warm Water," by Thomas D. SaviU, with remarks on the excretion of uric acid, by Alexander Haig. — Lancet, 1893, vol. ii., p, 133. It is generally possible to tell, when the urine is scanty, whether this is due to concentration of the blood, or to obstruction of capillaries preventing outflow of water from it (see efiects of opium previously mentioned). When it is scanty, owing to concentration of the blood, then there is no diuresis at night, but the water of the night hours is as scanty as that of the day. On the other hand, when it is scanty during the day, owing to collsemia and retention of water in the blood, it is profuse at night, when in the natural order of things the blood is cleared of uric acid and the capillaries are free, for all the water held back ia the day rushes out ; and this is well seen in that exaggeration of normal conditions, chronic morbus Brightii ; here the urine is scanty, and the blood dilute during the day, while collsemia and constant obstruction of ^ capillaries are greatest ; and the urine is profuse and the blood becomes relatively concentrated during the night, when the collsemia, just as in normal conditions, is less, and the vessels are relatively free. OEIC ACID AND THE CIKCULATION 201 Supposing that under pathological conditions the plus uric acid in the blood continues aU night, as sometimes occurs in the uric acid headache, then the water is scanty all night also ; but we have abundant evidence that it is not scanty owing to concen- tration of the blood, in the diuresis which occurs as the headache passes off. Under opposite conditions, when the blood is reaUy concen- trated, the urine is as scanty by night as by day, and the follow- ing is an instance : — On 18th March I took a long bicycle ride, and being out of training I perspired very greatly and found it very hot work ; the urine on this day was 920 cc. (on the previous day 1230 cc), = 40 cc. per hour in sixteen hours of the day, and 35 cc. per hour in eight hours of night. On the 19th it was 900 cc, 35 in the day and 42 in night. On 20th, 1030 cc, 39 in day and 50 in night, and on 21st, 1370 cc, 45 in day and 80 in night. It had now returned to nearly normal quantity, and the urine per hour at night was, as is frequently the case, nearly double that of the day. On the other hand, when the blood was concentrated, the water per hour at night was less, or not greater than that in the day. When the blood is thus concentrated there is great thirst, but when the urine is scanty, owing to coUsemia and obstruction of capillaries, there is an absolute distaste for fluids. Hence it is very common for those who suffer from chronic coUeemia and high blood pressure, as in chronic Bright's disease and conditions bordering on it, to say that they are never thirsty. With regard to the slow high tension pulse of Bright's disease, it is not only slowest and of highest tension at those hours (alka- line tide) when the excretion of uric acid is normally greatest, and quickest and of lowest tension in the acid tide of the night, but it is in our power to alter it, to quicken its rate and reduce its tension by the use of any of the drugs which diminish coUsemia, just as in the case of the temporary coUsemia of a headache. Thus in some cases of Bright's disease, where the pulse was slow, I have been able to nearly double its rate by influencing the uric acid, see fig. 36, where A shows a very high tension pulse, rate .52, and B, the pulse of the same patient ten days later, when drugs had had time to act, rate 80 ; and when several years ago there was some writing in the journals about the value of opium in nephritis, and in ursemic convulsions, I tried opium in one or two cases of Bright's disease, and where, in these cases, the pulse 202 UEIC ACID — CHAPTEE V was slow, it invariably quickened it and increased the urinary water, and appeared to me to do good, though in cases of nephritis I have generally preferred to use acids or drugs, such as the iodide of mercury, which act in the same way. It may interest those who have not a laboratory at their door, if I say that the main characters of the high and low tension pulse can be demonstrated by means of a Higginson's syringe, a screw clamp, and a few feet of soft rubber tube just large enough to fit over the nozzle of the syringe. Fill the syringe and tubes with water, and screw up the clamp so that the water can only run out very slowly from the end of the tube ; adjust a sphyg- mograph over the tube between the syringe, which with the Fig. 36.— Pulse Tbacinqs of High Blood PEEsstJKB in Beight's Disease AND OF THE EFFECTS OF DBUGS UPON IT. muscular hand outside it represents the heart, and the clamp, which represents the more or less obstructed capillaries. When all is ready set the clock-work of the sphygmograph in motion, and work the syringe regularly by the second hand of a watch. If the clamp is much screwed up, you will get a slow diastolic faU, the secondary waves being nearly obliterated. If it is open so that the water passes easily you get a quick diastolic fall with large secondary waves, as in the dicrotic pulse. If the finger is placed over the tube instead of the sphygmograph, you will be able to appreciate the difierence between an artery which is full between the beats and one which is empty. While speaking of mechanics and physics I will mention also the arteriometer, invented by Dr. G. Oliver, and produced by Mr. Hawksley, the -well-known instrument maker ; because it seems to me that it is of very considerable value in aiding the clinical demonstration of the efiects of uric acid on the circulation. I must here, however, only mention the most important points. UEIO ACID AND THE CIECULATION 203 and refer my readers to Dr. Oliver's work for further informa- tion.* The arteriometer professes to measure the distance traversed by a button in passing from one side to the other of any exposed artery, that is to say, the diameter of the artery or the distance it has to travel in efiecting its obliteration. The fact that the artery is obliterated is recorded by the finger of the observer, which notes the point at which pulsation ceases on the distal side of the instrument. To make a long story short, it is found with this instrument that the greater the blood pressure the larger is the diameter of the radial artery, and though Dr. Oliver has invented another instrument for measuring pressure as apart from change of dia- meter, since diameter practially varies with change of pressure, the arteriometer is alone sufiicient for most of the purposes that I have in view. The clinical value of its record may be best shown by giving an instance. Thus we may say of a patient that his pulse was slower and of higher tension in the morning hours, and quicker and of lower tension in the evening hours ; but with the arteriometer we may be able to say that his pulse in the morning was 55, and his radial diameter 2-0 millimetres, and in the evening his pulse was 65, and his radial diameter 1-5 miOimetres. Dr. Oliver goes into the efEects of posture (sitting, lying and standing) on the calibre of the radial artery,-j- and has found them very constant, but it seems to me that he does not completely work out the causes of the changes produced by posture, and certainly he says nothing about the force of gravity, to which, I believe, they are really due. On ordinary physical principles it appears that blood, like other fluids, will travel more quickly down hUl than up — that is to say, will go better with gravity than against it, and the sphygmograph, as has no doubt long been known, tells us that this is so with our own circulation. Take, for instance, a pulse tracing when sitting or standing with the wrist on the level with the head ; gravity is here acting against the circulation, 1| or 2 oz. pressure will be quite su£B.cient to develop the tracing which will show the ordinary signs of low blood pressure. Next take a tracing with the wrist on a level with the apex * "Pulse-gauging," by G. Oliver, M.D., F.B.C.P. H. K. Lewis, London, 1S95. + Previous reference, p. 13. 204 UBIO ACID — OHAPTBK V of the heart, here gravity is acting slightly with the circulation, in so far as the arteries of the arm are below the level of the aortic arch ; it will now be found, perhaps, that 3J oz. are required to develop the tracing which shows moderate blood pressure. And, lastly, bending forward, sink the wrist down between the knees, so as to increase the force of gravity ; it may now take 5 oz. pressure to develop the tracing, which will show high blood pressure. Now, do exactly the same with the arteriometer. With the wrist on a level with the head it will read "5 m., on a level with the heart, 1-1 or 1-2 m., and between the knees 1-5 — 1"6 m. Of course the absolute diameter will vary with the person, but these are average readings on my own radial. It follows from this that the changes of calibre noticed by Dr. Oliver, in difEerent postures, are the simple results of the various effects of gravity on the circulation in these positions. Thus, with the wrist at the level of the heart, or, as Dr. Oliver advises, about 2 in. or less below it, it is obvious that in the sitting or standing posture gravity acts with the circulation, because the radial artery is below the aortic arch, and in the recumbent position gravity is neutral, because the radial artery is on the same level as the aortic arch. Hence in the recumbent position one best gets the effect of the blood pressure on the artery pure and simple, but in clinical observation it is a very valuable thing to have a constant force like gravity at one's disposal, which one can add on to blood pressure at pleasure, because this constant force will obviously produce greater effects the less the original distension of the arteries, and smaller effects the greater the original distension. For, on the well-known prineiple that a candle added to the sun produces no visible effect, while a candle brought into a room from which the sun's light is excluded, produces very great efiects, the addition of the constant distending force gravity, to a vessel whose walls are already greatly distended by high blood pressure, will produce little or no efiect ; but the same force of gravity applied to a vessel whose walls are relatively lax from low pres- sure will produce quite a large distending effect. It follows from this that the higher the blood pressure the less will be the variations induced by change of posture, and the lower the blood pressure the greater these variations, and this I find to be the case. Thus the diameter of my radial artery is generally greater in URIC ACID AND THE CIECULATION 205 the moming and less in the evening, and the postural variations are less in the morning and greater in the evening, and the follow- ing are common readings : — Moming, sitting, radial diameter 1'2, lying, I'l ; evening, sitting, radial diameter 1"0, lying 0"8. We can now understand completely Dr. OUver's observation on p. 14, where he says : — " As a rule as years advance heyond the middle period of life the range of postural variation becomes gradually lessened, and it may thus mark the progress of physio- logical arterio-sclerosis, until the caUbre may at last become quite uniform in posture." For " physiological arterio-sclerosis " I should prefer to read physiological (? pathological) coUsemia, and the causation of this depends in the most simple manner on our first principles, for every man on ordinary diet stores in his body during his youth and prime a large amount of uric acid, and as he begins the decline of life this is got into solution and passes through his blood, causing, as we know, high blood pressure ; and this in its turn is the cause of the fact observed, the gradually lessening variations in the diameter of the arteries from change of posture, in accordance with the rule worked out above. Doubtless the high blood pressure and the blocked, obstructed, vasa vasorum, are between them the cause of the arterio-sclerosis, a pathological change which supervenes upon the physiological collsemia (see further on). It is part, of the very essence of my argument in this volume that this physiological collsemia can be diminished or controlled by altering the diet, and that when this has been done its patho- logical efEects will be diminished and postponed, and chief among these efEects is that gradual failure of combustion, metabolism and nutrition, which we call chronic Bright' s disease, because it is a mere prolongation or accentuation of the diminished combustion which is the result of aU coUaemia. This is seen (1) in its simplest form in the fall of urea as the result of exercise in those who have plenty of uric acid available for collsemia, and in every uric acid head- ache there is a fall of urea corresponding with the rise of uric acid, and a rise of urea as the uric acid comes down again ; and (2) in its most severe form in the fall of urea, and the excretion of unmetabohsed albumen in its place in acute Bright' s disease ; in the physiological condition the removal of the collaemia by mer- cury or its prevention by diet, suffice to prevent the fall of urea, and it is replaced by a rise ; in the pathological condition the same metal, if it can be got to act, will very soon reduee the 206 UKIC ACID — CHAPTER V albumen to a trace and send up the urea to a corresponding extent, increasing it by tens or even hundreds of grains. Then I believe that in all these conditions and intermediate conditions between migraine and morbus Brightii the actual rate of combustion and metabolism in the body can be estimated from the rate at which a simple food (such as half a pint of milk) pro duces a rise of urea such as we see in " Diet and Food," fig. 2 ; and the slower this rise and the less its extent the worse is the metabolism and combustion in the body in question. In epilepsy the pulse is often slow and of high tension just before the fits, and I have suggested that high blood pressure is the actual cause of the fits, and in the case of epilepsy I have shown that this condition of pulse corresponds with an excessive excretion of uric acid, and probably with more or less marked coUsemia. The urine excreted at the time of a fit is also scanty, and of high specific gravity. In ureemic convulsions I have pointed out Sir W. H. Broad- bent's opinion that the high tension is the cause of the fits, and in writing of Bright's disease I shall have to point out that the blood in that disease has been proved to contain excess of uric acid, and that it is easy to explain the fact, so that ursemic fits or the high blood pressure which produces them may be, just as in ordinary epilepsy, due to uric acid. Probably the same explanation may be apphed to puerperal convulsions, as the fits come at a time, as I have elsewhere said, when some coUsemia is almost certainly present {Brit. Med. Journ., Feb., 1889, p.^ 290 ; also previous remarks about the efEects of menstruation, pregnancy, &c.), and the value of milk diet in pre- venting eclampsia is now very generally recognised (see Char- pentier, Sem. Med., 16 Sept., 1896), and this quite coincides with my own experience, as I have had under my care from time to time a considerable number of pregnant women sufiering from Bright's disease, and these being placed on a milk or uric-acid- free diet for some months before delivery have all done perfectly well, without giving any sign of convulsive troubles. In mental depression and melancholia, as we shall see presently. Sir W. H. Broadbent has pointed out that the pulse is often slow and of high tension, while I have shown that these conditions are often associated with an excessive excretion of uric acid, and more or less coUsemia, and that they may be reUeved or cured by afiecting the uric acid. The fact on which I have laid so much stress above, that the UEIC ACID AND THE CIECULATION 207 urinary water varies from hour to hour or day to day, and in physiology as well as in pathology and drug action, inversely as the uric acid excreted along with it, seems to me to afford abso- lute and irrefragable proof of the action of uric acid on the capillaries. That the urinary water varies inversely as the uric acid, any- one who will trouble to estimate the excreta for a few days can easily convince himself ; and it does so because an excess of uric acid over urea in the urine comes from an excess of uric acid in the blood, and an excess of uric acid in the blood (collaBmia) obstructs the capillaries and diminishes the excretion of water, just as we have seen that digitahs and erythrophlseum do ; there- fore obstruction of capillaries varies directly as the uric acid in the blood (Q.E.D.). Obstruction of capillaries has no relation whatever to any of the drugs used to afEect uric acid, because these act quite differently in accordance with the amount of uric acid that is present for them to act upon ; thus an alkah given to a gouty person wUl cause high blood pressure and severe depression ; but remove the uric acid beforehand with a salicylate and it wiU cause none. Lithia pro- duces no depression and allows of a free flow of urine ; soda and potash cause depression and scanty urine ; they aU render the blood more alkaline and the urine less acid ; but lithia clears the blood of uric acid, while soda and potash produce uricacidsemia and coUaemia. I have just said that the obstruction of the capillaries varies directly as the uric acid in the blood, and pulse rate according to Marey varies inversely as arterial tension, which is the result of capillary obstruction ; therefore, pulse rate varies inversely as the uric acid in the blood. Now this brings me in contact with a subject about which a good deal has been written, namely, bradycardia, or slow action of the heart ; and Prof. Reigel, from whom I have quoted else- where, divides bradycardia into physiological and pathological ; and a close investigation shows that in aU the conditions he speaks of there is collsemia, which obstructs capillaries, and the bradycardia is due to this, in accordance with Marey's law. In the physiological group come (1) the bradycardia of ten to twelve days after confinement ; (2) that of conditions of hunger ; (3) that of individual peculiarity. After confinement, as I have pointed out elsewhere {British Medical Journal, Feb. and Nov., 1889), there is almost certain to 208 UEIC ACID — CHAPTEE V be coUamia, because there is an interruption of digestive and other functions at the end of a period of active nitrogenous metabolism (pregnancy), and these facts probably explain also the causation of puerperal convulsions. In certain conditions of hunger, also, there is a fall of acidity and temporary coUsemia. As to individual peculiarity. Prof. Reigel himself suggests that it often nieans some unrecognised disease. In the pathological group comes bradycardia associated with : — (1) Convalescence from acute disease. (2) Diseases of digestive organs. (3) ,, respiratory „ (4) ,, circulatory „ (5) „ urinary (6) Intoxications. (7) Diseases of blood and general nutrition. (8) ,, the nervous system. (9) Other diseases. Of (1) Acute diseases and the way in which they bring about coUaemia, I shall have to speak very often (see chapter viii.), but I wUl just mention here that I have no doubt that the free capillaries and dicrotic pulse of fever are due to the clearing of the blood of uric acid by the rising acidity which fever produces. The pulse of fever often much resembles that produced by the nitrites which I have suggested is due to the same cause, a rise of acidity, but it follows from my first principles that a rise of acidity clearing the blood of uric acid causes retention of uric acid, and this retention will be followed, as in the case of opium and other drugs, by a rebound and plus excretion ; that is to say, as the fever comes to an end and the acidity falls, the retained uric acid will be dissolved out and flood the blood, we shall have more or less severe collsemia according to the amount retained, and slow high tension pulse (post febrile bradycardia), subnormal temperature, &c., in proportion to it. Hence a knowledge of the efiects of uric acid enables us to explain the pulse conditions both in fever and convalescence, and to see that the pulse of the latter is the necessary sequence of that of the former (see p. 28). With regard to changes in the rate and rhythm of the heart, Marey says that while they are often attributed to nervous in- fluences, they are in not a few cases really due to pressure change in the vessels either of the systemic or the pulmonary circulation (prev. ref., p. 484). UEIC AOID AND THE CIRCULATION 209 Writers on this post febrile bradycardia have observed that it is often met with in its severe forms in those who before the fever were strong and healthy, and yet in apparent contradiction they go on to attribute the bradycardia to weakness of the heart muscle. Why should those who were previously strong and healthy have the weakest hearts after a fever 1 There is no doubt, however, that those who are strong and robust had the largest nitrogenous metabolism both before and during the fever ; they would, there- fore, store most uric acid and have the most severe coUsemia after the fever, and the bradycardia would doubtless be in proportion to this. As regards the heart, the only necessary quality for the pro- duction of bradycardia is that it shall be sufficiently strong to withstand the strain which coUeemia, pbstructed capillaries, and high blood pressure put upon it, and this power is, to my mind, much more likely to be met with in those who were previously strong and robust ; but if the heart faUs before the high blood pressure, we shall get palpitation or a quick, irregular pulse in place of a slow one, and some cases of tachycardia are no doubt thus accounted for ; and in such cases the importance of giving drugs such as morphine or mercury, that lower blood pressure, should be borne in mind ; and as the pressure falls the heart wiU slow towards the normal rate (see also effects of chloroform and nitrites in chapter viii.). Thus a very interesting case was mentioned at a meeting of the Clinical Society {British Medical Journal, 1897, vol. i., p. 144), where paroxysmal tachycardia came in sudden attacks in a chUd and was associated with enlargemesnt of the heart. And the possible relations between such a condition and that of Graves' disease, about which I have already spoken, are most interesting. Further, I would most earnestly caution those who wish to arrive at the truth about these matters not to be too ready to attribute either bradycardia or tachycardia to any nerves , or ganglia ; or to refer the benefit obtained from such drugs as valerianate of zinc or morphine to their action on such ganglia, tiU the possible presence of coUsemic high blood pressure, and the by no means remote possibility that these drugs have cured by relieving it, have been considered. For a very interesting account of some cardiac cases cured or relieved by morphine, see paper by Dr. F. 8. Toogood, Lancet, 1898, vol. ii., p. 1393. The causation of both bradycardia and tachycardia is o!f in- 14 210 UEIC ACID — CHAPTEB V terest, and my belief is that both of them may be organie and due to changes in the nerves, vessels, or muscle of the heart itself. But apart from such organic changes, the common cause of functional bradycardia is high blood pressure. Then let this blood pressure rise still higher the heart may first falter and flutter, as seen in fig. 37, and finally palpitate (=: functional tachycardia). On the other hand, it seems also possible that the heart may palpitate when surprised, so to speak, by a sudden fall of blood pressure. The natural thing for the heart to do is to quicken as the pressure falls ; a sudden fall acting on a perhaps imperfectly nourished heart may cause excessive quickening. And this may account for the cases, several of which I have seen, in which palpitation has been over and over again relieved by a good dose (grs. xxx.-xl.) of sodii bicarb. It would be possible to argue that this had relieved some dyspeptic condition which was interfering mechanically with the action of the heart ; but I think we must also not lose sight of the fact that it would increase coUsemia and raise blood pressure, which ought to slow the heart. Then one sees probably the effects of blood pressure pure and simple in the fact that palpitation is sometimes relieved by a few deep breaths ; now this undoubtedly lowers blood pressure as it relieves the high blood pressure headache. On the other hand, some palpitation may be stopped by holding a deep breath and pressing forward so as to compress the dia- phragm with the abdomen and thighs ; now this undoubtedly raises blood pressure and makes a migraine worse (.see Lancet, vol. i., 1902, p. 1318.) It seems to me then that we have probably two causes for functional tachycardia : (1) rising blood pressure with more or less heart failure, as in Graves' disease, and (2) a sudden fall of blood pressure such as may be produced by a nitrite {e.g., a tabloid of trinitrine) or a glass of an acid wine such as champagne. On the other hand, tachycardia due to high and rising blood pressure would probably be relieved by a nitrite or a glass of wine ; and I have often seen one of these put a stop to such irregularities as are shown in fig. 37, previously mentioned. On the other hand, we must give these drugs, which lower blood pressure by retaining uric acid and clearing it out of blood, with great care and caution, and must never forget that to leave them ofE suddenly is often most dangerous ; for the stored uric UBIO ACID AND THE CIECULATION 211 acid at once rushes back into the blood, the blood preasuie rises quickly to dangerous heights, and again heart failure or cerebral haemoixhage may result. I have myself seen several such cases after leaving off iodides or morphine, and have heard of many more, and the dire effects of suddenly leaving ofi an .opium-eater's dose are iwell kjiiown ; but in all these cases considerable safety may be attained, as I shall have ,to mention again in reference to ,the treatment of haemop- tysis, ,by giving a short course of salicylates before leaving off the drug that causes retention, and this is ,a plan I now^ foU&w. (2) ; Digestive disturbance generally entails a fall of urea and acidity and coUsemia results, and this js the common occasioning cause of the uric acid headache, also of fits, mental depression, fatigue, iasthma, glycosuria, anaemia, and albuminuria ; aU of these are ;jrequently found associated with dyspepsia or gastro -intestinal upset, •because these are, as we shall see in chapter x., the cause of the qoltemia, but the coUaemia once it has come into existence also tends to make the dyspepsia worse or to keep it going. (3) Respiratory disease may entail dicficient oxidation, and that, as I have pointed out in chapter iii., p. 91, means a fall of acidity and consequent coUaemia, and we shall see further on the very marked -effect of dyspnoea on the capUlary reflux and the blood pressure. (4) Circulatory disease may obviously cause coUaemia in several ways, for instance by producing dyspepsia or cyanosis. (5) Among the urinary diseases mentioned by Prof. Reigel, nephritis bulks largely, and of this and its eollaemia I shall speak in chapter xiii. (6) ;Intoxioation by lead, alcohol, digitalis, and bile are specially mentioned ; the action of lead and alcohol on uric acid I need not go into again. Digitalis acts in accordance with the same law, and slows the pulse by contracting the arterioles and raising the blood pressure. The digestive disturbances that accompany jaundice are probably sufficient to cause eoUsemia, and jaundice is not always accompanied by a slow pulse, which points to the action being indirect. (.7) I shall only have to mention anaemia or leucocythsemia in reference to what I say in chapter xii, of the coUaemia that occurs in relation to ithem. (8) As .regards the nervous system I admit that certain central irritation may contract the peripheral arterioles, raise blood pres- sure, and produce bradycardia, but I believe that disease of; the 212 URIC ACID — CHAPTBK V nervous system more often acts indirectly by producing nausea, vomiting, or gastric disturbance with secondary colleemia and capillary obstruction and its resultant bradycardia (see previous remarks and quotation from Marey). Under (9) are grouped fatigue, sunstroke, severe pain in various organs, and if necessary I should have no difficulty in proving that these may be accompanied by colleemia, and I shall speak of fatigue in connection with the causation of mental depression, chapter viii. Severe pain, especially when connected with any of the abdom- inal or pelvic organs, causes more or less complete arrest of digestion and absorption of food ; it thus brings about, increase of the alkalinity of the blood, and coUsemia just like any other digestive disturbance ; but whether this accounts for the effects of all pain, fright, &c., ia producing shock and coUsemia I am not prepared to say ; but certainly in many of these conditions much good may be done by clearing the blood of uric acid, and I mentioned above, a case in which this, was done by the natives of Morocco by means of a dose of urine, but as we shall see later, pain has probably also a direct effect in raising blood pressure. With regard to fatigue I will just remark, in passing, that while drugs such as morphine, cocaine, acids, &c., which clear the blood of uric acid and promote a free circulation in the nervous and muscular tissues, produce, as^they are weU known to do, feelings of mental weU-beiug and bodily strength, and greatly increase the powers of endurance, it is extremely Kliely that drugs and physio- logical or pathological conditions, which increase the uric acid in the blood, and so hinder the circulation through these tissues, will produce fatigue, or a condition on which it easily supervenes. With reference to sunstroke, we may bear in mind that external heat produces collaemia (see remarks on fig. 4), and some of the symptoms of this trouble may be due to high blood pressure and others to defective combustion, ia a word, fatigue with special variations (see chapter viii.). From the causation of bradycardia by uric acid in accordance with Marey' s law we pass without difficulty to the causation of angina (see chapter xiv.), and of syncope (see also Brain, Spring Number, 1891, p. 88). Acute dilatation of the heart and other effects of high blood pressure, and the value of nitrites and mer- cury in such conditions, are easily accounted for. I give here, fig. 37, a tracing showing an intermission in my own pulse, when the heart was labouring against the high blood pressure of collaemia, and I have suggested that epilepsy may in some cases be due to heart failure from this cause. UEIC ACID AND THE CIKCULATION 213 An interesting form of syncope is that whicli occurs during bathing, and it no doubt accounts for the loss of many lives every year. Now, bathing is commonly indulged in during the morning just at the hours of physiological collaemia, and when to this is added contraction of aU the surface vessels by cold, and, as we can now understand, some increase of the urate precipitation itseH by cold, it is little wonder that the heart is sometimes overpowered ; and it is acknowledged by Sir W. H. Broadbent ("Pulse," p. 153), that powerful contraction of arterioles may bring the heart to a dead stop. Pig. 37. — Pulse Tracings op High Blood Pressure. (A) Faltering. (B) Intermittent. As regards my own pulse, I look upon a fluttering, imperfect systole or a dropped beat, as in fig. 37, as conclusive evidence of high blood pressure. I have many hundreds of tracings of my own pulse, but none show these conditions without accompanying (causative) high blood pressure, and I have often produced this condition or removed it in myself and others. With reference to some of the points just mentioned it is interesting to notice that Marey says that the pulse in typhoid fever is, first of all, soft and dicrotic, and later, on the approach of convalescence, shows more or less high tension, and he goes on, " L' apparition du triple rebondissement [ = W pulse of high tension as in trace A, fig. 37] est un caractere important de I'approche de la convalescence ; nous le recontrerons a la fin des autres maladies febriles. Au moment de la convalescence le pouls presente parfois aussi un pen d'irregularite " (prev. ref. p. 569). That is to say, during high fever there is retention of uric acid, and little or none in the blood, but as the temperature begins to faU the alkalinity of the blood increases, it soon dissolves a considerable quantity of uric acid which obstructs the capillaries and produces high blood 214 UBIC ACID— -CHAPTER V pressure, and the heart often flutters or falters as the pressure riseSi Dr. Chapman, in his interesting lectures on the " Physics^ of the Circulation," says that when the heart gives a tumble or fliitter it- really makes two contractions, as an effort at compensa- tion {Lareoet, 1894, vol. i., p. 661). Again, with regard to alcohol, Marey says, "Certains agents I'alcool, par exemple, mettent la circulation dans un etat analogue a eelui de la fievre typhoide ; le pouls de I'ivresse a moins qu'eile ne soit aecompagHee de troubles gastriques presente a uil haut degre le dicrotisme " (prev. ref., p. 569). Why this exception in the case of gastric troubles ? Marey appears from the context to attribute it to irritation of the abdominal sympathetic, but I am only following his own rule with regard to heart rhythm, just quoted, in suggesting that the absence of dicrotism in gastric trouble is really due to uric acid, and to the intra-vascular pressure changes it produces, and not directly to the nervous system ; for gastric upset means that there is diminished absorption of alcohol, and of the acids so frequently ingested along with it, diminished absorption also of food with its resulting diminished formation of urea and acids, and the result of all this is an increase in the alkahnity of the blood, which at once takes up an increased quantity of uric acid, and this obstructs the vessels and prevents more or less completely the dicrotism which would otherwise be produced by alcohol and acids. Marey also says that vomiting brings on coldness of surface and extremities, and that this is a Very constant result, as- every- one who is seized with nausea gVows suddenly pale, has cold hands and a slow feeble pulse, in fact, all the signs of vascular contrac- tion ; he says also that John Hunter was struck by the coin- cidence of lowered temperature with vomiting, and drew from it the conclusion that the stomach was probably the seat of heat formation for the body. Marey proceeds to correct Hunter by referring to what is now known about the abdominal sympathetic and its supposed power of contracting the vessels all over the body, but he is probably himself quite as far from the truth as Hunter was. The real explanation is, I believe, that in all gastro-intestinal disturbance, whether culminating in vomiting or not, there is a diminished formation of urea and acids (and one has only to watch the efiects of dyspepsia on the excretion of urea for a few days to be quite sure about this), and consequently an increase UEIC ACID AND THE CIRCULATION 215' in the alkalinity of the blood ; as a result it is flooded with uric- acid wMoh produces deficient circulation throughout the body, and especially, as we have seen, in the skin. We now know that even in physiological conditions the temperature of the body is largely dependent on the quantity of uric acid in the blood (fig. 5), but from the vaso-motor or abdominal sympathetic point of view it would have to be shown that these centres were more active in the contraction of vessels in the a.m. hours of each day than in the p.m. hours. Some deficient circulation or vascular obstruction is the central symptom of every migraine in which the initial lesion is almost always some gastro-intestinal disturbance, though this is sometimes itself secondary to coUeemia produced in other ways, as in fatigue (see chapter viii.) ; but once the gastro-intestinal disturbance is present it afiects the alkaUnity of the blood and produces or intensifies the coUsemia to which everything else is secondary. If the' deficient circulation throughout the body in migraine is due to the abdominal sympathetic, why does clearing the blood and urine of uric acid control it ? Why does increasing the uric acid in the body and blood make it worse ? It is, no doubt, dehghtfuly easy to refer every ill-understood phenomenon to the irresponsible action of the abdominal sympa- thetic or the vasomotor centre, but no shadow of a reason is given us why these centres should fly into a passion and contract all the arterioles in the body simply because the stomach has had a slight disagreement with a pork chop. Migraine itself was said to be a neurosis till I showed that the nerve centres might bei neglected if the uric acid was controlled ; and the obstruction of vessels in this and all similar conditions is not nearly so sudden as Marey seems to suppose, for long before the stomach trouble is so bad as to produce vomiting, there has been more or lesS" complete suspension of digestion and absorption ; and during the whole of this time urea has been falling and the alkaHnity of the blood and the consequent collaemia have been increa.sing. Marey sees the final stage of the process, and looks upon the obstruction of vessels as sudden, but in migraine there is often very great obstruction of vessels without any vomiting at all. One cannot help thinking what a sorry plight these nerve- centre theories would be in if the action of uric acid on the circulation should prove after all to be mechanical. I do not deny that irritation of the sensory nerves may cause temporary contraction of vessels and a rise of blood pressure, but 216 ue:o acid — chapter v this may be due to contraction of the relatively large vessels, and is generally a very temporary matter, and differs in many ways from the steady and continuous high blood pressure which accom- panies an excess of uric acid in the blood (see also case recorded in chapter viii. in connection with the causation of chloroform syncope, and other instances of the direct effects of pain mentioned later on). In migraine again, where the pressure remains high for hours or possibly for one or two days, the only pain is in the head, and though there may be occasionally a little nausea, there is certainly no abdominal pain sufficient to account for irritation of the sym- pathetic. Then again in physiological conditions what possible source of vasomotor irritation is there in the a.m. and early p.m. hours which is absent in the later p.m. hours, or why does a dose of calomel affect the blood pressure at any time ? Still more in pathology, e.g., in chronic Bright's disease, when the blood pressure is high for days, weeks, months and years, does its remarkable relationship to uric acid come out ; clear the blood of uric acid by means of mercury, or watch it being cleared by an intercurrent febrile disturbance, and the high pressure vanishes in a comparatively few minutes and remains absent till the mercury or fever are gone, but no longer. In these physiological conditions we are quite certain that the high pressure is not due to the contraction of the larger arteries, because the arteriometer teUs us that the diameter of the radial increases with the pressure ; and, though these large vessels are no doubt exercising some pressure on the blood within them, this is with the object of helping the heart and forcing the circulation through the obstruction in front, it is quite obvious that as the large vessels are dilated the rising pressure cannot be due to their action. If we apply this to all the arteries that have obvious muscular tissue, and consider that they are aiding the heart by a certain amount of contraction to force the blood through the obstruction in front, and that they with the heart become hypertrophied in the process, then obviously the small vessels (arterioles) which are nearest to that obstruction will have most pressure to bear, and may become most hypertrophied as a result, just as the small pipe near a tap is subjected to the greatest strain when the stream is suddenly stopped. From one point of view then, we see one nerve centre both in UBIC ACID AND THE CIRCULATION 217 physiological and pathological conditions "fengaged in aiding the heart and arteries in forcing blood forward, while another is engaged in contracting the capillaries and keeping it back, and that internecine warfare goes on between these centres for days, weeks, months and years, to the detriment of the physiology and nutrition of the body. Is there any parallel to this condition of afiairs in the rest of the physiology of the human body ? Is there anything in the theory of evolution to make us beUeve that such a state of things is possible ? At this point comes in my observation on the constant relation- ship of these conditions of high blood pressure, both in physiology and pathology, to excess of uric acid in the blood, and we have to suppose that the uric acid irritates the second centre, and sets it against the first, for the moment uric acid is removed the strife ceases. On the other hand, if it should eventually prove that the con- nection between uricacidsemia and high blood pressure is mechanical and due to blocking of capillaries by colloid uric acid, we are at once reheved from the necessity of believing in physiological suicide, and can see that the whole physiological resources of the body are really harmoniously working, united in one common endeavour to prevent this mechanical obstruction from doing injury to the nutrition and functions of its tissues. 'i However this may turn out, one fact is, I believe, certain, that both Lq physiology and pathology high blood pressure is absolutely dependent on the amount of uric acid in the blood, and that if we remove the uric acid we shall, on the one hand lower the blood pressure, and on the other improve the circulation through every organ and tissue of the body, and we can do all this without the least regard to any nerve centre, however irritated or suicidally intent it may be. Marey also points out that a feeble pulse becoming almost imperceptible in the radial, but presenting the pulse tracing of extremely high tension, is the pulse of mal de mer, and of nausea or vomiting. I would point out that in sea-sickness there is very commonly a headache, which has, I believe, all the characters of the ordinary bilious headache (migraine) produced by uric acid, and I see no reason to doubt that the high tension pulse is pro- duced by uric acid, and that the headache represents the efEects of the high blood pressure on the intra-cranial circulation, and a similar headache can be produced in anyone who, like myself, is 218 URIC ACID — CSAPTEE V prone to sufier from it, by anything which wUl produce gastric disturbance, provided he has a supply of urate in his body which can be taken up by his blood ; and it is because I, thanks to a xanthine or uric-acid-free diet, have not this supply of urate, that I now have immunity from headache. On the other hand, where there is obstruction of capillaries, but the heart is powerful, perhaps hypertrophied, and refuses to give way, dilate or furnish imperfect systoles, blood pressure will rise to a dangerous extent, and especially where the vessels are already degenerate, haemorrhage will occur. This may be comparatively harmless in the form of epistaxis or a more or less profuse haemoptysis (and I have elsewhere* suggested that what the late Sir Andrew Clark has written about as " arthritic haemoptysis " may be due to coUaemia and its efiects on the circulation) or may be fatal and deadly as haemorrhage in the brain. I am now collecting records of cases of syncope, haemorrhage, &c., with the object of finding out whether a majority of them occur at the times of physiological coUaemia {i.e., the " alkaline tides" of the morning or afternoon), pathological exaggerations of which may satisfactorily account for these symptoms ; and so far as my records extend the evidence in favour of this is remarkable. As to the arteries themselves, high blood pressure means a certain amount of strain, and strain leads to degeneration of struc- ture. Then as the vasa vasorum are among the vessels affected by the urate, nutrition is soon involved, and as effects of both causes we have degeneration, atheroma and other changes. Hence in diabetes, a disease which is often associated with high blood pressure as pointed out in chapter xiv., we get arteriosclerosis, and gangrene associated with it (see British Medical Journal, Epitome, 1896, vol. ii., p. 17). In a recent (4th) edition of " Diet and Food," p. 80, I have quoted from " Human Physiology," by Eaymond (London, W. B. Saunders, p. 128), some remarks by a vegetarian doctor who suggests' that his diet causes degeneration of the arteries. But as he does not tell us whether his diet includes, as is most probable, such' deadly poisons as the pulses, tea and coffee, mushrooms, asparagus, &c., it is impossible to draw any useful conclusion from his statements. With regard to arterial degeneration, I have been brought up * Wood's Medical and Surgical Monographs, February, 1890, p. 359. UBIG ACID AND THE CIRCULATION 21& in tlte belief, wHcfi all my stibseqiieilt experiea'ce has tended: to confixm, ttat there is one -great cause of these trouhles, vi2., pressure and strain, for my pathological experience tells me that we find degenerate vessels in those who have had high blood pressure in life, and the longer they have been exposed to high blood pressure the more advanced are the changes. Then, other things etjual, the changes are more marked in those who, in addition to high blood pressure, have been exposed by their occupation to vascular strains, as for instanxje, by lifting heavy weights; Then again, when some vessels have been obviously more exposed! to strain than others one finds the degeneration mcst marked in those vessels so exposed. And though one finds most degeneration in the old as their vessels have been longer exposed to pressure and strain, one finds fairly marked changes in the vessels of high blood pressure cases (as Bright's disease) even when the duration of life has been less than a quarter of a century. Thus aU that I have learned from teachers on pathology and everything I have seen for myself, both clinically and in the f'ost- mortetn room, unite in saying that pressure and strain are far and away the most important causes of arterial degeneration, followed and aided to some extent, and only in certain cases, by such contributing causes as alcohol and syphilis. And I have long considered that the chief cause of pressure and stfain, alpart from the mechanical conditions mentioned above, is high blood pressure — in a word uric acid coUsemia, and its results ; hence the early and marked presence of such degeneration in cases of Bright's disease, and it is practically always in com- pany with chronic Bright's disease that we find the most advanced arterial degeneration of later life. My opinion is, therefore, very strong that this vegetarian doctor must have owdd his unfortunate results to the poisons rich in uric acid which his food probably contained, and this is quite in aCcoird with my praciiical experience, for some of the highest blood pressures I have ever measured, accompanied by more or less ' marked signfe of vascular degeneration, have been in pulse-eating' natives of India. And indeed if I am right, I beheve that this vegetarian has been hving, as I did at one time myself, on poisons, ' and then most imfoitunately mistook his foes for his friends by continuing the pulses, the worst of foods, and rejecting the bread, which was best of all. 220 UKIC ACID — CHAPTBE V On the other hand, if vegetarian foods which are free from uric acid such as bread, were a cause of high blood pressure and vascular degeneration, then my blood pressure should be higher now than it was on meat, and signs of vascular degeneration should be coming out in all directions ; but the facts as we see them in this volume are all exactly the other way. Another suggestion made by this unfortunate vegetarian is that vegetarian foods cause chalky degeneration of arteries by introducing excess of salts into the body. His suggestion then is that Nature is so feeble that when an excess of salts, e.g., lime, is presented to her in food or drinks she is driven to deposit some of these in her most vital tissues, impairing their function and destroying their vitality years before they would otherwise fail. Now we know that even Nature cannot make something out of nothing, for when the hen bird desires to lay a weU-sheUed egg she must and does eat lime salts to provide the lime ; but on the other hand we surely do know that Nature eliminates every poison, and that no poison would destroy life if we coidd ensure to Nature the time necessary for its elimination ; therefore, those only are deadly poisons which destroy Ufe quickly before there is time for their elimination. But in the case of the lime salts time does not come in, for they are introduced only very slowly and Nature has plenty of time to eliminate what she does not require. But those ignorant of physiology may be misled by the idea of lime salts into imagining that these pass solid into the body, solid into the blood, and are deposited solid in the walls of the Vessels. But of course this is not so, for practically nothing is absorbed from the intestines except it be either in solution or in very fine division, so that a man can swaUow for instance a pound or two of mercury without harm, because only a few fractions of a grain are absorbed from the intestines. And anything that can pass through the walls of the intestine into the blood can also pass through the walls of the renal capillaries into the urine, so that by failure to absorb from the intestines on the one hand, and by excretion of excess from the kidney on the other. Nature has absolute power to prevent any excess of noxious substance in her vital fluids provided she has time to eliminate them. And in the case of lime salts she has plenty oi time • these UEIC ACID AND THE CIRCULATION 221 lime salts, like mercuiy, are not very soluble, probably at least a part is left in the intestines, and aU tbat which is absorbed must at once by the mere fact of its absorption be in a condition to be eliminated by the kidney if Nature does not want it. And this elimination by the kidney is the immediate result of swallowing any salts, phosphates, sulphates, chlorides, for the moment Nature has more in the blood than she requires, out they come by the kidney ; and so much is this the case that Zuelzer proposes to tell the nature of any food eaten as brain, muscle, bone, &c., from the salts excreted in the urine (see prev. ref., p. 40). It seems to me, therefore, to be quite absurd to suggest that Nature is ever placed in the predicament that this vegetarian doctor has proposed for her ; and calcification of arteries is to my mind but a further stage in the degeneration which high blood pressure and strain produces, for all tissues which have been the seats of chronic irritation are apt to have some deposition of salts in them as a result of this process ; but the deposition is the final result of pressure, strain and chronic irritation, and not of Nature's hand being forced by excess of lime salts. And this calcification may be met with in old and in young, in those who have swallowed excess of lime salts and those who have not, provided only there has been some focus of chronic inflammation existing for years. The ultimate appeal, however, is not to theory but to fact. Do those who live on bread stuffs and other uric-acid-free foods get high blood pressure and vascular degeneration, or do they not 1 So far as my experience goes the answer must be in the negative, but plenty more evidence on this subject will soon be forthcoming. On the other hand it is no surprise to me to learn that vegetarians who eat pulses and drink tea suffer from high blood pressure, vascular degeneration, calcification, &c. Let this vegetarian doctor tell us whether he took 'these poisons or not, and when he has done so his testimony will be of some value. The same argument applies to the effects of high blood pressure on the heart. We get first hypertrophy and then degeneration, or we get sudden syncope or angina occurring in the alkaline tide, due to obstruction of capillaries for which it is unprepared, the fluttering heart of uric acid headache or epilepsy beiag minor stages of the same thing. I shall have more to say about syncope and angina in chapters viii. and xiv., but its causation by the obstructed capillaries of coUeemia follows directly from what I have said about fig. 37, and this explains completely its occurrence ■222 UBIC ACID — CHAPTBB V ,ja£ter feveis, influenza, &c., or in association witi gout, dyspepsia, Birigbt's disease and glycosuria ; it also explains the relief afforded 'hj mfircury, morphine and the nitrites, for aU these drugs clear the blood of uric acid. Several of my epileptic pa-tiejits have told me that they often shivered with cold (obstruction of the capillaries of the skim) or felt a fluttering in their tiliroat (sign of a single non-habitual intermission of the heart) just before a fit comes on ; aad it has often occurred to me that the so-called globus hystericus may be a '.similar phenomenon haviag a similar origin. As to the skin, there is the cold skin of migraine passing through all stages of severity up to Eaynaud's disease, or various interferences with function and nutrition, producing urticaria, ery- ■thema, &c., and where the skin has long been under the power of urates, perhaps leading to that atrophy and loss of structure which are described by Semmola (see chapter xiii.) as being present in Bicight's disease. With regard to Eaynaud's disease again, one cannot but see that there is some difficulty in believing that a spasmodic con- traction of living tissues should last so long as to produce d«ath of the parts, and Raynaud has shown (see chapter xi.) that the obstruction is not ia fehe arteries nor in the veins, but in the capillaries. But if the obstruction is due to colloid uric acid, we can see that the cooling of the blood in the exposed skin and •extremities of the fingers may increase the precipitation of the coUoid uric acid, just as it does in the test tube, and thus the local obstruction will not only be increased, but there will be no Umit to its duration so long as the colloidal uric acid remains undis- solved, and this possibly explains the remarkable way in which R-ayna lid's disesase is limited to surfaces and extremities, and does not affect deep parts of large limbs : but such limitation is very difficult to explain by reference to an irritated nerve centre (see chapter xi., remarks on Dr. Southey's case). In the brain we may have slow circulation or stasis as in head- ache, vertigo, epilepsy, and mental depression, and possibly oedema as in uraemia, all due to the effects of urates on its circulation, not to mention softening and haemorrhage from organic arterial •changes having similar origin. No doubt we have in the cord similar functional and nutri- tional changes, and in the peripheral nerves, neuritis and peri- neuritis, each and all due to vascular conditions produced by urates )> )> »j ,, ' 1 „ 11 7 »» Milk, fish and meat, beef tea added ,, . 3 in 17 1 „ 17 „ 21 „ 25 6" t) 16th. Beef tea ofi Meat ofi Fish ofi ,, 1 „ 27 io Average Milk only . . ,, 1 Mar. 10 11 ,, »> )j • • ,, „ 11 Milk and beef tea ,, . . ■ 3 in 30 1 „ 19 „ 21 9 ») Milk only ; last beef tea 16th Tea j> 2 „ 25 „ 29 6 Average Temp, raised slightly Farinaceous with 4 cups tea = 2-3 grs.th eine a day • 3 in 18 April 2 8 Average Farinaceous and tea None >, 6 4 ,} ij >> ,, „ 11 ,, no tea ,1 ., 17 ii • )j )i ,, „ 24 7 )) i» j( 3 in 29 May 5 „ 6 11 ,, and tea again „ 13 "s „ 21 8 Farinaceous and tea None ■ 3 in 36* 1 .,, 31 10 *} again Farinaceous and tea ,, ♦ Note.— The previous 3 in 18 was probably partly the result of the beef tea. After the fit on January 6 the iodide was left off, and the salicylate given alone, and aU drugs were left off on January 12. I now began to test the effects of diet. 20 306 UEIC ACID — CHAi'TEK VII On January 18 she had a fit, 12 days after the previous one, while she was still on mUk only. On January 21 fish was added to her diet, and on 24th meat was added, and she continued to take mUk, fish and meat till February 11, when beef tep was added, and she continued to take milk, fish, meat and beef tea till February 16, when the beef tea was taken off, on 21st the meat was taken off, and on 25th fish was taken ofi, and she was again on milk alone. She had a fit on January 31, 13 days after the previous one, making 3 fits in 32 days. At the dpte of the last of these fits she had been on fish for 10 days, and on meat for 7 days. So far, then, diet had not affected the frequency of the fits, for 13 days was the longest interval she had had ; indeed, it seemed rather as if the addition of flesh food had increased the interval, and I should not be surprised if this were the case ; for in the uric acid headache, taking meat steadily every day does not pro- duce a headache nearly so quickly as taking it only for one day or one meal ; and the reason is that the steady daily introduction of uric acid tends at first to keep the blood clear, while a single dose does not raise the acidity much, and as soon as the acidity falls uric acid gets into the blood and produces signs of its presence. The next fit was on February 4, 4 days after the previous one, and the next on February 11, 7 days after that, and the next on February 17, 6 days later,, making 3 fits in 17 days, a very different record from the two previous series. From February 25 to March 11, she was on milk only ; on March 11, beef tea was added and continued till March 16. On February 27 she had a fit ten days after the previous one, a second on March 10, 11 days after it, being on milk only, and a third on March 19, 9 days later, when she had been on milk and beef tea for 8 days ; this making 3 fits in 30 days, or the same record as the first two series. Now came what was rather a surprise to me ; on March 16 the beef tea was left off, and on March 21 she was put on farinaceous diet, which includes bread, puddings, and tea in addi- tion to milk. She now had a fit on March 25 (or rather 2 close together which I count as 1, as both were due to the same fluctuation of urates), 6 days after the previous one ; another on April 2, 8 days later, and a third on April 6, 4 days after that, making 3 fits in 18 days. Now, as I say this was rather a surprise, for though I expected EPILEPSY, CONVULSIONS AND HYSTBEIA 307 that the beef tea might have some effect, it was left off on March 16, and yet the shortest interval of all was that between the fit on April 6 and the one 4 days previous to it. I confess that at this point I felt rather at sea ; but I chanced one afternoon to go into the ward just as she had finished her tea, and looking into her cup I saw that what remained was very dark coloured, and it had evidently been rather strong. This led me to enquire how much tea was included in the farinaceous diet, and I found that she had four breakfast cups a day, two at breakfast and two at tea, and further enquiring as to the amount of tea leaves used to make this amount of tea and taking it that one pound of tea contains 175 grains of theine, I found that she was thus introducing into her body nearly 3 grs. of theine a day. And as we have seen that cafieine, theine, theobromine and all similar xanthine compounds are practically equivalent to uric acid (see fig. 29), she was thus quietly pouring in the equivalent of at least 20 grs. of uric acid a week. And it was thus little to be wondered at that with the help of the beef tea from March 11 to 16 her fits had been more frequent. After making this discovery I stopped her tea on April 11, leaving her farinaceous diet otherwise as before. She now had a fit on April 17, 11 days after the previous one, another on April 24, 7 days later, and a third on May 5, 11 days after that, making 3 fits in 29 days. On May 6 she was again given tea, her diet being otherwise unaltered, and she had a fit on May 13, 8 days after the previous one, a second on May 21, 8 days later, and a third on May 31, 10 days after that ; making 3 fits in 26 days, or slightly quicker than in the previous series. I now decided that I would try and diminish the frequency of fits, so I put her on farinaceous diet without tea, and gave her salicylate of sodium with iodide of potassium, the former to eliminate as much as possible of the uric acid she niight have in her body, and the second to prevent it from combining with an alkaU when in the blood, for it is apparently, as I have said, the combination of uric acid with alkaline or neutral phosphates in the blood which produces all the physiological and pathological effects which I have been led to attribute to uric acid. I also allowed her to get up, she having been in bed the whole of the previous period, about six months in all. With this change of diet and drugs she went without a fit for 308 UBIC ACID — CHAPTER VII a whole month, and had had no further attack when she left the hospital at the end of June. The diet treatment did not cause any loss of weight as in the case previously mentioned, for she kept about 90 — ^91 lbs. during the whole of her stay in the hospital. On several occasions the temperature was lower thirty minutes after a fit, i.e., when there was stiU plus uric acid passing through the blood, than at the same hour next day when there had been no fit (see fig. 5). Thus on May 5, half an hour after the fit, the temperature was, in the mouth 98° ; in the rectum, 98" 4°. May 6, same hour, in the mouth, 99° ; in the rectum, 99'4°. On May 31, half an hour after a fit, the temperature was in the mouth, "98"4° ; in the rectum, 98 "8°. On June 1 no fit, the temperature was, in the mouth, 98"8° ; in the rectum, 99'6°. On another occasion the temperature was again slightly higher on the day after the fit, and on a fourth occasion there was no difEerence between the temperature on the day of the fit and on the following day. It is remarkable that with the coUeemia with and after the fits there is not a greater distance between the temperatures in the mouth and rectum ; but if the coUaemia was severe and the obstruction of capillaries great and general, the nutrition and com- bustion of the .whole body might be hindered, and then there would be a diminished production of heat (see " Causation of Fatigue," chapter viii.), and then according to Marey's rule (see description of fig. 5) the two temperatures would tend to come together rather than to be wide apart, as they are in the physio- logical collsemia of the alkaline tide (fig. 5). And now for a general survey of the fluctuations shown in the table. The fits according to history were very regular — one in a week, or 3 in 21 days. After admission, on milk only and some drugs, they fell to 3 in 30 and 3 in 32 days ; then animal food was put on and they quickened up to 3 in 17 days ; this was left off again and they fell to 3 in 30 days ; some beef tea and tea were given, and they quickened to 3 in 18 days; these were left. off,, and they fell to 3 in 29 days, tea was put on again, and they quickened slightly to 3 in 26 days. And then when tea was left off and some drugs were given, as at first, they fell lower than they had been during the whole of EPILEPSY, CONVULSIONS AND HYSTEKIA 309 her previous stay in the hospital, 30 days elapsing without any fit. There are no doubt some who would argue that this was all pure chance, and that her fits would have varied in much the same way if no alterations in diet or drugs had been made. I can only say that such an argument has little in it to recommend itself to my mind, for it almost passes the bounds of possible chance that the fits should by accident have varied in such remarkable correspondence with the changes we made in the uric acid introduction. It leaves out of count also entirely the numerous cases in which a diet free from flesh food has produced a more or less marked alteration in the number of fits,* or a diet in which the flesh is only reduced has produced a distinct reduction.f I have seen it suggested that meat food acts as a general stimulant to the nerve centres, Uke corn in the food of horses ; but in the uric acid headache (migraine) this is certainly not the case, as this headache is not influenced at all by the general level of nitrogenous excretion, but only by the height of uric acid above urea, which is a measure of the quantity of uric acid pass- ing through the blood ; and this headache can be produced by the ingestion of uric acid or xanthine compounds equivalent to it which increase the excretion of uric acid, but hardly afiect total nitrogen ; and in the above case it rather appears as if beef tea and tea, which introduced xanthine and uric acid, had a similar effect on the fits of epilepsy. On the other hand, in migraine you may keep urea well on the physiological level (3J grs. per pound of body weight per day), and provided you do this with mUk and vegetable substances, which do not introduce much uric acid, there will be no increase of headache (see also fig. 73 and remarks on it). The point about migraine beyond which there is no appeal, is that if you control uric acid you control the headache, without attending to anything else ; I am suggesting that the same will be fouild to hold for epilepsy, only here the control must be more powerful and complete, and may be correspondingly more difiicult to obtain. This argument further takes no notice of the fact that it is almost impossible to regard the uric acid fluctuation above described as a consequence of the fits, seeing that it begins hours before them : while it is easy to regard it as a cause, looking * Lancet, 1895, vol. i., p. 96. + British Medical Journal, 1895, vol. i., p. 1088 and 1420. 310 U14IC ACID — OHAPTEB VII to the important influence which this substance exerts on the circu- lation, nutrition and function of all the tissues of the body in the uric acid headache, for instance. Then T believe that as a matter of fact all gradations are really to be met with from a mere temporary absence of mind up to a severe epileptic fit, and nothing is more common than slight, absence of mind in mental depression, or the uric acid head- ache (see also Sir J. Crichton-Browne, Lancet, 1895, vol. ii., p. 4, for many interesting connections between dreamy mental states, migraine and epilepsy). In the uric acid headache reasoning is difficult and has to be forced, and the mind becomes a complete blank for words or for names, which in ordinary conditions one knows almost as well as one's own ; on the other hand, either before or after the headache, when the blood is cleared of uric acid, there is mental brightness and well-being, a feeUng of pleasure in living and thinking, and work is done at double speed and with comparatively little trouble ; and aU these things, I can answer for it, vary absolutely with the uric acid in the blood, and can now be easily shown to vary with the capillary circulation and blood pressure which it controls. While speaking of gradations, I will refer to a very interesting paper by Dr. G. F. Still, on " Day Terrors in Children " [Lancet, 1900, vol. i., p. 292), where it appears that these terrors are met with in children who are nervous and excitable, and come of rheumatic families and of families that have also produced weak- minded, epileptic or lunatic members. Dr. StiU remarks that the aura of epilepsy sometimes consists of a feeling of fear, and he classifies these terrors with the " parox- ysmal neuroses," migraine and fetii mal. He also considers that the dividing line between these terrors and some forms of insanity, epilepsy and hysteria is but a narrow one ; and it almost seems as if there are all gradations between terrors and actual mania, or as if the one may pass into the other. These facts, which bring out so strongly the close relationship of all these diseases and the complete gradation from the forget- fulness of mere high blood pressure, or migraine, through tem- porary absence of mind to petit mal and on, up to a severe epileptic fit ; and the similar gradation from momentary terrors and hysterical excitement up to complete and lasting mania, are of the greatest possible interest, and form a stepping-stone from the causation of migraine and epilepsy to what I shall have to say in the following chapter about the causation of mental disease. EPILEPSY, CONVULSIONS AND HISTBEIA 311 For me there underlies in all these " paroxysmal neuroses " but one cause — coUaemia ; hence their occurrence in rheumatic families, hence the observed alternation of migraine and the others with rheu- matism, for when the uric acid is in the joiats there is no coUsemia. The action of intestinal disturbance, which Dr. StiU specially notices, is in all cases the same, and the dyspepsia of migraine disappears with the uric acid, as it is largely a co-result of the coUaemia. Dr. Still lays considerable stress on some puffiness of the lower eyelids as a sign of the above-mentioned intestinal disturbance ; but after what I have said of this very symptom as a result of the collsemia of migraine (see p. 223), I Heed only suggest that in such children the capillary reflux is slow and the blood pressure high if the heart is strong, and that the relation of these and their efiect on the eyelids to intestinal dyspepsia is through the coUsemia, which results from all dyspepsia. In the capillary reflux and the blood pressure we see the central factors of aU " neuroses," and their measurement is the clue to causation and treatment. The actual results depend: on such minor conditions as the form of the skull, the size of the arteries, their relations to the veins and sinuses, and, more than all (as we shall see more clearly in the following chapter), on the strength and nutrition of the heart and its power to stand up against coUsBmia and produce high blood pressure, with its results — ^headache, some forms of epilepsy and mental depression, up to melancholia; or on its failure to overcome the coUsemic obstruction causing temporary or per- manent low blood pressure with its results, the conditions of excitement, hysteria or mania, and some forms of epilepsy. Our " neuroses " are thus seen to fall into two groups — the high blood pressure group associated with a strong heart, and the low blood pressure group associated with a weak heart, these latter being especially prominent in women with their weak muscle powers ; but epilepsy is found in both groups, some cases being undoubtedlj? connected with sudden heart failure, (and hence the origin of epileptic mania) and others rather with the results of high blood pressure. Now that we have more complete knowledge of, and almost absolute control over, the circulation, the demonstration of these facts is as easy as the explanation of their causation and relation- ship is simple ; as in migraine, so in epilepsy and melancholia ; so also in excitement, hysteria, and mania, and in all minor and inter- mediate conditions, the cause being removed the efiect follows it. 312 UEIC ACID — CHAPTEE VH In a most interesting paper on " Hysterical Somnolence and States of Double Consciousness " {Lancet, 1900, vol. ii., p. 801), Dr. Ethel M. N. Williams says : " The question now naturally arises as to whether there is any pathological condition common to all these various states," and she then goes on to speak of the feeble tone of the vasomotor system and of the similar but more marked phenomena in post-epileptic conditions. This is but further evidence of the very close relationship between all these circula- tion disturbances, and the vasomotor system is unjustly blamed for the efEects of the coUsemia common to all. But the cause of migraine, epilepsy, hysteria and mania is the cause of a whole series of mental and moral defects of which the diseases seen in our asylums are mere exaggerations ; and long before the final stages have been arrived at the whole character has been slowly changed, and that selfishness, which is but diluted insanity, has more or less blotted out aU noble mental and moral qualities. From this point of view, then, the scientific avoidance of diet poisons (flesh and tea) means far more than the prevention or cure of the diseases named in this volume. It may eventually produce, as I have elsewhere already suggested ("Diet and Food," ed. iv., p. 120), even the complete physical, mental, moral and spiritual regeneration of the race. In the case of these terror-stricken children : bring them up on a uric-acid-free diet, and they will have neither the nervousness, the " neuroses," the mental and moral defects, nor the rheumatism, because in the absence of excess of uric acid there is nothing to cause arthritis on the one hand, or coUaemia on the other. What I said about the association of the uric' acid headache with nephritis applies also to epilepsy in any case that is due to uric acid, for nephritis means chronic coUaemia, and with this the fits will be more frequent and severe and less amenable to drugs and diet, than in cases where the kidneys remain sound. Do we not get here also a side light on the causation of the headache and fits of uraemia ? As I have pointed out, the treatment of collaemia removes the symptoms of uraemia (Brit. Med. Jour., November 30, 1889, and see also chapter xiii.). I owe to the kindness of Dr: C. Mordhorst, of Wiesbaden, the notes of a most interesting case which occurred in his practice. It was that of a lady whose knee and foot joints showed large deposits of urates, and who was ordered to take, in addition to hot baths, a strong alkaline water (Wiesbaden gout water). One EPILEPSY, CONVUIiSIONS AND HYSTEEIA 313 day she took more of the water than had been ordered for her, and at mid-day she had a very severe attack of epilepsy, the first she had ever experienced. Dr. Mordhorst had her urine collected, and found it to give a relation of uric acid to urea of 1 to 15. In another case Dr. Mordhorst put a patient who sufEered from epilepsy (1 to 2 attacks a week) on two bottles of Wiesbaden gout water a day, and while she took this quantity the attacks discon- tinued, this exactly paralleling the observation of Dr. Tyson (see p. 274) on the effects of Vichy Water on Migraine. She has now been on this treatment for three years always with the same good results, but if the water is left off the attacks return. This is very interesting and reminds [one of the value attached to the use of alkalies as additions to the bromides in epilepsy, by the late Dr. Eadcliff {Practitioner, 1883, vol. xxx., p. 95). Dr. Eadclifi used potash salts, and Dr. Mordhorst soda salts, but probably the efiect was in both cases the same. In the case of the above-mentioned lady the alkali met with a large amount of urate in the body, and brought into the bloOd on the day of the attack more than it could hold in complete solu- tion, hence there was for a time considerable coUsemia, resulting in high blood pressure, suf&cient to produce a fit. In the other case where the alkali was taken steadily for years, the quantity of uric acid to be acted on was probably never so large, and the alkali not only provided for a steady excretion of uric acid, thus preventing fluctuations (the great causes of attacks .both of headache and epilepsy), but it was able to hold the whole of the uric acid passing through the blood in fairly good solution (see remarks in chapter v.), so that coUsemia was never severe, but as soon as the alkali was left ofi, fluctuations in excretion again re- turned, and these presently sufiiced to reproduce the fits. And it is just, I may remark in passing, by producing such fluctuations in urate excretion as are seen in fig. 13 that lead and other metals produce fits and do harm in epilepsy ; and apart from the action of any metals, similar fluctuations are evidenced by the feelings of well-being which often precede the onset of a fit, so often in fact that patients have themselves got to look on them as warnings. I also owe to Dr. Mordhorst the copy of a paper by Dr. Ackermann, " Zur Aetiologie der EpUepsie," from Zeitsch. fiir die Behahdiung Schwachsinniger und Efileptischer, 1897. Nr. 2. In this paper reference is made to Dr. Mordhorst's cases and to my writings in this book and in the Neurolog. GerUralb. on 314 UEIC ACID — CHAPTBE VII epilepsy, and it is suggested that the cause of this disease is direct irritation either of nerves or nerve centres by uric acid, which is thrown down by a local or general diminution of the alkalinity of the blood. The natural outcome of this etiology is the treatment of the disease by alkali in the form of Wiesbaden gout water, and several cases are related showing improvement, though some are, just as we shall see to be the case with diet, worse at first and better later ; no doubt in these cases there was at first too much uric acid for the alkali to hold in complete solution. There are several points, however, in the above etiology with which I cannot agree, and it also, in my opinion, fails to explain all the phenomena. How, for instance, can any local irritation of nervous tissues account for the pain -of headache or its very obvious relation to position and blood pressure ? How can we explain the action of nitrites or the value of compression of the carotids in relieving headache or epilepsy, or again, the use of venesection in uraemia ? It is true that this latter may remove a small portion either of the acid or of uric acid, but its most obvious effect is surely that on blood pressure. Then again, acids are often decidedly useful both in epileptic fits and in the headache and drowsiness that precede or follow them, and the nitrites also diminish the alkalinity of the blood. It seems to me, therefore, that the only possible explanation of all the phenomena is that the fits are due to high blood pressure with or without heart failure ; that the high blood . pressure is due to. coUsemia, which again is dependent on the quantity of uric acid available and its complete or incomplete solubility in the blood, which explains the observed effects of the alkalies used. Among points of interest in the above paper I notice that Dr. Ackermann insists strongly on the absence of demonstrable changes in the anatomy of the nervous system, and the impossibility of reconciling any such changes with the irregular phenomena of the attacks. He is inclined to think, however, that epilepsy cannot be ex- plained without a disposition to formation of excess of uric acid, or the uric acid diathesis, and he is also in favour of a special disposition on the part of the nervous system in pregnant women during and after labour, and in children ; but as I have pointed out, all these points can be explained by the influence of these physiological conditions on the formation, solubility, and excretion EPILEPSY, CONVULSIONS AND HYSTERIA 316 of uric acid, and that if there is any disposition on the part of the nervous system, it has reference only to the size of the arteries that supply the brain. In this connection also he refers to the difficulty in explaining the absence of ursemic phenomena in cases of anuria, but here again, though the blood may contain excess of urea, it will also probably contain plenty of acid salts, it will therefore remain at least for some time but a poor solvent of uric acid, and there will be no severe collsemia and high blood pressure, such as occurs in uraemia, till near the end ; then with a general failure of nutri- tion and strength the blood becomes again perhaps a good solvent of uric acid, and more or less collsemia results. He lays great stress on the many points of resemblance between uraemia and epilepsy, and there are obviously stiU more points of resemblance when we consider also the headache, the eye-symp- toms, and the blood pressure changes. I am indebted to Dr. A. J. Hubbard, of Hemel Hempstead, for the interesting suggestion that the convulsions of bottle-fed infants are partly due to the fact that in taking cow's milk, which contains one-third more casein than human milk, they are relatively on a highly nitrogenous diet and hence form some excess both of uric acid and urea. Dr. Hubbard has also found that sahcylate of soda is of far more value in the treatment of these troubles than the alkalies which are commonly prescribed. Diagnosis. — The time has not yet arrived for any dogmatic statements on this point ; but where epileptic fits have recurred with more or less regular periodicity for a long time, and also resemble migraine in their relation to dyspepsia, muscular exertion, or menstruation ; where they are accompanied by scanty urine, and preceded by a slow or faltering pulse, with altered capillary circula- tion; and when also there is no syphilis or other organic cause to be found to explain their occurrence, I would suggest that they may be due to the effects of uric acid on the circulation in the skull or on the action of the heart, and that further investigation or treatment from that point of view is indicated. The Indications for Treatment are very much the same as in the case of migraine. An attempt may be made to break through the fits, or the stupor and headache which follow them, by the use of such drugs as acids, ■ calomel, morphine or the nitrites, with or without temporary compression of the carotid.* * For oases where this was done, see Lancet, 1892, vol. i., p. 358, and vol. ii., p. 662. 316 URIC ACID — CHAPTEK VII I have seen a considerable number of cases where acids did good by relieving the stupor and headache that follow the fits, and in some of these cases the patients used to ask for their dose as soon as they regained consciousness. And it~ is interesting to remember that a drug which was at one time regarded as a specific for epilepsy, viz., nitrate of silver, acts in exactly the same way as the acids and other drugs mentioned above. If epilepsy is due to uric acid in the blood, it follows that it may be temporarily relieved by uric acid precipitants that clear the blood and quicken the capillary reflux. And it the clearing is well done the tissues may act like a uric acid filter and keep the blood clear for some time. Thus in the Therapeniic Gazette, 1896, January 15, p. 30, some cases of epilepsy are reported as being cured by nitrate of silver, and it is further remarked that argyria relieves many nervous troubles ; but argyria means not only a deposit of silver, but a deposit of urate of silver, just as I shall explain in the' case of lead in chapter x., and the extensive deposit of urates in the fibrous tissues of the body means, just as in gout (see chapter xv.), that the blood is for a long time kept relatively clear of urates, hence there is no coUsemia to cause epilepsy or other nervous troubles. The diet treatment must, I think, be very strict, and milk in small quantities the only animal food, or better stiU perhaps no milk at all, and only the dry diet of bread stuffs and fruit advocated in chapter xvii. There must also be no playing with soup, meat extracts, strong tea or cofEee, as it is quite useless to cut ofi meat and allow those things which are worse, and contain no nourishment. When the heart is strong and the fits seem to be due to the effects of high blood pressure on the circulation of the brain, powerful purgation and a rather poor diet may not be bad treatment ; but where the heart is weak and the fits seem to be due to its temporary failure before high blood pressure, every care should be taken to reduce the uric acid in the body without unduly reducing urea and nutrition, and it may be well perhaps to try for a time the use of some digitalis, which I men- tioned above as having been found useful by Dr. S. West. But, as a matter of fact, I find that many epileptics have very high blood pressures : thus, a patient I saw recently, who had had fits for years and was a great drinker of tea, had a blood pressure of 180 between the attacks. It may be as well also to point out, with regard to diet treatment, that in this disease just as in headache, mental depression and chlorosis (see fig. 60) the first EPILEPSY, CONVULSIONS AND HYSTERIA 317 effect of a strict diet may be an increase in the frequency and severity of the fits. I mentioned this with a case in illustration in an article on the treatment of these diseases in the Spring and Summer Number of Brain, 1897, and pointed out that it was necessary in such cases to guard against discouragement either of patient or doctor, as the temporary increase of the trouble is merely one more proof of its relationship to the excretion of uric acid and coUsemia, and shows that the diet has only to be con- tinued to produce relief or cure, and I notice with interest that many recent writers are stating, as the results of their experience, that long-continued treatment by mUk diet very frequently diminishes both the number and the severity of the convulsions. My own practical results continue to be very encouraging, and I hear from many others of good results with diet after bromides had failed or been given up. I quite agree with Dr. E. J. Spratling {Journal of Nervous and Mental Disease, May, 1899), that recovery is only to be spoken of in the case of patients who have for two consecutive years been free from aU epileptic attacks, and it takes time to get records of many of those. I think also that in many cases the result will be as in migraine rather a great reduction in the severity and number of the attacks, than complete recovery in the above sense. I have, however, got some very marked results with diet alone as regards frequency and severity of attacks (the relatives often regarding the patients as cured, and wishing to relax the diet rules), and my results have been so good that I have not had to put in practice the severe purging previously mentioned. Among children I have records of several cases that have safely passed the above-mentioned time limit without an attack, and several of adults where the attacks have been nearly as markedly diminished as my own headaches have been ; others again, though showing a decided diminution, still have frequent attacks. One of these had in 1899 62 attacks. Diet was begun in the middle of 1900, and there were in this year 54 attacks, in 1901 41 attacks, and so far in 1902 they are keeping about the same level as in 1901. I find, however, that not a few sufierers have become so saturated with the idea that epilepsy is an incurable disease, that they will only give the diet a half-hearted trial for a few months, and if it does not do the impossible, and still more if, as I have pointed out may be the case, the attacks are more frequent at first, they give it up in disgust and yield to their unnatural craving for meat and stimulants of other kinds. 318 DBIC ACID — CHAPTER VII As we know from our experience in migraine, such people are merely wasting our time and their own, and nothing except a diet treatment of twelve to eighteen or twenty-four months is worth doing ; though long before that, and even in or after the first few months, there should be a distinct change for the better. If this does not occur and if the blood pressure still remains high and the capillary circulation defective more active measures, as the purging treatment, or the starvation treatment advised for migraine, may be put in force ; or these may be begun from the first in severe cases associated with very high blood pressure and very defective capillary circulation. And in all cases the efiects of treatment on the blood pressure and circulation must be considerbd along with those on the fits. In very acute 1 -# i ■s X-- ^^ '\ N. ^■r* ."' LOOD CIMAL -^ % ^ '. ,^' '•©- / \ i fe- -•BUI tCACIL f- •■i 0-. -^' \ r KEA \ A ,r- / 1 V ^ \/ / J Fig. 50. — Curves of Ubic Acid Excretion and of the Blood Decimal. and have followed as closely as possible the directions issued with the instruments. The blood decimal is the result of the fraction ^^e.Te'n.'.T;'"" or if log = I'O, but as 100 per cent, of haemoglobin is never met with, the results are always decimals as in the following curves ; and I agree with Dr. A. E. Garrod, Dr. Wilcox, and others (Pro- ceedings of the Royal Medical and Chirurgicd Society, February 9, 1892), that this is the safest guide to the condition of the blood. 534 UKIC ACID — CHAPTER XII representing as it does the hfemoglobin value of the individual cell: for the absolute quantity of cells and haemoglobin varies greatly according as the blood is concentrated by diuresis, or is diluted by retention of fluid in the body,* but these things cause no variations in the value of the blood decimal, which again can e^sUy be represented in a curve, for comparison with the curves of the urate excreted in the urine. Fig. 50 represents the results of simultaneous examination of the blood and urine in myself, the blood being examined only every two or three days, and the urine curves being obtained by dividing the total excretions of three days by three so as to shorten the figure. Notice here the general downward direction of the blood decimal curve and the general upward trend of the uric acid curve. The urea curve is given simply to show the height of uric acid above urea (the curves are super-imposed at the relation of 1 — 33) as the index of the probable amount of uric acid passing through the blood. On May 20, at the beginning of this figure, urea is close to uric acid, so that little or no uric acid passed through the blood, and the blood decimal is fairly high — "71. On May 23 uric acid exceeds urea by If grs., and this amount probably passed through the blood, and with this the blood decimal falls to "7. On May 26 more than 2 grs. of uric acid passed through the blood, and yet the blood decimal rises decidedly to "78, but the explanation of this is probably that the blood was not examined sufficiently often to correspond with the excretion curves, for uric acid was low on two days preceding the 26th, while a high rise on the 26th brought up the average in the blood for three days to 2 grs. per day. If the blood had been examined on the 25th, it would probably have been found above '8, a fall to '78 taking place with the high uric acid on the 26th. The blood is again examined on June 1, the uric acid in it averaging meanwhile 2 to 2;^ grs. per day, and with this there is a fall to "72. On June 10, with uric acid rising to 3| grs. per day, there is a marked fall of the blood decimal to '6 ; there is a slight rise on the 11th, corresponding to a fall of uric acid ; and a fall of the blood decimal to '56 on the 19th in accordance with the passage of 3 to 3J grs. through the blood on the days from the 16th to the 19th. Lastly, we see a rise of the blood decimal to "63 on the 22nd with a fall of the uric acid passing through the blood to IJ grs. per dav. See Journal of Physiology, vol. xiii., and Lancet, July, 1892. PABOXYSMAL H^MOatOBINURIA AND ANEMIA 535 This figure shows generally that the blood decimal is higher the nearer the uric acid is to urea, i.e., the less there is passing through the blood ; and lower the higher the uric acid is above the urea, i.e., the more there is passing through the blood. The high rises of uric acid on the 10th, and again on the 16th, 1 :i ill a /* 7 13 429 e 1 12 3SS S II 353 4 10 330 J a 237 X a 284 i Jane 23 24 2S 2e 27 JULY 28 23 Z-0 1 2 3 4 S 9 • ?'- -K UOOD ; >s 'CIMAL ^ / 5< 1 ^ 'v' V ■v' /> 0-- -- \- . y^.. ~~a / ' ; ^. ^13 A ; A r ■^ ^ \, \ / ; o / V W \ , 'C ACID t / -,1 \ \ / r 1£A / 5^ ri / 1 / / 1^ \ / V Fig. 51. — Cubvbs op Ubic Acid Excbetion and the Blood Decimal FBOM Day to Day. were due to uric acid taken by the mouth on purpose to increase the[J"amount passing through the blood. Fig. 51 shows similar curves of results obtained on myseH, the blood being examined every day. On the 23rd, uric acid exceeds urea by IJ grs. and the blood decimal is at "59. On the 24th, uric acid exceeds urea by 2f grs. and the decimal falls to "SS. On the 25th, the uric acid exceeds urea by IJ grs. only, and the decimal rises to -62. On the 26th, 536 DEIC ACID — CHAPTBB XII uric acid exceeds urea by less than 1 gr., and yet the decimal falls to -56, but it rises next day' to '63, uric acid remaining still about 1 gr. above urea. On the 28th, with a rise of uric acid to / 1^ grs. above urea, it falls to -58. Then on the 29th it rises to' •65 in spite of uric acid being IJ grs. above urea, and it remains at "65 on the 30th, uric acid being still about 1^ grs. above urea. On July 1 I tried an experiment, taking gr. xlv. of sodii salicyl., with the object of bringing a large quantity of uric acid through the .blood, and in this I was successful, as uric acid exceeded urea by nearly 7 grs. ; but the blood decimal did not fall, indeed it rose shghtly to "66. On July 2, uric acid fell close to urea, as the salicylate was left ofE, so that by hypothesis none passed through the blood ; and with this the blood decimal rose to "72 and remained there on the 3rd, though uric acid was about f gr. above urea. On the 4th, however, uric acid rose, being 2f grs. above urea, and with this the blood decimal fell to "66. On the 5th, uric acid fell again, being scarcely J gr. above urea, and with this the blood decimal rose to "69. The exceptions mentioned above only serve, I think, to show up the rule that uric acid and the blood decimal move in opposite directions. The exceptions are probably due to want of exact correspondence between the examination of the blood and that of the urine. The urine of the given date is the secretion of the 24 hours ending 7 a.m. on that date, while the blood was examined at 11 -a.m. each day. It is quite possible that a large amount of uric acid passing through the blood between 7 and 11 a.m. may depress the blood decimal more than the excretion of the previous 24 hours would lead us to expect, or a small excretion in those same hours might allow the blood to recover a little from the uric acid of the previous day. That salicylate of soda could bring so much uric acid through the blood without depressing the blood decimal was rather a sur- prise, but I would point out that these large excretions under salicylates are not accompanied by the usual symptoms of coUsemia. There is no headache, and but little mental or bodily depression, though if seven grains of uric acid had passed through the blood in combination with an alkali, there would have been severe headache, marked mental and bodily depression, slow high tension pulse and scanty urine, and with these probably a marked fall of the blood decimal (as in the case of the lady mentioned above). The rise of the blood decimal with the low uric acid the day after the salicylates is extremely interesting and illustrates probably PAEOXYSMAL H^MOGLOBINUEIA AND AN^IMIA 537 the way in which these drugs did good in the case of splenic leucocythsemia mentioned above, and in cases of simple ansemia and chlorosis in which I have also used them, when iron" did not seem to act well ; for as we shall see presently, uric acid is more powerful than iron, and when both are present in the blood together, its decimal falls instead of risiag. It seems probable, then, that the good effects of salicylates are due to two things : first, that they rapidly clear urates out of the body without allowing them to do harm in passing through the blood ; and second, that they thus, by elimination, free the blood from uric acid and allow the blood decimal to rise. ■3 ■SO ■50 S-SOAM FROM 11-40 PHI 9-20AM 12^50 PM 5-20 PM 9-50PM ^ , "'■ ■*. WO " 104 "'^ %-^^ IDS '* 0i024) \o5040 ' ■0S400r 08736] 057IZ BLOOD DCCIMAL Fig. 52. — Cobves of Ubic Acid Bxcbetion and the Blood Decimal FBOM HOUE TO HoUE. In watching the blood decimal curves over long periods of time as I have often done, and as is shown incidentally in fig. 74, I could not help noticing what I have mentioned above, that now and again where the uric acid had been low in the previous 24 hours the blood decimal had perhaps not risen as much as one would have expected, or on the other hand, when uric acid had been high it had not fallen as much as seemed likely from previous experience, and noting these slight variations led me to examine the relations of these curves to each other over shorter periods of time every few hours. And as soon as this was done the cause of these slight varia- tions became apparent, for I found that the blood decimal really 538 URIC ACID — CHAPTER XII varied from hour to hour with the uric acid passing in the urine, heiice a large rise of uric acid at the end of the 24 hours' period would depress the blood decimal more than the 24 hours' curve would lead one to expect, or, on the other hand, a large fall of uric acid for a few hours would cause the decimal to rise in spite of a large excretion of uric acid during most of the previous 24 hours. Now the curves in fig. 52 are given to illustrate that point. They do not show quite normal curves, either of uric acid excre- tion or of the blood decimal, for uric acid is generally high at 9 a.m. and lower at noon and 5 p.m., and the blood decimal is generally low at 9 a.m., rising again towards 1 p.m., but these curves do show exactly what I want to point out, that when the uric acid excretion is unusually small in the morning hours the blood decimal is unusually high, and when the uric acid is unusually high in the middle of the day the blood decimal falls instead of rising. Again, if there had been only one examination of the blood decimal, say at 9.20 a.m., it would have appeared too high, because there had been a large excretion of aric acid in the previous twenty-four hours; but examining more closely, we see that on this particular morning the uric acid excretion fell very much from 5.20 a.m. to 9.20 p.m., so the blood decimal rose above its usual level at those hours, and also above what one would have expected from the excretion of the previous* twenty-four hours as a whole. The figures below the curves in fig. 52 are 65 per cent, hsemo- globin, over 100 per cent, of cells and the resulting decimal = "65, and below these 513 the total urine in cc. divided by 5"6 the time in hours, and giving a resultant 91 cc. per hour ; below these is ■03024 the percentage of uric acid in the urine, and this X bv 91 r= '41 grs. of uric acid per hour, as indicated in the curve. As a rule the uric acid is high in the a.m. hours, falling towards 1 or 2 p.m. (fig. 3), rising again slightly later in the after- noon, and falUng again in the evening and early night hours. And the normal blood decimal curve is high in the early a.m. hours, falling later, and not as in this figure rising towards 9 a.m. But the uric acid in these curves is practically under complete control, and being altered from hour to hour at pleasure the blood decimal will follow, so that any desired curve of the blood decimal can be produced, and I am so confident that the results obtained are constant and reliable that I will undertake to alter the blood PAEOXYSMAL HiEMOGLOBINUEIA AND ANEMIA 539 decimal curve of anyone in eitter direction, or if I am allowed to examine the blood of anyone every two or tkree hours I will undertake to tell correctly the chief variations in the excretion of uric acid in the urine over the same periods. In an interesting paper in the British Medical Journal, 1898, vol. i., p. 1650, Dr. W. Edgecombe refers to Dr. Oliver's Croonian Lectures of 1896, and gives further observations of his own to show that there is a normal day fall and night rise in the worth (^- my blood decimal) of the blood, that active exercise increases tn i. ■^ . 0: ■ - o 4 Q §^ § 14 70 490 13 SO 455 12 50 420 II 10 385 IO3035O a; oS 0-7 oe 0-5 D * o N D 23 24 ME / A \8D \ /Ba / 1 GU 7/C A CID \ \ \ 1 / cibi: 7 / / UREA '6 URIC I si Pig. 53. — The Blood Decimal Cubve Showing the Obdinaby Diubnal Vabiations, theib Relation to the Excretion of Uric Acid, and THEIE BeVEBSAL BY REVERSING THE EXCRETION OP THE UbIC AcID. the day fall and the night rise, while rest diminishes the day fall. And his conclusion is that rest is of considerable value in the treatment of anaemia. I was much interested in his facts, though I could not accept his explanation, for I already knew that the blood decimal, as we have seen in fig. 52, follows the uric acid excretion from hour to hour, and will consequently fall during the day when there is much uric acid in the blood and urine, and rise during the night when there is little, and that it was the amount of uric acid in 540 UEIC ACID — CHAPTEE XII tke blood and not the rest or exercise fer se that affected the blood quality. But this article made me test the point for myself, and finding that the statement was quite correct, and that the blood decimal was, as a rule, higher in the morning and lower in the evening day after day, I then proceeded to diminish the excretion of uric acid in the day to see whether I could produce a corresponding alteration in the blood decimal carve, and one of the results I thus obtained I now give in fig. 53. To the left of the figure are the normal results obtained by separating the urine into three consecutive periods of twelve hours, 7 a.m. to 7 p.m., and 7 p.m. to 7 a.m. The lower curve is the excretion of uric acid in two days and one night, the totals being multiplied by two to make them comparable with the twenty-four hour curves, and the upper curve is that of the blood decimal. The uric acid excretion is thus seen to have been about 7 grs. during the day twelve hours, and a httle over 5J grs. in the night twelve hours, or 12J grs. in the twenty-four hours ; and the blood decimal in correspondence with this rises from the evening to the morning and falls from the morning to the evening. To the right of fig. 53 we see above the blood decimal curve, and below it those of acidity, urea and uric acid on two days, 23 and 24. On' day 23 uric acid is above urea by nearly 2 grs. and there would consequently be a fair quantity passing through the blood, and with this we see that the blood decimal falls as usual from morning to evening, and rises again from evening to morning, just as in the previous curves ; but on day 24 I purposely brought down the excretion of uric acid by taking freely of acid fruit at breakfast, in much the same way as I did to alter the circulation curves in fig. 39 ; and we see the rise in acidity I produced and its effect in the fall of uric acid, which on this day is considerably below urea, and with this the blood decimal rose during the day instead of falling. In another series of experiments I gave alkalies at night, with the result of increasing the excretion of uric acid in the night hours, and diminishing, more or less decidedly, the rise in the blood decimal that usually takes place in those hours, but I shall not take up further space by giving the curves here. Dr. Edgecombe's observation that exercise increases the extent of the day fall is not difficult to explain, for we see in figs. 46 and 47 and context that exercise increases the amount of uric acid PAKOXYSMAL H55MOGLOBINUEIA AND ANJ3MIA 541 passing through the blood, and thus just reverses what I did in day 24 of fig. 53, with just the reverse effect on the blood decimal. Dr. Edgecombe also shows in an interesting way, that if night is turned into day the fall then occurs in the night, as he gives curves from the blood of a hospital nurse, first on day and then on night duty ; and he points out, what is also interesting, that the falls at night when on night duty are less than the falls in the day when on day duty, no doubt because the exertion gone through on night duty is less than that on day duty. No doubt on night duty the excretion of uric acid is greatest at night and least in the day, because food and exercise are all ^ Ffa. MAR 1 17 Z* 3 10 /* . 18 22 27 30 \ i S 1 »« 5 «s lu :^. 6 j2-5i- ^ ■^ ^T" ' ^ ^t / ■ S! ^5 V^ S g /' ea "-^. 'LOOO ,^ ^ ^-- 7-*^ cTHal / y / s f fe 4 s fc^ i^ I s 5 t / k ^■' J % fe"^ -' 3 i|' % K •*. =; 2 lu ^ k.5 ^ fee^ ■^ ' Fig. 54.— Oueve op Blood Decimal in Ohlobosis Showing Effects of Iron, Beef Tea, and Alkalies. altered, and the blood decimal will here, as elsewhere, move in the opposite direction to uric acid. I will merely say in conclusion, that these and other experi- ments have left in my mind no doubt that the blood decimal not only fluctuates from hour to hour, and day to day, and season to season, with all the fluctuations in the excretion of uric acid, but that it can be made to alter in any direction at pleasure, just as the blood granules and the excretion of uric acid in the urine can be altered and controlled. And that the fluctuations in the blood decimal are a perfectly rehable guide to the daily, weekly or monthly changes in the uric acid in the blood and urine, so that an estimation of the blood decimal may take the place of the more troublesome or often impossible collection and estimation of the urine, and even an approximate estimation of the blood decimal 542 UEIO ACID— CHAPTER XII by tie colour card, which I have produced for the purpose, and shall mention later on, will often give valuable information not otherwise obtainable. I shall now go on to my other figures, showing some of the results I obtained in cases of chlorosis by causing excess of uric acid to pass through the blood. In these cases the urine was not collected, but no doubt the effects on excretion were the same as in my own case, and the administration of uric acid in one form or another always pro- duced, as we shall see, immediate and distinct efiects on the blood decimal. Fig. 54 shows the curve of the blood decimal in the case of M.B., aged 18, sufEering from chlorosis. On February 17, the blood decimal being only 3, she was put on pulv. ferri carb., gr. x. ter., and the curves show the rise of. the decimal to 'n on March 10, and its further rise to '6 on March 14, aft^r the iron had been left off. On the 14th half a pint of beef tea three times a day was added to her diet, and this beef tea was foimd on estimation to contain about 8'6 grs. of uric acid to the pint, and I may say that it seem 3d to be very strong and good beef tea ; she would thus take about 13 grs. of uric acid or xanthine a day. On March 18 the blood decimal has fallen to '54, and on the 22nd, when the beef tea was left off, to '52. I may point out, in passing, that uric acid given by the mouth to those who, like ansemic girls, have rather low nutrition, is more likely to remain in solution in the blood, because their blood is probably more alkaline than that of better- nourished individuals ; therefore the effect of giving uric acid is likely to be more marked in poorly-nourished individuals than in those who are robust and well fed, and dose for dose the effect on the blood curve will be greater and more immediate in the former, than in the latter. Though I stopped the beef tea on the 22nd, I gave the bicar- bonate of potash and soda, 15 grs. of each, three times a day, with the object of increasing the urate in the blood, and we see on the 27th that the blood decimal has further fallen to -48. The alkaUes were then left off, and on the 30th the blood decimal had risen slightly to '5. I have no doubt that the whole of this fall was due to the uric acid taken, for the general tendency is for the blood curve to rise slowly for a considerable time after the iron is left off. Fig. 55 is the blood curve of E. E., aged 23, also suffering from chlorosis. On May 4, her decimal being at -35, she was put on PAROXYSMAL HEMOGLOBINURIA AND AN.EMIA 643 pulv. ferri carb. as in the previous case. On May 26, the decimal having risen to "oG, the iron was left off. On June 2, when the decimal had risen to -57, she was given beef tea = 13 grs. uric acid per day, and this was continued till the 8th, the blood decimal falling on the 5th to -54, and on the 8th to -53. On the 12th, four days after the last dose of uric acid, the blood decimal had risen again to -55. On this day, the 12th, she was put on the equivalent of 6 grs. uric acid for one day, and 3 grs. each for the two following days, to try the effect of smaller doses, and on the 15th the blood decimal had fallen again to -53, so that the effects of a small dose were fairly marked, and I think that a small dose will, perhaps, get uric acid into the blood MAY •JULY 4. H a 2$ 2 5 8 12 15 1$ 22 26 23 3 S ■ - 3e ^ ? 6 t; A -V , 1. LOQD . ? / - f n V \ / S 1 r" 1 1" ^-*. •^•■"' _^-^ _ / V s V s '^ IS 1 =! ^ It; •* 1 % to '1 ^ s / ^ k ^ i ■^s b 1 .'' Si ^ S ^ s^ 1 5 3 .^■9- Pig. 55.— Cdbve or Blood Decimal in Chloeosis Showing Effects op Iron, Beef Tea, and Caffeine. more quickly than a large one, for uric acid, as I have said, inter- feres with its own solubility; and the salts contained in beef tea will in a similar way tend to depress the alkalinity of the blood, and cause the uric acid to be stored in the fibrous tissues and viscera instead of remaining in solution in the blood : and in pro- ducing changes in the blood decimal, we have not only to get it into the blood, but to keep it there so long as the kidneys will allow it to remain unexcreted. On the 19th there is a remarkable rise of the blood decimal to •62, making it look as though it would have gone on rising all the way from June 2, but for the uric acid taken. On the 19th iron was again given in the same dose as before, and it was rather a surprise, therefore, to find that on the 22nd the blood curve had fallen to -57, but I had forgotten the fact 644 TJEIO ACID — CHAPTER XII that, on the 19th, the patient was not only put on iron, but also on a milk and fish diet, having previously been on meat, and the change of diet no doubt produced a fall of acidity, acting hke the alkah given in the previous case ; this brought some of the pre- viously stored uric acid through the blood, and the uric acid over- came the iron, and produced a fall in place of a rise in the blood decimal. A similar explanation can be given of a point in fig. 54 which I omitted to mention. In this figure it will be seen that on March 10 the blood decimal failed to rise, j;hough the iron was still being taken, and this, I think, was the result of some abdo- minal pain and digestive disturbance which were unfortunately produced by some aloes pills given her for constipation ; the diges- tive disturbance no doubt produced coUsemia, and the uric acid, as in the other case, overcame the iron so far as to prevent a rise of the blood decimal. By the 26th, however (fig. 55), most of the uric acid has passed through the blood and been excreted, the iron then comes into action, and the blood decimal rises to "61. On the 26th the iron is left off, but the decimal again rises on the 29th to "62. On the 29th citrate of cafieine was given, 9 grs. on the first day, and 6 grs. on each of two subsequent days. Now caSeine may for all practical purposes be regarded as uric acid, and my experiments on myself (fig. 29) show that, like uric acid, it first raises the acidity and clears uric acid out of the blood, causing freedom of capillaries and a diuresis ; later, when the acidity falls, an excess of uric acid, proportional to the cafEeine taken, passes through the blood and into the urine ; * and we see from the curve that caffeine brought down the blood decimal, just as uric acid does, for on July 3 we have a marked fall to "52, which is followed by a rise to "6 on the 6th, the drug having been left off. Fig. 56 shows the blood decimal of J. K., suffering from chlo- rosis. From April 11 to May 7 she was on iron, and we see the rise it produced in the decimal. On May 11 iron was left oS, and on May 15 the blood decimal was the same as on the 8th. On May 15 and two following days the equivalent of 4 grs. of uric acid were given, on May 18 the blood decimal had fallen, but it rose again on the 22nd and 25th, after the uric acid had been left ofi. However, on the 17th and 18th menstruation was * See also Prof. See, Lancet, 1900, vol. i., p. 677. PABOXTSMAIi HiEMOGLOBINUEIA AND ANEMIA 545 present, and an this might have caused a fall of the blood decimal, I repeated the dose of uric acid on the 25th and two following days, and on the 29th the decimal had again fallen, to rise again on June 1, after the uric acid had heen left ofi. There seems, then, to be very little doubt that the adminis- tration of uric acid and its passage through the blood (for a similar administration to myself does cause it to pass in excess through the blood into the urine, figs. 24 to 29) cause a distinct fall of the blood decimal in spite of the presence of a considerable amount of iron in the body. But iron does not always succeed so well as it did in this case, and then, as we shall see in the, following case, it fails APRIL HAY June // n zt z 8 15 18 22 25 23 1 OS f^ x»> ^^ ^ OS r ■«s V 1 ^ J ^ ^ ■5 S. s^ ? fe § ° / r' / / / k. ^ r" .— ' Fig. 57. — Cubvb of Blood Decimal in Chlobosis Showing Effects of Iodide of Merouby. in [the blood, which explained her headache, scanty urine (for the urinary water is in everyone inversely as the uric acid excreted along with it), and her oedematous, almost myxoedematous, face caused by retention of fluids in her tissues, besides completely ex- plaining why the iron had for so long failed to do good. On March 10, however, there was a slight improvement, and the blood decimal had risen to 0-37, but as I had found such an excess of uric acid in the urine in spite of the iron, I decided to stop it and give a drug which I knew had more power of clearing uric acid out of the blood and urine. I accordingly put her on the ordinary mist hydrarg. perchlor. e. pot. iod. three times a PAEOXYSMAL HEMOGLOBINURIA AND ANEMIA 547 day, and the rest of the figure shows its efiect on the blood and urine. On March 13 there were 39 ounces of urine, containing 304 grs. of urea and 10'8 grs. of uric. acid, relation 1 — 28. Note the increase of water and urea and the decrease of uric acid in illustration of the law above mentioned. On March 16 there were 42 ounces of urine, containing 232 grs. of urea and 9"1 grs. of. uric acid, relation 1 — 25. On March 23 there were 45 ounces of urine, containing 332 grs. of urea and 9"7 grs. of uric acid — relation 1 — 34, or normal. ■ And with this clearance of the blood and urine of uric acid the blood decimal went up by leaps and bounds, and having risen in eleven days on iron only 0"03, it rose 0"06 in three days on iodide of mercury, and 0"15 in thirteen days, reaching 0"53 on March 23, a height which more than three months on iron had quite failed to raise it to ; and we now know why this was so, for the one drug cleared the blood of uric acid, and the other failed to effect this result. I know, however, from experience in other cases, that even the iodide of mercury may fail to clear the blood and urine of uric acid, and then, like iron in the above case, it also fails to produce any continuous improvement in the blood decimal. The marked rise in ifrinary water, which coincided in this case, as it always does, with the equally marked fall in uric acid, soon removed the excess of water from the tissues, and her face assumed a natural appearance, her appetite and digestion im- proved, and she considered herself cured. After what we have said in chapter x. it is most interesting to note the disappearance of the dyspepsia with the clearing up of the coUsemia, the latter being in this case the chief cause of the former. In this case I have very little doubt that but for the dys- pepsia the iron would have been able to clear out the uric acid at first, and then she would have been cured in six or eight weeks instead of remaining almost unaffected at the end of three months. Now it is well known that Murchison and others have pointed out that in some cases iron will not cure anaemia till the liver has been got into proper order, and the drug he used to get the liver into order was mercury (see Murchison, " Croonian Lec- tures," Lancet, 1874, vol. i., p. 504; and fig. 17, chapter iii.). We can now see that this mercury did good, not by any special action on the liver as was supposed, but because it cleared the blood of uric acid, and so altered at once the circulation and 548 UEIC ACID — CHAPTER XII nutrition of the whole body; and any other drug that clears the blood and urine of uric acid produces the same fall in excretion of uric acid and rise in excretion of urea, but some have more power, and will succeed in clearing the blood of uric acid when others have failed. I was much interested to hear Dr. Dandas Grant say at a meeting of the Hunterian Society (Lancet, 1897, vol. i., p. 1275), that chloride of ammonium is not only useful in headache, but is in his experience a hsematinic, and had been recommended as such by Dr. Barnes and others ; for there is no doubt in my mind that we have here one more substance which clears the blood of uric acid, and improves its condition by doing so ; here also is the explanation of the relief it afiords in headache, neuralgia, and hepatic congestion, for it produces a free capillary circulation and a fall of blood pressure. I have already pointed out with refer- ence to sp. ammon. aromat., that ammonium salts raise the acidity of the urine, and I shall have to point out later that they do harm in acute rheumatism ; and in the chloride we have not only the ammonium, but a powerful mineral acid also introduced into the body. It is interesting to note here one more instance of the great general law that precipitants do good in collaemic diseases and solvents do good in precipitation diseases, and vice versd (see p. 135). The precipitant ammonium does good in collaemia and anaemia, harm in arthritis ; alkalies which do good in arthritis do harm in collaemia and anaemia. Chloride of ammonium is also a well-known precipitant of uric acid outside the body, and as we have seen, it is possible by means of the microscope to watch its efiects on the uric acid and xanthines in the blood itself. On the other hand, we now know that you have only to intro- duce into the body and blood an excess of uric acid to quickly undo all the good that iron, mercury, salicylates, or anything else, have done, which still further emphasises the fact that they do good merely by clearing the blood of uric acid ; and if you give uric acid along with iron the decimal falls,' or at least fails to rise any further, so long as the uric acid is continued, which parallels what we have just seen in Nature, that when there is a great excess of uric acid in the urine and blood, iron may be administered for months without any efiect. In the Lancet, 1895, vol. i., p. 769, it is said that sulphate of copper is far better than iron for the treatment of anaemia, and the dose recommended is |^ to 1 gr. twice a day ; this dose is PABOXYSMAL H^MOGLOBINUEIA AND ANSiMIA 549 much smaller than that of iron, but much larger than that of mercury in the mixture given in fig. 57, but, like iron and mer- cury, copper is well known to form an insoluble compound with uric acid. I have myself used copper in the treatment of chlorosis with results quite as good as those with iron. I may say at once that these and other similar experiences have left no doubt in my mind that just as iron runs up the blood decimal uric acid brings it down; and that when the one is acting in opposition to the other the uric acid is the more powerful. But as soon as the blood is cleared of uric acid, the general metaiwlism, being freed from the incubus of obstructed capillaries, goes ahead, dyspepsia vanishes and there is a general rise of urea ns mn 21 a MAY « ■7 \ MYXSDEMA. CASE xr.SS. PROF. CRAIHGEK STEWAHT. 'PRACrniouEif juir IBS3 1 'v^ ^5 ^ ^X ^ *^ i^ s S XHn ?^' ^"^^ I-» Pig. 58. — Ouev£ of Blood Decimal in Myxcedema Showing the Effect . OF Thiboid Feeding. and acidity, which keeps the blood more or less clear of uric acid for some time, whether the iron is continued or not. I have every confidence that I can in this way do anything I like with the blood decimal, and that anyone who will take the trouble to repeat my experiments will get similar results. In addition to the figures given above, I have examined my own blood and urine side by side every day for many weeks, and find that the changes are practically constant, and that with every marked rise of uric acid excretion the blood decimal falls, and vice versd ; and indeed, I would undertake to tell correctly, from a daily examination of the blood of a patient, whether the uric acid had Tisen or fallen each day, the urine being examined by someone else. To conclude this part of the subject, I will just show a small figure, No. 58, which proves that others have obtained results 550 UEIC ACID — CHAPTER XII which are practically identical with my own, without knowing how they were produced. In my paper in the Journal of Physiology, vol. xv., I sug- gested that extracts of thyroid and other glands possibly owe no small part of their activity in myxoedema and skin diseases to the stimulant properties of the uric acid and other nitrogenous extrac- tives in which they are known to be rich ; and I can prove that in myse'lf the taking of thyroid glands or a thyroid extract pro- duces results which are identical with those produced by so much uric acid (see fig. 30) ; that is to say, there is a first stage of stimulation with rising acidity, well-being, free capillaries and diuresis (just as with caffeine also), followed later, when they are left ofi, by falhng acidity with plus excretion of uric acid, ob- structed capillaries and scanty urine, and with these latter a fall in the blood decimal, just as with uric acid taken in any other form. It is interesting to note in this connection that myxoedema, like asthma, Raynaud's disease, and dropsy, is better during pregnancy, or during fever, and we shall have an instance of the effects of the fever of measles on the dropsy of Bright's disease in chapter xiii. Again, myxcBdema, Hke certain skin diseases, may be worse at the menstrual periods, while arthritic troubles, which stand at the opposite pole of causation, tend to be worse during fever and may be worse during menstruation (see Lancet, 1893, vol. ii., p. 744 ; British Medical Journal Epitome, September, 1892, p. 43, and ibid., Februaiy, 1892, p. 25). I was therefore much interested to see in the Practitioner, July, 1893, a paper by the late Professor Sir T. Grainger Stewart, in which he gives the blood factors in a patient who was being fed with 30 to 60 grs. of thyroid gland every third day for myxoedema. Fig. 58 shows the blood decimal curve constructed from the figures which he gives, and demonstrates that this feeding with thyroids produced a steady fall of the blood decimal. It is true that the red cells rose from 80 to 96 per cent., but this is simply due to the concentration of the blood ; for thyroid gland, as I have said, just Hke uric acid and cafieine, causes diuresis (see fig. 30) ; the haemoglobin, however, did not rise proportionately, and on the last occasion it did not eyen rise absolutely, and so the result is a steady fall of the blood decimal, doubtless due, as in my own curves, to an excess of uric acid passing through the blood. PAEOXTSMAL HSIMOGLOBINUEIA AND ANEMIA 551 Professor Stewart's patient, it is interesting to note also, suffered very markedly with, all the symptoms of an excess of uric acid in the blood, such as weakness and general soreness, with tightness and oppression in the chest, passing later into severe dyspnoea, with blood-stained expectoration ; her asthmatic trouble being complicated by the presence of old disease of the mitral valve (see chap. ix.). It is now easy to understand the causation of chlorosis and ansemia, and their relation to dyspepsia and bilious attacks, for these disturbances cause excess of uric acid to pass through the blood, and are also themselves in part .due to the coUaemia ; but there are other most interesting relations between the development of girls and the causation of these troubles which furnish at least some explanation of the frequency with which ansemia is met with in young women. As to the way in which uric acid produces these blood changes it is not easy to say anything definite ; but we have seen that it obstructs the capillaries throughout the body and in this way diminishes the formation of urea and the production of animal heat ; and we shall see in the next chapter that the fall of urea it produces is contemporaneous with the presence in the blood and urine of an ill-metabolised and difiusible albumen ; and that when we give drugs that clear the blood of uric acid the urea increases just in proportion as the difEusible albumen diminishes. In a word, the urea which does not appear in the urine is accurately represented by the difiusible albumen which does, and by altering the amount of uric acid in the blood, and so controlhng circula- tion, metaboHsm and combustion, we can make the one give place to the other. It is clear, then, that uric acid controls the results of many metabohc processes, and determines the properties of some con- stituents of the blood ; and we have only to extend this power to the corpuscles to understand the phenomena both of paroxysmal haemoglobinuria and ansemia ; they and all their relatives are results of defective metabolism, which again, just as in the case of fatigue, is the result of defective circulation. And now as to the causation of chlorosis. It will, no doubt, be readily admitted that we meet with it chiefly in women between the ages of 16 to 25. How do girls and women of these ages differ from boys and men of the same ages ? As you know well, a girl at about the 13th year develops with enormous rapidity, and her weight may increase by as much as 11 lbs. in this one year, as she dashes at a bound from childhood into womanhood. 552 UEIC ACID — CHAPTEE XII Now, this very rapid growth and development entaik a corre- sponding rapidity of tissue change and metabolism, with a very large formation of uric acid and urea per pound of body weight— this being always much greater in the child than in the adult. But high urea formation is always accompanied by high acidity, that is to say, the urine will be highly acid and the blood lowly alkahne. The blood alkalinity being low, it will be but a bad solvent of uric apid, and hence a considerable proportion of the large amount of urate formed in these years of active metabohsm will not be held in solution in the blood and excreted, but will be retained and deposited in various parts of the body, giving local signs of which we shall speak presently. The same applies to the uric acid of introduction if the girl is fed on flesh and tea, &c., the nitrogenous metabohsm being large and active the alkalinity of the liver will be low, and a great part of the introduced uric acid wiU be retained. Unfortunately, later on a girl's metabohsm falls very greatly, and by the end of the 18th year her increase of weight is almost nil; with this there is a great fall in the formation of urea and of acids, and the blood becomes more alkaline ; as a result of this it becomes also a better solvent of uric acid, and it now takes up and passes into the urine as much uric acid — probably several hundred grains — as was stored in the tissues during the preceding period of active metabolism, from 12 to 14. Hence, from 16 to 19, or later, she wiU have an excess of uric acid passing through her blood, and will suffer from its efiects on the blood decimal — namely, chlorosis. I To illustrate this point a little further, I give in fig. 59, a curve showing the annual increase in weight of boys and girls.* From this we see that the greatest development in girls is in the 13th year, and in boys not till the 16th ; and though the boys' curve falls very greatly in the 17th and 18th years, they are still increasing about 5 lbs. a year when the curve ends. Now I think that girls in their more early development will probably form more uric acid and urea per pound than boys in their later development, and when later on the girls' increase is almost nil, the uric acid previously retained will pass through the blood both in greater quanoity and more suddenly than it does in boys, whose increase is for several years later very considerable and their acidity not so low. I have therefore added to Dr. * Copied from a paper by Dr. W. Stephenson, Lancet, September, 1888. PAEOXYSMAL HiEMOGLOBINUEIA AND ANEMIA 553 Stephenson's curves a line representing the probable effects of the girl's increase in weight on the formation of urea and acids, and a broken line below showing the efiect of this on the excre- tion of uric acid, and from these we see at a glance that the chlorosis and anaemia of 18 are the result of a passage of an i i 14- 12 10 8 S ♦ 2 YEARS 10 II IZ a » IS 16 17 18 r > ^ ' 1 j /- ■>, / \ 1 / / \ \ AH % NUAL INCR y J / / \ \ \ /At / S \ \ / K / A \ Sb< r GrRL \ /- ■v V f \ \ ..._ 1 f V \ v' : / \ s / 5 \ umc / / ^3 * S \; * A Ul l"7. / S > ei AC IDITY \ 1 1 * A 5 ^j a RIC A oo ^ ; •'* ^ ■^^^ . Or / Ul a* ACIDI TY Fig. 59. -CuBVES Showing Development in Boys and Girls and its Effect on the Excretion of Uric Acid. excess of uric acid through the blood, which again is the result of a previous storage of this substance from 12 to 15. Add to this that just at the time when a girl's increase of weight is coming down, and her urea and acidity falling, menstruation is established ; and that even if this does not upset digestion and appetite, it often obliges girls to keep quiet for several days, so 554 UEIC ACID— CHAPTEE XII that its result is to still further reduce urea and acidity, and still more markedly flood the blood mth uric acid, thus completely accounting for the increase of her chlorosis, and the functional troubles so often met with at menstrual periods (see also stages of life mentioned on p. 247). I notice that Dr. Luff {Lancet, 1897, vol. i., p. 946) thinks that there is no uric acid in the blood of men and animals in health, and I have already quoted Professor von Jaksch's observa- tions showing that he found none in a few cases ; but Sir A. Garrod, it may be remembered, did find some in healthy blood ("Gout and Rheumatic Gout," 3rd Ed., p. 113). I differ from some of these observers merely in thinking that a small quantity is generally present in the blood of man even in perfect health, and that there is more at some hours of the day and less at others, as shown by the changes in the blood itself and the corresponding changes in the excretion in the urine (see fig. 52), and, indeed, the results just shown in the previous figures are absolutely inexpHcable if an excess of uric acid in the urine does not mean a corresponding excess of uric acid or of xanthine in the blood. The blood changes can, as we have seen, be produced by swallowing either uric acid or xanthine, which are chemically so closely related (see Lea, " Chemical Basis of the Animal Body," p. 174) ; but the conditions which control the excretion of this substance in the urine correspond at numerous points with the known solubilities of uric acid and not with those of some of the xanthines ; and as I have already pointed out in chapter i., eating of meat has been found by very numerous observers to increase the excretion of uric acid in the urine, while the xanthines are present in that fluid only as mere traces; and yet meat, like tea, cofiee and cocoa, introduces into the body little or nothing but xanthine, which is, therefore, we must conclude, converted into uric acid. Again, I agree with all thef=e observers in finding some uric acid in the blood in disease ; and not only so, but my observa- tions are in complet"^ accord with those of Professor von Jaksch and Sir A. Garrod, as I have found most in the blood in exactly the same conditions as they have found most, and have shown that the quantity rises and falls in these conditions in exact accord- ance with the factors afiecting its solubility, which are practically identical both for physiology and pathology. Then, again, in several pathological conditions, as leucocythsemia on the one hand PAEOXYSMAL H^MOaLOBINUKIA AND ANEMIA 555 and acute rheumatism on tte other, the quantity in the urine is well known to correspond with that in the blood ; and if this holds in pathology it is difficult to see any reason why it should not hold also in a minor degree in physiology. The condition of the blood itself also varies in pathological conditions just as in physiological or artificial ones, with the quan- tity of uric acid in the blood and urine (see figs. 57 and 74). Dr. Lufi, I believe, does not tell us in how many cases he examined the blood, nor does he tell us what, from my point of view, is still more important, the hour at which it was drawn, as I should only expect to find it in quantities that could be identified in any blood that could reasonably be drawn from a living man at some hours of the day ; and even at alkaline tide hours, accidental variations, as shown, for instance, in fig. 52, might cause it to appear to be absent, so that a large number of results carefully published, with full details as to time of day, food, exercise, drugs, and conditions of the subject, would have to be produced to prove absence of uric acid from normal blood. And even then it would bs necessary to give some other explana- tion of my physiological and pathological results, which can be reproduced to any extent. It seems also to be quite unnecessary to postulate, as Dr. Luff does {Lancet, 1897, vol. i., p. 944), an altered condition of the renal epithehum to account for the accumulation of uric acid in gout, when the excretion of this substance varies from hour to hour with the acidity of the urine, and can be made to vary to almost any extent by administration oE acids and alkalies ; and why, if this substance does not come from the blood, does the blood show corresponding changes ? Again, as we shall see in the following chapters, an extremely diseased kidney may yet excrete a great excess of uric acid, and we have already seen that a perfectly normal kidney may, in conditions of low alkalinity of the blood, excrete very httle. As to the presence of uric acid in the blood of birds I see that Dr. Watson has published some results [British Medical Journal, 1899, vol. i., p. 205) showing that he found undoubted evidence of uric acid in the blood of birds. And this has a special interest for me, for when I showed the process of Mr. Barker Smith for precipitating urate granules in the blood (see p. 92), at a meeting of the Royal Medical and Chirurgical Society, in March, 1898, Dr. Luff, who objected to my saying that the test was one that demonstrated the presence of 656 UEIC ACID — CHAPTER XII uric acid in the blood, brought forward the fact that the granules were present in the blood of birds as conclusive evidence of the small importance of the granules, because, as he had shown, there was no uric acid in the blood of birds. I must leave him to settle the point with Dr. Watson, but meanwhile my further researches have shown conclusively that the granules in human .blood are uric acid or xanthine, and that I- have absolute and complete control over the number in which they are present in the blood stream, a control co-extensive with that over the quantity of uric acid in the urine. Then, again, if we look at this figure (59) we shall see that we have got not only a complete explanation of the causation of chlorosis, but that we have also unexpectedly come upon an equally complete explanation of the girl's great tendency to rheu- matism as compared with her brothers ; for I have for years been pointing out* that what we caU gout or rheumatism is really the irritation of certain joint structures by uric acid or urates retained in those structures ; and that they are retained in those structures by the same causes (namely, a rise of acidity, or the presence in the blood of any substance whose urate is insoluble), that prevent their excretion, and bring about their retention in the body in general. Now the retention in this instance is produced by a rise of acidity, and the joints are one of the places in which the urate is retained ; it is little wonder, then, that girls are specially liable at this period of their lives to acute rheumatism, and Dr. Cheadle' sayst that girls of 10 to 15 years old are twice as Hable to rheu- matic fever as boys of the same age ; these years including, I remark, the period of their most active metabolism. But we already know that migraine and rheumatism alternate, and we have recorded on p. 497 a quotation from Dr. Liveing which says that a woman became subject to megrim after fuberty ; now fig. 59 tells us exactly why her trouble came at that time as well as why epilepsy and chlorosis tend to originate at the same period of hfe. With retention of uric acid there is arthritis ; but with the plus excretion and excess of uric acid in the blood, which comes later, there is no arthritis, but headache, epilepsy, mental depres- * Practitioner, February, March, and April, 1891, and British Medical Journal, July, 1888. t Lancet, vol. i., 1889. PAEOXTSMAL HiEMOGLOBINUEIA AND ANSIMIA 557 sion, chlorosis and anaemia ; then there is low blood pressure and quick capillary reflux with the first series (arthritis), and slow capillary reflux and high blood pressure with the second series (the coUsemic series). Probably boys are liable to rheumatic fever from a similar cause at 16 years of age, but their active metabolism coming when they are older, they probably form less uric acid per pound than girls ; and further, they probably retain much less uric acid at this time owing to their more active habits of life. For it follows from our first principles of urate excretion that other things being equal, those in any given period of life retain most uric acid in their body who take least exercise, and those retain least uric acid in their body who take most exercise, which explains CuUen's well-known observation that gout seldom attacks those employed in constant bodily labour (see figs. 46 and 47). Now no one, I suppose, will deny that boys take much more exercise than girls all through school hfe, and especially as com- pared with girls at and after the commencement of menstruation. We see, then, that boys difier from girls in that their active meta- bohsm comes later, when their formation of uric acid per pound is probably smaller, and that owing to their greater bodily activity, they probably retain a smaller amount of the uric acid they form ; while, lastly, their activity and nutrition are better continued and maintained, and they are not subjected to the depressing effects of menstruation, so that any urates they have retained pass more gradually through their blood ; hence they escape more or less completely the chlorosis and ansemia from which their sisters sufier. But if a boy at this time of Ufe meets with an accident which lays him up and cripples his bodily activity and his nutrition, he will then probably sufier from anaemia nea,rly as much as a girl of the corresponding age, and many of the over-fed boys of our great pubhc schools show for -a time at least, about 17 or 18, a more or less marked tendency to anaemia. Paroxysmal haemoglobinuria represents, I have no doubt, a similar but more acute fluctuation in the excretion of urates, probably often related to dyspepsia and gastric upset in exactly the same way that migraine, epilepsy and Raynaud's disease are related to it, and it is paroxysmal just as they are paroxysmal, in relation to the fluctuations in urate excretion. Anaemia associated with enlarged spleen is doubtless related to the large quantities of uric acid met with in the blood and urine of these cases (see pp. 495 and 518). 558 UBIC ACID — CHAPTBE XII Tke way in which the excess of uric acid in the blood is brought about I have already gone into ; and as I have said above, the increase of white cells met with in these cases may be entirely secondary. In the Practitioner, August, 1890, Dr. F. W. Mott wrote an interesting paper on the spleen as a centre of destruction of red blood cells, and it may be noted in this connection that Dr. Hunter {Lancet, 1892, vol. ii., p. 1318) points out that certain substances (toluylene-diamine), which have a destructive action on the blood, act far less powerfully after the spleen has been re- moved ; and no doubt if uric acid destroys the blood elements, they are certain to meet it in concentrated solution in the spleen, and the facts just mentioned suggest strongly that the action of toluylene-diamine is indirect. This also suggests that in the case of splenic leucocythsemia mentioned above the salicylates did good by clearing the uric acid out of the spleen. The effect of fevers in producing anaemia is easy to under- stand, for they diminish the alkalinity of the blood and lead to a storage of urate in the body, and this, when the fever ends, finds its way back into the blood (see facts about Pneumonia, pp. 78 and 208), causing post-febrile collsemia with post-febrile bradycardia, high tension pulse, depression of mind and of metabolism and sub- normal temperature, an identical sequence of events with those producing chlorosis. The excess of uric acid met with in the blood and urine after malaria and other fevers, with or without enlarged ^ spleen, is thus, I believe, the result of the storage of urate that took place during the fever (compare also previous remarks on Eheumatism in Girls). In vol. Ixxv. of the Transactions of the Royal Medical and Chirurgical Society, Dr. A. B. Garrod has an interesting paper on the anaemia of rheumatism, and the relation of the blood changes to the excretion of uro-hsematoporphyrin. In several of his curves, " worth," which corresponds with my blood decimal, remains steady or rises during the fever, and falls afterwards as the temperature becomes subnormal, that is to say, during the fever the urate is all in the joints, and there is none in the blood except in combination with salicylates (see previous remarks on the Action of Salicylates in Anaemia) ; as the fever passes ofi there is post-febrile coltemia with a fall of the blood decimal, just as we should expect when urates combined with alkali are passing through the blood ; and in at least one of Dr. Garrod's cases, the " worth " fell at the end of the fever in spite PAEOXTSMAL HEMOGLOBINURIA AND ANiEMIA 509 of iron being given (see also Dr. Garrod's remarks, previous reference, p. 191). He also notices a corresponding increase of white corpuscles, just as in the similar condition I have mentioned above, and as observed by Dr. Wheaton (pp. 479 and 494). I should expect a fall of the blood decimal just before the onset of the fever, when according to my explanation of the causation of acute rheumatism, there is sure to be an excess of uric acid in the blood (see chapter xvi.), but Dr. Garrod's statements are not very definite with regard to this point. The efEect of all fevers on the blood decimal is probably the same as that of acute rheumatism, and I found in a case of pneumonia, that at the time of the post-febrile coUsemia with subnormal temperature the blood decimal was "55, while a few days later, after the temperature had again gone up to normal, it had risen to "6. I have now for some time been watching with interest the relation between the raised temperature of a febrile disease with its quick capillary reflux and low blood pressure, and the sub- normal collEEmic temperature with slow reflux and high blood pressure that follows it. And to avoid details and a long line of figures of my results, I may say shortly that their relation is nearly one to one, that is to say, for every day of raised temperature in the fever there will be one day of subnormal temperature after it comes to an end. But in those who were full of urates before the fever the sub- normal temperature may be very greatly prolonged with corre- sponding depression and ansemia. This is fairly well seen in short sharp fevers such as pneu- monia, less well seen in chronic fevers, such as enteric, where the temperature drags along often for days just above the normal. In a pneumonia there is a retention of uric acid every day there is fever, and when the temperature falls suddenly the alka- linity of the blood rises, and the store of uric acid takes just about as many days to dissolve and pass out as it did to accu- mulate, hence days of raised are to days of subnormal temperature as one to one. In a more chronic fever with debility, on the other hand, though the temperature is from 99 — 100, the debihty allows the alkaHnity of the blood to rise, the capillary reflux is inclined to slow and the blood pressure to rise, and in these days towards the end of the fever there is no retention of uric acid, but rather a plus excretion. 560 UEIC ACID — CHAPTEE XII Hence, to reckon those days as part of the fever would put out the relation of one to one. This also explains an observation made by the late Dr. Mahomed that you may get a pulse tracing showing high blood pressure in spite of a slightly raised tempera- ture near the end of a fever. We may express this result another way by saying that the store of uric acid begins to overflow before the end of a long fever if there is debihty, which allows the alkahnity of the blood to rise. I will now shortly give notes of a case in which salicylates were given early in the fever and perchloride of mercury towards the end, with the result that the saHcylate swept out some of the uric acid and diminished retention in the fever, and the mercury prevented to some extent the excretion of urates after it, the result of the two actions being that the days of subnormal tem- perature bore a relation to those of fever of only 1 to 2. The temperature chart is that of a child admitted under my care in the Metropolitan Hospital on Jidy 6, with pneumonia of the left apex. It was given salicylate on the 6th, but it had to be discontinued on the 10th, owing to some vomiting. From the 6th to the 13th the temperature rose from 102° to 105°. On the 13th, as it had some diarrhoea and ofEensive motions, it was given bismuth and Uq. hyd. perchlor., which were continued till the 24th. The temperature fell on the 19th from 103° to 100°, and on the 20th it was between 97° and 98° for two-thirds of the day ; on the 21st it touched 98° for four hours, on the 22nd it did the same, and again on 25th and 29th, and was below 98° for parts of July 31 and August 1. The rest of the time it was steady, about normal, or from 98-4° to 98-8° or 99°. There were here then, at least fourteen days of fever, and during the next fourteen days the temperature only touched 98° or went below it on seven days. I beheve that by giving salicylates all through a fever the days of subnormal temperature that follow can be greatly reduced ; in the above case the salicylate could not be given all through the fever, and part of the reduction of subnormal temperature was due to the mercury which was given later on. It is, again, quite easy to explain the efiects of hot weather and of tropical cHmates in producing anaemia, for heat increases the alkalinity of the blood and the urate it will hold in solution ' and this will have most efEect in those who eat meat and drink tea, and so introduce much urate into their body ; and least in tliosp •wlnn livft on a. nric-arJd-frpA f?ip+. iaaa ^'Ko■r^4-/^« -«■,«; \ PAEOXYSMAL HjBMOGLOBINUEIA AND ANEMIA 561 The efEects of diet also are well known and easily explained, Eor Dr. Mackenzie points out that meat diet increases the destruc- tion of red cells {Lancet or British Medical Journal, 1891, vol. i.), md others have pointed out that farinaceous diet does good, and that pale, ansemic children are most common among the " well fed " upper classes {British Medical Journal, 1890, vol. ii., p. -85) —in my opinion, " not wisely but too well " fed upper classes. The paper which immediately precedes mine on anaemia in the British Medical Journal, 1893, vol. ii., p. 670, is one with the heading " Prehminary Report on the Causes of Chlorosis," by E. Lloyd Jones, M.D., and this contains so many points of interest, and so many of which, I think, the causation by uric acid will be found to give a complete explanation, that I may as well mention some of them here. Thus, Dr. Jones points out that after fifteen years of age the specific gravity of the blood falls in the female while it continues to rise in the male, and that this is the age at which girls become anaemic. But if this^ anaemia and chlorosis are, as I am suggesting, the results of excess of uric acid in the blood, the causation of which at this time of life I have already gone into, it is not difficult to see that this coUaemia almost of necessity entails a fall in the specific gravity of the blood, because it prevents the outfiow of water from it by any or all the glandular organs of the body. It is easy for anyone to convince themselves in two or three hours' work that this is a fact ; let them produce in any of the ways previously described so much coUaemia as shall markedly diminish the excretion of water in the urine, and watch the blood meanwhUe ; they wUl find that hour by hour as the urinary water diminishes the water in the blood increases ; that is to say, there is a relative diminution of both cells and haemoglobin in the gi\en quantity; conversely, when they clear uric acid out of the blood and produce a diuresis, they will find that the relative quantities of cells and haemoglobin rapidly return to the position they held before the experiment began. In my own case, and in the cases of anaemia I have investi- gated, I have come to believe that I can tell from the concen- trated or hydrsemic condition of the blood whether there has or has not been a diuresis produced by any drug given ; and as you cure the chlorosis there is a rise in the urinary water, and the patient loses weight from diminution of the blood and tissue fluids (see fig. 57). And no doubt hydraemia goes with all anaemia, for 36 562 UBIC ACID — CHAPTER XII the excess of uric acid which causes the defective blood meta- bolism and anaemia must at the same time and in the same way cause retention of fluids in the body;. I look, therefore, upon the fall in specific gravity of the blood of the female which takes place at fifteen as the result of more or less coUsemia, which produces in the ways sketched out above both hydrsemia and anaemia, and this is itself the result of her very active metabolism at thirteen now coming to an end, and of her menstruation now estabhshing itself. As the male is not exposed to these grea* fluctuations in metabolism with the coUsemia they produce, he does not show any corresponding blood changes. His metabohsm goes more steadily ahead, and he Uves also, be it observed, at this time of his existence, a much more healthy life than his sister. I do not believe that there is any " natural tendency " either to a fall in the specific gravity of the blood or to chlorosis ; they are simply the results of our meat-eating and tea-drinking habits, and of our civilisation. If our girls did not eat so much meat, they would not store so much urate, and would suffer less from arthritis in their time of active metabolism at thirteen, and if at fifteen they led the life of healthy active savages, instead of resting, lying up and becoming semi-invaHds, there would be none of the present great fluctua- tions in their metabolism, but as in the case of their brothers, their development would go more steadily ahead, there would be no falling urea and acidity, no coUsemia, and, consequently, no hydraemia and anaemia. Further on, Dr. Jones seeks to establish a connection between chlorosis and disturbance of splanchnic innervation with dilatation of gastro-intestinal vessels, and he goes on to say, " This I con- ceived to be brought about in a reflex manner, and this appeared - to me to be the more likely since I had met with some cases in which the usual gastro-intestinal disturbance, together with marked chlorosis, had rapidly followed a shock or chill — generally a shock or chill occurring about a menstrual period." Exactly so, and causing, therefore, a great fluctuation in the excretion of uric acid and the amount passing through the blood (see figs. 31 and 32). The very constant relation of chlorosis to gastro-intestinal disturbance, bilious attacks, and chronic dyspepsia is most marked, and the way in which such dyspepsia will often for weeks and months prevent iron from doing any good and curing the chlorosis, PAKOXYSMAL H^MOGLOBINUEIA AND ANSIMIA 563 is with me a frequent experience in the out-patient room, so that my invariable rule is to treat the dyspepsia, or the iron will have no chance. Nature is here merely repeating the experiment that was performed for us in fig. 54, where the digestive disturbance produced by a pill put a temporary stop to the rise of the blood decimal under iron. In any case it is only necessary to keep up dyspepsia to ensure coUaemia, as there is always plenty of available uric acid in the body in these cases : and I believe it would be quite possible by administering a gastro-intestinal irritant, such as colchicum, and at the same time administering xanthines in food or drugs, but in larger quantities than I used in the previous figures, to produce most severe even fatal anaemia, and many facts seem to show that not a few of the cases called pernicious anaemia have this origin. They come also just at a time of life when from years of wrong diet there are sure to be large accumulations of uric acid in the body, and any chronic gastro-intestinal irritation supervening at such a time is certain to produce mora or less severe coUaemia and anaemia ; but up to a certain point all such anaemias are curable by any treatment that will relieve the gastro-intestinal condition and make it possible for other drugs to clear the blood of uric acid ; but once debility becomes very great and appetite and nutrition "ail, it is practically impossible to clear out the uric acid with any drug, and the disease is fatal. This is rarely the case with chlorosis in the young, because their more active metabohsm is not so easily overpowered by debility and anajraia, but in the anaemias of later Hfe there is less power of recovery from debility, and they are more often fatal. Before leaving the subject of anaemia, it may be useful to give a short summary of the facts of the case. First, then, by the clinical observation of paroxysmal haemo- globinuria, Raynaud's disease, splenic leucocythsemia, chlorosis and anaemia, and the relation of many of these troubles to " bilious attacks," dyspepsia, menstruation, cold, heat, fever and drugs, I was led to believe that there was an important connection between the blood changes and an excess .of uric acid in the blood and urine. As to these facts, I am at one with other observers, but differ from them merely as to their meaning and causation. Secondly, there is my observation that the value of my blood decimal alters from day to day, even from hour to hour, with the amount of uric acid passing through it, and that if intentional variations are produced in the uric acid, the blood decimal follows suit. 664; UEIC ACID— CHAPTEE XII I believe also that my blood will generally compare very favourably with, thatj of other men of my own age who eat more animal food than I do. Indeed, I rarely see anyone with blood as good as mine, except, perhaps, young children, and the blood of young patients who have been on my diet for a series of years is simply magnificent, and I believe is above all received standards. Then there are practically no meat eaters and tea drinkers whose blood is up to my highest standard, or whose capillary circulation is as quick as mine, and when uric-acid-free dietists and meat eaters are together it is easy to pick out the latter by their slow capillary circulation. Thirdly, there is my observation that the same holds good for others also, and especially for anaemic and chlorotic patients. Lastly, we see that the knowledge thus acquired enables us to explain many of the chief points in the causation of these diseases, and will, doubtless, in the future enable us to explain still more. Thus I believe that many whose professional experience goes back 30 or 40 years would agree that chlorosis is much more common now than formerly, and hence I< was interested in the remark of a woman among my out-patients at the Royal Hospital for Children and Women, Waterloo Road, who said with reference to her daughter's chlorosis, " Ah, sir, we never used to see this sort of thing when I was young." Now, if her observation is correct as to the facts, what has happened in the 30 or 40 years of hej recollection ? Why, agriculture has been ruined and the people driven more and more from the country into the towns, where they have aped the meat-eating habits of their social supsriors, and increase of chlorosis is one of the results of this. But even in country towns they are now vale, as observed by me in a visit to Carlisle, but Carlisle has a public abattoir, of which it is proud, and curiously enough, the next object of interest on the list (B.M.A. membership card, 1896), was the human cemetery; humanity itself being the cemetery of the animals, as I believe, to its infinite hurt. I have mentioned above that one of the blood changes met with in paroxysmal hsemoglobinuria is an increase of coagulabihty ; and several things seem to render it probable that if uric acid thus directly or indirectly increases the coagulability of the blood, it may exercise an important influence in the pathology of thrombosis. The frequent cHnical connection between thrombosis and gout or diabetes, of both of which I shall have something to say PAROXYSMAL HEMOGLOBIN UBI A AND ANEMIA 565 presently, is too well known to need more than mention ; and a similar relation is often found between thrombosis and certain post-febrile and puerperal conditions, the thrombosis of enteric fever is also an incident of the post-febrile coUeemic period ; and after what I have already said about these, I need hardly insist on the fact that one point common to all these conditions is the frequent presence of considerable excess of uric acid in the blood ; then again, unless my clinical observation deceives me, thrombosis is not very uncommon in Bright's disease, and in this disease (as we have seen in chapter iii.) the researches of Professor K. von Jaksch confirm my own in showing that an excess of uric acid is very frequently to be found in the blood [Centralb. fur Inn. Med., May 23, 1896). In the Lancet, 1894, vol. i., p. 1446, is the record of a case of thrombosis following an attack of influenza, and said to be due to the breaking up of white blood cells. I think it is much more probable that it was due to the post-febrile coUsemia which fol- lowed the influenza, and that the increase of white cells and the increase of coagulability were, just as in paroxysmal hsemoglo- binuria, the results of the collaemia (see previous remarks on this and on Splenic Leucocythoemia). From this point of view also I was very greatly interested in Sir J. Fayrer's article on " Intra-vascular Coagulation and Pul- monary Thrombosis " {British Medical Journal, 1893, vol. ii., p. 165), for in many of the conditions which he mentions, such as malaria, splenic disease, puerperal conditions, hot, damp weather (see also Causation of Fatigue, figs. 46 and 47), and especially surgical operations in hot, damp weather, it seems to me that there is hardly room to doubt that a great excess of uric acid would often be present in the blood. I shall mention in chapter xiv. the effects of surgical opera- tions in increasing the excretion of uric acid and urea, and I have no doubt that, combined with hot weather, these would greatly increase the quantity of uric acid passing through the blood. Then, again, I notice in the Lancet, 1896, vol. i., p. 475, a case of fatal pulmonary apoplexy in a girl of 14 years, which came suddenly after a walk just at the end of a perfectly normal monthly period ; but here we have at least three causes of collsemia, the exercise, the menstruation, and the girl's age, referred to in fig. 59. Similarly, a case of pulmonary thrombosis recorded in the British Medical Journal, 1896, vol. ii., p. 1504, coming after 566 URIC ACID — CHAPTER XII enteric fever is said to be due to debility, but here again, I think, we must not forget post-febrile collsemia. Lastly, if, as I have ' suggested (p. 173), colloid uric acid me- chanically obstructs the capillaries, and if from time to time small portions of this obstructing substance are carried past the capil- laries into the veins, we can at once see how they may come to form nuclei of thrombosis, if the colloid is not dissolved as the blood gets warmer in the deeper tissues. So that this colloid mechanical theory may also help us to understand the observed connection between gout and thrombosis. And once a coagulum has formed round such a nucleus, it will not dissolve even in the warmest parts of the central circula- tion, though the colloid uric acid alone may completely disappear there. Then there is another point among the symptoms of par- oxysmal haBmoglobinuria, of which I am now, I beheve, able to give a pretty complete explanation. It will be readily admitted by other observers, that in the urine of paroxysmal hsemoglobinuria oxalate crystals are very frequently present ; let us enquire further as to their meaning. In the British Medical Journal, 1885, vol. i., p. 167, Sir T. Lauder Brunton points out that it has been shown that when sulphuretted hydrogen is allowed to act on a concentrated solution of urates, oxalate of lime is produced ; now, in the urine of par- oxysmal hsemoglobinuria, we have undoubtedly a concentrated solution of urates, for I have demonstrated both the facts and their causation over and over again ; we have probably also sul- phuretted hydrogen in this urine, and the point of greatest interest is the way in which this sulphuretted hydrogen is produced. Sir T. Lauder Brunton points out that the sulphuretted hydrogen, which produces the oxalate crystals in the urine, is generally formed in the intestines during digestion of cabbages and other food rich in sulphur, and the way in which it comes to be produced in the intestines in the paroxysm of haemoglobin- uria, is, I think, a point of great interest. In chapter vii. I have pointed out, in answer to the arguments of Messrs. Herter and Sitiith, of New York, on the causation of epilepsy, that the intestinal putrefaction of which they noticed so many signs in this disease was the simple and constant result of an excess of uric acid in the blood ; and I argued that the excess of urate in the blood which obstructed all the capillaries and raised blood pressure to the extent of ■ interfering with the PABOXTSMAL H^MOGLOBINDEIA AND ANEMIA 567 intracranial circulation and producing the fits, would interfere also with gastro-intestinal digestion and absorption and allow putrefactive processes to take their place. I doubt not also that a precisely similar explanation may be given of the excess of bacteria in the intestine, and the poison found in the urine as a result of their activity in cases of pernicious anaemia (see Dr. Hunter, Lancet, 1891, vol. i., p. 260). Dyspepsia, often severe dyspepsia, is a very constant symptom of pernicious anaemia, and it follows from what I have been saying that all dyspepsia is a cause of collaemia and anaemia which are more severe and lasting the larger the amount of the available uric acid. Here also the uric acid in the blood is the first thing, while the bacteria in the intestines, and any products they may generate, are secondary, and as in the parallel case of epilepsy unimportant (see also a paper on " Hydrothionuria " in the Ne:v York Medical Journal of June 17, 1892). This in many cases accompanied digestive trouble or disease, and it is said that it (sulphuretted hydrogen) may also be formed by bacteria in the urine. Messrs. Herter and Smith say (previous reference), " We cannot say why there should occur in epilepsy so considerable a propor- tion of cases in which there are evidences of excessive intestinal putrefaction." To my mind the explanation seems as simple as it is complete ; and I would suggest that a similar explanation can be given of the presence of oxalates in the urine of haemo- globinuria ; for here also we have coUaemia and general obstruction of capillaries, and whUe the excess of uric acid is causing the blood destruction, the obstructed capillaries suspend gastro-intes- tinal digestion, and putrefaction doubtlejs, with the formation of more or less sulphuretted hydrogen, takes its place. A certain amount of that sulphuretted hydrogen passes with the excess of urates in the concentrated urine, and the frequent presence of oxalate crystals n this fluid is thus fuUy explained. Lastly, the explanation throws backwards a most interestiug hght on the actual causation of paroxysmal haemoglobinuiia, and demonstrates that it is contemporaneous with the presence of an excess of uric acid in the blood and urine, and deficient circulation in the intes- tines which we cannot see, as well as in the skin and extremities, producing the symptoms of Raynaud's disease, which we can see, and which are weU known to be so frequently associated with it (for a case in which sulphuretted hydrogen was formed in a dilated stomach, see CentraHilaU fiir Inner. Med., December, 1894). In a more recent paper {Lancet, 1903, vol. i., p. 367) Dr. Hunter 568 UEIC ACID — CHAPTER XII mentions at least three or four points of which uric acid causation enables me to give a simple explanation. Thus speaking of 25 cases observed in the last three years he says, " the average age was 51 years," and this, I remark, is just near the end of the middle life retention period, and near the beginning of the old age coUeemic period, and therefore just at the most favourable time for severe collsemia and its effect, anaemia (see p. 247). Again he says, " Sex : 19 cases were in men and six were in women." The '^explanation of this is again simple, for men retain most in the middle period of hfe, as women excrete a considerable amount at each monthly period. And those who retain most in the retention period of the prime of hfe will have the most severe collsemia in the decline of life about and after 50. Again Dr. Hunter says, " Station in life : there were 17 private patients and eight hospital patients." Here again the private patients no doubt put in more meat foods, tea and coffee, and hence had more collsemia than their poorer brethren. And last and most interesting of all he says, " Gastric or intes- tinal disturbance : a history of antecedent gastric or intestinal disturbance, as I shall presently show, was found in every case. In no case were these of sufficient character or intensity to account for the supervention of such an intense degree of ansemia." Can anything be more simple than the complete explanation of this relation : dyspepsia is tht^ one thing wanted to bring all the stored uric acid through the blood, and of course the ansemia is not proportional to the dyspepsia but to the amount of uric acid available, and so to the severity of the collsemia which the dyspepsia produces. This leaves on my mind no sort of doubt that pernicious ansemia will own to a causation practically identical with that of all other forms of ansemia, and I have already records of some cases which others have called pernicious ansemia, and which have cleared up completely on correct diet, sometimes without any other treatment. Diagnosis. — Ansemia associated with o-xcess of uric acid in the urine, and probably scanty urine, as in the case of A. P., fig. 57, and associated with these will probably be dyspepsia, dysmenoc- rhcea, heavy work or other cause of excessive fatigue, i.e., causes which tend to bring excess of uric acid through the blood when- ever such excess is available in the body ; thus what is called a " heavy place " is a very common contributing cause of chlorosis in young servant girls, and we already know the relations between fatieue and collsemia. PAROXYSMAL H^MOGLOBINUMA AND AN^JMIA 569 When an£emia occurs in such association with excess of uric acid in the urine and blood, we can treat coUsemia with full confidence of success, for we now know and can demonstrate that the collaemia is the cause of the blood changes, and not, as was previously supposed, their result. I am thus incUned to believe that all forms of destructive blood changes and anaemia are due to uric acid, and that when this poison has been successfully shut out of the diet such diseases will cease to be seen. At present I should not despair of curing any case where there was a reasonable chance of being able to clear the blood of uric acid ; but the chief things that tend to make that chance a small one are incurable or organic gastro-intestinal disease, great enlargement of the spleen which mechanically and otherwise inter- feres with digestion, and long continued and severe debility in those no longer young, especially if in previous years they have swallowed large quantities of uric-acid-containing foods such as flesh and tea. For treatment we must as far as possible reverse the conditions that produced the trouble, and remove the causes of excessive fatigue or dyspepsia. But if diet clears the blood of uric acid (1) by stopping intro- duction at once, and (2) by allowing the gradual eUmination of the uric acid already in the body, it follows that we ought to be able to cure chlorosis by diet alone without any drugs like iron, which directly clear the blood of uric acid, but provide also for an almost certain relapse, in that they do not remove the uric acid from the body, but store it up in the tissues. And I now show in fig. 60 the results of an attempt I made to do this in the case of a girl of 16 under my care in the MetropoUtan Hospital. At the beginning of the figure her blood decimal was found to be slightly above 0'3, and she presented all the ordinary signs of chlorosis. She was put on a milk diet with a little fish, and no drugs were given. Her blood decimal remained at exactly the same level in the two following weeks, in spite of nursing and rest in bed, and then on November 28 the fish was left ofi. On December 5 there was a decided fall in the decimal, and the patient had begun to siifier from headache, both being, no doubt, the result of the passage of seme excess of uric acid through the blood ; I would refer to a somewhat similar fall in the blood 570 UEIC ACID — CHAPTER XII decimal produced by a similar change of diet, i.e., from meat to milk and fisli in fig. 55 (June 19 to 22 and remarks on this). No doubt the change from meat to fish and milk produced a fall in the acidity of the urine, and allowed the passage of some excess of uric acid through the blood, and similarly in fig. 60 the leaving off the fish produced a fall in the urinary acidity and so some excess of uric acid in the blood, and a fall of the blood decimal ;. the same result being further indicated by the onset of headaches. The blood decimal recovers a little on December 12, but falls again on the 19th and 26th, the headaches continuing in spite of an acid mixture, and then it steadily rises to the end of the figure, the headaches being much less frequent and severe by 7396 ''*'^' Deer lull' wr- /* ,'i ^fl ,■> 1^ 19 ?fi P ■) 16 23 § •4 S, * 1 f 1 i 1 ■~1 II J ■0 ^ S «! 1 ^1 ii . 1 i II ^ '^ ^ ? s ^^ 1 S s ■3 10 ^ 10 « <0 ■C -. s V /^ Fig. 60. — Cuhve of Blood Deciital in Chlobosis SHOwiua the Effect op A Ubic-Acid-Pkbb Diet. January 2, and some salicylates being taken in conjunction with the acids on January 9 and onwards. Now my object in giving this figure is to show that the first effect of leaving all animal food out of the diet is a fall in the blood decimal, and that this fall is due to the passage through the blood of some of the excess of uric acid in the body, and this is further shown in this particular case by the onset of headaches, and we may note also that as the headaches got less the blood decimal steadily improved. I may say that this patient went on for some months beyond the end of the figure slowly improving; then she began to lose weight slightly, and it was then found that she was not taking her milk and farinaceous diet at all well, and so she was put back on to ordinary diet, and given iron, under which she improved more quickly, and in a few weeks she was able to go out. PAEOXTSMAL HiEMOGLOBINUEIA AND ANiEMIA 571 I will merely remark with regard to this that the quickest way out of chlorosis is to give iron, mercury, copper, zinc, or any other metal that quickly clears the blood of uric acid, but then a relapse is a matter of certainty, a longer or shorter time (generally within six months) after the metal is left off. To cure entirely by diet, however, is, as shown in the above case, often very tedious, and there will probably be a more or less decided fall of blood decimal at first, which may lead to com- plaints on the part of the patient and her friends ; the cure, however, though slow, is certain, and there is no relapse. I believe, however, that the best way to cure chlorosis is to combine the treatment by diet and drugs in the following way. When the patient first comes under treatment give ordinary diet, remove dyspepsia if present by means of bismuth and sodii bicarb, with a saline (sulphate) purge if there is constipation, and then go on to give any of the above metals, it matters little which ; I got just as good results with copper or iodide of mercury as with iron. I regard the. mercuric salt as the most powerful,* but then there is the chance of iodism, mercurialism, and intes- tinal irritation, the copper also may cause coHc and intestinal trouble. Or mercury may be given as pil. hydrarg. in small doses along with iodides, chlorides, and bromides, as advised in the next chapter, in the treatment of Bright's disease, and in cases of that disease so treated the blood decimal always improves as the albumen diminishes, and the urea increases, i.e., as the combustion is freed from coUsemia. Iron is probably the least powerful as regards the blood, but it is somewhat less liable to cause gastro- intestinal trouble than the other two. When by means of one of these metals the blood decimal has been got up to '5 or '6 or above, give salicylates, say every alternate week for six, eight or twelve weeks to clear out the uric acid, and towards the end of this time reduce and leave off all animal foods, altering the diet to that advised in chapter xvii. The patient is now quite well, and as long as she remains on a uric-acid-free diet will continue to be so. Thus Ellen W., aged 2-3, was under my care in the spring of * For a record of a ease of severe ansemia successfully treated by injection of bichloride of mercury and bichloride of quinine, see British njedical Journa Epitome, 1896, April 11, p. 59 ; and for a case of pernicious anaemia similarly treated with mercury and cured, see the same journal, 1896, Epitome, July 18, p. 11. 572 UBIC ACID— CHAPTER XII 1896 in the Royal Hospital for Children and Women sufiering from relapsing chlorosis ; after treating her with iron as in some of the preceding figures, I let her go out after showing her my diet and telling her that if she would take care to follow it she would not have any further relapses. She returned as an out-patient on February 18, 1897, on account of some little dyspepsia, due apparently to her eating a large amount of baker's bread, and suffering in consequence from constipation. She told me that ever since she left the Hospital she had been doing as I told her, and hving (though not quite as I told her) on nothing but bread and milk. But her blood was a picture ; I have never seen such blood in a woman of her age (and she said that all her friends remarked on her fine colour), and indeed I do not think in any man or woman of any age ; it was the only blood I have seen for months and months that would have any chance of comparing favourably with my own. Here then we have both constipation and dyspepsia existing with the most magnificent blood, and the reason is simple, there is no uric acid in the body, and there has been no introduction in her food, and therefore dyspepsia cannot bring it through the blood. I have also heard from Dr. Mackie, of Nottingham, that he had got some most interesting and successful results in the treatment of anaemia in young women, by applying my suggestions as to diet. I have recorded the improvements in my own blood that resulted from leaving ofi meat, and more recently from leaving ofi all animal food except milk and cheese ; and in every case where I have altered the diet for headache epilepsy, mental de- pression, or other similar troubles, there has been, a similar distinct improvement in the condition of the blood as one of its results. This generally first shows distinctly about the end of the first three months, and is greater at the end of 6, 9 and 12 months, till at the end of 12 — 18 or 24 months, a blood which was at first under 'i, reaches my own level '7, and above up to "8 , and these people have and continue to have a deep rich colour in their tongue and gums, which no meat eater can equal, and I often meet people who think their blood colour is good till they compare it with mine. In many cases, no doubt, there is a fall of the blood decimal as in fig. 60, on first going on to the diet, but this will vary a good deal with nutrition, and will be less marked where nutrition PAKOXYSMAL H^MOGLOBINUKIA AND ANiEMIA 573 is good and is adequately maintained on the new diet, and more marked where, as in the case of fig. 60, nutrition is poor and is not well kept up on the new diet. Then during ■ this primary fall of the blood decimal, if the patient suffers from headaches they will be worse, if from fits they will be more frequent and severe, and mental depression will in- crease, so that both patient and doctor may become disheartened and give up the diet. But to be forewarned is to be forearmed, and by looking carefully after nutrition this primary fall may be diminished, and as regards the headache, fits and depression, it is but one more proof that they are due to the uric acid in the blood, and that patient perseverance in clearing it out and keeping it out will eventually be crowned with success. These and similar experiences have led me to suggest that in the treatment of headache, fits, mental depression, &c., by diet it may be well to examine the blood every few weeks, or oftener, so as to have a guide to the effects of the diet on the excretion of uric acid" and the amount passing through the blood ; a weekly examination of which will do practically as well as a more frequent examination of the urine. And I have now gone further and produced a card for the approximate estimation of the blood decimal.* On this card are a series of colours, and under each is the probable blood decimal that would be found in a case when the tint of the tongue and gums approximates to that on the card. This card affords a definite standard of reference, and a means of estimating whether much or httle uric acid is passing through the blood ; in the former case the decimal falls, in the latter it rises. The capillary reflux will best tell us the hourly and daily fluc- tuations of uric acid, the blood decimal will give us the record of the balance of fluctuations over weeks and months. Ansemia is to-day an all-pervading feature of Ufe in London ; it is seen on all sides in marked and increasing severity. You see it in all but young children who are not so much dosed with animal flesh and tea, and whose active metabolism keeps their blood for a time free from the poisons. Let a child get ill, however, his fires burn lower and the all- enveloping coUaemia catches him also. This general anaemia has just as much to do with the atmo- sphere of a great city, absence of oxygen, and the wear and tear of modern life as it has with the mountains of the moon. * To be obtained from Messrs. Bale, Sons and Danielssou, Ltd., 83-89, Great Titchfield Street, W. Price Is. each. 574 UEIC ACID — CHAPTEE XII It has everytlimg to do with, and is the direct result of the increasing consumption of animal flesh and the drinking of tea, meat juices and extracts, and this will one day be proved beyond all doubt by the results that will follow a reversed of these habits. Men will then see once more the natural colour of human blood, and will stand aghast with horror at the terrible losses in mind, body and estate, that this generation has suffered for the want of it. Fact is sometimes stranger than fiction ; what fiction has por- trayed — millions of people dehberately poisoning themselves ! In this chapter we have been dealing with troubles due to collsemia found in association with slow capillary circulation, sub- normal temperature and many granules in the blood (see p. 136). Such troubles are therefore reHeved by precipitants, but in curing chlorosis for instance with precipitants, we often pro- duce a precipitation trouble, viz., arthritis ; but diet wiU prevent both the coUsemic and precipitation troubles and thus render drugs unnecessary. 576 CHAPTEE XIII. Albuminuria and Beight's Disease. One of my first papers on the uric acid headache (Practi- tioner, March, 1886) ends as follows : — " And further, as it is by no means uncommon to find in the post-mortem room that there are urates in the joints of persons who are not known to have had manifest gout, and that such urate deposits are often asso- ciated with granular kidneys, hypertrophied heart, degenerate vessels, and cerebral haemorrhage ; I think that many people who have the forms of headache and the history above described, and are easily affected by butcher's meat, and, indeed, resemble cases of Bright's disease in the manifest benefit they often derive from leaving it ofi altogether ; I think that many of these cases tend to degenerate in this direction as years go on, and perhaps finally to enter the post-mortem room under some or all of the conditions above mentioned. So that I am inoHned to beheve that the diet treatment of these, forms of headache may mean much more than the alleviation of their pain, and that if it is fortunately begun early in life, it may possibly be the means of preventing, or greatly delaying, the more serious and fatal develop- ments." I believe now much more strongly just what I was beginning to see then, that from the uric acid headache to chronic Bright's disease, the only change is one of degree, and I see no reason to doubt that if I had not altered my diet fifteen years ago, I should to-day be sufiering from albuminuria, hypertrophied heart and degenerate vessels, and be in danger of cerebral haemorrhage. Since I wrote the lines quoted above, I have seen quite a large number of cases in which periodical sufferers from the uric acid headache have come to suffer from albuminuria and chronic Bright's disease ; and even at this moment I have under my care 576 URIC ACID — CHAPTEB XIII several cases, of which I shall presently give a few notes, and in which I heUeve that the transition from migraine to morbus Brightii is occurring before our eyes. The alteration in my diet has not only prevented my having a headache more than two or three times in a year (in place of forty to fifty times), but it has rendered the attacks in every respect less severe, the coldness of the skin and extremities is much less, the pulse is almost never aS slow or of as high tension as it used to be ; so that a rate below 60, or tension as high as that shown in fig. 44 is now quite rare, and my general level of blood pressure has, I believe, been lowered to a corresponding extent. Thus the circulation and metaboUsm in my skin and other important organs have not been hindered to anything like the extent they would have been had I continued my meat diet during these years, and I have so far, therefore, escaped albu- minuria and Bright's disease. i Though I never found any in my own case, I beKeve it is by no means very rare for sufierers from the uric acid headache to have a little albuminuria at the time of the attack or just before it is over, and some sufierers have albuminuria with their bad attacks, but not with their slight ones. My experience in this respect is by no means singular ; as I notice an article by Dr. Stewart Lockie, in the British Medical Journal, 1886, vol. i., p. 1059, on the albuminuria of adolescence and headache as its chief symptom. He also mentions the frequent presence of a gouty family history in these cases. The analogy between cyclic albunrinuria and migraine is also pointed out in a paper abstracted in the Epitome of the British Medical Journal, 1896, June 6, p. 89. Then again it will have been gathered from what I said of paroxysmal haemoglobinuria in chapter xii., that I look upon it simply as a paroxysmal fluctuation in urate excretion, entaiUng the passage of an excess of uric acid through the blood. It is in fact a severe uric acid storm, and the headache in this case, jiist as in the cases of albuminuria mentioned above, is very frequently present. Then also it will be understood that I believe there are to be met with all gradations from the blood changes of anaemia pro- duced by uric acid, to the hetero-albuminsemia (Semmola) and albuminuria, and finally to the haBmoglobinaemia and haamoglo- binuria of the paroxysmal disease ; the factor immediately under- lying these blood changes being a deficient circulation in the skin and other important organs of metaboUsm, and behind this again. ALBUMINUBIA AND BEIGHt's DISEASE 577 and the cause of all subsequent changes, is an excess of uric acid in the blood. The obstructed capillaries, which raise on the one hand the pressure in the arterial system, diminish, on the other hand, the circulation through all the organs and tissues of the body ; head- ache, mental depression and fits, represent, probably, as we have seen, the effects of the high blood pressure on the intracranial circulation, while arterial degeneration and hypertrophy of the heart are some of its efEects on the vascular system ; on the other hand, the cold skin and extremities, certain alterations in the skin and other structures up to Raynaud's disease, the atrophied skin of Bright's disease, and certain changes in the blood and circulating albumens, ranging from ansemia to hetero-albuminaemia and hsemo- globinsemia (these being accompanied by diminished formation of urea just as we have seen it falling in fatigue (figs. 46 and 47), and indeed wherever, even in physiological conditions, there is an excess of uric acid in the blood), represent the efEects of the defec- tive circulation on the great metabolic tissues, where the com- bustion of the body. is carried on. In so far as these changes are due to uric acid, they are at first functional and may be completely recovered from, but when the uric acid storm is severe, and repeated every week for years, the interference with circulation is sufiiciently great and prolonged t^ produce atrophy and degeneratioii of tissues, and then the full picture of Bright's disease gradually unfolds itself, and complete recovery is no longer possible. The only course now is to reduce the metabolic needs of the body within the limits which atrophied structures may suffice to perform, just as occurs sometimes in phthisis, when a patient may _ last for years with only a lung and a half, or less, because the respiratory needs of the body have been correspondingly reduced. In saying this, it must not be lost sight of that external son- ditions, such as temperature, will very greatly influence in one way or another the effects of uric acid on the skin circulation ; while an internal condition, such as dyspepsia, by keeping up for weeks and months a more or less severe coUaemia (see chapter X.), may bring into existence, in a comparatively short time, its worst efEects on metabolism and nutrition. My clinical obseiVation leads me to beUeve that chronic Bright's disease, and possibly also the nearly alhed condition of myxcedema, not very rarely take origin in this way from chronic dyspepsia. See also a paper by Dr. Tirard in the Lancet, 1896, vol. ii. 37 578 UKIC ACID — CHAPTBB XIII . p. 377, on dyspepsia as a predisposing cause of morbus Brightii ; but it is far more than a predisposing cause ; it is one link in a chain of causation and itself also a result of coUeemia, which it helps to continue and intensify. The best proof that uric acid exerts the efiect on the vessels, which this pathology postulates,' is I think to be found in the fact (previously gone into, chapters ii. and iii.) that the urinary water varies from hour to hour, and day to day, inversely as the uric acid excreted along with it, and the further fact that very numerous drugs which diminish the uric acid increase the water, while others which increase the uric acid diminish the water. Add to this that excess of uric acid in the blood diminishes the formation of urea both in physiology and pathology, and determines the onset of fatigue (chapter viii., figs. 46 — 49), and we have some pretty convincing proofs of its great and far-reaching powers over the metabohsm and combustion of the body. The administration of urea in the treatment of tuberculosis is an interesting instance of the law that anything that clears the blood of uric acid acts as a stimulant to nutrition and metabolism (see p. 123). It has been pointed out that the urea taken is not excreted as urea, but is broken up and metabolised in the body, and as far as I can see this is true, for though when I, while fasting in the morning, took urea, there followed an immediate rise in the excretion, I think that this was merely due to stimulation, as there was a corresponding rise of acidity, and that here, just as with sugar and acetic acid in figs. 4 and 5 of " Diet and Food," the rise of urea was a result of stimulation and not a mere excretion of the' urea swallowed; hence urea is a stimulant of nutrition and combustion because it clears the blood of uric acid. As some appear to have misunderstood the bearing of my remarks on the circulation of the kidney (Sewell, Medical News, Philadelphia, Sept. 16, 1893), I may perhaps do well to re-state them here. It is no doubt quite true, as this observer points out, that physiological experiment has shown that the blood supply of the kidney varies directly with arterial blood pressure ; but in these experiments the capillaries of the kidney remained neutral, whereas my poiut is that in collsemia the capillaries of the kidney are not neutral, but hke the vessels of the skin, the eyes, and the salivary glands, they are more or less decidedly obstructed ; and what I suggested was that this obstruction overcame the power of arterial blood pressure to force blood through the kidneys, and the remarks ALBUMINURIA AND BKIGHt's DISEASE 579 I have quoted from Sir T. Lauder Brunton (p. 171) show that this is his opinion. Clinically I thmk we meet with scanty urine under two con- ditions : (1) when the heart, being normal, the obstruction of capillaries is abnormally great, and the kidney circulation is con- sequently defective ; (2) when the obstruction of capillaries is not above normal, but the heart is weak or diseased, and has not the power to drive the blood through them. The failure of circulation is, in both cases, due to the fact that the heart has not power to do what is required of it ; but a finger on the pulse will enable us in a moment to distinguish between them, for in the first case there will be high blood pressure, in the second almost none ; the same argument appUes to the circu- lation in all the tissues of the body, and- 1 have already alluded to it in connection with the incidence of Raynaud's disease in girls and women. This also explains completely the" absence of dropsy in chronic Bright's disease, for in this disease the heart at first hypertrophies and works up to its troubles, but when, later on, its nutrition with that of the whole body suffers severely, it fails and dilates, and then retention of water and dropsy quickly supervene, because the capillaries in the kidney and elsewhere get the best of it. When anything, such as previous pericarditis, prevents the heart from undergoing this conservative hypertrophy, the primary dropsy is marked and persistent, and the end is so rapid that there is no time for chronic changes in the kidney to take place. Having thus given an outline of the position I have been gradually led to take with regard to the causation of albuminuria and Bright's disease, I shall now give a little more in detail some of the facts on which it is founded. In a paper on " The Connecting-link between the High Tension Pulse and Albuminuria " {British Medical Journal, 1890, vol. i., p. 65), I mentioned certain points which seemed to me of interest in connection with the writings of the late Dr. Mahomed and those of the late Professor Semmola, as bearing upon the causa- tion of the disease, and suggested that hetero-albuminaemia, of which the latter writes, and to which the kidney lesions found fost mortem are secondary, gave us a good explanation of the causation both of Bright's disease and of so-called functional albuminuria. I will now mention a few of the points in this paper. The late Dr. Mahomed pointed out that though a high tension 580 UEIC ACID — CHAPTER XIII pulse is a common and charactoristic feature of Bright's disease, it might nevertkeless be preeent for several years before there is any albuminuria. He «aid tha+ the high tenj^ion and other signs oi what he called the pre-albuminuric stage of Bright's disease were probably due to a poison in the blood, and I suggested that many of the signs and symptoms he spoke of were those of coUaemia, and that the poison he was in search of was probably uric acid. Dr. Mahomed also showed that in certain cases of temporary albuminuria, about which I shall have to speak at greater length presently, the appearance of the albumen was preceded and accom- panied by- an increase of arterial tension. I then quoted at considerable length from the works of the late Professor Semmola, who shows that the appearance of albumen in the urine is due to the presence of an excess of diffusible albumen in the blood (hetero-albuminsemia), the kidney lesions found after death being due to the irritation which this foreign albumen eventually sets up in passing through its glomeruli and tubules. I pointed out in support of Semmola's thesis that Stokvis in one of his experiments with egg albumen did produce some kidney irritation, resulting in the passage of serum albumen into the urine. I pointed out that taking Bright's disease as a primary altera- tion (inflammation) of kidney -structure causing serum albuminuria, there is nothing to account for the excess of diffusible albuminoids in the blood, as to the existence of which in nephritis the obser- vations of the late Professor Semmola do not stand alone. I further said, that while the theory of primary kidney lesion quite failed to account for the cHnical symptoms of many cases of so-called " functional " albuminuria, the theory of primary blood lesion (hetero-albuminsemia) might account for them .com- pletely. The chief arguments of the late Professor Semmola are as follows, and I take them from the work of Dr. Labadie-Lagrave (Urologie Clinique et Maladies des reins, Paris, 1888, p. 714, et seq.) so as to give my readers the opinions of others, rather than my own, on the work of Professor Semmola. (1) The amount of albumen in the urine varies with the amount of albumen in the food and not with the renal lesion ; therefore the albuminuria is not due to the renal lesion. (2) The cause of Bright's disease is the action of cold and damp on the skin, but this cold and damp in chronic cases is not ALBUMINUEIA AND BEIGHT'S DISEASE 581 able of itself to determine hyperaemia of the kidney : that is to say. the lesion eventually found ''n the kidney is not the direct rfisult of the action of cold and damp on the skin, therefore there must be some intermediary. (3) This intermediary is unassimilable albumen ; certain por- tions of the circulating albumens being rendered unassimilable and difEosible by failure in the metabolism of th^ skin. (4) This unaosimilable albumen is eliminated by the kidneys and other organs, and gradually produces irritation and parenchy- matous and interstitial changes in their structure — Bright' s disease. Thus Labadie-Lagrave says (previous reference, p. 719), " Ainsi done : accumulation dans le sang d'albuminoides inassinulables : premier fait et consecutivement lesions renales. Tel serait d'apres Semmola I'enchaJnement du processus dans le mal de Bright." He then points out that as a result oi this doctrine there must be from the very outset a diminution of urea ; and that Semmola has long pointed out this diminution, and also the fact that it is due to diminished formation, as the amount of urea in the blood in early Bright's disease is less than in healthy blood, so that there is no accumulation, nor is there any increase of kreatine, kreatinine, or other intermediate nitrogenous products. I have also pointed out in chapter iv. the way in which coUaemia, by interfering with the circulation in the liver, muscles, skin, &c., may hinder metaboUsm, and lessen the formation of urea, and the further fact that the formation of urea, as well as the symptoms of fatigue, can be controlled by controlUng the collaemia ; here, indeed, we have in fatigue an epitome of Bright's disease ; prolong the coUaemia over weeks and months and we have to deal with actual Bright's disease, which again, so long as it is recent, can also be controlled in exactly the same way that fatigue can be, and with the same drugs, or even the same metal (mercury). But this theory of hetero-albuminaemia is no mere hypothesis, for Semmola bleeds his patients, and demonstrates that their blood contains excess of albumens that diffuse ; also that blood which contains this excess will produce albuminuria when injected into a dog, and this albuminuria will be proportional to the amount of diffusible albumen in the blood injected. Labadie-Lagrave (previous reference, p. 727) further points out that Semmola has shown that in Bright's disease there is not only anaemia of the skin, but that its glands, epithelium and cells of the Malpighian layers have undergone most extensive atrophy, this 582 ^ UEIC ACID — CHAPTER XIII doubtless carrying with it great interference with, function and healthy metabolism ; while in albuminuria due to other causes, as morbus cordis, alcoholism, gout, there is no alteration whatever in the structure of the skin, and he concludes his notice as follows : — " TeUes sont les derni^res recherches toutes recentes du professeur Semmola, qui viennent si brillamment h I'appui de la tlieorie dont il est I'ardent defenseur " (p. 728). On this theory an albuminuria is on all fours with a glycosuria. No alteration of kidney structure has been suggested to account for the latter. On the contrary, it is known that any excess of sugar in the blood at once passes ofE by the kidney, and that this sometimes causes hypersemia and irritation of the kidney. On Semmola's theory albuminuria is due to excess of difiusible albu- men in the blood, and this, in its passage through the kidney, causes more severe irritation and nephritis. Lastly, I pointed out that uric acid (the poison of which Mahomed noted the effects, and which I identified from the cHnical symptoms it produced) might bring about hetero-albuminsemia, with secondary albuminuria and nephritis, and thus form the connecting link between the high tension pulse, &c., of the pre- albuminuric stage, as observed by Mahomed, and actual Bright's disease. I suggested that uric acid by obstructing the capillaries (as it does when it raises the tension) might interfere seriously with the metabolism of albuminoids both in the liver and the skin (which accords with Semmola's facts as to the causation of hetero- albuminssmia), and that when this action is very intense we might get breaking up of haemoglobin itself as in paroxysmal hsemo- globinuria (the most intense condition of hetero-albuminsemia), the symptoms accompanying-^ which I pointed out are just those of a uric acid storm (coUsemia). On the other hand, I pointed out that the violent action of uric acid on the capillaries might account for that disease which is most nearly related to paroxysmal hsemoglobinuria, and hke it is accompanied by marked clinical signs of coUsemia, namely, Raynaud's disease ; and that the symptoms of the pre-albuminuric stage according to Dr. Mahomed, are cold hands and feet, imperfect digestion, bronchitis, gastric catarrh, headache (especially hemi- cranial), loss of memory, depression, weariness, cloudiness of intel- lect and hypochondriasis, and after what I have said in previous chapters as to the causation of these symptoms by uric acid I must leave my readers to judge of their meaning. ALBUMINUEIA AND BEIGHT's DISEASE 583 We can now also see in reference to Semmola's facts as to the effects of cold and damp on the skin, that these may not only, as he supposed, directly contract the vessels of this impor- tant tissue, but by precipitating a coUsemia, just as in the test- tube (see p. 175), may still further hamper its circulation, nutrition and metabolism, especially in those who have on the one hand much uric acid available in the body, and on the other a heart which (as so often happens, in pregnancy, for instance) is weak relatively to the increased work required of it. It seems then that at this point we have three chief theories as to the causation of albuminuria. (1) That it is due to heart failure (which applies, I suppose, only to temporary albuminuria and not to Bright's disease), though no doubt heart failure may greatly intensify the evil efiects of coUeemia on nutrition and combustion, as I shall have to point out further on. (2) That it is due to irritation of the kidney by a poison in the blood (Mahomed). (3) That it is due to hetero-albuminsemia, just as glycosuria is due to glycaemia, 'and that irritation and structural change in the kidney are secondary (Semmola). And to this last I have added the suggestion that, while hetero- ^.Ibuminsemia may be due to the action of cold on the skin, the obstruction of vessels which uric acid produces may bring about very similar efEects, or at least greatly increase the power of cold, and cold as we now know does in its turn act as a precipitant of uric acid. Then in the Guy's Hosfital Reports of 1881, we find Dr. Mahomed speaking of cases of nephritis, and also of convalescence from scarlatina, in which there is no albumen while they are in hed, but it occurs on getting up and going out ; and with refer- ence to this he says (p. 416), " The rapidity of the change is too great for the kidney condition, determinibg it to be a structural one ; it must be functional, or more probably a vascular pheno- menon. The fact stands, therefore, that the same kidney, and that a diseased one, can produce alike normal and albuminous urine." This observation, it will be noted, is in complete accord with that of Semmola quoted above, that the albuminuria does not correspond with the kidney lesion. I do not deny that certain vascular conditions can produce albuminuria (notably congestion in severe morbus cordis), but I do deny that cardiac weakness and congestion account for the albu- 584 UBIC ACID — CHAFTBE XIII minuria in the cases of so-called functional albuminuria (mentioned in my paper in the British Medical Journal, January, 1890, p. 65)^ or for temporary albuminuria in cases of chronic Bright's disease such as those spoken of by Dr. Mahomed. I also deny that uric acid in the blood directly irritates the kidney and produces albuminuria and eventually nephritis, though I have no doubt that an accumulation of urates, or for that matter of pigment or other matters in the kidney, or even the mere passage through it of sugar or bile, cantharides, &c., may 'produce congestion and slight albuminuria, but that is in many ways a very different matter from nephritis. Urates also may accumulate to a large extent in the kidney just as they do in the joints and other fibrous tissues — " gouty kidney " — but this also is probably a different thing from parenchymatous and interstitial nephritis. As to heart failure, there is no doubt that this may pro- duce congestion of the kidney and albuminuria. Semmola himself admits this, but he points out that when albuminuria is due to this cause the blood does not contain any excess of diffusible albumen, which at once distinguishes cardiac cases from those of Bright's disease ; and cardiac kidneys are generally easily differen- tiated from those of Bright's disease fost mortem. In transitory albuminurias in apparently healthy subjects not due to mechanical causes, in albuminuria in the course of maladies dyscrasiques, and in the albuminuria of convalescence from scarlet fever, Semmola finds excess of diffusible albumen in the blood — an excess which is proportional to the amount of albumen that is eliminated in the urine. Mahomed's theory regarding the local irritation in the kidney produced by his hypothetical poison as the cause of albuminuria and Bright's disease fails to explain two points of great importance in that disease : (1) Semmola's excess of diffusible albumen in the blood, and (2) the diminished output of urea which is generally acknowledged to accompany or even precede the onset of Bright's disease. As Semmola remarks, his hetero-albuminaemia gives the best possible explanation of the diminished urea, for if albumen is not metabohsed but excreted unaltered, the formation of urea must obviously be reduced. I would also remind my readers again that in all coUaemia there is a diminished formation and excretion of urea, and that from my point of view chronic collsemia is equivalent to the pre- albuminuric stage of Mahomed, and leads inevitably to chronic ALBUMINURIA AND BRIGHT's DISEASE 585 Bright's disease, so that I can easily account for the diminished urea. But if these theories faU, let us see how far the theory of hetero-albuminsemia will carry us in explaining the history and symptoms of Bright's disease. Semmola says that anything that interferes with the functions of the liver or the skin may hinder the proper metabolism of albumens and produce hetero-albuminsemia, which he regards as the first stage in the causation of albuminuria and nephritis. I have suggested that uric acid, by its action on the capillaries, may interfere in the way sketched out above with the functions of the liver, and by obstructing its capillaries, as it clearly does during an attack of uric acid headache, may also seriously inter- fere with the functions of the skin ; hence, in accordance with Semmola's reasoning, it may produce hetero-albuminaemia and albuminuria (see also chapters iv. and v.). We now know that no taker of meat and tea ever has as quick a capillary circulation in the skin as he who abstains from these poisons ; hence aU takers of these poisons are visibly moving in the direction of Bright's disease. I pointed out in my paper on albuminuria (previous reference) that the theory of heart failure would not explain the cases de- scribed by Dr. Dukes [British Medical Journal, 1889, vol. i.), in which, in association with high tension pulse, there was albu- minuria when the patients were up and about, except when they were on milk diet, but no albuminuria when they were in bed, no matter what diet they were given. These cases differ from those of Mahomed previously mentioned in that another factor in causation (namely, diet) is introduced. Mahomed's cases might have been due to heart failure, because the albumen appeared when they were up and about, and disappeared when they were in bed ; but in Dr. Dukes' cases the patients might be up and about, and yet have no albuminuria so long as they kept to milk diet : and it appears to me to be nonsense to say that the heart failed on ordinary diet, but did not fail on milk. Then again we know that in these cases there was no primary failure of the heart, for the blood pressure was above normal. Hetero-albumin- jemia, however, will explain these cases easily, for milk is, according to Semmola, the form of albumen which requires least elaboration by the skin, and I have suggested that this is due to the fact that it is really the product of a skin gland ; but the meat of ordinary diet introduces some uric acid, which will increase the 586 UEIC ACID — CHAPTER XIII colleemia in the blood. Tten again, ttey have no albuminuria while in bed, no matter what diet is taken, because the warmth of the blankets counteracts the eSects of uric acid, by preventing the precipitation of colloid uric acid (see p. 175). I have also spoken of the albuminuria that sometimes follows a cold bath, and have suggested that it is due to hetero-albu- minaeinia following the contraction of the vessels of the skin by cold, more or less aided by aric acid, which is generally in excess in the urine and blood in the morning hours ; ""heart failure, again, seems to me an inadequate explanation, as the heart has just had the benefit of a night's rest and recuperation. Again, in Dr. Dukes' cases the albumen is excreted in greater quantity after meals, especially after breakfast, than at other times of the day. Why should the heart fail in the morning after break- fast more than at any other time ? In a more recent paper {Lancet, 1891, vol. ii., p. 1327), Dr. Dukes attributes the albuminuria of adolescence, and the Bright's disease into which he thinks it may eventually develop, to more or less chronic congestion of the kidney ; but as I have before remarked a congestion of the kidney will not explain an excess of diffusible albumen in the blood or a diminished formation of urea. My explanation of Dr. Dukes' cases is collaemia producing obstructed vessels and high blood pressure, hampering the func- tions of the liver or skin, or both, producing hetero-albuminsemia and albuminuria ; and the albuminuria is most marked at those hours at which, in the natural physiological cycle, the coUsemia is most , intense, the pulse slowest, and the urinary water lowest (see figs. 2 and 3). Dr. Saundby points out (" Lectures on Bright's Disease," p. 15) that in Bright's disease also the albuminuria is greatest after meals, and especially after breakfast, and in one or two instances in which I have been able to examine the point this has certainly been the case ; so that these " functional " cases resemble, in this respect at least, the organic disease, and I for one am quite ready to beUeve that they may pass into it. On the other hand a mechanical albuminuria, or one due to actual lesion of kidney structure, does not show this increase after breakfast. It is interesting to note that a precisely similar relation to morning hours is found in glycosuria and diabetes, and no doubt for the same cause ; and as we shall see in the next chapter an allowance of bread, which if taken at breakfast will cause or increase glycosuria, will, if taken later in the day, produce no such effect. ALBUMINUEIA AND BEIGHT's DISEASE 587 Dr. Dukes considers that this albuminuria of boys is dependent on some condition of the vasomotor system, but he overlooks the fact, or at least gives no explanation of it, that the vasomotor system is quite happy in any position vertical or horizontal, so long as the boys only take milk. Again he tells ua that these boys very often faint or feel faint in the morning hoars, and that this is so common a symptom of albuminuria that it at once leads him to examine the urine ; but surely after what has now been said on the circulation in previous chapters we want nothing more to tell us that these boys have high blood pressure, that their high blood pressure is due to col- laemia, and that it is highest in the morning hours because the coUsemia is then greatest (see figs. 38 — 43). And every word that I have said in previous chapters on the effects of coUsemia on circulation, nutrition, and combustion, on anaemia, hsemoglobinsemia, hetero-albuminsemia, and shall have to say of glycsemia, applies to these cases of albuminuria of boys, and explains completely every fact with regard to their causation. They are boys of the upper classes unwisely fed on a great excess of animal flesh, they are coming to the end of their period of most active growth (16) and are getting some collsemia just as their sisters do a year or two earlier, and the intensity of this coUaemia will be proportional to the amount of meat they have eaten, and the greatness of their falUng off in developmental activity j and any febrile disease coming at this time and followed by post-febrile coUeemia may precipitate this condition. The collsemia causes slow capillary reflux and high blood pres- sure, and this may cause more or less heart failure or fainting in the morning ; but colleemia with heart failure means, as we have already seen in the case of Raynaud's disease, combustion, which is very defective indeed. This defective combustion is completely upset by the albumens of meat but is still equal to the combustion of the albumens of milk ; the meat albumens, however, produce hetero-albuminsemia and albuminuria, and, if the real cause is not detected and treated, may lead on to Bright's disease. Practically, all conditions in which the capillary reflux is slow and the blood pressure more or less high in consequence, are con- ditions of defective combustion, and this defective combustion will be greatly increased by heart failure if it occurs. I most strongly advise those whose children suffer from any such troubles and have well marked slowing of the capillary reflux 588 UEIC ACID — CHAPTER XIII to pay no attention to vasomotor nerves, which, even if they can find them, they cannot control ; but to waste no time in clearing the blood of the poison which prevents its circulation. This can be done with ease and certainty in from a few weeks to a few months, and then the anaemias, the headaches, the faint- ings, and the albuminurias wiU vanish together. Now let us look at the etiology of acute Bright's disease. The late Sir W. Roberts says (" Urinary and Renal Diseases," 4th Ed., p. 471) : " That complex of impressions, which is familiarly known as taking cold, is the common cause of Bright's disease in its acute form ; " and in common with other writers he mentions also scarlatina and alcohol. Now I hope that after what I have said in previous chapters it is unnecessary again to point out the way in which all these factors act in. producing a fluctuation in the excretion of uric acid, the fluctuation resulting in the production of more or less severe coUaemia which brings about, we are supposing, hetero-albumin- aemia, albuminuria, and nephritis. I do not deny that high blood pressure and obstructed capil- laries, which interfere with the circulation in the kidney and produce scanty urine, do probably, to some extent, also interfere with its nutrition, and that where such high blood pressure is very frequently present the interference with nutrition may be carried to the extent of producing structural change ; but granting all this we are no nearer to the explanation of Semmola's facts — the excess of difiusible albumen in the blood, and the diminished formation of urea in Bright's disease. It has over and over again been pointed out that we have to deal with diminished formation, not with diminished excretion of urea ; now a primary Iddney lesion cannot possibly account for deficient formation, though defective combustion accounts for it completely, and this same defective combustion is seen in minia- ture almost every day in physiology, and fig. 3 shows, I think, that the rise of urea that follows breakfast is much less rapid and less marked than that which follows lunch, not because lunch is such a much better meal than breakfast, but because meta- bohsm and combustion are held down throughout the morning by the coUsemia represented in the large excretion of uric acid in the same figure. And hence, of course, there is an increase of albuminuria in these same morning hours. And I believe it is possible by administering to a patient a test meal and watching the hourly excretion of urea that follows, ALBUMINUEIA AND BEIGHt'b DISEASE 589 as is done in physiological conditions in the figures of my book on " Diet and Food," to gauge with considerable accuracy the activity of metabolism and combustion in that patient's body. Then we shall also see in the cases that follow that albumen diminishes and urea rises in pretty definite and precise relation to the quickening of the capillary reflux and the reduction of blood pressure, and I shall be interested to see how those who hold to the theory of kidney lesion can explain these facts. Let them tell us if they can why iodides and mercury will cure a kidney lesion, while citrate of potash makes it worse ? Why 2 ozs. of bread cause glycosuria at breakfast while 4 ozs. do not at dinner ? In the Wien. Klin. Rund., January, 1895, the late Professor Semmola again puts forward some of the main points of his im- portant researches, such as the fact that the subcutaneous injection of egg albumen in dogs causes albuminuria, which is not at first attended by any histological changes in the kidney, and draws the conclusion that egg albumen can pass through the kidney without there being any lesion of its epitheUum present. But continue the passage of albumen through the kidney for more than forty-eight hours and hyperaemia and progressing chronic nephritis ensue. Here we have produced experimentally exactly what we see occurring almost daily before our eyes in Nature ; thus a man may have migraine every week for a long time and the passing of a httle albumen for a few hours at the worst part of the attack may produce no change in his kidney whatever ; but it his coU- aemia becomes more chronic, and if the albuminuria is continued from day to day or even week to week, the result is very different. The patient perhaps tells you that during the last month or two his • headaches have been more frequent and severe, and you examine his urine and find distinct evidence of kidney lesion. In these two months the change has been made from. functional to organic, from migraine with temporary albuminuria, to Bright's disease with chronic albuminuria, and .though we can stiU control the uric acid and the hetero-albuminsemia and functional aljjiu- minuria, the high blood pressure and the headaches it produces, we cannot put back the damaged kidney structure or prevent the passage of serum albumen through its injured tissues, or reinstate in their original integrity the skin, muscles, liver, &c., the great metabolic tissues which are similarly damaged. Such cases, I believe, occur daily under our very eyes, and only the mists of erroneous pathology have hitherto prevented our seeing them. So far as they are functional, true pathology gives 590 UEIC ACID— CHAPTER XIU US complete power to control them, and even the kidney lesions tend to repair themselves if the cause of irritation is removed before the damage is too great. Combustion here again explains what a mere local kidney lesion theory cannot, namely, why the result continues after the cause has ceased to act, why the acute disease passes on into chronic when the cold, wetting or other cause which originated the acute disease has long passed away. But a fire that has been nearly put out by water will burn low for a long time after the water has dried up, and so will the human fire that coUsemia has nearly extinguished, especially when owing to large coUectiohs of urate in the body the coUaemia can be kept in constant operation for months and months. The late Professor Semmola also points out that the amount of albumen eventually excreted in these experimental injections corresponds in no way with the amount of albumen injected, nor yet with the extent of the kidney lesion, but rather with a change in the composition of the blood itself, which makes the serum albumen morbidly difiusible ; or in other words, the continued injection into the skin of an abnormal albumen eventually brings about such changes in metabohsm and nutrition that the blood serum itself becomes imperfectly elaborated or metabolised, and in consequence abnormally difiusible. In any case the quantity of albumen excreted in Bright's disease depends on these blood conditions, and not at all on the extent of the kidney lesion, just as in paroxysmal haemoglobinuria we get an enormous quantity of albumen with blood changes, but no kidney changes in proportion to it. On the other hand, in the case of direct kidney lesions, such as those produced by cantharides, the amount of albumen is small compared with the kidney lesion. Semmola says that continued injection of egg albumen even- tually produces albuminuric retinitis, and that true Bright's disease can be artificially produced in this way ; (from my point of view this would be equivalent to putting out the fire by too much coal) also that in acute infectious diseases, toxic, rheumatic and gouty dyscrasias, the albuminuria is due to modifications in the difiusibihty of the albumen of the blood. And the facts with regard to the presence of these diffusible albumens in the blood of Bright's disease, or, at least, in certain stages of Bright's disease, seem to be confirmed by the researches of Freund, and have been accepted by Vulpian, Labadie-Lagrave; ALBUMINURIA AND BKIGHT's DISEASE 591 and others I kave quoted. But I shall have more to say on these points when I come to deal with cases. Now cold raises acidity, fever raises acidity, most alcoholic drinks raise the acidity, and these last, acting over long years, hold back and retain in the body large quantities of urate which pro- vide the material for eventual chronic and severe coUsemia in old age or other failure of nutrition ; and this coUsemia is to my mind the cause of the chronic nephritis so often found in the fost- mortem room with chronic gout (see Dr. Norman Moore, St. Bar- tholomew's Hospital Reports, vol. xxiiL., p. 289). Further, the excess of urates which under these conditions passes into the blood and out in the urine, is the cause of the gravel and calculus so frequently met with in the declining years of life (compare also case mentioned on p. 49). But where the coUsemia is more sudden and severe, as when it results from sudden severe chill (a case under my care got his disease by being called from the stoke-hole of a steamer to stand twelve hours or more on deck, where he got wet through in five minutes and had to remain so), it may produce not only hetero- albuminsemia ; but the urate may, as I have suggested, acting in sequence to the chill, attack also the red cells and cause hsemo- globinsemia and haemoglobinuria, and it appears that in some cases paroxysmal hsemoglobinuria has formed the starting point of acute Bright's disease (Lancet, 1889, vol. ii., p. 1007). With regard to the causation of paroxysmal hsemoglobinuria, the late Sir W. Roberts says (loc. cit., p. 162) : " Most observers are now agreed that the solution of hsemoglobin in the serum pre- cedes its appearance in the urine, and that the symptoms of kidney affection which are sometimes present are due to the irritation produced by the passage of the hsemoglobin through these organs." Here, then, in the case of paroxysmal hsemoglobinuria the whole of Semmola's contention is quietly admitted ; first of all that the escape of the blood constituents in the urine is due to their breaking up in the circulation itself, and- second, that their passage through the kidney causes irritation in that organ. If it is granted that in place of such violent and temporary destruction of blood elements we may have severe hetero-albu- minsemia lasting continuously over several days (less intense, but of longer duration), may we not see in this the causation of acute Bright's disease as it is met with cUnically ? And there is no difficulty in granting this, as numerous observers (notably Dr. 692 UEIC ACID — CHAPTEE XIII Stephen Mackenzie, Lancet, 1884, vol. i., p. 243) have seen albu- minuria both preceding and following the hsemoglobinuria. Further, the albuminurias which accompany migraine, epi- lepsy, or convalescence from acute disease, all conditions in which there is often the most obAdous and severe collaemia and of which paroxysmal haemoglobinuria is so clearly a mere exaggeration, almost of themselves suffice to demonstrate that the association of albuminuria with collaemia is no accident, and when we further consider that even in physiology uric acid controls the formation of urea, we can at once understand the fall of urea as seen in the above functional troubles as well as that which is so marked a feature of the onset of Bright's disease. Then, in Bright's disease, we shall further see that when we clear the blood of uric acid and allow combustion to go on freely, the albumen diminishes exactly in proportion as the urea increases, so that there is not much room for doubt as to the real relation between these two substances. The following case throws, I think, some Ught on the causation of albuminuria in the way I am suggesting, by the action of cold or uric acid or both on the vessels of the great metabolic tissues. E. H., aged 44, a patient of Dr. Tomson, of Luton, Beds, to whom I am indebted for the history of the attacks — Complains of attacks of " liver " every three months or oftener accompanied by extreme mental depression, shivering and retching, and followed by rise of temperature. Subject to these attacks as long as he can remember. Had fits at 5 and 12 years of age. His mother died of phthisis at the age of 50. His father is still ahve and well, age 83. Two brothers (one an imbecile), and one sister died of phthisis. One sister has functional twitching and contractions of the muscles of both arms. Other members of the family exhibit evidences of an insane neurosis. Patient was operated on for anal fistula in 1892. The following is Dr. Tomson's account of an attack he saw in December, 1892. " Condition distinctly hysterical ; throws himself about on the couch, and repeatedly cries out ' Oh, I'm so bad ! Oh, I'm so bad ! ' A constant restlessness. He shivers, and the teeth chatter ; occasional retching, but nothing brought up ; pulse 108 ; artery contracted, high tension, temperature just under 100°, liver much ALBUMINURIA AND BBIGHT's DISEASE 593 enlarged, three fingers' breadth, below the ribs. Urine high coloured ; no albumen. " In this condition he remains for two or three days and then gets better. The more noticeable features are the rapid enlarge- ment of the hver, and its equally rapid subsidence at the termina- tion of the seizure, and the intense misery of the patient. He has severe attacks Uke this about every three months, and less severe attacks between times." When I saw him he told me that he had had a headache on the previous day, which began at 11.30 a.m. His pulse was only 54, and both to finger and sphygmograph showed extremely high tension ; the first sound of the heart was prolonged or redupUcated between the apex beat and the sternum, and the second sound was loud ; he had thus both the cardiac and arterial signs of high tension (p. 225). The hver dulness was not enlarged, and its edge could not be felt ; and now we come to a point of very great interest. The urine which he passed here (12 noon) was high coloured and specific gravity 1020, contained a large quantity of albumen, 4 per 1,000 (Esbach), and no sugar. Under the microscope it showed numerous -oxalate crystals, and a few casts hyahne and shghtly granular. This was the first time albumen had been noticed in his urine. Let us try to group these symptoms and estimate their mean- ing. Obstructed capillaries and high blood pressure are shown in the attack described by Dr. Tomson, in the condition of the pulse, the shivering and teeth chattering, the high coloured and probably scanty urine. The hysterical conditions on the one hand, and the mental depression on the other are the efEects of the alterations in the intracranial circulation as I have already explained in chapter viii., just as the shivering may be the efiect of the deficient circulation in the skin ; I have myself had just such shivering or shght rigors in my attacks of uric acid headache when they used to be severe. What is the meaning of the marked enlargement of the Uver ? I would suggest that it is a venous congestion or hypersemia due to failure of the heart in its efEort to overcome the capillary obstruc- tion ; when I saw this patient there was very high blood pressure, but the pulse rate was only 54 ; there was therefore no sign of heart failure and with this there was no enlargement of the hver ; but in the attack described by Dr. Tomson the pulse rate was 108, and yet he says the tension was high ; now such a pulse rate with high blood pressure almost certainly means heart failure, and it is possible 38 594 UEIC ACID — CHAPTBE XIII that the vessels of the lungs were at the same time greatly obstructed (see chapter ix.), and that this told specially on the right heart and the hver. What was the cause of the high blood pressure ? Excess of uric acid in the blood ; the urine was high coloured and pro- bably scanty, and we know that the urinary water is inversely as the uric acid excreted along with it ; therefore there was an excess of uric acid in the urine and probably also in the blood. I look upon these so-called " liver " attacks then as uric acid storms almost if not quite identical with my attacks of uric acid head- ache ; and in these attacks in myself I have often noticed some distinct evidence of more or less temporary congestion of the liver, such as pain, weight, fulness, or a feeling of heat or tension in the right hypochondrium, and these sensations are at their worst when the blood pressure is greatest, and I now rarely or never sufEer from them. Now we come to the trouble at the time I saw him ; again the signs of obstructed capillaries and high blood pressure are most marked in the heart and arteries, there was a headache, no doubt the result of this tension, the previous day, and the urine is found to contain a quantity of albumen together with some casts and some oxalates, the urine was free from albumen a day or two before, and it became again free from albumen a day or two later. We have, then, here almost completed the picture, not of paroxysmal heemoglobinuria, but of the next thing to it, paroxysmal albuminuria. 5 Now the point on which the whole of this chapter hinges is the way in which this albuminuria was produced ; let us look closely at the meaning of the symptoms accompanying it. A urine of high colour and specific gravity, and therefore almost undoubtedly containing some excess of uric acid. Again, we have seen in the previous chapter that oxalates may mean the simultaneous excretion of intestinal putrefactive products (sul- phuretted hydrogen) with an excess of urates ; so that here again we have independent evidence that an excess of urates was ex- creted in this urine, but why was there intestinal putrefaction ? Because the vessels of the intestines, like all the vessels in the body, were obstructed by uric acid, the very uric acid which was passing in excess in the urine. Again, we know that the vessels were obstructed on the day before the albuminuria, because high blood pressure was the probable cause of the headache from which the patient told us that he sufiered. ALBUMINUEIA AND BEIGHt'S DISEASE 595 We have, then, some very strong evidence of the presence of high blood pressure and obstructed capillaries, and evidence that these had been present for at least twenty-four hours before I saw the patient and found albuminuria. We have also some very good evidence that these capillaries were obstructed, owing to the presence of an excess of uric acid in the blood. We have seen also in previous chapters that excess of uric acid in the blood may not only account for the blood changes of anaemia, but also for those of paroxysmal haemoglobinuria, and we know that albuminuria may both precede and follow haemo- globinuria, so that it is extremely probable that hsemoglobinsemia and hsemoglobinuria are but more advanced stages of hetero- albumineemia and albuminuria. I am suggesting, then, that the chain of causation in the case of this albuminuria was as follows : a uric acid storm or fluctua- tion of excretion resulting in collaemia, general obstruction of capil- laries, deficient circulation in the skin, Hver, intestines, and other organs of metabolism ; as a result of this retrograde changes in the albumens of the blood and tissue fluids (hetero-albuminsemia of Semmola), which in some cases may go on to hremoglobinsemia ; but in this case stopped short at hetero-albuminaemia and albu- minuria. Some may say, " You spoke of congestion of the hver just now ; why may not a congestion of the kidneys similarly produced account for the albuminuria ? " First of all, at the time of this albuminuria there was no evidence of congestion of the liver, and again, even if we grant that there was congestion of the kidneys, that would not account for all the conditions ; suppose that instead of stopping short at albuminuria the attack had gone on to haemoglobinuria, how could any congestion of the kidneys account for the destruction of a million red cells in the blood stream itself ? No doubt in congestion of the kidneys due to morbus cordis, for instance, one gets a trace, even a considerable cloud of albu- men, but I think not as much as in this case, 4 per 1,000. No congestion of the kidneys can account either for hsemo- globiuEemia or the hetero-albuminsemia of Semmola ; any such explanation therefore falls to the ground. The relation of such a case to some of those called eclampsia, as in the Lancet, 1901, vol. ii., p. 1610, is too obvious to need further explanation ; aU these conditions are uric acid storms, in which in some cases the headache, in others the nervousness or 596 UEIC ACID — CHAPTER XIII depression, and in still others the albuminuria or hsBmoglobinuria, are the most prominent symptoms ; as in the most interesting cases previously referred to (p. 515), recorded by Dr. Attlee, and in the case which he mentions as being under my care, fits occasionally replaced headache and nervousness. Taking the view, then, that this patient's troubles were of the nature of paroxysmal albuminuria, and due to recurrent uric acid storms, the obvious indication was to reduce the uric acid income and formation ; I accordingly suggested a considerable reduction in the amount of meat and animal food, and I believe he went beyond my suggestions and changed the diet completely. In'J the six months that have elapsed since this, change of diet he has had no attack of " liver," no albuminuria, and is in many other respects much better, and a more recent report says that he has now not had an attack for more than- a year. Thus the treatment seems to have had the very same effect that it had in myself — with the removal of the cause the effect has disappeared. And this is another point on which I wish to lay special stress, namely, that when the diagnosis of uric acid disease has been well and properly made, treatment of the uric acid should without fail effect a cure. On the other hand, an intentional increase of the uric acid should equally without fail make all the symptoms worse. Further, it is a distinguishing mark of these metabolic albu- minurias that they are greatly influenced by diet, that, as pointed out by Semmola and others, the amount of albumen excreted is to a considerable extent proportional to the amount ingested, and that by reducing this amount and, further, by taking it in a form which is easily assimilated (milk, Semmola), these albuminurias, so long as they remain functional, can be greatly reduced or cured ; and the experiences of Dr. Dukes quoted above confirm what I am saying. The parallel between an albuminuria and a glycosuria is here again absolute, both in their early stages are functional, and in both during this stage the whole of the albumen or sugar can be removed. A little later there is a residue in both cases which neither diet nor drugs will suffice to remove ; in the interval some of the great metabolic tissues, being continually exposed to the results of defective circulation, have undergone atrophy and change of structure, and the furnaces of that human body will never again be capable of consuming quite as much sugar or albumen as they did before. ALBUMINUEIA AND BEIQHT'S DISEASE 597 Supposing, on the other hand, that nothing i& done and the patient continues to form and take in large quantities of uric acid, not only will his attacks continue, hut they will get more and more severe as he gets older ; for the slackening metabohsm which comes with age will favour the passage of a larger and larger excess of uric acid through the blood, and thus the metabohc albuminuria, which was at first paroxysmal and functional, will become organic owing to waste of the metabolic tissues ; structural changes will take place in the kidney owing to the constant irrita- tion of hetero-albuminsemia, and so we gradually pass from a mere uric acid storm to fully developed morbus Brightii, and I have seen, as I say, quite a number of cases in which periodical sufEerers have found their attacks getting more frequent and severe, and have then, on examination for insurance or other cause, dis- covered both albumen and casts in their urine. On the other hand, I have seen quite a number of cases of albuminuria, either temporary or intermittent, where diet treatment has almost at once removed the albuminuria and many of its con- comitant symptoms, and the cure has appeared to be permanent. In further illustration of some of these points, I will now give a few notes of a case of great interest, which I owe to the kindness of my friend. Dr. C. P. Handson, of New Cross, S.E. He says : — " I am writing to tell you of a case in which your uric-acid- free diet was eminently successful, and only regret that owing to having taken no notes, or made any estimation of the uric acid in the urine, my account will be very fragmentary. " Augustus M., aged 13, has always been a dehcate boy, and frequently absent from school with severe headaches. Has never had rheumatism. One of the mother's relatives has rheumatism. Family history otherwise unimportant. Before November, 1901, he was much interested in a cantata in which he was to sing. After it was over he appeared to lose all interest in his school work, and sufEered from constant headaches, pain in the left side, and increasing weakness. This, in spite of tonics, feeding up, &c. (much beef-tea and bovril), became steadily worse. ' " I saw him for the first time on February 19, 1902. He was not markedly anaemic, but was emaciated, and there was great muscular wasting. Standing was impossible owing to vertigo. If left to himself he generally fell straight backwards. If led he could shuffle along slowly, and even be got up and down stairs. There was marked scohosis (from muscular weakness). Headache 598 UEIC ACID — CHAPTEE XIII was almost constant, as also a feeling of nausea, which on two occasions ended in actual vomiting. Tte vertigo persisted even while lying down. Knee jerks exaggerated on both sides ; plantar reflexes absent ; other reflexes normal. Optic discs normal (this was afterwards confirmed by Dr. Gee). Urine loaded with urates, very acid ; sp. gr. 1024 ; no albumen or sugar. Pain over prse- cordium and left hypochondrium almost constant, and sometimes intense enough to wake him up at night. The apex beat is diffuse and thumping ; in normal position, the second sound ring- ing and accentuated. The capiUary reflux is very slow. Nothing of note in any other organs. Has attacks in which he says he feels ' dreadful,' ' desperate,' and seems to lose control of himself ; once he bit his mother's arm. There was no anaesthesia or hyper- aesthesia. The muscles reacted sluggishly to faradism, correspond- ing to considerable wasting. " I at once omitted the beef-tea and bovril from his diet, but otherwise did not alter it, and gave iron and strychnine internally, and ordered a belladonna plaster to the heart. His condition, however, deteriorated, and on March 17, 1902, Dr. Gee saw him in consultation. He was puzzled to give a diagnosis, and s^d the only definite thing was the paralysis. He at first gave a bad prognosis ; but wrote to me the next day to say that on thinking the case over, he thought it might possibly be hysteria, and, if so, that the boy would recover. He ordered a tonic containing liq. strychn. and hq. arsenici hydrochlor., which was taken until April 30, when, as there was no improvement, I substituted mist. acid, nitro- hydrochlor. dil. before meals, and sodii sal. after meals, ter., and ordered a uric-acid-free diet. " For a time his condition deteriorated still further [coUsemia from change of diet]. On May 14 I changed the medicine to ferri et ammon. cit. On May 28 the urine was alkaUne, sp. gr. 1028, contained phosphates, but no albumen or sugar. The signs of high blood pressure were very marked, and the pain over the heart was said to be worse. On May 31 he was taking hyd. c. cret. gr. ii., bis, the iron being omitted. On June 4 I gave him a mixture containing sodii bromid., pot. iod. and tr. strophanthi, in addition to the hyd. c. cret. He then very slowly improved. On July 12 he could walk a httle about the room by making sudden rushes. If he walked slowly, his gait was somewhat like that of a drunken man, and unless someone was at hand he would fall. I then went for my hohday. While I was away he took the pills (hyd. c. cret.), but no medicine, and continued with the ALBUMINURIA AND BEIGHT'S DISEASE 599 diet. When I saw him again on August 5 the improvement was very marked. He could walk about by himself, though he had occasionally attacks of vertigo and swayed. The pain over the heart appeared only intermittently. I saw him again the other day, when he walked up to my house, a distance of about three- quarters of a mile. He is practically as well as ever he was, takes walks by himself, though he prefers a companion owing to occasional vertigo, and is fairly reconciled to his diet. His mother has, however, occasionally given him tea of late, of which course I have pointed out the folly. " The signs of high blood pressure have not improved to an extent corresponding with the general symptoms, the capillary reflux at 8.30 p.m. being still 10 to 12 half seconds. I beheve if the diet is persisted in that the boy will become well and strong, but that otherwise there will be a relapse. He has grown several inches during his illness, and is beginning to gain flesh, though the scohosis persists. " In this case I at first sight thought the symptoms were probably due to chronic nephritis. When an examination nega- tived this, I went for cerebellar tumour. This was negatived by the absence of optic neuritis. His condition was so suggestive of some grave organic disease, that it was not until Dr. Gee had failed to find any, and aftsr his tonic had failed to effect improve- ment, that I felt justified in trying the effect of your diet. I certainly think that the end would have been death from some intercurrent disease at no distant date, but for the stopping of all supphes of xanthines. " It was the resemblance of his case to that described by you on p. 526 of ' Uric Acid ' '^- that suggested the treatment to me, after organic disease began to appear improbable." In a later letter he adds : — " Reverting to the case of Augustus M., as you say, it was most interesting that he got worse when first put on a uric-acid-free diet. Knowing, however, that according to your theory it was exactly what ought to happen, I looked upon it as of hopeful augury, and was able to encourage the mother to persevere." I should have very little doubt that in this case the only disease was coUasmia and slow capillary reflux, with more or less * The case of E. H. given a little before ; Dr. Handson's page reference is to the fifth edition. 600 UBIC ACID — CHAPTER XIII heart failure; but all heart tonics failed till the cause was re- moved. It seems to me also that we have here a condition related to that already mentioned on p. 386, as " Family periodic para- lysis," though here the loss of power was chronic and persistent, rather than temporary and periodic. In all such conditions we see mere modifications of the' cardiac failure which occurs when an ordinary migraine is complicated by syncope ; and thus Dr. Handson's most interesting case was but an exaggeration of the migraine and vertigo on which it supervened. The diagnosis of hysteria is most interesting, as I have always maintained that hysteria is a circulation disease (collaemia plus cardiac failure), and the two cases just narrated would almost suffice to prove this even if they stood alone ; but as a matter of fact one finds almost all gradations and intermediate conditions between headache, ver tigo, mental depression, nervousness, hysteria, epilepsy and paralysis, just as one also finds all gradations from paroxysmal albuminuria and anaemia of migraine through paroxysmal heemoglobinuria to Bright's disease, and through paroxysmal glycosuria to diabetes ; and thus migraine is a veritable epitome of all these circulation diseases owning a common cause. Some evidence in favour of Semmola's theory of hetero-albu- minsemia is given by the late Dr. Cranstoun Charles in a paper on " Intermittent Albuminuria " (St. Thomas's Hospital Reports, vol. xxi.), and he mentions that in one young man he found, just as Semmola had done, some albumen in the perspiration and saliva, as weU as in the urine. The same author mentions several interesting cases of albu- minuria associated with high blood pressure, mental depression or headache ; one case in which there was albuminuria at the emn- strual periods, and another case in which it was associated with constipation, and relieved by blue pill and salines. I should have no doubt that the mercury and the salines afiected the capillaries all over the body as well as the intestines. He also speaks of the effects of exposure to cold and its possible influence on the skin, and mentions several other points which are in favour of the metabolic origin of these albuminurias. I have already said that the cases of albuminuria described by Dr. Dukes are associated with high blood pressure, influenced greatly by diet, and that he himself considers that they often pass on into Bright's disease. I difier from him, however, in believing that such albuminuria ALBUMINUKIA AND BKIGHt'S DISEASE 601 and such Bright's disease are not due to hypersemia of the kid- neys, but are the result of a failure in metabolism and hetero- albumineemia, which alone will explain all the facts of the case. When the failure of metabolism is slight and the hetero-albu- minsemia occasional, very sHght change in diet, clothing, exercise or climate, may suffice to remove it, as in some of the cases I have mentioned : but when it is more severe, and especially when owing to atrophy of metabohc structures it has become organic, or still more, if it is complicated by a kidney lesion, these measures, will no longer remove the albumen, and complete cure may be impossible. The kind of albumen excreted seems also to tell the same tale, for it is now pretty generally recognised that in functional cases as well as in paroxysmal hsemoglobinuria, the albumen in the urine is mostly globuHn, which dialyses freely, while in advanced cases with probably distinct and definite kidney lesion, serum albu- men is present, which will not dialyse (Lancet, 1889, vol. ii., p. 1806). Now the late Professor Semmola pointed out many years ago that in early and acute cases there is an excess of diffusible albumen in the urine and in the blood ; while in advanced cases with distinct Iddney lesion, the albumen in the urine may be almost entirely serum albumen. The serum albumen passes only when there is a kidney lesion ; the diffusible albumen passes at any time, because it is diffusible. Its presence in the urine is a sign of hetero-albuminsemia, just as glycosuria is a sign of glycaemia. Where diffusible albumen is alone present, the conditions are still functional, and diet treatment which removes the hetero-albu- minsemia may cure quickly and completely ; but where serum albu- men is passing, diet will no longer cure, promptly, and may not cure at all, for the removal of the hetero-albuminaemia does not do away with the kidney lesion which is now present and allows the serum albumen to pass. It has been pointed out that pyrogalhc acid, toluylene-diamine, &c., when used to produce beemoglobinuria in animals, do event- ually bring about severe nephritis [Lancet, 1885, vol. i., p. 115). Is it the substance itself, or its effect on the blood, that pro- duce the nephritis ? Semmola, at least, would probably have attributed a share of the result to hetero-albuminsemia and hsemo- globinsemia. The late Dr. RaHe suggests (Lancet, 1886, vol. ii., p. 764) that functional albuminuria is but a minor degree o paroxysmal haemoglobifluria ; and I have pointed out that in both 602 UKIC ACID — CHAPTEE XIII troubles there are often abundant signs and symptoms of collsemia ; and tkis author himself points out, that in functional albuminuria there are frequently bilious attacks, which I should translate by the one word coUeemia (see above case of E. H.). He also says that arsenic diminishes the hsemolytic action of the liver, and strengthens the resisting power of the red cells ; it did not appear to do so in the case of Daniel H. given above (p. 517) ; but there was severe coUaemia, and treatment of this was followed by general improvement. Arsenic, as we shall see in chapter xvi., probably clears the blood of uric acid, and would no doubt in this way affect its quality, but it failed to clear the blood of uric acid in the case of Daniel H., because of its great alkalinity due to his feeble nutrition, and therefore it did no good. Several writers have suggested that bile salts afiect the haemoglobin (Mac-Munn, British Medical Journal, 1888, vol. ii., p. 117 ; Oliver, Lancet, 1885, vol. i., p. 977). They may do so, but it seems to me that the known effects of uric acid give a better explanation of concomi- tant symptoms, and in many cases, as I have shown, there is evidence of collsemia. But supposing the uric acid in the blood can thus bring about hetero-albuminsemia, albuminuria, and nephritis ; the nephritis, when it has come into existence, will have an important effect on the excretion of uric acid ; for anything in the nature of inflammation* in the kidney must diminish its alkalinity ; and if the alkahnity of the kidney is less than that of the blood and tissue fluids gener- ally, it follows from my first principles (chapters ii. and iii.) that any uric acid that comes to the kidney wiU be • rendered insoluble and retained, instead of being excreted, hence it comes about that though we have plenty (too much) of uric acid in the blood, we have too httle in the urine in Bright's disease (see also previous remarks and references on the subject of Uric Acid Infarcts in- chapter iii., p. 80). Hence it comes about that in acute nephritis (but not so much in very chronic disease), no matter what may be the alkalinity of the blood, we get a holding back and retention of uric acid in the body, because the diminished alkalinity of the kidney is unfavour- able to its solubiHty and excretion. Hence, in nephritis we have chronic collsemia and its signs, obstructed capillaries, high blood pressure, if the heart is a strong one, slow action of the heart (bradycardia), scanty urine, retention of water in the body and general dropsy, with other signs of collsemia, such as headache, mental depression, tendency to suicide all of which are well known to occur in Bright's disease. ALBUMINUBIA AND BEIGHT's DISEASE 603 An interesting case, illustrating some of these points, was admitted under tte care of my colleague. Dr. Tooth, at the Metro- politan Hospital, and he very kindly gave me leave to mention it. A boy, 8 or 9 years old, admitted with subacute nephritis and general dropsy. Urine only 15 to 16 ozs. in twenty-four hours. Measles was accidentally introduced into the children's ward, and this patient, with others, took the disease. The efEect was magical. As soon as the fever had reduced the blood-pressure, the urine ran up, and was for several days about 80 ozs. in the twenty-four hours, and in two or. three days the dropsy had nearly all gone. Here the rise of temperature and concomitant rise of acidity cleared the blood of uric acid, freed the capillaries, among others those of the kidney ; the result was a copious diuresis and removal of the dropsy. Now precisely the same can be done with drugs, acids, opium, mercury, any of those in chapter ii., mentioned as causing retention of uric acid, and the result will be proportional to their power over uric acid. In some cases of nephritis I have, with these drugs, altered the pulse rate from about 44 to 80 or above (see fig. 36, p. 202), at the same time reducing its tension ; and with this went increase of urinary water, removal of dropsy, and diminution of albumen. Nature is, however, generally more power- ful than any drugs, as the above case well illustrates ; but I beheve that she acts in the same way by clearing the blood of uric acid. It may be asked, why, in chronic interstitial nephritis, while there is still high blood pressure, do you get no holding back of water and no dropsy ? I have suggested, as the result of my own observations on the matter, that in chronic nephritis the coUeemia is greater in the alkahne tide of the morning, and, as a result, the pulse is slower and the urine more scanty at this time. Later in the day — the evening and night — coUsemia is less, the capillaries are relatively free, and a considerable diuresis makes up for the scanty excre- tion of the other hours (see quantities of urine per hour in table given by Saundby, previous reference, p. 15). For a case in which this was so, see Lancet, 1890, vol. ii., p. 133. In this way there is no retention of water in the body in chronic Bright's disease, for though the capillaries are obstructed and the tension high, the heart is equal to its work, and especi- ally at night the circulation is free. In acute Bright's disease, the sudden obstruction of capillaries may overpower the heart and dropsy results. In all cases I beheve it is a struggle between the 604 UEIC ACID — CHAPTER XIII heart and the obstructed capillaries ; if the heart fails there is dropsy, if it wins there is none (see Marey's observations, quoted in chapter v., p. 169). There are no doubt two factors in dropsv : (1) that water in the blood cannot get past the kidneys, or for that matter the skin, or any other excreting glands, because of the block in the capillaries ; and (2) that the water in the tissues is only very slowly taken up into the blood. This is very well shown by the experiments of Reechel {GerUralbl. fur Inn. Med., October, 1898), who infused saline solution, and showed that in renal cases it took a very much longer time to be absorbed from the tissues than in healthy individuals. No doubt it would be much slower in all takers of meat and tea than in those who abstain from them, just as the capillary reflux itself is slower in the self-poisoners. The fact is, of course, that slow capillary reflux always means defective circulation, defective nutrition, defective interchange between the blood and tissues, and defective combustion ; it is really albuminuria, Bright's disease, glycosuria, diabetes, polysarcia? obesity, oedema or dropsy in embryo ; and it may develop into any one of these or all four of them, more or less combined, as is sometimes seen. The capillary reflux is thus the index not only of the circula- tion, but also of the nutrition and combustion of the body ; and when we know the cause of the defective circulation we can at once control both it and its effects ; and in all cases pathology is thus seen to be a mere exaggeration of physiology, as collsemia controls formation of urea and excretion of water in the latter. •: If we wish to understand dropsy thoroughly we must study most carefully the relation between the excretion of uric acid and that of water in the physiology of every-day life ; in the morning hours even in physiology there is more water in the blood and tissues than in the evening, and in the uric acid headache the water in the tissues often increases so as to be visible ; and between this and dropsy, either cardiac or renal, the difierence is only one of degree : in cardiac dropsy the water fails to pass the kidney because the heart has lost the power necessary to pass the blood through the kidney vessels ; in Bright's disease the heart power may be undiminished, but the kidney, vessels are obstructed by uric acid. In chronic nephritis, also, the alkahnity of the kidney is less reduced than in the acute disease, hence the holding back of uric acid and consequent collsemia is relatively less severe. ALBUMINUEIA AND BKIGHt's DISEASE 605 Collaemia is probably, therefore, more severe in sudden and acute cases, and this corresponds with the relation of uraemia, the poison of which is, I believe, simply uric acid ; and its symptoms, at least the most prominent ones, are the results of the action of this poison on the vessels, and so on the circulation of the brain. And by measuring the capillary reflux and blood pressure at the same time the real causation and sequence of events can be proved. Before the attack, as is well known, the urine is often extremely scanty, and the pulse may be as slow as 40 (intense uricacidsemia and coUasmia). The case in which I altered the pulse rate from 44 to upwards of 80 had slight convulsions, severe headache and other signs of uraemia at the time of admission under my care. The very close parallel between the symptoms of collaemia and those of uraemia has long interested me, and I believe that tUl a fatal lesion is produced, I have the same power over the one as over the other. Iiet us look for a moment at the main symptoms of uraemia, and first, epileptiform convulsions. I have shown that similar convulsions may be the work of uric acid ; then as regards headache, giddiness, drowsiness, cold skin, cold sweats, local arterial spasms, " dead hand," vomiting, slow high tension pulse, scanty urine — these are merely the signs of the uric acid headache (migraine). Amaurosis, again, is probably only an exaggeration of the well- known eye symptoms of migraine. I have obtained considerable quantities of uric acid from the blood of uraemic patients, as '0025 per cent, from a case under the care of my colleague, Dr. Tooth, at the Metropolitan Hospital, and •0021 from a case under the care of Dr. R. Kirk, of Glasgow, who kindly sent me the specimen, and "0048 per cent, from a patient of my own at the Royal Hospital for Children and Women, who was 17 years of age, and had a large, pale kidney. Her temperature was 105° soon after the blood was drawn, and when a little later she came out of the coma she complained of a severe headache, in many respects resembling that of uric acid. In the first case the temperature was 103"8 at time of cupping, and the amount found was probably only a fraction of the quan- tity in the blood when the uraemic symptoms began ; but even so, it is nearly four times as much as is found in other diseases asso- ciated with fever, e.g., '00067 per cent, in pneumonia with temperature 102°. We have here then, as I have shown, all the causes which produce collaemia ; and all the signs of its presence, and, further, 606 UKIC ACID — OHAPTBE XIII all the drugs, which do good in treatment (opium, acids. &c.), clear the blood of uric acid, while bleeding mechanically reduces the tension and pressure by means of which the uric acid fatally affects the nerve centres (see p. 259). The great value of morphine in eclampsia is further evidence of the same thing, and everything that does good in these serious results of coUsemic circulation, either lowers the blood pressure mechanically as bleeding or purging, or clears the blood of uric acid, which is the action of morphine, and it acts in exactly the same way in the less severe conditions of coUeemia such as migraine and depression. Thus in a case under my care I believe that I can trace all the factors that led up to a fatal ursemic convulsion. Lydia M., age 44, admitted into the Royal Hospital for Children and Women, on April 2, 1897, suffering from chronic Bright's disease, heart failure, and dropsy. On admission, temperature 97°, pulse 80. High tension. I saw her two days after admission and found that she had been put on pulv. jalapse co., and a pill containing mercury, squill and digitahs, to be taken three times a day. Heart's apex beat fifth space, one inch outside the mid-clavicular Hne ; the first sound was long or reduplicated, and the second sound loud and sharp both at the apex and base. Her temperature had risen to normal, pulse 84, and the bowels were open two or three times every day. Urine had sp. gr. 1012, and contained a considerable amount of albumen. April 8 and 9 there were some teeth troubles, ending in stomatitis. April 10, pill left off, and a mouth wash was given. The pulse had gradually slowed down, no doubt owing to the digitalis and the rest in bed, to 72 on 7th, 66 on 8th, 60 on 9th, and 56 on 10th, and it now further slowed to 52 on 11th, and 42 on 12th April. The first part of this slowing was no doubt due to the rest in bed and the digitalis, and with this improvement in heart power the dropsy had all cleared up. On the 11th and 12th there was very marked stomatitis, and the pulse slowed still more to 52 and 42 in spite of the digitalis having been left off, and showed still higher tension. I saw her for the last time on the afternoon of 12th, after the resident medical officer. Dr. Key, had noticed some twitching of the face. ALBUMINURIA AND BEIGHT's DISEASE 607 The pulse was then regular and only 36 in the minute and showed very high blood pressure, and the patient was dull and inclined to be drowsy. I concluded that she was suffering from severe collaeniia as a rebound after the mercury, and ordered some iron and other drugs with a view to stop this and lower the blood pressure. Before these had had any time to act, however, at 6.30 p.m. the same evening she had a severe convulsion fit, in which she died. Now these symptoms tell their own tale. On admission, she had coUsemia with subnormal temperature and quick pulse (heart failure) and their result — dropsy. A week's rest in bed, with the help of squill, digitalis and mercury restored the temporarily disabled heart, its rate of action slowed to normal, and the dropsy disappeared. Then came the stomatitis, necessitating the stopping of the mercury, and the natural result was a post-mercurial coUaemia, or rebound, and in some of the cases that follow it will be seen that I now take precautions to prevent this unfortunute result, so far as it is possible to do so. But the heart was now fairly strong, and so the pulse got slower and slower as the pressure rose, and the high pressure in the skuU produced first twitchings of face muscles, then drowsiness, and finally a convulsion which was fatal. I now regret that I did not order her to be bled on the after- noon of the 12th, when things were clearly very threatening ; but if she had survived the first convulsion, this treatment, the only one I expect much from in acute ursemia, would no doubt have been carried out. In a case of uraemia more recently under my care at the Royal Hospital for Children and Women, Louisa L., aged 58, there was a blood pressure of 180 and a capillary reflux of 10. The blood contained granules in proportion to the red cells of 1 to 2, and blood drawn by venesection yielded '0029 per cent, of uric acid. There is an interesting note on the relief of the severe head pain of some high blood pressure conditions of Bright's disease by with- drawal of cerebro-spinal fluid by lumbar puncture in the Lancet (1902, vol. i., p. 609). The relief was often only temporary, but the interesting bearing of the facts on the pathology of uraemia is obvious. I wiU now give a few notes of some of the more interesting cases of Bright's disease that have come under my care. 608 UEIC ACID — CHAPTEB XIII Charlotte W., aged 15, admitted at the Royal Hospital for Children and Women, October 28, 1890. She had been seen hy my colleague, Dr. Wheaton, on October 22 at the Surrey Dis- pensary, complaining of numbness and loss of power in the right hand and of " fainting fits." On October 26 she was quite comatose for some time after a succession of convulsions. On admission she was noticed to be quiet and drowsy and slow in answering questions. The face was pale and the eyelids puffy, and there was some oedema of the back and chest. Pulse 66, high tension, with a well marked W tracing, as in fig. 35 A. Heart's apes outside left nipple line, first sound long (? systoUc murmur), second sound very loud both at apex and base. Lungs, a few rdles at both bases. Some little ascites. Urine 1025, some ^blood, and albumen 7 p. 1000 (Esbach). October 30 she was given pulv. jalapae co., a hot air bath at night and some citrate of potash with a little nux vomica. October 31.— Some headache this morning, but no fits since admission. November 1. — Pulse, morning, 48 ; still some headache. Pulse, evening, 60. Heart, second sound still very loud. November 3. — Pulse, morning, 48 ; evening, 48. November 6. — Pulse, morning, 50 ; evening, 44. Citrate of potash left off and saHcylate of soda given after meals with acid mi.xture (nitro-hydrochloric acid) before meals. November 8. — She had a little diarrhoea, so all drugs were left off. November 9. — Pulse, morning, 54 ; evening, 54. November 10. — Salicylates and acids began again yesterday. Pulse, morning, 60 ; evening, 60. November 15. — Pulse, morning, 72 ; evening, 72. November 17. — Salicylates and acids left off. Pulse, morning, 72 ; evening, 86, and a tracing now showed comparatively little tension. November 27. — Pulse rate had fallen again, and was, morning 56 ; evening 68. Soon after this she was allowed to get up and the pulse rate quickened in consequence. The albumen, which was very high in the specimen on admis- sion, was not much more than 1 per 1000 in a 24 hours' speci- men. On November 10 and 13 it was still I'O per 1000, but on the 17th it was -5 per 1000, and it remained at or about this amount during the rest of her stay, with the exception of the 24th, when it was -6 per 1000. ALBUMINUEIA AND BEIGHT's DISEASE 609 The urine at first contained fairly numerous casts, hyaline, with granules and degenerate epithelium. She was given fish on November 27, and she went on well, having no fits, no headache, and no increase of albumen, and she was allowed to go home on December 5. This case seems to show, as does also one previously men- tioned, in chapter v., that citrate of potash neither quickened the pulse nor lowered its tension, while sahcylate of soda and acids did both very decidedly, though it tended to slow down again after these drugs were left off ; and the most decided fall of albumen coincided with their action and the lowered blood pressure they produced. Ahce M., aged 8. Admitted into the Metropohtan Hospital under my care December 4, 1891. December 5. — Pulse, morning, 68. Tracing shows very high tension, predicrotic wave rising above the upstroke. Urine, 18 ozs., 1018. Albumen 5 per 1000 (Esbach).' Fairly numerous hyaUne and granular casts. Given acid and salicylate mixtures as in the previous case. December 9. — Much better in self. Pulse 84, and first wave is now well below the upstroke. Urine, 24 ozs., albumen Uttle more than a trace. After this albumen remained about a trace only, and she went home at the beginning of January. AH drugs were left ofE on December 23, and the pulse on December 27 had fallen to 58. Ada P., aged 16. Admitted under my care in the Eoyal Hos- pital for Children and Women on November 23, 1893. She had recently recovered from scarlet-fever. Urine, 40 ozs. in 24 hours, containing 2'0 per 1000 of albumen (Esbach). Casts very numerous, large hyaline and granular, some fatty and some epithehal. She was put on iodide of [potaissium and nux [vomica, and was given hot air baths frequently, and aloes and iron pills for the bowels occasionally. The urine became alkahne, the temperature remained sub- normal, and she remained for a long time mthout much improve- ment or decided decrease of albumen. After she had been in for more than two months, it struck me that the hot air baths were really doing harm, causing weak- ness both general and of the heart, depression, alkaline" urine, increased alkalinity of the blood (see fig. 72 as to the effect of a 39 610 URIC ACID— CHAPTER XIII Turkish bath), and subnormal temperature ; that, in a word, instead of increasing the combustion and metabolism of the body we were diminishing it. Here there was no doubt a large amount of uric acid, and there was not enough alkaU to hold it all in complete solution, hence it produced collsBmia and did harm ; and any increased weakness of the heart would similarly tend to diminish combustion. The baths were accordingly reduced and left ofi, and with this the temperature rose to normal or shghtly above it, and remained there till she went out in February. With this she improved more decidedly, and the albumen was reduced to a trace when she left. Her case left on my mind the impression that the hot air baths did harm, and that if we had left them entirely alone and trusted to drugs, such as the iodide of mercury, which clear the blood of uric acid, we should have got rid of her albumen much sooner. In any similar case in future, I shall take the temperature as my guide, and refuse to believe that any treatment is doing good and increasing the metabolism of the body while the temperature remains subnormal ; and, indeed, it is an important characteristic of the best action of the iodide of mercury in these cases that as the pulse softens and quickens, the temperature rises to normal and remains there. Isabel M., aged 46. Admitted under my care into the Royal Hospital for Children and Women on June 14, 1894. She complained of general oedema and shortness of breath with occipital headache. Her temperature was 102° and her pulse 78 in the evening and 60 in the morning, being thus very slow relatively to the temperature. A tracing showed a very high first wave, and took 4^ ozs. pressure to develop it. The heart's apex was displaced to the left beyond the nipple hne, its impulse was forcible, and the second sound everywhere loud. There was some twitching of the arms. Urine 1020, and contained albumen and blood. She was put on milk diet, iodide of potassium and nux vomica. June 18. — Urine 89 ozs., albumen 2 per 1000 (Esbach) and a httle blood. A few large hyahne casts with epithelium granules and fat upon them. Pulse 84, temperature 99-6°. Still some occipital headache, with nausea and occasional vomiting. ALBUMtNUEIA AND BEIGHT's DISEASE 611 Mist, liydrarg. perctlor. cum pot. iod. given in pkce of the other iodide mixture. June 28. — Urine 54 ozs. (there is little or no oedema left, i.e., there is no more water to be run out of the tissues and blood), sp. gr. 1010 acid. Temperature 99°. Pulse 90. There were now some signs of sahvation, so I cut off the mercury and put on the iodide of potassium again. July 5. — Urine 50 ozs., sp. gr. 1010. Alb. (Esbach) '5 per 1000. July 7. — Pulse 80-90, much lower tension and only 3^ ozs. pressure is now required to develop the tracing. July 17. — Urine 61 ozs., 1010 acid, albumen only a trace. No symptoms. July 18. — Allowed to go home and given the iodide of potas- sium mixture to continue. I concluded that her troubles on admission were due to uraemia, and that we drove it off by clearing her blood of uric acid, relax- ing her pulse and freeing her metabohsm, so that her albumens were combusted, and not eliminated unchanged. Lily T., aged 5. Admitted into the Royal Hospital for Children and Women, February 23, 1894. She had general anasarca, her face was pale and puffy, and there was a history of scarlet fever two years ago. Pulse 60, high tension. Temperature 99"2°. First sound of heart long or reduplicated ; second sound loud. Urine 20 ozs., smoky, 1018. Albumen (Esbach) . . . . 2 per 1000 = 18-4 grs. Urea . . . . . . . . 1-4 per cent. = 129 „ Uric acid -04032 per cent. = 3-7 „ Relation of albuijien to urea . . . . . . 1 — 7. „ uric acid to urea . . . . . . 1 — 35. Casts numerous with much epithelium. Here we have subacute Bright's disease with, no doubt, a large amount of uric acid in the blood, accounting for the slow high tension pulse, but no large excretion in the urine owing to the irritation of the kidney interfering with its solubility and preventing its passing, as it usually does in physiological condi- tions, from the blood into the urine. And with this we have scanty urine, low urea = 3-7 grs. per pound, her weight being 341bs. and a considerable excretion of albumen equal to 1 grain for 7 of urea ; and with the cold pale 612 UKIC ACID — CHAPTER XIII skin and anasarca we have every sign of obstructed capillaries and consequent diminished combustion and its results. She was put on the mist, hydrarg. perchlor. cum pot. iod. and milk as her only food. She went on well, and on March 2 her urine was 50 ozs., sp. gr. 1020, containing 1*5 per cent, of urea =: 375 grs. Albumen a mere trace, too small to estimate. Temperature normal. Pulse 120, soft. Second sound of heart still loud, but the first sound is not long. Surface warm. Here was indeed a different state of things all in one week. Her urea had increased to 11 grains per pound and the albu- men had diminished to such an extent that it could not be accur- ately estimated, while her diet had not been altered. March 19.^Urine 18 ozs. ; there was no anasarca. Urea . . . . . . 1'8 per cent. ^149 grs. Albumen . . . . -5 per 1000 (Bsbach) = 4-1 „ Albumen to urea . . .' . . . . . . . 1 — 36. April 7. — Is now up and about. Urine 26 ozs., sp. gr. 1020 acid. Albumen too small to estimate, say '25 per 1000 = 3 grs. Urea 2'2 per cent. = 263 grs. = 7 grains per pound. Relation of albumen to urea 1 — 87. She was now on milk diet. She went on perfectly well and was allowed to go home. I have no doubt that if she went on well and had no acci- dents such as over-feeding, or exposure to cold, the albumen would in eight to ten months have completely disappeared and that no one who then examined her urine would ever guess that she had had Bright's disease. With regard to the large excretion of urea on March 2, we can now see from the experience we have had with the effects of uric acid on metabolism, and especially its efiects on the causa- tion of fatigue and the excretion of urea during and after exer- cise (figs. 46 and 47), that this excretion was to some extent a measure of her previous defective metabolism. It was not due to any increase of food or to better assimila- tion of food, for food and assimilation continued the same and yet the high urea did not last, and on April 7 urea was 7 grs. per pound as against 11 grs. per pound on March 2. It is clear to my mind, therefore, that this high urea about ALBUMINURIA AND BEIGHT's DISEASE 613 March 2 was the result of her previous colleemia and defective metabolism, of which, as I say, it was a measure, and represented the imperfectly metabolised nitrogen, which was accumulating in her muscles and other tissues, while their circulation was obstructed by uric acid. But as soon as the blood was cleared of uric acid her circula- tion was set free, combustion became more complete, and the large excretion of urea represented the products of the previous incomplete metabolism which, owing to defective circulation, were left in the interstices of her tissues. Here we have merely an enlarged edition of what we have already seen to occur in the physiology of fatigue where the col- laemia produced by heat and perspiration obstructs the capillaries and reduces metabolism, causing an immediate fall of urea ; then later on when the circulation has again become free we get a rise of urea which more than compensates for the fall of the previous day (see figs. 46 and 47, and p. 378). In both conditions, fatigue as well as Bright's disease, we have only to get rid of the collsemia to get a free circulation and meta- bohsm and a complete reversal of all the effects of the obstructed circulation. With regard to the future of such cases, I will now shortly mention the after history of another case, Susan B., aged 13, who was treated in the same way as some of the above cases, and Uke them discharged at the end of some two months with the albumen reduced to a mere trace, and who continued to attend^ as an out-patient. I first saw her on January 19, 1891, and she left the hospital for a convalescent home on April 4. Her mother seemed to be a sensible woman, and I impressed upon her the great importance of giving her no animal food except milk, of clothing her in flannel from head to foot, and as far as possible guarding against exposure to cold and wet. She came to see me about once a month, and in October, 1891, I have a note that at this and the previous visit I was unableto detect any albumen in the specimen brought. In 1892 this improvement continued, and she was now growing a strong and healthy-looking young woman. In 1893, she had during some cold and wet weather, a slight relapse, and there was a trace of albumen in the specimen brought, and she had not been feeling quite so well and looked a little pufEy again. 614 UEIC ACID — CHAPTBE XIII Bear in mind here the direct effect of cold on the circulation of the skin and also its indirect effects through precipitating collsemia. But I put her on iodides and she soon got all right again, and the urine remained free from albumen as before. In 1894 this condition continued and I again began to regard her as completely cured, provided she kept to diet and regulations. In the spring of 1895, however, she returned with some albu- minuria and had also some malaise and the general signs of eoUeemia and defective combustion. And this time she had to confess that she had been doing wrong, she had been doing some work, and what was much worse, had been eating some meat. This was a great disappointment to me, as I had begun to look upon her as cured ; but after all it is nothing more than what would have occurred if her trouble had been migraine instead of morbus Brightii ; in both diseases immunity depends upon a steady continaation of the diet, the moment the introduc- tion of uric acid is increased the trouble returns. If she had been content with her milk diet she could have worked as hard as most other people without any harm ; but she went out to work, and was, I fear, practically compelled by circumstances to eat meat as others did. I have again seen her more recently ; she has been keeping strictly to diet, refusing to indulge even on Christmas Day. Her appearance does the diet every credit, and the urine is quite free from albumen, and has sp. gr. of 1017. I have since seen this patient several times in 1896 and 1897. She now keeps faithfully to the diet ; there has never again been any albumen in the urine, and the sp. gr. runs from 1015 to 1020, and collsemia being impossible, cold weather has been unable to affect her. In a case under my care, a patient suffering from chronic arthritis, periostitis (believed by Mr. Walsham, who saw him with me, to be rheumatic), and also from parenchymatous nephritis, I was interested to find that both troubles fluctuated together ; that when he had increased trouble in his joint he also had increase of albumen or even recurrence of blood in his urine, so that it looked almost as if the condition (? rise of acidity) which drove the uric acid into and produced increased irritation of his joint, had driven some also into the kidney (gout of the kidney) and increased the renal trouble, and I think we must not alto- gether lose sight of this possibility; but, on the other hand, it is ALBUMINURIA AND BRIGHT'S DISEASE 615 clear that any arthritis which is due to uric acid is due to a fluc- tuation of uric acid — that is, there is first an excess of uric acid in the blood (coUeemia) and then some rise of acidity precipitates it on the joint (see chapters* xv. and xvi.) ; and though both troubles appeared to get worse together the increase of albumen may have been due to the coUsemia in the way I have suggested and not to the local irritant action of uric acid in the kidney. I was greatly interested in this case because, when I put him on a milk diet, both his arthritis and nephritis steadily improved together, and he was greatly pleased with the result of this treatment. I have no doubt that both were due to uric acid, the action being direct in the arthritis, probably indirect in the nephritis. Another case somewhat similar to those given is that of Edwin R., aged 52, admitted into the Metropolitan Hospital under my care AprU 1, 1896, suffering from swelling of the legs and head- ache for two weeks. There was a history of some kidney trouble on and ofE for about six years. On admission the face was puffy and there was some cedema of the legs. Temperature subnormal. Pulse 90. Heart's apex beat well outside the left nipple line. Impulse diffused and heaving. April 4. — Urine full amber, pale deposit, 1020 acid, quantity 30—48 ozs. per day. Urea 2'2 per cent. Albumen (Esbach) 1'5 per 1000. Eelation 1—14. Microscopic examination of deposit. Numerous casts, hyaline with granules, degenerate epithelium and fat. Pulse rate 100. Diameter of R. radial artery with arteriometer while lying down --= 2'2 mm. On milk diet. Given mist, hydrarg. perchlor. c. pot. iod. ter. April 8. — One pint of milk added. Mixture to be taken quater in die. R. radial diameter 2-2 mm. Pulse rate 112. April 11. — Urine shows some slight increase in quantity. Blood examined at 4 p.m. : — Haemoglobin _ 60 per cent _ ^^^^^ ^^^.^^^ _ .gg Cells 106 per cent. April 13.— Urine 68 oz. April 16.— Urine 72 oz., 1014 acid. Urea 1-3 per cent. ] Albumen -3 per 1000 J '- R. radial diameter 1-7 mm. i 616 UEIC ACID — OHAPTEK XIII April 20. — R. radial diameter 1-7 mm. Albumen is now reduced to a trace too small to be estimated. i April 28. — Up and about in the ward. Blood to-day : — • Haemoglobin 65 CSE "" 103 = ■^^■ Here as the result of three weeks and three days on iodide of mercury and diet, we have the urine increased and the dropsy removed ; the blood pressure lowered, as shown by the fall in the diameter of the radial artery, the capillaries freed and combustion stimulated, as shown by the fall of albumen which was reduced from a relation to urea of 1 to 14, down to something less than 1 to 43, and lastly we have a very distinct improvement in the quality of the blood itself produced here, just as in chlorosis and by the very same drug (see fig. 57), showing conclusively that all the above results of the removal of coUaemia by iodide of mer- cury were due to a general improvement of nutrition and meta- bolism. But after all said and done this is but the same effect on a larger scale which can be produced any day and in any one in' the physiology of fatigue. This patient continued to do well and the iodide of mercury mixture was now only given three times a day. He was put on a uric-acid-free diet containing milk, and cheese with bread, puddings and farinaceous dishes ad lib., also vegetables and fruit. When he was suificiently instructed in this diet he was allowed to go home, still continuing the mixture, which was later on changed for one containing iodide of sodium and nux vomica, which he kept on with together with the diet for a long time. November, 1896. — Is keeping faithfully to the diet, which he likes, and is very much pleased with the improved health he has gained. I have examined several specimens of urine lately and have found no trace of albumen in any of them. Here as in other cases there was a comparatively quick reduc- tion of albumen at first, as it fell to a trace in the third week of treatment ; but that trace remained for several months more only gradually diminishing and becoming invisible. This, I think, shows the. two origins of albumen in such a case ; the larger amount, which disappeared at once, was the albumen of defective combustion, which was at once metabolised into urea as soon as the capillaries were cleared and the fire burnt up ; the small lingering trace was the organic albuminuria, the measure of the injury done to the kidney, and possibly, as the late Professor ALBUMINURIA AND BEIQHT'S DISEASE 617 Semmola suggests, to the blood albumens ttemselves by the expe- riences they had passed through, and these injuries take some time to repair and pass away. If all cases of Bright's disease were like those just narrated, and if in all cases the iodide of mercury acted just as it did in these, I should have little or no doubt of my power to cure every case of Bright's disease that came before me ; but as this is unfortunately not the case, I must not forget to mention the other side of the picture— the cases in which I fail, and the reasons of such failure. Of course if mercury disagrees, if it causes salivation, dys- pepsia, or diarrhosa, as I have already pointed out, it quite fails to control uric acid coUsemia, and is worse than useless in the diseases which are due to collaemia ; iodides also may cause iodism and have to be left ofi for this reason ; and in some cases we are deprived of the use of these most powerful drugs by such results, though, as will be seen further on, there are ways of getting over some of these difficulties. In this case we should remember the effects of salicylates with acids, or saUcylates with opium in small doses, for though less powerful than iodide of mercury, they may chance to succeed. But even when the iodide of mercury does not cause sahvation or upset the stomach and intestines, it may fail to cure, and that for a reason which will be best illustrated by a record of a case in which it twice succeeded, and then in a second relapse failed to reduce the albumen at all. Edgar G., aged 18, first admitted under my care into the MetropoUtan Hospital on September 18, 1895. There was a history of Bright's disease extending over more than two years. He had now considerable general anasarca, and- some ascites, and the urine contained nearly 7 to 8 per 1000 of albumen. He was given iodide of sodium with some nux vomica and occasional small doses of calomel, but he did not improve much. October 20. — Abdomen tapped and 7^ pints of fluid withdrawn. October 23. — Given mist. hyd. perchlor. c. pot. iod. with nux vom. and digitalis. Pulse 92. Temperature subnormal. October 25. — Abdomen again tapped and 8J pints withdrawn. Pulse 104. October 27. — Temperature rising towards normal. Urine increas- ing. Pulse 92, and this was the beginning of a very marked improvement, the iodide of mercury coming into action, and being 618 - UBIC ACID — CHAPTEB XIII aided by the nux vom. and digitalis, and last but not least, by the tapping and removal of ascites. November 1. — Much better ; oedema all gone ; is passing 40 — 70 oz. urine. Pulse 88. November 19. — Pulse 88 ; urine 66 oz. ; sp. gr. 1011 ; neutral albumen -1 per 1000 ; urea 1-1 per cent. ; relation 1 — 91 ; allowed to get up. December 5. — Left hospital ; albumen a mere trace ; urine plentiful ; advised to keep always on milk diet. May 20, 1896. — Re-admitted with a relapse ; had been at work as a stable boy, and was not able to get proper food ; tempera- ture subnormal (sign of defective combustion) ; general anasarca and shght ascites as before. May 22. — Urine 16 ozs. ; amber turbid, 1024, acid. Albumen (Esbach) -625 % = 46-2 grs. ] Urea . . 3-7 % =-^ 279 grs. J Microscope shows very numerous casts ; much degenerate epithe- hum and fat ; very difierent from the urine when he went out in December last. He again improved on the same iodide of mercury mixture with nux and digitahs, and after the ascites had been tapped once or twice, but he did not respond to the drugs so quickly as on the previous occasion, and there were evidences of increasing cardiac dilatation and quickening of the pulse. However, by June 13, and especially after a paracentesis abdominis on June 1, the urine increased to 48, 56, and 60 oz., and began to contain little more than a trace of albumen, giving a relation to urea of 1 — 25 and less. After this the amount of albumen became so small that it could not be estimated, and the urine at the beginning of July went up to 98 and 106 oz. He now again went out having received full directions and cautions as to the importance of diet ; but this time he was too weak to work, and being dependent on others he had more than ever to take what food he could get, and then he was sent to a convalescent home and fed on soup, fish, meat, and what is generally called the fat of the land. He did not improve on it, however, but soon again got ascites and anasarca and was confined to bed, and then he got some sloughing sores on his legs, when an attempt was made to run off the fluid from the skin with tubes ; and then he thought of me, and finally was again sent back from thiff convalescent home to the hospital to be under my care once more. ALBUMINDEIA AND BBIGHT's DISEASE 619 But this time I could do notliing for him, though a more suit- able diet did some good, and the sores on his legs healed ; but the drugs that had been useful before now quite failed either to increase the urine or diminish the albumen, and even repeated tappings failed to give them a start, and he remained like a marsh, fuU of water, and the water ever slowly rising and rising putting out more and more completely the fires of combustion. And the explanation of this is fairly simple if we look upon Bright's disease as a failure of combustion, which again is due to defective circulation, which in its turn is the result of coUsemia overpowering say a normal heart (acute Bright's disease), or as in this case a heart which grew gradually weaker and weaker as the general strength and nutrition failed. And it is obvious that with a given amount of coUsemia we shall get ever greater and more disastrous efiects on the circula- tion, nutrition and metabohsm of the body as the nutrition and power of the heart fail. Then the scanty urine is a measure of the obstruction to the •circulation in the vessels of the kidneys, and this is an index of the larger and more important obstruction to the circulation in all the great metabolic tissues of the body, which is the cause of the defective combustion. Now there can be very little doubt that something of this kind happened in the case of Edgar G. With his first attack his trouble was almost entirely functional, a defective combustion due to acute coUsemia. His heart was strong and well nourished, his tissues were young and moderately well formed and sound, and as soon as the coUsemia was cleared up by drugs, circulation and combustion were resumed, and he was soon again in a position to deal with all the albumens in his food. Hence urea increased, and albumen in the urine diminished till only a trace was left, and that trace was due to some little irritation in a few cells of the •kidney, resulting from the passage of the albumen, while certain cells in the liver, skin, &c., had suffered a corresponding irrita- tion and were also slowly undergoing regeneration. But with these slight exceptions he was a sound man, and had only to make further coUsemia impossible, by living on a uric- acid-free diet, to remain well and strong and be as in the pre- viously-mentioned cases, completely cured of his disease. Unfortunately, however, he was unable to control his diet, so that coUsemia, in place of being rendered impossible, was allowed to return, and he was once more subjected to a severe attack of 620 UBIC ACID CHAPTER XIII defective combustion, with further damage to blood, metabolic tissues and kidneys. And thus we find that with each attack he recovered more slowly and with greater difficulty ; in his first attack a mere clearing up of the collsemia by iodide of mercury would have sufficed to free the capillaries of the kidneys and run o£E the water, the fires would at once burn up, and the albumen be quickly reduced to a trace. At the next attack, nutrition is not quite so good, and defec- tive nutrition means defective power of muscle, especially of that most important muscle the heart, hence something more must now be done besides clearing up the collaemia, and nux vomica has now to be added to strengthen the heart in this attack ; also there is now a slight but quite distinct falliag ofi in the nutrition of the kidneys and metabolic tissues. Nevertheless, he again becomes solvent, and can again meta- bolise completely all the albumens of his food, and has once more a chance of life if he can control his diet. At the next attack, however, things are stUl worse, and now both digitalis and nux vomica are required to get the heart up to its work ; but the fires burn lower, the water rises higher, and the difficulty which the drugs meet with in clearing up the col- laemia is greatly owing to the increasing defectiveness of nutrition. And so the issue is for some days in doubt whether the heart wiU get sufficient power to drive blood through the kidneys even when the coUaemia has been removed ; if it fails to do so the water wiE rise ever higher and higher, and the fires wiU soon be extinguished. And under these circumstances comparatively small matters suffice to turn the scale one way or the other, either for the heart or agaiost it. And one of these is no doubt the presence of a little fluid in the great serous cavities, the pleura or the peritoneum, and these, by hampering the function of the lungs, the heart, the diaphragm, or otherwise impeding the circulation in the great digestive viscera, the liver, the kidneys, and the great abdominal vessels, may turn the scale against the heart and lead to its further dilatation, failure, and final defeat. Hence we see that the last time the iodide of mercury suc- ceeded in the case of Edgar G. it only did so with difficulty and after every help had been given it by clearing the fluid out of the peritoneum ; and I have had several hard-fought cases in which the fluid in one or both pleura had to be removed in the ALBUMINURIA AND BBIGHT'S DISEASE 621 same way ; but each time the effect became less and less, the fires burnt lower and lower as the metabolic tissues wasted, and the water rose in them ever higher and higher, and the heart muscle got weaker and weaker and less well nourished. This heart failure is the final and absolutely hopeless stage of all Bright's disease ; now it is of little use to clear up the coUsemia, for the nutrition of the heart is so bad that it could not keep up a proper circulation, even if there was no coUsemia ; and circulation being so bad, the fluid is not run off by the kidneys, and the tissues of the body are like a marsh with great stagnant pools in the serous cavities, and the water and the collsemia between them now quickly extinguish the flickering flame of combustion. But if this is the common and final ending of ordinary Bright's disease, and if as I said above, oollaemia will produce more and more severe results in proportion as it supervenes upon an other- wise more and more defective circulation, then it follows that a collsemia which would not of itself suffice to produce Bright's disease, may yet produce it if it chances to supervene upon either a condition of weakness or debility of the cardiac muscle, or, on the other hand, on a mechanical condition which more or less seriously obstructs the general circulation. I think, therefore, that it is extremely probable that some people, suffer from Bright's disease not because they have more severe collsemia than those others who do not suffer, but because they have rather weaker hearts, or more obstructed circulation, which allows the collsemia to do greater damage to nutrition and combustion than it would in an individual with a normal circu- lation ; and thus acute Bright's disease may be not infrequently the result of collsemia with acute heart failure. Now one special condition I have in my mind's eye in making these remarks is that of pregnancy, for here we have, especially in primiparse, a condition affecting the pressure relations in the abdomen, affecting the work of the diaphragm, the circulation in the great digestive viscera and the great abdominal vessels, play- ing in fact, exactly the part of the ascites in the case of Edgar G. And I find in Fagge's " Medicine," second edition, vol. ii., p. 624, the statement : " In women pregnancy is often the cause [of Bright's disease] as the late Dr. Lever showed many years ago, especially in primiparse, and above all when there are twins." The bearing of primiparse and of twins on the pressure rela- tions of the abdomen are too obvious to need further remark, and it is also, I hope, clear, as it follows from my first principles, that 622 UEIC ACID— CHAPTER XIII pregnancy is an enormous stimulus, especially in young women and primiparse, to tte nitrogenous metabolism of the system, and this means both excessive formation and excessive retention of the uric acid in the body, that is provision of the material for a more or less severe coUaemia in the future. And we already know from the relationship of pregnancy to headache, epilepsy, mental depression, Raynaud's disease, &c., as treated of in previous chapters, that normal pregnancy is accompanied by retention of uric acid, and its clearance out of the blood. But if the pregnancy is not normal, if thsre is dyspepsia, and still more if there is vomiting, then it follows also from my first principles that the blood will become again a good solvent of uric acid and then some of the .large formation of uric acid, or some that has been already retained before the vomiting began, will pass into solution in the blood and a more or less severe collaemia will result. Now vomiting is exactly one of those things which, I believe, may thus precipitate Bright's disease on preg- nancy. And the following case will illustrate several of these points : — Ellen G., aged 24, admitted into the Metropolitan Hospital under my care on October 12, 1895, being then in the fourth month of her first pregnancy. Her history showed that on September 28 hsematuria had been noticed. On October 1 she had several " fainting fits." On October 6, suffered from pain in the left side. On October 8, sufiered from vomiting, which continued up to admission. There was some anasarca and csdema of legs ; pulse 68 • temperature 98° to 100°, irregular ; heart's apex outside left nipple line ; abdomen slightly distended ; uterus easily felt in hypogastrium ; urine, 1014 ; alkaline, blood-stained. Albumen (Esbach) . . -4 % ) Urea .9 o/^ [ or nearly 1 to 2. Left radial artery measured with the arteriometer, 1-9 mm. Put on iodide of mercury in small doses. October 19. — Pulse 72 ; left radial measures 1"7 mm. October 23. — Pulse 72 ; albumen to urea 1 — 4 in place of 1 — 2 as on admission. October 24. — Iodide of mercury in full doses. October 25. — Pulse 84 ; left radial 1-5 mm. October 30.— Pulse 96; left radial 1-3 mm. ALBUMINUEIA AND BRIGHT's DISEASE 623 November 8. — Heart's dulness has diminished and apex come into left nipple line. November 16. — Pulse 92 ; left radial 1-5 mm. There is some increased heart dulness, apex has gone again a little to the left and there is some increased csdema of the legs. Some digitalis given. November 19. — Same condition ; pulse, 88 ; left radial measures 1-6 mm. Iodide of mercury further increased. November 23.— Pulse 85 ; left radial 1-0. November 30.— Pulse 72 ; left radial 1-0. December 6.-jPulse 88 ; left radial 1-1. There is still con- siderable oedema of the legs. I now came to the conclusion that the iodide had twice cleared up the coUaemia and freed the capillaries on October 30 and November 23, but on neither occasion had this been followed by diuresis and removal of fluid, and similarly combustion remained defective and albuminuria profuse. The inference seemed to be that the increasing abdominal pressure, and the increased work that pregnancy, now in the sixth month, was throwing on the heart, prevented it reacting to the removal of the collaemia. I therefore gave up the attempt to do anything with drugs and trusted to nature with uric-acid-free diet and rest. I have no doubt whatever that if we could have cleared out the abdomen the heart would have recovered somewhat and become equal to its ordinary work, and then the iodide of mercury would very quickly have improved the combustion and reduced the albu- men to a trace ; and the question of terminating the pregnancy was carefully considered with my colleague. Dr. Gow, but put on one side as being on the whole more dangerous than trusting to nature. I could not but feel, however, that while we were thus wait- ing, the kidneys and great metaboUc tissues were suffering serious damage, how serious it was difficult to say, but I knew from previous experience that such cases kept carefully on milk often got over parturition quite well, and that the Bright's disease then subsided to a greater extent than might have been expected. Accordingly she was "now watched for some months, during which the conditions remained much as before, the pulse ran' about 80, and the radial artery measured from 1-7 to 1-9 mm. Urine scanty, loaded with albumen and a little blood. In February, 1896, after reading the most interesting lectures 624 UEIC ACID — CHAPTER XIII of Dr. Handfield Jones, " The Heart, in its relation to Pregnancy, Parturition, and the Puerperal State " {Lancet, 1896, vol. i.), to which I shall have to refer again, I made a further careful examin- ation of the heart and came to the conclusion that the quick pulse rate with a long and indistinct first sound, and a loud second sound both at apex and base, with increased dulness and apex displacement to the left, meant some heart failure before colleemia and the increased work and pressure in the abdomen, and I accordingly put her on a mixture containing phosphoric acid and strychnia, and it appeared to do some little good, for the pulse on February 25 had fallen to 72, and the left radial diameter to 1'6 mm., and the urine had increased somewhat to 46 oz. per day, but still there was as before no important result as regards the removal of anasarca and improvement of combustion. On March 14 I examined the blood and found Haemoglobin .. .. 33% Cells 70%' ^Bl«° • • J) ' 124 „ (Plastic operation for ventral hernia,) „ . . June 8 . i22 „ „ . . J) " 528 „ „ 10 . 401 „ „ 11 . 322 „ Sarah H., aged 49. Ovarian Tumour. Before operation 151 grs. urea. 1st day after „ 192 „ 2nd „ „ „ 354 „ 3rd „ „ „ 188 „ M. H., aged 56. lUo-femoral abscess. Before operation . . 232 grs. urea. 1st day after „ 276 „ 2nd „ „ , 452 „ 3rd „ ,, „ , 345 „ In each of these cases the urea doubled after the operation, the greatest excretion of urea taking place on the second day after it ; and for some cases in which the efEects of an operation were still more marked, see Lancet, 1893, vol. i., p. 1413. Then, as I have shown, the acidity of the urine rises with the urea, and urates in the blood and urine vary inversely as the acidity ; hence a surgical operation, which causes a marked rise in urea, will clear the urates out of the blood, free the capillaries and increase the metaboUsm. Probably this is the explanation of the curative efiect some- times seen to follow incision in cases of abdominal tubercle ; no doubt we get here also, as in other operations, a marked rise of urea and increase of metabolism and combustion, and this is just the efiect of the ordinary medical treatment of pulmonary tubercle by fresh air and excess of food. In the abdominal tubercle we get the increased combustion exactly at the focus of the disease, in the medical treatment we get a general increase of metaboUsm and combustion. In both cases the result is inimical to the bacilli, it makes matters too hot for them, or burns them up. I will now also give a figure to show the remarkable way in which, in a case of glycosuria, the uric acid and sugar fluctuate together. The curves are from the case of Kebecca M., aged 45, who was under my care at the MetropoUtan Hospital in 1889, sufiering GLYCOSUEIA AND DIABETES MELLITUS 663 from enlargement of the spleen, excess of white cells in the blood, and glycosuria. I have also pointed out (p. 76) that in cases where the spleen is enlarged, there is nearly always a great excess of uric acid in the urine, and others have pointed out, just as I should expect, that it is in excess in the blood in these cases, and I notice with interest that Dr. H. A. Hare has published a case of splenic anaemia complicated by diabetes in the Journal of the American Medical Association, December, 1899. I'i II oec/e ij IB IS 20 21 \ UURS ENO" 30AM ^ 05 J/ - 27 tt.- 1 1 « s 1 ^ >< ACID ®\ ;^ St ^ II \ \ / T ^ \ X Sl/l ■AR 23 / \ \ '^ 1 i 13 \ V'' 1 i / '-~,jc, \l,Y \ \ / / / 15 435 40 1100 f Sl~ — V ./ / \ i II 3ff3 30 300 / \ je- .U . t/ni A 1 y^ — -^ y 7 231 20 700 f ^- Fig. 61. — Cubves of Excretion of Uric Acid and Sugar in a Case of Glycosukia. It follows, therefore, that this is just the condition of things in which we should expect to find just what we do find in this case — a glycosuria as the result of the coUsemia, which is common in such cases. On December 16 (fig. 61) we see that uric acid and sugar are both high, urea and acidity low; on the 17th urea rises a little and acidity stUl more, and with this there is a fall of uric acid and a fall of sugar. There must have been some cause depressing the acidity on the 16th, for it rises on the 17th out of proportion to the rise of urea. 664 UEIC ACID — CHAPTEE XIV Talking of low acidity reminds me of the fact of which we shall see instances among my cases, that patients sufiering from diabetes or glycosuria, often say that alkalies, such as the bicar- bonates of sodium or potassium, do them harm : and we see in this figure the way in which they do it, namely, by increasing the collsemia, and in this figure the uric acid is high because the\ acidity is low, and the sugar is high because the uric acid is high. So that not only do all drugs, fevers, and surgical operations, which diminish collsemia, do good, but drugs Hke alkalies, which increase collsemia, do harm. Some of my readers will probably remark that alkalies are often of great use in diabetes, and may reduce the sugar very markedly. Now I have mentioned in previous chapters the effects of alka- lies on metabohsm in health, and the way in which they increase uric acid and diminish urea ; is it to be doubted that they have the same effect in disease, and that when they reduce the sugar, as there is no doubt they may, they have done it by interfering with the digestion, absorption, and metabolism of food, and have reduced the urea quite as much, or even more than the sugar ? And in what I shall have to say presently on the use of sahcylates in diabetes, I shall point out the great importance of estimating the urea as well as the sugar, and of not regarding as a curative effect a diminution of sugar which depends on an equivalent diminution of urea. But to return to our figure ; on December 18th the patient took nix. of acid nitro-hydrochlor. dil. twice : urea fell a little and acidity also slightly, and would no doubt have fallen more but for the acid taken ; uric acid and sugar fall decidedly and reach their lowest points. On December 19th she took iTlx. of the dilute acid four times ; urea rose a Uttle, acidity more decidedly as the result of the acid taken ; uric acid and sugar both rose a little, though uric acid bears much the same relation to urea that it did on the previous day. On the 20th the patient again took nix. of the acid four times a day ; but now she has some diarrhoea, so urea falls a little. Acidity did not rise; uric acid rose, but sugar remained about the same as on the 19th. This is the only occasion on which uric acid and sugar did not move in the same direction, and I think this is due to there being, on account of the diarrhcea, a lessened absorption of food, and therefore \ a lessened income of sugar (compare previous remarks on the effect of alkalies). GLYCOSURIA AND DIABETES MELLITUS 665 On the 21st the diarrhoea was stopped by means of bismuth and opium mixture, and urea rose ; but acidity fell as the result of leaving ofE the acid and the efiect of the diarrhoea on the previous day. Probably the acidity was really low in the early part of this day (21st), and this allowed of the large urate excretion which we see ; later in the day, as the result of the opium, it rose sharply, and the balance of the two fluctuations resulted in only a slight fall of acidity in the whole twenty-four hours. I con- stantly meet with such results in my own experimental work on excretion. And lastly, on this day there is a great rise of sugar corresponding fairly well with the rise of uric acid. Taking the whole figure, I think it must be acknowledged that the curves of uric acid and sugar run parallel to each other in a remarkable way, and some of my other cases to be given presently seem to show much the same thing. I here therefore suggest that just as we saw in the previous chapter albuminuria and Bright's disease may originate in a lowering of metabolism which brings about hetero-albuminsemia, albumin- uria and nephritis, so also is glycosuria or diabetes due to a similar lowering of metabolism which hinders the final combustion of carbohydrates and, leaving them to circulate in the blood, produces glycsemia. And. as I have already pointed out in chapter xiii., one and the same patient may have to-day albuminuria, and to-morrow glycos- uria, or vice versd. The lowered metabolism may in each case be due to uric acid, which brings about a deficient capillary circulation in all the great metabolic tissues ; its evil efEects being no doubt either increased or diminished by concomitant conditions. We have already seen in previous chapters that the quantity of uric acid in the blood controls the formation and excretion of urea and the presence or absence of fatigue under exertion, and probably also the formation as well as the distribution of animal heat ; it controls, in a word, the metabolism, nutrition, and func- tion of the whole body, and thus accounts in the most simple manner for a whole series of physiological and pathological sequences. In this connection there is a most interesting note in the epitome of the British Medical Journal, 1895, vol. i., p. 1, on , " Alimentary Glycosuria in Lead CoHc." This has reference to an article by Brunelle {Arch. Gen. de Med., December, 1894), in which it is pointed out that the hver is imphcated in lead colic because 666 UBIC ACID— CHAPTER XIV ttere are modified pigments in the urine, a subicteric tint in the conjunctiva and a diminished excretion of urea. Accordingly, the author gave from 150 to 300 grm. of syrup a day, with the result of producing glycosuria in eleven out of twenty-one cases of lead colic. The glycosuria fluctuated with the colic and generally dis- appeared with it. It would be difficult indeed to find an observation more inter- esting and instructive than that above quoted. The fall of urea would alone be sufiicient to prove that there was severe coUsemia present, even if we did not already know that in lead colic there is always a slow high tension pulse and all the other signs of coUsemia (see fig. 13 and remarks on lead colic), and if we did not also know that coUaemia is the one certain result of all colic and gastro-intestinal upset. And the rest of this observation shows that these patients were, during the continuance of the coHc, unable to burn up and meta- bolise the whole of this sugar, so that some of it was eliminated in the urine ; but as soon as the colic and coUsemia departed, their metabolism was again equal to the task and the glycosuria ceased. The fall of urea shows not only that the liver is implicated in lead colic, but that all the tissues of the body are implicated and have their metabolism hindered and their combustion reduced by the all-pervading coUsemia, and similar transient glycosuria, no doubt similarly caused, is seen in cases of strangulated hernia &c. (F. Neugebauer in Wien. Klin. Wochenschnft, September 10, 1896). The altered urinary pigments and the subicteric tint of the conjunctiva are also very interesting, but point rather, I think, to increased blood changes and destruction of cells, which is sure to take place as another result of the coUeemia (see chapter xii.), than to any special implication of the liver ; though no doubt this important gland is implicated along with all the great meta- bolic tissues. And this argument receives, I think, interesting confirmation from the researches of Dutournier and others, on what has been called " Bronzed Diabetes." See British Medical Journal, Epitome, December 28, 1895, p. 101, where it is said that the above-named author " suggests that in these cases there is a decomposition of haemoglobin, brought about by some as yet unknown cause." From my point of view the cause is well known, and the associa- tion of this slight hsemoglobinaemia with diabetes is completely explained by their being, as shown in this and the previous chap- ters, two results of one and the same cause, coUsemia. GLYCOSUKIA AND DIABETES MELHTUS 667 Some oases whicli it is interesting to bear in mind along with these are recorded by Professor Osier in the British Medical Journal, 1899, vol. ii., p. 1595, in a paper on " Hypertrophic Cirrhosis of the Liver with Bronzing of the Skin, Hsemochromatosis." In one of these there were numerous attacks of purpura and urticaria on the skin of the legs ; in the other there was a history of malaria in the Tropics, and in both there was enlargement of the liver and spleen in conjunction with the progressive pigmenta- tion and bronzing of the skin. It seems to me that these cases must be very closely related to those of paroxysmal hsemoglobinuria and blackwater fever dis- cussed in a previous chapter, and after what has been said in this chapter on the relation of congestion of the liver to coUsemia and to blood changes, and as to the causation of enlargement of liver, spleen, and glands by uric acid in other chapters, there need be no difficulty in explaining the observed association of such important blood changes with enlargement of the liver and spleen, and with chronic eruptions and pigmentation of the skin. It follows from this that coUsemia is the central factor in the causation of diabetes and that clearing the blood of uric acid will do good, while increasing the amount it holds in solution will do harm; and I have just pointed out that acids, opium, iodide of mercury, and other drugs which clear the blood of uric acid are useful, also that fevers and surgical operations, which have the same effect on uric acid, are well known to diminish the output of sugar ; while on the other hand alkaUes, which increase the uric acid, do harm. Acids and opium often have a similar good effect in albumin- uria ; and a fever may not only, as I have shown, diminish the dropsy, but also reduce the total output of albumen. Then in reference to the interesting case of colic above men- tioned in which glycosuria was produced, we have seen in fig. 61 that sugar follows the uric acid, rising when it rises, and falhng when it falls ; and it follows from this that other things equal there will probably be a larger 'excretion of sugar in the morning hours when the excretion of uric acid is large, and a smaller excre- tion of sugar in the evening hours in which the coUsemia is slight, the blood granules scanty and the excretion of uric acid relatively small ; and I see in an interesting paper by Dr. F. Kraus, jun., of Carlsbad, of which he kindly sent me a reprint, that this has actually been observed and recorded. His paper has the title " Notes on the Variation of Glycosuria 668 UEIC ACID — CHAPTEE XIV in Diabetics," and it appeared in the Albany Medical Annals of August, 1899. In this he points out that several observers have noted that cases of diabetes which have reached a certain amount of tolerance for carbohydrates show a measurable amount of glucose in the urine if they take the smallest amount of carbohydrates for break- fast, although they are able to assimilate large quantities perfectly if taken later in the day. He then records two cases, in the first of which 50 grms. of bread at breakfast caused glycosuria, while four times that quan- tity later in the day did not do so. In the second case 30 grms. of bread at breakfast produced glycosuria, but he could take 120 grms. in the day without glyco- suria if given at the later meals. He also mentions a case recorded by Naunyn, a diabetic patient aged 28, who became glycosuric when only 5 grms. of bread were taken at breakfast, but could take 100 grms. bread, 60 to 70 grms. potatoes and an apple later in the day without glycosuria. The explanation given by Naunyn which Dr. Kraus quotes is " that in the empty intestines the introduced carbohydrates more quickly digest and absorb, and so the diabetic organism is suppUed with more sugar at once than it can assimilate." It seems to me that those who have regarded diabetes from any and every point of view except as a failure of combustion, which it really is, have here put forward an explanation of the facts observed which will not cover them ; for we have seen, in the last chapter especially with regard to my reference to fig. 3, that the rise of urea which foUows breakfast is slower and less marked than that after the later meals of the day ; are we to con- clude that the carbohydrates are more quickly digested and meta- bolised in the morning, while the albumens on the contrary are more slowly dealt with ? We know why the rise of urea is slow and less marked after breakfast ; it is but a single instance of the universal law that urea falls with high and rising uric acid, and rises with low and falling uric acid ; that in the collsemia of high uric acid, circula- tion, digestion, metabolism, and combustion are all slowed down, and neither albumens, carbohydrates nor fats are quickly digested or quickly metabolised. But we have seen in fig. 61 that sugar follows uric acid, being high when it is high and low when it is low, and in this respect it exactly follows another urinary product of defective combus- , GLYCOSUEIA AND DIABETES MELLITUS 669 tion — albumen. This also is high when uric acid is high and low when it is low ; and we have seen in the previous chapter that by controlling the aric acid we can control the albumen, and that as we bring down the albumen up goes the product of its final metabolism, the urea. Albumen and sugar then are the indices of incompleta com- bustion, and that is the reason they move together and in the opposite direction to urea, which is the index of complete com- bustion. But as we have seen in the previous chapter, albumen in Bright's disease is Uke sugar in diabetes, always more after break- fast in the morning than after other meals later in the day ; but if this rise of albumen after breakfast is due to increased absorp- tion of albumens from an empty digestive canal why is it that urea is lowest at that time and rises less than after other meals, for, as a rule, and as I have shown in my figures in " Diet and Food," urea is the index of digestibility and of the rapidity of digestion and absorption, so that we are landed in a contradiction ? There is only one explanation that will relieve us of this con- tradiction and meet all the facts of the case ; albumen we know is a product of defective combustion, hence it rises and falls with the uric acid in the blood and urine, and urea moves in the opposite direction. Sugar bears exactly the same relation to uric acid because it is also a product of defective combustion ; are we to believe that in the absorption of a food hke bread the carbohydrates are taken up four times as quickly after breakfast as after any other meal, while the albumens which surround them are not only not taken up more quickly but actually more slowly ; or are we to believe the only complete explanation of all the facts, that sugar is high in the morning just as albumen is high and urea low, because uric acid is high, and because uric acid coUaemia causes, as we can also see for ourselves, defective capillary circulation, nutrition and combustion throughout the whole body in the morning hours ? Dr. Kraus goes on (previous reference) : " A similar fact, in the contrary sense, is the paradoxical diminution of glycosuria con- nected with gastro-intestinal troubles (von Noorden) where with equal amounts of carbohydrates in the food less glucose appears in the urine, the result of diminished digestion and diminished and retarded resorption." I have quoted the passage in full, but it certainly seems to me to be by no means a similar fact but one of the very opposite 670 UEIC ACID — CHAPTER XIV meaning ; for if, as I have always insisted it should be, urea is estimated along with sugar we shall at once see an important difference between the rise of sugar after breakfast and the fall of sugar which takes place in conditions of diminished absorption of foods from gastro-intestiaal disturbance and dyspepsia. For, as I have over and over again pointed out, in diabetes if we irritate the stomach or intestines, or allow any food to upset them, or give opium which diminishes appetite and the taking of food, sugar and urea fall together, that is, they move in the same direction. But we have seen that in the case of breakfast, sugar and urea move in offosiie directions, the sugar rises more quickly than usual while the urea rises more slowly than usual. It is clear then that the rise of sugar in the urine after breakfast is not due to increased absorption of sugar into the system but to diminished combustion in the system; later in the day with four to twenty times the amount of bread taken, the absorption of carbohydrates is no doubt far larger in. the given time ; but now the coUaemia has diminished, the capillary reflux has quickened, circulation, nutrition and combustion have improved, the fires of life bum up brightly, and there is no sugar left uncombusted, no glyciemia and no glycosuria. The completeness of the parallelism between albuminuria and glycosuria here brought out will not escape notice, and we are at once provided with an index of the cause of their fluctuations, for changes in their excretion which are due to defective combustion move in the opposite direction to urea, while those which are merely due to difierences of absorption of food move in the same direction with it. Dr. Kraus goes on to point out that the facts above mentioned show the importance of not merely regulating diet as to quantity and quality but also in reference to time of day. He remarks that it is only in mUd cases of diabetes that such regular fluctuations are met with ; but it my explanation of the facts is correct the indication for treatment applies to aU cases, for in all probably combustion is at its worst in the morning hours ; but in bad cases there is more uric acid, and coUsemia is severe nearly all day, so that changes are less evident though probably still there. I am interested to see also that Krehl {Centralbt. fur Innere Med., 1897, No. 40) found in some experiments he made on students at Jena that five had glycosuria out of fourteen who GLYCOSUEIA AND DIABETES MBLLITUS 871 drank beer in the morning, but out of nineteen who drank it in the evening only one had glycosuria. Here is an almost exact reproduction of the experiment I pro- posed to make in a previous chapter with a test meal of albumens in cases of defective combustion bordering on Bright's disease. No doubt in the above students the capillary reflux would have been found slower and th* blood pressure higher in the five who had glycosuria than in the nine who had none. The record also shows that combustion can be directly tested both with sugar and albumen, and thus the direction in which it is most Ukely to fail can be predicted, so that prevention may be improved and made more precise. And in patients with slow capillary reflux we may be able in this way to tell several years beforehand whether their defective combustion will eventually afiect the albumens or the sugars or both ; while the defective combustion of fats so" common in middle life (when the retention period of good nutrition is coming to an end, and the coUsemia of decUning life is establishing itself, see p. 248) speaks for itself in the form of obesity. I shall now go on to show that sahcylates which clear the blood of uric acid by efiecting its elimination are also very useful in glycosuria and diabetes, just as we have seen in chapter viii. that they are useful in preventing coUsemia and fatigue ; for a favourable record of results of their use in glycosuria and diabetes, see paper by Dr. R. T. Williamson, British Medical Journal, 1901, vol. i., p. 760. Mary A. D., aged 55. — An out-patient at the Royal Hospital in January, 1888. Complains of thirst and irritation of vulva. Urine pale amber, 1020 ; 3"2 per cent, sugar. Alkalies and nux vomica no efiect. After four weeks of salicylate, urine 1014, with no sugar. Drinks much less. Salicylate left off, and in two weeks urine 1020 and 3 per cent, of sugar, and again salicylate reduced it to 1011 and no sugar. Mrs. C, aged 45.— May, 1888. Urine 1032-1040 and containing 5 per cent, sugar. Put on salicylate, and in seven days' time the urine was 1035 and 2"5 per cent, sugar. Treatment continued, and two weeks later urine dark amber, 1030, and only "5 per cent, of sugar. Drinks much less. I then altered her diet ; left off the excess of meat she was taking, and put her on mEk, fruit, and vegetables, and so long as she took the salicylate these did not increase the sugar, except on one occasion when it reached 1"6 per cent. She found that pota- 672 UEIO ACID — CHAPTEE XIV toes were worse than other vegetables, and produced diuresis (pro- bably from the large amount of alkali they contain interfering with the action of the salicylate, see p. 43). She attended for many months ; the sugar in spite of the above diet keeping about 1 per cent. Her husband then left the district in search of work, but a year later, October, 1889, she came b?lck asking for more of the medicine which had done her so much good. She is paler, and has wasted considerably since last seen in 1888. Urine is now 1030 : contains .5"7 per cent, of sugar, urea 1"5 per cent., and uric acid •08736 per cent., uric acid to urea 1 — 17, urea to sugar 1 — 3"8. A large excretion of uric acid, and no doubt collsemia contem- poraneous with glycosuria. Fourteen days later, after a course of salicylate, the urine only contained '6 per cent, of sugar. November, 1890. — Returned again after considerable absence, and again salicylates reduced her sugar in a week to 2'5 per cent. She was, however, upset by home troubles, and could not take her medicine or attend regularly. February 16, 1891. — Took her into the Royal Hospital, Waterloo Road. No drugs except a little dilute phosphoric acid, a little sal volatile for feelings of " weakness and sinking " (patient pro- bably indulges in alcohol at home for these feelings). Urine of twenty-four hours 990 cc, 1046. Sugar 7'1 per cent., urea 1"6 per cent., uric acid "06720 per cent. Uric acid to urea 1 — 23. Urea to sugar 1 — 4'4. Total sugar 2*4 oz. Here we see very clearly what I believe occurs in all cases, a progressive increase of sugar, together with increasing debility as time goes on. The first slackening of combustion causes eventually debility, and debility of that most important muscle, the heart, causes a constant increase in the defect of combustion, even if the coUsemia does not also increase. Here we have, just as we have already seen in Bright's disease, a vicious circle, defective combustion, heart weakness, increased defective combustion, increased heart weakness, and so on, steadily downward. Here also, just as in Bright's disease, the onset of the disease means probably collsemia, intensified by heart weakness or failure : hence the origin of diabetes just as of Bright's disease, in preg- nancy, associated no doubt with some absolute or relative heart failure (see case of Jane B. to be mentioned later) ; hence in diabetes just as in Bright's disease we have not only to clear up GLYCOSUEIA AND DIABETES MELLITUS 673 the primary collsemia but have also to save and strengthen the heart muscle by every means in our power. On February 26, after ten days on salicylates, urine was 1335 oc, 1034, urea 1-5 per cent., sugar 3"6 per cent. Urea to sugar 1 — 2"4. Total sugar 1-6 oz. Salicylates had here reduced the total sugar, and had also reduced it relatively to the urea, which is perhaps the safest guide of aU. She remained in for several weeks, during which the sugar was reduced to 2 per cent, or less, with the relation of urea to sugar 1 — 1'2. Patient, however, became unruly, dissatisfied and dis- obedient, possibly owing to alcohol and stimulants being cut ofi, and took her discharge. During the first part of her time in Hospital she was men- struating, and this appeared to increase the feelings of sinking and faintness, as it doubtless also lowered the acidity, produced increase of coUaemia, and also interfered with the full action of the saUcylates. Henry F., aged 54, November, 1888. — " Glycosuria and acute gout," under the care of Sir Dyce Duckworth, who very kindly allowed me to examine the urine. Urine on two days without treatment gave 2000 and 1650 cc. Uric acid to urea 1 — 48 and 1 — 33. Urea to sugar 1 — 6"2 and 1—5-9. There was here a minus excretion of uric acid with glycosuria, but the fact that the relation on the twenty-four hours was 1 — 48 and 1 — 33, is no proof that there was not considerable coUsemia for several hours during the alkaline tide of each day. After three days on salicylate the total sugar was less by 200 grs. than at first, and the relation of urea to sugar was 1 — 4'8. But the patient was now up and free from his gout, so the examination could not be carried further. The notes of his case do not say whether he had the glycosuria along with the acute gout or not. He continued to take salicylate for some time, as he said it did him good ; but he also indulged freely in beer and brandy, and this latter would no doubt aid the uric acid in pro- ducing congestion of the Uver. Jane B., aged 33, November, 1888. — Complains of weakness and languor ; drinks all day long and passes much water, espe- cially during last two months. She first noticed excessive thirst about eighteen months ago, the time of commencement of her last pregnancy. Urine pale amber, 1043, urea '6 per cent., uric acid ■02016 per cent., sugar 10 per cent. Uric acid to urea 1 — 30, 43 674 UKIC ACID — CHAPTER XIV urea to sugar 1 — 17. She was given some instructions about diet and put on alkalies and nux vomica. These did no good, and at the end of a week sugar was still 10 per cent. December 1. — She was put on salicylate, and told to try and estimate amount of water in twenty-four hours. December 8.— Urine 1040 ; sugar 9 per cent. December 16. — Passed twenty pints of urine yesterday ; thinks she has passed considerably more than this. Urine 1042. Sugar 8 per cent. Urea to sugar 1 — 12. After this sugar fell steadily to 7 per cent., with relation to urea 1 — 8*7, and she began to gain weight and get more colour. In April, 1889, during my absence, salicylate was stopped, and nux vomica and alkalies repeated ; the mixture made her worse, and she threw it away after two or three doses (it is a remark- able fact that nearly all the patients with glycosuria or diabetes say that alkalies make them worse and acids make them fsel better. The former increase, but the latter diminish coUffimia). She did not come again till August 17, when she was obviously worse — pale, feeble and with quick pulse. No urine brought ; given salicylate again. August 24, 1889. — Better and less thirst : when thirst is great nothing under two pints of water is any use. Urine to-day 1040, sugar 10 per cent. In September urine had fallen to ten pints a day, sugar 6 per cent., and urea to sugar 1 — 6 ; and at the end of this month sugar was 6'5 per cent., and urea to sugar 1 — 5"5. In October, sugar 5 per cent., and urea to sugar 1 — 5, and she got on so well that she refused to leave her children and come into hospital. The urine was reduced to less than one-half of the original amount, and the percentage of sugar to one-half also, so that the total sugar was reduced to one-fourth of the original quantity, and the relation of urea to sugar altered from 1—17 to 1 — 5. She improved and felt better in every way while taking the sahcylate, and while the sugar was diminishing she steadily in- creased in weight. She continued to attend for many months after this, and so long as she took the salicylate did well. I found that small doses of morphine increased its effect, and gave her for some time gr. ^ in pill three times a day. By this means sugar was reduced to 4'5 per cent., and on one occasion to 3"5 per cent. But unfortu- nately, in the spring of 1890 there was a change ; she again GLYCOSUEIA AND DIABETES MELLITUS 675 became pregnant, and this produced a considerable amount of vomiting ; this interfered with the taking and action of the sali- cylate, and she went rapidly down hill. She still obstinately refused to come in, and soon ceased to attend. My last note is dated October 7, 1890, when she was much weaker and worse, and salicylate had been left ofE for some time and bismuth and other treatment of symptoms made use of. As she refused to come in, in spite of all I could say, nothing more could be done, and I fear that she soon died. The case, however, illustrates well the power of salicylates in what no one probably will deny was severe diabetes ; and I have no doubt that the drug prolonged her life by at least two years^ as when I first saw her I did not expect her to Uve a month, and but for her unfortunately again becoming pregnant (which is in itself strong testimony to the improvement in her condition), still better results might have been obtained. With regard to this patient's history and the fact that her diabetes probably originated in a pregnancy, we have seen that in her last pregnancy she had considerable vomiting and then got much worse, and I think it is probable that in her former preg- nancy there was vomiting also, and the diabetes thus originated in the severe collamia and the heart failure so produced. In this case almost every word written in the last chapter with regard to the causation of albuminuria in pregnancy would apply equally well to the causation of this glycosuria and diabetes ; only in the one case the defective combustion affected the starches and sugars, in the other the albumens, and in some intermediate cases as we know it may afiect both, or now one and now the other altern- ately. I think it is not too much to say that if this patient had had normal pregnancies free from vomiting, which increased both coUsemia and heart failure, she might have been alive stUl and possibly never have .had diabetes. So that if Bright's disease is collsemia, plus cold, plus heart failure, diabetes is also coUsemia plus heart failure, both these conditions tending, as we have seen, to produce congestion of the Uver, the chief pathological change met with in diabetes. Another case is that of Winifred H. F., aged 8 years, who was admitted under my care at the Koyal Hospital for Children and Women, January 22, 1891. Complained of thirst and nocturnal urination ; pale, wasted ; weight 2 St. 5 lb. Some increase of liver dulness, and constipation. Urine 2220 cc. pale amber, 1040. Sugar 5'5 per cent., uric acid 676 UBIC ACID — CHAPTEE XIV to urea 1 — 33. (No excess of uric acid [?] due to phosphoric acid given as a drink.) Urea to sugar 1 — 5'5, urea per lb. 10"3 grs. She was put on diet ; no drugs except a little dil. phosphoric acid. The sugar fell to 5 per cent, and then to 4'1 per cent., but urea fell very considerably also, and on February 9 it was only 4'6 grs. to lb. Diet here was interfering seriously with nutrition, and though sugar fell, urea fell more ; very difEerent from what had occurred in the previous case with sahcylate (see also previous remarks on relative movements of urea and sugar). She was given some salicylate, but it unfortunately upset the stomach and made the failure of nutrition greater ; sugar and urea both falUng considerably. Her pulse on several occasions was relatively slow, showed considerable high tension and occasional intermissions. The salicylate was therefore stopped, and she was given two pints of milk and some brandy. She had previously been taking food (diabetic diet) badly : but she liked the milk and began to improve on it, and urea and sugar both increased. February 12. — When urea got back to 9 or 10 grs. per lb. and sugar to 5 per cent, sahcylate was again given in small, slowly increasing doses. Both urea and sugar, however, continued to increase, though on February 18 urea was to sugar 1 — 3'2, and on the 19th 1—3, and on the 21st 1 to 2-9, and on 24th 1 to 2-3. Salicylates now apparently caused some dyspepsia and diarrhoea and all drugs were therefore stopped, and on February 28 urea was to sugar 1 — 3'3. It looked, therefore, as if the sahcylate had had some effect in lessening the sugar relatively to the urea. March 2. — Slight rise of temperature, and sugar fell in conse- quence, the urea relation being 1 — 2'2. Salicylate was begun again, gr. vii. four times a day, but again diarrhoea followed its use and some tr. opii was given, March 4. — Urea to sugar 1 — 3'1 ; salicylate had not begun to act. March 5.— 1—3. March 7.— 1-2-3. March 12. — ^Opium stopped. Given codeina gr. I three times a day, and salicylate gr. x. four times a day, urea to sugar 1 — 2-2. March 18. — Rather more languid. Codeina stopped and liq. morph. hydroch. nix. given four times a day with the sahcylate. March 26. — Going on much the same, but there is occasionally some vomiting, and the diarrhoea has not completely ceased. Urea to sugar 1-2-2. Total urea 739 grs. or 22 grs. per lb. She is GLTCOSUEIA AND DIABETES MELLITUS 677 now taking a considerable quantity of milk and is not kept on strict diabetic diet, as it was found that she took this badly, uiea diminished, and she got into a lethargic condition, which disap- peared as the diet was improved. March 27. — Some diarrhoea again, so sahcylate and morphine stopped. March 31. — No diarrhoea or vomiting ; given codeina gr. J three times a day. April 4. — On codeina ; temperature raised to 101°. Takes badly and has some nausea ; urea to sugar 1 — 2"5 (effect of fever), but urea has fallen to 54:0 grs., 16 grs. per pound. AprU 6. — Not so well ; very drowsy, especially in the morning after breakfast, when she falls asleep and does not wake for several hours. Takes badly, some nausea. All drugs stopped, mUk in- creased to three pints, brandy 2 oz. April 9. — Better and brighter much ; takes better, but urine has increased in quantity and specific gravity. Salicylate and morphine mixture repeated. She died on April 19 (while I was away for a holiday) with some symptoms of diphtheria, and another child in the ward had a suspicious throat and was isolated. Permission for a post-mortem examination could not be obtained so the exact nature of the case remains in doubt. There was no optic neuritis, and such vomiting as occurred seemed to be the result of drugs rather than of any central cause. The only physical sign was a moderately well-marked increase of liver dulness. As to drugs, the salicylates on several occasions reduced the sugar relatively to the urea, and that without in any way reduc- ing the urea. The codeina diminished both urea and sugar {i.e., it diminished appetite, digestion and absorption) ; but the salicylate diminished the sugar relatively to the urea {i.e., it increased the combus- tion). On one occasion the codeina appeared to cause drowsiness. Diabetic diet was an absolute failure, causing a great fall of urea and producing a lethargic condition which would no doubt have been fatal if the diet had not been improved ; possibly diet was begun too suddenly. This is in complete accord with the observation of Hirsshfeld (Deiitsch. Med. Woch., June 27, 1895) that inanition is the cause of the coma in diabetes ; and my own observation decidedly leads me to agree with him, for I have in several other cases noted the approach of such conditions along with a marked fall in urea, and if I could run up the urea, as 678 UEIC ACID — CHAPTBE XIV above, by increasing the milk I appeared to bs able to ward off the coma. It has also been pointed out by Maurel (BtUl. Gen. de TMrapeutique, 1897) that milk diet wards ofi both the gangrene and coma of diabetes. In such cases it is obviously of the greatest importance to examine the urea ; anything that interferes with the taking and digestion of food will reduce both sugar and urea, but this is not a curative action. Sahcylate reduced the sugar rela- tively to the urea, and the child fully held her own while taking it. Unfortunately, however, it appeared to produce some nausea and diarrhoea. I shall also give the notes of a case in which salicylates given along with small doses of calomel eventually acted well, though at first they appeared to fail. W. H., aged 36. Admitted under my care in the Metropolitan Hospital, January 18, 1893. Complains of increase of appetite one month and increase of thirst two weeks. His father is alive and well, but suffers from lumbago and piles occasionally. His mother has " rheumatics " in the hands. He has five sisters, who are well. Patient has not had any fevers, not even the influenza. His tongue is slightly red at the tip and edges, but not specially clean. His bowels are constipated. There are no physical signs. January 19.— Weight, 92 lb. 10 oz. Put on a modified diet, gluten bread. Milk 2 pints, and imperial drink without sugar. No potatoes, bread or sugar. January 22. — Urine, 74 oz. ; sp. gr. 1035. Acid. No albumen. Sugar, 3-1 % = 1059 grs. ; urea, 2-4 % = 819 grs. ; relation, 1—1.2- January 24.— Bowels opened by mist, sennae co. Thirst is rather less. January 28. — Sodii salicy. gr. xv., with aq. menth. pip., given every six hours. Weight, 103 lb. February 1.— Urine, 58 oz. ; sp. gr. 1036 ; sugar, 3-1 % — 830 grs. ; urea, 2'6 = 696 grs. ; relation, 1 — I'll. The salicylate appears to cause some nausea, and he is not taking his food so well. Try to take the salicylate in powder. February 4.— Urine, 56 oz. ; sugar, 1-4 % = 361 grs. ; urea, 2-4 % = 620 grs. ; relation, 1—0-58. Weight, 103 lb. 8 oz. Appetite still bad, so salicylate was stopped and iodide, of sodium gr. vii., given in place of it three times a day. GLYCOSURIA AND DIABETES MELLITUS 679 Here we see again that the sugar has fallen greatly down to almost one-third of the amount on January 22, but urea has also fallen by as much as 200 grains, and we know that this was due to deficient income of food from nausea and loss of appetite, and if we add, say, 200 grs. to the sugar on this account, the relation would come out nearly 1 — I, or close to what it was on February 1. February 8. — Urine, 98 oz. ; urea, 2-1 % ^ 950 grs. ; sugar, 2"0 ;= 905 grs. ; relation, 1 — 0'95. Iodide increased to gr. x. February 10. — Urine, 80 oz. ; urea, 2-4 % = 837 grs. ; sugar, 3-1 % = 1145 grs. ; relation, 1—1-2. Weight, 103 lb. 8 oz. February 14. — Iodide left ofi, and salicylate again given in difierent form. February 15. — Uriae, 90 oz. ; urea, 2-4 % = 997 grs. ; sugar, 3-3 % =x 1372 grs. ; relation, 1—1-3. February 18.— Urine, 94 oz., sp. gr. 1037 ; urea, 2-7 % = 1130 grs. ; sugar, 2-6 % = 1088 grs. ; relation, 1— -96. Weight, 105 lb. 6 oz. February 22.— Urine, 86 oz., sp. gr. 1031 ; urea, 2-3 % = 913 grs. ;- sugar, 2-5 % ^ 993 grs.; relation, 1 — 1 (nearly). February 25.— Urine, 102 oz., sp. gr. 1036 ; urea, 2-3 % =3 1082 grs. ; sugar, 2-9 % = 1365 grs. ; relation, 1—1-2. Weight, 106 lb. Here, again, though the salicylate at first reduced the sugar relatively to urea, the improvement was not maintained. Liq. morph. hydrocHor. nxxii. was added to each dose of the mixture. March 1. — Urine, 46 oz. ; urea, 2-7 % = 572 grs. ; sugar, 1-2 % = 254 grs. ; relation, 1— -44, Weight, 106 lb. 4 oz. Here again a great diminution of sugar, but also a great fall of urea, and no doubt the salicylate and the morphine upset appe- tite and digestion and accounted for this. March 8.— Urine, 71 oz., sp. gr. 1032 ; urea, 2-0 % = 710 grs. ; sugar, 2-0 % = 710 grs. ; relation, 1 — ] . March 10.— Urine, 73 oz., sp. gr. 1024 ; urea, 2-2 % = 791 grs. ; sugar, -8 % = 287 grs. ; relation, 1— -36. Weight, 106 lb. 8 oz. Here is some improvement, and, as urea is rising, it is probably due to the drugs. March 14.— Urine, 64 oz., sp. gr. 1025 ; urea, 2-7 % = 797 grs., sugar, "5 % = 147 grs. ; relation, 1 — -19. Allowed a small bit of toasted bread twice a day. March 17.— Urine, 70 oz., sp. gr. 1023; urea, 2-4 % -= 776 680 URIC ACID — CHAPTBE XIV - grs. ; sugar, -75 % = 241 grs. ; relation, 1 — -3. Weight, 107 IW. 4 oz. March 24.- Weight, 108 lb. 8 oz. March 29.— Urine, 74 oz., sp. gr. 1036; urea, 2-4 % = 751 grs. ; sugar, 3-3 % = 1127 grs. ; relation, 1 — 1-5. Toast was left ofi and liquor pancreatious given, also calomel gr. J twice daily. April 1.— Urine, 62 oz. ; urea, 2-7 % = 773 grs. ; sugar, 2-5 % = 716 grs. ; relation, 1— -9 ; weight, 106 lb. April 11. — Has had vomiting in the morning since 6th. Urine 44 oz. ; urea, 3"5 % -- 711 grs. ; sugar, -5 % = 101 grs. ; relation, 1— -14. April 14.— Weight, 108 lb. April 19.— Urine, 54 oz., sp. gr. 1026 ; urea, 3-3 % = 822 grs. ; sugar, -7 % = 174 grs. ; relation, 1 — '21. April 22. — Has had some pain in connection with the sac of a femoral hernia ; but this has now been relieved by rest and ice locally. Urine, 52 oz., sp. gr. 1021 ; urea, 21 % = 508 grs. ; sugar, -15 % = 20 grs. ; relation, 1 — "03. April 26. — Urine, 44 oz., high colour, sp. gr. 1030 ; urea, 3"8 % = 671 grs. ; sugar, -4 % =- 81 grs. ; relation, 1 — 1 ; weight 104 lb. 12 oz. ; given claret, oz. ii. April 29.— Urine, 64 oz., sp. gr. 1019 ; urea, 2 % =. 591 grs. ; sugar, -1 % = 56 grs. ; relation, 1 — -09. May 3.— Urine, 38 oz., sp. gr., 1030 ; urea, 3-4 % --= 595 grs. ; sugar, -03 % = ? nil. Here sugar is reduced to nil, though urea is as high as at last note. Toast allowed again. Is still on salicylate, morphine, calomel, and liq. pancreaticus. May 6.— Urine, 48 oz., sp. gr. 1029 ; urea, 3-2 % =: 708 grs. ; sugar, none ; weight, 104 lb. ; liq. pancreaticus left ofE. May 10. — Quantity and sp. gr. as at last note ; still no sugar. ' May 13.— Weight 106 lb. May 19. — As sugar continued to be absent and he was going on well he was allowed to go out, taking the salicylate mixture and calomel with him. August. — Attends at the hospital every few weeks and continues the mixture and the calomel powders. Sugar remains absent, and he is quite holding his own. I think the credit of this improvement remains with the salicy- late and calomel ; the liq. pancreaticus appeared to have no effect whatever ; the salicylate and morphine also appeared to account for an improvement in March. GLTCOSUEIA AND DIABETES MELLITUS 681 As mentioned in a previous case, morptine helps tie action of a salicylate, and I believe that it may do this by keeping up the acidity, and preventing any of the uric acid, which salicylates bring through the blood, from gettiag into combination with an alkali, because it is the combination of uric acid with an alkali which affects the circulation and does all the harm to the com- bustion. And my object in giving calomel was just the same, namely, to keep the blood clear of uric acid combined with an alkali ; and calomel does this by directly combining with the uric. acid (see p. 66), and it appears from the results in this case that it helps the action of the salicylate more than the morphine does, possibly because its efiects are independent of acidity ; and under certain conditions the morphine may not be able to raise the acidity (see p. 60). Considering that in this case there was only 3'1 per cent, of sugar to begia with (though, by the way, this was on diet), I should have expected a more decisive result with salicylates alone ; but their partial failure was, I think, largely due to their being taken badly and producing nausea ; when they do this they are no use ia any case. They are also no use when there is nausea or vomitiag from other causes (see case of Jane B.). I believe because there is then so much alkaU in the blood, that a good deal of the uric acid is sure to combine with it. Still, I consider that given along with acids or small doses of morphine or calomel, the salicylates are the most useful drugs we possess for the treatment of these troubles, and they act by elimi- nating uric acid, and so clearing the blood of it. I have often seen the sugar greatly reduced by opium or codeine, but they have also appeared to me to reduce urea very considerably at the same time, while with the best action of the sahcylates urea rises. Frerichs says that salicylates reduce sugar by interfering with digestion, but in several of my cases sahcylates not only greatly reduced the sugar without reducing urea, but the patients steadily gained weight while taking them. In my paper on the use of salicylates in diabetes I mentioned that two cases had been reported as cured by them, and since my paper I have heard from others who have followed up my sugges- tions and used them with great benefit (see Dr. Mansel Sympson, Practitioner, August, 1891) ; and Dr. Brooks, of Lincoln, read a paper before the Lincoln Medical Society in 1891 On the Use of Salicylates in Diabetes. 682 UEIC ACID — CHAPTEE XIV To illustrate the possible relationship between diabetes and the uric acid headache, I will now give a few notes of the case of Edith E., aged 29, single, admitted into the Koyal Hospital for Children and Women in October, 1897. She complained of loss of weight for nine months. Abdominal pain and absence of men- struation for three months. She is the youngest of three, having two brothers older. Her father died of phthisis at the age of 47. Her mother is alive, but has always sufiered from bilious head- ache. The patient herself has been subject to bilious attacks with headache every three weeks since childhood. Her tongue is red and clean. Pulse fast, 92. The second sound of the heart is loud at the right base, but at that time I had no means of accurately estimating capillary circulation and blood pressure. The abdomen was sKghtly distended and tender all over ; there was some little pain in the left inguinal region. The liver dulness was full large but its edge was not felt. Urine on admission, 1040, passes from 80 to 100 oz. per day, containing 7 to 8 % of sugar. Unfortunately she was only in hospital for a short time, during which she was gradually got on to diabetic diet, and just as we were going to watch her carefully with a view to testing the action of drugs she went out, as her family had left London for the North of England and she wished to follow. I give the case merely for the history, and I may say that I have had another similar case in private, in which a lifelong migraine was followed, later in life than in the above case, by diabetes. A more rec.ent case of the same sequence is that of M. B., female, aged 57, sent to me by Dr. Monro-Grier, of Mevagissey. Pulse 84 ; capillary reflux 8 ; blood pressure 150. Subject to sick headaches all her lite. Has had several attacks of vertigo and one attack of temporary coma. Has both gout and rheuma- tism in her family, and her mother died of gall-stone. Urine 1028, pale amber, minute trace of albumen, and sugar 6 %. Urine 60 — ■ 80 oz. per diem. Highest sp. gr. observed, 1035. Israel W., aged 31, admitted into the Metropolitan Hospital in April, 1898. He made the usual complaints of thirst and loss of weight, and had no prominent physical signs in head, chest, or abdomen. His weight on admission was 7 st. 11 lb. 8 oz. Urine was from 80 — 100 oz. in twenty-four hours, sp. gr^ 1042, and contained from 35 — 40 grs. of sugar to the ounce. His capillary circulation was slow, his blood pressure high, and his left radial artery measured with Oliver's arteriometer 1'3 to GLYCOSURIA AND DIABETES MBLLITUS 683 1"4 mm. The first sound of the heart was long, and the second sound loud at the base and apex, the ordinary signs of rather high blood pressure, and the above arterial measurement is large, relatively, as the patient is a small man. He was put on to diabetic diet, and possibly the change was: made too suddenly, as he lost weight considerably, falling to 7 st. lb. 8 oz. in the first few weeks. This diet reduced the urine somewhat, but he was still passing a considerably increased quan- tity, containing fully 30 grs. of sugar to the ounce. He was now put on the following treatment, the alteration on to which was made gradually, and he was given salicylate of soda grs. xv. three times a day. Milk, 2 pints. Cheese, 2 oz. Mutton or fish, 2 oz. •Four* protene diabetic biscuits. Gluten bread, 3 oz. No tea or coffee, a little green vegetable with salad oil. It was my intention to have cut off all animal flesh, thus stop- ping as far as possible all introduction of uric acid, but the patient was very fond of meat or fish, and lost weight if they were further reduced or cut off. On this diet the patient quickly regained the weight lost, and the water and sugar steadily dimin- ished, so that in two or three months the urine was about 60 oz., containing about 10 grs. of sugar to the ounce, a total excretion of 600 grs. of sugar in place of 3500 grs. per day. The same treatment was continued, though he occasionally had the salicylate four times a day instead of three times, and now and again for a few weeks J gr. of calomel two or three times a day in addition. In October, 1898, his weight was 7 st. 12 lb. and steady, his urine from 40 — 50 oz., sp. gr. 1032, containing 6 grs. to ounce of sugar, and some days (six or eight in the month) only 4 grs. to ounce, a total daily excretion of sugar of only 160 grs. His condition in May, 1899, was as follows : — Weight, 7 st. 11 lb. 12 oz., steady. Urine, 40 — 50 oz., containing from 6 — 10 grs. of sugar to the ounce in spite of two pieces of ordinary bread toasted (about IJ oz. bread each) being added to the above diet. And this, I should say, has been done all along since the sugar fell the previous summer to comparatively insignificant quantities ; * Protene is the albumen of milk freed from sugar and fat, and can be obtained from "Protene," Limited, 36, Welbeck Street, London, W. 684 URIC ACID — CHAPTEK XIV when the sugar is at 4 or 5 grs. to the ounce I give him three pieces of toast, but if the sugar rises I diminish to two pieces. His capillary circulation is still slow, capillary reflux 6 — 8 ; probably it was still slower when he came in. His heart still gives the signs of high blood pressure, but also of some heart failure, as its rate is quick 80 — 90 and above, and the blood pressure is 135. He has some excess of blood granules, 1 — 9, and this was probably more marked when he first came in, but it was not recorded. The colour of tongue and gums is now fair, not much below normal, and this is probably an improvement on his original condition. Israel W. remains under my care. He was sent out for a month or two in the autumn of 1899 to see how he would get on with- out treatment, and on such diet as he could manage for himself : but he got decidedly worse and lost weight, falling down to 7 st. or slightly below it when he came back to us in December. Now, January, 1900, he has again improved ; he is back on the old diet above mentioned and is taking salicylate of soda grs. XV. three or four times a day ; with this, sugar has diminished and weight has again gone up to 7 st. 9 lb. 10 oz., but his capillary reflux is still slow and his blood pressure still raised, his pulse is - still quick and tends to quicken more and more as time goes on, and it is, I think, this progressive failure of the heart before the obstructed capillaries that drags him down and prevents his attain- ing complete combustion. This patient remained under my care till April, 1902, when he went home to Russia at his own wish. He held his own, and the last record of weight was 7 st. 9 lb. I quite think we should have done better in his case if we had been able to alter his diet completely, leaving out all meat and fish, as was done in the successful cases of Bright's disease ; and the drugs I think do not succeed or do so only with much greater difficulty even in Bright's disease if this cannot be done. This we see to some extent, at least, in the case of Mary W., and I may say that I have since been treating her as an out-patient, and having persuaded her to alter her diet she is improving more quickly, and blood pressure is falling decidedly. For contrast with the above, and as showing perhaps the original condition of his circulation, I give the notes of Fred E., aged 32, admitted under my care more recently, who is at present being slowly got on to diet and having no drugs. Urine 130 oz. and above, sp. gr. 1040 — 1044. Sugar 38 — 40 grs. per ounce. Pulse slow, 56 — 58, and the heart gives the signs of high blood pressure GLYCOSUKIA AND DIABETES MELLITUS 685 as in the case of I. W. Blood pressure 180. Capillary reflux 7 — 8, half seconds. Blood granules to red cells 1 — 4. Colour in tongue and gums is bad, probably less than half the normal, say blood decimal 'i. In suggestiag that glycosuria and diabetes may be due to a failure of combustion and a slackening of metabolism, which, again, may result from the vascular effects of uric acid, pointed out in previous chapters, I am very far from claiming that all such cases are due to uric acid. I believe, however, that the connection between gout and dia- betes is both wider and deeper than has hitherto been suspected ; and that some of the riddles of this sphinx (Frerichs, Ueber den Diabetes p. 275), may be solved by admitting provisionally the power of uric acid over metabohsm ; and by thus admitting it provisionally, we are by no means bound to forego any oppor- tunity that may ofier of putting the point to the most careful test we can devise. And the more careful and complete our tests the more evident will it become that glycaemia, glycosuria, and not a few cases of diabetes, are really due to a failure in the metabolism and combus- tion of carbo-hydrates, just as hetero-albuminaemia and albuminuria are due to a similar failure in the combustion of albumens, and that the action of uric acid on the circulation is amply sufficient to account for the failure of combustion in. both cases, and so for the fact that both may occur in the same individual (see p. 638). Then, as pointed out in an article mentioned iu the British Medical Journal, Epitome, 1896, vol. u., p. 97, and January, 1897, p. 5 of Epitome, there may be occasional excretions of a little sugar for years before there is true diabetes. And this is the exact parallel of what we see in migraine, when there is often occa- sional albuminuria for years before Bright's disease and constant albuminuria supervene ; and as before mentioned I have had under my care cases in which periodical migraine of many years' stand- ing has ended, not, as is usual, in albuminuria and Bright's disease, but in glycosuria and diabetes. It seems then that there is here between these two diseases, albuminuria and Bright's disease on the one hand, and glycosuria and diabetes on the other, a most extensive paraLeUsm — one might almost say identity — and one cannot help feeling that just as in the cases of headache and epilepsy previously mentioned there must exist below this parallelism its one possible cause — community or identity of causation. 686 UEIC ACID — CHAPTEB XIV And this common factor, the cause of both diseases, is defec- tive circulation, bringing about defective combustion, and we now see that the best and most complete explanation of the defective circulation is capillary obstruction by uric acid coUaemia, which is to be seen in every case so caused. There are also some indications that while the defective com- bustion thus produced may affect either albumens or sugars, or first one and then the other, its actual effect in any given case depends on associated conditions. When the stress of the defective circulation, as determined by other concomitant conditions, such as cold and damp, falls on the skin, we are likely to get albuminuria and Bright' s disease ; and when it falls specially on the liver and chylopoietic viscera, then glycosuria and diabetes is the more likely result. And we see such a determining factor perhaps in the hernia from which W. H. suffered. In similar cases it might be well to operate on the hernia and free the intestines from any local irritation that may be the precipitating cause of dyspepsia, coUaemia, and deficient combustion. Cases which are still functional wiU respond most decidedly to the treatment of the uric acid factor ; while those which have become organic, owing to changes in the metabolic tissues, will be afiected only to a certain extent ; and those which are from the begmning organic and due to lesions of the great nerve centres, will hardly respond at all to the treatment of uric acid. The indications for the treatment of such a glycosuria or dia- betes are to diminish the introduction and formation of uric acid, and to clear out that which has accumulated in the body. A long course of salicylates will satisfy the last indication; and if they, at the same time, remove the sugar, we ought, I think, to go gradually back to ordinary diet, and even beyond it ; event- ually reducing animal food to small quantities of milk and cheese ; and, unless we are able to do this, I beheve that relapse is often merely a question of time. As I have said, I believe that the large amount of meat com- monly given in diabetes acts as a stimulus, and therefore, just like opium or mercury, keeps the blood clear of uric acid for a time ; but like these drugs it can only do good for a short time while the stimulation lasts, as it not only does not clear the uric acid, out of the body, but, on the contrary (and in this respect it is worse than the above drugs), it steadily pours into it a consider- able quantity of this substance day by day. Whether this great excess of uric acid has anythins f rl GLYCOSURIA AND DIABETES MBLLITUS 687 ■with the coma that often ends the disease may be doubtful, and I have already made some observations on this point, showing that in the opinion of myself and others, the coma was due to inani- tion : but I am not at all sure looking to the terrible effects of uric acid on nutrition and combustion that the inanition in its turn may not be due to uric acid coUeemia ; and this would fit in very well with the fact I have observed, that a rise of urea which entails a corresponding rise of acidity generally suffices to clear ofi the inanition and the coma, for nothing clears the blood of uric acid like a rise of urea : nothing so certainly produces coUsemia and a plus excretion of uric acid as a fall of urea. And I shall have to refer again in the following chapters to the evil efiects of a pure meat diet when given for chronic arthritis, and in one of the cases there mentioned, the patient was insensible for some thirty-six hours. But be this as it may, I would make this practical suggestion, that probably the only way out of diabetes is to clear the body and blood of uric acid, and that it is quite impossible to do this while an almost pure meat diet is pouring in the xanthines in large quantity every day. The three things we have to do, now stand out quite clearly : (1) To clear out uric acid by means of salicylates ; (2) to maintain by every means in our power the nutrition and strength of the heart muscle ; and (3) to introduce into the body no grain of uric acid or xanthine which we can leave outside. I could easily give notes of further cases, but they do not show anything not also shown by the above cases. And these show, I think, that in a considerable number of cases of diabetes, a course of salicylates with the help of opium or calomel will decidedly reduce the output of sugar, and check the progress of the disease, and that where they fail it is doubtful whether anything else will succeed. Opium and codeina seem to me to labour under the fatal objec- tion that they often interfere with appetite and cause a fall of urea as well as of sugar. They cure also, if my pathology is correct, merely by clearing the blood of uric acid, and as no provision is made for its elimi- nation, this is almost certain to be followed sooner or later by a rebound, with serious or fatal efEects. So far as I have been able to watch the use of opium and codeina by others, they have not presented any advantages over salicylates, and have often appeared to me to fail in prolonging life as much as the salicylates might reasonably have been ex- pected to do. 688 UBIC ACID — CHAPTER XIV I tave never cured a case of diabetes, but I believe that if cure is to be efiected it will be by the careful following of the above indications. W. H. died later on under my care, his disease having lasted more than four years. In the intervals he had tried several hospitals and as many physicians, and he told me that nothing had done him so much good as salicylates with small quantities of opium or calomel. When he returned to me the last time his case was quite hope- less, as he had wasted very much during the last few months, and had several bedsores, showing most feeble nutrition ; and he had also some consolidation at the apex of one lung, and a trouble- some cough. Here all drugs quite failed to produce an efEect, and as in the corresponding stage of Bright's disease the fires were so low and the tissues so wasted that it was impossible to stimidate them again. Exercise may be very useful in diabetes, as shown by a case mentioned in the British Medical Journal, 1899, vol. ii., p. 104. It must be regular, not spasmodic, for though exercise at first may increase coUsemia, its steady daily use improves nutrition and diminishes collaemia. Dr. S. West published in the British Medical Journal, August 24, 1895, his experiences of the treatment of diabetes mellitus by uranium nitrate, which he thinks may act by checking the rapid digestion of starch and some forms of albumen. I have made a few experiments with this drug, and the results show very clearly the way in which it acts. It causes a distinct rise of acidity and a diminished excretion of uric acid with well being and diuresis, and these efiects are so marked that quite small doses sufiice to demonstrate them. Thus on a day when no drugs were taken, urinary water was 1520 cc, acidity 57-4 grs., and the relation of uric acid to urea 1—27. On the following day gr. iii. of uranium nitrate were taken three times a day after meals. This produced marked mental and bodily well being, the urinary water rose to 1860 cc, and the acidity to 61'2 grs., and the rela- tion of uric acid to urea was 1—38. I think, therefore, that there can be no doubt that nitrate of uranium clears the blood of uric acid and increases metaboUsm and combustion ; and like many of the drugs mentioned above dimin- GLTCOSUEIA AND DIABETES MELLITUS 689 ishes the excretion of sugar in diabetes, because it increases the combustion. I may say that I have had a patient under my care on uranium nitrate for more than eighteen months ; she is a somewhat similar case to W. H., and is at present holding her own, though the dose of the drug has had (as one would expect) to be steadily increased ; but this is obviously prolongation of life, not cure. Calcium is another drug which, taken in the form of powdered egg-shell, has been credited with curing or relieving diabetes, and from what has been said of the effects of calcium salts on p. 59 it is clear that it may also, hke the uranium salt, clear the blood of uric acid and improve combustion. I have also heard from Mr. Barker-Smith that he has known of one or two cases in which chalk has appeared to cure diabetes. I will merely say in conclusion that the facts above mentioned appear to me so strong, backed up as they now are by our power of estimating capillary circulation and combustion in all cases, and noting the effects of our drugs and treatment on these, that those who wish to do the best they can for their cases of diabetes can no longer afford to lose sight of them. I have not yet cured a case, but I have great hopes of doing so in the near future, for though small points in treatment still require adjustment, the main lines are clear enough ; and I have but little doubt that the great power of control and cure which we now have in Bright's disease will presently be equally evident in the case of diabetes. These two diseases are so absolutely and completely parallel, both as to causation, symptoms and reaction to treatment, that similar results in both are only a matter of time ; and even to prolong life for several years in a case of severe diabetes is no small matter. As regards the importance of diet in diabetes I may mention some reports I have had from Dr. A. Ghose, of Calcutta, where I understand that diabetes is a common disease, due I have little doubt to the large quantities of pulses eaten by the natives. Thus in a letter dated November, 1899, he says : " As regards your theory about diabetes it is perfectly true, and we do it here to the great satisfaction and prolongation of patient's life, though some physicians still stick to meat diet." And in a more recent letter he adds, " Now I am recommending all my diabetic patients a vegetarian diet." By which I understand that he means a diet free from pulses, 44 690 UBIC ACID — CHAPTER XIV as I had previously discussed with him the evil eSect of these vegetables ia the causation of rheumatism and stone. Dr. G. S. Keith has recorded (Lancet, 1902, vol. i., p. 589) an interesting case of diabetes apparently cured by a restricted diet, and cutting down especially the quantity of nitrogenous food stufis. His records of the case are somewhat incomplete, but ap- parently both weight and strength were regained on the reduced food, and it seems to me that it is possible that in this case the dimin- ished introduction of uric acid, which is what I always attempt to bring about in these cases, together with some diminished formation, enabled ths combustion to recover itself, and thus pre- vented the loss of unmetabohsed sugar ; and' I certainly think this is worth trying in some similar cases, but this case was not very severe diabetes, as the highest sp. gr. of the urine was only 1037. The association of excess of uric acid in the urine with nu- merous granules in the blood, and of these with slow capillary circulation, high blood pressure, low surface temperature and anaemia, is constant ; and my researches show that the uric acid is the cause, the other phenomena the results, just as Bright's disease and diabetes themselves are final or exaggerated results, of the defective combustion. The returns of the Registrar- General seem to show that this disease, like many others due to uric acid, is a steadily increasing cause of death from year to year as more and more meat is eaten. Bright's disease is only too often not recorded, and death is put down to cardiac failure or cerebral haemorrhage, when Bright's disease was the real underlying condition. But diabetes is generally recorded as such, and not under the head of its complications or results. This is no place for statistics or their discussion ; but I would advise those who are interested to look at the figures of the last thirty years and judge for themselves. The moment a man has a constant excess of uric acid in his urine, of granules in his blood, has defective capillary circulation and subnormal surface temperature, with or without high blood pressure, he is on the road to anaemia and Bright's disease, or diabetes or obesity, or a mixture of them all, in various propor- tions, as some other minor factors may from time to time determine. But if you control the uric acid and with it the capillary cir- culation, and will measure and watch the latter, and see that your control is real and effective, the above diseases, in spite of their GLYCOSUEIA AND DIABETES MELLITUS 691 difierent names with their long and respectable history, will prove that they are mere incidents of defective combustion by departing in considerable haste and confusion to those desolate regions where stimulant poisons like uric acid, xanthine, theine, cafEeine and meat extracts are still regarded as foods. 692 CHAPTER XV. Gout. Since I first discovered that in driving uric acid out of the blood while curing an attack of headache or mental depression I produced pricking and shooting pains in the joints, the explana- tion of the arthritis of gout has never seemed to me to be a very difficult matter. And when we have obtained a complete knowledge of the chemistry and solubiUty of uric acid under the conditions present in the human body, we shall have no difficulty in explaining com- pletely all the phenomena of gout. I am quite prepared to undertake to produce a uric acid arthritis in anyone, provided my instructions are carried out, but the clinical result will often resemble what is described as the arthritis of rheumatism rather than that of gout. From my point of view the arthritis in both diseases is due to uric acid, which, in acute rheumatism, is suddenly driven into a large number of joints, where, however, it remains generally only for a short time, and is then more or less completely removed ; but in gout a great part of the uric acid in the blood is (generally by the action of some external causes) concentrated on one par- ticular joint where it is not only present in greater quantity, but remains longer than in the case of acute rheumatism. I beheve, however, that it is quite possible by imitating nature to produce at pleasure an arthritis which would be called rheu- matism, or one which would be pronounced gout, by those who did not know how it was produced. If, in the arthritis called rheumatism, the uric acid is removed in the course of a few days, only microscopic lesions are produced which are quickly repaired, and leave no trace after death, but if injury, cold, or other external causes prevent the removal of the GOUT ey3 urates from one or more of the joints, they may set up and maintain an irritation in its fibrous structures which may ohtain a considerable hold on the tissues, and causing in them a marked lowering of alkalinity will bring about the retention of further uric acid in the same place, either attracted by the uric acid already there or retained because of the diminished alkalinity ; and so the local trouble enlarges and extends so long as there is excess of uric acid in the body and blood. In this way are brought about extensive lesions of structure which even after acute rheumatism are sometimes visible after death, and where uric acid has been again and again precipitated (from causes I shall pre- sently speak of) on the irritMed areas, or where these areas are constantly bathed in a blood rich in urates, changes commonly called rheumatoid are at length produced. These rheumatoid changes, when extensive, should be regarded as in part the direct effects of the irritant uric acid, and in part due to the smouldering on of the irritation it causes, so that I have been accustomed to speak of the uric acid as the fire, and the rheumatoid changes as the ruins, and obviously the treatment of the ruins is a very different matter from that of the fire. To remove the uric acid is the best treatment of the fire, but that will not rebuild the ruins. I was interested to see that in his address in the section for diseases of children at Bournemouth, Dr. Goodhart speaks very strongly as to the relationship of gout and rheumatism. Thus {British Medical Journal, 1891, vol. ii., p. 252) he is reported as saying : " In the first place I hold that gout in children is not to be discriminated from acute rheumatism " ; and further on he says : " I think in summing up what gout is we must say that under some circumstances, or at one period of its Ufe, gout is acute rheumatism." I have shown that under all circumstances and at all periods gout is rheumatism and rheumatism gout, and that while both are due to uric acid the clinical picture varies with age and other factors, the action of which can be completely explained, but I am glad to- see so great an authority as Dr. Goodhart arriving at the same conclusion from different premisses. Then again, I note that Mr. Jonathan Hutchinson says (Trans, of International Med. Cong., 1881, p. 92) that rheumatism and gout occur in the same families, and the one is as much heredi- tary as the other ; and he also says, " Thousands of specimens will be found in museums showing rheumatism only, but of those 694 UBIC ACID — CHAPTBE XV which show gout (lithate deposits) there are but few which do not show some traces of the changes characteristic of rheumatism " (p. 96) ; and on the same page he remarks that " rheumatoid arthritis is seen in children as the result of descent from gouty parents ; also a special form of iritis, especially seen in those who inherit also proneness to chilblains." There is no lithate deposit in such cases, but later on, especially if disease of kidneys comes on, then they get urate deposit. It is necessary to make these preliminary remarks, or the position I shall take in this and the following chapter would not be understood. And this position is ; that much arthritis and many irritations in other fibrous tissues are the direct local irritant efEects of uric acid, which' efEects tend to come on and increase under conditions which hinder the solubility of uric acid, and tend to diminish and get better under conditions which favour its solution and removal ; that the ultimate results depend upon the reaction of the individual and his tissues to the irritant, and that this will vary with growth, develop- ment, time of life, state of nutrition, and other minor concomi- tant conditions. In a word, any arthritis which does not react and has not reacted to conditions which would certainly affect the solubility of uric acid is probably not due to it, and only ignorance of these conditions has prevented this from being obvious long ago. What evidence have we that uric acid produces such irritation as that I am speaking of in the fibrous structures ? I have often quoted Sir A. Garrod's remarks on the effects of wines, &c., and have suggested that it was the acid in these beverages that drove the urate into the joint and produced the inflammation, of which the pricking pain is the sign ; he says (p. 245), " Where a few glasses of wine, ale, or porter quickly and invariably produce in any individual an inflammatory affection of a joint, such inflammation is of a truly gouty character ; " and in the hues preceding this he mentions how some sufierers have heat, throbbing, stifiness, and pain in their gouty joint after two glasses of port or a single glass of champagne. Now it is easy to demon- strate that champagne is intensely acid — more so than the other wines and malt hquors mentioned, and Sir T. Lauder Brunton, in the debate on my paper on " SaHcylates and Rheumatism [Pro- ceedings of the Royal Medical and Chirurgical Society, April, 1890, p. 109), mentioned a case in which champagne had apparently produced symptoms of poisoning by its great acidity. GOUT This time observation of Sir A. Garrod's furnishes also a strong argument against the idea that the cause of the irritation ia joints and fibrous tissues is the precipitation of needles of biurate, for the late Sir W. Eoberts shows (" Croonian Lectures," 1892, p. 97) tkat in solutions of a strength at all likely to be met with in the human body, the biurate does not begia to be thrown down even in glass for more than thirty-three hours, and in the living tissues it is hardly likely to deposit more quickly than in glass, while Sir A. G-arrod tells us (previous reference) that wines may produce gout " quickly " — " before quitting the dinner table." We have evidence that urate in solution produces irritation, while almost every student knows that in the post-mortem room biurate deposits may be found in joints without any recent history of pain in them, and without any sign of recent inflammation in surrounding structures. And Magnus-Levy found uric acid in the fluids of an acutely gouty joint, but no crystals. See also Drs. E. Schreiber and Zandy {ArcJiiv. fiir die ges. Physiologie, Bd. 79, s. 97) who also give other reasons for believing in the toxicity of uric acid. There can then, I think, be no doubt that these beverages acted as doses of acid more or less strong, and drove the uric acid out of the blood into the already irritated joint, and for the effects of sherry on the acidity of the urine see fig. 63 ; but all these things can be easily shown to aSect, not only the acidity of the urine, but the excretion of uric acid and the condition of the blood itself, as shown in fig. 52. Then, as mentioned by the late Sir W. Eoberts, in the above debate, Ebstein has shown that urate dissolved in phosphate of soda produces irritation and morbid change when injected into the cornea, while the phosphate alone produces none. Then again Sir A. G-arrod has pointed out (previous reference, p. 292), that the cartilages and fibrous tissues of joints have but little vascularity, and are less alkahne than other tissues, or than the blood, and if this is so we can easily see why urates should become " less soluble and more easily retained " (to quote Sir A. Garrod's words) in the neighbourhood of joints. Further, the joints in the old are probably both less vascular and less alkaline than those of the young, so that such external causes as injury or cold will more easily diminish their alkalinity in the old, and produce a local concentration of urate and a gouty arthritis. In the young, on the other hand, the efiects of local cold or, 696 UEIC ACID — CHAPTEE XV injury will be less, the alkalinity will be better maintained, and it , will only be when general causes act all over the body, such as severe chill and wetting during perspiration, that the alkaUnity o^ all the joints will be reduced at once, and the more general arthritic of acute rheumatism will result. Hence the joint irritation pro- duced by urates tends to be general and acute in the young Fia. 62. — CUBVBS OF THE EXCBBTION OF UBIC AcID IN Goni AS PUBLISHED IN St, Bartholomew's Hospital Reports,- 1888. (acute rheumatism), local and subacute or chronic in the old (gout). With regard to the action of acids, I have produced pricking and shooting pains in my own joints many scores of times, when using them to remove the uric acid headache or mental depression (see also remarks on fig. 63), and in a case of gout under the care of Sir Dyce Duckworth in St. Bartholomew's Hospital, where he kindly allowed me to examine the urine, I was able to show {St. Bart. Hasp. Reports, vol. xxiv., p. 217) that every time the acidity GOUT 697 rose the uric acid fell below the urea (relation 1 — 45 or 1 — 50, a great retention of uric acid), the temperature tended upwards and the pains increased and became severe, and conversely whenever the uric acid was above urea (relation 1 — 24, excretion in excess of formation) — whether this result was produced by saUcylates or alkahes — the pains diminished or ceased, and the temperature subsided. As back numbers of St. Bartholomew's Hospital Reports are not very widely available I reproduce here one of the figures of the above paper as fig. 62. From this we see that on May 27, with a high rise of acidity, uric acid was below urea and temperature at night was 101"6°. On 29th with a fall of acidity uric acid was close to urea, and the evening temperature only rose to 99'6°. On 30th and 31st with rising urea and acidity there is some increased retention of uric acid, and the evening temperatures reach 99-8° and 100-2° respectively. On the 1st and 2nd of June the uric acid is rather nearer urea and the temperature is more steady and below 100° aU day. On the 3rd, 4th, and 5th, again ,with rising urea and acidity uric acid is again retained, and the evening temperature rises on the 3rd and 4th to 101° and 101-2° respectively. On the 5th, however, as the pains were bad saUoylate of soda was given in the dose of grs. 15 four times a day, and this came in time to reheve the pain, which it did as the patient said soon after the first dose, and to keep down the temperature on the evening of the 5th to 99-8°. On the 6th uric acid was considerably nearer urea, and the temperature again only reached 99-8°, and on the 7th the uric acid was 3J grs. above urea, and the temperature only reached normal in the evening, and in the following days fell below it, the irritant urate having for the most part been removed from the tissues. But very few words are required to emphasize the very con- stant relation here seen between retained uric acid and rising temperature (and with the temperature there was always pain), and excreted uric acid, reUef of pain and faUing temperature. No doubt the temperature at the beginning of the figure was due to some retention which we do not see before it, and this was merely reinforced by the retention on 27th. For the rest, considering that probably no collection of urine or estimation of uric acid ensures absolute accuracy, the correspond- ence is really remarkable. 698 UEIC ACID — CHAPTER XV I tope that anyone who is still sceptical about the effects of acids in gout will look at the curves given in fig. 62, and will then try acids on themselves, or any gouty patient who will consent to the experiment, and I am confident that the results will remove all doubts ; and for a similar observation in an attack of gout see chnical note by Dr. Lyddell, Lancet, 1893, vol. ii., p. 631. For the other figures, which all show the same thing, that tem- perature rises with low uric acid and falls as salicylates produce a plus excretion, I must refer to the original paper. These results of mine were obtained twelve years ago, and with the much, but very unjustly, abused Haycraft's process, and I have therefore been most interested to see that a recent observer. Dr. Chalmers Watson, working with a different process, has obtained results which are identical with my own. He pubhshed his results in the British Medical Journal, 1900, vol. i., p. 10, and in the table I. on p. 12 we see the following figures : — On May 31 the patient was put on pot. iod. and sodii sahcyl. aa grs. x., and with this treatment we get relatively small excre- tions of uric acid and large excretions of urinary water, for naturally the retentive action of the large dose of iodide would overcome the excretive action of the small dose of sahcylate, and the water as usual moved in the opposite direction to the uric acid. On June 13 these drugs were discontinued and the patient was left without any, being on a mixed diet. And what I have spoken of as a rebound then took place, the uric acid increasing and the water diminishing, and with this no doubt there was considerable colleemia with slow capillary reflux, raised blood pressure and its results. The lowest water was 936 cc. On 16th and 17th, however, the uric acid dimiaished in relation to urea, the water ran up to 1515 cc, and with this the temperature rose for a few hours just above normal, having been below 98° with the large excretion of uric acid and the low water on the 16th. It will be noted how, when we have the key, all the facts fall into place. I could not possibly have produced results to illustrate the laws I have expounded in the previous chapters better than do these figures of Dr. Watson's. On the 18th uric acid again rises in relation to urea, and water falls to 1015 cc, and, with this, temperature is not above normal on the evening of the 17th. On the 19th uric acid again falls in relation to urea, water uuuT Day uses to 1285 cc, and temperature on evening of 18th reaches 99-6.° On the 20th uric acid falls still more markedly in relation to urea, the water rises to 1440 cc, and the temperature rises on the evening of 19th to 101.° With this we are told that the pains reached their maximum m the early morning of 20th, and in that day either two or three doses of sodii sal. grs. xx. were given,* and the very acute pain disappeared on the afternoon of 20th. The urine of the 20th also showed a very marked rise of urea which then reached the highest level in the table, and this no doubt was the result of the free capillaries and active combustion of the evening of the 19th when the blood was nearly cleared of uric acid, and when, had it been examined, but few granules would have been found. And now see the effect of the sahcylate ; the uric acid rose greatly in relation to urea, the water fell to 775 cc, the lowest excretion in the whole table, the pains were relieved on the night of 20th, and the temperature fell next morning to 97-6,° the lowest temperature in the chart, this coinciding, I remark, with the largest amount of uric acid in the blood and the greatest number of granules in the blood (see previous records of " Effects of Sahcylates on Blood Granules," p. 97). The uric acid maintained a relatively high position on the 22nd also and the water only rose to 815 cc, so that the salicylate no doubt continued in action part of the following day ; and though the temperature in the morning was not so low and the uric acid in the blood less, it is clear that the drug had cleared out most of the urate and broken the back of the attack. It must be evident how almost every law I have propounded is illustrated in this table : how with high uric acid we get low water, low or falling urea, and low or falling temperature ; all corresponding no doubt with the skin sign of coUsemia — a slow capillary reflux. On the other hand, with low uric acid we have high urinary water, high or rising urea, high or rising temperature, again no doubt corresponding with the skin sign of absence of coUsemia — a quick capillary reflux. And we have produced all these changes ourselves, and know * In the table we are told that it was given twice, but in the notes below it three doses are mentioned, at 12.15, 5.30 and 8.30 p.m. 700 UBIO ACID — CHAPTEB XV exactly how and why we produced them in the cases of Bright's disease and diabetes, recorded in previous chapters. There as here, as the blood was cleared of uric acid and the combustion improved, the temperature rose from subnormal to normal or shghtly above it. Indeed, I may say in passing, that I beheve the normal tem- perature of a person who is as free as possible from uric acid coUsemia is above 98-4° and more like 98'8°. Those who refer to Dr. Watson's table from which I have been quoting will find that the figures of the relation of uric acid to urea do not correspond with those I give in this book. His lowest uric acid is 1 to 76, and his highest 1 to 32. My lowest is above 1 to 50 and my highest 1 — 15 {i.e., in the patient whose gout attacks are recorded in fig. 62). The difference is due to the different process used for the esti- mation of uric acid : Dr. Watson might say that Haycraft's process estimates uric acid too high, and I might reply that the process he used estimates it too low ; but when this had been said we should not be any better off ; and what I want to point out here is : that the large and important fiuctuations of uric acid come out quite clearly with almost any of the processes now in use, and that for that matter I could have told nearly everything that happened to this patient from the excretion of water alone ; that I could have told the water from the temperature, or the tempera- ture from the water, and the uric acid from either ; and that so far from its now being necessary to use elaborate processes for the estimation of uric acid, anyone who is provided with a ther- mometer, or even with the point of his finger and the second hand of his watch, anyone can now teU correctly all the chief fluctua- tions in urate excretion recorded in this table. The capillary reflux is a quite satisfactory guide to the quantity of uric acid in the blood, or the blood itself can be drawn and examined ; so that for clinical work it is rarely or never neces- sary to waste time and trouble in the collection and estimation of the uric acid ia the urine. Some of Dr. Watson's conclusions I am unable to understand, and they scarcely seem to me to be in accordance with his facts. Thus he says (previous reference, p. U), " The alkalinity of the blood is not diminished during the attack," which is probably equivalent to saying the acidity of the urine is not increased during the attack. But in fig. 62 the acidity of the urine is high or rising each time the temperature rises, and in Dr. Watson's table the excre- GOUT 701 tion of PjOj is stated as 3"14:4 grains on the day that uric acid is relatively low, corresponding to the temperature of 101° on June 19 ; on the previous day the PaOg was only 1'745 grains. Then he says, " The excretion of uric acid is not diminished by the attack, but the reverse." The only ground for this statement, which is diametrically opposed to my results, and also as it seems to me to his own, is that Dr. Watson appears to date the attack in his patient from June 17, when there was a slight rise of temperature in the mormng, but it was again subnormal in the evening ; whereas the real attack and the great rise of acidity and diminished excretion of uric acid were not tiU the evening of 19th, and everything corresponds with this, namely, the rise in urinary water and the rise of urea as already pointed out. Then in fig. 62 we see that the further uric acid] falls below urea the higher is the temperature ; the absolute height of uric acid has but little to do with it, though it is always far lower absolutely in the attack than when salicylate cures it. His last conclusion is, " The amount of uric acid in the blood is not greater during the attack than in the interveniag period." With this I quite agree, but it is an under-statement of the facts, for there is far less uric acid in the blood during the attack than before and after it. This is shown by the excretion of uric acid in the urine which Dr. Watson gives ; it is shown by the temperature during and after the acute pain ; it is shown by the urinary water, and it would 'certainly have been shown by the capillary reflux and the blood granules had they been examined. In fig. 62 it is shown by the relation of uric acid to urea at the time of the raised and subnormal temperatures respectively, and in Dr. Watson's own chart the lowest temperature of aU was clearly due to the excess of uiic acid in the blood which the saHcylate occasioned. As I can only admit one of his three conclusions, I cannot of course foUow his final point which is dependent upon them when he says, " If these points be accepted we must start de novo in search of the cause of the acute paroxysm." To my mind the cause has been staring me in the face these twelve years, since I got the results shown in fig. 62, and it seems as I have said, to be just as clearly visible in Dr. Watson's own figures as in mine. Let those who wish start de novo as much as they please, but meanwhile I have almost absolute power either to produce or 702 URIC ACID — CHAPTEE XV relieve the acute paroxysm, and by means of the water, urea, tem- perature, capillary reflux, and blood granules, can watch every change as I produce or control it. In Dr. Watson's case the attack was due to the uric acid introduced in mixed diet or thymus ; but the idea of watching the efEect of feeding thymus, while keeping on a drug like iodide, that prevented excretion, is rather original, and no possible con- clusion could be drawn as to the amount of uric acid or xanthine in the thymus. When the iodide was left off, the uric acid previously stored rushed into the blood, lowering the excretion of water, and pro- ducing, as we see on June 15 and 16, a subnormal temperature. While this was the state of affairs some acids, or acid-forming food in the mixed diet, ran up the acidity of the urine (as we see), diminished the alkalinity of the blood and its solvent powers for uric acid, and the urate being driven into a joint, the rise of temperature, the pain and the diuresis were the natural results. I have produced and seen the production of scores and scores of practically identical results, and my general laws suffice, as I have shown, to explain every fact in the record. In reference to physiological relations I would point out that the attack of gout commonly occurs at night during the acid tide, when the excretion of uric acid is at its lowest, and during the course of the attack the pains are always worst and the tempera- ture highest at night. The curves in my paper above referred to show this well. Sir A. Garrod (previous reference, p. 42) quotes" from Sydenham's description of the attack in which the hour of onset is mentioned as 2 a.m., and on p. 44, still quoting from the same authority, we find this statement : " One thing, however, is constant — the pain increases at night and abates in the morn- ing." I hope that no one who has followed my reasoning will have any difficulty in understanding the meaning of this. It is in absolute accord with my statement, that the excretion of uric acid is inversely as the acidity, and that when uric acid fails to be excreted, it is retained in the joints and irritates them. As regards season, Sydenham's account is equally emphatic. He says (p. 42) : " Towards the end of January or the beginning of February suddenly and with scarcely any premonitory feehngs the disease breaks out." That is to say, at the very coldest season of the whole year, when, as I have shown, the acidity is highest and the excretion of uric acid least (see p. 31). But indeed, the whole of Sydenham's description can be easily GOUT 703 explained in terms of uric acid excretion by anyone who is con- versant with it. Thus he says (same reference, p. 42) : " But a few days before this (that is the attack) torpor comes on and a feeUng of flatus along the legs and thighs." This means a slight fall in acidity (no doubt due to the stomach derangement he speaks of as a forerunner of the attack), a plus excretion of uric acid, and its excess in the blood causing " torpor," or as I have described it, mental, metabohc, and general depression( see also previous remarks on Dr. Watson's case). Then see what happens ; he goes on : " Besides this there is a spasmodic afEection, whilst the day before the fit the appetite is unnaturally hearty. The victim goes to bed in good health and sleeps," and at 2 a.m. is roused by the pain. We have seen that there was dyspepsia with fall of acidity and coUaemia with " torpor " as its sign. Then the stomach im- proves : " the appetite is unnaturally hearty." Up go urea and acidity at a time when the blood is highly charged with uric acid, and the natural result is that it is driven into the joints, and this occurs just at an hour when the acidity has been rising for some time and is nearly at its highest point. We can now see all our factors quite clearly, almost as well as if we had produced the attack ourselves. (1) Dyspepsia pro- ducing a fall of acidity and coUsemia. (2) Improvement of diges- tion and appetite raising acidity and driving the uric acid out of the blood into the joints. Can anything be more simple ? and this sequence can be imitated at pleasure to any required extent. But it is only by acting on a natural or artificially produced coUsemia that arthritis can be caused ; when there is no uric acid in the blood we cannot drive it into the joints : hence as we shall see all treatments by drugs, salts (sulphates, &c.), mineral waters, or pure meat diet, which stimulate nutrition and combus- tion, and keep the blood free of uric acid for a time by doing so, do for such time also keep off arthritis ; and conversely the worst conditions for chronic arthritis are those where joints are already irritated, and a constant supply of urates in the blood keeps up the irritation. With regard to pure meat diet, all uric acid absorbed in the intestines has to pass the liver, and as we have seen, a large nitrogenous metabohsm means high acidity of the Hver, and high acidity of the liver means retention of every grain of uric acid that comes to it (see uric acid filter experiments, p. 177). Thus in spite of large introduction, a pure meat diet keeps the 704 UEIC ACID— CHAPTBE XV blood clear of uric acid, and so long as it does so arthritis cannot be produced. The moment that stimulation and acidity fail, however, the acidity of the liver falls, and then there is a correspondingly large rush of uric acid into the general circulation, and this is no doubt what also occurs when morphine, mercury, iodides, and other retentive drugs are suspended. In connection with this causation of arthritis, I was much interested to hear Dr. OUver, of Harrogate, say at a meeting of the British Balneological and Climatological Society in April, 1896, that in olden times he had often seen gout flare up in patients coming to Harrogate, as it was then the custom to put them in hot immersion baths, and these seemed to develop the gout attacks : and I hear from Dr. D'Oyly Grange, of Harrogate, that some patients stiU have acute gout on first coming there, and this is, no doubt, due to the salts and sulphur in the Harrogate water ; but if a gouty patient is put into a hot bath, which acting Kke the Turkish bath (in fig. 72) is sure to flood his blood with uric acid, then the Harrogate water will be almost certain to produce an attack of gout. Why does gout come in January and February ? (1) Because during part of November, the whole of December, and January the weather is cold. This diminishes the excretion of acids in perspiration, and keeps the acidity of the uiine high (Sir A. Garrod) and the alkalinity of the blood low ; hence, during this period, the excretion of uric acid falls short of its formation and introduction, and it is retained and accumulated in the body, the opposite condition to mental depression and at the opposite end of the year (see fig. 4). (2) When, at the end of January, dys- pepsia lowers the acidity for a day or two, there is a large store of uric acid in the body which is at once washed out into the blood, producing intense coUsemia with " torpor " as its sign. (3) On this supervenes a sharp rise of acidity which quickly clears the blood of uric acid, driving it into the joints. (4) Daring the " good health " of the day before the attack the patient has probably taken a little extra exercise as well as a little extra food, and during the exercise he has produced a little warmth and diminished alkalinity in some of the joints of his feet. This has not subsided when the rising acidity of night not only pre- vents its fall, but increases it. Hence, at 2 a.m., certain joints in the feet are the least alkaline structures in the body, and the whole, or nearly the whole, of the uric acid in the blood is con- GOUT 705 centrated upon them, a uric acid filter is here set up, and acute pain and inflammation result. The whole thing is a fluctuation in the excretion of uric acid, which, as I have said, can be imitated to any required extent. In experimental work a gout attack can be produced by acids or any drugs which directly or indirectly raise the acidity or other- wise interfere with the solubility of uric acid. But these drugs will not produce an attack unless there is plenty of uric acid in the blood for them to act upon^ so that the mere fact that an acid or a dose of mercury, nux vomica, &c., has been taken without producing any pain proves nothing. If you are going to produce an experimental arthritis you must first bring a quantity of uric acid into the blood in solution probably with a salt of potash or soda, and then administer some of the drugs which wiU interfere with its solubility and drive it into the joints and fibrous tissues ; this is what invariably occurs in nature, otherwise an attack of gout or rheumatism does not result. A rise of acidity or the taking of a drug which causes retention when the blood is already free from uric acid naturally produces no result. From what has been said, it must be obvious that an acid may fail to produce an attack of gout for several reasons. (1) It may fail to be absorbed from gastric irritabihty (nausea, vomiting, &c.), or it may irritate the stomach, and prevent its own absorption and that of food also, and so lower rather than raise acidity. It is specially hkely to do this when given too concentrated, or in too large a quantity at one time. (2) When absorbed it may be overpowered by alkaline salts of potash or soda present or produced from other sources (as debility, perspiration, &c.). It is always necessary, therefore, to see that an acid given raises the acidity of the urine. (2) There may be no uric acid in the blood owing to its previous removal by a course of salicylates or other solvents, and then there is obviously nothing for the acid to act on, and no gout results. I notice that Dr. Lufi in his Goulstonian Lectures (Lancet, i., 1897, p. 1070) objects to my statement that diminished alkalinity of the blood causes retention of uric acid in certain tissues, and he then goes on to speak of the solubilities of sodium biurate. But why trouble about sodium biurate ? I should acknowledge that the uric acid if long retained may eventually become sodium biurate, but we have to deal with it at the time it is in the blood, when according to the late Sir W. Eoberts it is a quadriurate ; ior acids diminish and alkalies increase the excretion of uric acid 45 706 UEIC ACID — CHAPTBE XV in the urine from hour to hour, almost from moment to moment, • and the presence of more or less irritation in some fibrous tissue is a frequent concomitant of the diminished excretion in the urine ; but here we are dealing with uric ucid as it is in the blood and tissue fluids, and that it eventually becomes a biurate when deposited in the tissues is a matter of no consequence. All the uric acid with which I am concerned in this book probably exists as uric acid or a quadriurate, either in solution or in colloid form ; and only in this and the next chapter have I to deal at all with the biurate of sodium, and that only aper the arthritic irritation has been produced. For we often see the biurate plastered over joints and not causing an atom of irritation (see also my reference to Pfeifier's experiments on himself m chapter xvi.). When uric acid is being retained in the body by the action of an acid it is as a spherical or colloid urate, but still in suspension and non-crystalline. And when uric acid is being excreted in excess as the result of taking an alkah, this alkali meets with it in the blood or tissues, -probably as uric acid or a quadriurate (see Mordhorst's results quoted on p. 187). Now, the late Sir W. Eoberts tells us (" Uric Acid, Gravel, and Gout," p. 86), that the acid urate of sodium is not thrown down from a solution of quadriurate in serum till the second or third day, and it seems probable that in the living tissue fluids it will take even longer than this. But Sir A. Garrod tells us in the passage already quoted above, that " a few glasses of wine, ale or porter quickly — pro- duce," &c., and we see in fig. 66 that the arthritic pains were very marked within an hour after swallowing the dose of acid ; obviously then the arthritis could not be dae to deposition of the biurate, but was probably due to retention of uric acid either in solution or more probably in colloid form, and this is what I have been suggesting for years past in previous editions, not deposition, but retention. And if this is correct we have here probably one rather impor- tant difierence between the arthritis of gout and that of acute rheumatism. In acute rheumatism the arthritis is often only a matter of a few hours, for even if it continues, the irritation may leave one joint and go to another, proving that the urate is soluble and can be moved from place to place. And this alone is a very powerful argument against Dr. Luff's contention that the biurate is the cause of the irritation in gout ; for in gout we have the biurate GOUT 707 deposited without any sign of irritation round it, and in rheuma' tism we have very severe irritation without any biurate deposit, or time for it to be deposited. And this is almost certainly due to something more soluble than the biurate, which has not had time to be deposited : hence in acute rheumatism there is but a passing inflammation similar to that in gout of the fibrous tissues as described in chapters xvi. and xvii. and in fig. 74 ; and here the soluble urate is all taken up again into the circulation, and leaves little or no deposit of acid urate behind it (see also chapter ix.). In gout, on the other hand, the urate is not only present in greater quantity in the one joint afiected, but it remains longer, and so the biurate is deposited, and this may go on for some time attracting other urates to it as long as the blood is rich in urates, so that the tophus grows steadily larger and larger. Here we have undoubtedly to deal with the biurate, and have to consider its solubility in any attempt we may make to dissolve and remove it. But here again the chemical facts are not nearly so difficult to reconcile with cUnical experiences as some appear to beheve. Thus the late Sir W. Roberts tells us that the biurate is not entirely insoluble in blood serum, and again he says (previous reference, p. 108), " The solvent relation of the bodily fluids to the material of gouty deposits is simply a question of saturation or subsaturation. If the lymph or synovia at a certain spot became saturated or rather supersaturated with sodium biurate, precipitation of that substance will inevitably take place into the contiguous fibrous tissues. And if after such an event the lymph or synovia recover their purity and become approximately free from biurate, as in due course usually comes about, a process of slow resolution will of necessity set in." Now this is very interesting, and it explains a clinical experi- ence of mine that one often appears to get more benefit as regards the clearing up of old gouty troubles, from several short courses of salicylates with pauses between them, than from a single long course ; and each time one starts fresh, one gets a large excretion of uric acid, though towards the end of the previous course it had been but little increased. And the results given in my curves show that the effect of leaving ofE salicylates after some days' administration, is a great fall in the excretion of^uric acid in the urine, which is thus for some days considerably below its normal relation to urea, and it 708 UEIC ACID — CHAPTEB XV seems probable that during these days the lymph is in a condi- tion of subsaturation and some resolution of biurate deposits con- sequently occurs. Again, and this is a matter of the greatest interest, Sir W. Roberts shows (previous reference, pp. 79 and 80) in his experiments, that the biurate is comparatively soluble in water, and that the solvent power of serum or a sahne solution increases as the percentage of saHne it contains diminishes. And it follows from this that a blood which is watery and poor in salines, is a much better solvent of biurate deposits than a blood which is concentrated and rich in salines. And this is exactly what we find in nature, for as I have been pointing out over and over again in the previous chapters (see p. 256 and elsewhere), it is in the old, feeble, debihtated and water logged, that we get a constant excess of uric acid in the urine, and what appears to be a comparatively rapid removal of biurate deposits from gouty joints, soon leaving httle but erosion to mark the place where they were. Now, as we have seen in previous chapters, the mere presence of an excess of uric acid in the blood makes it dilute and watery by diminishing the outflow of water from the kidneys, so that wo get in chlorosis, as Dr. Jones has pointed out (see chapter xii. p. 561), not only a lowering of the blood decimal but a fall in the specific gravity of the blood. And the same in Bright' s disease, when there is retention of water and dropsy, the blood (as in the case examined in chapter xiii., p. 624, for instance) is poor and watery, and contains but a low percentage both of haemoglobin and cells. And this is not all, for in conditions of weakness, debility and emaciabion, we get low nutrition and slackening of digestion and metabolism in general, and as a result of these, very low excre- tion of urea per pound of body weight. But the urea is the index of the breaking up of albumens and albuminous tissues, and while the nitrogenous portion of these goes to prodxice this urea, their salts and acid-forming radicles no doubt furnish the corresponding saline constituents of the blood and urine, and hence, as I have shown, the acidity of the urine varies up and down with the urea. Therefore, in conditions of debility, wasting, and especially if there is dropsy, we have two very powerful conditions tending to make the blood and its serum watery and poor in sahnes, and this will, as we have seen, directly increase their power of dis- solving biurate deposits. GOUT 709 Again, it is not to the point with regard to the large excretion of uric acid in the urine produced by the administration of alka- lies or the diminished excretion produced by acid and acid salts, &c., to show that the solubihty of the biurate is not increased by alkahes ; for in all physiological conditions, and probably in all pathological ones also, with the exception of gout and rheumatism of some standing, we have to deal only with uric acid, or a urate of which the solubilities are as we know very diSerent from those of the biurate, and which do, comparatively easily, pass into solu- tion in combination with an alkaline base, and are also precipi- tated from such solution by an acid which takes the base from them. In so far as alkalies and their administration afiect the solu- tion and removal of biurate from the tissues, their first eSect is no doubt to remove uric acid or urates and ehminate them from the body, and if this, as in the case of the salicylates above men- tioned, causes subsaturation of the blood and tissue fluids, then some biurate is taken up from the deposits. Hence the ehmination of gouty deposits by the administration of alkahes is probably, as the late Sir W. Roberts points out (previous reference, p. 129) a somewhat slow process : though in taking his estimate of their efiects we must make allowance for the constant daily introduction of uric acid or xanthines in food, which was probably, in the case he is speaking of, neither pre- vented nor allowed for. And when introduction is prevented, as I constantly aim at doing by diet, the subsaturation of the tissue fluids is increased and the resolution of biurate deposits accelerated. Again also, it is little to the point to show that salicylates have but small effect on the solubility of the biurate, for both in physiology and pathology, when they cause a plus excretion of uric acid, they have to deal probably entirely with a soluble urate ; and if chemistry is correct they apparently have the power in conditions obtaining in the living human body of splitting this up into its constituents, and combining with only one of them, the glycocoll ; and this power has, as I have pointed out in chapters ii. and iii., some relation to the salines in the blood and the acidity of the urine in relation to urea, and cannot therefore apparently be exercised in dogs. Other things which interfere with the solubility of uric acid (such as iron, lead, mercury, lithia, zinc, manganese, calcium, &c.) may also produce an attack of gout, but compared to acids they are rarely met with in nature, and are not generally so powerful 710 UEIC ACID — CHAPTEE XV in action, because a good supply of alkaline phosphates or other allialine salts easily prevents their producing much retention. Still at night, when the acidity is high, they produce a little or increase any pain that is present. Of iron salts, Sir A. Garrod says (p. 383): "These prepara- tions, when indiscriminately given to gouty subjects, are apt to excite paroxysms of their disorder, and are, for the most part, contra-indicated." That lead precipitates gout attacks is so well known that I need hardly quote anything concerning it, but Sir A. G-arrod has shown that gout is much more common among those exposed to lead, such as plumbers and painters. He also pointed out that uric acid is almost invariably present in the blood in cases of lead poisoning. I would remark, in passing, that it is during the secondary action of lead that there is coUsemia. Its primary action is, as I have shown, to diminish the solubihty of uric acid, to bring excretion below formation, and to retain it in the body, and at this time there is little or none in the blood. Then, when from dyspepsia or intestinal pain (due to urate of lead in the intestinal walls, see pp. 452 and 456), the urea and acidity fall, the retained uric acid is washed out into the blood stream, and coUssmia with slow high tension pulse accompany and follow the lead colic. If my researches are correct, the slow high tension pulse which is often very marked in plumbism may be taken as proof positive of the presence of excess of uric acid in the blood, and the pulse can be quickened and its tension reduced by drugs that act on uric acid, and they may produce gout when so acting. Again, I have in my own case often produced (as it is easy to do) both the primary and secondary action of lead. As to mercury, I have shown that its administration brings the excretion of uric acid below the level of formation (British Medical Journal, 1890, vol. i., p. 1241 ; also fig. 17, p. 67), and clears the blood of it, producing mental well-being, free capillaries, and quick low tension pulse and diuresis, all results of the free capillaries. It also resembles lead in that it produces in my own person at least some intestinal pain of a griping character. Sir A. Garrod says of it (p. 236) : " It is a well-established fact that metallic impregnation is capable of inducing pains in the extremities, which bear a close resemblance to those of rheuma- tism." Artificers exposed to mercurial vapour often sufEer from what is termed " neuralgia mercurialis." GOUT . 711 With regard to lithia, I must refer to wkat I have said of its action on p. 57. My results show that it diminishes the excretion of uric acid, and at the same time frees the capillaries and quickens the pulse, causes mental well-being, and a free flow of urine, and when it does all this it generally causes, hke lead and mercury, some pricking and shooting pain in the joints also. Now the mineral waters containing sulphates spoken of in the previous chapter as curing glycosuria and diabetes, and as doing this by clearing the blood of uric acid, are many of them, strange as it may seem, useful in the treatment of gout also. Now, they cure the diabetes by clearing the blood of uric acid and allowing cornbustion to improve, and we should expect that in doing this they would produce more or less arthritis, and this is exactly what we find to be the case ; still, nevertheless, they do some good for gout, because once this first arthritis has passed over they tend to keep the blood free from excess of uric acid for some time, and in this way keep ofi attacks. But, unfoitunately, the first arthritis does not always disappear and the blood is not always kept constantly clear of urate, but it fluctuates back and forwards; in this ease a patient may come to the spa walking but leaves it on crutches. This result varies with the conditions present in each individual patient, with his strength, his nutrition, and above all with his digestion. If digestion is good the stimulation will succeed, the blood will be cleared of uric acid, and the smouldering arthritis will come to an end, as the joints are no longer bathed in uric acid. If, on the other hand, digestion is feeble the blood will not be completely cleared of uric acid, there will be collaemia with fluctuations, and the arthritis will continue or increase. It is by clearing the blood of uric acid that a large number of drugs (as iodides, salts of calcium, cannabis indica, lithia, guaiacum, other resins and compounds of sulphur, such as the troch. sulph. co. of Sir A. Garrod) act in relieving chronic arthritis associated with debihty and almost completely free from febrile temperature. These troubles are due to the fact that there is chronic coUsemia, and a very Uttle rise of acidity, such as that which occurs every night, tends to drive almost every evening a little more urate into the joints, and keep the irritation smouldering on, but if any of the above-mentioned drugs can keep the blood relatively free from uric acid, much of this chronic irritation may be prevented ; but these drugs also when first used may make the pains worse for a day or two. 712 UEIC ACID— CHAPTER XV This is exactly the condition (chronic arthritis associated with debility) in which saUoylates will do no good, and may even, as we shall see in the next chapter, do harm. Exactly the same thing holds with regard to the mineral waters which contain sulphates ; the patients arrive at the spa with a considerable quantity of uric acid in their blood, and the sulphates drive this into their joints and produce an arthritis, and I believe that at several such spas the physicians are in the habit of telling their patients that this first attack is a sign that the water is going to do good. And this is quite true, for once the first attack is over the sulphates keep the blood relatively clear of uric acid, and thus prevent future attacks for some time. And they produce these results (1) by clearing the blood of uric acid, and (2) by the increase of metaboHsm and combustion which results from this, and which, as we have seen, cures the diabetes, and the result of this upward metabolism is that the fires of life in this patient burn for a considerable time both brighter and better, acidity of urine remains high, alkalinity of blood low, and the blood is kept relatively clear of uric acid for some months, so that there is no arthritis. Indeed, it is obvious that so long as the blood contains no excess of uric acid an arthritic irritation (uric acid filter, see p. 177) cannot take up much urate from it. But let the patient leave ofi the drug or the mineral water, and when after a few months his combustion has come down again he will again have colliemia, and each rise of acidity will then increase the irritation of his joints. In this way the cure of the arthritis is not permanent, but has to be repeated from year to year ; indeed, there is obviously no cure for these diseases but such alterations of diet as limit the introduction and formation .of uric acid, and, at the same time, provide for its steady and continual elimination, thus gradually removing the quantities previously stored in the body. Speaking generally, it may be said that aU the diseases in the preceding fourteen chapters may be cured by such a drug as the iodide of mercury, which clears the blood of uric acid, but that this drug, or any other acting like it and removing the collaemia, may, in doing so, very probably produce arthritis (as we shall see in the cases recorded in the next chapter), but if it does not produce arthritis at once, then its continued administrabion will keep the blood clear of uric acid, and, for a time, prevent arthritis ; GOUT 713 such drugs can, in fact, produce arthritis only when they find a quantity of uric acid in the blood on which to act. On the other hand, it is nearly always possible to produce an arthritis by giving a solvent of uric acid, such as an alkali ; thus, if some bicarbonate of soda is taken in the afternoon, this brings a little extra uric acid into the blood provided there is an available store, and when the ordinary evening rise of urinary acidity (or fall of blood alka- linity) supervenes upon this, there is pricking and shooting in the joints ; but this would not have occurred if the alkali had not been taken, because there would have been less uric acid in the blood — so little, in fact, that the rise of acidity would have pro- duced no noticeable effect on the joints ; and we have here as it were a summary of the whole action of uric acid in the causation of disease ; and diet alone will cure or prevent the whole series of diseases, whether coUsemic or retentive, because it diminishes the available uric acid. In the same way a purely nitrogenous, or highly animal diet, may, like the drugs and mineral waters mentioned above, not make a chronic arthritis worse, but better ; for meat, and even uric acid itself, are stimulants to nutrition, because they clear the blood of uric acid and start an upward metabolism, and so long as the fires of Ufe bum brightly the blood is kept clear of uric acid, and there is relative freedom from arthritis. But a time comes in every case when this stimulation is no longer possible, when the fires of Ufe, from age, over-work, and other causes of exhaustion, bum so low that they will not re- act to any stimulus, and then neither meat nor uric acid wUl do any more good ; and then, instead of acting as stimulants the uric acid gets at once into the blood, and causes the most terrible depression of mind and metabolism. So long as stimulation continues the patient is very pleased with the result, his arthritis is better, and he is better and stronger in himself ; but he cannot leave off his stimulants, they have, on the contrary, to be steadily increased, or all his troubles tend to return, and at the end, which is sure to come, he will have the most disastrous collaemia without any chance of escape from its fatal results. I believe therefore that the treatment of chronic arthritis by a pure meat diet is a most dangerous treatment, though in some cases, and where it acts as a stimulant, it does, for a time, reheve the arthritis : but where it fails to act as a stimulant, or after the stimulation passes off, it will produce most serious results, and 714 UBIC ACID — CHAPTEE XV even in the last few years I have seen it apparently produce severe depression, headache, sleeplessness and anaemia (all the signs in fact of collsemia), and in one case even fits ending in prolonged coma. Then I notice that Dr. Armstrong of Buxton, who read a paper at the Medical Society on this treatment in chronic gout (see British Medical Jmirnal, May 1 and 15, 1897) gives as one of his conclusions in the original paper that patients " recover equally well whether on this (pure meat) dietary or on the meat-free dietary suggested by Mr. Alex. Haig " ; if this is so, there is no shadow of doubt in my mind as to which diet is the safer of the two, and after the above experiences, no one for whom I am responsible shall ever be put on a pure meat diet. In pathology we see that a gout attack is brought on by in- dulgence in wines and beers, which are more or less strongly acid. Champagne is about the most acid of wines, and the cheaper beers are generally more acid than those of better quality. I found acidity equivalent to 18 grs. of oxalic acid in a pint of 4d. ale, and -25 grs. in a pint of stout. Sherry 37 grs. in a pint. Port about the same. Claret 46 grs. to the pint, and champagne 49 grs. to the pint. Sir A. Garrod says (p. 226) : " As regards acidity, Dr. Bence Jones has ascertained that wines may be arranged in the following order, beguming with the least acid : — Sherry, Port, Champagne, Claret, Madeira, Burgundy, Rhine wines, and Moselle. All the wines are found to be more acid than malt liquors," but as the quantity of malt liquor taken is generally much greater than that of wine, the total amount of acid taken may be greater in those who drink beer than in those who take wine. Then the late Dr. G. Harley has pointed out the interesting fact {Lancet, 1896, vol. ii., p. 309) that the Champagne used in England is often more acid than that used in other countries. A good class cider has an acidity equal to 58 grs. of oxalic acid to the pint, but it also contains a quantity of soda and potash, and the efiect of taking it as regards the acidity of the twenty- four hours' urine is almost mi ; I suppose, therefore, that its acidity is due to acid salts of vegetable acids which in the body are converted into carbonates, and as the acids and alkalies in cider or apple juice are nearly balanced there is no efiect on the acidity of the urine. With wines and beers, however, this is not the case, for either by formation of acids during fermentation, or by loss of alkaU during fermentation and keeping (in the case of wine there is a GOUT 715 deposit of acid tartrate of potash, tartar) the alkalies no longer balance the acids, and these beverages have a much more decided efEect in raising the acidity of the urine than cider has: beer also IS made from barley, in which acids preponderate over alkalies. Fruits, again, are acid, owing to the acid salts they contain, but these become carbonates in the body, and act as doses of alkali rather than of acid, and they tend to lower the acidity of the twenty-four hours' urine. I conclude, therefore, that while many wines and beers have quite a distinct efEect in raising the acidity of the urine, and will consequently cause retention of urates in the body, and help to pave the way for gout, good cider made from pure fruit, unso- phisticated, and apart from impurities such as lead, will do but little harm, and will tend to lower the acidity of the urine rather than to raise it, so that it may even do good and prevent gout. In reference to this point about cider, I have been told by my friend. Dr. Bonus, that ,a great friend of his, a native of Normandy, used to teU him that gout, gravel, and rheumatism were rare forms of disease there, and that this was attributed to the use of cider in place of wine : I beheve that the same has sometimes been said of the cider-drinking counties of England, and I have known one or two people who asserted that their gout or rheumatism had left them on their giving up wine and taking to cider. I have also seen similar records with regard to gravel, so that I am incbned to think that cider or apples are good prescriptions in this trouble. Now gravel is a coUaemic disease, arthritis is a gout or precipitation disease, how is it then that one treatment will cure both ? The gravel is a collsemic disease, and in accordance with the rule is reheved by a precipitant, therefore the cider acted as a precipitant: but how did a precipitant cure arthritis ? The answer is that the arthritis spoken of was chronic, not acute, and that it was being kept up by coUeemia which allowed constant fresh uric acid to be brought to the filter : the cider relieved by putting a stop to this process, acting in just the same way as iodides, sulphur, guaiacum, and many sulphate waters, all of which are precipitants not solvents. Very chronic arthritis is thus under some conditions a coUaemic disease, and is relieved by precipitants or by feeding up (see chapter xvi.). Many fruits having a distinctly acid reaction tend to raise the acidity of the urine and diminish the alkalinity of the blood for an hour or two after they have been taken, and while they do this they often cause mental exaltation and well-being, with, perhaps, 716 UEIC ACID — CHAPTBE XV some pricking and shooting pains in the joints, or in a very gouty person an attack may be precipitated ; but at the end of this time their alkaline bases come into action, and there is a fall in the acidity of the urine and a rise in the alkalinity of the blood, which more than compensates for the previous fluctuation in the opposite direction, so that the efEects of such fruits on the re- action of the urine of the twenty-four hours is to produce very little change. Fruits, therefore, may be freely eaten by those who have not much urate in their blood, and they will not tend to cause a re- tention or accumulation of uric acid in the body, but rather the reverse. I must confess that I find it difficult to understand the logic of those who, wishing to know the efEects of wines on the human body, have satisfied themselves by looking up the percentage com- position of such wines in a work on chemistry, and then finding that their order of acidity did not correspond with their apparent order of gout production, have thence concluded that their acids or acid salts had no effect on the human body, and nothing what- ever to do with . the production of gout. Surely if the object is really to find out the efiect of wines on the reaction of the fluids of the human body, it might be almost worth while to pour a known quantity of one or two of them into a human body and watch their efiects on the reaction of the urine for instance ; and this is an experiment which can be begun and completed in three to four hours of any single day. The above view that the acids of wine are not the cause of genit because their acidity does not correspond with their recorded production of gout, appears to me also to quite lose sight of the obvious fact that the efiect on the body depends not only on the acidity of the wine but also on the quantity taken, so that beers of comparatively low acidity taken by the pint may nevertheless produce as much or more efiect than the more acid wines only taken by the ounce. Now fig. 63 shows the effect on the acidity of the urine of 2 oz. of sherry taken at 8 a.m. The first point on the curve is the excretion of acid for the hour ending 8 a.m., the other points are the excretions of half- hours multiplied by two to make them comparable to the first point. The figures below are the hourly and half-hourly excre- tions of urine in cc. multiplied by the number of cc. of standard soda solution required to neutralise them. GOUT 717 The lower broken curve is that of a control day for comparison. No food was taken for an hour after the sherry, by which time it had caused a very distinct rise in the acidity of the urine, a rise which is never seen in the normal curve of these hours (see fig. 3). Note also that with the rising acidity the urinary water rose to 40 cc. in the half hour ending 9 a.m. ; that it fell to 24 cc. at 9.30 and 10 is the generally constant result of the commencement of digestion, fluid being then required for gastric juice, as seen with every meal in fig. 3 : the rise of acidity at 11 common to both curves is also a constant result of the later digestion of breakfast. 1 -I fcS A.M. a-30 9-0 9-30 10-0 10-30 11-0 s 5 1 ^rt/ms/y" •' — *■ — same i ours ^ ^ ? i is T M K i5 '4 M syx-g Z7X/-6 YWxi-4 24" Zi 24X/-2 ZS'l-O 2SX/.4 Pig. 63. — Cubvb op Ubinaky Acidity showing the Effects of 2 oz. of Shebby. It seems clear then that these 2 oz. of sherry produced a very distinct eSect on the acidity of the urine. Fig. 64 shows a somewhat similar result from taking gr. xx. of citric acid in 6 oz. water at 7 a.m. The upper curve is that of water in cc. per half hour, and the lower that of acidity of urine in grains per half hour, and as they are all for periods of half an hour none of them are multiphed by two. The taking of the acid is followed by a rise of acidity to -39 at 7.30, and to "63 at 8, and a fall to "3 at 8.30, when the ordinary curve appears to be resumed. And now again note the urinary water (upper curve). It fell to 29 cc. in the first half hour, but rose to the great height of 110 cc. in the second half hour after the acid, this corresponding to the greatest rise in the acidity curve. 718 UEIC ACID — CHAPTER XV Note also the effects on tte pulse rate and tension in the figures under 7.30 and 8 a.m. These read • from left to right. 7.30 a.m., pulse rate 68, position sitting, diameter of left radial by arteriometer TO millimetre ; and under 8 a.m., pulse rate 74, sitting, left radial diameter '9 of a millimetre. We see then that along with the rise of acidity at 8 a.m. there was a quickening of the pulse, a fall of blood pressure allowing the diameter of the radial artery to diminish, and a marked diuresis; and these last were all results of one and the same cause, the relative clearing of the blood of uric acid which the fall of the blood's alkalinity produced. s ' 7-0 AM /-30 S-0 B-30 9-0 lis Z 100 1 50 1' A ». 1'^ Is j i /\ \ 1 i r ^ \ Il3i ■36 ■30 ■34-. £ /maioncm 68 / t-0 74/ -9 ■39 ■63 «x-9 29 X /■•♦ 110 x-6 32 X 1-0 IB 'Z-O TOTAL mrcR 231 C.C. Fig. 64. — Curve of Ueinaby Acidity and Water showing the Eitects OF 20 Grains of Citric Acid. We see also that the total urinary water in the two and a half hours ending 9 a.m. was 231 cc. And now look at fig. 65, which is a control on another morn- ing, when 6 oz. of pure water were taken at 7 a.m. We see here that the acidity curve is nearly a straight line, that the water also fluctuates but little, its highest point being at 8 a.m., which is also the highest point of acidity ; but there is no diuresis corresponding with that in fig. 55, though the same quan- tity of water was taken at the corresponding hour, and we see also why there was not, for the pulse remained slow and was indeed slower at 8 than at 7, and there was no reduction in the diameter of the radial artery. And we know why this was so, for there was no appreciable GOUT 719 rise of acidity and no clearing of the blood from uric acid, and consequently the capillaries of the kidneys remained obstructed and the blood pressure did not fall. Hence we see that the total water in the two and a half hours ending 9 a.m. on this day was only 162 cc, as against 231 in fig. 64, thus again proving what I have been saying for years, that the uric acid controls the excretion of water, and that the water does not control the excretion of uric acid. It is true that the water in the half hour ending 7 a.m. was 39 cc. in fig 65 and 42 cc. in fig. 64, but that in the half hour ending 8 a.m. was only 49 cc. in fig. 65 against 110 cc. in fig. 64, and this accounted for most of the excess of the one total over the other, and it was clearly due to a freeiag of the capillary cir- culation in the kidneys. s 7-0 AHl^ 7-30 8-0 a -30 3-0 1 .50 MM n *— y y- ^. ^ "-■X Aao '■->i2-* Zl "Z-B 162 cc. Fig. 65. — Cdbvb op Ubinabt Acidity and Watbe, a Contbol Expeei- MENT TO Pig. 64. That the acidity curve as a whole is higher in fig. 65 than in fig. 64 is merely due to the fact that urea was higher on the one day than the other, as acidity rises and falls with urea when other things are equal. I think these figures show pretty clearly not only the effects of citric acid on the acidity of the urine and the alkalinity of the blood, but also demonstrate once more what I have long known, namely, that I can alter at pleasure the rate of the heart's action and the diameter of the radial artery that is the blood pressure, and can free from obstruction the capillary circulation not of the kidneys only, but also of the lungs, liver, muscles, skin, and indeed of the whole body ; but that I have absolutely no power to do this at all except by altering the quantity of uric acid in the blood of which the quantity passing in the urine is the index ; 720 UEIC ACID — CHAPTBE XV and this again explains the fact whicli is practically constant in physiology that the excretion of uric acid and of water in the urine move from hour to hour and day to day in opposite direc- tions, and everything that alters the uric acid may be depended upon to alter also the water. I did not estimate the uric acid in fig. 64 at 8 a.m., but I am as certain that it fell then, as I am sure that I should have found increased excretion of water from the lungs as well as from the kidneys if I had looked for it. It is not everyone who can give the time required to estimate the acidity of the urine or the diameter of the radial artery, still less the excretion of water from the lungs from half hour to half hour, but everyone can measure the urine from half hour to half hour and note the alterations in the pulse rate, and these would often give quite sufficient indication of the action of the drugs taken on uric acid ; and when the doses taken and effects produced were somewhat larger than in these figures, quite distinct effects on the blood decimal could no doubt also be produced (see figs. 54 and 74). They must not expect, however, to produce results like those shown in these figures, except under the conditions which obtained in these experiments ; that is, they must attempt to raise the acidity at a time such as the morning hours, when it is naturally steady or falling, and those again whose hourly excretion of acid is from differences in diet, &c., much greater than mine, must not expect to produce results comparable to mine except by using larger doses of acids. Fig. 66 shows the similar results of taking 5 fl. oz. of stewed rhubarb and juice at 7 a.m. Here again we see a marked and decided rise in the acidity of the urine in the first hour after taking the dose, followed by an almost equally marked fall in the third half hour after it. Here the pulse rate was counted, but no measurements of the radial artery were made, and we see that the pulse quickened from 65 up to 78 with the rising acidity, and fell to 76 as the acidity fell; that it rose again to 78, 86 and 84 at 9, 9.30 and 10, merely shows that the digestion of breakfast was then going on. But part of the quickening of the pulse at 7.30 and 8 a.m. was no doubt due to the digestion of the rhubarb then going on in the stomach, and we see the same thing from the urinary water, which instead of rising with the rise of urinary acidity at 7.30 and 8, as in fig. 64, fell from 52 cc. at 7 a.m. to 14 and 18 cc. GOUT 721 rose to 24 and 29 cc. at 8.30 and 9, and again fell to 25 and 26 cc. at 9.30 and 10, owing to the demand for water in the digestion of breakfast. In fig. 64 there was practically nothing for the stomach to digest, and so the water was free to rise when the rising acidity- cleared up the collajmia and freed the capillaries of the kidney. In fig. 66 these capillaries were no doubt also free at 8 a.m., but the blood was then poor in water owing to the pouring out of digestive fluids, and there was no diuresis. 'IzHOUR CNDIHC Z OS" Fig. 66.— Cueve of Urinabt Acidity showing the Effects of Stewed Rhubaee. And this effect of digestion must always be kept in mind in estimating the effect of drugs on coUsBmia and the renal capillaries as shown by diuresis. The very marked arthritic pains about 8 a.m. (fig. 66) in the ankles and shoulders showed where the uric acid had gone to, and no doubt if there had been any available water there would have been a diuresis. A large number] of fruits containing acids or acid salts produce similar rises in the acidity of the urine for an hour or two after they are taken, with similar quickening of pulse rate, and a rela- tive diuresis, with'^mental brightness and well-being, and more or less arthritic pain ; but very few of these in the quantities com- monly taken suffice to produce any visible effect on the acidity of the twenty-four hours, the effect is no doubt there but it is so 722 UKIC ACID — CHAPTER XV slight as to be only with difficulty distinguished from that due to other causes. It is clear, then, that acid wines and acid fruits do affect the acidity of the urine, the alkahnity of the blood, and the solubility of uric acid. In the case of fruits this effect is temporary and transient, for later on their alkaline bases come into action, and reverse the above effects ; but ia wines the alkali has either been removed from the grape j uice or fresh acids have been formed or added ; and beer has, for other though similar reasons, an excess of acid. Before leaving the acidity of wines, however, we have to con- sider the effects of one of their other constituents, namely alcohol. Now Professor Vaughan Harley has pointed out that alcohol increases the excretion of uric acid, and it is scarcely likely that it does this in any way except, like very numerous other substances mentioned in this book, by affecting its solubihty. I have therefore taken alcohol in various forms, with a view of testing this effect, and my results seem to show that it more or less distinctly diminishes the acidity of the urine, and like other things which do this, increases for a time the excretion of uric acid. In fig. 67 I show the effect of two small doses of brandy, the first at 11.30 a.m. and the second at 3.30 p.m., and in both cases its ingestion appeared to be followed by a distinct break Ln the upward curve of acidity. In the half hour ending 11.30 before the brandy, the acidity rose from '90 to 1"18 or '28, but in the half hour ending 12 noon it only rose to 1"24 or '06, and in the half hour ending 12.30 it rose again more quickly to 1-44: or a rise of "20, and it seems therefore evident that the effect of the ^ oz. of brandy was to diminish the rise in the half hour ending 12 noon, just after it was taken. Similarly in the half hour ending 3.30 p.m. the acidity rose from 1'57 to 1"66 or "09, but in the half hour ending 4 p.m., after the brandy was taken, it did not rise at all ; but it does rise again slightly in the half hour ending 4.30, making it probable that it would have risen at 4 p.m. also but for the brandy. If the curve had risen steadily from 11.30 to 12.30 it should have stood at 1'31 at 12 noon, but it only reached r24, a loss of •07 ; similarly the dose of brandy at 3.30 appeared to do away with a probable rise of about "09. I have several curves showing what appear to be very similar results from taking small doses of alcohol without water, and if GOUT 723 we may look upon them as results we shall not have much diffi- culty in understanding how they are produced. For alcohol and spirits generally act as irritants of mucous membranes whether of mouth, throat or stomach, and this is especially the case when they are taken alone without any added water. Now i£ brandy thus irritates the mucous membrane of the stomach it may stop for a few moments the processes of digestion and absorption there going on. si Hhour 2 •Si , A.M. — * — '• ii-n ii-an ip-n ip-ao i-n i-.-^n ?-(J pon s-o 3-30 4-0 4-30 ::: ^^ s -■i>r ■ ^ --V ^ ^ "^ s v' ^ ^ K- -^ - •f no 1-18 h?4 1-44 t-44 1-5 /•?,« I-4S I SI y-fff? i-i;i; 1-7 '4-6-6 SA-H iS^i m-s-i SO'TS sr»T< a"xj« 'g-'fS 'e-ii-i ^m. iO'^M JffxT Fig. 67. — Curve of Urinary Acidity showing the Effect op takinVs Brandy Undidctbd. But as we already know the rise of acidity from 11 a.m. on- wards is almost certainly due to the digestion of breakfast and the absorption from the stomach of acids and other products of diges- tion ; just as the rise from 2 onwards is due to the similar diges- tion of lunch, therefore anything that interferes with digestion will interfere with the rise of acidity. And we have tolerably clear evidence that alcohol does interfere with gastric digestion in the well-known fact that in those not accustomed to it, or in those who take it in unusually large doses, it may cause nausea and complete loss of the contents of the stomach at once by vomiting, or it may merely suspend digestion, the contents of the stomach being vomited more or less unchanged several hours later. I think, therefore, that in the case of some wines rich in alcohol their effect on acidity would really be somewhat greater than that shown in the case of sherry (fig. 63), but for the alcohol they contain and its irritant action on the gastric mucous membrane. 724 UEIC ACID — CHAPTER XV It may also be interesting to remember here, as I have already pointed out in chapter ii., that the mineral acids, if given in too large quantity, or insufficiently diluted, irritate and cause pain in the stomach, and then cause a fall in the acidity of the urine in place of a rise. Before leaving the question of the effects of acids and acid salts on solabihty and excretion, I will refer shortly to a paper which Dr. LufE read before the Royal Medical and Chirurgical Society in June, 1898, and which is published in vol Ixxxi. of the Transactions, p. 375, on " The Influence on Grout of the Mineral Constituents of Various Vegetables." In this he showed that he tried the ash of sixteen vegetables and found the order in which they affected the solubility of sodium biurate. He then shows that this efiect is not due to any one constituent of the vegetable ash as the quantity of sodium, potassium or calcium salts, the phosphates, sulphates, or chlorides, and he leaves us in doubt on the point as to what the effect really is due to, and concludes by advising the use of spinach, which he places at the head of his solvent ashes, or of a salt which he prepares from this and other vegetable ashes. But as I pointed out at the time this paper was read (see Proceedings of the Royal Medical and Chirurgical Society, Third Series, vol. x., p. 154), if Dr. Luff had carefully read my previous researches he need never have made these experiments at all ; though I really am very glad that he did make them, as they confirm in a beautiful manner my results and those of Sir A. Garrod and others which preceded them. And when we throw Dr. Luff's results into a table like that which follows, showing from his own figures the solvents (potash and soda) in each vegetable ash ; and on the other hand the sub- stances which had been shown by Sir A. Garrod and myself, to hinder solubility, we at once see why the vegetable ashes produced exactly the effects Dr. Luff records. It is a simple matter of balance and the strongest wins : when the alkalies were in excess over calcium and acid radicals, solution predominated ; when calcium and acid radicals were in excess over potash and soda solution was much less. And this I would point out is no doubt just what happens with all animal and vegetable mixtures as the wines, beers, cider and other fluids we have just been discussing ; the resultant is the difference between the solvent forces and the retentive forces present in the given substance. GOUT 725 And when we apply this to Dr. LufE's results, order at once takes the place of chaos. Order of Solvent Effect. Potash and Soda. Spinach 54-8 (1) Brussels sprouts 47-6 (2) Cabbage 40-1 (9) Cauliflower 34-2 (14) Sea-kale .36-4 (15) Green peas 44-6 (16) Calcium. 10-64 6-16 17-14 23-33 27-56 4-98 Acid Radicals. 20-78 25-51 28-36 41-13 43-24 42-08 In this table I give only six out of Dr. Lufi's sixteen vegetables ; in the first column we have their names, and under each the number in brackets is the number of their place in his table of solution power of ash, that of spinach being most powerful, that of green peas least powerful. In the second column is the total of potash and soda from Dr. LufE's figures. In the third column the total of calcium and in the fourth the total of acid radicals. From this we can at once see why the ash of spinach stands at the head for its solvent effects ; it has the largest amount of alkali, the smallest amount of acid radicals, and a moderate amount of calcium. Green peas, at the other end of the scale, have less potash and soda than spinach, but more than double the amount of acid radicals. Peas also containing much more albumen than the other vegetables will raise more acidity by the metabolism of their albumen. The rest are more or less intermediate, thus cabbage has only slightly less alkali than green peas, but it has only two thirds of its acid radicals, and only a microscopic quantity of albumen. It appears that the falling off in solvent power follows the increase of acid radicals more closely than that of the calcium, and this may be due to the fact that acid radicals are more soluble than the calcium salts. But anyone can now see that the effect on solubility in glass, just as on the excretion of uric acid from the human body, is the resultant of the opposing forces. It is quite useless, though it is an experiment which I have often made, to give mercury or a sulphate to retain uric acid with 726 UEIC ACID— CHAPTER XV the one hand, while giving alkali or salicylate with the other, the victory or resultant rests with that which is present in largest force, or is favoured by external forces as acids or alkalies in the food, or cold or heat in the surroundings. It is also quite useless, as I have over and over again pointed out, to give uric acid or xanthine in any form, and expect a corre- sponding increase in excretion while administering mercury, iodides, sulphates, or other drugs that cause retention, or while there are powerful acids or acid-forming substances in the food, or even while the patient is exposed to cold. The resulting excretion will be the resultant of all these oppos- ing forces, and the excretion of uric acid will only be proportional to the amount swallowed when its solubility in the blood is in no way hindered or interfered with. Thus the things in an ordinary dinner might be arranged into those that hinder solubility and excretion and those that aid it somewhat as follows, and the result of a given meal will depend on the balance of forces. Hinder Excretion. Aid Excretion, Soup. Xanthine and flesh salts. Fish. „ „ „ Potatoes. Meat. „ „ „ Spinach. Pudding. Sulphates and phosphates. Cheese. Salts. Sulphur and phosphorus of albumens. Fruit. Salts of acid reaction Soda and pota Wine. Acids and acid salts. It will be seen then that in such a meal the only things that aid excretion are the potatoes, and spinach, and the alkali in the fruit, if it is present, in a proportion nearly equal to the acid radicals, as in apples before mentioned. The practical efiect of most meals is a rise of acidity in the urine (see fig. 3), and this will be so in the above meal most cer- tainly, unless the experimenter took very little soup, fish or meat, and no wine, or acid fruit, and a large quantity of potatoes and spinach. The excretion of uric acid after such a meal will, apart from the stores already in the body, depend partly on the amount taken in, in soup, fish and meat, and partly on tte relative balance of alkalies over acid radicals. The result in twenty-four hours will also depend upon whether GOUT 727 the patient is warm in bed the whole time, or is out and exposed to cold during any important part of the twenty-four hours, and this exposure to cold will have most effect when it occurs in the morning hours of the alkaline tide excretion, and we see the effects of this, for instance, in fig. 40. And what appUes to excretion applies also to the causation of gout or rheumatism, to arthritis, myalgia, lumbago, &c. ; the result wiU depend partly on the amount of uric acid available, and partly on the power or predominance of the forces that make for reten- tion (acids, substances forming insoluble compounds, cold), over those that make for solution and excretion (alkalies, substances forming soluble compounds, warmth). Thus expose a man for two or three hours to a cold, north- east wind at a temperature of 32° F., and he will come home with sufficient lumbago, sore throat, or tracheo-bronchitis, if he had excess of uric acid in his blood at the time of exposure ; but he might be exposed to just the same temperature on another occasion, when from high acidity in the evening perhaps his blood was already almost clear of uric acid, without any ill-efiects. And those who are as far as possible free from uric acid, and pass out day by day' in good solution all they form, will take practically no harm from exposure to cold at any time, although, as shown in the fig. just mentioned, cold in the morning hours causes a quite visible fluctuation in my circulation curves. But if I were full of uric acid that fluctuation would be not merely interesting, but painful and dangerous. It is clear then that Dr. Luff's treatment of gout by vegetables and vegetable salts is merely sweeping out with one hand the poison he introduces with the other ; as he pays no attention to its introduction in flesh and tea, &c. And the vegetables have no occult action in the matter, but simply that which is due to the preponderance of excretants or solvents over precipitants or retentives. Sir A. Garrod says (p. 212) : " That women are less subject to gout than men is beyond doubt." He attributes this to difference in character and habits, and adds, " Besides which, a most power- ful counteracting influence exists in the presence of the catamenia during a considerable portion of their lives." As to habits, women are generally less exposed to weather (cold and wet), and take less of beers and wines than men, and as to the catamenia I have shown (fig. 31) that menstruation lowers acidity and produces collsemia and a plus excretion of uric acid. 728 UEIC ACID — CHAPTEK XV and this occurring for four or five days in every month may , sensibly diminish the amount of uric acid that is stored in the body. I As to the effect of age I mentioned some points at the beginning of the chapter and shall speak of it again in the chapter on rheumatism. In estimating the effects of beers, wines, and other beverages on different races, it is necessary to bear in mind the amount of meat or nitrogenous food they consume, as this determines the introduction as well as the formation of uric acid, and obviously an acid will produce most efiect and most quickly store sufficient uric acid to cause gout where it has most to work upon, and the formation and introduction are greatest. Thus in England beers produce more gout than in Germany, because the English consume more meat per head of population than any other nation in Europe (see Lancet, 1890, vol. ii., pp. 409, 468, and 589; and for similar facts about the incidence of gout in Persia see chapter xvii.). Speaking of nationahty leminds me of the fact that the Scotch suffer from gout comparatively little, so that our brethren north of the Tweed have difficulty in finding cases on which to work. I have no doubt that this is due to the fact that the national beverage of the Scotch, namely, whiskey, contains little or no acid, and affects acidity but little, and the Scotch also, as a sale, eat considerably less animal flesh than the English. If a Scotchman comes to England and drinks beer and wine and eats meat, he suffers from gout like the Englishman. Sir A. Garrod says : " The least acid of all alcohohc fluids are geneva and whiskey." It is generally agreed that excess of animal food is a cause of gout, and Sir^A. Garrod quotes several authors to this effect, and he also says, on p. 230, " CuUen remarked that gout seldom attacked persons employed in constant bodily labour, or those who live much upon vegetable diet." Figs. 46 and 47 demonstrate what would probably be the effects of constant bodily labour, and the evil effects of a highly animal diet are evidenced by the figs, from 24 to 28. Dyspepsia may have an important influence, as I mentioned in speaking of Sir A. Garrod's quotations from Sydenham. It seems probable also, as pointed out by Bouchard, that acids may be formed under certain conditions or out of certain articles of food, and these would, no doubt, affect the solubility and excretion of uric acid, so long as they continued to be formed. It has been assumed by several writers, notably by Murchison, GOUT 729 that in certain conditions of functional disturbance of the liver there is an excessive formation of uric acid. If they mean that uric acid is formed in greater proportion to urea than 1 — 35, I can see no good evidence of it, and I look upon the excess of urates in the blood and urine as the sign of excessive excretion, the result of previous minus excretion or retention, and dependent upon increased alkalinity of the blood. If they mean that in certain liver troubles, especially tljose accompanied by slight fever, there is excessive formation of both uric acid and urea, in their normal relation to each other, I should raise no objection. Among the symptoms of the dyspepsia connected with "the uric acid diathesis " mentioned by Sir A. Garrod (previous reference, p. 232) are many which I have attributed to coUeemia, as " oppression and frequently sleepiness after food." " Saliva and buccal secre- tion often more adhesive than natural." I have pointed out that saliva is scanty in the coUaemia of the opium rebound, and at the time of the uric acid headache, mental depression, &c., in all cases no doubt due to the same cause, namely, obstruction of capUlaries by uric acid. " Accompanying these symptoms there is a scanty secretion of urine which is highly coloured and strongly acid." I have pointed out that the urine is scanty in the coUaemia of the uric acid headache and mental depression, and that the water in fact varies inversely as the uric acid excreted along with it, and the water is scanty probably for the same reason that the saliva is scanty because the vessels of the kidney are obstructed. As to high acidity, that is only relative to the water. If the urine of twenty-four hours is saved it will be found that the total acidity is really considerably lower than that of the previous day, when there was less uric acid and more water, unless, as I have before explained, there is a very great excess of uric acid in the urine, such as is met with in severe headache, epilepsy, paroxysmal hsemoglobinuria, and similar conditions, and then the quantity of uric acid present may be sufficient to raise the acidity of the urine very decidedly. Much sedentary work tends to produce gout. Sir A. Garrod quotes (p. 233) Sydenham as saying, " Whenever I returned to my studies gout returned to me," and I have already given his quotation from Cullen about the preventive power of bodily labour. I have pointed out that the excretion of uric acid is greater in summer than in winter, and Sydenham speaks of gout as a winter disease. Now, there is no doubt that a labouring man has, so to 73.0 UBIC ACID— CHAPTER XV speak, summer all the year round. His exertions keep his skin constantly active. He gets rid of a large amount of acid in this way, hence the acidity of his urine rules low, and the alkalinity of his blood is well maintained ; he therefore excretes uric acid freely, and retains but little in his body, and so, as observed by CuUen (previous quotation), he but rarely suffers from gout, and this is so almost without regard to his diet, for he excretes all the uric acid he introduces, as well as all that he forms. As to the acidity of the sweat, see also Heuss, Monatsch. fiir Prakt. Dermatol., Band xiv., Nos. 9, 10, and 12, and Lancet, 1892, vol. ii., p. 1118. A sedentary man has not only higher acidity and reten- tion of uric acid, but his circulation, especially in peripheral parts like the hands and feet, is less well maintained, and as a result the alkalinitj' of the fibrous tissues in such parts is also less well maintained. Though, as I have said, I used to have headaches when my life was not sedentary, I have no doubt that I could indulge in meat and beer with comparative impunity if I lived the life of a labourer. After what I have said about the effects of summer, it is not surprising to find Sir A. Garrod saying (p. 235), " Goat is un- doubtedly much less prevalent in hot than in temperate climates," though, no doubt, as he remarks further ()n, food and habits have also something to do with its absence. The reverse effects of cold need hardly be gone into, but Sir A. Garrod says (p. 247) ; " When cold acts as an exciting cause the efieet is due, at least in part, to its arresting the secretion of the skin, and checking the escape of acid firom the surface," and my experimental experience is in complete accord with this statement. I notice with interest that Dr. Solly says (previous reference, p. 179), " The geographical distribution of gout is chiefly due to diet, drinking, and the social habits of the residents in countries where it is most prevalent, as in England, for example " — a state- ment which I can most cordially agreee with, for gout owes, not only its geographical distribution, but its entire existence, to diet. Local injury will, no doubt, diminish the alkaUnity of the afiected part, just as fever diminishes the alkahnity of the whole body, and Sir A. Garrod says, " Local injury not only acts in exciting gout, but frequently determines the situation in which the inflammation will show itself. Thus, injury to the knee or ankle will usually cause these joints to be primarily afiected, although 1 the great toe or some other part may subsequently become implicated." GOUT 731 We shall see presently that in rheumatism local injury has the same efEect, and compare the above quotation with what I have said as to the efEects of exercise in determining the seat of the gouty arthritis. Haemorrhage is recorded by Sir A. Garrod as an exciting cause, and he attributes its efiect to -the " nervous depression " it pro- duces. It seems to me, however, that another explanation is possible. First of all the blood is alkaline, and loss of blood is practically equivalent to removal of alkah from the body. Then it is well known that when the temperature is normal severe loss of blood from any cause will raise it, and fever, as we have seen, raises the acidity. We have, therefore, two results of severe haemor- rhage, which, acting together, diminish the alkaUnity of the blood and tissue fluids. This interferes with the solubility of uric acid, and tends to precipitate it upon certain of the least alkaline tissues, namely, the fibrous tissues in the joints and elsewhere. With regard to the raising of the acidity by fever, I am not quite sure that it should not be put the other way, and that it might not be more correct to say that rise of acidity or fall in the alkahnity of the blood causes fever. We have seen that acids stimulate nutrition, metabolism' and combustion throughout the body, and cause a rLse of urea and a rise of temperature if they produce a fall of uric acid ; and if microbes and other materies morbi reduce the alkalinity of the blood they must of necessity cause an increase of metabolism and combustion, and this, as I have suggested, may be Nature's reaction, and an attempt on her part to burn up the invading microbe, in which endeavour we should, in my opinion, be ready to give her all the help in our power (see p. 425). It is not a little interesting to find that acids stimulate both animal and vegetable nutrition, as, T believe, it has been shown that the growth of seeds and very young plants can be greatly stimulated by watering them with very dilute acids. In any' case the difference between the increased combustion we can produce with such drugs as the iodide of mercury, which quickens the pulse, raises the temperature, increases urea and diminishes albumen or sugar, and that of fever, cannot be more than one of degree, and I have also shown that in physiological conditions the quantity of uric acid in the blood really controls to a very considerable extent both the formation and the distribution of body heat (see fig. 5 and also chapters 'viii. and xiii.). That, as Sir A. Garrod relates, sudden stoppage of menstruation 732 UEIC ACID — CHAPTEE XT should produce gout, is not very extroardinary, for menstruation is commonly accompanied by coUaemia and its signs (figs. 31 and 32), and any exposure to cold or febrile disturbance supervening upon this would, undoubtedly, drive the urate out of the blood into the joints, and it seems to me that in many of these cases the action of the nervous system", like that of Jupiter in ancient mythology, has been unnecessarily invoked from ignorance of the real cause. One of the most interesting points about gout is the way in which it has been observed to alternate with the troubles produced by coUsemia, such as high blood pressure, headache, depression, &c., as mentioned in the chapters treating of these; and this is, no doubt, due to the fact that for some little time round each attack of gout the blood in general is kept relatively free of uric acid, so that severe coUsemia is prevented. Now it seems that there are two chief factors concerned in bringing about this result. One of these is the fact that uric acid attracts uric acid ; and everyone knows that if a few crystals of urate or uric acid are inadvertently left on a urine collecting glass they will increase very greatly from day to day, and every dirty urinal crusted with urates bears evidence to the same fact. And there seems to be very little doubt that precisely the same thing occurs in the body, and that blood or tissue fluid passing near a deposit tends to give up its uric acid to the deposit (see p. 177). And there is probably another factor as well, as shown by Sir A. Garrod's observation (" Gout and Eheumatic Gout," Ed. iii., p. 110) that there is no uric acid in the serum drawn over an inflamed joint, which led him to suggest that inflammation destroys uric acid. But as I have pointed out, the effect of the inflammation is probably to diminish the alkalinity of the blood and tissue fluids in the inflamed area, hence any blood that passes through this area wiU tend to leave its uric acid behind it in colloid form, because as we have seen in chapter v. slight acidification of a solution of uric acid in phosphate of soda tends to throw it down in colloid form, and the urate so retained eventually becomes a biurate, and is deposited in crystals. But if the inflammation lasts only a short time it never becomes a biurate ; but remaining in colloid form is quickly redissolved, as the normal alkalinity is restored ; and here we see the chief differ- ence between the arthritis of rheumatism and that of gout, i.e., bptwfip.n acute and teirmorarv and chronic and np.Tsis+.ATit. GOUT 733 It is probably, therefore, as the result of the action of these two factors that a patient who has for years, perhaps, suffered from headache, mental depression, or other signs of uric acid col- Issmia gets one day, as the result of some strain, blow, injury, or other local cause of alteration in alkalinity, an attack of gout in his toe, and then, perhaps, for several years he has recurrent gout in this toe or other joints, and ceases more or less completely to sufier from the signs of collsemia, but meanwhile he is accumu- lating a fine tophus in his foot, which acts for a time as a uric acid filter for his blood and most of his body. Later on some shock, illness, or severe injury depresses him, and then his blood, as already explained, becomes a better solvent of uric acid, and takes up from the tophus in place of adding to it ; and so the gout in the toe ceases, and the colliemia, headache and mental depression return, together with an increased excretion of uric acid in the urine. Later, the same sequence repeats itself, and the coUsmia is brought to an end by a fresh attack of gout, and this is the explanation of the well-known tendency of gout and rheumatism to recur and recur often in the same fibrous tissue once they have attacked it, whether this be part of a joint or of the mitral valve, of the pharynx, larynx, trachea, bronchi and fibrous tissues of the lungs, or of the cellular tissues in the stomach, intestines and pelvis ; for there is left in such fibrous tissue either a condition of diminished alkaUnity, or a few crystals of urate as mentioned in chapter ix., or both. And this completely accounts for the alternation between the symptoms of coUsemia and those of arthritis, and the action of cold, acids, and numerous metals and drugs in changing the former into the latter. From Dr. Ewart's very interesting work on gout,* the state- ment of some points may be useful. Thus I notice with interest, that from what he says on p. 310, he would agree with me that the assumption of the unknown factor " Diathesis " is unnecessary, and on the next page he says that " marked uricacidaemia and demonstrable deposits of biurates are the features of declared gout." But on the other hand he declines to credit gout to mere excess of uric acid, because it (gout) is not a constant phenomenon of * "Gout and Goutiness." By William Ewart, M.D., Cantab., P.E.C.P. London, 1896. 734 UBIO ACID — CHAPTER XV leucocytlisemia, and does not very often occur in children, whose production of uric acid is so great. If, however, it be granted that rheumatism is due to urates, and is, as above hinted by several observers, but gout in a child, one of these objections at once falls to the ground ; and leucocy- thaemia is a somewhat rare disease and occurs generally in con- ditions where there is great depression of nutrition and metabolism, and when consequently the condition of the blood and tissue fluids is, as regards acidity or alkaHnity, at the very opposite pole to that at which gout occurs ; but in the similar conditions of en- larged spleen with or after malaria, with the fluctuations in alka- linity of the fluids produced by recurring attacks of fever, gout is, I believe, not at all uncommon ; the leucocythsemia end of the cycle being represented, as in the case narrated in chapter ii., p. 49, by attacks of gravel. Later on he quotes the views of others, which make a " depressed and faulty metabolism " the " first departure " and abnormal secre- _ tion its result ; and makes the goutiness resulting from such faulty metabolism the basis of all articular gout. He then goes on to mention Horbaczewski's researches, and suggests that increased uric acid production is not largely derived from nitrogenous food, though he acknowledges that it follows an excess in nitrogenous diet, but is the result of altered metabolism in the tissue cells owing to their paralysis by excess of nitrogen. This, however, drives them into the difficulty of explaining why the faulty metabolism persists when the occasioning cause (the excess of nitrogenous food) is withdrawn ; and he goes on to attribute this to faulty habit in the tissues partly assisted by faulty innervation. He blames especially the liver, and congestion and fulness of the portal circulation, but thinks that the faulty habit may be in time replaced by a healthy habit. Similarly he speaks of the kidney, and says that a renal defect may originate the uric acid trouble, though gout attacks may come on without any obvious kidney trouble, and again granular kidney causes neither retention of uric acid nor gout. Again, following the cell malnutrition theory, he thinks that there may be an inherited goutiness of the whole man, which is there before any articular attacks, and that gout evolves from functional troubles to structural changes. And again, " some structural gouty peculiarities are transmis- sible and may be inherited even by those whose uric acid function is not perceptibly modified : hence uric acid troubles are not the. GOUT 736 Hence, " the history of acquired gout is one of functional dis- order leading up to organic lesions, whilst the history of inherited gout is often that of toxtural delicacy leading to functional disorders." He then proceeds (p. 319) to refer to the various nervous system theories, but is inclined himself to limit the action of the nervous system to the comparatively insignificant influence which a nervous system may exert on nutrition, as the result of its own failure of nutrition originating in causes outside itself ; it is thus merely a link in the causation, not an originator of gout. It is obvious that with regard to most of the theories here so ably marshalled, I cannot do more than suggest what seems to me a simpler explanation, trusting to the fature and its increase of knowledge to strengthen my positions if they are true. My behef is, and it is steadily increasing and gaining strength, and just as I said at the Medical Society in November, 1896, with reference to headache, that "the uric acid diathesis" is a myth; if uric acid is controlled, that is, if there is neither excessive intro- duction nor excessive formation from excess of nitrogen, both gout and goutiness would gradually disappear or cease to be evolved, and this is a proposition which in one sense or other can be demonstrated. I need not here again go into my reasons for believing that depressed and faulty metabolism is a result of excess of uric acid, and not its cause : but I can scarcely follow Dr. Ewart's reason- ing in saying that the large excretion of uric acid which follows excess in nitrogenous food is not derived from the food. It will be seen from my facts and arguments as to hospital beef -tea, in chapter xvii., that a pound of meat from which it is made probably introduces the equivalent (in xanthines) of seven grains of uric acid, and if we credit a man who is taking excess of nitrogen with only half a pound of such meat a day, that would account for an introduction equivalent to 1200 grains of uric acid in a year, and if he also takes an absolute excess of nitrogen and forms say 100 grains of urea per day more than he has any physiological right to do, he will also form nearly three grains a day of excessive uric acid, or some 1100 grains in a year- It is clear then that if such introduction and formation do not account for any excess of uric acid met with in the urine after excess of nitrogenous food, especially in the form of animal flesh, it is not because these will not furnish the required quantity. In this connection I will just mention a case I have been told of by my friend Mr. Hope Lewis, of Auckland, New Zealand. It 78fi UEIC ACID — CHAPTER XV was that of an hotel-keeper who consulted him for bad temper, worst in the mornings, and general myalgia. On inquiry, however, it came out that he was most moderate in meat and wine, lived carefully, and ate plenty of fruit, so that Mr. Lewis was at a loss to account for his condition, when the patient said : "I take several cups of beef -tea every day — really good stuff it is — my hotel is famous for it." And this is just my own experience, as I often see patients who take little or no meat; but then one is sure to find either that this is made up for in eggs and fish, or that soup, beef-tea, or some of the urine-like fluids and extracts so largely advertised, are being taken in its place. Indeed, one almost wonders that the manufacturers of these delicacies do not take a hint from the inhabitants of North Africa and South America, mentioned on p. 123, and obtain a still larger supply of the same products by evaporating urine. I may just mention here that a butcher at one time under my care with gout, Bright's disease, and cardiac failure, acknowledged to consuming two pounds of his own commodities per day ; and it is little wonder that urates and their work were visible all over him, or that they had altered his joints* and his blood, irritated his kidneys, and dilated his heart, in the manner described in previous chapters. And now for Dr. Ewart's difficulty as to the persistence of the faulty metabolism after the excess of nitrogenous food has been removed. I believe that the solubility of uric acid suffices to explain it completely. Why, the tissues of the above-mentioned butcher are absolutely full of uric acid, and if I were now to put him on a uric-acid-free diet he would still go on excreting excess of it for months and years, and during the whole of this time he would have the signs of coUeemia, with the depressed nutrition and metabolism it produces. And with the obstructed capillaries of the coUeemia and his failing and dilating heart, he would have what we always find with these conditions, congestion of the liver (nutmeg), and of the circulation behind it ; so that the poor liver again is blamed for the fault of others, and is not an original sinner. Exactly the same applies to the kidneys ; these organs never, I believe, refuse to pass uric acid unless they are inflamed, and then they have no choice, as the altered alkalinity of their tissues and fluids afiects the solubility of uric acid. * These joint changes were marked, and would undoubtedly have been called rheumatoid arthritis if there were no urates to be seen. GOUT 737 What do we see in migraine while the kidneys are sound ? A large exeretion of uric acid, though urea may be diminished ; but this is simply due to the fact that urea is diminished in the blood while uric acid is in excess in that fluid. Similarly in the chronic stages, and absolutely uninflammatory conditions of granular kidney, we get, as I have often pointed out, a very large excretion of uric acid, so large that it may consider- ably raise the specific gravity of the urine and so upset the dia- gnosis of granular kidney (see cases in chapter xvi.), or may cause more or less severe symptoms of gravel or calculus, and this because, for reasons already given in this chapter, the blood is full of uric acid. The kidneys, just as the liver, muscles, skin, and all other tissues, are importantly afiected by the uric acid, but they them- selves always pass out uric acid when it is present in excess in the blood, except perhaps when, as in acute Bright's disease, they have their alkalinity diminished; but this is a chemical not a physiological refusal to pass it. As to inherited gout, I would again ask how much of the inheritance is that of dollars and habits of feeding, and as in the cases of the children, with reference to whom Mr. Hutchinson is quoted at the beginning of the chapter : did they not live in their father's house, and did they not repeat his errors of feeding, both as to excessive introduction and excessive formation of uric acid {i.e., excess of nitrogen) ? Again, as to the faulty metabolism persisting after the excess of nitrogen was cut off, did the introduction of uric acid cease, or were such things as eggs, fish and tea continued as before, introducing, no doubt, still many grains of uric acid per day ? As to the nervous system, it appears to me to be exactly in the same position as the liver and kidneys, it is sinned against, and the signs it gives are the results of defective circulation, and of lesions or irritations of its fibrous tissues. To my mind, gout is poisoning by animal flesh, with tea and similar vegetable-alkaloid-containing substances ; and the nervous and all other theories have arisen from inabihty to understand and appreciate the introduction, formation, and solubihties of uric acid, and their bearings on the various results produced. Where the gout attack comes suddenly in the night and is in every way typical, there is not much to be said about the dia- gnosis, and salicylate of soda in sufficient quantity will very quickly relieve it, as in my case in St. Bartholomew's Hosfital Reports, 47 738 UEIC ACID — CHAPTBB XV previously mentioned. It is necessary, however, to give sufficient, and if gr. xx. can be given every two hours for acute rheumatism, I fail to see why it should not, if necessary, also be given for acute gout ; certainly neither disease can be expected to yield to a dose of gr. x. three times a day. I have seen salicylates fail to cure, but only under conditions where failure could have been foretold. They are very little use by themselves in chronic rheumatism, and very little more in chronic gout without rise of temperature ; again, where alkalies or colchicum have already been used sali- cylates will not only be of no use, but may do great harm, and again, they are incompatible with the use of hot or Turkish baths for reasons which will appear in the following chapter, and in the descriptions of figs. 62 and 6.3. Where alkalies, colchicum or hot baths have been used they had better be continued, unless all treatment can be left off for several days to allow intestinal digestion to recover from the col- chicum, and the alkalinity of the blood to recover from the effects of alkaHes and dyspepsia before the salicylates are given. In very chronic gout their action may be improved by giving them with sp. am. aromat. or with iodides, or in alternate doses with acids or other substances which raise acidity. And in these chronic cases salicylates may eventually do much good if steadily persevered with ; either salicylic acid or its ammonium salt or aspirin will sometimes succeed where the sodium salt appears to fail. Salicylic acid with pulv. opii co. in a cachet is sometimes very useful in more chronic conditions. Again, where we have to deal with real uratic arthritis, the local application of salicylate of methyl should not be forgotten. This may be painted on night and morning, and covered with gutta percha tissue and a bandage. It may be used either alone or along with administration of sali- cylates by mouth. In this case care must be taken not to give too much of the drug, as the methyl sahcylate promptly gets into the blood and urine and produces constitutional symptoms, and if painted on too often or over too large a surface these may be severe, but for many local troubles it is by far the best way to use salicylates. And where salicylates by mouth upset the stomach it can replace them entirely. In chronic conditions alkalies are decidedly useful, and the only rule I go by is to give them when the acidity of the urine is low and it does not appear likely that it can be raised. Then all acids must be cut out of the food and alkalies may be given to the extent of from 60 — 90 grs. per day. GOUT vay When giving alkalies you may cut down the quantity of food decidedly, as low urea and low acidity of urine help the alkali : but when giving salicylates, especially when there is Uttle or no fever, you must feed up and even give acid fruits or wine, as fever, high acidity and acids help the action of salicylates. It is a very common mistake in the treatment of gout to cut down food when ordering salicylates : but this just ensures a condition in which they cannot possibly produce their best effects, and may do absolute harm. I may mention here, as it bears specially on treatment, the well-known connection between gout and certain teeth troubles. And indeed, it has been quite a common experience with me that the dental troubles called periostitis, or other inflammation of the pulp or surroundings of a tooth, such as are started by a cold wind in spring or autumn, yield at once and promptly disappear if salicylates are taken for any purpose. And it seems to me quite possible that we have here again to deal with a gout of fibrous tissues, originating just like gout or rheumatism elsewhere in the local action of cold, and like these yielding at once to the administration of salicylates. I have gradually come to use salicylates with the utmost con- fidence in all such troubles, and I have even found that their power is so great that the local application of a little salicylate of methyl to the face over the painful tooth and its roots, night and morning or oftener, very promptly reUeves and removes such irritation, so that in many cases there is no necessity to administer salicylates internally. But drugs never go to the root of the matter, diet is the only thing that does so ; and though drugs may relieve for a time I regard it as worse than useless to sweep out urates with salicylates, and at the same time pour them in day after day in soup, fish, flesh, and tea. Here, as elsewhere, the results produced by diet can be estimated either from day to day or week to week with great precision, from the changes in the capillary circulation and the blood decimal. Gout is the great central type of the precipitation group, and practically the only things that have ever been found to reheve it have been solvents of uric acid, but better and more satisfac- tory than any such relief is the absolute and complete prevention of the trouble which a correct diet produces, and I will now mention shortly one or two of the very numerous records I get from gouty patients. One patient writes after two years on diet 740 UEIC ACID — CHAPTER XV " This was the first winter that I had passed during which I have had no cough or cold, and had been entirely free from rheumatic pains," and then the same patient, speaking of his general condition on diet, says " I am as hard as nails." Then I have a large number of records from patients who have been on the uric-acid-free diet for from one to three years, and whose arthritis has more or less com- pletely taken its departure as the result. Thus it is recorded, "^^two years on your diet has cured the gout to which I was a martyr, and made me a new man " ; and another, "Your diet has had a wonderful effect on her hands. The gouty swellings on fingers and thumb gone, and she can again play the piano like a young girl. Time on diet two and a half years." A general practitioner writes that he was a cripple, and retired from work with gout and pneumonia, but now, a year later, he is heavier, stronger and happier than for years. From many similar records I gather that the diet takes one and a half to two years, or in bad cases two and a half to three years to cure arthritis, as I say in my diet notes. 741 CHAPTER XVI. Rheumatism and Morbus Cordis. Much of what I have said about gout will apply also to rheu- matism, and though they can often be cUnically distinguished, I do not draw any hard and fast Une between them, beheving that the arthritis is in both cases due to the irritant action of uric acid on the fibrous structures of the joints. An arthritis may or may not be due to uric acid, but it becomes certain that it is due to it if the patient is found to have less than the usual quantity of uric acid in the blood at the time of the attack of arthritis, and if the arthritis is found to be relieved by solvents and increased by precipitants of uric acid ; and when any arthritis, accompanied by fever, is not relieved by uric acid solvents, properly administered, the possibility of septic arthritis, tubercle, or new growth should be considered. I have suggested that salicylates cure acute rheumatism by effecting the eUmination of urates, and I have further shown that as regards the action of salicin, salol and a salicylate, the latter has most power, dose for dose, in eliminating uric acid, and has also most effect over the arthritis, while salicin has much less effect on uric acid, and requires to be given in much larger doses, and salol is in both respects intermediate between the two (see Medico-Ghirurgical Transactions, vol. Ixxiii., p. 297). I have further suggested that the action of uric acid as an irritant of fibrous tissues may quite as easily account for the endocarditis and pericarditis of acute rheumatism as for its arthritis (see Practitioner of February, March and April, 1891). I have also remarked on several occasions, that while the chemistry and physics of uric acid appear to me to be capable of completely accounting for all the phenomena of acute rheumatism, and the action of all drugs and diets that are useful in treatment, much cannot be said for any other theory of its causation. 742 UEIC ACID — CHAPTER XVI For instance, no satisfactory explanation of the value of alkalies among drugs, or of milk and farinaceous diet, or again of hot baths, blankets, and other sudorifics in general management, can be given on the theory that acute rheumatism is due to a miasm or microbe ; while on the other hand, a comparatively rudimentary knowledge of the solubility of uric acid and the processes which promote its excretion and elimination will suffice to explain them all. In reference to these points I have formulated the statement : " All substances which promote the free excretion and elimination of uric acid do good in the arthritis which is due to it, and con- versely all substances which hinder its excretion and elimination do harm " {British Medical Journal, 1888, vol. ii., p. 10). And though, as explained in the previous chapter, some substances which hinder excretion may yet, by keeping the blood clear of uric acid, prevent arthritis, it is quite true that these substances, when first given, are hable to do harm and produce an attack. And again, the pathological condition, which most hinders the solubility and excre- tion of urates (namely, fever), has just the same effect as the drugs which do this, and frequently precipitates an attack of general uratic arthritis ; hence we are told by a writer in the Lancet, 1893, vol. i., p. 918, that " Enteric fever at its very commencement may present the picture of acute rheumatism." I believe that any acute fever may present this same picture, provided there was in the blood, at the time the temperature began to rise, sufficient uric acid to irritate the joints when it was concentrated upon them ; for fever diminishes the alkahnity of the blood, and dimin- ishes its powers of holding urates in solution ; and I have already pointed out in chapter xv. that the blood is in this way most completely cleared of urates at the beginning of the fever, which corresponds exactly with the observation of the writer quoted above. And I have myself seen, either alone or with others, several cases in which the onset of enteric fever has been mistaken for acute rheumatism. The theory that acute rheumatism is an infective disease and due to a micro-organism which causes the production of lactic acid, has been prominently brought forward by Dr. Newsholme, in the Milroy Ijcctures (Lancet, 1895, vol. i., p. 589), where he points out that there have been epidemics of rheumatic fever in certain years, and that rheumatic fever is an urban disease more than a rural. I have always ■ acknowledged that rheumatic fever may be pro- duced by any fever however caused, whether by a specific micro- EHEUMATISM AND MOKBUS CORDIS 743 organism as in the above cases of enteric, or by acute dyspepsia as commonly seen in a schoolboy from (?) natural causes. Any- thing that diminishes the alkalinity of the blood, and all fevers do this, may produce rheumatic fever if there is plenty of uric acid in the blood at the time. Now we are Uable at many seasons to epidemics of catarrh, in- fluenza and tonsillitis, not to mentioil cases of ill-developed specific fevers such as measles, scarlet fever, &c., which are overlooked and pass unrecorded, and any of these may produce corresponding epidemics of rheumatic fever, but there is here not the smallest proof that the rheumatic fever is due to the specific micro-organism and not to the effect of the fever on the alkalinity of the blood. And Dr. Newsholme himself tells us that other specific febrile diseases as enteric, scarlet fever and erysipelas, are affected in the same way as rheumatic fever, by season, rainfall, &c. Exactly so ! the epidemic of rheumatic fever varies with the epidemic of these diseases because the rheumatism is, to a large extent, the result of these diseases. Then as to rheumatic fever being an urban disease rather than a rural, this may show merely the relation of acute rheumatism to increased meat eating, which is more common in urban dis- tricts, and gout is, doubtless for the same reason, an urban rather than a rural disease ; but I have never heard this used as an argument for its being an infective disease. Dr. Newsholme looks upon throat symptoms as a part of the disease, and the place where no doubt the micro-organism obtains an entrance into the body ; but if this is so how does an alveolar abscess serve to precipitate a relapse ; or, how does an injury to an ankle or shoulder when the skin is unbroken and no micro- organisms are introduced, serve to bring on acute rheumatism ? In a word, every micro-organism ; specific or other, that pro ■ duces fever may produce rheumatism, but then there are several other things, not in any way connected with micro-organisms, which will do the same, but all these things— injuries, micro- or>»anisms and drugs — afiect in one and the same way the solu- bility of uric acid in the blood, i.e., they hinder it and render it insoluble in that fluid. Again, Dr. Newsholme points out that the tendency to relapse is common to rheumatism and other fevers ; but he is also kind enouo^h to allow that frequent relapses occur when animal food is given too early after an attack. This parallel is little more than skin deep on the surface of 744 UEIC ACID CHAPTER XVI the word relapse, for surely a relapse after enteric fever is one thing, and a relapse after rheumatic fever another and a totally different thing. It is surely possible to prevent the relapse of acute rheumatism by continuing the salicylates, or by abstaining from giving the animal food or the iron ; but is it possible by any means what- ever to prevent the relapse of enteric fever ? Then again, the relapse of acute rheumatism can be produced — is, in fact, generally produced — by some error in treatment. I have seen many such relapses, and know exactly how they were produced, and so would anyone else who knew anything about the solubility of uric acid, and watched the treatment carefully ; and I will undertake to produce relapses in any patients who will consent to its being done. Then again, if acute rheumatism is due to a micro-organism, how is it that salicylates cure it (as I have pointed out that they do) in proportion to their power of ehminating uric acid ; and I can now also show (see cases narrated further on) that if any- thing prevents their acting as solvents of uric acid they fail to cure it. From the other side it would have to be shown that salicylates prevent the growth of the micro-orgamsm ; and that iron, lead, mercury, and other metals increase its growth as they make the pains worse. The finding of a few micro-organisms in the fluids of a case of acute rheumatism is to my mind a very long way from affording proof that the acute rheumatism is due to the parasites ; except quite indirectly. I should admit at once that it might be due to them if they altered the alkalinity of the blood, or produced fever : but never- theless in a person who was free from excess of urates in the blood th«y would have no power to produce either arthritis or any other irritation of fibrous tissues, and as I have pointed out in previous chapters, many parasites seem to be unable even to produce fever in those whose blood is practically free from col- Isemia : and in illustration of this we generally find that those who suffer frbm arthritis with the onset of enteric fever are patients who have previously had arthritis, or have well marked signs of the presence of coUsemia at the time of onset of the fever. Again, to have an attack of a microbic disease very often protects the individual afiected from further attacks ; but in rheu- matism this is not the case, for the patient who has had one RHEUMATISM AND MOBBUS CORDIS 745 attack is more liable ever after to have another. And this is also a marked characteristic of gout, for which a microbe has not, I think, as yet been suggested, though it is certain to be so if the profession continues to suffer from microbe mania much longer. In the case of gout, however, we have a quite satisfactory phy- sical explanation, which we have discussed at length in connection with the phenomena of the uric acid filter, and I see no reason why the same explanation should not apply to the arthritis called rheumatism ; indeed my practical experience convinces me that it does so. I shall now pass on to examine the points of diSerence between rheumatism and gout, and see how far the different conditions under which the uric acid acts at difierent periods of life will enable us to explain them. My friend, Dr. A. E. Garrod, mentions my researches on uric acid in the most kindly manner ("A Treatise on Rheumatism," p. 27), but yet objects strongly to my suggestion that acute rheumatism may be due to uric acid. He says : " Many objec- tions present themselves to such a theory of acute rheumatism, which appears to me to attach undue importance to the articular troubles, whilst offering no explanation of the occurrence of the cardiac and other visceral lesions of rheumatism." I believe, as I have already said {Practitioner, February, 1891, et seq.), that uric acid is quite capable of producing all these lesions, and I shall go into the matter presently ; and Dr. Garrod goes on : " Again we have the fact that uric acid has not been found in the blood of rheumatic patients, which Dr. Haig explains by supposing that this substance is driven out of the blood into ,the joints by the high and rising acidity due to the fever ; but no deposit of sodium urate is found in the joints. Lastly, it is difficult to believe that the same materies morhi is capable of giving rise to two such _ different disorders as rheumatism and gout." This last statement is somewhat indefinite, but I hope to be able to show that the difierences are those of degree rather than of kind, and that they are due to differences in metabolic activity, in functional activity, or in chemical condition, which affect differ- ently the solubility of uric acid, while the total quantity present also differs in the two conditions. It has never been a matter of surprise to me that Sir A. Garrod was unable to find uric acid in the blood in acute rheu- matism ; on the contrary, if he had found a large quantity in the blood, it would have been a death-blow to my theory of the causa- tion of acute rheumatism. 746 URIC ACID — CHAPTER XVI He does find it in the blood in gout because, as I have pre- viously said, gout is a local disease ; in which the acidity of one or two joints is specially raised, and in these all the uric acid that the blood brings in their direction is rendered insoluble and re- tained, giving rise to irritation and inflammation ; but there is no general and complete clearing of the blood from uric acid, except in so far as the specially affected joints take it up. In acute rheumatism, on the other hand, the conditions are different ; there is a general rise of acidity which clears all the uric acid out of the blood, driving it into the j oints and elsewhere ; little or none remains in the blood because the alkalinity of the whole circulating fluid is diminished ; while in gout, though alka- linity generally is diminished, it is only in the especially affected joints that the urate is rendered completely insoluble. This explains a fact previously mentioned, that when I inten- tionally produce an arthritis by giving acids, the clinical picture resembles rheumatism rather than gout, because I diminish the alkalinity generally, and drive the uric acid out of the blood into joints and fibrous tissues generally ; if I . want to imitate gout I must diminish the alkalinity generally, to some extent : but I must also produce local irritation and rise of acidity in a joint by a blow, seton, or other injury, and this will precipitate the uric acid locally, while the blood still contains some. In further objection to my explanation Dr. A. E. Garrod goes on to say, " but no deposit of sodium urate is found in the joints." He evidently considers the fact that the urate is not found there after death, as equivalent to proof that it has never been there. My researches have led me to take a very difierent view, and to believe that even in gout, when urate is retained, so to speak, in mass, and eventually thrown down in crystals of biurate, it may be removed so completely as to leave little or no trace of its presence after death, except the erosions in cartilage, &c., which some weeks, months, or years before death were completely filled up by it. Much more so in acute rheumatism, where the urates are never present in mass, are only present for a few hours and in the form probably of colloid urate, and produce only a little interstitial irritation. So soon as the acidity which drove them into the joints falls away, and the alkalinity of the blood rises, the urates in the joints are quickly taken up in solution in the blood, and passing through it arrive at the kidney and are excreted. Hence the ex- KHEUMATISM AND MORBUS CORDIS 747 cretion of aric acid is, as I have pointed out, directly as the alkalinity of the blood, and inversely as the acidity of the urine, a relation which holds both in disease and in health, and can be demonstrated artificially at any time by using drugs which afiect the alkalinity. As previously pointed out, Sir A. Garrod suggested that uric acid, when in the blood, is attracted difierently by dif- ferent organs, and that in certain organs, which for various causes are less alkaline than the blood, " the uric acid becomes less sol- uble and more easily retained." (" Lumleian Lectures," British Medical Journal, 1883, vol. i., p. 549). If this suggestion be granted, and if it be further granted, as also shown by Sir A. Garrod, that the cartilages and fibrous tissues of joints are both less vascular and less alkaline than the other tissues or the' blood (see previous chapter), then the arthritis produced by uric acid is a simple matter of solubility, and can be produced at pleasure to almost any extent, and this, I have good reason to believe, is the case. But there are other fibrous tissues in the body besides those of the joints, and what is to prevent them from being occasionally less alkaline and from suffering in consequence from a precipita- tion of colloid urate upon them, and the irritation it sets up ? What about the fibrous tissues in the great lumbar fascia (lum- bago), of those that form the sheaths of great nerve trunks (sciatica), and of those again that support the various coats of the intestinal walls (cohc), of which I have already spoken, or of the fibrous tissues in the pelvic organs and fascia, especially in women, not a few of whose pains and inflammations in these organs may have an identical pathology with that of gout of the intestines (chapter X.), and that some of these inflammations in women are rheumatic, has, I believe, already been suggested by Dr. Gervis ? But there are fibrous tissues in a more vital organ than any of these, an organ which is sometimes said to be in part analogous to a joint, and is often affected along with the joints in acute rheumatism. I mean the heart. Will anyone who has looked at a transverse section of the heart wall tell me that the visceral layer of the pericardium is not con- tinuous with fibrous tissue, which fibrous tissue forms the fascia of the heart muscle, and that the fibrous tissue of the endocardium on the opposite side of the wall is not also continuous with the fascia of the muscle in the same way ? Now muscles become acid as the result of contraction (Foster, " Physiology," 1877, p. 49), and if in some regions of the cardiac 748 UEIC ACID— CHAPTER XVI muscle, in proximity to its fibrous investment, the products of functional activity and contraction are not quickly removed, the muscle and its adjacent fascia may have their alkalinity so far reduced as to form foci, in which the uric acid circulating in the blood becomes according to our premisses " less soluble and more easily retained." Such retention, also in accord with our premisses, giving rise to local irritation, which still further reduces the local alkalinity, more uric acid is deposited, and so on till a considerable area of inflam- mation going on to prohferation of fibrous tissue and scar forma- tion is the result. If this may be the effect in the lumbar fascia, why not also in the pericardium and endocardium ? The same causes that drive uric acid into the joints and set up arthritis may drive it into the fibrous tissues of the heart and produce endo- and pericarditis. Then with reference to microbic origin, it has been pointed out (^British Medical Journal, 1900, vol. ii., Epitome, p. 64) that the pericarditis of Blight's disease, when the blood, we may reinember, is full of granules, is aseptic and sterile. And a somewhat new light is, I think, thrown on the effects of pericarditis on the function of the heart by the ingenious sug- gestion of my colleague, Mr. H. L. Barnard {Lancet, 1899, vol. i., p. 1080), that the pericardium bears to the heart muscle the same relation that the leather case of a football does to its expansile inner casing, or that of the outer case of a bicycle tyre does to its inner case. In a word, that the heart is protected from sudden and disastrous dilatations by the strong fibrous pericardium, its outer casing. It follows from this that if there is general inflammation of the pericardium its. strong resisting support may be replaced by bulg- ing and yielding in various or all directions, and thus severe and fatal dilatation of the heart may qaickly supervene. We can now see more clearly than ever the importance of absolute and complete rest in all such cases, and the value of the method mentioned on a future page of giving iodides with salicylates to keep down the blood pressure as much as possible, till the inflammation of the pericardium subsides, and it has time to con- solidate and get strong once more. For Mr. Barnard's very interesting remarks on the rush of bloodj into the heart, which muscular contraction, especially the action of the abdominal muscles, can produce, and the value of the peri- cardium in resisting undue distension of the heart by such forces, I would refer to his very interesting paper. EHEUMATISM AND MOEBUS OOKDIS 749 But I will here point out that witk the useful instrument which Mr. Barnard and Dr. L. Hill have invented (see chapters v. and xviii.), we can gauge very accurately from day to day what the systemic blood pressure is doing, and what power it may have of dilating the heart and pericardium. And Mr. Barnard also points out that once serious softening and dilatation have taken place, the pericardium like the outer casing of a tyre may be beyond repair. But here, I think, the parallel does not hold entirely, for the pericardium is not made of lifeless fibre and rubber, but of living fibrous tissue, which given time and freedom from pressure, will certainly consolidate and contract, and become perhaps even stronger than before ; but then, unfortunately, its undue thickening and contraction may become a danger to the nutrition of the heart muscle within it. These facts, and my own experience of cases, leave in my mind no doubt that the two great causes of dilatation in rheu- matism are, (1) the softening of the fibrous pericardium, or similar injury of the cardiac muscle which rheumatic inflammation pro- duces, and (2) the high blood pressure which excess of uric acid in the blood also produces. And in rheumatism the one condition is constantly alternating with the other. No sooner has uric acid strained the heart valves and pericardium and then been precipi- tated on those fibrous structures causing inflammation and soften- ing, than the debility which supervenes brings uric acid again in excess into the blood (colliemia), and this again dilates the heart and strains still more the damaged valves and pericardium. A rational understanding of this causation is the first thing, and a rational treatment of uric acid, and coUajmic high blood pressure, the extent of which we can now measure in capillaries and larger vessels with great accuracy, is the most important point. The value of iodides and salicylates in treatment is probably due to their afiecting both the great causes mentioned above. The salicylate removes uric acid from the damaged fibrous tissues and lessens their inflammation, while the iodide prevents the excess of uric acid, which the salicylate brings into the blood, from com- bining with alkali and producing severe collsemia, and thus pre- vents it from increasing the strain on the damaged valves or pericardium. We know (p. 97) that the effect of sahcylates in rheumatism is to slow considerably the capillary reflux, as they increase the granules in the blood. 750 URIC ACID — CHAPTBE XVI The efEect of an iodide, on the other hand, is to diminish the granules in the blood and quicken the capillary reflux, and we must take the capillary reflux and the blood pressure as our guides, and use the one drug to neutralise the evil efiects of the other. But as regards the endocardium at least, this is by no means the whole story, as there are causes just such as those which are active in the case of the joints, namely, friction and percussion, which may afiect its alkalinity also. And we can now also see that the pericardium is subjected to pressure and strain by any force that tends to dilate the heart. Just as in the case of the joints, the heat and friction of exercise often determine which joints shall be least alkaline, and so get the largest share of the uric acid ; so in the heart the fibrous tissues of the valves may suffer from friction and percus- sion, and so be rendered the least alkaline of all the fibrous tissues of the heart at a time when there is a general fall of alkalinity. Now, the effects of exercise on the reaction of the valves of the heart will be greatest where the work and strain are most severe, this possibly accounting for the incidence of the chief rheu- matic changes in the left side during extra-uterine, and the right side daring fcetal life. In this way any unwonted exertion or strain on the heart by giving rise to a little local irritation on the opposing surfaces of the mitral or aortic valves may diminish the local alkalinity, cause a local precipitation of uric acid and consequent irritation, and this irritation may, we will suppose, be repeated and repeated till what were at first scarcely visible pin-point nodules of irritated connective tissue, come at last to form well-marked nodules and scars. Such a process of reasoning helps us to understand how, what is at first a small local irritation in the mitral valve is carried on and on by a frequently recurring uric acid irritation till the whole valve is reduced to the condition of a thickened scar, and we have to deal with the final stages of mitral constriction. And if, as we now know, an excess of uric acid in the blood obstructs all the capillaries and raises blood pressure (pp. 167 and 235), it is clear that it must throw increased work on the left side ■of the heart, first of all on the aortic valves, and then during systole, owing to the increased resistance to be overcome, on the mitral valves also : and anyone who has listened to the loud banging of the aortic valves during a uric acid storm (in migraine, for instance) will have no difficulty in realising what I mean. ' RHEUMATISM AND MOEBUS CORDIS 751 So that the valves of the left side of the heart are most ex- posed to injury by friction and percussion, just at the very time when there is an excess of the irritant uric acid in the blood ready to be precipitated upon them should the heat of action cause them to lose for a time their normal alkalinity. And once a spot has become invaded by uric acid the irrita- tion is always liable to be kept up and repeated until a serious and extensive lesion has been produced. We have then certain conditions to which fibrous tissues of the heart are liable in common with all the fibrous tissues of the body tending to precipitate uric acid upon them, and we have certain other conditions which are common to the fibrous tissues of the heart valves and those of the joints. Can we wonder that these structures are so often affected in acute rheumatism at the same time, and doubtless the liability of the endocardium to friction, percussion and strain accounts for the greater frequency of endo- carditis as compared with pericarditis. With regard to the causes that determine the structures that will be invaded by uric acid, I will quote what Dr. A. E. Garrod (loc. cit., p. 82) says as to the order of invasion of joints : " The influence of external causes in determining the seats of the lesions is far less conspicuous in rheumatism than in gout, but as has been already stated, when rheumatic fever follows an injury, the joint nearest to the seat of injury is usually the first to suffer." Exactly so ! the injury diminishes first of all the alkaUnity of the affected structures, and then if the injury is sufficiently severe to cause general fever, the alkalinity of the whole body is dimin- ished. The uric acid is first rendered insoluble near the injured structures (hence these are the first to suffer), and later on in other fibrous tissues of the body (see Uric Acid Filter experi- ments, p. 177). Dr. Garrod also says (same page) : " Dr. Puller has laid special stress upon the liability of joints Which have been the seats of local mischief. Dr. Maclagan also regards strain as the most important influence at work in determining the seat of rheumatic lesions, and Dr. Peter Simpson and others have expressed their belief that the joints which are most exercised are specially liable to rheu- matism. M. Besnier, who is inclined on the whole to agree with them in this opinion, does not think that the rule is sufficiently general for the establishment of a definite law." There is no necessity to establish a definite law, but every one of the conditions here mentioned can be quite easily translated in terms of uric acid causation. 752 UEIC ACID — CHAPTER XVI ^ Joints that have been the seat of local mischief will contain a certain amount of fibrous scar tissue, which, as we know, is very- lowly vascular, and this will easily have its alkalinity reduced and very slowly recover it again, and meanwhile uric acid will be accu- mulated and retained in it. And the same argument will apply whether the local mischief was in the first instance due to uric acid or to external agencies. Once a scar has been produced, uric acid will account for its continued irritation and progressive enlargement. Thus, suppose a young woman has acute rheumatism, and a few pin-point nodules are left on the mitral valves ; she apparently recovers from her attack, and perhaps no murmur has been heard, but the valve, nevertheless, has been damaged to the extent of the above nodules, and these form microscopic scars, on which, however, uric acid will be again precipitated at the firgt opportunity. And it may not have very long to wait, for, as I have shown above (fig. 31), every woman has more or less coUaemia at her menstrual period ; and this, by the increased blood pressure it pro- duces, may strain the mitral valve, diminish the alkalinity of the damaged nodules, and then, as the alkalinity is generally dimin- ished at the end of menstruation, clearing the blood of uric acid, and putting an end to the coUsemia, some of the urate in circu- lation may be precipitated upon the mitral valve, especially upon its damaged portions, and, increase of lesion results (see pp. 141 and 157). And when this process is repeated month after month for years, we can easily understand how a microscopic scar becomes at last a leathery and calcareous mass, and why a button-hole mitral is more commonly met with in women than in men. We can also understand the connection which some have noticed between dysmenorrhcea and certain rheumatoid joint changes : for dysmenorihoea means a more than usually marked fall of urea and acidity, a more than usually severe collsemia, and consequently more severe and widespread irritation in the already damaged tissues of joints or valves. So that these changes in fibrous tissues due to the irritation of uric acid are more liable to progress from small to great in women than in men, and are still more liable to do so in those women who suffer from dysmenorrhcea, and this dysmenorrhcea is often simply the result of congestion due to collsBmia, and when we understand this causation we cease to wonder that correct diet so often makes a clean sweep of all these troubles. RHEUMATISM AND MORBUS CORDIS 753 Before leaving ttis subject I must quote what Dr. A. B. Garrod says (loc. ait., p. 53), on the influence of sex : " Dr. Cheadle has called attention to the greater liability of girls to almost all the individual manifestations of the disease, and my own observations lead me to think with him, that not only chorea, but also sub- cutaneous nodules, erythema, and rheumatic heart afiections, are considerably commoner in female than in male children. It should be mentioned, however, that Hirsch found that rheumatic fever occurred more commonly in boys than in girls under the age of fifteen." From this latter statement we may, periaps, infer that is is more common in girls after fifteen, when the menstrual in- fluences I have spoken of come into play. In addition to this, the great activity in nutrition and metabolism, when at this time of life girls dash at one bound from childhood into womanhood, must afiect the formation and excretion of urates, and greatly increase for a time the possibilities of acute rheumatism and of collsemia and its various results ; and Dr; Cheadle says {Lancet, 1889, vol. i., pp. 824, 871) that girls of 10-15 years old are twice as liable to rheumatic fever as boys of the same age (see also fig. 59). I quite agree with the authors quoted by Dr. Garrod, that the joints which are most exercised are specially hable, and believe that it is often possible to tell the occupation of the patients, by observing the joints chiefly affected. With regard to this point, I am indebted to Dr. Aylmer Dumat, of Durban, for the interesting observation that precisely the same relation to exercise holds for the severe myalgic pains which ac- company the onset of dengue, and he narrates how both in himself and in patients, an attack coming soon after a long or hard ride was accompanied by pains which were most severe in the adductor muscles of the thighs. He also gives it as his opinion that the feeKng of intense fatigue which precedes the myalgic pain is due to uricacidsemia. It almost seems as if dengue furnishes but one more instance of the power of a febrile epidemic disease, perhaps akin to malaria, or still more to influenza, to produce rheumatism just as is done by the febrile diseases discussed in reference to Dr. Ncwsholrae's theory on a previous page. As regards physiology, the pains of rheumatism resemble, I believe, those of gout in being worse at night and better in the morning ; that is to say, they correspond with the natural fluctua- tions in the uric acid excretion, though this may be often less conspicuous in rheumatism than in gout, as the former, being an acute disease, overpowers for a time the natural fluctuations ; and 48 754 UEIC ACID — CHAPTBB XVI in accordance with this the first symptoms may occur at very various hours. The causes which appear to precipitate the attack are just those which would be certain to raise the acidity of the urine and diminish the alkalinity of the blood — e.g., a chill, getting wet through, or sleeping in a damp bed ; the excretion of acid from the skin is interfered with, up goes the acidity, a certain amount of uric acid is driven into the joints, this causes some fever, and the rise of temperature still further diminishes alkalinity and sends all the uric acid into the joints. Temperature in rheumatism at times resembles that of gout in being high at night and lower in the morning ; at other times the highest point is in the morning. Of the temperature curves given by Dr. A. E. Garrod (loc. cit., p. 60) of rheumatic fever treated upon the expectant plan, in fig. 1 the highest points are in the evening, in fig. 2 they are for the most part in the morning, and in fig. 5 there are some in the morning and some in the evening, though the morning preponderates. I think, however, that this is not very difficult to explain, for in rheumatic fever after the first start ofi (which is due to a very abnormal rise of acidity which may occur at any time, as it overpowers and obliterates the normal curves) the joints have their alkaUnity very considerably diminished, and then the only efiect of the alkaline tide or its representative will be to bring more uric acid to these joints where it is further rendered insoluble and retained, increasing the irritation in the joints, and so raising the temperature in the morning (see previous remarks in chapter XV., on the Causation of Arthritis in Gout, also uric acid filter ex- periments, p. 177). But there is still one important fibrous tissue of the body which we have not mentioned, and I was reminded of the possibility that it also may be attacked by uric acid by receiving a copy of a paper read by my friend Mr. Hope-Lewis at an Inter-Colonial Medical Congress at Brisbane. I gladly avail myself of his kind permission to reproduce it, as his suggestion as to causation is a most interesting one, and if he is correct we shall no doubt soon meet with other cases of which a similar explanation may be given. Here as elsewhere a true explanation is soon found to explain everything, a false one is quickly found to be useless. The paper is headed " The Brain Fever of the Drama," and I reproduce it as sent to me : — KHEUMAa?ISM AND MOBBUS COEDIS 755 " Me. President and Gentlemen, — I feel that in reading a paper under the above heading some introduction is demanded. I intend to give such an introduction, and at the same time to ask physicians to bear with a surgeon who has essayed to read a" paper in the medical section. I by no means claim to have discovered a new disease. The case I am about to describe presented symp- toms which were of an extremely interesting character, and which called for a reasonable explanation. " I have endeavoured to give such an explanation, and only regret that I am unable to quote several cases of a similar cha- racter. This may be rectified. There may be amongst my audience others who have seen cases of a similar character, and who were unable to classify them. " All medical men who for relaxation and pleasure go to the theatre will remember how at the end of the first act of a modern drama, or possibly in the second, the heroine receives a frightful shock at seeing the villain attempt to shoot or stab her lover. She thinks her lover is dead, and promptly has ' brain fever.' It is an invariable consequence of severe mental shock in the case of the heroine. Six or twelve months are supposed to elapse before the next act. The exigencies of the play demand an interval. The heroiae is not ill aU the time, but judging by the pallor of her face and the dressing wrap she wears in the next act, her convalescence has been delayed, and she always leans somewhat heavily on the rector's (her father's) arm. You do not have an opportunity of watching her illness. You only ascertain from the stage nurse that the heroine was desperately ill for some weeks and was unconscious, and that her mind was a blank from the time of the shooting or stabbing until one day she recognised that , she was being Idndly attended to by loving hands. Could it have been enteric ? No. For years I had wondered what this illness was. I had no opportunity of seeing the heroine after the shock — the curtain had dropped, except when the audience demanded her appearance before the curtain to receive its plaudits. In the next act she was convalescent. She had no sequelse to guide one to a diagnosis except mental debility and fear of another appear- ance of the villain. That did not help one much. At last I met such a case in actual practice, and as it must needs be interesting to the profession I herewith narrate it. " Mrs. A., aged 47, nullipara, married nineteen years, while apparently in her ordinary health, received news by telephone one morning while at breakfast of the sudden death of her sister who 756 UEIC ACID — CHAPTER XVI resided some eigtt miles away. She at once drove to her sister's house and was busily engaged during that day in duties connected with her sister's decease. She was deeply attached to her sister and felt the loss most acutely. She returned to her own home that night, a drive of about eight miles, and again next day drove to her sister's house and returned about 4 p.m. to her home, and went immediately to her bedroom with a splitting headache, and lay down on the sofa. Both days were windy and cold for the time of year. On account of excitement she had taken hardly any food on these two days. She was a very nervous woman. On leaving the sofa to go to bed she fainted. I have no accurate account of the case for the next two days, February 2 and 3, but on February 4, her p.m. temperature was 103'8. The chart gives a good idea of the progress of her complaint from that date." [I regret that want of space prevents my reproducing this chart, but it obviously difEers from that of an enteric case in that the highest points 104°-105° are on the 7th and 8th days of illness ; then it falls steadily till on the 20th to 22nd days it is between 100° to 101°, then rises, reaching 103° on 26th day, keeps above 102° till the 30th day, then falls slightly below 102° to the 32nd day, when salicylate is given, and thence more decidedly to touch normal on the 39th day, and is below normal all the twenty-four hours on the 42nd day, and never rises again to 99°. " I saw the case in consultation with Dr. A. G. Parchas on March 4th, the •32nd day of her disease, and her condition was then as follows : Her body had kept up its fat very well. Her pupils reacted to light sluggishly and were unequal. Her speech was slow and tedious in utterance. She had distinct ' tacJie cerebrcde ' on the skin of her chest. Her tongue was red, clean and dry. Pulse thin and very rapid. She had the general appearance of a meningeal case. Her symptoms all through had a neurotic character. She would say she could not swallow, if asked to turn round she would say she could not do so. She had great intolerance of light and sound. The room was kept dark and tan laid on the road near the house . She never had any diarrhoea, nor had she any spots. She had a great deal of flatulence and retching and had bilious green vomit- ing. She complained of aching in the legs, which were rubbed well and thereby somewhat relieved. She was very fat at the commencement of her illness, and at the end though the arms and legs got thin, the abdomen and back kept fat. She was very flushed at times. She had fluid food principally, and water and* nutrient enema ta as necessary. She took very little food bv BHEUMATISM AND MOEBUS COEDIS 757 the mouth. She lost her hair during her convalescence. My dia- gnosis of her case at the time of the consultation was that she was suffering from aric acid meningitis, and with Dr. Purchas' approval she took twenty-grain doses of salicylate of soda. There was a marked improvement in her general condition from this time. My opinion of this case is that it was a case of deposit of urate of soda on the meninges in the same way as that salt is showered on the serous surface of a joint. Dr. Purchas who has had a very large experience in enteric cases was certain it was not a case of typhoid, and was at a loss to classify the disease under any satisfactory heading. Doubtless many practitioners have had similar cases of a feverish prolonged attack following worry or serious and sudden mental shock, which have run a certain ex- tended course to a successful termination, aided by or in spite of medicines. On questioning our patient and her husband it was ascertained that she had rheumatic pains prior to this attack for some considerable time, and that she was of a rheumatic diathesis. Her pains had been most severe in the posterior cervical muscles and fascia. " Since observing this case I have come across another patient who some years ago had an illness of a very similar character to the one already described, and which also was caused by, or at any rate came on after, a severe mental shock. This second patient's hair turned white during the illness and has remained so since. Her age was 38 at the time of her attack. I am well aware that in describing this case as one of uratic meningitis I am treading on dehcate ground, but since my personal acquaintance with Dr. A. Haig commenced some five years ago, I have been keeping a sharp look-out for cases that one can fairly and reasonably classify as being due to the vagaries of that potent toxic agent. This, I submit, is a reasonable explanation of the cause of the illness before described. It is, no doubt, a rare manifestation of the uratic storm, but that uric acid causes migraine is now an established fact. In the case of migraine the position of uric acid is in the blood in greater proportion than it is in the large glands, joints or muscles, and with it in that position we get high arterial tension. If when in this condition we get an injury or a severe impression conveyed to any particular part my theory is that at that spot the uric acid storm bursts and expends its energy. "I saw Mrs. A. just before leaving Auckland. She is now in good health with the exception of rheumatic pains about shoulders. She informs me that her mind was a complete blank from the 758 UEIO ACID— CHAPTER XVI second day on which she visited her deceased sister's residence until her convalescence commenced. She was not aware that she had been seen by me until she recovered." Since these notes were in my hand, I have seen one case in the journals that made me think of the possibility of a similar origin, and if it had been under my care, I should certainly have tried salicylates. It is recorded in the Lancet, 1900, vol. i., p. 533, by E. F. Eliot, F.R.C.S., L.R.C.P.Ed., under the heading "Measles in a patient aged 18 years, comphcated with meningitis and spinal myelitis ; recovery." The cerebral trouble began on the fourth day of the rash with restlessness and teeth grinding followed by convulsions. There was a scanty menstrual flow for a few hours on the previous day. Did this produce the collsemia the uric acid of which was subsequently precipitated on the meninges ? Then two weeks later when the temperature was 100" 6, she was put on iodide of mercury alternating with quinine, iron and digitahs, and the temperature rose to 102°, and this alone would have raised in my mind the question of urate irritation as these drugs would cause retention, and therefore do harm in all urate irritation of fibrous tissues. That she eventually recovered is no argument against this, for as we know, even acute rheumatism treated with acids may eventually recover. And measles, as we shall see further on sometimes causes endocarditis. Was this a case of rheumatic meningitis precipitated by measles acting on the coUsemic fluctuation produced by menstruation ? The future will no doubt tell us whether Mr. Hope Lewis's most interesting and suggestive case is the key to the causation of a number of others ; and I will conclude by suggesting that in any case of obscure origin, and that might conceivably be due to uratic irritation of fibrous tissues, salicylates should be tried, espe- cially if the administration of drugs that hinder the solubility of uric acid, such as iodide of mercury, iron, &c., appears to raise the temperature ; and that I have acted on this myself, will be seen in the description of figs. 69 and 70. As to season. Acute rheumatism is not generally considered to present any definite relationships ; and this is in accordance with what I have said, namely, that the attack is often the result of a severe cold or wetting, which may come at almost any season of the year, and that this interferes sharply with the action of the skin, producing a marked fall in general alkalinity which over- powers the natural curves ; the only thing that is necessary for EHEUMATISM AND MOEBUS COEDIS 759 acute rheumatism to result is, that at the time of the wetting the blood should contain a considerable amount of uric acid ; and this coUiBmia would for the reasons previously gone into (fig. 4), be most Ukely to be met with in the spring and summer rather than in the winter, though severe exercise and perspiration would probably produce a temporary collsemia at any time, hence the very serious effects of a wetting following close upon these conditions of muscles and skin ; and my friend the late Dr. Eccles read a paper at the West London Medico -Chirurgical Society (see Lancet, 1891, vol. i., ■p. 1433) showing that exposure to cold and damp after fatigue, had important influence in the causation of rheumatic arthritis, and mentioned that his experience in over a hundred cases sup- ported my views on the etiology of the trouble. After what I have said about fatigue (figs. 46 and 47), there should be no difficulty in completely understanding this sequence of causation (see also " The Practice of Massage," by A. Symons Eccles, p. 86). As regards experimental work, an arthritis resembling that of acute rheumatism can be produced without difficulty, or when present can be made worse or a relapse can be produced in exactly the same way and with the same drugs as in gout ; indeed, as I have said, when one produces a relapse of gout by raising the acidity, the symptoms more often resemble those of rheumatism in that they affect several joints. In my own person I have often produced symptoms which would, I have no doubt, have been pronounced rheumatism by anyone unaware of their origin. And in hospital cases it is often quite easy to see how diet weather, or other independent sources of inflammation produce a rise of acidity (diminished alkalinity) and cause a relapse or aggra- vation of the rheumatic symptoms. Thus I have related* how in a case under my care, a peridental abscess raised the temperature and produced a relapse of the rheumatism ; and as I can now see, but did not understand at the time, the action of the rise of temperature was probably aided and abetted by the quinine which I gave for his dental troubles (see Action of Quinine, p. 49). The treatment of acuta rheumatism by lemon juice (combined, by the way, with plenty of hot water, blankets, and other sudorific treatment) has been supposed by some to be an instance of the cure of rheumatism by the administration of an acid which would be strong evidence against uric acid causation. • Wood's "Medical and Surgical Monographs," February, 1890, p. 355. 760 UEIC ACID— CHAPTER XVI But closer investigation hardly bears this out, for first of all, the lemon juice is given with copious draughts of hot water, and the patient is in bed wrapped up in blankets ; so that the skin is kept active, and there is a considerable excretion of acids by this channel. Secondly, the effects of considerable quantities of lemon juice on the acidity of the urine is very slight and transi- tory, as I can vouch for from my own experiments. On several occasions I took either strong infusion of lemon in hot water, or strong doses of citric acid so far as I thought it safe to go (as citric acid in large doses is a powerful gastro-intestinal irritant), and the result as regards the acidity of the urine was very small (see previous remarks on the Effect of Taking Cider, Fruit, &c.) ; on one or two occasions taken from hour to hour, my curves show that it rose a little at first ; but the effect on total acidity of the twenty-four hours was little or nothing, and where the lemon is combined with copious hot water and blankets, I have no doubt that the result is a fall of acidity and an increase of the alkalinity of the blood, which will account for the cures lemon has been said to effect in some cases. On this point Dr. A. E. Garrod says {loc. cit., p. 200) : " Dr. Fuller, on the other hand, found lemon juice do good in only three out of a series of twenty-nine cases, and ascribed to it the production of depression, griping and diarrhcea." If it produces griping and diarrhcea this would bring about a fall of acidity of the urine, and an increase of the alkalinity of the blood, and it might in some cases be of use in this way, just as a drug about which I have previously written, and which has been more in favour for the treatment of rheumatism than lemons, namely, colchicum. We now know also that griping and diarrhoea are merely a uratic irritation of the fibrous tissues of the intestinal walls (chapter x.). They represent the early and local action of the lemon juice where it raised the acidity ; later on the intestinal irritation and diarrhcea would greatly lower the acidity. Dr. A. E. Garrod says {loo. cit., p. 201) : " The extensive em- ployment of colchicum in the treatment of acute rheumatism was doubtless owing to the supposed intimate relationship of rheuma- tism and gout." My own experience of colchicum showed that it produced considerable intestinal pain and irritation, and as the result of this a fall in urea and acidity, and the falling acidity brought about a plus excretion of uric acid. It should, therefore according to my rule, be useful in all arthritic trouble which is due to uric acid. About its value in gout there is no dispute and it is interesting to note, as I have previously remarked, that some EHEUMATISM AND MORBUS COEDIS 761 have considered that in gout where it fails to purge it fails to do good, which is in favour of my argument. In rheumatism it has been, next to salicylates and alkalies, one of the best known treat- ments, and if I am correct, it really acts as an alkali in the way I have mentioned. But it is indeed difficult to believe that either the lemon juice or the hot water or the blankets have any eSect upon microbes. About cinchona or quinine, opinions are divided, but combined with alkali Sir A. Garrod, Sir Dyce Duckworth and others are in favour of its use. If it is given with sufficient alkali to keep the urate in solution, I think it may do no harm, though its action is, as I have said, to produce considerable coUeemia ; where there is much urate in the spleen, especially where the spleen is large, and where it produces such coUsemia, there would probably be con- siderable headache as its result. Besides this quinine contains a xanthine element, and this will go to increase the available uric acid (see p. 49). Of alkahes Dr. A. E. Garrod says {loc. cit., p. 203) : " The alkaline treatment renders the highly acid urine neutral or alka- line, without causing any increase in its quantity. The blood is found to coagulate more slowly, and the frequency of the heart's beats is considerably diminished." The reason why the urine is not increased and why the heart's beats are diminished is not, I hope, difficult for anyone to understand who has read my previous chapters, and I regard these as conclusive signs that the alkali has produced considerable collsemia, which, under the circumstances, we should expect ; and Dr. Garrod goes on : " But the chief claim of this treatment was that it diminished the liability to cardiac im- plication, and in support of this claim the statistics of Drs. Dickenson, Senator, Chambers and others may be quoted, all of which show a considerably smaller proportion of cases with endo- carditis and pericarditis among patients treated with alkalies than amongst those treated by other methods " (see also my case of endocarditis further on). It is interesting to remember also that those who used ammonia in the treatment of acute rheumatism found that the urine remained acid and the pains severe, but that if alkaline salts of sodium or potassium were substituted the urine became alkaline and the pains were reUeved (see Dr. Fuller, Lancet, 1862, vol. ii., p. 669, and my paper on the " Action of Salicylates in Rheumatism," Medico- Chirurgical Transactions, previous references). A similar claim of cardiac immunity has now been made for 762 UBIC ACID — CHAPTER XVI salicylates by Dr. Mitchell Bruce* and others', and if the cardiac troubles are due to uric acid it is easy to explain the action in both cases, but it seems to me that no other rational explanation has as yet been suggested. Both drugs have the same action on uric acid, but otherwise they have little in common. As regards the treatment by salicylates, I have pointed out that the excretion of urate during the first few days of their use in acute rheumatism is enormous, that the excretion is not only ab- solutely large, as 26 grs. in the twenty-four hours, but that uric acid bears an abnormally large relation to the urea excreted along with it, as 1 — 17 in the case which excreted the 26 grs. and 1 — 14 in the case of a boy of 14 also under my care (see fig. 68). This figure showfs an enormous excretion of urate in the first twenty-four hours in which salicylate of soda was taken, the abso- lute quantity being upwards of 26 grs., but taking urea as our standard only 16 grs. of urate were formed on this day (in the relation 1 — 35). Therefore about 10 grs. of urate came from some source other than formation, and probably it was this urate which caused the arthritis, and with its removal and excretion under sali- cylate there was a marked fall of temperature and amelioration of all the symptoms ; and the slowing of the capillary reflux and the increase in the granules in the blood after salicylates, as re- corded in previous chapters, also tell us of a large excess of uric acid in the blood. And I have previously suggested that this urate was present in the joints as a urate in colloid form, and that if it had remained untreated or otherwise unremoved, it might have gone on to the deposition of the biurate, crystals of which might then have been afterwards found in the tissues ; but that as a rule in acute rheu- matism it does not reach this stage, and so crystals are not found so frequently or to such an extent as in gout (see also previous remarks on Dr. Mordhorst's Researches in chapter v.). With regard to November 8, the excretion of six hours of the alkaline tide period (all that could be got before treatment) was . multiplied by four and counted as a day. This accounts for the slight plus excretion of urate and the low acidity. If the whole twenty-four hours could have been collected, urate would, no doubt, have been far below urea and acidity much higher ; this condition of things corresponding with more or less complete absence of uric acid from the blood and the existence of acute arthritic symptoms from its presence in the fibrous tissues. * British Medical Journal, 1890, vol. 1., p. 491. EHBUMATISM AND MORBUS COEDIS 763 On November 10 the urine was lost by mixture with another specimen, and on November 11 we see that urate is below urea in spite of 80 grs. of salicylate in the twenty-four hours. Most of the available urate had been removed on the previous days, and it had nothing to act upon, but with this the temperature is normal and the patient convalescent, and next day he wants to get up. And we have here as regards the excretion of uric acid and the fall of temperature a mere reproduction of fig. 62.' • Compare this with the excretion of urate under salicylate in lH-Hrs endiry 60pm N0V.8 9 10 11 12 13 24 792 60 103 22 726 50 102 lEUPERATUfl 20 660 to 101 la 591 30 too AC/t Uff/C/ 16 526 20 33 It liryi \ cioi \A V^ !■ / ^ e x N. y i O JO i Fig. 68. — Cubve of Excbetion of Ubic Acid in Acute Rheumatism UNDEB Salicylate op Sodium. physiological conditions (fig. 8). The curves are seen to be very similar. The only difference is in the absolute quantity. Now, in accordance with my premiss that uric acid is never formed in greater proportion to urea than 1 to 35 (see my Facts and Deductions in chapters ii. and iii.), in both the above cases about half the uric acid excreted under salicylate must have come from some source other than the formation of that day, and I have suggested that this extra urate came from the joints, and that its removal accounted for the subsidence of pain, irritation 764 UBIC ACID — CHAPTER XVI and temperature, and, as I have also pointed out, the value of the saHcyl compounds in acute rheumatism is proportional to their power of dissolving and eliminating uric acid {Medioo-Chirurgical Transactions, vol. Ixxiii.). In this connection one often hears people speak of uric acid as if it were so much sugar, and as if 10 grs. of it could be intro- duced or formed; passed through the blood, and excreted in the urine any dS,y, almost any hour, without producing any effects. Many years of sorrowful experience have completely oonvinc'ed me that it would be difficult to make a statement which could contain less of the truth. Even one-half of this quantity, if added on to the ordinary daily excretion and passed through the blood in a few hours, will cause very distinct signs of its presence, such as slow capillary reflux, high blood pressure, headache, mental depression, dyspepsia, congestion of the Hver ; and even a fraction of this amount, when driven out of the blood into the joints and other tissues by drugs taken to clear the blood and relieve the above symptoms, may produce pains in the joints which are decidedly uncomfortable, and, if continued for more than an hour or two, may in turn require to be reUeved by salicylates. I must say, therefore, that I do not envy the position of any man who has from four to five times this amount of uric acid in his joints irritating them. I have often had quite as much pain as I could bear with very much smaller quantities (see fig. 74). Do not let me be misunderstood. T am quite aware that any gouty man may have more than 20 grs. of urate in one single joint, and may suifer but Uttle inconvenience from it ; but then such urate is not in solution, but is deposited and lying quiet in the tissues. The condition I am speaking of is that of a man who has 10 to 20 grs. of uric acid driven rapidly out of his blood into his joints, where it remains in strong solution, or colloid form, and with full powers of causing irritation in all the tissues with which it is in contact ; such irritation leads on to an inflam- matory effusion, pressure and tension, and the painful arthritis of acute rheumatism is thus accounted for. Some years ago Dr. E. Pfeiffer, of Wiesbaden, told me that he had for purposes of experiment injected urates in suspension under his skin, and that they caused pretty decided local irritation. He then proceeded to take acids and alkalies alternately, and he found the alkalies increased the irritation produced by the urates, but that acids diminished it, and he evidently seemed to think EHEUMATISM AND MORBUS CORDIS 765 that this was in direct contradiction of my assertion that solvents reUeve the pain of arthritis, while drugs which cause retention increase them. But PfeifEer's urates were in suspension, and the alkalies in- creased the pain by getting some of them into solution, and the , acids relieved the pain by preventing their solution (see Dr. Mord- horst's results, some of which are quoted in chapter v.). The urates that cause acute arthritis are in solution or colloid form in suspension, and not crystalline, and they are deposited later on as crystals, and are then comparatively unirritating. I think, however, that we must bear the point in mind, as it is quite possible that the getting of old urate deposits into solu- tion, as occurs in ordinary old age and the decline of life, may for a time increase the pains. And this also may to some extent explain the action of drugs of the iodide, sulphur and cannabis indica class in relieving chronic gout and rheumatism. In chronic rheumatism, associated with debility, it seems to me that there is almost a continual excess of uric acid passing through the blood ; and every rise of acidity increases the joint irritation, in this case the pains will always be worse at night. But if there 'are considerable urate deposits, and the getting of these into solution causes increase of pain, then the pains will be worse in the morning, and then stimulating drugs or diet (such as pure meat diet) which prevent the re-solution of these old deposits will relieve the pains. I have also pointed out that acids do harm in acute rheuma- tism, and that cases so treated take a longer time to get well, than those which are given only mint water ; also that, as observed by others, ammonia, which keeps the acidity of the urine high, does harm, while soda and potash which lower the acidity of the urine do good, and if we are dealing with uric acid as a cause of rheu- matism these facts require no further explanation. An arthritis practically indistinguishable from that of acute rheumatism, and an endocarditis also indistinguishable have been produced, as pre- viously pointed out {Practitioner, 1891) by giving and injecting acids respectively (see also cases recorded further on). We must not forget either that, as Sir A. Garrod has shown, urate of ammo- nium is insoluble, and that ammonium compounds may act like those of lead, mercury, and other metals in clearing the blood of uric acid, and precipitating it on the joints. I have also pointed out that acute rheumatism is a self-curing 766 URIC ACID — CHAPTER XVI disease, that the pain, sleeplessness, failure of appetite and diges- tion, and the absolute rest which the pain enforces, bring about at last a fall in urea and acidity, and that acidity is still further reduced by a considerable excretion of acids in perspiration ; so that when the alkalinity of the blood has thus to a considerable extent been restored, the urates are dissolved out of the joints and excreted, and the fever comes to an end, with the production, however, of considerable coUsemia, anaemia, and debility (p. 560). Hence the alternation of rheumatism with anaemia so common in girls and young women. More or less headache and slow high tension pulse are also the common signs of this uric acid coUaemia, and Dr. A. E. Garrod (previous reference, p. 64) gives tracings of such a pulse in con- valescence, while, as I have previously pointed out. Dr. Stephen Mackenzie says migraine alternates with acute rheumatism, and he deduces from this the suggestion that both diseases are nerve storms ; but I think that my remark about Jupiter in the chapter on " Gout " will apply again here, for migraine we know corre- sponds with excess of colloid urate in the blood and the rheuma- tism which alternates with it, with the presence of the same urate in the joints. And it is most interesting to note, as pointed out by Dr. Latham {Lancet, 1901, vol. i., p. 999), that Trousseau and Eemak found that rheumatoid arthritis in women is often pre- ceded by migraine. In pathology, acute rheumatism may be produced by anything that produces a sharp rise of acidity or fall in the alkahnity of the blood at a time when there is a considerable supply of urate in the circulation (collaemia), but if there is no urate a rise of acidity may produce little or no effect, hence those who eat most meat (see Bouchard*) and drink most beer, and have in conse- quence most uric acid stored in their body, will be most likely to have occasionally considerable collaemia, and when exposure to cold and wet, or the sudden onset of any fever supervenes upon this, acute rheumatism may result. Now tonsillitis is very commonly a forerunner of rheumatism, and indeed some have claimed it as a part of the rheumatic process, but if this is the case it must often be its only sign, as there may be no other symptom of rheumatism either before or after it. But tonsillitis is, in my experience, very often associated with * Legons sur les Maladies par Balentissement de la Nutrition, p. 241. EHEUMATISM AND MORBUS COEDIS 767 conditions of fatigue and over-exertion, and these are just the con- ditions which might bring ahout considerable coUsemia (see p. 359), and when tonsillitis , with fever supervenes upon this, it is hardly to be wondered at that we should have some joint pains or even acute rheumatism. I do not deny that pharyngitis or tonsillitis may originate in a gout of the fibrous tissues and glands of the throat, and I know that this often is its cause, but I want to point out here that any rise of temperature, even a traumatic temperature, may under certain conditions produce arthritis. Influenza again, with its rapid rise of temperature, generally produces some pain in joints and fibrous tissues, and several cases have been recorded in which it has also produced endo- or peri- carditis. A fever, however, has a double action, for supposing that at the time of its onset there is no coUaemia, it will not produce any rheumatic symptoms, but as the fever rises the acidity of the urine rises also, and the alkahnity of the blood is diminished, the excretion of uric acid falls below formation, and while the fever lasts a considerable amount of it may be held back in the body, in the liver, spleen and elsewhere ; and when the fever comes to an end and the acidity falls, more or less coUsemia will result from the washing out of this stored uric acid. On this let us suppose there supervenes a sharp rise of acidity (from diet, exposure to cold, or the inflammation of any organ occurring as a complica- tion), and acute rheumatism of more or less severity may be the result ; that is to my mind the explanation of the rheumatism that follows scarlatina, and may follow other fevers, as measles (see Sansom, quoted by Dr. A. E. Garrod, p. 182 ; and paper read at the Royal Medical and Chirurgical Society on " Measles as a Cause of Endocarditis," see Lancet, 1891, vol. i., p. 880), and compare this with my remarks on the effects of measles on the urine in a case of morbus Brightii, p. 603. The rise of acidity in the fever which cleared the blood of uric acid might, under certain condi- tions, have driven that urate into the fibrous tissues of the joints or heart ; the clearing up of the uric acid coUsemia freed the capil- laries of the kidney, and profuse diuresis and removal of anasarca resulted. We here, perhaps, see the relationship of nephritis with the chronic coUsemia which so often accompanies it, to the disease of the aortic valves, which is not rarely found along with it in the post-mortem room (see Dr. Norman Moore, St. Bartholomew's Hosfital Eeforts, 1887, pp. 290 and 291), though no doubt the 768 UBIC ACID — CHAPTEK XVI kigh blood pressure of the collBemia will directly strain the aortic valves. There is, I think, evidence to show that the acids of beers and wine, and the excessive formation and introduction of urates in a highly nitrogenous diet play much the same part in rheumatism that they do in gout, only in acute rheumatism where the onset is violent, and the sharp rise of acidity is probably due to the action of several causes working concurrently, it is difficult to apportion to each its actual share in the result ; but it is well known to be dangerous to give meat, beer, &c., too soon after an attack, and the way in which they tend to produce a relapse is now, I hope, obvious. And in not a few cases of rheumatism, just as Sir A. Garrod observes to be the case in gout, the effect of giving iron is very promptly to bring about increase of pains and rise of temperature ; and in a patient suffering from angamia under my care, who had had acute rheumatism, it was found to be quite impossible to give iron on account of the rheumatic symptoms it produced, and in several cases of what appeared to be chronic rheumatoid arthritis I have had to give up the administration of iron for the same reason, and if the joint symptoms in these cases are due to chronic irritation by urates there is no difficulty in understanding the facts. With regard to the tonsillitis mentioned above there are several points of great interest which I may as well give here : for not only has tonsillitis often been considered to be related to rheuma- tism, but Le Clere (Journ. de Med., January, 1899) points out that it may precede attacks of gout in exactly the way that it has more often been observed to precede attacks of rheumatism. And this observation is exactly what I should expect to be the case, for I am certain that many acute inflammations of pharynx, tonsils, larynx and trachea in arthritic subjects are just as cer- tainly due to uric acid as the arthritis which may or may not follow them, and my own case given in fig. 74 is as near to conclusive proof of this as anything can be. But the notes of the following very interesting case which I owe to the kindness of my friend Dr. C. Gayford, seem to show not only that a tonsillitis may have a uratic origin, but that a similar uratic irritation in fibrous tissues may spread from the throat to the glands of the neck causing inflammation and very marked enlargement of these structures, and that the irritation thus set up may continue for many months, and is in no way relieved by tonics and change of air, which would not aid the elimination of EHEUMATI9M AND MOEBUS COEDIS 769 uric acid but tte reverse ; while the irritation at once begins to clear up and the size of the glands to diminish on a change of diet, which stops the introduction of uric acid while providing for its elimination. Dr. Gayford also observes that the original acute trouble in the throat was relieved by salicylates just as if it had been a gout or rheumatism, while the enlarged glands which it left behind in- creased and diminished on several occasions in exact relation to the animal flesh in the diet. Dr. Gayford had, for some years before this case came under his care, taken an interest in my work on the influence of diet and drugs on uric acid, and in his letter telling me of the case, he acknowledges that it was my investigation which turned his atten- tion to the possibility that gout was at the bottom of his patient's trouble and suggested to him that diet might relieve it. " ' G. G.,' aged 20, consulted me on April 18, 1894, suffering from general malaise, sore throat (tonsillitis), anorexia, the tem- perature 101°, pulse 120. " I ordered him home and to bed, and gave him a mixture containing sodii salicylas and bark, with a powder pulv. hydrarg. subchlor. pulv. ipecac, co., aa gr. iii. statim. " The next day his temperature was 99°, pulse 96, headache less ; but anorexia still continued. " On the 21st, he first called my attention to swellings on both sides of his neck, the glands in both anterior and posterior tri. angles being enlarged. He was very prostrate and ill though the temperature had fallen to normal. " 24th, he had rallied somewhat, the pulse being stronger, the temperature subnormal. " The glands were larger, tender to the touch, the skin was tense over them. A string of enlarged glands extending from just below the ear down through the whole length from base to apex of the anterior triangle, and from apex to base of the posterior, deep into the root of the neck and were felt in both axillse — the largest of them was as large as a pullet's egg. They were separate and mobile but continued very tender to the touch. " There was no enlargement of either liver or spleen, nor were any joints afiected. The temperature continued normal or sub- normal, there were no night sweats. " There was continued pallor, profound prostration and anorexia, evidence of deep-seated constitutional disturbance. " Being a relative, naturally I felt considerable anxiety at his 770 UEIC ACID — OHAPTBE XVI condition. He, however, gradually mended, and in about ten days was able to get about again, though continuing to look ill. He was soon tired out and unfit for much exertion. " The glands were less tender but continued enlarged, hard and dense and freely movable one upon another; there was no sign of matting together. The question which arose in my mind was, were they tubercular or not ? " The condition persisting on the 21st of May, a month after the attack set in, I took him to see Mr. Butlin, who after care- fully examining him told me he feared there was not much room to doubt that they were tubercular, and he advised that he should go away from England to 8. Airiea, or some other warm high and dry sub-tropical climate and remain abroad. The glands en- larged were so numerous and so deep-seated that operation was out of the range of practical treatment. " As there were strong reasons against my relative's leaving England permanently, he suggested that a prolonged voyage in the Mediterranean to and from S. Africa or New Zealand, might result in so far re-establishing his health, and reducing the number of glands involved, that then operation might become practicable. " He went for a prolonged cruise in the Mediterranean and came back greatly improved in health ; he had gained weight con- siderably and looked robust, but the number of glands had 'not decreased nor were they smaller. " Hence we waited on events, treating him meanwhile with good food, open-air exercise, iron, strychnia, arsenic with quinine ; calcium sulphide tabloids gr. i., were taken frequently and over an extended period of time ; tabloids of bone marrow and spleen were tried ; externally ung. iod. cadmii was ordered as an inunction, but in spite of all there was no further redaction either in the size or numbers of the glands. " I had frequently thought over the question of tubercle either actually present or imminent, and as the autumn came on I felt that this question was a pressing one, for the danger of spending the winter and spring in England to one seriously threatened with tubercle was very real. "" His family is not tubercular at all, no member of it except- ing a half sister of his father, and she an only child of the marriage, and her mother's family were consumptive, having suf- fered from phthisis. In this case there was no evidence of the presence of tubercle in an active form. His ancestry on both sides were gouty. RHEUMATISM AND MORBUS COEDIS 771 " After reading Dr. Haig's book on uric acid, the query arose was it a case of rheumatic tonsillitis followed by enlarged glands ? " In November, 1894, I determined to try what a radical change in his diet would do, accordingly I ordered him is a mple milk diet, prohibiting meat iu any form. " He took to it, taking fully five pints of milk a day in various ways, for several weeks supplementing it with bread and farina- ceous foods and fruit. " He put on flesh, and to my delight the glands soon showed unmistakable evidence of resolution. Just before Christmas there was only one to be felt at all, situated in the apex of the right posterior triangle just where the sternomastoid is overlapped by the trapezius. " During the festivities of Christmas season he was once tempted to take a httle turkey at dinner, two days afterwards when I saw him the glands had again enlarged on both sides, on the right more than on the left. " Resuming his milk diet they again disappeared, the sHghtest indulgence in meat diet always being followed by enlargement, and this was a matter of constant and repeated observation. " For fuUy nine months he kept steadily to a milk diet, with the result that his health was completely re-established and the glands disappeared. He then gradually resumed an ordinary mixed diet, the quantity of meat he took being strictly hmited, for he had learnt to know how much he could take. " Since the middle of 1895 his health has been uniformly good. He is a Volunteer and gladly takes up his drill duties, and is as fit as any of them for long marches and field operations. During his hohdays he has taken long tours on his bicyle or long boating trips up the river. " He has been actively engaged in business, and only quite recently (1898) he made a proposal to insure his Hfe in a first- class Life office, and after giving the medical examiner all the facts as to his glandular trouble of four years ago, he has been accepted at ordinary rates. The medical examiner for the office has all along been cognisant of the case, and he at first advised operation before Mr. Butlin was consulted. The last item of interest in this interesting case is the marriage of the patient. Reviewing all the facts of this case, it seems to me clear enough that it was one of rheumatic tonsilUtis and adenitis. The acute stages of both yielded readily to the action of sodii saUcylas. But the consequent chronic hyperplasia persisted for months with but little evidence of 772 UEIC ACID — CHAPTER XVI progress towards recovery, though various forms of treatment were tried. If was not until the radical change in diet was instituted that this condition yielded, and then the resolution was both prompt and complete." In support of his argument that the glandular enlargement was due to rheumatism, Dr. Gayford refers to the writings of various authors on enlargement of glands, and also to a paper by Dr. Still on "A Form of Joint Disease in Children associated with Glandular Enlargement," read before the Royal Medical and Chi- rurgical Society, and reported in the British Medical Journal, 1896, vol. ii., p. 1446. Among Dr. Still's cases was one in which there was enlarge- ment of the spleen as well as of the glands, and he quotes Dr. Still as being " inclined to the view that the disease was infective in nature." Dr. Gayford also mentions that while in his relative's case there was clearly no tubercle from first to last, he had seen other cases in which he believes that tubercle has become engrafted upon such enlarged glands or similar rheumatic irritation of the throat ; thus repeating the suggestion of Dr. Backler with regard to the lungs, which I have quoted and supported in chapter ix., p. 431. Some people still seem to be of opinion that when they have discovered a microbe in association with any febrile condition they have discovered the cause of the fever, though it must be remem- bered that many have failed to find any microbe at all in relation to acute rheumatism. To the believer in microbes I reply that I shall continue to beheve an arthritic fever to be due to uric acid so long as it is relieved by solvents and made worse by precipitants ; but I do not doubt that microbes and their products may act as precipi- tants and produce a uratic arthritis. So long as the arthritis is reheved by heat and alkalies, which are solvents of uric acid, but have never been claimed as anti- septics ; so long as saUcylates cure the arthritis in fever and in cold chmates, but fail to do good in hot ones; so long shall I believe that these drugs act as solvents of uric acid merely, and not as antiseptics at all ; if they are antiseptics, why will they only act in cold climates ? For these and other reasons already mentioned I consider that, if the solubility of uric acid is attended to, the bacteriology of acute rheumatism may be neglected with impunity both in theory and practice ; and diet, though not an antiseptic, will do infinitely EHBUMATISM AND MOEBUS COBDIS 773 more for all forms of rheumatism than any drugs, as Dr. Gayford's case well illustrates. This case is one of such great and far-reaching importance that I find diificulty in deciding which point is the most interesting. It shows, I think, as clearly as anything can be shown, that the glandalar enlargement in G. G. was not tubercular, was not infective or contagious, and was due to the irritation of urates which, till the diet was altered, were being constantly introduced in the food. Then, as we know, a very large proportion of the drugs used would have the efEect of driving urates into the tissues instead of dissolving them out and removing them, and hence would rather keep up the irritation than remove it. Dr. Gayford clearly wishes to raise the question whether many other glandular enlargements of obscure origin are not really due to rheumatic irritation, that is to uric acid, and I should myself also take this view most strongly, for I have not only suggested that uric acid may irritate any and every fibrous tissue in the body, but that cancer itself may take origin in the irritation so produced (chapter x., p. 461). Thus, had Dr. Gayford's patient been an old man, he might have suffered from cancer taking origin in the irritated throat or glands, or if he had been exposed to a large dose of tubercle bacilh while in a condition of low combustion and unable, as I have suggested, to burn them up and destroy them, these might have found entrance through the irritated throat to the enlarged glands. In either of these cases he would have lost his life, but so long as the irritation was only due to uric acid a change of diet removed it, and he was no longer a possible prey to cancer or tubercle. I think it highly probable that, as Dr. Gayford suggests, many forms of glandular enlargement, with or without splenic enlarge- ment, and with ansemia or leucocythsemia, will eventually be proved to be, hke splenic leucocythsemia, which I have mentioned above and about which I have quoted Eaynaud's parallel opinion, mere diseases of the blood and blood glands produced by uric acid, in a word, their reaction to excess of uric acid ; the anaemia being due to its circulation efiects which I have already explained, and the glandular and splenic enlargement to its local irritant effects. The glands in such cases generally enlarge at the time of a rise of temperature, this representing a gout of the fibrous tissues of the glands ; and a similar enlargement of the spleen does, as we know, occur in malarial fever, and I have already suggested that 774 UEIC ACID — CHAPTER XVI in those who are free from excess of uric acid, malarial fever either does not occur at all, or is greatly modified (chapter xii., p. 467). I have seen at least one or two cases of arthritis in which there was enlargement of neighbouring lymphatic glands, and this did not lead me to think of microbic infection, but I concluded that uric acid had irritated the fibrous tissue in the glands as well as that in the joints, and for records of cases in which some tonsillitis was associated with enlargement of cervical glands see article by Mr. J. Snowman, British Medical Journal, 1898, vol. ii., p. 1744 ; and in the following number a letter from Dr. G. Mahomed, who mentions in one case the presence of " neuralgic- gouty habit." Dr. Gayford tells me that he has seen several cases which directly support the theory that tubercle bacilli have found entrance through a similar rheumatic throat to similarly irritated glands, the patients eventually developing tubercle in the larynx, the neck glands, and in the lungs ; and the case of phthisis I mention in chapter ix. came of a very gouty family, and had, as I suggested, rheumatism in his shoulder and his mitral valves. These cases are suggestive merely, though what they suggest is of extreme interest : but Dr. Gayford's case, given in full above, is far more than merely suggestive or theoretically interesting, for it tells us in no uncertain language that extensive and serious enlargement of glands in gouty subjects and others (I think many others) may, even though believed to be tubercular, be cured by the diet treatment of uric acid. I have also seen several cases of enlarged neck glands following febrile sore throat, in which salicylates and diet have very obviously quickened the disappear- ance of the glands. I have long regarded tonsillitis and pharyngitis as rheumatic, and have cautioned mothers and others concerned to diminish meat and cut off tea, with good results. I have long regarded all the chief forms of anaemia as representing the direct effects of uric acid on the blood, and we now seem to be coming in sight of the real connection between malaria, leucocythsemia, enlargement of the spleen and of other glands as well, and this knowledge may presently give us as much power over these glandular enlargements as we already have over the blood. I have always held that the effect produced by uric acid will vary in different individuals ; soma will have great changes in joint structures and fibrous tissues, others little ; some will have great enlargement of glands with an attack of tonsillitis, others BHEUMATISM AND MORBUS CORDIS 775 little or it quickly goes away ; but these difEerences do not suffice to show that the irritant is not uric acid, and when the irrita- tion is promptly put an end to by salicylates or a uric-acid-free diet, that is fairly satisfactory evidence that it is so. Age is a very important point, because it furnishes probably the chief causes of the difEerences between gout and rheumatism, and I have akeady pointed oat that the condition of the joints is probably very different in the young and in the old. Sir A. Garrod has shown that the tissues of joints are not only less vascular, but are less alkaline than the blood and other tissues, and there can, I think, be no practical doubt that as life goes on, as the arteries become tortuous and degenerate, and as activity of mind and body lessens, the circulation in these joints becomes less and less well maintained, and their alkalinity is not only con- tinually reduced, but slighter and slighter causes will suffice to render them neutral or even acid, and it is this sequence of events probably more than any other which produces the stifi and pain- ful joiuts so common in the aged, even where no rheumatoid changes are obvious. So that while the joints of the young are both more alkaline and are better able to maintain their alkalinity, this may, never- theless, be overcome by a great and general fall of alkalinity, which afiects many joints at once, and is due to a powerful external cause (acute rheumatism). In the old, on the other hand, the joints are less alkaline, and have also diminished power of maintaining their alkahnity ; so that comparatively trivial external causes (a slight injury, a little extra exertion, cold, &c.) may diminish the alkalinity of a given joint, especially those of the hands and feet where the peripheral circula- tion is feeble, and gout results. And it is extremely probable that uric acid coUaemia itself may by obstructing the vessels render the circulation in the extremities less active, and so aid in diminishing the alkahnity of certain peripheral joints, in which the uric acid from the blood is eventu- ally collected and deposited, and we can now watch it doing this in the skin. But age has an important influence on another factor of uric acid arthritis, namely, the absolute quantity of uric acid that is formed, for while in adults urea is formed in about the proportion of three or four grains per pound of body weight per day, and uric acid in its natural relation of 1 — 35 would be about '09 to •11 grs. per pound per day; in a child of 3 or 4 years old urea 776 URIC ACID — CHAPTEE XVI may be as much as 9 or 10 grs. per pound, and uric acid "27 to ■3 grs. per pound. A child or young person is thus by nature placed much in the position of an adult who eats largely of meat. The daily forma- tion of uric acid is large, and uric acid coUsemia and the arthritic irritation, so far as they depend on formation for supplies, are correspondingly easily produced (see also p. 247). It is Httle wonder then that when young persons who have naturally this extensive nitrogenous metabolism, increase it by eatiag largely of meat, meat extracts, juices, and essences, the introduction and formation of uric acid should both be very great, and the possibilities of resulting mischief considerable, and that, as pointed out by Bouchard (previous reference), children fed on meat and meat extracts should often suffer from gastro-intestiaal derangements, skin diseases (see chapter x. and xi.), and early migraiae (uric acid headache), and that rheumatism and its most serious manifestations should come early. It seems to me that if I have escaped from migraiae (uric acid headache), by reducing_the introduction of uric acid, it is no very extraordinary thing that children whose naturally large nitrogenous metabohsm has been increased by inordinate indulgence in meat should sufier severely, and the facts carry their own moral. Age also influences one or two minor points, which, however, may at times have considerable power in precipitating rheumatic (uric acid) arthritis. One of these is the fact often insisted upon by a teacher of whom I have the most kindly recollections, the late Professor RoUeston, of Oxford, that small animals have necessarily much more surface in proportion to bulk than large animals ; for surface increases as the squares, but bulk increases as the cubes of the dimensions. Hence external influences, such as wet and cold, will have proportionally much greater efiects on small than on large animals, and wet and cold, as we have seen, raise the acidity of the urine, and diminish the alkalinity of the blood by checking the excretion of the skin (Garrod), and it follows that rises of acidity from this cause will be greater and more powerful in the young than in the old. Another point is that in children and young persons (probably in consequence of their more active metabolism) slight disturbances will produce great increase of temperature, and rise of temperature means, as we have seen (pp. 90 and 338), rise of acidity, the two things (fever and acidity) being probably co-resultants of increased EHEUMATISM AND MOEBDS COBDIS 777 metabolism ; wMle the extraordinarily rapid development of girls at the age of thirteen (fig. 59) may quite account for their liability to acute rheumatism about that age, as well as to chlorosis and anaemia a few years later. Young persons then are,, from the action of natural causes, often liable to have considerable uric acid collaemia, and whenever external cold or slight febrile disturbance supervenes upon this, a powerful rise of acidity will drive the uric acid out of the blood into the joints and other tissues, for these tissues no doubt share largely in any general fall of alkalinity. A child with gastro -intestinal disturbance and loss of appetite has a headache and slow pulse, the signs of uric acid collaemia. On this there follows exposure to cold and wet, a slight sore throat, a peridental abscess, or other cause of febrile movement, and the resulting fall in alkalinity quickly produces a multiple arthritis with endo- or pericarditis, and changes the picture to that of acute rheumatism. Tn this way the production of acute rheumatism may be com- pletely accounted for by the action of causes that are to be met with every day, and the wonder is that any children should escape an attack, but it is fortunately necessary that a good many causes should act together, and this can only occasionally be possible. Thus uric acid coUaemia means a large excretion of urate, and where this has gone on for several days the amount in circulation wiU be reduced. Again, gastro-intestinal disturbance means dimin- ished metabohsm and lessened formation of urate, so that unless external cold or febrUe movement supervene at an early date there will not be enough urate to produce the most severe effects on the fibrous tissues. I shall now shortly quote three cases which were under the care of Dr. Savill at the Paddington Infirmary, the notes of which he has very kindly placed at my disposal, as they serve to illustrate several of the most important points I have mentioned. Case I. — John G., aged 69, coachman. Admitted February, 1886. Rheumatism and gout very badly for years in knees and ankles. First severe in 1853, in right hand, then in feet, and then general. Father asthma and sUght rheumatism, died at 82 years of age. On admission, February, 1886 : — Urine 1018. No albumen. March, 1886. — Much better, gets about fairly well ; is taking cod-liver oil. 778 UEIO ACID— CHAPTER XVI April, 1886.— Urine 1020. Cloud of albumen. October, 1886. — Left hip painful, 2 in. shortening and joint disorganised. November 30, 1886. — Giddy and headache in morning two or three days ago ; better now. December, 1886. — Much pain in hip. Hands show marked rheumatoid change and distortion of fingers. 1887. — Much the same, giddy on exertion. Pulse compressible, arteries thick. Urine 1008. Trace of albumen. 1888. — Many joints afEected : marked rheumatoid changes in hands, elbows, shoulders, knees, and left hip. 1889. — Urine occasional albumen, joints somewhat relieved by soda baths. 1890. — Pains vary with weather, and are worse in east wind. Can walk with the aid of a stick. August, 1890. — Urine 1014. Albumen ^. Anasarca of both legs, petechias on right. November, 1890. — Pulse tension plus. Urine 1016. Petechiae on both legs. January 6, 1891. — Urine 1012. Albumen large trace. January 30. — Diarrhoea and collapse. Died 9.15 p.m. Post-mortem. — Body exceedingly well nourished. Eigor marked. Petechia on legs numerous. Heart. — 17 oz. Left ventricle large. Valves normal. Atheroma of abdominal aorta. Arteries tortuous and thick. Lungs. — Emphysema and congestion. lAver. — 40 oz. Hobnail cirrhotic. Kidneys. — 2| oz. each. The right contains a cyst as large as a hen's egg. Cortex much reduced. Capsule adherent, surface granular. Spleen. — .5 oz., capsule thick. Joints. — Deposit of urate of soda in cartilage of metatarso- tarsal, and metatarso-phalangeal joints of right great toe. We may sum up the post-mortem by saying gout with exten- sive rheumatoid changes, granular kidneys, cirrhotic liver, hyper- trophied heart, and degenerate vessels. Case II. — Charlotte W., aged 62, laundress. Clinical paper headed " Progressive Chronic Articular Rheumatism." Father died at 70 of rheumatism. Mother died at 68 of asthma. Patient had rheumatism first in toes, then in ankles, and then knees. RHEUMATISM AND MORBUS CORDIS 779 Admitted July, 1888. An aneemic woman, with enlargement of second phalangeal joints affecting the bone ends. Metacarpo- phalangeal joints also enlarged. Some tilting of fingers to ulnar side. Left knee much enlarged ; very tender on the inner side ; brawny oedema of lower part of joint. Heart. — Systolic murmur at apex and left base. Pulse 90, Artery thick, tense, tortuous. August, 1888. — Pulse tracing to-day shows a large first wave high up. Urine, Albumen \. Bullae forming on ankles. September, 1888. — Cough and dyspnoea increasing. Died on 21st. Post mortem, September 22, 1888. — Body somewhat emaciated ; rigor absent. Heart. — 18i oz. Left ventricle hypertrophied. Aortic valves incompetent, with thick attached borders. Mitral valve slightly thick. Lungs. — Contain infarcts, with general congestion and oedema. Kidneys. — Numerous cysts, small, hard, granular. Right 3 oz. Left 4 oz. Liver. — 57 oz., nutmeg, with fatty degeneration. Joints. — Copious deposit of urate of soda, much erosion of carti- lage, tissues around thickened and infiltrated with deposit. This, then, is another case of gout with extensive rheumatoid changes (diagnosed during life as " Progressive Chronic Articular Rheumatism "), granular kidneys, but to these are added disease of aortic valves, and the condition of the lungs and liver was no doubt secondary to this. Case TIL — Mary C, aged 65. Dressmaker. Admitted January, 1890. Case headed " Progressive Chronic Articular Rheumatism," with gouty history. Father dehcate, suffered from rheumatics in early life. Mother and one sister died of diabetes. One brother has rheumatism. One brother has gout. Patient had inflammation of the kidneys when a girl, and in 1885 an abscess on the face, which discharged for thirteen months. Note the way in which all these diseases, gout, rheumatism, diabetes and Bright's disease, come together in a family. The rheumatics came on twenty-seven years ago when she was 780 UKIC ACID — CHAPTER XVI pregnant, and got worse after her confinement. First came in her ankles and feet. Did not finally give up work till eight years ago. Is now able to get about on crutches. Present condition. — Metacarpo-phalangeal joints seem most thick- ened and distorted, and their movements are very limited. But all the joints, elbows, knees, ankles are thickened and distorted, and more or less fixed. Ankles seem to be completely so. Hips and shoulders least involved. Spine movements impaired. Skin pale and smooth, not glossy. No fluid in any joint. Hearts sounds normal but feeble. Lungs emphysema, but natural otherwise. Urine normal. March, 1890. — Gets more helpless. May, 1890. — Urine pale, cloudy, acid, 1028. No albumen. August, 1890. — Lin. terebin. relieves pain. December, 1890. — Great pain in right arm. Urine 1022. — Acid, cloudy. No albumen. March, 1891. — Suffers a great deal from pains, but they are lessened by lin. terebin. May 19, 1891. — Face pale. Pain between shoulders and across abdomen. Breathing laboured. Bronchitic sounds front of chest. Bronchial breathing over right upper lobe, and crepitation on both sides of back. Sputum thick, purulent, not rusty. Slightly better the next day (May 20), but there is bronchial breathing all over left back now. She died on May 24. Post mortem, May 26. — Pleurae, a few old adhesions both sides. Heart. — 12 oz., substance firm. Aortic cusp of mitral valve shghtly thick. Lungs — Eight, 22 oz. Left, 23J oz. Considerable consolidation. Liver. — Pale, fatty, 40^ oz. A few small gall stones in bladder. Kidneys. — Bach 4 oz. Cortex a little diminished. Capsule peeled fairly easily, leaving a somewhat roughened surface. Joints. — Left great toe. Cartilage eroded. Cancellous tissue ex- posed. No urate deposit. Left knee similar changes. No urates. Metacarpo-phalangeal joint of right index finger in same condition as great toe. Here we have extensive rheumatoid changes afiecting the same RHEUMATISM AND MOEBUS COEDIS 781 joints in the same way as in the previous cases where urates were found, but there are no urates. Kidneys slight fibrous changes. Heart not markedly hypertrophied. Death from pneumonia. Here, then, we have three most interesting cases, aU diagnosed during life as chronic rheumatoid arthritis or progressive chronic articular rheumatism. In two of them urates are found in the joints after death. In the third none. Now, according to ordinary pathological nomenclatiire, the first two cases would be called gout, and the third rheumatoid arthritis, but during life they were indistinguishable. There is then some confusion of ideas between clinical medicine and pathology. T think, however, that my knowledge of the solubility of uric acid enables me to clear up the matter. From my point of view the joint changes in all three cases were the work of uric acid, but in one of the cases after it had set up the mischief which ended in the more or less complete destruction of joints, it was got into solution and passed in the urine, so that at the post mortem none was left in the joints ; in the other cases, no doubt, a good deal of urate had been passed in the urine, and if the patients had lived a little longer none would have been found in their joints either, and all three cases would have been called rheumatoid, which is absurd. It wiQ be observed that the case in which there were no urates difiered from the others chiefly in this, that she was much more crippled by her disease than they were. We are told that she had done no work for eight years before admission, and when in the infirmary for the last year or eighteen months of her life her joints were so stiff and fixed that she was practically bedridden. Now the effect of this helpless condition would be to diminish metabolism. Urea and acidity of urine would steadily fall, the alkalinity of the blood, and therefore its solvent power over uric acid, would increase, and it would become more watery and poor in salts (conditions discussed in the previous chapter) and excess of uric acid would be excreted so long as there was any in the body to be got into solution. The liver and spleen would first be cleared, and then gradually during weeks and months the urates in the joints would also be got into solution and passed out in the urine. And excessive excretion of uric acid was no doubt occurring in the other cases also, as metabolism was probably low in all ; but in these cases the plus excretion had been less marked or less continuous, and some urate was left undissolved at the time rvf flAa.tll. 782 UEIC ACID — CHAPTEE XVI It will be seen that Case I. had well-marked granular kidneys, and yet the specific gravity of the urine was, on some occasions^ as high as 1018 or 1020. I have very little doubt that on these occasions he was excreting an excess of uric acid, which raised the specific gravity of his urine in spite of his having granular kidneys. I will just metion a case I was fortunate enough to see in the fost-mortem room at St. Bartholomew's. It was that of a man aged 41, who had extensive joint-troubles with granular kidneys, endo- and pericarditis. Of his joints, some had urate and others none ; thus there were rheumatoid changes in both knees and both elbows, the right ankle, and the right great toe, and there were urates in both elbows, the left knee, and the right great toe. Sir Dyce Duckworth, who was looking at the fost mortem, said that seen apart these joints might be called gouty, and those rheu- matoid. This man also had granular kidneys, and if I may trust my memory this had not been diagnosed during life because the specific gravity of the urine was too high ; doubtless this was due to an excessive excretion of urates, which would have been found if the urine had been examined. The amount of urate was probably from the action of various causes, not exactly the same in any of the joints to start with, and when the increased alkalinity and watery condition of the blood began to act and remove urate equally from all, the result was that some were cleared before others, for if equals be taken from unequals, the remainders are unequal ; hence some joints contained a little urate, others none. " According to Trousseau and Eemak, in women the disease [rheumatoid arthritis] is often preceded by megrim," i.e., by paroxysmal excess of uric acid in the blood (Latham, Lancet, 1901, vol. i., p. 999), a very interesting record, as others have pointed out a similar relation between rheumatic fever and migraine. We thus see that the " intimate relationship of rheumatism and gout " is not a supposition but a fact, and a fact founded upon community of causation ; that some very simple facts with regard to the solubility of uric acid will enable us to explain all the phenomena and symptoms of both diseases ; and lastly, that the failure to find urates in the joints after death is no proof that they have not been there, and produced or assisted in producing the lesions of cartilage and fibrous structures which are found. With regard to the causation of joint changes it is interesting RHEUMATISM AND MOEBDS COEDIS 783 to note that M. Potain says {Sem. Mid., Dec. 18, 1896), that the deformity in arthritis is due to loss of muscle power, which again is due to atrophy of muscle, and that similar changes are found in traumatic arthritis. We now know a good deal about the causes that affect the solubUity of uric acid in the blood and their mode of action ; we know also something of its relation to the joints, fibrous tissues, and organs " of the body ; we know that a large number of drugs which interfere with the solubiUty of uric acid in the blood appear to precipitate more or less irritation of fibrous tissues and joints ; and we also know that everything which we used empirically in the treatment of acute rheumatism — alkahes, colchicum, hot baths and blankets and sahcylates — have this one effect common to them all, that they increase the solubihty of uric acid in the blood. So long as we persist in believing that rheumatism is due to some unknown cause, miasm or microbe, we shall continue to say that the patient had an attack or a relapse with endocarditis, which resulted in serious heart lesion and a crippled life, and shall regard these things as inevitable, much as do the jury who bring in a verdict of " death by the visitation of God." But once we reahse that these diseases depend solely upon the quantity and solubUity of uric acid in the blood, and that, as I have further pointed out, the quantity of uric acid in the blood and its solubility in that fluid are absolutely and completely within our control, we shall pass at one bound from the unknown to the well known, shall see that these deadly diseases are not the result of unpreventable causes, but of our own dietetic follies ; and that our children need not be crippled or decimated by them, if we allow them to live according to their own inclinations on milk, bread and garden produce, and abstain from forcing down un- willing throats the stimulating but deadly products of animal metabolism and the equally poisonous and stimulating vegetable alkaloids. For some years past I have been in the habit of asking all rheumatic children I have seen this question : If I offered you a plate of fruit and a plate of meat, which would you take ? I have never seen a child who would have taken the meat. I have already referred to the well-known cases of Sir W. Foster, who, with the object of diminishing the amount of sugar, administered lactic acid to two patients suffering from diabetes, with the result of producing severe arthritis resembling acute rheu- matism, and in one of the cases six attacks were produced by rnnpntprl administration of the acid. 784 UBIO ACID — CHAPTEB XVI I Lave every reason to believe that any acid that is absorbed and afEects the alkalinity of the blood will produce similar efiects if it is given at a time when there is an excess of uric acid in the blood, and the only point about diabetic cases is that they very frequently have an excess of uric acid in their blood and the defective capillary reflux and the high blood pressure it produces, as I have pointed out in chapter xiv., and not only acids, but any drug (and there are many of them) that interferes with the solubility of uric acid in the blood will do the same thing. Sir T. Lauder Brunton speaks* of cases in which both rheu- matism and endocarditis have been produced by injecting acids into the blood, and he also mentions an instance in which drinking the red wine of Southern Europe appeared to keep up a lumbago from which he was suffering, and that it had often acted similarly in other cases. With regard to endocarditis, he refers to a thesis for the degree of M.D. in the University of Edinburgh, presented by Dr. J. A. MacDougall in 1865, and says that he was able, by injecting phosphoric acid into the blood, " to produce undoubted evidence of endocarditis." Coming a few years after these remarks of Sir T. Lauder Brunton's were made, the following case startled me very greatly and made me fear that I had inadvertently caused both rheuma- tism and endocarditis. M. J., aged 30, was suffering from phthisis of the left apex, with some tuberculous troubles also at the left base. In March, 1894, he had some fresh signs of consoHdation at the left base, with a temperature of 102°. After a few days in bed the tem- perature began to come slowly down, and on March 9, as his appetite was bad and he was a good deal pulled down by night sweats, I gave a mixture containing some nitro-hydrochloric acid and a few minims of liq. strychninse. On March 10 he complained of pain and tenderness about the left shoulder- joint, increased by movement of the limb ; the temperature had risen very decidedly, and on listening over the apex of the heart I was horrified to find a distinct systoHc murmur which I had not noticed before. I at once stopped the mixture and gave salicylate of soda in its place, and on March 11 the temperature was lower and the pain in the shoulder had gone ; but the systohc murmur remained, and though I saw him from time to time for six months after this, it never completely disappeared. I have no doubt whatever that I * Proceedings of the Royal Medical and Chirurgical Society, April, 1890. EHEUMATISM AND MORBUS CORDIS 785 thus caused some arthritis, and I fear also some endocarditis as well. Since this I have several times seen just such an arthritis of a neighbouring joint (the shoulder) supervene on a gout of the re- spiratory fibrous tissues, such as is described in fig. 74 ; and that others have recorded similar experiences is shown in chapter ix., pp. 433-436 ; and such a metastasis is often a good sign, for as the arthritis gets worse the irritation of the much more important respiratory tissues will diminish. J. B., aged 7, sufEering from chorea, was admitted under my care at the Royal Hospital for Children and Women, on October 29, 1894. The temperature on admission was 99'6°, the pulse 80 to 90. I examined the heart, and, finding no murmurs, put her on a mixture containing nixv. of liq. arsenioalis to be taken three times a day. On October 30 the temperature was nearly normal, on October 31 it rose to 100° in the evening, on November 1 to 100-6°, and November 2 to 100-4° in the evening. It then kept between 99° and 100°, but on November 6 the pulse had risen to 140 and above, and it remained quick for some time after this ; the large dose of arsenic was left off. On November 7 the highest temperature was 99-8, and liquor arsenicalis iT|.iij. was given three times a day. On November 8 the highest temperature was 99-8°, on November 9, 98-8°. From this the temperature remained just about 99° until November 21, when the arsenic was left off alto- gether. On November 22 a well-marked post-systolic murmur was observed at the apex. From this onward the temperature kept about 99°, rising to 100° on December 14, and 100-6° on December 18. By this time the chorea, which had improved markedly on the large dose of arsenic given at first and more slowly afterwards, was quite gone. She was allowed to get up, and on December 27 she went home, the murmur at the apex of the heart remainiag well marked to the last. With regard to the onset of this murmur, I should say that Dr. Huntley, our very able resident medical officer, believed that there was a very slight systohc murmur at the apex from the first ; but that it became more marked while under observation. It is quite certain, however, that I heard no murmur on admis- sion, for my rule is not to give arsenic, and certainly not the large dose I gave in this case, if there is any sign of endocarditis (see remarks on The Causation of Chorea, further on). The fairly marked rise of temperature under the arsenic, and its fall later on when it was reduced and left off, point, I think, 50 786 UEIC ACID — CHAPTER XVI to some inflammatory trouble in the body, and there was no evi- dence of any except in the heart ; and then the very marked rise in the pulse rate about November 6 may, I think, be taken as pointing to some fresh heart trouble. I may say that my re- searches show that arsenic, so long as it does not upset digestion, causes a diminished excretion of uric acid in the urine ; it will therefore clear it out of the blood, and tend to drive it into the fibrous tissues. A. S., aged 7, was admitted under my care at the Metropolitan Hospital, on February 12, 1895, suffering from broncho-pneumonia, coming on pretty suddenly, with headache and shivering. The temperature on admission was 104°, but it at once began to slope downwards, touching normal on the evening of February 16. On February 17 it rose slightly above 100° in the afternoon and IS95 mitc 12 \ 13 /4 15 16 17 in 19 20 21 22 23 104' 103' 102- lor 100' 99' 96' 97' ■? -c f •31 I- n--^ i. 1 ^ V \ ' \ A 1 10 / / V A t \A r^ y n s \ / / X / / \l y Fig. 69.- -Tbmpbbatube Chabt op Rheumatic Endooabditis showing the Cause and Cube. evening, but from that up to February 20 it kept between normal and 100°. On admission dyspnoea was the most obvious sign, and percussion was altered over several portions of the left lung, but a few days later there were more obvious signs of consolidation at both bases (was this a gouty or rheumatic inflammation of the respiratory fibrous tissues causing broncho-pneumonia ? and was the subsequent endocarditis a mere spreading of this trouble ? See chapter ix.). There was no murmur over the heart and no increase of dulness. On February 20, after the temperature had been at 100° or below it for four days, a systolic murmur was noticed at the apex of the heart, and the cardiac dulness was also found to be a little increased to the right. The temperature now continued RHEUMATISM AND MOBBUS COEDIS 787 for some time between 98° and 100°; on February 28 it became subnormal, making, however, daily excursions from 96° to 98°. On March 6 it became more steady and kept nearer the normal, but occasionally ran up to 100°. On March 9 the systolic murmur was still heard at the apex, and reduplication of the second sound at the left base. On March 13 I gave, three times a day, a mixture containing tincture of digitalis iTliiss, dilute sulphuric acid TTlv., and some glycerine. I gave this because I was not very certain whether the slightly raised temperature and the apex murmur meant endocarditis or not ; and, on the other hand, if the murmur was merely due to dilatation, the digitalis might be of some use. As there was some doubt, however, I told the house- physician to stop the drugs at once if the temperature rose. Fig. 69 shows the effects produced, and in it we see that on March 12 the temperature ran from normal in the morning to 98"8° in the evening. On the 13th the mist, digitalis acida was given, and the evening temperature rose to 99'6°, on the 14th to 100°, and on the 15th to 100-2°, and on the 16th and 17th it touched 101° three times, and was never below 100°. On the 18th the mixture was left ofi, and though the tempera- ture again rose to 101° that night, it was only 97° next morning, and during the following days never quite reached 100°. The cause being removed the effect began to diminish and disappear ; but to aid and quicken its disappearance some salicylate was given on the 20th, and on the 22nd and 23rd the temperature began a further steady fall. Here, just as in Dr. Watson's case of gout previously men- tioned, we got the lowest subnormal temperature, and no doubt the slowest capillary reflux and the largest number of granules on the first morning on sahcylates. If there had been any arthritis I should have said the tempera- ture was due to that, for it rose on the administration of drugs which would have made arthritis worse, it fell when these drugs were left off, and went down still further when salicylates were given. There was, however, no sign of arthritis, but there were signs of its nearest relation — endocarditis. The systoHc murmur remains, and if anything is now more distinct than before, and can be heard outwards in the axilla. The rest of the history is uneventful ; the temperature during April and up to his discharge on May 8 kept between 98° and 100°. The systoHc murmur continued, and on April 3 the whole of the first sound was re- placed by a murmur. 788 UEIC ACID — CHAPTBB XVI I have very little doubt that we had here to deal with an endocarditis possibly originating, as I have suggested, in the great strain which falling temperature and its consequent rising blood pressure put upon the valves of the left side of the heart (post- febrile uric acid coUaeinia about February 16 and 17), or as above suggested, part of an inflammation of fibrous tissues which was due to urates from the first. That this went smouldering on for some time, and accounted for the irregular temperature which followed convalescence, and then blazed up again at once on the acid and digitalis mixture, for the digitahs not only put extra pressure and strain on the valves of the left side, but the sulphuric acid very probably precipitated some fresh urate upon them. The temperature fell at once when these drugs were left off, and became still more steady when salicylates were given, but the local irritation went on smouldering as before, though before he went out his temperature had been practically normal on several occasions for a few days. This chronic irritation of fibrous tissues with little or no fever (I may remark in passing) is exactly the condition in which sali- cylates win not completely cure ; but in which a uric-acid-free diet may be expected in the course of a few months to completely extinguish the smouldering disease, a disease which under ordinary diet is practically certain to go on for years with slowly increas- ing lesions till death ends the scene. Indeed, it must be evident that while urates and xanthines are being constantly poured in day after day in the food, neither salicylates nor anything else can keep the tissues completely clear of them. If anyone were to say to me this was rheumatic endocarditis due to a microbe, I should only require to ask him one question, viz.. How then did the digitalis and sulphuric acid affect the microbe and cause the rise of temperature ? or how was it that the ammonia of the ancients did not overcome the microbe, while their potash and soda did ? The answer to the one question is the answer to the other ; all the drugs mentioned acted on the solubility of uric acid, and the microbe, if present, was of no consequence. For comparison with fig. 69 I will now give fig. 70, the tem- perature chart of a patient, Amelia M. J., aged 21, admitted under my care into the Eoyal Hospital for Children and Women in March, 1897. Her history showed that she had had diphtheria badly in 1895 and rheumatic fever in November, 1896, being seriously ill and in bad health ever since. BHEUMATISM AND MORBUS COEDIS 789 Examination of her chest showed obvious hypertrophy and dila- tation of the heart, with well-marked evidence of mitral disease and some doubtful evidence of trouble at the aortic orifice also. Her temperature on admission was 97-6° and her pulse 114, decidedly irregular both in time and force. As the temperature remained subnormal on the day of admis- sion and on the following day, I ventured, on March 29, to give her some nux vomica and digitalis, for which there were all the usual indications, these being added to the mist, ferri et am. cit. of the hospital. We had then in this mixture three drugs which would tend to retain uric acid in the tissues and make arthritis worse, namely, 1897 mRCI 27 28 29 30 31 APRIL 1 2 F 105° 104' 103' 'l02- 101* 100° 99° 1 .wj :» ■^ ^ .^;& ^ a % •s4 K A n 98° A / \i 1 f •-'* L /^ / / • ^ / » 1 . Pig. 70. — Tempebatube Chabt op Khbcmatic Endocabditis, Anotheb Case. the iron, the ammonium, and the nux vomica ; and the digitalis would probably raise the blood pressure and put some little extra strain and tension on the valve structures of the left side. But there was no sign of endocarditis, for the temperature was subnormal and the pulse was quick, and gave all signs of heart failure ; and though the rheumatic history was recent, the fires of inflammation seemed to have quite died out. It was, therefore, a surprise to me to find that on the evening of March 30 the temperature rose to 98"8°, and on the evening of the 31st to 99'6°. Accordingly, on April 1 I stopped the mist, of March 29 and gave salicylate every six hours. The temperature rose that evening to 100'4:°, as the salicylate had not had time to come into action, but fell next morning to 97"4:°, and never rose again above normal. I have here again no doubt whatever that the drugs given relighted a smouldering rheumatism of the heart valves, an en- docarditis which, owing to the serious valve lesions and the de- pression produced hy very defective circulation, had previously given but little sign in the temperature chart. These figures seem to me to speak for themselves, and to demon- strate the causation of a relapse of endocarditis by drugs which clear the blood of uric acid at the same time that they put pressure and strain on the fibrous tissues involved. And I should take this view of the matter even if I did not already know that I can produce at any time a relapse of arthritis in anyone who has previously suffered from it with these same drugs or with others which act in the same way. While speaking of these cases I will just mention the sugges- tion of my friend, Dr. Theodore Fisher, in a most interesting article (Lancet, 1896, vol. ii., p. 170), that Dr. Caton's treatment, by rest, and iodides with salicylates, and local blisters, of which I shall speak further on, cures such cases, because forty days' rest in bed allows dilated hearts to recover themselves. In the case of which the temperature is given in fig. 69, rest in bed for nearly three weeks produced no obvious efEect on the heart's condition, and the administration of drugs that would pro- bably have done good for a dilated heart, but which would have caused arthritis in anyone who had previously suffered, at once sent the temperature up and probably aggravated the heart lesion. Where, as is often the case, there is great difficulty in the diagnosis between dilated heart and endocarditis, perhaps standing as in the case d A. S., entirely alone and apart from any arthritis, I would suggest that some of the drugs used in these two cases (figs. 69 and 70) should be given, for if we have to deal with a dilated heart its condition should improve under this treatment and the temperature should remain steady ; while if there is recent smouldering endocarditis, the temperature wiU at once run up aS in these figures, and its careful treatment with sahcylates followed by diet is indicated. I may say also, in this connection, that I am quite unable to agree with the remark of Jaccoud (British Medical Journal, Epitome, 1896, November 28, p. 88) that sahcylates are contra-indicated in rheumatism with visceral lesions, that is, if these include endocarditis. EHBtTMATISM AND MOEBUS COBDIS 791 I should acknowledge that severe visceral lesions, by upsetting the nutrition and metabolism of the whole body, often produce conditions which are unfavourable to the best action of salicylates, to which I shall have to refer when speaking of fig. 71 ; but I am decidedly of opinion that in conditions of acute endocarditis, such as we are probably dealing with in figs. 69 and 70, there is no better drug than a salicylate, which, if it cannot be taken by mouth, should be applied to the skin as salicylate of methyl. In chronic endocarditis without rise of temperature, these drugs, just as in chronic arthritis, are comparatively of but little use ; and here diet will, I believe, be found to yield more and more frequently, the oftener it is resorted to, the most satisfactory results. L. G., aged 45, was admitted into the Metropolitan Hospital on January 22, 1891, suffering from gout in the fingers of the right hand. He had gout first in toes and instep in 1882, and since that in the fingers, toes, ankles, or knees. The pain and swelling in the fingers, which were swollen, tense, and shining, began two days before. Temperature on admission 101°, rose at night to 102°. He was given a mixture containing gr. xx. of salicylate of sodium four times a day. On January 24, the pain in the fingers had ceased. The temperature fell in the evening to 99'6°. After this he went on well, and the salicylate was left off on February 7. On February 9 and 10 he suffered from pain due to an alveolar abscess. On February 11 the temperature rose at night, and there was some return of the gout in the fingers and in the bursa of the olecranon process on the left side. On the morning of February 12 the temperature was 100'4° ; the teeth stumps were extracted and some salicylate given again, and the temperature soon fell to normal and the pain went. Note the speedy relief of gout by a sahcylate ; in my experience it relieves all arthritis due to uric acid, provided that it is fairly acute, which means that the alkalinity of the blood is low. I have already mentioned the case of a boy where similar teeth trouble brought about a relapse of acute rheumatism ; and I have also seen a case where the fever of an attack of pneumonia produced a relapse of gout in a patient who had had previous attacks. E. S., aged 36, admitted into the Metropolitan Hospital on December 31, 1894, suffering from acute rheumatism ; had been confined nine weeks before (for the Effects of Parturition on Uric Acid, see p. 153). The pains began three weeks before admission, first in the head and then in the limbs, shoulders, knees, wrists lifA UBIC ACID — CHAPTBB XVI and elbows in that order. The joints were all very tender. The temperature was 102°. She was given a mixture containing sali- cylate of sodium gr. xv. and bicarbonate of potassium gr. x. to be taken at first every two hours. On January 2 the temperature was 100°, but the joints were still tender. The bicarbonate of potassium was omitted from the mixture. The temperature ran up that night to 102-8° (the highest it had been since admission), and there was a sharp return of all the pains. It fell to 100° the following morning, soon went down to normal, and never rose again. Now what was the meaning of this sharp and sudden relapse when the drugs were altered ? Was it due to the untamable microbe ? I beheve it is in my power to show that it was simply and solely a matter of the solubility of uric acid, for I have observed the same thing before under similar conditions. Some years ago I had under my care a patient suffering from subacute Bright's disease whom on admission I had put on a mixture containing citrate of potassium. After she had been on this for several days she got some pain and swelling in several joints, so I stopped the potash salt and put her on salicylate of sodium, and in a few days her pains were very much better and the salicylate was therefore left ofi and the potash mixture resumed ; here again, just as in the case of E. S., there was a sharp but temporary return of all the joint pains as the result of the change of drugs. It seems then quite clear that when arthritic pains are being relieved by a salicylate it will make them worse to add potash, and conversely, when arthritic pains are being reheved by potash, it will do harm to add a salicylate. My own personal experience quite bears this out, for when some years ago I had my uric acid under less perfect and complete control than at present, I used occasionally after severe exercise in hot weather to get some pain and stiffness in the fascia either of the neck or the lumbar region ; and I often found that these troubles were completely removed by a few doses of salicylate of sodium, so long as I kept quiet and cool in the house in the morning ; but if in the afternoon I went out and got overheated, still continuing the salicylate, my pains returned, and were worse — perhaps much worse — than if I had taken nothing. Now what is the efiect^of going out and getting hot ? It has been shown by Sir A. Garrod and myself that it produces a fall in the hourly excretion of acid in the urine — say the hourly excretion of acid in any individual is equal to 3 grs. of oxalic acid, then RHEUMATISM AND MOEBUS CORDIS 793 going out and getting very hot will, other things being equal, reduce Lt to 1^ or 2 grs. in the following hours ; that is to say, getting tot is equivalent to a dose of alkali. But we have already seen that alkalies and salicylates do not pull well together, and we know that uric acid may be excreted in excess under alkali or under salicylate, and it must be extremely annoying to preconceived opinions that giving the two together APRIL ■ 2".' 3" *"" S* 6f ZIQQ laoQ 1700 1500 1300 t; 70 eo so *Q 30 ? 1 — 1 „ f8 17 16 IS 14- J3 /2 II 10 (J ^5 4SQ 4-20 3BS 350 1 I' 1 1 1 ( 1 ( 6 lie A ID 1 IT" nr v V J \r^ '■., ' . 1 =^ v'^ t s k c> S 1 "5 s- 5> «0 Fig. 72. — Effects of a Tubkish Bath on the Acidity of the Urine feom houk to houb. would thus have probably a very distinct effect on any arthritis that was due to uric acid. The first effect of such a bath would be to increase the excre- tion of uric acid and relieve the pains of arthritis ; but later on, when the alkalinity of the blood began to fall again, as at 11 p.m., some urate would again be driven into the joints, and the pains would be increased ; and this increase of pains would be very marked if a patient, after a bath, unwisely exposed himself to cold and damp, which would quickly check perspiration, or drank acid wines, which would also diminish the alkalinity of the blood. The case of J. B., mentioned above, in which the treatment of chorea by large doses of arsenic seemed to produce or increase EHEUMATISM AND MORBUS COEDIS 803 an endocarditis, almost raises the question of the causation of chorea, for unless there was some excess of uric acid in the blood along with the chorea, the arsenic would not have produced an endocarditis ; and this suggests the further question, does arsenic cure chorea by clearing the blood of uric acid, or is chorea one of the efiects of excess of uric acid in the blood ? And there are a few facts in this connection which it may be as well to bear in mind, even though they do not as yet justify any definite conclusion. First, then, chorea has a fairly definite relation to acute rheu- matism, and this relation seems to be that it precedes or follows it, but does not often accompany it. Now migraine bears just the same relation to rheumatic fever as we have seen above, and migraine is due to uric acid coUsemia. Again, chorea, like migraine, comes along with conditions of dyspepsia and debility, in which it follows from our first princi- ples there is certain to be an excess of uric acid in the blood. Then, again, the mental conditions in chorea, the dulness, in- ability for work, and the increase of irritability, are these not also the symptoms of collaemia ? The late Dr. Sturges considered that chorea was an exaggera- tion of fidgetiness, and is not fidgetiness a sign of coUsemia in not a few gouty adults ? Then chorea has been said by Dr. Dickenson and others to be due to widespread hyperaemia of the nerve centres, and Dr. Hand- ford {Brain, 1889, p. 129) has pointed out that overwork produces such congestion of centres and tends to make it persistent, and that this condition of centres is evidenced in adults by trembling of hands, nervous starting, twitching of orbicularis palpebrarum, and fidgetiness ; but overwork (fatigue), as we know, also produces collsemia. Then, again, chorea is not very distantly related to the tremors of the aged and feeble, and I observed a good many years ago that these tend to be worse in the alkaline tide hours of the day, and I gave acids with the object of diminishing them, in some cases with apparent success. Dr. Handford also mentions a case where chorea began during menstruation which followed mental depression and hysteria, and in this case embolism and thrombosis of certain vessels were found at the fost mortem. Then, again, chorea often follows shock, fright, or emotion, and these conditions, as we know, often sufiice to depress the meta- 804 UEIC ACID — CHAPTBE XVI bolism of tie body and produce collsemia as the result of the depression. We have seen in chapter iv. that Graves' 'disease bears a similar relation to shock or depressing emotion, and the same is true to some extent of Bright's disease, diabetes, and all collsemic diseases ; and more recent observations seem to show_ that the capillary reflux is markedly slow in chorea. And, if chorea is the result of hypereemia, stasis, or thrombosis in certain nerve centres, it is not difficult to see how the obstruc- tion of capillaries by uric acid in the way previously suggested may account for this. Then as to the drugs which cure chorea, arsenic probably clears the blood of uric acid, and I have suggested in the above-men- tioned case that it produced endocarditis in doing so. Antipyrin appears to have been used with advantage by some {British Medical Journal, 1894, vol. ii., p. 1227), and it also cures migraine. Lastly, salicylate of soda may do harm in chorea and make the movements much worse, and though salicylates do no harm in migraine when given at the right moment, they may make it much worse if given wrongly, i.e., at a time when there is much gastric upset with debility and depression ; they also, as we know, slow the capillary reflux. Under thsee conditions they bring excess of uric acid into the blood, and if the blood is strongly alkaline owing to dyspepsia and debility, the uric acid will combine with the alkali and make the migraine much worse ; and this is the reason I first use mercury in migraine to clear the blood of uric acid, and set things going upwards, and then foUow it by salicylates to carry off the uric acid. I can easily understand, therefore, that salicylates may make chorea worse, for it is so commonly associated with conditions of debility. In migraine there is no heart failure as the pain is due to high blood pressure, which heart failure renders impossible ; but in chorea there is heart failure and low blood pressure, and salicylate increases collsemia and makes heart failure worse. We see then that there are numerous connections between chorea and coUeemia, and that if chorea is due to coUsemia we can at once see the explanation of its relation to acute rheumatism, which is similar to that of migraine. Chorea, therefore, may be but a variation of migraine, the uric RHEUMATISM AND MORBUS CORDIS 805 acid coUsBmia and its circulatory disturbances producing more serious and lasting effects on the more unstable nerve centres of the child; But in addition to the theories just mentioned there is another, due apparently to the late Dr. Kirkes, which makes chorea due to embolism of the minute vessels of the brain (corpora striata), the emboli taking origin from the previously inflamed valves of the heart. And it seems to me that we can explain all the conditions by a slight modification of this theory, if we may suppose that the embolic particles originate, not in the valves of the heart, but in what I have called a snowstorm of colloid uric acid in the blood, and that some of the urate particles collect and form here and there more or less permanent obstructions in the minute vessels of the brain. Such a condition would help us to explain, not only the occasional morbid appearances found after death, but would more or less completely account for several points with regard to chorea which remain inexplicable on other theories. This condition of the blood, which I have called coUsemia, is, to my mind, the cause of the general obstruction to the circulation and the consequent high blood pressure which uric acid produces (see chapter v.). The obstruction is partial and temporary only ; the colloid particles pass through the capillaries, though slowly and with difficulty, and then being carried by the veins to the deeper and warmer parts of the body are, as a rule, re-dissolved. But under slightly altered conditions several of these snow flakes may adhere together, and form a mass capable of completely ob- structing a capillary or set of capillaries, and so alter, for a longer or shorter time, the function and even the structure of the sur- rounding portions of the brain. I have for a number of years been suggesting that embolism or thrombosis, thus originating in colloid particles of uric acid in the blood stream, may account for the well-known relationship between such troubles and gout (see also my remarks on throm- bosis in chapter xii., p. 564). I have also pointed out that causation by the obstructing in- fluence of colloid uric acid in the blood will account for one feature of Eaynaud's disease which is otherwise inexplicable, namely, its limitation to surfaces and extremities, i.e., to exposed portions of the body, and the effects of local cold in producing Raynaud's disease, as by washing the hands in cold water, are well known. 806 UEIC ACID— CHAPTER XVI I have already mentioned, also, the probable relation of oollsemia to cold, acids, &c. And now we come in sight of one of the altered conditions which may make the difference between mere temporary and more per- manent obstruction of capillaries by collaemia, and it will be found also to give us an explanation of the well-known large prepon- derance of chorea cases in girls, which seems to be from two or three to one. I have already given this same condition in chapter xi. as the cause of the increased frequency of Raynaud's disease in girls ; and I have there suggested that as girls differ from boys chiefly in having a less well-developed muscular system, they will have also, probablj'-, a less powerful heart ; and this may just make the dif- ference between the slight temporary obstruction of their capillaries by collaemia which produces cold hands, and the more severe and permanent obstruction which brings about actual Raynaud's disease ; and we can see that the washing in cold water will act just as cold in the test tube (chapter v.), by determining or increasing the precipitation of the colloid, and make the difference between a few flakes of snow and a blinding storm. Now, obviously, exactly the same explanation will apply to the preponderance of chorea in girls if it is due to collsemic embolism, for a little weakness of the heart muscle may just suffice to make the difference between such slight and temporary obstruction of capillaries as causes general high blood-pressure, and the more per- manent or lasting obstruction which is the possible cause of chorea. The same fact may also serve to explain the great value of rest in bed, which will relieve the heart of much work ; and arsenic not only clears the blood of uric acid, but, as is well known in countries where it is eaten, strengthens the heart and the muscles in general. In a case under my care the blood pressure rose during treat- ment by rest in bed and arsenic, though the capillary reflux was slow the whole time, showing that the cure was due rather to strengthening the heart than clearing up the collaemia. Francis M., aged 12, admitted into the Metropolitan Hospital January 5, 1900. A day or two after admission the pulse was 92, slightly irregular, the blood pressure 90 — 100, and capillary reflux 7. About two weeks later, when movements^ were less, capillary reflux was still 7 — 8, but the blood pressure had risen to 120. And a week later when there were no movements at all, capil- lary reflux was the same as before, but the blood pressure had further risen to 130. EHEUMATISM AND M0KBU8 OOKDIS 807 The ctorea in this case followed an attack of sore throat, joint pains and catarrh some three weeks before it, and I should read the sequence as post-febrile coUsemia, heart failure, chorea, and this was followed by recovery of heart and disappearance of the chorea, in spite of the continuance of some (but probably less severe) coUaemia. I have now observed similar changes of blood pressure in quite a number of cases of chorea — in all, in fact, that have come under my notice : the blood pressure is low at first, but as the heart condition improves with rest and tonics, and the pressure rises to and above normal, the symptoms get less and less. The above case is typical, and I have no space to give more. I look upon arsenic merely as a cardiac tonic, and other tonics will do quite as well. Then again the endocarditis, which may or may not accompany chorea, is probably one of the results of the high blood pressure which, as ha.s been already explained in this chapter, if it strains and irritates the fibrous tissues of the valves may lead to'iihe pre- cipitation of urates upon them, and so to this further irritation and the origination of endocarditis. Here, again, the presence or absence of endocarditis may depend upon whether the heart is rested or worked at the beginning of the disease. Again, such a causation will enable us to understand completely the relationship of chorea to shock and to fatigue. Almost every shock, mental or bodily (and they are generally both), suffices, if at all severe, to suspend digestion, to lower the hourly excretion of urea and of acid in the urine, and so to increase to a corresponding extent the alkalinity of the blood ; and thus, especially in children, to flood it with uric acid ; hence shock often sufiices to bring on megrim, epilepsy, or mental depression in those who sufEer from these. Graves' disease, which I have already suggested (p. 142) may be due to unrelieved high blood pressure, may also originate in a similar mental shock (see Sir W. Broadbent, " The Pulse," p. 90). The effect of fatigue in producing coUsemia in those who have large stores of uric acid, has already been treated of at great length in chapter viii., and its bearing on the coUaemic causation of chorea is obvious. Some interesting suggestions are made by Dr. Churton {British Medical Journal, 1896, vol. ii., p. 715) bearing on these points, one of which is that chorea may be due to direct irritation of the nervous 808 UEIC ACID — CHAPTBE XVI system by shock or excitement determining the toxin to that system, just as a wetting determines arthritis of the upper or lower ex- tremities as the case may be. And further on he says : "But arthritis is never the first result of fright, and chorea is never the first result of chill." Exactly so, for fright causes depression and coUsemia, which is the opposite condition to arthritis ; and chill causes a fall in the alkalinity of the blood and clears the uric acid out of it into the joints producing arthritis, which is the opposite condition of uric acid coUtemia, and chorea. These considerations explain also what some regard as excep- tional and seem quite unable to understand, namely, why, if uric acid is the cause of arthritis there is none in conditions of anaemia and debiHty, such as splenic leucocythsemia when the blood and urine are full of uric acid. But everything as regards arthritis depends upon whether the blood is a good or a bad solvent of uric acid, is taking it up from the tissues or throwing it into them ; and in all these conditions of ansemia and debihty the only reason for an excess of uric acid in the blood is that its powers of dissolving it and holding it in solution are increased ; and this is exactly the condition which it is our aim to bring about when we want to cure arthritis. On the other hand, it is not very di£B.cult (and it has been done or has done itself in many of the cases mentioned above), to drive some of the uric acid out of the blood into the joints and produce arthritis, hence the commonly observed alternation of aneemia and rheumatism ; with many girls of the present day, lif« is made up of such alternations for some years. It is only fair to say that Dr. Churton adds to the above-quoted lines " unless fear or brain excitement accompanies the chill " ; but I am concerned with the rule and not with the exception, and the rule is that fear causes coUsemia and depression, and chill clears the blood of uric acid either locally or generally, and may thus produce arthritis, or inflammation of any fibrous tissues. I will now shortly mention in illustration of some of these points a case under my care. It is that of a girl, aged 16, admitted into the Metropolitan Hospital with her third attack of chorea on March 14, 1897. There is no sign of endocarditis, either recent or of old standing, so that this cause is probably absent. Her mother is a sufierer from megrim, and one of her mother's sisters had chorea in childhood. The patient herself suffers from such headache (uric acid head- ache) from time to time, and had several bad attacks in rather quick succession just before this last attack of chorea came on. EHEUMATISM AND MOEBUS CORDIS 809 The determining cause of this last attack seems to have been an injury resulting in a severe cut on the thumb of the right hand, which formed a rather ugly, wound at the time of admission. Here then we have a shock as the determining cause, and we have this supervening upon the passage of a considerable amount of uric acid through the blood, as shown by the frequently recur- ring headaches. On admission she was also noted as being extremely anaemic, and as having suffered more or less from this for some time. She also presented all the signs of debility and exhaustion. But we know much more than this — we know why she was anaemic, why she had collaemia and frequent headaches, for she was in service in what is known as a " hard place," and this would undoubtedly produce fatigue and coUsemia ; and we know also that collaemia at her age, three years after the year of greatest growth (see chapter xii. and fig. 59), would of necessity be severe, and this would, as is common in girls of her age, produce chlorosis ; further, the collaemia would be signalised by exactly what we find in her history — severe and rather frequently recurring headaches. It may not be without interest to remark in passing that epilepsy very frequently begins in girls just at the age of this patient, and no doubt it does so as the result of exactly the same causes as those that rendered her headaches both more frequent and severe ; and epilepsy also is another disease closely gissociated with col-- Isemia, and may apparently be originated by a fright or shock. Then the progressive fatigue, collaemia, and anaemia would be certain to react on the nutrition of the muscles and the heart, and weaken them. This then was her condition when, on March 9, a china basin fell on her hand and cut it severely. This no doubt caused a considerable shock, which intensified the coUaemia by further upsetting nutrition. The collaemia would have raised the blood pressure and caused headache, but the heart had now failed before its accumulating misfortunes to such an extent that it was no longer able to keep up the blood pressure ; and so, as she herself tells us, there was no headache, but the choreic movements soon began, for there was collaemia, and collaemic block- ing of the capillaries of the brain was favoured by the very weakness of the heart which rendered headache impossible (see remarks on Antipyrin on p. 268). The palse on admission five days later was 144, with a tem- perature a little above 99°, but the very violent movements may 810 UEIC ACID — CHAPTEB XVI quite account for this and the signs of exhaustion, which were also most marked. I may say that I have now observed that capillary reflux is in these choreic cases always slow, and the blood pressure slightly above normal, though no doubt but for the heart failure it would be higher still, as the capillary reflux is slow enough to account for higher blood pressure than one finds. She was given injections of morphine to quiet her on the first day, and then put on a small dose of arsenic ; and in two or three days she was much quieter and even able to speak a few words. The movements continued, but less violently, for many weeks, but by the end of April they were almost gone, and she was allowed to be up for a little ; she was continuing the arsenic, and gaining weight. She was still, however, decidedly anaemic, say blood decimal by sight '35 to '4, and had a quick pulse. Her previous attacks of chorea, first at ten years old and second at 12 years old, were much less severe than the third, and this is interesting, as she would probably have less uric acid avail- able before her year of greatest growth than after it ; and I can- not help thinking that if she had been on a uric-acid-free diet from the date of her second attack she would now have escaped the collsemia, anaemia, headaches, and chorea. For an interesting case in which chorea apparently followed on depression, hysteria, and excessive irritability, these being all signs of- colleemia and coming during menstruation, its frequent cause, and in which embolism and thrombosis of certain vessels were found after death, see Brain, July, 1889, p. 175. And for a case in which chorea came on as rheumatic fever left off, that is, when there was almost certainly collsemia, see British Medical Journal, 1894, vol. ii., p. 1227. But chorea follows other acute diseases besides rheumatic fever, for every acute disease in a child is followed by post-febrile colleemia (see also article in Progres Medical, April, 1888, p. 301). With regard to diagnosis I have little to say. When I see an arthritis which appears to have originated under conditions which might have precipitated uric acid, and when I can find no other obvious cause, I treat the uric acid and judge by the results ; if the trouble is relieved by solvents there, is no room for doubt. I have, no doubt, occasionally been misled, especially by malignant and other new growths ; and perhaps one should view with a certain amount of suspicion arthritis in a single joint, KHEUMATISM AND MORBUS COEDIS 811 standing alone and yet not having exactly the characters of regular monarticular gout ; similarly, in what appears to be rheu- matism standing alone in one single joint, we must not forget that there are some other things besides uric acid which may cause such trouble. In one or two cases of deep-seated new growths the myalgic and neuralgic pains have for a time resembled the work of uric acid, and, strangely enough, in some of these cases salicylates have even for a day or two markedly relieved such pains though due to new growths ; possibly they have exerted an influence indirectly through the blood pressure ; though even in new growths the presence of uric acid may increase a local irritation, and its removal will at least do no harm. I notice, in St. Bartholomew's Hospital Journal, December, 1899, -in an article on " Primary General Acute Gout " (by which is meant, I gather, polyarthritis, clearly due to uric acid coming in middle life with a history of rheumatism preceding it), that Dr. Parker attenapts to explain the (for him) difficult questions : (1) Why so many of these cases gave a history of rheumatic fever (28 per cent.) ; (2) Whether rheumatism predisposes to gout and gout to rheumatism ; and then goes on to say, " Are we, with Dr. Haig, to regard both gout and rheumatism as manifestations of an uric acid diathesis ? " I trust that none of those who may do me the honour to read my writings up to this point will think that they are with me in believing in any such product of hopeless ignorance as " An uric acid diathesis." As I have already said, gout is rheumatism and rheumatism is gout, for the arthritis in both is clearly due to uric acid, and this is the only pathology that wiU satisfactorily explain all the condi- tions met with ; while the above is a good instance of the diffi- culties in which others land themselves, in trying to work out any other explanation of the facts that nature presents to them. But no situation is made clearer by the mere substitution of one unknown factor for another ; as those do who fly from a gouty or rheumatic diathesis to one of uric acid. Diathesis altogether is but a cloak for ignorance : away with it, and substitute that which can be demonstrated in every case, namely, poisoning by flesh and tea, or similar alkaloid-containing substances. Has, then, the sufierer from arthritis nothing to fear from the uric acid he forms ? No doubt he has, for his joints having been injured will long be liable to further irritation from comparatively 812 UEIC ACID — CHAPTER XVI slight causes, and if they contain, any urate residues these will attract fresh urates from the blood and tissue fluids at every opportunity (see uric acid filter work in chapter v.) ; but the point is, that if these people had never, from the time of leaving their mother's breast, eaten flesh or swallowed substances rich in alkaloids, which we shall discuss further in the next chapter, they would have had no arthritis either in early, middle or late life to puzzle the morbid anatomists : but their joints at 60, 70 or 80 years would, except for accidental traumatisms, be as clear and free from disease and disorganisation as at 6, 7 and 8. Diathesis is a myth, a shadow which cannot be brought to book, and is therefore hard to slay ; but food poisoning is a reality which can be demonstrated in every case, its effects can be measured and its progress stopped ; but better than all, its beginnings can be prevented, and when this has been done the phantom diathesis will have no more dark corners in which to hide, and we shall see the empty shadow that it was. As regards treatment, it should never be forgotten that there are two ways of curing arthritis : — (1) Elimination, as by sali- cylates, and (2) Retention, which clears the blood and prevents more uric acid being brought to the irritated joint structures, and this is the action of iodides, guaiacum, sulphur, sulphates, sul- phate and calcium waters, &c. Now elimination is useful in acute conditions, and when it is completely successful in relieving pain and reducing temperature it afiords positive evidence that the arthritis was due to uric acid ; for in arthritis due to other things elimination of uric acid has no effect. Retention is useful only in chronic cases, when the irritated joint is acting like the uric acid filter and attracting and retain- ing all the uric acid that comes near it in the blood and tissue fluids, and with each increase of uric acid in the joint there is an increase of pain and trouble. But if the retentive drug clears the blood of uric acid there will be less to come past and get caught up in the irritated joint, and so the irritation will have time to subside ; and thus chronic arthritis can be relieved by drugs which cause retention. Then I think that cases of arthritis can best be considered as falling into three groups : (1) Acute. (2) Chronic. (3) Chronic with marked debility and anasmia. RHEUMATISM AND MORBUS CORDIS 813 In acute cases with, fever, salicylates have, as a rule, only to be given freely to be given successfully. The salicylates must be given in a sufficient dose, because, other things being equal, the amount of urate eliminated depends on the amount of salicylate in the blood to combine with it. I have seen gr. x. of salicylate of soda given three times a day in acute rheumatism without the smallest efiect, when gr. xx. every two, three, or four hours promptly relieved. Salicylate of ammonium is by some considered to be less nauseating than the sodium salt, and for the reasons previously mentioned it has probably some advantages over it as regards the elimination of uric acid, especially in subacute or chronic conditions. There are but few reasons for not giving a good dose, the head symptoms which the salicylates produce are generally trivial, and in albuminuria and Bright's disease there is but small evidence that they really increase the albumen. If they do cause a little depression, what is that to the depres- sion of a prolonged attack of acute rheumatism ? And it seems that at least a part of the depression they have been credited with is really due to impurities which we are gradually learning to eliminate (see an interesting article by Dr. Lees, Lancet, 1893, vol. ii., p. 190), When the temperature is not high you must keep the patient cool, and on no account allow perspiration in hot weather, as this will quite upset the action of the salicylates. Under these circum- stances (subacute cases in hot weather) you must not only clothe very lightly, but you may also have to give small doses of the mineral acids two or three times a day in alternation with some of the doses 'of saUcylate, before their best action in removing uric acid and relieving arthritis is obtained. This treatment will also prevent the salicylates from causing depression, as their de- pressing effect, when not due to the above-mentioned impurities, is generally the result of their meeting a large amount of uric acid in the body and sweeping this into the blood, where, in the absence of much fever and in the presence of perspiration and debility, it may meet with much alkali with which the uric acid then combines, producing very marked coUsemia, with its terribly depressant effects on circulation, nutrition, and metabolism. The depressant efiects of the salicylates are thus due partly to the quantity of uric acid met with, and partly to the meeting of this uric acid with much alkali in the blood, producing collsemia. And I believe that I have seen salicylates produce the most 814 UBIC ACID — CHAPTBB XVI severe coUsemia, with most unpleasant cerebral and aural symptoms, perhaps heart failure, with collapse, delirium, or mania (see chapter viii.), when given with alkali, or in cases where the fever was not high enough to keep up the acidity of the urine and keep down the alkahnity of the blood, or again in cases where the patient was kept boihng and stewing under heavy clothing. And I have seen them all do this without much relief of the arthritis, perhaps even while making it rather worse. My own practice is, therefore, in acute cases to give plenty of • salicylate, and to see that the patient is in no danger of being made to perspire. In less acute cases, to keep the patient distinctly cool, and even to give some acids if the weather is hot ; and with these pre- cautions the arthritis is generally quickly relieved, and the patient suffers no other troubles. Aspirin, a combination of salicylic and acetic acids, is often very useful in subacute conditions, as the acid radicles keep down the alkalinity of the blood and prevent uric acid combining with alkali, and the dose is the same as that of salicylate of soda. Very good results with aspirin have also been reported in pleurisy with efiusion (no doubt rheumatic), and in pericarditis (see British Medical Journal, 1902, vol. i.. Epitome, p. 12) ; and it is in such serious conditions, causing fall of temperature and depression, that the greatest good may be expected from it. When salicylates, given with all proper care, and in satisfac- tory quantity, relieve the arthritic pains and reduce the tempera- ture somewhat, but it still keeps on without any sign of falling to normal, you 'must consider whether you have not to deal with enteric or some other fever, of which the arthritis was a mere complication in an arthritic subject. Where salicylates fail either to relieve pain or reduce the tem- perature to any noticeable extent, even after all conditions have been made favourable to their action, and aspirin has also failed, the possible presence of pyaemia should be considered.. If salicylates act quite satisfactorily, relieving the pains and bringing down the temperature, they should be continued for a longer time in small doses (weeks, perhaps months) to clear out as much as possible of the stores of uric acid and prevent a relapse ; for if any urate (even a quite microscopic quantity) is left in the affected structures it will act as a uric acid filter does, and attract more from the blood and fluids as soon as the solvents are left off, and the patient should never be allowed to go back BHEUMATISM AND MOEBUS CORDIS 815 to a diet which, will introduce any further xanthine or uric acid into the body. Patients are put on a milk and cereal diet during the fever ; let that diet be continued with the addition of cheese, vegetables and fruit. The treatment of morbus cordis, so far as it is due to valve or pericardial lesion, has hitherto comprised little beyond the use of tonics and stimulants, but it is evident from the case of A. S. mentioned above, that we must be very careful not to use these tonics and stimulants too soon, or while there is any heat or irri- tation remaining about the valve, or we shall only make it blaze up again, and, precipitating more urate upon it, make matters worse. While valve lesions are recent, I think we can hardly do much better than follow the treatment suggested by Dr. R. Caton {Lancet, 1895, vol. ii., p. 399), which consists in giving gr. x. of an iodide three times a day, in addition to sahcylates, and placing repeated small blisters on the chest wall over the damaged valves. The salicylates effect the elimination of uric acid, while the iodides keep it from combining with alkalies and raising the blood pressure, which would increase the work the heart has to do. Recently I think that I have got equally good results by leaving out the blisters and replacing them by a free painting over the cardiac area of salicylate of methyl, covering this with gutta percha tissue, and over this an ice or iced water bag ; and the same treatment can be applied to any local trouble which is sufficiently near the surface to be afEected by local treatment, using either salicylate of methyl or salicylate ointment and ice, the ice acting the part of an acid, and increasing the solvent action of the salicylate (see also Treatment of Pneumonia, p. 445). It seems to me that we must rest the valves as much as possible and not expose them to any strain that can be avoided, and that we must do all we can to restore their normal alkalinity ; and, lastly, I think we must keep on with salicylates for a good long time, I should be inclined to say for several months at least, to protect them from the evil efiects of exposure to cold or the accidental use of acids or other things that affect the solubility of uric acid, and also to make as sure as possible of sweeping out every atom of urate from the affected fibrous tissues (see previous remarks, especially those in chapters xv. and ix., also remarks on Pericarditis, p. 747). We now come to chronic arthritis cases in which the tempera- ture is nearly normal, except, perhaps, for occasional evening rises, but cases in which there is no marked anaemia or debility, and in which digestion is sound and food is well taken. 816 UBIC ACID — CHAPTER XVI These, again, are cases for the salicylates, they do not represent the most favourable condition for their eliminative action ; but with time and perseverance they will do good — probably more good than anything else. Here salicylate of soda may be given in doses of gr. xv. to xx., three or four times a day, provided appetite and digestion are not upset by it ; or it may be given along with an iodide or other retentive drug to keep the urate from combining with alkali and causing depression, or acids or opium may be given along or con- currently with it for the same purpose. With this object in view saHcylate of ammonium may do better than the sodium salt or aspirin, er salicylic acid may be better stiU, and this last may be given in cachets with or without small doses of pulv. opii co. to make the conditions favourable for it. At first, under the chronic conditions when there is no fever to help the salicylate, ordinary meat, fish, egg and wine, or beer diet should be continued ; but when the salicylates have been in action some time, and the pains are somewhat better, and it is thought that a considerable amount of uric acid has been removed from the body (for salicylates remove that which is introduced each day, as well as that which is retained in the tissues), an attempt may be made to alter the diet. This should be done slowly and gradually, with great care not to lower nutrition, or upset digestion, or increase the alkalinity of the blood. Substitute bread stufis, milk and cheese for flesh, fish, fowl and eggs, as near as may be in exactly equivalent (albumen) values ; continue the beer or wine as before, or very gradually reduce them, substituting acid vegetables and fruits to prevent any fall of acidity, and thus avoid everything that may make the conditions unfavourable for the salicylates. And we must not forget that these drugs not only do good under right and proper conditions, but do actual harm under wrong conditions, as we have seen in the cases previously men- tioned. When the changes have been completed, continue the diet and the salicylates for months and years ; one and a half, two, or even three years may not be too long a time to allow for clearance of urates from the tissues, and I have had a good many patients who have wilKngly gone on for such a time and have expressed them- selves as greatly pleased with the results. On the other hand, to expect that salicylates will act in EHEUMATISM AND MOBBUS COEDIS 817 chronic conditions with, anything like the same power and promp- titude that they do in the favourable conditions of acute disease is to expect the impossible. What we have to do in chronic cases is to make the condi- tions as like those of acute cases as possible, and to continue the saUcylates, always making the conditions as favourable for them as we can. On the other hand, to be discouraged by the small efEect of the sahcylates without understanding the causes of this, and to give up these drugs in favour of half a dozen other treatments to be tried one after the other, is, I think, to court failure. I think that statistics clearly show that saUcylates have done great good in rheumatism, diminishing its frequency and its death rate, and greatly diminishing its serious complications (see Sir Douglas Powell, Lancet, 1900, vol. i.,- p. 922), and I am constantly pointing out that when its relations to cold and heat, to acids and alkaUes are more generally recognised, still better results will be obtained ; but I notice with horror that even the above observer still advises the use of salicylates with alkalies and woollen wrap- pings — conditions in which they cannot possibly produce their best effects, and this may account for his opinion (previous reference, p. 921) that acute rheumatism is still a matter of four to six weeks. If pain and temperature have not vanished in four to sis days I consider that I have done very badly, and with proper care in continuing the drugs there should be no relapses. With regard to this my friend. Captain W. G. Beyts, tells me of some excellent results he has obtained in acute rheumatism by the application of cold. In some cases he has applied snow or cloths wrung out of ice cold water, in spite of the obvious terror of the patient at such an extraordinary application to a rheumatic joint ; but these being applied along with salicylates have done nothing but good to the patients, and they only need a few hours of experience to see that the cold is really their best friend, and they soon wish to have it appUed to all their joints. These results are very interesting, and completely confirm my deduc- tions from the chemistry of the subject. A recent experience of my own may also be mentioned. A boy was admitted under my care in the Metropolitan Hospital sufiering from arthritis, chiefly in the left knee. He was given saKcylate, and the joint was enveloped in cotton wool and a bandage (the very opposite to Captain Beyts' treatment, which is sahcylate of methyl or salicylate ointment and an icebag). When I came 52 818 URIC ACID — CHAPTEE XVI to see tim a day later the temperature had not fallen and the pain in the joint continued, so that the question was raised whether the arthritis was rheumatic. On seeing the joint I at once ordered the removal of the warm wrappings and substituted a cradle to keep it cool. In another twenty-four hours the sali- cylate had cured it, and all doubt as to diagnosis was at an end. Lastly, we come to the very chronic cases of arthritis asso- ciated with anaemia, debility, dyspepsia, and generally feeble nutrition. Here we have the most unfavourable condition for the elimina- tive action of salicylates, and in such cases they may be expected to fail, and should not, I think, be given unless and until the con- ditions have been made more favourable to their action. The first thing to be done here is to get digestion into some sort of order, to increase appetite and to feed up and diminish the anaemia with tonics, as ' iodide of iron, iodide and cinchona, arsenic, acids, chloride of calcium, guaiacum, cannabis indica, cod- liver oil, or best of all perhaps urea, anything and everything that will improve appetite, digestion, nutrition and the blood condition. I notice that Dr. Kent Spender records in the British Medical Journal, 1902, vol. i., p. 697, a case of " Chronic Rheumatic Arthritis " which was greatly benefited by a three months' course of opium — J^ S^- every three or four hours. This no doubt acted- just like some of the retentive drugs I have named above, kept the blood relatively clear of uric acid, and prevented the uric acid filter action of the affected joints, and so allowed the pain to subside. Sometimes these measures will succeed if combined with change to a bracing mountain climate, and then when digestion is good and blood fair, we may give the salicylates as in the previous class of chronic cases without debility, and later on alter diet also. Are we to alter on to a uric-acid-free diet cases of chronic arthritis with debility ? As a rule I should say no, for the only effect will be to increase coUeemia, anaemia and debility ; the only exception being perhaps in cases where a patient can digest and prefers the bread stufis, milk and cheese of a uric-acid-free diet to anything else. As a general rule we must use tonics, change of air and ordinary diet at first, just as I have advised in the treatment of chlorosis in a previous chapter ; and then if digestion, nutrition and the blood improve, go on to salicylates and uric-acid-free diet as in the less debilitated cases of chronic arthritis. EHEUMATISM AND MOEBUS CORDIS 819 As to diet, what I think about it will be pretty evident from what I have said above. It alone goes to the root of the matter by cutting off the supplies of the poison from without ; but, as with all other treatment, there are certain conditions in which it cannot and must not be used. There is absolutely nothing, however, to prevent its being used in the bringing up of children of gouty and rheumatic families, who have as yet no active disease. Here it can be begun at once (never too early), as weaning is being carried out, and such chil- dren will develop far better than any others ; no dyspepsia, no bilious attacks, no headaches, epilepsy or mental failure, no tonsill- itis, no adenoids, no rheumatism, no ansemia, no gout, no colds or influenzas, few or no fevers, and certainly no deadly com- plications or sequelae. I do not need to quote cases in illustration of this, for instances may be seen any day in the cottages of country peasants. Too much credit for the result has always been given to the air, too little to the frugal fare which poverty has kept them to, and in doing so has presented them with a priceless blessing, which wealth only too often cannot buy. But even in cottages this mag- nificent health is not so common as it should be, for tea has spread even faster than meat, and this has been closely followed by the more terrible meat extracts and decoctions, and all have now penetrated and done their deadly work to some extent even in the cottage. Diet combined with oi in sequence to drugs will, I believe, not only stop the progress of arthritis, but will in the same way arrest, and allow the repair of, the more serious endocarditis. Here we cannot see the lesion, and can only judge of it from its external signs, but I am decidedly of opinion that after the treatment by iodides, sahcylates and blisters has had its turn, and produced its efiects, diet should be continued for months and years, and in cases where this has been done, some of which I have seen with D?. Gayford, whose record of an interesting case I give on a previous page, I have certainly seen reason to think from the physical signs that there was at least no increase of lesion, but on the contrary, that it was being more or less dis- tinctly diminished and wiped out. And I have had reports of children who were seriously affected both in joints and endocardium at an early age, who have yet developed into vigorous and healthy adults on treatment similar to that advised above. 820 UEIO ACID — CHAPTBE XVI This brings me to local treatment, which we have already men- tioned in the case of the heart, and with this exception I con- sider that local treatment is a matter of very small importance as compared with such things as diet and nutrition ; and one of the things we must make as certain of as possible, with our local treatment, is not to do harm, not to hinder digestion and nutri- tion and the action of our important drugs. For, obviously, local treatment does not go to the root of the matter, does not control the disease ; it merely palliates certain symptoms, and to allow any such treatment to interfere with the main treatment is to sacrifice the whole to the part. I consider therefore that massage, hot air and hot water must never be allowed to produce or increase general debility. Salicylate of methyl is betwixt and between, it is in part a local treatment, but i£ applied in large quantity over a consider- able surface so much is absorbed that it becomes a general treat- ment as well. In acute arthritis, where there is gastric upset, with vomiting, or where salicylates by mouth are not well taken or cause gastric trouble, salicylate of methyl will take their place, and painted over several joints or a large surface, will relieve and cure acute arthritis in much the same way as if taken by mouth. In chronic arthritis some xv.-xxx. drops may be painted over the most troublesome joint night and morning or more often, and covered with gutta percha tissue, kept in place with a bandage, or an icebag or cold bottle may be placed over the gutta percha. And this may be done as an aid to the salicylate by mouth, or while tonics are being given to pave the way for salicylate. Where acute arthritis has subsided and salicylates are being continued, while one joint remains perhaps specially tender and puffy, a few small blisters or a touch with the actual cautery, do as much as anything to relieve the local swelling and tenderness, and enable the joint to be brought into use. Then my friend. Captain W. G. Beyts, suggests that an ointment of lanoline or vaseline containing xx. or xxx. grs. of salicylate of soda to the ounce may be very useful not only in uric acid arthritis, but also in traumatic arthritis (sprains and injuries) in those who consume meat and tea, for in those who are full of urates a traumatic arthritis promptly becomes a uric acid arthritis. The ointment is to be spread thickly over the seat of the injury and an icebag or ice cloths over that. EHEUMATISM AND MOEBUS COEDIS 821 Then there is the local appUcation of heat which may un- doubtedly be of use as regards a single joint, or a series of joints which are rebellious to other methods or hang back from a general improvement. For such single joints I have no objection to it, though it must never be forgotten that general heat to the body, as a whole, is a treatment by alkali, a,nd as such is absolutely incompatible with treatment by salicylates, and any attempt to combine the two will only lead to disaster, and even a single joint will probably not.be improved by heat while salicylates are iu the blood (see cases previously mentioned). In certain cases general treatment by heat to the whole body may be used with advantage, and the arthritis may improve under its local and general effects, but it is a treatment by alkali and promotes the removal of urates just as an alkali does (see British Medical Journal, 1899, vol. i., p. 853), and like this also it is more or less decidedly depressant, causing or increasing anaemia. Local cold, on the other hand, will, as pointed out by Dr. Ewart {British Medical Journal, 1899, vol. i., p. 854, and Lancet, 1899, vol. i., p. 955), often relieve the pain of chronic arthritis, and this is not incompatible with the administration of salicy- lates but aids their action. Dr. Ewart apparently used rubbing of the surface with a block of ice or the appUcation of an icebag. In several cases I have found this local use of cold do good, and I look upon the increase of arthritic pains which so often occurs on getting warm in bed at night as an indication for it. With regard to this local use of cold, we must not forget that cold apart from the salicylates interferes directly with the solu- bility of uric acid, throwing it down in colloid form from solutions, and its reheving pain in chronic cases reminds me of Dr. Pfeifiers' experimental observation on himself previously men- tioned, that acids, which act like cold, diminished the local irritation of injected urates, whUe alkaUes increased it; and all chronic arthritis with debility is urate irritation under alkali, for with increasing failure of nutrition the blood and tissue fluids become increasingly alkaline, and the increase of arthritic irrita- tion may be due to uric acid previously deposited being got again into solution. This should of course eventually end in complete solution and removal of the urate, and cure, and I am incHned to think that this does occur in some very chronic cases ; but during this removal the pain and damage to fibrous structures and also to blood and general nutrition, may be very 822 UEIC ACID— CHAPTEE XVI great, so that the patient dies of debility or some complication. But in any case the action of cold is the parallel of that of the iodides, tonics and certain mineral waters mentioned above. It favours the best action of salicylates, so that an icebag is the best local appUcation while these drugs are being given, whereas heat not only hinders their action but makes them do harm. Massage has the effect of improving the local circulation, it probably increases the alkalinity of a given joint, and thus in- creases the solubility of uric acid in its fluids, but in so far as its efiects are more local and less general than those of heat, it may do good to special joints without much general depression. With regard to massage I think we must bear in mind that by improving the circulation through the injured tissues, and flooding them both with fresh blood and fresh alkaline serum, it may really do a great deal in removing the irritating urates. While these urates are present or are liable to recurrent pre- cipitation on the damaged structures with the daily, almost hourly, fluctuations in the alkalinity of the blood, we may have to deal with a progressive condition of irritation, leading to ever increased fibrosis and stifiening, and that whether the original condition was uratic or traumatic ; for in those whose fluids are full of urates every traumatism of flbrous tissue is sure to be irritated by their presence and recurrent precipitation, so long as the seat of injury is less alkaHne than the blood and tissue fluids of the body, for in this condition it acts as a uric acid filter as regards the blood and tissue fluids, giving up uric acid to them if they are very alkaline, taking it up from them if they are not. Now the eSect of massage on an injured fibrous tissue is 'to flood it with fresh blood and to bathe it through and through with fresh serum, as shown perhaps by considerable increase of swelling after the massage. The swelling, however, goes down again, and the serum is taken back into the circulation, and not only takes with it some of the urate that caused the irritation, but also some of the acid salts that rendered the fibrous tissue a seat for urate accumulation; hence it comes about that repeated massage every two or three days for a couple of weeks may not only remove the urates which are the cause of the irritation in the fibrous tissue, but may render it as alkaline as the blood and tissue fluids in general, and therefore no longer a seat for chronic and recurrent retention of urates ; it breaks through the uric acid filter action and this may be the end of the trouble. EHE0MATISM AND MOEBUS COBDIS 823 Here we see possibly another reason for the rapid and satis- factory repair of wounds and injuries in those nations, as the Turks, who live on an almost uric-aoid-free diet ; they have not only, as already pointed out, a greatly improved circulation owing to absence of coUsemia and a better supply of alkali for their damaged fibrous structures, but they have also far less uric acid to be precipitated upon these structures and keep up the irritation, and where those living on a uric-acid-free diet have required , operation it is my experience that the surgeons have nearly always remarked on the rapid and satisfactory repair of the wound. Hence these people get well simply and naturally with- out the opium and without the subsequent massage that are so often required by the urate-laden meat eater. -'•"i Do we not here see also, at least a partial explanation of the good results produced by so-called " bone setters," who break down and subject to massage the fibrous tissues round an old traumatism ? For an interesting case where gout was cured by massage see a paper in Edinburgh Medical Journal, 1898, vol. i., p. 561 ; Dr. G. W. BaHour, the author of the paper, suggests that "the massage cured or prevented the thrombosis ; but I think it is much more probable that the massage really cured, as I have suggested above, by flooding the afiected tissues with fresh and more alkaline serum, which would increase the solubility and aid the removal of uric acid, thus bringing its action into line with that of alkalies and salicylates, which, as I have shown, cure gout by removing and eliminating uric acid. When joints are distended by fluids and surrounded by much pufiy fibrous tissue, a horse shoe blister, or a series of smaller blisters, wUl often do much good by removing the fluid ; it thus relieves the pain which is due to tension, and may enable the patient to use the limb once more, and thus we may be able to produce some improvement in general health, which it is so impor- tant to do in chronic and debilitated cases. I am much interested to see in reference to what I have said in this chapter and in chapter x. that Dr. T. Stacey Wilson says in an article "On Colon GaXaxila." British Medical Journal, 1902, vol. ' ii., p. 1764, " the key to the treatment of this disease is in my opinion the recognition of its relation to gout." The result is that he uses salicylates and uses them with success, and this I may remark is the key to the treatment not only of colon catarrh but of all irritation by uric acid of any and every fibrous tissue throughout the body. My treatment of rheumatism is in a word salicylates followed 824 UEIC ACID — CHAPTBE XVI by alteration of diet ; elimination followed by or combined with stoppage of introduction ; and where conditions are unfavourable to the best action of these powerful drugs, I devote my whole attention to making them favourable. Acute rheumatism is, like gout, a trouble due to retention of uric acid ; it is therefore relieved by solvents. In very chronic cases with ansemia and debility it may be associated with coUaemia, the irritation being kept up by the uric acid filter action of the irritated tissues and local deposits, and this condition may be • reheved by precipitants and a highly nourishing and stimulating diet, which clear the blood of uric acid and stop this action. The rule is, troubles that get worse with solvents get better with precipitants, and vice versd ; but when an arthritis is affected by neither, some cause other than uric acid should be looked for. 825 CHAPTER XVII. Treatment. ' AiTBK all " the proof of the pudding is in the eating," or rather, in this case, the proof of the poisonous nature of flesh and tea hes iq the efEects of refraining from eating and drinkiag them, and the best possible tests of the truth and stabiUty of the above considerations are the results that can be obtained by applying them in practice. It matters little to those who sufier whether the poison in the blood is uric acid or xanthine ; but it matters every- thing to them if, by altering their diet and getting their nitrogen from one source rather than from another, they can free their blood of the poison, and themselves of the diseases it produces. Many volumes of theory did not suffice to prevent one of my headaches, but, once I found out that they were due to poisoning by meat and tea, prevention became both certain and simple, and relapse is now a mathematical certainty, if these poisons are again taken in any form. The diseases treated of in the first fourteen chapters are more or less directly due to excess of uric acid in the blood, those in the fifteenth and sixteenth are due to this excess of uric acid being driven out of the blood into certain fibrous tissues. The diet treatment of these diseases is the keeping the body and blood free from an excess of uric acid, and we have now to consider the way in which this can be done. Now uric acid is met with in excess in the body and blood chiefly, as we have seen, from three causes: (1) that it has been introduced in excess by the consumption of articles of food such as meat, eggs, fish, pulses, mushrooms, asparagus, tea, coffee; cocoa and guarana, which contain it or other members of the xanthine group equivalent -to it ; or (2) because so much nitrogen is taken that the uric acid formed out of it in the relation to urea 826 UEIC AOID — CHAPTBE XVII of about 1 — 35 is, owing to tte high acidity which the salts and other products of nitrogenous metabolism produce, not all excreted,, and a store is gradually formed in the body to the extent possibly of from 52 — 400 grains in a year ; (3) the high acidity which results from the taking of much animal food prevents the excre- tion of the uric acid introduced with this animal food, as well as of that which is formed out of its nitrogen along with a certain quantity of urea. In a word, animal food increases the introduc- tion and formation of uric acid and at the same time prevents its elimination, and the allfaloids of tea, cofiee or cocoa and certain similar vegetable products, e.g., those contained in the pulses, act in the same way. Speaking of guarana, reminds me that it is probably by its nitrogenous or xanthine elements that it cures sick headache (uric acid headache), because strange as it may seem at first sight, a dose of uric acid itself will cure a uric acid headache, and as we have seen in chapter iii., the first effect of a dose of uric acid, and probably also of ammonia and nitrogen in other forms, is to raise the acidity and clear the blood of uric acid ; and I remember years ago, before I began to study medicine, pointing to a big plate of meat in front of me, and saying, " My headache will be all right when I have eaten that." I now know that the nitrogen and salts so introduced diminished the alkalinity of the hver, started a uric acid filter there, and so cleared the blood of the uric acid that was causing my pain : a rise in the acidity of the urine following and showing what had occurred. But I would earnestly warn any fellow-sufEerer against treating his trouble in this way, for I believe it to be a most dangerous course ; the uric acid thus cleared out of my blood was not cleared out of my body, and in addition more was introduced, and for years after- wards I suffered with most terrible headaches, while the urates thus stored up were passing through the blood, and I believe that damage was then done to my heart, vessels, liver and other structures, which no subsequent chknge of diet has sufficed to wipe out. I would say, further, do not under any circumstances resort to caffeine or guarana for rehef ; they are practically uric acid, and present relief is obtained at the price of future suffering ; and I have seen several cases in which the employment of these sub- stances for some considerable time for the relief of headaches, &c., has been followed by very deplorable consequences. With regard to diet, we can give the main point in very few words, for we have seen that as flesh diet increases the introduc- TREATMENT 827 tion of uric acid, it increases the formation of uric acid, and its salts diminish the excretion and elimination of uric acid. A milk and vegetable diet, provided that no excess of albumens is taken, introduces less uric acid, causes the formation of less uric acid (because urea is not unnecessarily high), and its salts promote the free elimination of all uric acid that is introduced into or formed ia the body. Thus we see (p. 16), that I excrete now 12 grs. of uric acid, of which 10 grs. are formed in the body, and 1'9 grs. are introduced ready formed, while a fraction of a grain is accounted for by the excretion of urates previously stored in my body. With this low formation and introduction of urates I have but rarely any excess in my blood, and consequently sufEer little or not at all from headache and other signs of such excess. In former years on ordinary diet I used to excrete 500 to 600 grs. of urea, and in the above proportions I must have formed 14 — 17 grs. of uric acid and introduced from 5 — 6 grs. ready formed in my food. It is easy then to see why I often had an excess of urates in my blood, and frequently suffered from the effects of such excess, namely, defective capillary circulation, high blood pressure, head- ache and mental depression. Further, I believe that the section of mankind that hves to eat may possibly introduce as much as 3 or 4 grs. of uric acid with each meal, or 9 — 12 grs. in a day or more, and sooner or later will suffer in proportion. We can now quite understand why in Persia, where only the rich eat meat, gout has come to be known as the rich man's disease (see Proceedings of the Royal Medical and Chirurgical Society, third series, vol. v., p. 46, where this interesting fact is contri- buted to the discussion on my paper on the iodides by the physi- cian to the Shah), and we have already seen on p. 561 that the children of the rich *re in this country specially liable to anaemia, no doubt due to excess of meat in their food, and in chapter xvi. we have seen that M. Bouchard considers that children thus over- fed are liable to many troubles, including migraine and acute rheumatism, and the anaemia and coUsemic circulation of such chil- dren can be seen at a glance. We have, then, two things to do to attain our object : we must cut off all food which contains much uric acid, and which is not absolutely necessary ; and we must not take more nitrogen than is necessary to keep our urea at the physiological level of 3"5 grs. per pound of body weight per day, or S'O grs. per pound for sedentary adults of middle age. With regard to cutting off we may, I think, at once forbid tea, 828 UEIC ACID — CHAPTER XVII cofEee and cocoa, or permit them only in tte smallest possible quantities as flavourings. "We may cut ofi such animal food as contains much uric acid, and give only so much of the less harm- ful kinds as is necessary for nutrition. This raises at once two questions : — (1) What animal foods contain much uric acid ? (2) How much animal food is necessary for nutrition ? There can be very little doubt after what I have said, that the best answer to our first question is to be obtained by the physio- logical test which I have used ia the case of meat (see p. 109 ; and Journal of Physiology, vol. xv., p. 168). That is to say, when a person is on a practically constant diet, and is watching his uric acid and urea excretion from day to day, if the taking of a known quantity of some substance, such as fish or meat, always, without exception, increases the excretion of uric acid out of proportion to urea, such substance probably contains some uric acid which it introduces into the blood, and should consequently be as far as possible avoided. Such a physiological test is much more valuable than any mere estimation of the xanthines contained in meat can possibly be, for what we want to know is the effect" of these substances on the living human body, and in so far as meat eating produced my headaches, it was no doubt, as we can now understand, the xanthines it contained, which probably by conversion into uric acid slowed the capillary circulation, raised the blood pressure and increased the excretion of uric acid in the urine. In eggs, for instance, T have been unable to find any uric acid or other members of the xanthine group, such as I have iound in meat, and yet their steady and graduated administration invariably brings about a large rise in the excretion of wric acid, and all the evil effects of its passage through the blood, so that I have had to exclude them entirely from my diet. We must, therefore, take the following table as at best. but a very rough guide to the amount of uric acid or xanthine in any food, and the ultimate appeal must always be to the eSects of administration on the excretion of uric acid from day to day (see also p. 8 and figs. 73 and 75). StTBST ANCB. Ubic Acid and Xanthines. Grains PER CENT. PEE LB, Lamb (cold roast leg) •050 3^5 Soup (made from bones) •0068 0^48 ,, (made from meat) . . •0202 1-4 Hospital beef-tea •0980 7^0 TREATMENT 8S Substance. Ubic Acid and Xanthines. Grains PBB CENT. PER LB. Saddle of mutton •020 1^4 Mutton (cold roast leg) . . •016 1^1 Veal (outlet) . . •049 a-5 Beef (oold sirloin) •016 1^1 Kidney of sheep •049 8^5 Liver „ „ •091 6-5 Fowl (breast) .. • > •024 1-7 Eabbit ■015 1-0 Mackerel •032 2-2 „ (boiled only J of an hour) •015 1-0 Plaice • - •0039 0-2 Herring (fresb) •0040 ■ 0-2 „ (Looh Pyne, kippered) . . •0900 6'4 „ (bloater) •031 2^2 * Beef -steak (treated raw) •019 1-3 * Meat-juice •697 49-7 * Meat extract . . •888 63-0 Tea .. . 2^5 175 •O Coffee . . . 1^0 70-0 Cocoa . . •84 59^0. The tissues were extracted as cooked, and ready for eating, # except as mentioned, and I give uric acid in grains per pound as well as in per cents., as it has been suggested to me by Dr. Eushton Parker that this would make the table more useful. We see from this that young meat (lamb and veal) contains more than old (beef and mutton), and that, as we should expect, soup made from meat contains considerably more than soup made from bones. We see also that the kidney and hver of sheep con- tain considerably more than their muscles, just as is the case in man, and some kinds of fish appear to contain a considerable quantity, even more than meat, and any increase in the fish taken has certainly appeared to me to markedly increase the amount of uric acid passing through the blood. The fact that hospital beef-tea contains so much uric acid is interesting, and a pint of this beef-tea, I am informed, was made by cooking 1 lb. of meat for eight hours. It appears, then, that this process extracts about five times as much as I have obtained from similar muscular tissue, but then I only boiled it for half an hour (see chapter xviii.). This seems to render it probable that I have only extracted from the tissues in the above table from a quarter to half of the uric acid they really ' These are from p. 80, placed here for comparison. 830 URIC ACID — CHAPTEE XVII contain ; getting relatively more from the younger or softer tissues whicli broke up more easily, and relatively less from the older and tougher tissues. As regards the animal foods, their infusions and extracts, the figures given represent uric acid plus other members of the xanthine group, and tea, coffee, and cocoa contain xanthine compounds, not uric acid ; but as I have pointed out in the early chapters of the book, these may, for all pathological and physiological purposes, be regarded as one and the same substance, producing throughout the body and its tissues the same effects. Then I find that a single supper or dinner of soup, fish, and meat appears to increase the urate excretion of the following three or four days by about 4---6 grs. ; but the animal food taken at such a dinner, including soup and meat extracts, probably does not exceed the equivalent of three-quarters of a pound of meat, so that the results of digestion appear to correspond fairly well with those of long cooking in the case of the above beef-tea. It needs also but a very simple calculation from the figures in the above table to show that tea is by no means the harmless substance it has been supposed to be, and that in place of causing^ a little dyspepsia by tanning the gastric mucous membranes, it may really bring about, in the course of a year, the introduction of a huge quantity of uric acid, and thus account for some of the most serious effects of collaemia or arthritis, of which we had probably one instance in chapter vii., p. 307. I may mention, while speaking of tea, some figures kindly sent me by Dr. C. E. Lockwood, of New York, as obtained by a friend of his. Dr. W. J. Morton, while experimenting on himself with tea. He took from 4 to 8 drachms of green tea infused in a pint of water, and continued it for seven days, and as a result uric acid rose from 5 grs. up to 8, 10, 11, and 13 grs., while urea fell steadily from 591 grs. to 422 grs. in the same time, this fall of urea probably illustrating the depressing effects on metabolism of excess of xanthine or uric acid in the blood. And now for our second question — How much animal food is necessary for nutrition ? I havfe had in my own experimental work the most absolute proof, if further proof is needed, that a sufficient supply of nitrogen is the prime necessity of nutrition. For before I became aware that the uric acid which poisoned me was being poured in day after day ready formed in flesh foods tea, cofiee, &c., I believed that the only way to reduce uric acid TREATMENT 831 ■was to reduce total nitrogen, and this I proceeded to do with the unfortunate result of reducing myself to a condition of extreme debility and asthenia. But when I found out in 1893 that all uric acid and xanthine swallowed got into the blood and eventually into the urine, I was at once able to see that I could take as much nitrogen as was necessary for nutrition as long as I avoided substances which con- tained much uric acid or xanthine. I will now show in fig. 73 an epitome of my results during four years, each dot in the curves there given corresponding to a month's excretion. The figure begins with December, 1893, where we see urea is very low, at 10,000 grs. in the month, or 322 grs. a day, which for 125 lbs. of body weight is only about 2-6 grs. per pound per day ; but uric acid is high, 12'8 grs. per day, giving a relation of uric acid to urea of 1 — 25. And this I may say was a condition of considerable danger, as my tissues were not only under nourished from want of albumens, but their circulation was very defective owing to collsemia ; and I was thus exactly in the condition in which tubercle or any of the exanthemata, or other parasitic diseases, might have flourished greatly at my expense, and this was so in spite of a very free allowance of fat, sugar and starch, and these would never have saved me from death had I gone on with the low diet of albu- mens (see also my remarks on these points in " Diet and Food," fourth edition, pp. 28 and 112). And I trust that this experience of mine may act as a warning to others not to try the starvation road out of their difficulties, as it is at once dangerous and' unnecessary. From this onward we see a steady rise of urea tiU in Feb- ruary, 1895, it has reached about 387 grs. a day, and in June, 1896, to about 419 grs. a day. And uric acid, which was above 14'7 grs. several times in 1896, and above 13'7 in 1895, falls towards the end of this year (1895) to 11'9, and has remained about this level ever since, its relation to urea in the early part of 1897 being very close to the supposed level of formation, 1 — 35. So that at the present time the uric acid excreted in a year is nearly 500 grs. less than in 1894, and urea is nearly 30,000 grs. a year more. The great fall in uric acid is entirely due to the gradual elim- ination from my diet of substances containing it or its xanthine relatives. Thus up to the early part of 1894 I was taking both 832 UEIO ACID — CHAPTEE XVII 1 ^ • < — ~ K§1 < ^ __ ^ ^ t= - ^1 ^ — — ■"* "" 8 *z ; y 1 __^ • ; d g It — rC '/ 1' 1 \ V > ^ Il ;N 1 \ <^, _J s /- \ r-~* ■1 > ^• -' \ .n^ > •^ \ :i y . ^> > s < _,'' -'' ( r •■:'. -.. V ^ ^ ^ .^ ;;■ -~» > g. 1 > .-- -"' r g L • \ \ ^ s " \ > s B ^ '• < !■ < ""' i^ >• ,,. ^g n s • . > ^1 V *>v "'^' • ^ g > ^ k "^ ^ < < y ^ V V < S > \ ,> g f X < ^ y i > ^ '4 s m-' < 1 'x '' 'v ,^ |, 'P * > 1 ^ ^ * ^ 3:^ mt c /., §? ■^ N <$; ^~~ %. A^ N ' 'v ^ ^^ 3. <: M I ^ 1 5 V 3 S 5 2 5 s ^ s 1 i 5 C s 1 1 1 1 V3yn I ^ Si ^ I I £2 00 CM § I OQ Cm 1 1 TREATMENT 833 fish and eggs, in 1895 I took fish perhaps once a day, at the end of 1895 I took neither fish nor eggs, and in the latter part of this year and the whole of 1896 I gradually eliminated from my diet all articles that contained even the smallest quantities of egg, such as puddings of various kinds, and cakes, as I got very distinct evidence that these when taken every day very decidedly increased the excretion of uric acid. The curves tell their own tale and show that I am now prac- tically free from uric acid, and that the small output of this sub- stance is not due to its small excretion or retention owing to rising acidity and urea, for in February, 1897, I took a large amount of alkaU and greatly reduced the acidity of the urine, and yet the resulting rise of uric acid was very small indeed, showing that there were practically no stores in the body available for solution. I would point out that with this great fall of uric acid my blood decimal has gone up since 1894 fully 10 per cent. ; that my pulse is now never so slow or my blood pressure so high as it used to be, that headache and mental depression are steadily and completely absent, while nutrition, strength, and power of endur- ance are better now than at any time during the last fifteen years. It may be said that the improvement in the blood decimal is due to the rise of urea, and this is no doubt correct to some extent, for the nutrition of this circulating tissue must have im- proved along with the rest ; but this will not explain the fact that the blood decimal fluctuates with the hourly and daily fluctuations in the excretion of uric acid, and that both in myself and others the swallowing of uric acid or any of its xanthine relatives will promptly bring it down without affecting urea at all. My blood decimal has further improved since 1898, and is now between -7 to '8, which is on or above the normal of any other scale. This figure, therefore, shows that the excess of uric acid and the diseases it produces are almost entirely matters of introduction, that no reduction of urea compatible with life will bring down uric acid so long as introduction is continued ; but on the other hand, so long as uric acid is not introduced, urea may be kept up at any height required by physiology to furnish the greatest amount of force the body is capable of producing; that with suificient urea and in the absence of all excess of uric acid, it can furnish force for nutrition and strength and power of endurance, to an extent 53 834 UBIC ACID— CHAPTEB XVII which is very greatly in excess of anything that can be done when fed on animal flesh and vegetable alkaloids; and the rate of the capillary circulation tells us in a moment whether we have to do with an organism which is hampered by the friction causing coll- semia, or with one which has a free circulation, and- which will consequently excel both in force production and in endurance. My experience, therefore, leads me to answer the question of the quantity of animal food necessary for nutrition as follows : — No animal food at all is necessary, for the whole of the required nitrogen can be got from the vegetable kingdom, but as mUk and cheese appear to have no power of increasing the excretion of uric acid, they may, if necessary, be used along with the vegetable foods. As to the quantity of nitrogenous food required, my experience leads me to beheve that the allowance given in most works on physiology of 3'5 grs. of urea per pound of body weight per day, is very close to the mark for a healthy and active adult man. Children may require nearly three times as much, as they have to grow as well as to keep up nutrition ; sedentary adults require less, and those who are old as well as sedentary much less. Thus, for myself, I believe that somewhere between 3 and 3J grs. per pound per day is the best amount of urea, near the higher limit when I am taking a considerable amount of exercise regularly, and near the lower when I am very sedentary, as in bad weather in winter. Then as urea multiplied by three equals roughly the albumen required to produce it ; if the weight is known, it is easy to calculate approximately the quantities of the various food sub- stances that will have to be taken by any given person. Such a calculation should, however, only be used as a rough guide ; as appetite on the one hand, and nutrition, the blood decimal, strength and power of endurance on the other, are the most certain indications of the necessary quantity and quality. The rule then for an active adult is — find the body weight in pounds ; if there is much adipose tissue deduct it ; i.e., take the weight of the individual before he began to get stout, multiply by 3"5 and the resultant by 3 and you will have the amount of albumen in grains that he will have to consume each day. Thus a man of 1401b. X 3-5 = 490 x 3 = 1470 grs., the amount of albumen to be taken by him each day. He must leave out all meat, fish, fowl, game and eggs, which contain say 20 to 25 per cent, of albumen, and replace them by — TREATMENT 836 Milk . . Cheese . . Bread .. Cereal foods . . . . containiag 3 — 4% of albumen. 33% „ „ 8% „ „ „ 5-12% „ „ Nuts or almonds „ 15-25% „ „ Dried fruits . . ,. 2-3% „ „ He may also have garden vegetables, but these often contain mere fractions of a per cent, of albumen, or garden fruit, contain- ing from -5 up to 1-0 or 1-5 per cent, of albumen only. Practically, then, he wUl have to replace his flesh foods by bread and corn foods and a little milk and cheese, with nuts and dried fruits if he likes and can digest them ; and he should regard garden vegetables and fruits as sauces for the dry or less interesting bread and cheese. I am sorry to see that Dr. Hall finds S'i grs. of purin (= uric acid and xanthine) in a pound of oatmeal (British Medical Journal, 1902, vol. i., p. 1462), and I am still more sorry to find that my own experiments seem to confirm his result. With regard to this, I will only say that some xanthine is probably universal throughout the vegetable kingdom, just as some uric acid is universal throughout animal tissues ; both are products of the metabolism of life, and are probably inseparable from this,* and all we can do is to choose those things which contain least. In the same way the whole wheat grain is by no means free from xanthine, but a large part of it is removed with the germ and coverings ; hence white bread, according to Dr. Hall (previous reference), contains none ; and white bread in my experience also contains little or none. But some other breads which retain the germ and coverings contain quite appreciable quantities, and one of these which I estimated contained 2-7 grs. per lb. This of course raises the question of the separation of xanthines from other grains and the pulses, and many manufacturers claim that they do thus remove a considerable quantity, and my results seem to show that this is true ; but I still prefer to work with cereals which only contain from 2 to 4 grains per pound in their original condition, rather than with the pulses which my researches show to contain as much as 16 grs. to the pound, or twice as * Dr. Sheridan Lea in his "Chemical Basis of the Animal Body" (p. 174), says : " The relationship of the xanthine bodies to certain vegetable alkaloids is further interesting when it is remembered that the latter are regarded by plant physiologists as waste products of the vegetable organisms, and are thus iound chiefly in those parts of the plant which are on their way to removal, ■viz., the bark, leaves and seeds." 836 UBIC ACID — CHAPTER XVII much as most meat (muscle). "But if xanthines are completely removed from the pulses then there is no more harm in taking their albumens than those of (white) hread. The ultimate appeal is of course to the urine and the blood ; for a man fed on meat with tea and coffee excretes some 20 grs. of uric acid a day, and has slow capillary reflux and many granules in the blood ; while another man fed on cereals, milk, cheese, nuts and fruit, excretes only 10 — 12 grs. of uric acid per day, and has quicker capillary reflux and fewer granules in the blood; albumen, nutrition and urea being the same in both cases. Again there is an immense difierence between taking cereals that ■ contain 600 — 800 grs. of albumens and 3 — 4 grs. of xanthine per pound, and taking tea which contains practically no albumen and about 175 grs. per pound of xanthine ; here man is taking pure poison and no nourishment whatever, and with the introduction and diffu- sion of tea and coffee throughout the land there has come about a very great increase of all uric acid disease (see facts given further on). With regard to all these cereals, and the breads and puddings made from them, we must bear in mind that the outer husks of all kinds of corn contain some xanthine, and that therefore whole- meal bread, brown bread, whole meal and bran, and foods, bread and biscuits, containing them, must be avoided by all those who would be as free as possible from xanthine. What you want is a flour containing the whole of the grain without any of the husk and without the germ, and this is what is commonly called » best seconds flour. There is not much diSerence in nourishment between white bread and wholemeal bread, but the most nourish- ing bread of all is that made with seconds flour. Obviously most of our fruits contain so much water that huge quantities would have to be taken to get the necessary albumen, but this does not apply to the denser fruits or to those which have been dried or compressed, which may contain almost as much albumen as the cereal foods or bread. So our man of 140 lb. would have to take, in order to get his 1470 grs. of albumen — 14 oz. bread ( -- 8% of albumen)— 476 grs. of albumen. 2oz.rice (= 5% „ „ )- 43 „ 2 pints milk ( = 3% „ „ )— 525 „ 2 oz. cheese ( = 33%'] „ „ )— 281 „ Total ,. 1325 TKEATMENT 837 and the remaining 145 grains will probably be made up out of the cereal or other vegetable products he takes as puddings and out of the garden vegetables and fruits ordinarily consumed. Now many modifications of this diet are possible, and the best plan is, I think, for each individual to take that which suits his own taste. For my part I regard a diet consisting chiefly of bread stuffs and cereal foods as having more advantages than any other, and this was the diet on which the athletes of Greece and Rome per- formed their feats. For practical purposes I divide bread stuffs into three classes — (1) The breads proper ; (2) the biscuits ; (3) the puddings and pudding stufis, and 8 oz. of each of these three would form a large part of a day's food for anyone, and the remainder of the albumen would no doubt be made up from the fruits and vegetables taken as sauces to the breads. One , pound of cereal meal alone would equal about 800 to 900 grs. of albu- men, and those in active work would no doubt eat from li to 1| lb. of this, and when fruit and vegetables have been added this would be a very ample diet for anyone. Those who cannot take these quantities of cereal foods can add a certain amount of milk and cheese untU they can learn to take the cereals. A very large variety is to be obtained in each class of bread stufis. The fruits cannot be kept the same from month to month, and the vegetables also necessarily vary with the season. There is thus endless variety ; but these foods have been neglected till to-day they are but little known.* When appetite is very good, which generally means when exer- cise and fresh air are plentiful, the quantities of the more nourish- ing foods should be diminished, because their place is taken by the increased quantity of fruits and vegetables then naturally con- sumed, and conversely when appetite is poor, miUc, cheese, and bread may have to be increased, because less of the other things are taken. If these points are not attended to, we may get either too much nitrogen (urea and uric acid) as shown in fig. 74, or too *To meet this dif&culty a home has now been established at Apsley House, Slough, Bucks, as a gift to the cause of diet reform from a grateful patient, where I am able to give some practical instruction in food and feed- ing. When I enumerate to patients the foods that must be left out they often remark that there remains but little to live on, but after a visit to Apsley they are ready to admit that many of the things they have been neglecting are better than the things they have been eating, and that there is still plenty and to spare to suit aU tastes. 838 UEIC ACID— CHAPTER XVII little, with general debility and asthenia, as shown in the early part of fig. 73. With regard to these points I notice that Dr. Goodhart says (Lancet, 1900, vol. i., p. 4), " Children will pass uric acid even upon an excess of milk." Of course they will ; aU children form a large amount of uric acid and urea, and it is quite the best thing they can do to pass both out of their bodies as soon as possible. But why a physician should find it necessary to give them " excess of milk," or excess of albumen in any form, I quite fail to understand ; they have enough difficulty in getting rid of the uric acid they ordinarily form without its production being unnecessaAly increased. Everybody passes uric acid on every diet, and always will do so till the race evolves to a higher stage, which at present rate of progress will be a matter of considerable time ; but we are left in doubt whether the children were passing an actual estimated excess of uric acid in relation to urea, or had merely a little visible red sand in their urine, showing probably no excessive excretion of uric acid, rather the reverse ; but only perhaps that the urine was sufficiently acid to throw it out of solution, a condition which a little potato, or some alkaH in other form, would quickly remove, while actually increasing the excretion of uric acid. A few lines further on Dr. Goodhart tells us that " the forma- tion of uric acid and the formation of sugar seem to me to run on somewhat parallel lines," which is no doubt intended as an endorsement of my fig. 61, though it has escaped mention. But surely the facts would have been more correctly stated if he had said, that the excretion of uric acid runs parallel with the excretion of sugar, without mixing this up with what is a mere inference, that excretion means formation. For in the case of the uric acid it often does mean nothing but introduction (witness figs. 24 to 29 and others), and in the case of the sugar mere defective combustion ; as in reference to fig. 61 we Imow that the excretion of sugar parallels the excretion of uric acid, because excess of uric acid in the blood hinders the meta- bolism and combustion of sugar ; and we have seen that no other explanation will cover all the facts of the case, and had previously found that the excretion of albumen parallels the excretion of uric acid in exactly the same way, and for the same reason. Now the above-mentioned diet of bread stuffs, fruit and vegetables would work out into three meals a day somewhat as follows :^The total for the day being, say, 30 oz. of bread stufEs TKEATMENT , 839 and 24 oz. of fruit and vegetable, we get for each meal 8 to 10 oz. of bread stuff and 8 oz. fruit and vegetable. This will further sub-divide into, say, 4 oz. of toast, 3 oz. of biscuit, 3 oz. of pudding, 4 oz. of dry fruit and 4 oz. of vegetable and fresh fruit. Those who cannot take these quantities (and only a young adult leading a very active life would require so much) must take as much as they can and add some milk or cheese, or both, to make up for the bread stufEs left out, and they will gradually learn to eat more of the latter as they go on. Now 18 oz. sounds a very large meal, but we must remember that vegetables and fruits weigh heavy and contain, even the dry ones, a large amount of water ; the really solid food is the 10 oz. of bread stufis. The best way to eat this diet is to select several kinds of bread stufis, as toast, biscuits, and pudding, and place them at one's side, and then one or two fruits and vegetables which are to serve as sauces. The bread stufis must be weighed at first to test the amount eaten and to know how much milk and cheese have to be added, and it follows from their percentage of albumen that about 3 oz. of milk or about one third of an ounce of cheese have to be taken for each ounce of bread left out. Thus a person who falls short of his quantum of bread stufis by 8 oz. in the day will have to add 24 oz. milk or 2J oz. cheese. Thus as a person of 140 lb. wants about 30 oz. of bread, it follows that roughly speaking a little more than two ounces of bread is required for a day's food for each 10 lb. of body weight. Butter or oil may be taken ad lib. by those who are not too stoat, or in fear of becoming so, and a good way of taking them is to mix them with the vegetables. The way to take these foods is to eat the bread stufis steadily, with an occasional mouthful only of the fruit, or of the vegetables, which with butter or oil, are the sauces. Or nuts can be taken by those who can digest them, a ad then part of the oil or butter can be got from this source, and those who can take considerable quantities of nuts or nut foods can considerably reduce their bread stufis, as one ounce of nuts taken is equal to two ounces of bread stuffs left out. As I have said, the variety in these foods is very great, and with a little ingenuity may be made almost endless, but with this diet the taste for simple foods returns, so that it is often easy to make a meal of two, or at the most three things, say toast, potatoes and oil, and dry fruit. In this way the labour of the house-keeper may be greatly reduced, and life yields more time for other things besides eating and drinking, and this without any diminution of the natural pleasure of taste 840 UEIC ACID — CHAPTEE XVII and the satisfaction of hunger, which indeed are often much increased on a natural diet (see " Diet and Food," ed. iv., p. 54). I myself make but little use of nuts, but they are very valuable foods for those who can digest them, and might, if necessary, be increased, and biscuits and various foods made from them can be used as additions to the diet. They have the disadvantage of being relatively expensive, but an increased demand would, no doubt, soon reduce the price. It thus appears that I live on bread and cereal produce which might be varied, if necessary, to a much greater extent than is above indicated, with a little milk, cheese, and a liberal allowance of butter or oil, and that to these are added a little vegetable and fruit. I think it must be acknowledged that my nitrogen is sufficient, and .could easily be increased if necessary, and that I do not starve, and have plenty of variety in food. Constipation is an almost constant bugbear of the meat-eaters, but on the above diet it is practically unknown. Those who have to take much milk and cheese may continue to sufEer a little, but as a rule it is completely absent on a diet of bread-stuffs, fruit and vegetables. Some of those who have been in the habit of eating much animal food and but little bread and starchy foods, may have trouble with these latter when they begin to alter their diet. This trouble comes chiefly in the form of discomfort, disten- sion, or flatulent dyspepsia, and is largely due to the fact that bread and starch foods cannot be bolted, as flesh can be, with little mastication and without being mixed with saliva ; bread and starch thus treated are apt to digest very slowly and may begin to ferment in the process. The remedy is quite simple ; put the bread and starch foods dry into the mouth, so that the saliva can mix with them easily, and eat them slowly and chew them well. With this object eat bread which has been cut in slices and toasted right through in the oven, or toasted biscuits ; there is no objection to a Uttle butter with them, or fruit may be taken with them, but the bread stufis must go dry into the mouth, not in the condition of slops or milky puddings. Another rule for those who saffer from similar dyspepsia is never to drink when not thirsty. As a rule such people can manage one and a half or two pints of milk in the day without having dyspepsia from too much fluid ; but in cold weather and when TREATMENT 841 sedentary even that may be too much, and the milk may have to be reduced still further, the bread stuffs and cheese being increased to replace it (for further details see " Diet and Food," ed. iv., p. 63). The question of salt eating is one which requires consideration from several points of view, and I will shortly state my own expe- riences. On ordinary diet I used to be an ordinary taker of salt (sodium chloride), and I continued to take it for many years on a uric-acid-free diet ; but I gradually found that I had less and less desire for it, and unconsciously took less as time went on- Then two or three years ago, when making some experiments on the acidity of the urine, I decided to give up salt entirely for a little and watch the results, and I found after doing this for several weeks that whenever I took salt again I got very decided nasal catarrh, almost as if I had taken an iodide, and this has continued up to the present time, so that the moment T take a little extra salt in my food my nose begins to run. For myself I have drawn from these facts the conclusion that what is at once thrown off in this way is not wanted by nature. I am not pre- pared to deny that some chloride is wanted in the body for gastric digestion and other functions, and I have seen at least one case in which dyspepsia appeared to result from leaving it off. On the other hand, it seems clear that I get all the chloride I want with- out its being added in noticeable quantity to my foods, for as soon as salt can be tasted in my vegetables or my cheese I get symp- toms of chloridism. As regards the excretion of uric acid, salt does harm, for the addition of a mineral acid raises the acidity of the urine and diminishes the alkalinity of the blood and tissue fluids, and it is no use to clothe warmly and to eat patatoes and avoid acid fruits while swallowing considerable quantities of salt. My own practice, therefore, is to take no salt except on the rare occa- sions that I feel a distinct desire for some ; and I even go further and avoid those foods to which salt has been added in appreciable quantity (see also remarks as to the causation of cancer in chap. x.). But while most uric acid troubles are due to introduction of uric acid formed outside the body, it is also quite possible to suffer from excess of it in the blood, if the formation in the body is excessive, and if all that is there formed is not excreted. Now, as uric acid is always formed as far as we know only in the relation to urea of 1 — 35, there will be no excessive formation of uric acid unless there is also excessive formation of urea ; unless, in fact, more albumen is taken in than the body requires for its 842 UKIC ACID— CHAPTBE XVII nutrition, or more than will form 3'5 grs. of urea for each pound of hody weight per day. But such increased intake of albumen and excessive formation of urea and uric acid entail also increased formation of acids, and these last, by diminishing the alkalinity of the Uver and the blood, bring about defective excretion of uric acid ; thus excessive forma- tion of uric acid is generally accompanied by defective elimination, and these two causes working together soon produce an accumula- tion in the body which eventually comes through the blood, or is driven out of it into the fibrous tissues, producing trouble. Now, when 3'5 grs. of urea are produced for each pound of f : a s g MARCH 2 3 4 5 6 7 s ,9 in II IP 13 14 15 IS n IS IS 20 ?i P^ ?.V4 ISIS27 2S2930 g 20 700 " 19 661 1 1 IS €20 i - - r - 1 ■ 17 535 - - 1 '-' - - r ^, .., 1 1 15 525 / ' r-i-- ..■l'"~- V '•- :j ■v - _ i: - / '•- 1 ■( J 14 490 A f \ __ / \ 1 \ /^ . ' - ^ ^\ 1 ^ ,i 437 / V h 1 V \ 1 \ (1 1 A / \ - F J. f\ 1 M V 'N \i \ J \ A ) V j Y "*" 375 _s _1 __ ... ._ ._ _-. .. -t 10 310 V \l \ \] •~i, r \ \ -^\ S JI5 I / ■ I W • 7 24S BLOOD DICIMAL ]?iG. 74. — Uric Acid and Ubba Excretions and the Blood Decimal from Day to Day ; showing the Effects op Diet in the Production of an Attack of Gout, and its Cube by Salicylates. body weight per day, 35 grs. of urea and 1 gr. of uric acid are produced for each 10 lb. of body weight ; and if 7 grs. of urea are produced for each pound, then 70 grs. of urea and 2 grs. of uric acid are produced for every 10 lb., and -though such a rate of production as this can only very rarely be met with except in children, it is by no means uncommon to find urea IJ or even 2 grs. above the physiological level of 3J grs. per pound. TEEATMENT 843 Now this may be done on any diet, whether animal or vegetable, and those who do it will undoubtedly very soon come to have considerable excess of uric acid in their bodies, which sooner or later will produce its usual efiects. Now fig. 74 shows that I have myself on some occasions taken too much albumen, and have consequently formed too much urea and too much uric acid ; as a consequence of high acidity I have failed to excrete some of this uric acid, and have eventually suffered from some of the troubles it produces. This figure also shows two lines across it, one a continuous one at the level of 437 grs. of urea, that is of 3-5 grs. per pound per day of my weight ; and a broken line at the level of 375 grs. of urea, which is 3 grs. per pound per day of my ■ body weight. And the proper level for my urea is between these lines ; if it is above them I am forming too much urea and too much uric acid, some of which I tend, especially in the cold season, to store or retain in the body ; if it is below them I have less urea than is required for the best condition of nutrition, strength and power of endurance. As regards uric acid troubles, however, it is better to be below these lines than above them, but it is best of all, and not really very difficult to attain, to keep between them. T shall now go on to describe this figure and explain how it was I got above the lines. In this figure we have really only to regard the two curves, the unbroken line urea, and the broken line of strokes the uric acid ; the upper dotted line, the blood decimal, is merely given because I happened to be investigating it at the time this figure was evolving, in farther illustration of what I have already said on the subject in chapter xii. With perhaps one exception on March 10 the blood decimal and the uric acid always move in opposite directions, and that one exception is probably to be explained in the way I have already pointed out in reference to fig. 52.* We see then on following the urea line, that it was above 437 grs. level on March 3, 4, 5, 7 and 13 to 17, and again from 23 to 25, that it was only below the 375 gr. line for two days near the end of the figure. * I may say with regard to the average height of my blood decimal, "65 to -7 as shown, and it has since risen above this, that the great majority of those I see suffering from urio acid diseases have a blood decimal of only -4 or -5, and the enormous difference that this factor alone must make as regards func- tion, nutrition, and the power of resisting microbio diseases, is obvious to all physiologists. 844 UEIC ACID — CHAPTEE XVII The uric acid curve fell most below the urea exactly at those times when urea was highest, March 2 to 6 and 11 to 18, and this means, not that the natural formation of uric acid was altered but that its excretion was hindered and diminished. Now if we estimate the quantities by which uric acid fell short of urea on these days, which is easily done by adding up the number of grs. included between the lines of the two curves, thus, say 8 grs. from March 2 to 6 inclusive, and 22 grs. from March 1] to 17 inclusive, we get a total of 30 grs. of uric acid thus kept back and retained in the body. Subtract from this the quantities by which uric acid exceeded urea, namely, rather less than ^ gr. on 7th, and rather more than J gr. on the two days 9th and 19th taken together, and J gr. on 18th, making a total of 1| gxs. of plus excretion, and 1-5 from 30 gives us a total retention in the body of 28-5 grs. On the 19th, I had a iheumatic pharyngitis and a slight similar affection of the larynx, probably as the result of some fluctuations in acidity, because I had taken some alkali on the 17th to increase the excretion of uric acid, and this was unfortunately followed by a dinner with wine on the evening of 18th and some exposure to cold winds. I may say that these are very common ailections with me when I have too much uric acid about ; and a little exposure to cold, or fluctuation in acidity otherwise caused, then suffice to bring them on. Their pathology, as already explained, is that of gout of the fibrous tissues in any part of the body ; they are due to a coUec. tion of uric acid in those tissues, and are reheved by anything (alkalies or salicylates) which increases its solubiUty and removes it from the tissues. When I have no excess of uric acid in the body, neither cold acids nor anything else will produce such a pharyngitis or \a,Tyn- gitis. But to return to the story ot fig. 74. When I felt the slight pharyngo-laryngitis T tried to get rid of it by taking more alkali, but I suppose I did not take enough to counteract the exposure to cold or the rise of acidity produced by the wines ; in any case the trouble increased and I began to feel rather ill with a rising temperature. I then decided to give up alkalies and take salicylates, as with rising temperature their action would soon be the most satisfactory. I knew, however, that this was a dangerous course, for the reasons TREATMENT 845 given in chapter xvi., and that I should undoubtedly be worse when the allcaUes I had taken and the salicylates I intended to take, met and came into collision. But I had not at the time fully appreciated the meaning and extent of the retention shown in the early part of the figure, and still less the serious introduc- tion in the pulses I had been taking (see fig. 75), and therefore wrongly concluded that I had but little uric acid in my body, and could afford to play with it. The result, however, was a lesson which I shall remember for years, and I hope it will instruct many people besides myself, and save them from making a similar mistake. On the evening of 19th the salicylates and alkalies met in the blood, the alkalies were stUl in some force from the doses taken in the morning, and the salicylates were just coming into the blood from the doses taken later, and the result of this was that my pharyngo-laryngeal trouble increased and extended downwards to 'the trachea, and there was also added a new centre of inflamma- tion in the intestines, with severe pain in the region of the umbilicus. With this on the 20th my temperature went up and up, first above 101° and then above 102°, so that in the early part of the day I was too ill to do anything but lie in bed as quiet as my cough would allow me to remain. Towards evening, however, the salicylates which I continued began to get the best of it. The pain in the chest and abdomen moderated, and I was able to get some sleep ; but I was not even yet over my troubles, as at about 4 a.m. on the morning of the 21st I woke to find myself with again very severe pain in the chest behind the sternum, and a frequent and painful cough (acute gout of the trachea and bronchi). Now the explanation of this relapse was fairly simple, for the salicylates had got the best of it on the previous evening with the rising acidity ; but in the natural course of events there would be a fall of acidity in the early a.m. houjs and with this the dead point, as I have called it, between alkalies and salicylates would come once more into possession of the field (see fig. 71 and remarks on it). I accordingly took some doses of ammonia and dilute acids, and reinforced the salicylates by repeated small doses, and in the course of an hour or two they again got the upper hand, and the gout passed off. But while the struggle lasted I was in most severe pain, and had a frequent cough feeling as if it must tear my chest open, but 846 UKIC ACID CHAPTER XVII with. DO expectoration, and I lay beyond and above my pain in no little fear of danger to Uf e itself ; for though. I had had and re- covered from a similar tracheo-bronchitis, I knew that I had in this case done what was very foolish, and I did not quite know how soon my drugs would relieve me, or how much damage might in the meantime be done to structures of vital importance. For if there is one thing more than another certain, it is that these acute uratic inflammations of fibrous tissues regard neither persons nor places, but tend to spread along such tissues in any and every direction, affecting with equal indifference and impar- tiality both vital and non- vital organs ; and I was uncomfortably conscious that close to what now felt like my blazing red-hot trachea and bronchi were the fibrous tissues of my pericardium and heart. I had not only this constant burning pain in the affected struc- tures, but the trachea and bronchi were as sensitive to cough as though they had been pounded with a hammer for half an hour. Fortunately for me the salicylates gradually again got the upper hand, the pain moderated, the cough became loose and effectual, and the expectoration of large mouthfuls of yellow pus gave ocular evidence of the acute inflammation that had been going on. And now occurred a repetition of a result 1 had several times previously seen with salicylates, which were now in possession of the blood and getting the urates into solution from the inflamed tissues, and that was an alternation or migration, so to speak, of the gout from the trachea to the intestines, and from the intes- tines to the trachea. If I had too much clothing, over me and kept the chest very warm, the pain would begin to return to it once more, and then if I threw off the clothes, so that there was more over the abdomen and less over the chest, the chest got better, but the pain in the abdomen tended to increase, so that I was forced to reduce cloth- ing altogether and keep both as cool as possible, and then sali- cylates acted well, and I was soon comparatively free from pain. This was obviously but a repetition of many previous expe- riences on myself and others as to the effects of heat in preventing the solvent action of salicylates on urates, and so preventing their relieving uratic irritation, whether called gout or rheumatism, as I have often already pointed out (see chapter xvi.). Here we also see what I have pointed out in the previous chapters, that those, who are subject to catarrh, lumbago, rheumatic or gouty arthritis, and who under ordinary conditions would probably have TREATMENT 847 attacks of these things brought on by cold, will, while taking sali- cylates, be not only absolutely immune as regards ■ cold, but cold will help the salicylates to cure them. Heat, on the other hand, which apart from drugs would have prevented or relieved the arthritis, myalgia or catarrh, will, when used along with salicylates, not only not relieve the pains, but will make them very decidedly worse (see Dr. Co wen's case, previously mentioned). This is a point which is not only of very great importance for those who wish to treat these conditions successfully, but it is also a point about which those who hold that any of these troubles are due essentially due to microbes, have got, if they can, to give a different and satisfactory explanation. Any arthritis, or for that matter any inflammation that is made markedly better by salicylates and cold, and markedly worse by salicylates and heat, is undoubtedly due to uric acid ; and the solubility 'of uric acid gives, it appears to me, the only possible explanation of the facts. I need not describe my convalescence at length. By the even- ing of the 22nd the saUcylates had complete command of the situation, the pain was all gone, and the temperature was falling to about 100°, and next morning it was almost normal, and I was able to get up. Only a cough with considerable expectoration, becoming more fluid and less tenacious, and the passage of a con- siderable quantity of mucus with the first actions of the bowels, now testified to the existence of the inflammations which had raised the temperature and occasioned the pain. It will be noted that the excretions of uric acid and urea in fig. 74 on March 20, 21, and 22 are in a straight line, and this is due to the fact that on these days I was much too ill to do anything but collect the urine, and I consequently estimated the excretion of these three days at once and divided the totals by three, so that the actual excretion was not exactly as shown ; probably there was a comparatively small excretion of uric acid on the 20th while the salicylates and alkali were fighting and the temperature rising, and a much larger excretion on the 21st and 22nd, when the salicy- lates got full power and were removing the materies morbi, to my infinite reUef , both in body and mind. If we count the grains between the curves of urea and uric acid on these three days, we find that uric acid exceeded its normal relation to urea by 8 grs. on each of them, or 24 grs. on the three, and if we add to that 1 gr. on the 23rd we have an 848 UEIC ACID — CHAPTEB XVII excretion of 25 grs. out of the 28| grs. known to have been retained in the body. Sublatd causd toUitur effectus. Though no doubt, as we shall see presently, there was considerable introduc- tion in pulses, as well as retention by high urea and acidity. Had the salicylates been continued a day or two longer the whole might have been got out, and the fall of uric acid towards the end of the figure is only what generally occurs when salicy- lates are left ofi, and does not show that all available uric acid has been cleared out. The rise of urea on the 23rd and 24th indicates, I think, that there was some defective formation of urea with the high uric acid on the 21st and 22nd, which was soon made up for and passed out with the improved circulation on the 23rd and 24th, just as I have shown to occur in the case of exercise when there is excess of uric acid available for solution in the blood, and also when the similarly produced defective combustion, which we call Bright's disease, is put an end to by suitable treatment (see p. 612). And now I have a story to tell as to the way in which I came to have the high urea shown in fig. 74, and how I consequently came to have both excessive formation of uric acid and its defi- cient excretion, thus accumulating nearyl 30 grs. in my body with the disastrous results recorded above. Just as the (3rd) edition of this book was in preparation there appeared a very interesting work by Dr. George S. Keith, called " Plea for a Simpler Life,"* dealing largely with diet questions, and giving a most interesting account of his lifelong experiences in the matter. From this it appears that he had like myself been a sufEerer from migraine, which improved very greatly when he gave up butcher's meat in favour of fish, fowl, game and eggs, in small quantities. ^ In this most interesting little book he dissents as much from the old remedies — bleeding, vomiting, purging, and sweating — as from the new — stimulants, tonics, and plenty of good food and wine — and believes rather in a middle course — rest in bed, water hot or cold to drink, and Uttle or no food tiU there is some appetite and power of digestion. He narrates not a few very remarkable results with this treatment in cases of cerebral haemor- rhage, dyspepsia, bronchitis, phthisis, and especially in mental diseases, which are most interesting, and strongly support the re- * Adam and Charles Black. London, 1896. TEBATMBNT 849 suits I have obtained and the suggestions I have made with reference to the causation and treatment of these diseases. And in a more recent work, " Fads of an Old Physician,"* 1897, he extends his arguments, and mentions more cases and more experiences, and he also compares my diet with his own, pointing out that I take far more food than he does. But though this is quite true, I am a younger man, and do much more work in a day than he does. Dr. Keith also rather seems to infer that a great part of the treatment of uric acid disease is a small quantity of food, and that when this is attended to you may take small quantities of fish, fowl, and tea without harm. I quite agree, as fig. 74 shows, that excess of nitrogen or albumen from any soarce will eventually produce trouble, for it will produce excessive formation of uric acid as well as defective excretion, as in this figure ; but I think that where no excess of nitrogen is taken, greater freedom from uric acid disease and far better physical powers will be obtained, by getting that nitrogen or albumen from substances which do not already contain uric acid or xanthine ; and that, though Dr. Keith's experiences of giving up meat and substituting fish and fowl have been favourable — just as my own were, for 4 grs. of introduced uric acid per day are better than 8 or 10 grs. — he has evidently not had complete im- munity either from headache or from gout, and he would, in my opinion, have had much more complete immunity from both if he had obtained the nitrogen required for a physiological allowance of urea from sources which were entirely free from the poison, and if he did this he might eat any quantity of albumen necessary for strength and nutrition without the least fear of harm. In so far as Dr. Keith takes less than, the physiological allow- ance of albumen he of necessity produces also less force than he might, and as he still swallows some uric acid he still further diminishes the force produced by increasing the friction in his machinery. In this way he may no doubt escape some headaches, for it takes as we have seen some force and power to keep up the blood pressure necessary to produce headache ; but he only lives half a life when it is open to him to live a whole one ; and so do all those who deliberately underfeed. In summer, and when leading a fairly active life, I can take * These two books have now been republished under one cover. A. and 0. Black. London, 1900. 54 850 UEIC ACID — CHAPTER XVII albumens sufficient to produce about 3| grs. of urea for each pound of body weight per day without retaining or storing any uric acid. But in winter, and when sedentary, it is necessary to take several precautions, otherwise retention will occur ; very little it is true, but still at the end of days and weeks it will mount up to 4, 5, or even 6 grs., and if anything brings all that through the blood in one day there will be very distinct alterations in the circulation curves, and with high blood pressure there will be more or less mental depression or headache. The chief precautions to be taken with a view to avoiding such retention are : — (1) To keep warm and not expose yourself for any length of time to cold, especially in the morning hours and up to 2 p.m. (2) Not to eat acid fruits or vegetables, or much jam or sugar with breakfast. (3) Not to take more albumens than are necessary for nutri- tion, and as life is sedentary less will be required than when it is active. The reason for this is that acidity and urea rise and fall together, for with large production of urea there is also a large production of the acid products of the combustion of the phosphorus and sulphur in the albumen molecule, and uric acid will be retained by this high acidity in the liver and elsewhere, as previously explained. Absolute freedom from uric acid coUaemia can only be attained by keeping introduction as near zero as possible, while excreting day by day all that is formed. To take some alkali in the shape of potato or sodii bicarb, is to be on the safe side as regards excretion, and it does no harm when uric acid is low and there are no stores, and a good supply of alkali prevents stores. A meat eater cannot take alkali or keep very warm with impunity, as they flood his blood with uric acid and cause anaemia and debility. But those who do not swallow uric acid can keep warm or hot and take alkali with impunity. And I am inclined to believe that given this absolute freedom, or the nearest thing to it, when the blood is practically free from coUsemia, and the tissues from irritation and stifiening, when the heart can drive the blood easily through free capillaries, and the joints, muscles, and fascia work without creaking and jar — when, in a word, the friction in the machinery is reduced to its lowest point — I think there is good reason to believe that the machine TREATMENT 851 will work and produce a given amount of external force on rather less albumen than it would require under the opposite conditions, for the force produced by complete combustion of a given amount of albumen is the same under all conditions ; but if the internal work in the friction and resistance of the machinery is reduced, the external work or result will be greater. In other words, I believe that when I am as free as possible from uric acid, I can perform my ordinary day's work on some- what less albumen and urea than when I am not free ; and that so long as I keep up this freedom I can get on quite well on the albumen which will produce 3 grs. of urea per pound of my weight per day. And when I do this I am also, by keeping down acidity which falls with urea, favouring the daily elimination of all the uric acid I form. The remedy, then, for all minor uric acid troubles, when you are free from all accumulations in your body, is not to eat more food but to eat less food ; cut down the albumens for a little. And those who are free from stores of urate can do this, while those who are full of uric acid from previous wrong diet, cannot do it ; in these latter fall of urea and acidity means increasing coUsemia, high blood pressure, mental depression and anaemia. In those who are free the diminution of albumens can do but little harm to either the blood or its circulation. There is no uric acid available, and the reduction of albumens is but a further guarantee that aU their uric acid of formation is eliminated, and that there will be none available to do harm. In the same way those who live on a uric-acid-free diet and are relatively free from uric acid, can clothe themselves much more warmly without sufiering from debility, lethargy, and depression. A meat eater cannot get warm without increasing the alkalinity of the blood, and getting at once coUsemia, ansemia, depression and lethargy ; but it is the uric acid that produces these results, not the warmth, hence those who are relatively free from uric acid can keep warm, even very warm, without incurring severe collsemia, debility and ansemia. In their case warmth does good by preventing retention and removing the" possibility of future coUsemia. The same appUes to the taking of alkaU, and uric-acid-free dietists can do it with impunity ; meat eaters and tea drinkers cannot. The former are bright and clear in the mornings, the latter never are, and have to take more tea to make themselves so. It follows from this that it is always a good thing to clothe warmly and a 852 UEIC ACID — CHAPTEB XVII bad thing to be cold, for cold, especially in the morning hours, diminishes the excretion of uric acid and stores it in the body. But the object of all must be to introduce no uric acid, to form as little as may be, and to excrete day by day all that is formed, so as to get as free as possible from accumulation and its results. Those who get collaemic and pale on an insufficient diet are those who are full of uric acid ; those who are free from uric acid will not be able to produce so much force on an insufficient diet, but they will not become either coUsemic or pale to any great extent ; if they do so it is a sign that albumen and urea are much too low, and their position should be observed and tested. Then those who are pale will not improve on a uric-acid- free diet unless they take sufficient albumen. This explains also Dr. Keith's observation that uric-acid-con- taining foods do less harm if you take them, and also all other foods, in small quantity, for the acidity being low the uric acid (both that formed and that introduced) passes out at once and there is less tendency to accumulation in the body. But in passing through the blood it does harm, causing col- Isemia and ansemia, so that obviously those will have least through their blood who have to do with formation only, and those will have most through it who have to do with both introduction and formation. And these latter will, work for work, require more albumen, because they have to expend more force in overcoming the fric- tion that uric acid produces, as seen in the skin circulation, as measured in the blood pressure and heart work, and in the mental and bodily power of endurance ; and the wear and tear on their tissues will also be greater. So that while I quite appreciate Dr. Keith's position, the course he indicates is very far from that which is best, for below a certain point, probably 3 grains of urea per pound per day, albumens cannot be reduced with impunity or for any length of time, with- out diminishing nutrition and increasing the risk of microbic inva- sion (tubercle, carbuncle, &c., previously mentioned). And now I come to the causes which led me to take too much albumen and to suffer so severely as already recorded. In " Fads of an Old Physician," Dr. Keith refers to another work on diet, by Dr. Dewey, of Meadville, Pennsylvania—" The True Science of Living "; * and the chief point in this book is that temporary com- * Henry Bill Publishing Company and 3. and J. Bumpus, Limited, Oxford Street, London, 1895. TEBATMENT 853 plete starvation till there is once more a healthy appetite is the best cure for a host of dyspepsias, debilities, depression, mental and bodUy, headaches, and numerous other troubles, and that for similar less severe disturbances of nutrition the great remedy is to leave out the breakfast, so as to give the stomach a long rest of sixteen hours or more, with the object of allowing it to recuperate and accumulate secretions after the last meal- of the previous day. It seems from internal evidence in Dr. Dewey's book, a copy of which I owe to the kindness of Dr. Keith, that his plans have been completely successful in a large number of cases, and it seems to me that his logic is unanswerable, and that in his main contentions he is perfectly right. Having arrived at this conclusion, I proceeded forthwith to put the matter to the test of experience by placing myself on two meals a day — that is to say, I left out my breakfast, and the result was that I ate such a good lunch at 1 p.m. that it was impossible to take anything more till dinner time, 7.30 or 8 p.m., so that I reduced myself at once from four meals a day to two. The result was exactly what Dr. Dewey describes. I fslt ex- tremely bright and well in the morning, and capable of very good work, both mental and bodily. At 1 p.m. I had keen hunger, even for dry bread ; such hunger as I had not experienced for years. After lunch (breakfast) I felt a Httle bit dull and occasionally sleepy, and the mental work of the first hour or two after it was not as good as usual. About 5 p.m., I was very thirsty, and had to have a drink of water, but there was not the least desire for food till several hours later, though by 7.30 or 8 p.m. I was able to manage another fairly good meal ; and thus my meals automatically, so to speak, reduced themselves to two. The effect of this change of meal times was, I think, unques- tionably that my stomach and intestines did better work, the girth of the abdomen diminished, probably from the absence of undigested residues and the comparative absence of flatus. The faeces diminished in bulk, and I experienced a general stimulation of nutrition and strength. The total quantity of food taken was somewhat increased, and urea and acidity went up in spite of my somewhat feeble attempts to reduce the quantities taken, and no doubt, having a good appetite at 1 p.m., I took more pulses than I should have taken on the four meals a day plan. As a result of all this I got high urea and acidity, and exces- 854 UBIO ACID — CHAPTEE XVII sive formation of uric acid corresponding to the excess of urea, and, as fig. 74 shows, retention of uric acid. The rest of the story has been told. The result then was to leave on my mind no doubt that in Dr. Dewey's plan of two meals a day in place of four we have a most powerful stimulant to digestion and nutrition. Digestion is more perfect, just as with better appetite one would expect it to be, and nutrition is stimulated ; the fire burns more brightly and combustion and absorption are more perfect. That it led me into so great misfortune was no fault of the plan, but was due to my own folly in allowing my relatively huge appetite to fall to work on such highly nitrogenous food as pulses, cheese, and milk, which were appropriate enough for the more feeble digestion and lessened appetite and nutrition of four meals a day, but contained far too much nitrogen for the stimulated appetite and nutrition, and improved digestion and absorption of two meals a* day. If I had let my new appetite have its fiing on less nourishing , fruits, vegetables, and bread, and taken only my ordinary allow- ance of milk and cheese, all would have been well, and fig. 74 would never have been evolved or published, and I should have escaped much pain ; but it is through these things we learn, and I have learned a very great deal from this sharp lesson in diet. First of all I have learned exactly how two meals a day cures dyspepsia, and the headaches, mental depression, &c., dependent upon it. My verdict is that the dyspepsia is cured just as Dr. Dewey says, by resting the stomach and enabling it to do much better work, and that it is prepared to do this is shown by the presence of the keen hunger otherwise quite unknown. I certainly had not experienced such dry bread hunger, as I call it, for years. If any- thing will demonstrate the insane foUy of stuffing a dyspeptic stomach with fresh food every three hours, an experience of this kind ought to do it. Then the cure of the headaches, depression, &c., is the simple result of the stimulus to digestion and nutrition, for acidity and urea rise and the blood is promptly (as my case showed only too effectually) cleared of uric acid, and this no doubt is still more marked in Dr. Dewey's patients, as they are given animal flesh in any quantity and in any form they like. With such stimulation it would be quite impossible for any uric acid to get into the blood and remain there ; hence headache and mental depression vanish and remain absent as long as the stimulation, lasts. TEEATMENT ba& But these patients, while thus taking meat, are introducing uric acid in their food, as well as forming it in their body in excess^ and they are retaining it in large quantities from both sources ; and if at any time the stimulation of two meals a day falls through — if any accident or shock depresses them beyond the power of two meals to revive them — then I do not envy them the result that must ensue from all the store of uric acid they are thus accumulating. I should mention that it was no doubt partly because I gave up or became irregular with my two meals a day about March 17 and 18 (fig. 74), that I got the uric acid through my blood and suffered from the gout and other troubles ; but my experience shows that my uric acid was not destroyed or burnt up by the improved nutrition, bat was merely retained in the body ready to get into the blood when the conditions were favourable for this. *■) While, therefore, I quite appreciate the value of Dr. Dewey'* plan of two meals a day as regards the treatment of gastric feeble-^ ness, debility, and dyspepsia, that plan does not in any way pre- vent the evU effects of uric acid on the body and blood ; but acting as a stimulant to nutrition, it keeps the blood clear so long as the stimulation lasts. But if this plan is used in combination with a uric-acid-free diet, and if proper precautions are taken to avoid the consumption of excess of albumen in the unaccustomed pleasure of satisfying a keen appetite, one may obtain freedom from uric acid both for the present and for the future, in that there is neither excessive formation nor unnecessary introduction nor reten- tion, and this without sacrificing any of the advantages arising from the stimulus to digestion and nutrition of two meals a day in place of four. It may seem extraordinary to those who look at the matter merely from the outside, that almost the only danger attendant on taking two meals a day in place of four is that of over-eating yourself. As a result of these experiences in my own person, I now make use of Dr. Dewey's plan for those of my patients who suffer from dyspepsia and deficient appetite, and would thus be in an unfavourable condition for beginning a uric-acid-free diet. Such a case cannot take milk, has dyspepsia from cheese, and terrible wind and pain after the smallest quantity of puddings ; but after a few weeks on ordinary diet, with only two meals a day, appetite is so much better and digestion is so vigorous, that all the above foods can often be freely taken and easily and pain- lessly digested. 856 UEIO ACID — CHAPTEB XVII It is a good rule to eat slowly, for man does not live by what he eats, but only by what he digests. Thus vegetable food, ii not well chewed and mixed with saUva, or if taken in a sloppy condi- tion with too much fluid, ferments instead of digesting, and again if so much is taken as to distend the stomach digestion may be brought to a stand, and fermentation and putrefaction may take its place. In both these ways, then, eating slowly will do good and prevent harm, and it is quite possible for a man to be better nourished on a little food eaten slowly than on a great deal eaten quickly. I have also seen several cases where people appeared to be under-nourished on my uric-acid-free diet taken in four meals or more in the day ; but when the same foods and the same quan- tities have been taken in three meals a day, or sometimes better still in two, they have with better appetite done better digestive work, have absorbed more of it into their blood and passed less of it through them undigested, and consequently have been much better nourished. It is quite possible also to be under-nourished from the above causes when the quantities of albumens swallowed are considerably in excess of those required for body weight. These people may starve and die as Dr. Dewey (previoas reference) shows, not from want of food, but from digestion being constantly overpowered by its excess. Then again, a diet which consists so largely of fruit and vegetable products will keep the blood well suppUed with alkaUes, and so all the uric acid which is formed will remain in solution and be excreted, and there wiU be no storage or accumulation in the body, and not only will there be no storage, but the stores and accumulations laid down on the preceding ordinary diet will be gradually got into solution and passed out of the body. In all these ways, then, we shall get the uric acid in the body and blood under our control, and so long as we keep up this control we shall find that we have prevented the diseases which are due to its presence in excess, and this is the real and ultimate test of the truth or falsehood of all that I have said on the subject. It will have been noted that I have left out all pulses (peas, beans and lentils) in the diet table given above, and I have now a story to tell with regard to the reasons for this. As a matter of fact I had never been in the habit of taking pulses regularly or in any large quantity, but in the autumn of 1898 I began by mere accident, as it were, to have pulse soup regularly two to three or even four times in a week. TEEATMENT 867 As usual I was estimating my excretion every day throughout that autumn, and I soon could not help noticing that the uric acid was often high and the excess of excretion over formation considerable. At first I attributed this to some storage or retention from possible over-eating during my autumn holiday, when of course I was not measuring food accurately or observing my excretion. But as the excessive excretion went on and on, being 80 — 90 and even 100 grs., I had to give up this idea ; for nothing I could possibly have retained in my holiday would suffice to account for it. Then I got ill, having rather severe lumbago and having to take salicylate to cure it, and with this again I got an enormous excretion of uric acid, so that excretion was in excess of formation {i.e., relation to urea of 1 — 35) by as much as 140 grs. By this time I had begun to suspect introduction, but in what ? My diet was entirely vegetable, except milk and cheese. I was obliged to suspect something, and among other things I began to suspect the pulses. I had now got into January, 1899, and in order to watch for introduction more carefully I lowered the acidity by increasing my potatoes, so that my introduction should at once show in excretion. After keeping this on for some 6 — 8 days, I found well-marked rises of uric acid on three of these days, and on then sending to the cook to enquire which days we had had pulse soup, I found to my astonishment that each rise corresponded exactly with a pulse soup day. I had now got a definite clue and was not long in following it out. It was a simple matter to alter my dose of pulse soup to one half on the one hand and to double it on the other, and with each alteration there was a corresponding change in the excretion of the uric acid in the urine. I now shut ofE the pvilses entirely, and put myself on saHcy- lates to clear out, again getting enormous excretions, so that by February 17, 1899, from the middle of October, 1898, uric acid had exceeded its normal relation to urea by something over 300 grs. To state this more exactly, I had found an excessive excretion of 308 grs. of uric acid in 126 days, during which I had had pulse soup about four times a week, or on 72 days, which gave about 4 grs. of uric acid for each soup, and each soup corre- sponded apparently to 4 oz. of pulse. So that pulse contained about 1 gr. of uric acid or xanthine to the ounce = about '23 per cent. 858 UEIC ACID — OHAPTBB XVII I then made some careful experiments with weighed quantities of pulses, and the results of one of these I now give in fig. 75. This shows that 4 oz. of lentils taken at lunch on August 19 produced an excretion of uric acid on 20th equal to 2J grs. above its normal relation to urea. So that if all the above uric acid came from xanthine in the lentils, these lentils contained 0-62 gr. to the oz., or 0'14 per cent. .Pig. 75. — Escbetion of Uric Acid afteb Pode Ohhces op Lentils. Effects on the curves of blood peessobb and capillaby beflux of its passage THBOtJGH THE BLOOD. It must be remembered that the pulses I took in the previously mentioned 126 days were not all lentils; but some days they were peas, and others haricot beans, and in my other experiments with weighed quantities I got excretions working out somewhere between 0-11 and 0-20 per cent. So that I am positively certain that the pulses contain xanthine. TBEATMENT 859 to the extent of Ol to 0-2 per cent., and tkat at least two-thirds of the above 308 grs. of uric acid came from them, if not the whole of it ; but some may, no doubt, have come from stores in the body and previous retention. The rest of the figure shows the effects produced by the 2| grs. of uric acid as it passed through the blood, the upper curve being that of blood pressure, and the lower that of the capillary reflux, which we may compare with the similarly produced curves in figs. 38—43. These show that on the evening of the 19th the pulses having been taken at lunch time, the blood pressure did not fall to its usual low evening level, and the capUlary reflux was not as fast as at 10 p.m. on other evenings. About 8 a.m. on the morning of 20th, the blood pressure rose a little above 130 and there was a feeling of dulness and a threat- ening headache, and the capillary reflux was slower than on other mornings at the same hour. Here the increased excretion of uric acid could have been told quite well from the capillary reflux or the blood pressure, and the feelings of dulness, heaviness and threatening of headache, were quite distinctive. I have many similar curves produced by taking uric acid or xanthine in one form or another ; but it must not be imagined that every time 2J grs. of uric acid in excess passes through the blood it affects the circulation curves as it does in this figure. Here it just happened that the excess was passing through the blood about the time of the evening observation on 19th and the morning observation on 20th ; but when recently I was testing the amount -of uric acid or xanthine in a meat extract I produced a very similar rise in the excretion curve to that in fig. 75 ; but this did not show at all in the blood pressure and capillary reflux curves, because the excess passed through the blood between the morning and evening observations. But I knew when it did pass, for there was dvdness and heavi- ness which were quite distinct, and the capillary reflux was then found to be slowed and the blood pressure raised. This fig. 75 shows that it is a perfectly easy and simple matter to test the amount of uric acid or xanthine that any given food substance contains ; but I must again caution any one who wishes to repeat these experiments that they must not forget to keep acidity low or the uric acid administered will be retained and not excreted. 860 UEIC ACID — CHAPTEB XVII In fig. 75 acidity is only equal to aboat 35 grs. of oxalic acid in the day and bears a relation to urea, as we see, of about 1 — 10, and to make perfectly certain of free excretion of uric acid or xanthine swallowed I would recommend a relation of acidity to urea of from 1 — 15 to 1 — 10 ; the acidity being kept down with potatoes or alkaline salts of potash or soda. We see also that by watching the capillary reflux even morning and evening we may get some fairly clear evidence of what is going on, and that by making observations every two hours we may be able to tell from this circulation curve alone, whether a given food increases the uric acid in the blood and the number of hours during which the increased excretion lasts. And from this circulation curve alone, which only takes a moment to do morning and evening, I have been able to form at least some idea of what my uric acid excretion was doing during my summer holidays, when I have no chance of collecting the urine ; and I can see in these curves quite clearly the effects of exercise in increasing the excretion and causing temporary coUsemia of slight fatigue, and the effects of acid fruits in quickening the capillary reflux at night, or of cold in slowing it next morning. In the above record with the pulse foods we see very clearly the efiects that continued introduction produced on me, how I got gradually worse and worse, how some was excreted but some re- tained in my tissues, producing among other things severe lumbago ; how I was obliged to take salicylates to get relief, and how these produced large excretions and upset my digestion and appetite and powers of work as the excess passed through my blood into the urine. Had I suspected the pulses sooner it might have saved me a great deal, and I am sorry to say that some of my patients, especially those who were stout, and had therefore been advised to take puLses freely, suffered more than I did, some of them even giving up the diet entirely. And we need not be very much surprised at this now we see that while ordinary meat (muscle) only contains about O'l per cent., pulses may contain from 0-1 to 0'2 per cent., or some of them nearly twice as much as meat. Since I found this out in the spring of 1899 I have cautioned all I could not to eat the pulses, but among those who are being treated on my lines by others, I fear some are still suffering, and that some failures to cure the uric acid headache and other col- Isemic or arthritic troubles are due to this cause. TREATMENT 861 Lastly, this record of the pulses shows that some of my sufier- ings in fig. 74 were due to introduction by pulses, and were not all due to retention by high urea and acidity; but even with the greatest possible freedom from introduction of uric acid, high urea and acidity will produce some retention, especially if aided by cold weather and acid fruits, &c., at breakfast, and this will also event- ually suffice to produce all the evil effects recorded in reference to fig. 74. Then this record of the pulses will, as we shall see presently, throw quite a new hght on the diseases of India ; a light which is not only new, but one full of hope and promise ; of promise that true knowledge will give us real power to relieve and prevent the sufferings of our fellow subjects. For if they are suffering, not as I had previously supposed from retention of uric acid, but mainly from introduction, that introduction can just as in this country be prevented, and some at least of their many deadly diseases can be mitigated or relieved. I have also shown in a paper on " The Human Body as an Analjrtical Laboratory," published in the British Medical Journal, 1901, vol. ii., that asparagus, like the pulses, contains a consider- able quantity of a xanthine body. I was led to this discovery by finding that in the asparagus season I got changes in my curves of eapUlary reflux, pains in my joints, and eventually more or less catarrh, which had to be treated very much as in the case of the pulses ; and my other records showed that on eating definite quantities of asparagus I got results very similar to those in fig. 75, and I drew from these the conclusion that the growing tops of the asparagus contain the equivalent of 1-2 or 1-3 grs. of uric acid to the ounce. I have had somewhat similar experiences with mushrooms, and more recently with various kiuds of brown and wholemeal bread, so that I now leave out of my food all mushrooms and all bread stuffs containing the outer husk, which, as mentioned above, con- tains some xanthine ; and once any food is suspected it is easy to put it to a similar test. Before going further there is one good old fallacy — the off- spring of imperfect observation — to which I must again devote a little attention. Several years ago {British Medical Journal, 1888, vol. ii., pp> 10 and 11) I pointed out that Sir A. Garrod had fallen into an error of some importance in his argument regarding the results in a table which he quotes from Lehmann. 862 UEIC ACID — CHAPTEB XVII From this table it may be seen tbat the uric acid urea relation on a Mixed diet is . . 1—29. Animal diet . . 1 — 38. Vegetable diet.. 1—22. And Sir A. Garrod draws from this the inference that uric acid is not so much influenced by the nature of the food as urea is, and further, that animal diet does not increase the formation of urate, but rather the reverse, while a vegetable diet does increase it. But these results refer only to short periods of time. They refer, therefore, to excretion merely, and tell us nothing whatever about formation and introduction. Undoubtedly the first efiect of animal diet, as of uric acid itself, is to diminish the excretion of uric acid because it raises the acidity of the urine and diminishes the alkalinity of the liver and blood (p. 123), and conversely a vegetable diet increases the excretion of urate because it lowers acidity ; but if these investi- gations had been continued for weeks and months straight on, it would have been seen that the diminished excretion on animal diet would have been balanced later on by a plus excretion of more than the equivalent amount, and the plus excretion on vegetable diet would gradually have fallen towards the level of formation, 1 — 35, when all previous accumulations had been removed. As a matter of fact, formation never varied in relation to urea one jot, being the whole time at or about 1 — 35 or 1 — 40, only on animal diet part of the urate formed and introduced failed to be excreted and was kept back and retained in the body, while on the vegetable diet some little urate previously formed obtained enough solvent alkali to effect its solution and excretion. The figures are, I doubt not, perfectly correct, and agree in every way with my own results ; they refer, however, only to short periods of time, and owing to the prevailing idea of excessive formation of urate, the conclusions drawn from them are, I believe, erro- neous in the extreme (see also p. 88). Liebermeister {Vorlesungen ilher Specielle Pathologie u. Therapie, vol. iii., p. 42) falls into similar error, as he says (my translation) " in early times it used to be thought that in gout one ought to limit the use of proteid substances as much as possible in order to put a stop to the excessive formation of uric acid. One forgot, however, in taking this simple view of the matter, that it is not of much consequence how much nitrogenous material is oxidised, but only whether it is more or less completely oxidised " ; and he TREATMENT 863 goes on to say a healthy man excretes so much urea and so much uric acid in twenty-four hours, but an increased consumption of proteids increases to a corresponding extent the urea but not the uric acid. That is to say, he infers that because the excretion of urate is not increased by a meat diet, relatively less urate is forined, or, as he would probably put it, it is further oxidised into urea and got rid of. The real fact is, I believe, that urate is formed in proportioli to urea just as it is on any other diet, and animal food also intro- duces some urate ready formed," but excretion falls short of forma- tion and introduction owing to rising acidity, and some part of that formed and introduced is held back in the body, and can be washed out and produced at any future time by administering a dose of salicylate, alkali, or other solvent (see fig. 74) ; or, if the curves of excretion are watched sufficiently long, it may come out of itself when from some natural cause the acidity falls. I think, therefore, that once for all we may free our minds from this bugbear of formation, oxidation, and other more or less theoretical myths, and believe that for all practical purposes uric acid is always, and on all diets, formed in the relation to urea of about 1 — 35, while certain foods also introduce a more or less important quantity of uric acid or xanthine ready formed (for some interesting results obtained by administering hypoxanthine to animals, see Lea, " Chemical Basis of the Animal Body," p. 182, and compare this with my remarks ia chapter iii., p. 129). I am interested to see in this connection that a writer in the Journal of Physiology (vol. xxii., p. 146), W. J. S. Jerome, gives as one of his conclusions after an investigation of the subject, that the daily output of uric acid is probably due to the larger or smaller amount of the alloxur-holding bodies {i.e., xanthines) absorbed from the food ; this conclusion being practically identical with that I have drawn from my own researches published in the same journal, vol. xv. See also the New York Medical Journal, 1896, vol. ii., p. 578, for the record of toxic symptoms produced in a rabbit by the administration of hypoxanthine in the food. I have often pro- duced some similar symptoms in myself, and I have not the least doubt that I could reproduce them in anyone who would volunteer a corfus vile for the purpose. Oxidation is no doubt important, and oxygen is occasionally useful, and I have consumed a quantity of it experimentally. When T managed to raise the acidity of the urine and diminish 864 UBIC ACID — CHAPTBB XVII tte alkalinity of the blood, I cleared that fluid of uric acid and no doubt improved nutrition, combustion and metabolism ; but it is not nearly so powerful in this way as a few fractions of a gram of mercury, or one of its salts. And I do not for a moment believe that all the oxygen and oxidation in the world will alter in the least the relative formation of uric acid and urea in the human body ; and the diseases from which we sufier have far more to do with introduction than formation, and complete power of prevention will eventually prove that this is correct, even if it has not already done so. Whether uric acid will be excreted in the relation 1 — 35 is a totally difierent question, for excretion, as I have pointed out, can be varied at pleasure in almost any direction, and within very con- siderable limits. And it is by taking excretion as proof of forma- tion that the authors above quoted have fallen, I believe, into serious error. I do not assert that uric acid is never formed in excess of the relation to urea 1 — 35 ; my experience is too small to carry such a proposition ; but I do assert, of all the diseases of which I have written, in so far as they are due to uric acid, that they are due to its accumulation in the body from introduction with failure of excretion; that I have never met with any evidence of formation in excess of the above ratio to urea, or any reason to think that all the urate I have met with, could not have been easily accounted for by failure of excretion. For my part, I return without hesitation to the doctrine of early times, and fight uric acid disease by reducing the introduc- tion of uric acid, and where necessary, its formation also, believing that the clinical observation of Cullen, " that gout seldom attacked persons employed in constant bodily labour, or those who live much upon vegetable diet," is a more valuable guide in treatment than many more recent conclusions founded on imperfect observa- tions. We now know that constant bodily labour facilitates excre- tion (figs. 46 and 47), while vegetable diet diminishes introduction and also facilitates excretion. I have now also] the best of all proofs of the correctness of my. reasoning in practically complete immunity from a disorder which formerly threatened to interfere seriously with my work and even to cripple and shorten my life. Such a result must speak for itself, even if the theory on which its explanation is founded is destined eventually to give place to a better one, the product of still wider knowledge. The late Professor^^Humphry says {British Medical Journal, 1888, TEEATMENT 865 vol. i., p. 512) that 62 per cent, of the aged take but Httle animal food, and I should link this with Cullen's observations, and the very deadly effects of many of the diseases mentioned in previous chapters. In altering diet, however, it is necessary to exercise some care, especially in regard to the amount of urate that may be stored in the body. In a man of middle age or beyond it, who has lived heartily, without stinting either meat or wine, there is sure to be a large collection of urate in the body ; and if his animal food is reduced, and his acidity runs down, this will be dissolved out and flood his blood ; for weeks and months there may be a plus excre- tion of urate, and its results will be more evident than pleasant ; he win worry you with continual complaints that he is getting weak, that he is dying, that he has headache, depression, &c., and may even talk of suicide. Similarly, in cases which have been put on what I regard as the most dangerous of all modern diet cures, that of meat and hot water, it is wiser to go slowly and get them back gradually on to ordinary flesh diet, and then from that on to a uric-acid-free diet with vegetables and fruits ; but to make a sudden change on to this latter at once may bring about severe collaamia, with high blood pressure and all its most serious results, especially in those who are no longer young. In all cases also it is necessary to see that nutrition, strength and power of endurance are quite as good on the new diet as they were on the old ; ia the majority of cases they are very decidedly better on the new ; but if there is the slightest suspicion of theic not being so, some mistake is being made, or a great flood of uric acid is putting out the fires, and the matter should be investigated. In other cases, where the accumulations are not so large, one may gain so much by stopping the large daily introduction that it is better to alter diet at once, especially to cut ofi soups, meat extracts, strong tea or cofiee, giving perhaps cold baths, a tonic or some drug which will cause a Uttle retention and keep the blood moderately clear of uric acid for a little ; or, if the diet alteration is being made in spring or summer, the patient may be sent for a few months to a bracing chmate ; and lastly, some cases with high blood pressure may be bast treated just as if they were Bright's disease (see chapter xiii.). As I have said several times before (see Practitioner, April, 1891, p. 279), I believe that the great majority of Britons of the present day could live very healthy and hearty lives on such a diet as I recommend, if they woidd make a rational attempt to do so. 866 URIC ACID — CHAPTER XVII To get them to make the attempt, however, is generally the difficulty ; they think the diet must be lowering, and believe that beef steaks and beer are necessary for their continued existence, and undoubtedly, where the change of diet is allowed to produce considerable coUsemia, the resulting mental depression, with languor and disinclination for exertion, are sufficient to give some support to their assertions. But, as I have shown, such results are quite unnecessary ; they are not due to the new diet, but to the amount of urate which has been accumulated on the old one, and to the fact that these people have become accustomed to a stimulating diet, just as they might have become accustomed to an allowance of alcohol ; but few people would in these days argue that alcohol is either a necessary food or a source of strength, though this is what was believed not long ago. Another objection sometimes urged against the diet is that people tend to grow stout on it, and no doubt if they eat large quanti- ties of butter, cream, and cream cheese, and drink much milk, this may be the case ; but this is not a necessary part of the diet by any means, for milk may be skimmed or left out entirely, butter and cream may be avoided, and skim-milk cheese may be eaten in place of cream-containing cheese. Where cases of obesity have also, as is very often the case, very high blood pressure and slow capillary reflux, where in fact the obesity is, as I expect it generally is, a result of defective cir- culation and its resultant defective combustion, in a word, a result of coUsemia, they should, I think, be treated just like the cases of Bright's disease in chapter xiii., where we saw that a case that did well steadily lost weight as the circulation quickened and the temperature rose and the albumen diminished ; while a case that did not do well, in which the temperature did not rise or the albumen diminish, steadily gained weight. These cases will lose weight as the circulation quickens and the combustion improves, in spite of a uric-acid-free diet, though the fats should as far as possible be removed from it by substituting protene, plasmon or gluten for milk ; or let them go on to a diet of bread, fruit and nuts, which practically does not fatten anyone. When obesity is treated as a failure of combustion it will be treated with success ; but to treat it on a pure meat diet is to obtain temporary success perhaps, but only with the certainty of a great increase of coUsemia, and diminished combustion in the future ; and all the necessary albumens can easily be obtained from the TBEATMENT 867 above substances without introducing uric acid, and without the terrible sameness of lood which so often disgusts those on a meat diet. Obesity has, from this point of view, many features of interest, for women get stout first of all just in the period of coUsemia and anaemia that follows their years of greatest growth (13 to 14) about which I have spoken in reference to the causation of anaemia (see fig. 59). So that here again we have failure of combustion with colleemia. Then the great time for obesity, both in men and women, is the decline of life, the collsemia of advancing age, as nutrition begins to run down, and the uric acid stored in previous years begins to enter the blood, and then we get not merely defective combustion of fats but also very often defective combustion of albumen and sugar, either together or one after the other, but one and all associated with the same signs in the circulation, slow capillary reflux, and high blood pressure (see p. 247). Thus slow capillary circulation is the cause of the defective combustion, and collsemia is the cause of the defective circulation. In butchers we often see much obesity, because there is much collsemia ; and this alone should warn us not to treat obesity by a butcher's diet. We must not forget also that collsemia means defective pul- monary circulation (see chapter ix.), and so defective aeration of the blood : then defective oxidation means defective formation of acid products of combustion, defective acidity of urine and increased alkalinity of blood ; and increased alkalinity of the blood in its turn increases collsemia, and so on in a vicious circle with ever- increasing defect in combustion. Later the obesity by its very mass becomes a direct hindrance to circulation, respiration and metabolism. If we can stop the coUeemia even for a week we can stop the downward progress and substitute an increasing meta- bolism for a diminishing one, and then all is soon well, the fire burns up brightly, and this of itself soon suffices to prevent coll- semia. And so intimate is the relationship between obesity and collsemia that practically every relapse of collsemia is accompanied by an increase in weight, just as the relief of coUsemia, and still more the relief of the severe collsemia of Bright's disease, is accompanied by a loss of weight. As I have said, the difficulty is to get people to try ; they are often so frightened by the proposal that they will make only a very half-hearted attempt, which is insufficient to carry them 868 UEIC ACID — CHAPTEE XVII through any little troubles, that they meet with at first, into the smooth water beyond, when all accumulations of urate have been eliminated and introduction reduced. I have never seen any- one who wished to go back after arriving at this stage. A good many people consider fruit and sugar, either mixed or separate, to be deadly poisons, and things which the gouty should altogether avoid ; and I have no doubt that, as regards an ordinary mixed diet, this is perfectly true. If these things, directly or indirectly, raise and keep up the acidity by originating fermenta- tion or forming acids in the intestinal canal, they will, undoubtedly, tend to precipitate urates upon the joints, and do harm in any arthritis, which is due in part, or in whole, to urate irritation; but if the urate be first of all removed, and is not continually introduced in excess, they will have nothing to act upon, and will do little or no harm, though I should often advise caution as to their use at breakfast (see fig. 39). Some interesting points with regard to the possible effects of diet are brought out in the Reports of the Sanitary Commissioner with the Government of India, and I owe these facts to my friend. Dr. de Watteville, who kindly suggested that it might be worth while to investigate these Reports. The following figures are from the Annual Report for 1892, issued in Calcutta in 1894, and they refer to the incidence of the diseases mentioned in the English and native armies respectively. The English army numbered, according to the Report, 68,162, and the native army 145,340, and the ratio of English to native is about as 1 — 2"1. My cousin. Colonel . P. de H. Haig, I.M.8., informs me that the English army in India eats as much meat in a day as the Indian native army does in a week, man for man ; that the native army lives chiefly on grain and rice, that they have a long service system, not short as for the Enghsh, and that the natives have been exposed to malaria from childhood. 6S.lfi2 145,340 Ratio, Disease. English. Native. Bug. to Native Alooliolism 273 . 11 54 to 1 Kheumatio Fever 115 . 48 5 „ 1 Gout 13 . 9 8 „ 1 Megrim . . 7 . 57 1 „ 4 Epilepsy . . 78 . 63 2 „ 1 Melancholia 61 . 22 6 „ 1 Syncope . . 6 . 8 4 „ 1 Dyspepsia 1,037 . 454 4 „ 1 Typhlitis 32 . 16 i „ 1 TREATMENT 68,162 146,340 Ratio, Disease. English. Native. Bng. to Native Colic 311 . 51 12 „ 1 Piles 452 . 196 4 „ 1 Congestion of Liver . . 660 . 117 ■• 12 „ 1 Ague Spleen 46 . 1,405 1 „ 14 Bright's disease (all forms 51 . 40 (nearly) 3 „ 1 Suicides 25 . 9 6 „ 1 Ague 28,842 . . 65,944 1 „ 1 Anaemia 209 . 909 1 „ 2 Bronchitis 1,925 . 4,234 1 „ 1 869 Now we see that in the case of almost every disease treated of m this book, there is a more or less large excess of incidence on the meat-eating English, as compared with the rice and grain- eating native. There is an apparent exception in the case of migraine, but it is evident that this is not the disease treated of in chapter vi., but is really a neuralgia related to malaria, and hke ague spleen, more frequent in the native army, which is more saturated with malaria. The ratio of alcoholism is enormous, but probably factors of race and reUgicai come in here as well as diet, but in any case it is not a record of which we need be proud. Eheumatic fever and gout are fairly prominent, epilepsy is 2 — 1, while melancholia shows much greater excess ; and probably the exposure of the English to heat from which they have not been accustomed to protect themselves wiU account for this, but none the less it powerfully endorses chapter viii. Syncope again, 4 — 1, and yet we are accustomed to look upon the Englishman as strong in his beef eating, and the native as thin and weak. Dyspepsia 4 — 1, and yet the Enghsh are, I suppose, yonnger men. than the natives, and dyspepsia, as a whole, tends to in- crease with age. One cannot but be struck also with the enormous incidence of dyspepsia in girls just at the age when as I have shown (fig. 59) they have most coUsemia, and the comparative J absence of similar troubles in boys ; then again on ordinary diet dyspepsia increases in both sexes after middle life, and so does coUsemia. Typhlitis and coHc are again remarkable records in relation to •chapter x. Piles and congestion of the liver teU the same tale, though no doubt they are in part related to the large alcohol record above. Ague spleen is related to the long exposure of the native army, 870 UKIC ACID — CHAPTER XVII and is also connected with, migraine above, and anaemia further on ; the last named being no doubt specially related to the large fluctuations in urate excretion, which recurrent malaria with en- larged spleen will occasion. Bright's disease and suicide again represent the efiects of capil- laries obstructed by uric acid, and show a great excess among the English meat eaters ; and for suicide we may notice that the ratio is the same as that for melancholia. Lastly, bronchitis is nearly the same for both ; but inasmuch as the native army is composed of longer service, and, therefore, older men than the English, and as bronchitis generally increases with age, it is relatively less in the native than in the English army. I have no doubt that in such a record other factors besides diet will have to be allowed for, but it is very unlikely that any of these will account for the great differences in disease incidence all along the Hne, and I commend these facts to the careful consideration of those who believe that the Englishman's beef is the source of his health, strength, and powers of endurance, or his superiority over other races ; it is at least clear that he has no superiority over them in the matter of disease incidence, and this is an important factor in efiiciency. I am indebted to my friend. Dr. E. G. Horder, who has spent a good many i years in China, for the information that the great bulk of the Chinese eat about 3 oz. or 4 oz. of fish a day, while the rest of their diet consists of rice. He says they are fine, big, and strong men, and more than a match for an average or even a picked British sailor, the only Briton generally available for com- parison ; and he adds that their wounds heal easily and generally by first intention. A similar record with regard to the Turks as to their great powers of endurance and wonderful vitality in resist- ing wounds, is to be foand in the 1897 numbers of the daily papers. Thus in the Standard of May 6, 1897, we find : " The doctors also remark upon the extreme rapidity with which their patients recover from their wounds, and attribute it to the ab- stemious lives they lead, drinking no wine and eating very little meat, but plenty of vegetables." Here again in England, do we not die younger, and in greater number than there is any necessity for 1 Are we not afflicted with an infinite number of diseases which cause far more pain and misery than is at all necessary 1 Are we not given to all kinds of debauchery and excess, and have we not huge asylums full of lunatics and prisons full of criminals ? TEEATMENT 871 I look upon all ttese things as serious and widesjftead diseases in the human race, and, as I am not one of those who believe"^ that Nature herself, if she had a free hand, would tend to destroy us, but rather to preserve what is good, and eliminate what is evil, and, further, cannot believe that the tendency to these evils is part of the ground plan of Nature's work, or that the unalterable bias to have headache, epilepsy, mental depression, mania, and their results — murder or suicide — alcoholism, morphinism, cocainism, &c., is originally implanted in our nerve centres, I am driven to the conclusion that not a few of these evils are the result of unnatural conditions, and that prominent among these is unnatural diet, the evil action of which we are now in a position to follow out more completely through a knowledge of the powerful effects of urates on the function and nutrition of the whole body. , Such a provisional conclusion is justified by my own experience and results. I was originally told that my tendency to headache, high arterial tension, and other evils, was inherited — in fact, a part of my structure and function, which, though it might be modified and reHeved by drugs, could not be eradicated ; and no one ever suggested a radical change of diet. By great good fortune, and more or less by chance, I found out that a change of diet was the one thing needful,, and what is practically a complete cure has resulted. I have now only one sub- ject for regret, namely, that I did not find this out earlier in life, as I cannot undo the evils and injuries that were accomplished while the warnings of functional disturbance remained unheeded, through ignorance of their causation. To a very large extent, therefore, I disbelieve in inherited weak- ness, innate dehcacy, or transmitted neurosis, in so far as such ex- pressions apply to the diseases mentioned in the preceding chapters. The only factor concerned with my headache that I inherited was probably a slight variation in the size and distribution of the arteries at the base of the brain, rendering my intracranial circulation specially hable to be affected by unduly high blood pressure ;* the other factors in its causation were improper food, impure blood, and consequent increased blood pressure, but the improper food being done away with, the " neurosis " became ^ matter of history, in spite of the anatomical factor which remains as before. I notice also a very interesting clinical note by Dr. Brain, Spring and Summer Number, 1893, p. 250. 872 UEIC ACID — CHAPTBK XVII Bavid Drunvnond, of Newcastle, in tlie Lancet, 1897, vol. i., p. /1338, on " neurotic " symptoms of uricacideemia in the young, in whicli lie exactly describes tte headaohe, epilepsy, cold hands and feet, low surface temperature, high blood pressure, and slow pulse mentioned in previous chapters, and finds them associated with meat eating and excess of uric acid in the urine, and cured by milk diet, and, as he tells us he had formerly treated the neurotic element in such cases with unsatisfactory results, his observations confirm my own in every respect. He also notices a symptom which I have not noticed, namely, diminished knee-jerk apparently in association with mental and bodily depression and lethargy. i I believe that much the same argument applies to nearly every disease mentioned in this book, and that while certain anato- mical or physiological peculiarities may undoubtedly dispose cer- tain individuals to sufier sooner than others, or in one way rather than in another, nevertheless the food factor is common to all of them, and its adequate consideration and treatment will always result in prevention or cure. The first step towards this object is the full and complete recognition of the fact that for all practical purposes they are diet diseases, and that gout and rheumatism, for instance, may depend quite as much on the inheritance of the dollars necessary to obtain meat and wine as of any anat'omical or physio- logical peculiarities. Might it not be worth while to make a determined effort to treat our criminals (who are often criminals only because diseased) with a uric-acid-free diet ? If the alteration in their cerebral cir- culation is functional, it will do more than anything else to remove it, and if after that has been done they look at life and the world from a different standpoint, the practical knowledge how to live cheaply on an unstimulating diet may be of no small advantage to them ; and lastly, it will, or should, greatly diminish the cost of maintenance, and, if I mistake not, the cost of disease and crime already presses heavily enough on the less diseased portions of the ' community. Then precisely the same will apply to our vast asylum and poorhouse populations; the inhabitants of the former must often owe their disease to unsuitable diet, acting in the manner depicted in previous chapters; and the tenants of the latter may owe their poverty in no small degree to a life-long habit of spending their money on stimulation in place of nourishment, thus constantly losing both in power and pocket. I see plenty of poor women who live from week's end to week's TREATMENT 873 end on little but bread and butter ; but tbe husbands of these women still think that it is impossible to do a labourer's work without beef and beer, and know but little of the nourishment values of cheese and bread-stufis, a position about as far from the truth as it is possible for an ignorant man to arrive at. About one half of what the man spends on stimulants would provide both himself and his- wife with all that nourishment requires. Then, in spite of his insular position, the British workman is even now suffering reverse after reverse at the hands of the foreigner, who has learned from stern necessity the lesson of cheap living. I am very pleased also to be able to add that quite a large number of fellow-sufferers have now had experience similar to my own — not that the diet is successful in every case. I have never met with any treatment which could honestly lay claim to so large a proportion of cures. Some are unable to alter their diet, being unable to eat at aU when a change is attempted ; others apparently alter their diet and yet are not cured, but these cases are the exception, and require further investigation before anything definite can be said : and I sometimes find that such cases have been making the mistake of continuing a little meat or fish, or in the case of ladies, some tea. On the other hand, a considerable number of sufferers in the profession have appUed my suggestions to their own cases, and report that they have every reason to be pleased with the result. One of these concludes a letter by saying : " Beyond doubt I have established the fact that much, if not all, of my ill-health and moral disturbances were caused by eating butcher meat, the metabolic products of which I was unable to eliminate." Another professional patient writes, after narrating other cases in which the treatment has been equally successful : " Personally my debt to you and to the theory is a heavy one. Four years ago I was an old man at 37, with the enthusiasm and vigour of life quite crushed in me, retired to a pottering country practice to eke out a miserable existence. All that is now thrown to the winds, and I am back to town work in the forefront of the battle, and with the keenest enjoyment of life." This record shows us in a few words how much those who do not lose their lives may yet lose in the mental and physical enjoy- ment of them, by remaining the slaves of diet and the victims of collsemia. Speaking of morals reminds me of the very moderate and much needed warning given by Dr. Keith (" Fads of an Old Physician," ch. xiv.) with reference to the effects of high living on the morals 874 UBIC ACID — CHAPTER XVII of the young, which, my own experience leads me to endorse most thoroughly (see also p. 334).* I have also heard from my friend Dr. W. Young, of Wellington, N.Z., of the case of a man aged 50, who some three years ago sufiered from headaches ard loss of energy (collsemia of decline of lifef), and then adopted a system of treatment by cold baths with abstinence from meat. The result was that he soon got a distaste for meat and left it ofE altogether, and Dr. Young, who met this man while attending his wife, goes on to say, " he is very pleased with the result of the three years' vegetarianism, and says that though during these three years he has lost weight, yet he feels stronger, and is more energetic and rarely has a headache. The improvement he attributed to the baths." I think the author of the above-mentioned system is to be con- gratulated on his knowledge of human nature, for this man would not have altered his diet except to help the baths ; and would have indignantly repudiated the suggestion that he was eating meat which did not agree with him. Of course he had been eating it all his life, and knew much better than that ! The case is a beau- tiful illustration of the value of the oblique method in deaUng with people who are absolutely ignorant and full of prejudice. With regard to alcoholism, I think the vegetarians can make good their claim that the adoption of their diet does as much to cure this trouble as anything that is known, and the reason that it does so is simple enough. Meat, as I have said on pp. Ill, 123, is a stimulant, and causes a fluctuation in the excretion of uric acid ; its stimulation is due to the diminished excretion or increased retention of uric acid, because, as we have seen, every drug which clears the blood of uric acid is a stimulant ; but this is followed by an inevitable corres- ponding and more than corresponding depression, when the urate at first driven out of the blood gets back into it along with the urate introduced in the meat itself. For the relief of this depression more meat must be taken, and when meat begins to fail in causing sufficient stimulation alcohol is added ; when alcohol begins to fail morphine or cocaine are called in, and so on down the road to ruin. * I was interested to see that in a discussion in the Lancet, 1897, vol. ii. p. 685, on schoolboy morals, one of the writers advocated a reduced allowance of meat ; but I fear that the tide of custom at schools and colleges still runs strong in the opposite direction. t See remarks on p. 828, on the most common age for suicide ; also p. 247. TREATMENT 875 Now vegetarianism cuts through this vicious circle at one blow- by making it impossible for there ever again to be any great excess of uric acid in the blood, and so removing the cause of the depression which leads to the craving for stimulants. But even this is not quite the whole story, for meat is not only a stimulant, it also causes thirst. We have seen that every drug that clears the blood of uric acid causes diuresis, that this leads to concentration of the blood, and that thirst is the expres- sion of the blood's wants, and goes along with diuresis (p. 30) ; therefore the meat eater is always thirsty, and if he from one cause or another — occasional depression, it may be — acquires the bad habit of quenching his thirst with alcoholic drinks, he soon gets too much of them.. The vegetarian, on the other hand, is not often thirsty, because he is not subject to urate fluctuations and diuresis, and also because the fruits in his diet list themselves supply him with a very large amount of water. My own practice is not to cut patients ofE from any form of alcohol they may be taking when they come to me, as I know that after eighteen to twenty-four months of a correct diet they will cease to feel the want of any stimulants and will give them up of themselves. My personal experience is identical, for on meat diet it used to be one almost continuous course of tonics and stimu- lants, from May to October {i.e., in the coUsemic season) each year ; now I never touch one or the other, because I feel no desire for them ; they seem to be quite unnecessary, and if taken, merely make me feel uncomfortable. In reference to the term vegetarian, it is evident that I am not a vegetarian in the strictest sense, because I take some milk and cheese ; on the other hand, I differ greatly from many who call themselves vegetarians in this country in not taking eggs, pulses, mushrooms, asparagus, tea, coffee, cocoa, bran tea, and other vegetable substances which are stimulants because rich in xanthine compounds. I am only concerned in these diets and -isms in so far as they bear on the prevention and treatment of disease, and so far as these are concerned pulses and eggs are as bad as meat. I prefer therefore to call my diet " uric-acid-free diet," to emphasise the points in which it difiers from vegetarianism. I am also decidedly of opinion that still better results would be obtained in the prevention and treatment of alcoholism if a uric-acid-free diet is substituted for a vegetarian one containing 876 UEIO ACID — CHAPTBB XVII pulses, eggs and tea. The latter is nothing but a stimulant, and if stimulation is as I believe always wrong, it is doubly wrong in cases where it has already led to abuse. Stimulation, as I have said in " Diet and Food," is not strength but only force rendered a little more quickly available. A stimulant calls out the reserves, it introduces no fresh force into the body, and when the reserves have been all called out a stimulant will produce no efiect at all. On the other hand a food digested and absorbed introduces fresh force from without. A stimulant has thus to be constantly increased to produce the same or even a diminishing efiect, and the more uric acid there is in the body the more stimulant is required to keep it at bay. On the other hand half a pint of milk produces the same amount of force time after time as often as it is repeated and digested. I will now say a few words as to the most usefnl drugs for "clearing the blood of uric acid. Of the very numerous drugs which have this efiect, I prefer the iodides and chlorides, mercury in some form, or the iodide of mercury, or, if it is necessary to act quickly, the nitrites, or a subcutaneous injection of morphine. If there is any good reason for not using mercury, other metals, as copper, zinc, silver or gold, or their salts, may be used with equally good results as regards uric acid ; and I have no doubt that the tonic action of these and other metals is due to their effects on the solubility of uric acid. The iodides seem to be specially useful where the efiect has to be kept up over a long period, as in relieving the high blood pressure of chronic Bright's disease. Mercury is useful in head- ache or mental depression, and iodides in asthma. All these drugs, however, have the drawback that their action is followed by a rebound as soon as they are withdrawn ; the uric acid which they clear out of the blood is not cleared out of the body, and as soon as the drug is withdrawn, the blood soon takes up the uric acid which has been accumulating during its action. The best way out of this difficulty appears to be to alternate these drugs with a course of salicylate of soda, which eliminates the uric acid and prevents the accumulation from becoming very large. But retentive drugs continued with a uric-acid-free diet do well, as we see in the case of Bright's disease. And salicylates are themselves useful in lowering pulse tension and clearing the blood of uric acid : but their greatest efiect in this direction takes a day or two to come out, for, during the TREATMENT 877 first two days of their action, while the excretion of uric acid is very large, the urine is scanty and the capillaries are not so free as they would be under drugs of the mercury and iodide class, which clear the hlood of uric acid to some' extent within an hour or two. Salicylates are useful also in headaches to follow the morphine or mercury that have been used at first, and remove the uric acid they have retained, and in the same way they may be useful in mental depression ; and they may, as I have said, completely prevent fatigue, and will relieve it and its myalgic pains when present. Salicylates are also very useful in some cases of asthma and in what are known as feverish colds. They will often relieve dyspepsia, especially if there is pain ; and in what I have called gout of the intestines thfeir efiect is sometimes wonderful. Similarly in anajmia they are of use, and apparently pass the uric acid through the blood without allowing it to do much harm ; thus we see in fig. 74 that the blood decimal fell with the high uric acid on March 22 and the previous day, but the fall was proportionately small; and the same holds in paroxysmal heemo- globinuria and Raynaud's disease, though in the attacks drugs - belonging to the mercury and iodide class may be used in the first place. In a word, it might almost be said that iodides, chlorides and bromides, with mercury and diet, wiU cure all the diseases in the first fourteen chapters which are due to excess of uric acid in the blood, and that salicylates followed by diet will cure the rest. In albuminuria and Bright's disease, sahcylates when they in- crease the excretion of uric acid often make the urine scanty and the albumen appears to be increased ; but I have never been able to satisfy myself by actual estimations that there was in these cases much absolute increase of albumen. Still, in these diseases I generally prefer drugs of the iodide class, and only use sahcylates occasionally to clear out accumulated urates. Of the use of salicylates in rheumatism, glycosuria and diabetes, I need hardly say any more, and in arthritis I believe that they have only to be given in proper cases and conditions and in suffi- cient doses to have their powers fully appreciated. I am glad to see that Professor Tyson, of Pennsylvania, considers them by far the best remedies in this disease (Therapeutic Gazette, November 15, 1895), and the cases narrated in chapter xvi., in which they failed, will serve to point out the conditions in which similar failure may be expected, and the means of avoiding it. 878 UEIC ACID — CHAPTER XVII It is not my purpose to go uoinutely into the drug treatment of each condition, for, in so far as any of these diseases are due to uric acid, the only real treatment is that by diet, which is both preventive and curative, while drugs for the most part (except the saUcylates) reheve only for a time, and the trouble will return as soon as they are left ofi, and in not a few cases will be worse than if they had never been used. Practically those who live on natural foods and also guard against excess by occasional temporary fasts, will never want drugs for dyspepsia, nor soporifics for insomnia, nor tonics nor stimu- lants for debihty, lethargy or anaemia ; they will live uniformly busy and happy hves, and have also very considerable immunity from infectious and contagious disease, and almost complete immu- nity from their serious and deadly sequelae. If any of the troubles in the first fourteen chapters are asso- ciated with a slow capillary reflux and scanty urine the presump- tion is in favour of an excess of uric acid in the blood, and this and the urine may be examined ; but if this is impossible, the temperature in the mouth and rectum may be taken as a guide (fig. 5), and drugs may be given, which would have the effect of clearing the blood of uric acid, and their efiects on the temperature observed ; or, on the other hand, caffeine or uric acid in some other form may if necessary be given to see if it eventually makes matters worse. When the diagnosis has thus been fortified, treat- ment by drugs and diet may be proceeded with. Dyspepsia may complicate any or all of these conditions, and when it is severe may to some extent prevent drugs from raising the acidity and clearing the blood of uric acid. It will not, however, interfere with the drugs which are inde- pendent of acidity, such as mercury and other metals, whose uric acid compounds are insoluble, unless it prevents their absorption from the stomach and intestines, and in this case mercury can be administered in other ways. In all cases, however, it is necessary to reckon with dyspepsia, and if possible to cure it ; it is partly a cause and partly an effect of the excess of uric acid in the blood, and it fortunately happens that the diet and many of the drugs which are useful for coUaemia will also relieve or cure the dyspepsia ; for instance, my so-called bilious attacks, with the congestion of the liver and the dyspepsia which preceded and] accompanied them, have disappeared along with my headaches. Dy.spepsia also mustbe kept in mind both in gout and rheu- TREATMENT 87.9 matism, and in chronic rheumatism it is often an important factor ; it very probably keeps up more or less constant excess of uric acid in the blood (hence its important effects in the production of anaemia), and then, owing to formation of acids, exposure to cold, or other cause, a rise of acidity retains some of it from time to time in the joints, and then this acts as a uric acid filter, con- stantly taking more from the blood and increasing the joint irritation. Dyspepsia may also be treated by altering the meals in the way described with reference to fig. 74. The treatment of uraemia is, I think, the treatment of high blood pressure, together with more or less oedema of the mem- branes and excess of cerebro-spinal fluid, which have been caused by the high blood pressure ; the treatment of the high blood pressure may be the same here as in other conditions ; but it may be neces- sary to do something more to remove the oedema, and it seems probable that venesection would be the most likely thing to succeed, for it would not only complete the reduction of blood pressure, but would probably cause the blood to take up available fluid from all directions ; and we know that morphine and venesection have been found useful in this and kindred conditions. Uraemia also has occasionally been observed to terminate in an attack of gout, which of course would mean the practical clearing of uric acid out of the blood and relief of high blood pressure (see paper by the late T)r. Kalfe in Transactions of the Medical Society of London, vol. xvi., p. 216 ; and Lancet,, 1893, vol. i., p. 415 ; also case in Lancet, 1889, vol. ii., p. 1118). I have mentioned in several places (pp. 49, 127, 256, and 267) some points in the pathology of gravel and stone, and I shall now merely remark that whatever the influence of other factors, an excessive excretion of uric acid is not very rarely the most impor- tant point in their causation. Thus they are met with in old people who have suffered for years from gout and other signs of excess of uric acid in their body and blood, and are a natural result of failing metabolism in such people. Thus I have explained that those who have much urate in their joints may, as appetite and digestion fail and their acidity runs down, excrete for weeks and months an excess , of uric acid till the joints which at one time were full of urates, show nothing but empty erosions of cartilage (see pp. 247, 708). As the excess of uric acid from this source passes through the blood, it obstructs the capillaries and diminishes the flow of water from the kidneys, so that we get a large excretion of urates and 880 UBIC ACID — CHAPTEE XVII very little water to carry it ofE, and it is little -wonder that some of this urate is occasionally deposited in the kidney or the passages below it ; and as I have shown in reference to fig. 64, it is the uric acid which controls the excretion of water, and not the water the excretion of uric acid. Now this is a very painful and troublesome condition, and one with which it is very difficult to deal satisfactorily ; thus it may be difficult to stop the plus excretion of urates, for the patient is often so feeble and his acidity so low that acids are overpowered ; but mercury and iodides will act, and these wiU not only diminish the excretion of urates, but will, at the same time, increase the excretion of water. Soda and potash may be given, but they will- not increase the water, and will increase probably the actual excre- tion of uric acid. The urates are probably doing no harm in the joints, and nothing will be lost by letting them stay there a little longer, or by allow- ing them to come out into the blood and urine more gradually, so that I am inohned to think that the iodides form the best line of treatment to adopt. I am here speaking merely of the greater or less excretion of urates from gouty joints and other places of deposit in the body, and not of the treatment of a calculus in the kidney or bladder already formed ; the line of treatment I suggest is intended to prevent their formation if possible. As regards mere expulsion of the calculi when formed. Dr. Hermann, of Carlsbad, has pointed out that large doses of glycerine (1 — 4 oz. by weight) are often very useful (see Medical Chronicle, January, 1900). It is an obvious conclusion from my reasoning that if a patient such as we find thus suffering from gravel in old age had altered his diet, in the way I am suggesting, twenty or thirty years before, he would in all probabihty never have suffered either from gout or from gravel. I am indebted to my friend Captain Ernest Roberts, I.M.S., for the following interesting observations with regard to the effects of diet on the incidence of calculus in India. Among the poorly nourished, rice-eating population it is rare. Among the wheat-eating, meat- eating and generally better fed provinces it is frequent ; and in these provinces it is specially common among the men and boys, rare among the women and girls ; and this is largely due 'to diet, j for the men feed best and the boys with them, the women have their leavings, and the girls what they can get ; the last-named being very little thought of, and badly fed. TEEATMENT 881 It seems to me that this is extremely interesting,! or in the meat- eating provinces there is most introduction of uric acid, and those introduce most who are best fed (men and boys), and those intro- duce least who are least fed (women and girls) ; and then the warm climate of India conduces to high alkalinity of the blood and the relatively rapid progress through it of all the uric acid introduced ; and it will be excreted most quickly and completely in those least well fed, and retained and accumulated most certainly in those who are best fed. During the discussion of a paper which I read at the Medical Society in November, 1896, and in which I suggested that " the uric acid diathesis " was a myth, inasmuch as all the diseases referred to it are really due either to the excessive introduction of ready formed uric acid or the excessive consumption of albuminous food, both of which dietetic errors can be corrected, and the diseases due to them removed, I was askad by Mr. Freyer, who appeared as a champion of the " diathesis," how it was that many of the natives of India, who lived on exactly the kind of food I advised, yet suffered severely from stone ? After what I have said with regard to the efiects of excess of albuminous food (i.e., of excess of quan- tity without reference to quality), and especially after my remarks on figs. 74 and 75, I do not think that the question requires any further answer; but the discussion thus begun was continued after- wards in the British Medical Journal, and was brought to a close with the pubhcation of the most interesting letter of my friend. Captain E. Eoberts {British Medical Journal, 1897, vol. i., p. 625), and in this discussion several facts of considerable interest were brought to the surface. First of all it became evident that in spite of adverse criticisms the above-mentioned habits of the natives in feeding the men and boys best really exist, and no doubt account both for some extra introduction of uric acid as well as possibly for some excess in albuminates in males as compared with females. That more meat is really eaten by the natives of India than might be supposed, that large numbers of Mohammedans eat it regularly, and that the lower caste of Hindus take it whenever they can get it ; and I am also indebted for corroborative evidence on these points to my friend, Dr. Bonus, and his brother. General Bonus, who served in India for many years in various official positions, bringing him into contact with the natives in various parts of the empire. And, speaking generally, it seems to be just in those meat-eating portions of the population that stone is most common. Further, 66 UEIC ACID — CHAPTEB XVII Captain Roberts shows in the letter above mentioned that stone is most common in the districts where wheat is the staple food, and least common where rice is the most important food, and I may mention that Parkes gives the percentage of albuminates in rice as 5, while in wheat flour he gives it as 11, or more than double, and it is thus evident that the wheat-eating population are much more likely to get excess of albuminates than the rice-eating (see also remarks in chapter viii., p. 369, on " Causation of Fatigue and Rheumatism in Horses "). Further, it is evident from statistics kindly sent me by Captain Roberts, and which are extracted from a paper on " Vesical Calculus in India," which he presented to the First Indian Medical Con- gress in December, 1894, that the diet of the native soldier in India, though containing no meat, does, nevertheless, contain nearly one quarter more albuminates than the diet of the European soldier, and also that in some parts where certain kinds of pulses are plentiful and are freely eaten, the diet of the natives contains a still larger excess of albumens, and will, as we can now see, cause the introduction of quite a large amount of uric acid (see fig. 75). With regard to some of these points Captain Roberts says, in the letter to the British Medical Journal above referred to : — " Out of a total of over 4,000 cases of calculus operated on annually in India, one-half are reported from the Punjab, in a population of 20 millions, 1 million of whom are reported by Hunter as rice eaters, 97 per cent, of the arable area being under wheat, barley, and millets. Next come the North-West Provinces, with less wheat, but still only .3 per cent, of the cultivable area under rice, which is said (Hunter) to be eaten by 4 millions out of the 47 million inhabitants — a doubtful point to anyone who knows the North- West Provinces — and from this area from 900 to 1,000 stone cases are reported annually ; thus three-fourths of the eases are reported from a wheat-, barley-, and millet-eating population of about 70 millions (or fewer). " On the other hand, the ratio of calculus incidence to population is lowest, and there is a huge contrast between lowest and highest — in Bengal, Madras, and Burmah, where rice is the most important food staple. The contrast is seen even in one provincial area namely, Lower Bengal ; for Behar, the western part thereof, which is pre-eminently a wheat-producing and wheat-eating country, fur- nishes altogether a disproportionate number of the cases in the Bengal statistics. TREATMENT 883 " In this connection I must add tliat I have definite statistics from the Punjab dispensaries, showing that ont of a total of 1,446 cases 1,199 were Mohammedans, and only 247 Hindus, a ratio of 5 to 1. These cases were not picked out to demonstrate a fore- gone conclusion, but are taken as reported. It is difficult to explain this special proclivity of Mohammedans unless the food factor be taken into consideration." I am told also by others that among the Hindus who abstain from fish, meat and eggs, and eat largely of rice and vegetables, rheumatism is like calculus, rare or unknown. I am inclined to think that in all these diseases of the natives of India the introduction of aric acid in pulses probably plays a far larger part in causation than retention by acids in grain foods, for exercise and climate both strongly antagonise the latter while they have no efEect on the former. One further fact of interest came out in the above correspon- dence and discussion, namely, that the ratio of women to men in stone is very close to the ratio of women to men in gout ; for if there is any truth in the pathology I have been endeavouring to defend, this must of necessity be the case, for when the urates are in the body they may have arthritis, and when the same urates are being dissolved and passing out of the body they may have gravel or calculus. They are but two stages of one process, and the ratio of women to men affected will almost of necessity be much the same for each. In India, owing to the effects of warmth on the alkalinity of the blood, plus excretion of mates is the rule, retention the excep- tion, a fact also mentioned by Captain Roberts in his paper on " Calculus " ; and there men and boys suffer most from ston because they eat most meat and most albumen. In England, with its cold climate, high acidity of urine, and low alkalinity of blood, retention of urates is the rule and plus excretion the exception — an exception associated mostly with the debility of advancing life ; and here men suffer most from gout because they eat more in quantity ; also, in my experience, more — often much more — meat than women ; so that they have both excess of albumen and excessive introduction of urates. And Sir A. Garrod remarks (" Gout and Rheumatic Gout," third edition, p. 212) that when, in the degenerate days of the Roman Empire, women Lived like men, they became " the subjects of acquired gout equally with men." There seems to me in all this just nothing to necessitate the 884; UEIO ACID — CHAPTBK XVII continaed existence of tte "uric acid diathesis," though: doubtless many will still regard it with some affection, because for quite a large number of years it has played the part of a very respectable and convenient cloak for considerable ignorance. The publication of the above correspondence also brought me a most interesting contribution of experiences from Surgeon-Major T. Holmested, formerly civil surgeon at Hyderabad Sind, which he has kindly given me leave to mention. Thus he says : " In Sind all Hindus but Brahmins eat goat and fish and lentils. Stone is very prevalent even in girls. I used to attribute it to chill, for 1. have had suckhng infants with stone [the youngest he ever operated on being 14 months old]. " In Sind and North India in the cold weather the night and early morning is piercingly cold and midday hot — little children go about naked ; the chill, I thought, upset the action of the Uver. Enlarged spleen very common in Sind, and fever and pneu- monia in cold season." H« also says that fruit and vegetables are deficient in the diet, at least for a large part of the year in a great part of Central Sind, and that amongst natives a modified scurvy, as shown by the teeth, is common. I think that Surgeon-Major Holmested is quite right about the effect of chill, which may affect the active metabolism of a child very powerfully ; in them cold will act as a stimulant and raise the acidity of the urine ; it will probably diminish for several hours the natural morning excretion of urates, causing retention either from day to day or throughout the whole cold season. The uric acid thus held back will come out either at some other hour of the day or at the end of the cold season with a rush, just as appears to occur in this country in March, April, and May, and on to July, and the result may often be insufiB.- cient solution and deposition of gravel or calculus. The effects of fevers, pneumonia, and enlarged spleen in causing increased retention of urates in the body I have already men- tioned several times ; and a deficiency of fruit and fresh vegetables and the alkali they supply, will obviously help the other causes making for retention or accumulation, which in this country, just as in India, furnishes the material for subsequent gravel or stone. And in other parts of the world it is the same, as Dr. T. Sinclair Browne, of Barbadoes, writing under date 30th March, 1000, says : " I tell people that out of our population of 200,000, about lijOOO don't take meat, and a finer body of labourers do TEBATMENT 885 not exist. A negro will work all day in the sun and never tire, and they are splendidly developed, with not a bit of fat about them. People here {i.e., whites and Europeans) eat meat three times a day, and if they have no appetite they take cocktails before meals to give them an appetite. They also take no exer- cise. The result is that rheumatism, gout, dyspepsia, liver, heart and kidney disease abound in the better classes." In Cairo, as I saw for myself (January, 1902), it is just the same as among the natives of Barbadoes — no meat is eaten and rheumatism and gout are unknown ; and though this might be to some extent due to the dry warm climate, there is also no aDcTsmia except that due to parasites (anchylostomum), and blood decimals of 6-7 and 8 are the rule, as against 4 and 5 here. Is this also due to climate ? If so, to what is the severe anaemia from which Europeans suffer in India due ? Obviously to the meat, which accounts for all the diseases enumerated by Dr. T. Sinclair Browne in meat eaters of Barbadoes. Our anaemia is not due to our climate but to our flesh food, and when we carry this with us we are anaemic all the world over. The splendid colour and physique of the Arabs and Egyptians is not due to their climate but to the absence of meat, and absence of meat in this climate wUl produce the same results. In this country we get some retention, that is, men and boys may sometimes go on introducing excess of uric acid in their food and yet not passing excess in their urine ; but then some accident occurs and lays them up, they get a fever, a disease like splenic leucocythsemia, or, later in life, carcinoma, and down goes nutrition and up goes the alkalinity of the blood, and all their urate accumulations pass through it in such quantity as to cause more or less deposit in the urinary passages, as occurred in the case mentioned by Sir T. Lauder Brunton, p. 49, or the case on p. 127, or the migraine case on p. 267. Some are very fond of the idea of washing out uric acid from the body and pas- sages by drinking large quantities of water, but I cannot see any evidence that this is of much value. For we see from fig. 3 that considerable quantities of fluid taken in the morning hours do not pass through the kidneys, but remain in the blood till uric acid comes below urea in the afternoon, and yet it is exactly in the morning hours that most uric acid is excreted, and most water is required to wash it out of the urinary passages. I think, therefore, that it is very little use to give large quan- tities of water, for it gets through the kidney just when it is not 886 UEIC ACID — OHAPTEE XVII wanted, and it cannot get through the kidney when it is wanted, i.e., when large quantities of urates are passing into the urine. Again, the drinking of much water may increase the excretion of uric acid by causing dyspepsia, hydremia, or both, and thus do harm in gravel and calculus, where our aim should rather be to diminish for a time the excretion of uric acid, and at the same time free the excretion of water, as with an iodide. Now, when an excess of water {i.e., in excess of normal thirst and the requirements of the blood and tissues) is taken it often causes very marked dyspepsia, possibly by diluting the digestive secretions, and dyspepsia, as we know, causes coUeemia and a plus excretion of uric acid in the urine ; but in gravel and calculus this is a harmful and not a helpful effect. And, apart from gravel, in other conditions of uric acid disease, I see no reason to think that water drinking in excess is of any real value in treatment, for, as we have seen in previous chapters, it is the uric acid that controls the excretion of water, and not the water that controls the excretion of uric acid. Apart from the dyspepsia it may produce or increase, I doubt whether an extra pint of water swallowed has any effect on the excretion of uric acid in the hours which follow its ingestion : but where people habitually over-eat, it may be useful, in default of other measures, to cause a little dyspepsia and perhaps some increased action of the bowels, so as to sweep out some of their unnecessary supplies before they are digested and absorbed. As an amusing patient said to me some years ago, " What a world it is, one half dying of too much to eat and the other of too little," and in all uric acid diseases it is far easier to prevent introduction than, having got it in, to provide for its. safe and satisfactory removal. The excretion of uric acid is controlled by its solubihty in the blood, and, so far as I know, apart from dyspepsia, excessive water drinking affects this but little, and though as previously pointed out with reference to th3 late Sir W. Eoberts' results in chapter xv., the more water there is in the blood the greater power it will have of dissolving bi-urate deposits, still if such urates are in this way brought into the blood in any quantity and assume the colloid form, they will obstruct the capillaries of the kidneys and allow only a scanty excretion of water to pass with the urates into the urine. I have thus come to look upon water drinking for the cure of uric acid diseases as practically useless ; but in all high blood pressure cases it is not only useless but positively harmful. For TEEATMENT 887 obviously the more fluid there is in the body the higher will be the blood pressure, other things equal. But headache, epilepsy, mental depression, vertigo, uraemia, dropsy, eclampsia are all made worse by rise of blood pressure, i.e., by increase of fluid ; hence the importance of withholding fluid as much as possible in such conditions and of giving a diet as dry as possible of bread stufis and fruit, and no fluid unless there is decided thirst. To give fluid in such cases with the idea of eliminating the poison is not only useless, but absolutely unphysio- logical to the extent of being silly. The effects of exercise on nutrition, metabolism, and the excre- tion of urea and uric acid I have already gone into at great length in chapter viii., and from the fact that it stimulates and increases metabolism, and improves the circulation through almost all the organs and tissues, it is easy to understand that regular exercise, short of fatigue, should be extremely useful in many of the disease processes of which I have been speaking. Thus in high blood pressure and headache it frees the capillaries and relieves the intracranial pressure ; in mental depression Professor Lange has specially pointed out its value ; then want of regular exercise is one of the most common causes of dyspepsia, with all its train of bodily and mental ills. Again, in albuminuria and glycosuria so much regular exercise as will keep up the nutrition of the skin, the muscles, and the important glands, is often one of the chief points in treatment. In gout also, as we have seen, regular exer- cise will prevent attacks. In many cases, then, I consider such regular exercise as second only in importance to diet, and the two can often be employed together with advantage. Where the surroundings or the condition of the patient prevent satisfactory exercise, massage, which is, in many respects, equivalent to exercise, may take its place, and especially where nutrition is low, it is often an important help at the commencement of treatment. Then, again, massage is extremely useful, as has been so ably demonstrated by the late Dr. A, Symons Eccles,* in improving the circulation and nutrition in joints and other structures which have been damaged by urates, or have had their nutrition seriously afiected by the circulatory changes which these substances produce, thus completing the cure of which * British Medical Journal, 1888, vol. ii. ; Ibid., 1891, vol. i., p. 1075 ; "Sciatica," Macmillan and Co., 1893; Lancet, 1893, vol. ii., p. 924; and "The Practice of Massage," Macmillan, 1895. UEIC ACID — CHAPTER XVII the removal of the urates is only the first step, for obviously the removal of urates, while perhaps preventing further structural or nutritional change, will not restore the tissues to their original healthy condition. It is important, however, to bear in mind, as suggested in previous chapters, that massage, by flooding the injured fibrous tissues with fresh blood and fresh and more alka- line serum, may really help considerably with the removal of urate from the tissues and the suspension of the chronic irritation, fibrosis and stiSening which their presence produces and perpetuates ; and this may apply equally, whether the original injury of fibrous tissues was uratic or traumatic, or as so often happens, a mixture of both. And this constant presence of irritating urates may really account for much of the observed difierence in the rate of repair of wounds and injuries between those who eat meat and those who live on an almost entirely uric-acid-free diet, the other most important factor being an improved circulation in the absence of collsemia. On the other hand, it is also true that exercise will do little or nothing for the relief of uric acid diseases so long as diet is left unaltered and uric acid is being continually introduced into the blood in excess. Looking to all these facts it is most difiicult to avoid the con- clusion that all sufferers from the diseases treated of in this volume owe their sorrow, suffering, and early death to nothing in this world but their own folly. Hence I often say that whatever one may think of a meat eater's humanity and morality it is impossible to question his bond fides, for he is so obviously ready to die for the cause. Certainly the meat eater has no right to blame Nature either as to the origin of the troubles or their inheritance ; in human nature, just as elsewhere in the Cosmos, the punishment follows the broken law, and comparative anatomy should long ago have warned him of his error in diet (see " Diet and Food," Ed. iv., figs 6 and 7). That it is easily possible to sustain life on the products of the vegetable kingdom needs no demonstration for physiologists, even if a majority of the human race were not constantly engaged in demonstrating it ; and my researches show not only that it is possible, but that it is infinitely preferable in every way, and produces superior powers both of mind and body, as the result of improved circulation in muscles and nerve centres. But with regard to many of the vegetable feeding races men- tioned we can now see that they would have had a much better record than they have, if they had known more about the poisons THBATMENT 889 in vegetable foods ; and I have no doubt that the future will demonstrate this fact to their great advantage. They would also no doubt have done better if they had not suffered more or less constantly from insufficient food (see facts previously mentioned). Hence it is easy for well-fed Europeans to sneer at the small natives of some parts of India : but prevent famine and conditions bordering upon it, and the record might be very different. And as I have shown in chapter viii., the small natives of India not very rarely beat Europeans both in strength and endurance. Lastly, there is the extraordinary and almost inexphcable fact that most of the advantages of a diet from the vegetable kingdom have been pointed out by one man after another for well on to three thousand years, and their words have apparently fallen on the almost absolutely deaf ears of the meat eaters ; from which we may perhaps conclude that the ingestion of these poisons blinds the eyes of its consumers to knowledge and wisdom, and prevents them from realising that they and their fellows are constantly suffer- ing many and terrible things for no reason. It is true, however, that this knowledge of the ancients was very imperfect, so that in running from one danger they must have often fallen into another. Hence, such success as can now be attained, is to a corresponding degree an exact measure of knowledge, but there is still plenty to do in improving both know- ledge and power. I should advise those who would like to know what diet may do in the matter of health, strength and power of endurance, both of body and mind, to read Mr. Miles' book " Muscle, Brain and Diet," previously referred to. It is practically a record of the effects of my diet by a patient ; and this diet shows that whereas he was diseased, he is now well, and that he has improved quite 50 per cent, in activity and endurance both of mind and body. His experience is a parallel of my own, but it is much more valuable because, being well known in the athletic world, his powers have always been on record, and he has won championships in America as well as in England. There can then be no doubt about his improvement, and that, as he himself points out, at an age when improvement in games is not generally met with. Among points of special interest in his record, I note the im- portance he attaches to the desire for stimulants as a sign of bad 890 UEIC ACID — CHAPTBE XVII health. Thus he says (previous reference, p. 30), " I can posi- tively assert that I consider my health to be not so good as it. should be, if I can even be induced to take stimulants at all." Now this is most certainly true, and there is nothing that I know of that would induce me to take a glass of wine, because its effect would be anything but pleasant, and it would promptly render me dull, morose, irritable and uncomfortable. And this has, I think, a simple physical explanation, for owing to my fruit and vegetable diet the alkalinity of my blood is high, and in that blood I have only a httle uric acid, and that in good solution with abundant alkali, so that my capillary reflux is quick and my blood pressure low. But throw a little acid into my circulation (and that is the- effect of a glass of wine), and the alkalinity of my blood is reduced, the solubility of that uric acid becomes less complete, it moves in the direction of the coUsBmic point and tends to blocking of capil- laries ; hence my capillary reflux slows and my blood pressure rises with the usual mental results of irritabiHty and depression. Wine also in those not accustomed to it tends to irritate the stomach and upset digestion, acting like the brandy in fig. 67, and causing irritability and depression in place of stimulation. We see, then, that uric-acid-free diet not only removes the desire for stimulants, it brings about a condition in which acid stimu- lants actually do harm and produce irritability and depression, I not only do not crave for a stimulant, but I hate it because it makes me miserable. As a result of this experience, I now rarely trouble to cut off stimulants in altering diet, as I know that most people who live as I do for twelve to eighteen months, will also learn to hate and avoid them. Then on p. 48 Mr. Miles says, " the better the ' condition ' I am in, and the better my games and work are, the more I feel errors of diet." This also is exactly my own experience, and the cause is, I think, very simple ; for we have seen above that uric acid inter- feres with its own solubility in the blood, and that uric acid is itself a stimulant, for its first efiect is to clear the blood of uric acid. Now it follows from this that the less the uric acid in the blood the more solvent power will the blood have for fresh uric acid, and the more quickly will any uric acid that is swallowed pass into the blood, combine with alkali and produce coUsemia. TREATMENT 891 Hence those who have got nearly free from any daily introduc- tion of uric acid are much more quickly affected by any chance error in diet causing fresh introduction, than those who are con- stantly introducing a little every day. And it is only those who, like myself, are nearly free from introduced uric acid, and have plenty of alkali available in the blood, who can test with any accuracy the quantity of uric acid or xanthine in any substance, as I have done in many of the figures in previous pages. Mr. Miles, it will be noted, includes pulses in his food list, and after what I have recorded of these in fig. 75 it may be a matter of surprise to some that he attained to such good results while taking them. But a reading of his book shows, I think, that, like myself up to the period of which I have given records above in reference to fig. 75, Mr. Miles did not eat pulses regularly or in any large quantity ; and at worst a little pulse once a day is a great improvement on meat, fish, fowl, game, eggs, tea, coffee and alcohol. Mr. Miles' result was a very great improvement in every direc- tion, but he has not attained, and indeed has not attempted to attain, to the greatest possible freedom from uric acid, and the best possible results of such freedom. With much of what he says as to the influence of diet on mental and moral conditions I most strongly agree, and I have quoted the parallel opinion of others in previous pages, and as I have pointed out in " Diet and Food," hfe, as a whole, assumes a totally different aspect for those free from coUsemia. On a diet of flesh and stimulants man becomes ever more and more selfish, till he is absolutely insane ; on a simple diet he becomes ever more simple, more natural, hardworking and unselfish. It would now be easy to add a considerable list of athletes who are constantly making records on diets such as those I advocate, but as I have gone into this subject at some length in speaking of training in " Diet and Food " (fourth edition, p. 94), I shall not take up space by repeating it here. It is now possible to say in a moment which athlete of any group is hkely to win, for obviously that man will win who has least uric acid in his blood, the most normal capillary circulation,- and hence the least friction in his machinery. A most interesting record of the experiences of herself and others with the uric-acid-free diet has now been given by the 892 UEIC ACID — CHAPTEE XVII writer of the well known " Pot-pourri from a Surrey Garden " ; in her " A Third Pot-pourri," * Mrs. C. W. Earle speaks out bravely and tells all whom it may concern what she thinks on the subject of diet. In my opinion it does indeed concern a very large number of people, and Punch, April 1, 1903, has been laughing about her advocacy of " vegetarianism " ; but what matters a few wrong names and a little laughter ? If once people begin to think about it, truth is sure to win, and reform will follow. The matter is now so very simple that anyone can see it, and a single glance at the capillary circulation will tell who is a meat-eater, and who is not. The quantity of uric acid in the urine can be made anything we like from 10 to 30 or more grains a day simply by swallowing or refraining from swallowing it, and the capillary reflux and blood granules can be made to move in any direction in proportion to the quantity ingested. When all these points have been realised and by use have become common knowledge, it will be seen how many names and theories of causation have been wasted over what are after all not diseases, but mere results of food poisoning, it not having been possible to see till now that one single poison accounted for them all. It will also be seen that if man had kept to the foods which Nature obviously intended for him this poison would have been avoided; and all so-caUed disease due to uric acid can be cured or prevented by simply omitting to swallow it, in flesh food which is unnatural, and iu tea a poisonous stimulant ; and the result can now be gauged and tested with that simple implement which was made before knives and forks, the point of the finger. * Smith, Elder and Co., 1903. 893 CHAPTER XVIII. Instruments and Methods. It is not my intention to devote space to a general considera- tion of instruments and methods ; I shall merely state shortly those I have used, with a few remarks as to what I think about them. Acidity of the urine can be estimated with a graduated solution of soda, of which 1 cc. = 6"3 milligrammes of crystalUsed oxalic acid, and a solution of phenol-phthalein, which gives a pink colour in alkaline solutions. Process. — 10 cc. of urine are placed in a small china saucer, and a drop or two of the phenol-phthalein solution added. The soda solution is then run in from a graduated pipette till a slight pink tinge is permanent. The amount of soda solution used is then read off, and multiplied by the number of 10 cc. in twenty-four hours' urine, and ' this worked out gives the total acidity of the twenty-four hours in grammes or grains of oxalic acid, and this is the way it is recorded in my curves. Urea. — ^For this I have used the apparatus of Dupre, which can be obtained from Messrs. Griffin and Sons, Sardinia Street, W.C. Its essential point is that the inner tube which collects the gas has two openings at its upper end, one communicating by a rubber tube with the reaction bottle, and another ending io a short rubber tube, which can be clamped just before using, when all the levels have been adjusted. I Ij The chemicals required are a saturated solution of caustic soda and some bromine, which can be obtained in glass tubes contain- ing the exact amount used (2'2 cc). Process. — Measiire 22'8 cc. of the soda solution, and place it in the reaction bottle. Drop in a bromine tube so that it breaks on coming in contact with the bottom of the bottle; remove, the broken glass, and mix the chemicals by shaking round and round. 894 UEIC ACID — CHAPTEE XVIII The result is a pale yellow solution, which is now ready for use, though if it is at all warm it should first be allowed to cool. Measure 5 cc. of urine into a small tube about two inches long, supplied with the reaction bottle ; place it gently with a pair of forceps inside that bottle ; adjust the cork in the bottle, and lower the inner collecting tube till the water stands at the line marked ; lastly, clamp the upper tube of the collecting tube. Now take up the reaction bottle, and incUne it to one side so that the urine in the little tube and the hypobromite solution mix, and continue to move the bottle from side to side for a minute or two till they are thoroughly mixed and the resulting effervescence is over. Place the reaction bottle on the table, and allow five minutes or so for it to cool, then raise the inner tube so that the water stands at the same level both outside and in, and read off the amount of gas on the graduations of the inner tube, which is so arranged that it gives, not the quantity of gas, but the percentage of urea which has been calculated from it. Say that the percentage on the tube is 1'5 ; this must be corrected for temperature and pressure, and the method of doing this can be found in any general work on physics. It is important to see that the bung or cork and the tubes fit well, and continue in good order ; this can easily be tested by raising the inner tube and clamping its openings when it is full of air ; it can then be lowered into the water, and if the fluid rises into it, gradually replacing the air, there is a leak, which must be found and repaired. Uric Acid. — The process originally described by Professor Hay- craft in the British Medical Journal, 1885, vol. ii., p. 1100.* Afparatus. — A water or mercury suction pump to be obtained from Grifiin or other instrument makers. A flask fitted with a rubber bung perforated in two places. A small funnel is fitted into one of these perforations, and an elbow tube into the other. The elbow tube communicates, by means of a rubber tube, with the suction pump, and the funnel is half filled with broken glass, the surfaee of which is shaken level, and then a pulp of asbestos. * Note.— This process will be found given in Hoppe-Seyler's " Handbuoh der Ohemischen Analyse," p. 359, .Berlin, 1893 ; Hammarsten's " Lehrb. der Physiolog. Chem.," 2nd edition, Wiesbaden, 1891 ; Neubauer and Vogel's " Analyse des Hams," last edition ; Sutton's " Volumetric Analyses " ; Sheridan Lea's work " The Chemical Basis of the Animal Body"; and other text-books of physiology. INSTBUMENTS AND METHODS 895 shaken up with water, is poured on to it, and the water allowed to run through while the suction pump is worked, till a uniform felt of asbestos J ineh thick has collected on top of the broken glass ; this is further washed by passing distilled water through it till the washings are clear of fibre, and then the filter with suction pump attached is ready for use. The other things required are several glass flasks of 100 — 200 cc. capacity, a 10 cc. and a 50 cc. measure glass, and several pipettes graduated to ^ cc. The following chemicals are necessary :* — Bicarbonate of soda. Strong ammonia sp. gr. '880. Ammoniated silver nitrate solution. Special dilute nitric acid. Ferric alum, a saturated solution. Centinormal ammonic thiocyanate solution. Strong solution of common salt (NaCl). Bottle of distilled water. All being ready, a sample of 25 cc. of the twenty-four hours' urine should be measured out and placed in a glass flask. Before doing this I always note the colour, clearness, specific gravity, and the acidity (as above) from the whole bulk. If there is a turbidity or a deposit of urates, and if, as is generally the case in these circumstances there is a high sp. gr., i.e., above 1020, I generally add to the whole bulk an equal volume of warm water which, as a rule, clears it completely. If in addition there is a deposit of red pepper crystals at the bottom of the collecting glass (and it is well to have a 3000 cc. glass jar graduated to 50 cc. and fitted with a bung for collecting the twenty-four hoiirs' urine), I generally warm the whole bulk of the urine, adding some bits of solid caustic potash (the acidity having been previously estimated) and shaking till it is clear that all the uric acid has passed into solution. A 25 cc. sample is then taken, and it must be cooled by placing the flask in cold water before proceeding. To this add bicarbonate of soda (Haycraft says 15 grs., Herman says 30), about 30 grs., or a trifle more, then 2 or 3 cc. of the strong ammonia, and about 2 cc. of the ammoniated 'silver nitrate solution. This last brings down a gelatinous precipitate of urate * These chemicals, with directious for carrying out the process, can be obtained from Messrs. Savory and Moore, 143, New Bond Street, W. 896 UEIC ACID — CHAPTEB XVIII of silver, and if there is much of it the fluid is quite thick, and rapidly comes to rest after shaking round the flask. If the patient is taking an iodide it will be necessary to add far more of the silver solution than the 2 cc. mentioned, but I will return to this point again. We have now a precipitate of urate of silver, together with silver not combined with uric acid in an alkaline solution ; the next process is to separate the silver combined with uric acid from that not combined with it. The liquid containing the precipitate is now thrown on the filter, and the suction pump put in action; the gelatinous urate of silver remains on the filter, the fluid passes through, and the urate on the filter is washed with distilled water till the fluid passing con- tains no trace of silver. The best way to ascertain this is to take two test tubes, and in one of them place 1 — 2 cc. of salt solution, and then pour into both test tubes some of the liquid passing through the filter. So long as the liquid in the tube with salt solution is distinctly more turbid than that in the tube without salt solution, more washing is required. When the urate precipitate is thus got quite clear of uncom- bined silver, the special nitric acid solution is poured over it filling the filter up to the top, and keeping it full for a minute or two by pouring a little more on as it runs down. As soon as all the nitric acid with the urate of silver in solu- tion has run through, fill the filter up with distilled water, and let that also run through, and we are now ready for the final stage of the process. Take the flask containing the urate of silver dissolved in nitric acid and water, detach it from the suction pump by removing the rubber bung. Add to the solution two or three drops of the ferric alum solu- tion (indicator) and run in from a graduated pipette the ammonic thiocyanate solution till a permanent pink colour is produced. Eead off the amount of thiocyanate used in cc, say it is 18 cc. ; then 18 X "00168 gives the amount of uric acid in 25 cc. of urine, i.e., •03024 grammes, and this multiplied by 4 gives grammes in 100 cc. = •12096, and this multiplied by the amount of urine passed gives the total uric acid for the twenty-four hours in grammes. When the urine contains iodides, the silver combines first with the iodide, and second with the uric acid ; in other words, till enough silver has been added to combine with all the iodide INSTRUMENTS AND METHODS 897 present urate of silver is not formed, so that if only the ordinary quantity of the ammoniated silver nitrate solution is added the amount of uric acid may be greatly under estimated. The best way out of this difficulty is to add at once 4 — 6 cc. of the silver solution, then to filter and add to the filtrate more silver solution and see if any more iodide of silver comes down ; if it does filter again, again add more silver ; when iodide ceases to form on the addition of the silver solution add 2 cc. of that solution and filter finally ; you will now get all the uric acid combined with silver and retained on the filter, and you can then proceed as before By this process, which I owe to the kind suggestions of Mr. J. . Saul, F.I.C., I have been able to obtain the same amount of uric acid from a urine both before and after the addition of an iodide. Hayciaft's process takes from thirty to forty minutes to complete ; longer for high sp. gr. urines, shorter for dilute, for much urate of silver clogs the filter and greatly increases the time required for the washing process ; so that time is saved by diluting high sp. gr. urines ; but when a urine of sp. gr. 1025 is diluted to 1 in 4 there is probably some increased loss of urate in the washing process, as the urate is not absolutely insoluble in water; on the other 'hand, the gelatinous urate clogs the filter and aids its own separation, which, up to a certain point, is more perfect the more there is of it. I think that Haycraft's process thus described, while taking quite a moderate amount of time, gives very accurate and constant results ; where there is any doubt I repeat my observation, and very rarely find a difEerence of more than J cc. of thiocyanate solu- tion between the two ; if there is a greater difEerence than this I go in for further investigation, and may find that a fragment of glass has perforated the asbestos and put the filter wrong, and when this has been put right I again repeat my observation. Though the process takes thirty to forty minutes to complete, a large part of that time it requires only an occasional look to add water when it runs through, and other matters can be attended to, and then if the suction pump is powerful, several filters can be connected with it and several urines worked through at the same time. It is, I think, a distinct advantage of this process that it can be worked on 25 cc, or even 12| cc, of a high specific gravity urine for when the urine of a single hour or less, which you may want to estimate in a case of headache, fits, or paroxysmal- hsemo- 57 898 UBIC ACID CHAPTBE XVIII globinuria, amounts only to some 20 or 30 cc, processes which require 50 or 100 cc. of urine cannot be used ; and it would by other processes often be quite impossible to estimate the uric acid in small quantities of blood, muscle, or other organs which can be done by this process. To estimate the uric acid in organs and tissues, I have used a process given by Salkowski and Luebe (" Die Lehre vom Ham," p. 94) for blood. It consists simply of throwing the blood or tissue finely divided (I pass solid tissues through a mincing machine) bit by bit into ten times its volume of boiling water. The coagulated albumen is removed by filtration or decantation, and the fluid evaporated down to about the bulk of the original blood or tissue. I then apply Haycraffc's process just as for urine (see remarks on p. 8). As I found that long boiling of tissues appeared to increase some- what the amount of uric acid obtained from them, I adopted the uniform plan of boiling for half an hour after all the tissue is in the boiling water. It is by this process that I obtained the results given in chap- ters ii. and xvii. When tissues contain uric acid visible under the microscope or to the naked eye, this process yields a very large quantity, and the final evaporation need not be carried so far. Supposing, however, that such great accuracy is not required, and that for clinical purposes all one wants to know is that a patient is passing about half as much uric acid again to-day as he was yesterday, or that the urine which was excreted at the time of a fit or headache or an attack of paroxysmal haemoglobinuria contains two or three times as much as that passed in the previous hour when these troubles were absent, this knowledge can be arrived at in a very few minutes and without much trouble. I have been pointing out now for several years that the urinary water is both from hour to hour and from day to day inversely as the uric acid excreted along with it ; so that by measuring the water from hour to hour we can estimate the greater or less amount of uric acid excreted along with it. If the water in any hour is twice as much as in the previous hour, the uric acid will probably be only one half of what it was or vice versd, provided there is some water in the body to be excreted, and provided there has been no haemorrhage, vomiting or diarrhoea to remove all the available water from the body. Taken over a long period of time, my lowest excretion of water is about 700 — 800 cc. in twenty-four hours, or about 30 cc. an INSTKUMBNTS AND METHODS 899 hour, and with this the excretion of uric acid in relation to urea varies from about 1—18 up to 1—25. On the other hand, my largest excretion of water is about 2000 cc, or about 80 cc. an hour, and this corresponds to a relative excretion of uric acid of about 1—35 to 1 — 45. In single hours the excretion may fall below 30 cc, or rise a good deal above 80 cc, but the urine is most scanty in those hours of the day in which the excretion of uric acid is greatest, and most profuse in those in which it is least (see fig. 3). If at any time when the urine is scanty there is a doubt whether this is due to coUsemia and retention of water {i.e., if there are no other signs of coUsemia being present), the blood should be examined, and if the scanty urine is due to coUifimia and reten- tion of water it wiU be found to be dilute (i.e., both haemoglobin and red cells will be relatively diminished), but if the scanty urine is due to want of water in the body, it having been removed by the skin or bowels, &c., then the blood will be concentrated {i.e., both haemoglobin and red cells will be relatively increased). In this latter case no inference can be drawn from the urinary water as to the presence or absence of collaemia. But bearing these things in mind, if at any time, as often occurs in the uric acid headache, epilepsy, or hysteria (see case records in chapter vii.), the urine is 30 — 40 cc. in one hour, and 100 CO. or above in the next hour, no fluid having meanwhile been swallowed, if the urea is estimated in both hours, one will prob- ably not be very far out if one puts uric acid as 1 — 20 of urea in the first hour and as 1 — 40 in the second, and precisely the same if the water fluctuation occurs in days instead of hours. For many clinical purposes, and when the uric acid excretion is not required in grains for publication, this is all that one wants to know, and I am in the habit of thus reasoning from the water to the uric acid in scores of cases which I should have no time to estimate ; making an estimation hers and there to support my inference, if there seems to be any reason to doubt it. Then again, as pointed out with reference to fig. 5, the differ- ence between the temperature in the mouth and that in the rectum will often give a very decided indication of the quantity of uric acid in the blood, and when this agrees with the record of the urinary water there is not much room to doubt. Lastly, the quantity of uric acid or xanthine present can be demonstrated in the blood itself (see p. 92) and the capillary reflux and the blood pressure will also tell of the quantity present, and 900 UJRIC ACID — CHAPTBE XVIII SO accurate are these records that quite small quantities swallowed intentionally can be seen as they pass through the blood (see fig. 75), so that in most clinical cases it is a needless waste of time and energy and a useless trouble to the patient to collect the urine at all. Blood Decimal. — I have estimated the cells and haemoglobin with the hsemocytometer and hsemoglobinometer of Dr. Gowers, and the decimal spoken of by Dr. A. E. Garrod and others as "worth," is obtained by dividing the percentage of haemoglobin by the per- centage of red cells, thus ^'^ '°"; ","j"°-,'°'"" if both are at the supposed normal (100), the result is a whole number, and not a decimal, but as this is only very rarely the case a decimal is generally obtained which represents the haemoglobin value of each red cell. This is as low as S or less — in chlorosis, and '6 to •? or above in more normal conditions (see also p. 574). From this decimal with daily observations a curve can be con- structed comparable with the curves of uric acid and urea excre- tions (see figs. 50 to 60 and 74). And with similar daily observations, it will be found that when there has been a diuresis both the cells and haemoglobin are increased as regards the given quantity, while, when fluid is being retained in the body (dropsy), they are both diminished as regards the given quantity, and the daily excretion of uric acid can be roughly estimated from these facts alone. But the greater or less quantity of water in the blood does not directly afiect the value of the blood decimal, though when excess of water is due to excess of uric acid (coUaemia), the blood decimal will be found to fall. A hsemoglobinometer and hsemocytometer have been brought out by Dr. Oliver, the inventor of the arteriometer, to be presently mentioned. The hsemoglobinometer is an adaptation of an instru- ment used commercially for determining shades of colour. It has to be used by the light of candles of constant power. The hsemocytometer depends on an observation by Dr. Oliver that the appearance of the reflection of the candle as a streak of light through a mixture of blood and diluting fluid in a special tube always corresponds with the presence of a definite number of cells, hence the tubes can be graduated in per cents, to correspond with the dilution required to bring out the streak of light. I have used both these instruments, and compared them with those of Dr. Gowers, and I find Dr. Oliver's hsemoglobinometer very useful in the dark days of winter, when one has to work by artificial light, but on the whole I prefer Dr. Gowers' instrument INSTEUMBNTS AND METHODS yOl when daylight is available. Dr. Ohver's hsemocytometer is easy to work with when you have got into the way of using it ; the results are fairly quickly obtained, and with care appear to me to come very close indeed to those obtained by counting with Dr. Gowers' instrumenb. Water in Expired Air. — I have estimated this by means of U tubes filled with calcium chloride ; each arm of the tube is about eight inches long, and has a diameter of Uttle less than one inch. It is closed at each end by a rubber bung perforated by a glass tube bearing a bit of rubber tubing and a glass mouth-piece on one end ; the rubber tubes are closed by spring clamps. The whole is carefully weighed before use and again afterwards, and the difference recorded equals the moisture in the expired air. It is used as follows : — Remove the clamp from the rubber tube at the far end of the U tube, and plaos the glass mouth-piece on the near end between the hps. Sitting quietly and comfortably, and when respiration is quite regidar, and the second hand of a watch is at a given place, begin to expire through the tube between the lips, inspiring through the nose ; the clamp on the near tube is to be opened at each expiration and closed at its end. After a Httle practice it is possible to continue to respire quite regularly, and to open and shut the tube at the right moment in each act. This is continued for five minutes by the second hand of a watch on the table, the clamp is then shut and the distal tube also clamped, and the U tube is ready to be weighed. I may say that Messrs. Savory and Moore kindly did the weighing for me, as I have no instruments sufficiently accurate. I measured the urine passed in fifteen minutes, including the five minutes of expiratory estimation, and divided the result by three to compare with the expired water in five minutes. The results show that when the urinary water is scanty owing to coUsemia, the expired water is also scanty, and this afEords the best proof that uric acid afiects the capillaries in the lungs as well as those in the kidneys and elsewhere throughout the body. Pulse Tension or Blood Pressure. — Apart from the signs to oe obtained by an educated finger on the radial artery, and an edu- cated ear at the apex and base of the heart, the sphygmograph furnishes a good cUnical record of arterial tension, and has this further advantage, that the tracing can be kept indefinitely for comparison with aU future tracings. By pulse tension one practically means blood pressure, or such 902 UEIC ACID — CHAPTBK XVIII blood pressure as results from blocking of capillaries on the one hand, and the pumping power of the heart on the other. There is no doubt that the sphygmograph is but an indifferent gauge of blood pressure, but it tells us what is clinically of far more value— the effects which obstruction of capillaries prodaoes on the heart and large vessels behind them; that, in two cases lying side by side, the actual blood pressure may be identical; but in one case, say, with a well-nourished and hypertrophied left ventricle, this blood pressure may be produced by a shght obstruction of capillaries, while it produces almost no effect, except a little slowing of the heart's action ; in the other case, with an ill-nourished heart, the pressure may be produced by very great obstruction of capillaries, while the heart is acting irregularly, palpitating and flutter- ing, in a word, faiUng and dilating before the peripheral resistance ; all this the sphygmograph will tell us with considerable accuracy, while to be told that the blood pressure is the same in these two cases is information of almost no clinical value. I have used the sphygmograph of Dudgeon, and have had one fitted with a pen, the invention of my friend, Mr. W. H. Symons, which I beheve to be a great improvement on the old point scratching on smoked paper. The pen consists of a little cone of metal, open at both ends, and threaded with a bit of cotton. The small end of the cone with the cotton below it rests on the paper, and is moved over it in exactly the same way that the old point was moved. The only thing to attend to is that the paper must be highly glazed and very smooth, to reduce friction, and then the pen runs over it perfectly, making curves which are identical with those obtained by the old process. The instrument thus modified, with directions for use, can be obtained from Messrs. Maw, Son and Thompson, London. The pen works best with a solution of aniline, a little of which is placed on the upper end of the little cone, and is conducted down by the cotton. In this way there is no limit to the number of tracings that can be taken, as paper after paper can be passed through the machine, so as to catch irregularities of the pulse, which only occur now and again, or a continuous tracing can be made on paper several feet long. The tracing is permanent from the moment it is made, and there is no black to rub off, and no fixing required, so that this useful invention renders the process both more cleanly and more expeditious, and is a great help to clinical recording. INSTRUMENTS AND METHODS 903 I have already mentioned Dr. Oliver's inventions — ^the arteriometer and the palse pressure gauge — to be obtained from Hawksley, of Oxford Street, and have said that I believe they may be found to be of very great clinical value for recording changes of blood pressure produced by uric acid, or by drugs which act upon it, and have given some instances in which this appeared to be so. My results, so far as they go, are very favourable to their accu- racy and the value of their records ; and it will be seen that I have used the arteriometer in several figures and elsewhere to obtain indications of blood pressure. One is no doubt liable to make errors with, the arteriometer by not getting exactly over the artery, which one may manage fairly well on one occasion and not on the next ; but this error is always on the side of making the diameter of the artery appear too great, so that the smallest reading to be obtained is the most correct, and the best way is to make repeated observations with the object of obtaining this. My results with this instrument gener- ally agree among themselves, like conditions yielding Kke results, and also with the changes in the rate of the heart's action and of the sounds at the apex and base. Of the three I regard the changes in the rate of action as the best guide in physiology, so constant and true is Marey's law ; but when all three agree there is not much room for doubt that the dianleter of the artery has been correctly measured. The sphygmometer mentioned in reference to figs. -38 to 43 and 75 is to be obtained from Messrs. J. and J. Hicks, of 10, Hatton Garden, B.C. The small form, price 30s., can easily be carried in the pocket. ' The capillary dynamometer also used for the same figures is to be obtained from T. Hawksley,- 357, Oxford Street, W., and he now makes it in a small form which can be carried in the waistcoat pocket, price 10s. 6d. With these two instruments we can tell all variations of the capillary circulation and the blood pressure, and -a great deal as to the cause of the variations. Thus a slow capillary reflux (i.e., more than five half seconds) with normal or low blood pressure, means a weak heart ; for the capillaries are obstructed, but the pressure is not raised because the heart is weak. This condition is met with in some forms of morbus cordis, especially where there is dyspnoea with heart weak- ness, in the heart failure of Bright's disease, and in post-febrile conditions after long fevers, such as enteric, when the heart has been weakened by the fever. 904 URIC ACID CHAPTEE XVIII As a rale, a quick capillary reflux is found with a pressure below 100 and means fever. And a slow reflux with a more or less raised pressure, in accordance with the strength of the heart, is found in all condi- tions of coUsemia, as dyspepsia, colic, Bright's disease, diabetes, obesity, post-febrile conditions, &c. The capUlary reflux is the guide to the amount of uric acid in the blood, and with the blood pressure, tells us the strength or weakness of the heart. Thus in myself a capillary reflux of six half seconds or above corresponds with a uric acid excretion of "6 gr. an hour and above ; while one of four to five half seconds corresponds with an excretion of -3 to -4 gr. per hour, and with very sUght variations this holds also for others ; and in Bright's disease, with a reflux of twelve half seconds, we get an excretion of -75 gr. per hour or more, and in fever, with a reflux of two or three haH seconds, we get an excretion of -25 gr. per hour or less. The reflux can also be slowed or quickened at pleasure by drugs that affect the quantity of uric acid in the blood, and it is mechanically quickened by local or general venous obstruction, as Eaynaud himself pointed out. The mean blood pressure is the point at which the column of fluid in the sphygmometer makes the largest excursion up and down, when it is pressed over the artery. It is necessary to get the instrument fairly over the artery, and to get a good movement of the column of fluid and to observe it in a good light. The capillary dynamometer has the advantage of giving a con- stant area of pressure and a known and measurable pressure, and time can be measured by the second hand of a watch or by counting half seconds, which it is easy to learn to do, or when at home by a metronome beating half seconds. Though such marked differences as Bright's disease on the one hand and fever on the other can be distinguished, at once with the point of the finger, it is better to use the more accurate capil- lary dynamometer and some measure of time when small differ- ences have to be estimated, as between the amount of uric acid in the blood of morning and evening, or the slight fluctuation of a little exposure to cold, a dyspepsia, or a httle mental depression ; but with these instruments the real fluctuations in the excretion of uric acid from day to day can be distingaished with very considerable accuracy, as seen in figs. .38 to 43 and 75. INSTRUMENTS AND METHODS 905 In very many, if not most, cases it is now quite useless to trouble the patient to coUect the urine, for the uric acid in the blood can be directly estimated in a few minutes from the capil- lary reflux or the blood granules ; and as regards hour to hour and day to day fluctuations this is quite sufficient ; while for longer periods the blood decimal is an absolutely certain index of the _ quantity of uric acid that is passing through the blood over days and weeks ; and the fact that a patient has not been quite faithful to diet during a holiday is often evidenced by a fall in the blood decimal which is visible on his return to town. INDEX. Abdominal tubercle, explanation of curative effect of incision for, 662. Aoid, citric, effect on flow of urine, acidity of urine, and blood pressure, 717, 718. Acidity of beer, 714. ,, cider, 714. „ „ fruit, 715. , , , , geneva and wbisky, 728. ,, ,, urine, 14, 21, 26. ,, ,, ,, curve of, 25. ,, ,, ,, effect on, of dyspepsia, 55. „ ,, „ „ „• fever, 28, 90-91, 221-222. ,, ,, „ „ ,, oxidation, 26, 52, 90-91. ,, ,, ,, ,, ,, perspiration, 52. ,, ,, ,, estimation of, method, 893. ,, ,, ,, meat, beer and wrine, produced by, 714-715. ,, ,, ,, urea, relation to, 14, 26, 51-52. ,, ,, wines, 714, 717. Acids : cold weatber, to be avoided in, 186-187. „ epilepsy, in, 316. ,, intravenous injection of, 341. „ oxidation and, 26, 90. ,, poison, considered as, 183-184. ,, salicylates and, given concurrently, 228, 460. ,, stomacb-aobe due to, 464. ,, swallowing and injecting, efiects of, 341-342. „ urate : excretion affected by, 51, 126, 180-182, 188, 275, 322-323 ; solubility affected by, 176, 183. ,, wasting disease, in, 257. Ackermann, Dr., on the etiology of epilepsy, 313-314. Adenoids and the uric acid diathesis. Dr. MacMe on, 433. Age, efiects of, on difierences between gout and rheumatism, 775. ,, ,, ,, formation of urio acid and urea per lb. , 775. „ ,, „ suicide, 332. ,, ,, ,, uratic arthritis, 775. Agostini on the gastric juice of epilepsy, 284. Aitken, Dr. Crawford, case of Raynaud's disease with ursemia, 501. Albumens : body weight, relation to, 834, 835, „ diet, required in, 831, 836, 852 ; effects of taking too much, 842, 843; too little, 830-831. , , perspiration and saliva, in, 600. ,, urea, relation to, 205-206, 834. ,, uric acid excretion and, 129. Albumens of the blood, 577 ; excessive difiusibility of, in Bright's disease (hetero- albuminsemia, 581. Albuminuria : age, influence on, 597. ,, blood changes, relation to, 297. ,, boys, of, 587. ,, causation of, 576-577 ; by coUsemia, 577, 592 ; where theories of, fail, 585. ,, diet and, 580. ,, dyspepsia and, 577. INDEX 907 Albumin ria : epilepsy and, 297. „ functional at first, 577. ,, glycosuria and, parallel causation, 582, 675. ,, headache and, 297, 575. 1, hetero-albuminsemia, proportional to, 583. ,, kidney lesion, -not proportional to, 580, 583, 589. ,, meals and, 586. ,, morning hours and, 586, 587. „ post-febrile, 339-340, 591 ; its relation to Bright's disease, 340. ,, urea excretion and 592, 611, 612. Albuminuric retinitis, effects of diet upon, 646. Alcohol, acid action of wines diminished by, 723. ,, acidity of urine, efieot on, 722 ; explanation of, 723. ,, circulation, efiect on the, 399 ; Marey on, 214. ,, stimulant action of, when meat fails, 111. , , uric acid, afiected by, not the abdominal sympathetic, 214 ; excretion of, increased, Professor Vaughan Harley on, 722. Alcoholism, diet and, 336-337, 875. , , increase of, 408. ,, suicide and, 332. „ treatment of, 336-337. Alkalies, action of, proportional to the uric acid in blood, 343, 377-378. ,, blood and. brain, effect of, on, 341. ,, bromides and, in epilepsy, 313. ,, bronchitis, in, 446. ,, chronic gout, in, 738. „ excretion of water from the lungs diminished by, 417. , , headache, in, effect of dose, 184. , , lithia contrasted with the effect of other, 197. ,, meat-eaters cannot take, with impunity, 850. , , salicylates and, cause retention, 182. „ solvent action of, on urates, 39, 126, 176, 179-180, 182, 183, 188, 192, 274-275. „ value of, in cold weather, 186-187. Alkalinity of blood, 39-40, 90 ; diminished, 420 ; increased, 428 ; relation to acidity of urine, 39-40, 90-91. Alkaloids in urine, relation to excretion of urates, 296, 303, 399. Almonds, quantity of albumen in, 835. Alopecia, a post-febrile symptom, 505. American spirit weed, 199. Ammonium : effects on acidity of urine, 548, 761 ; rheumatic fever, 761. ,, solubility of its urate, 800. Amnesia, causation of, 264. Amyl, nitrite of, reduces blood pressure, 395. Aniemia, alkaloids in urine of, 567. , , artificial production of, 156. causation of, 9, 517, 519, 631, 556, 567, 568-569, 573-574; conclusion as to causes, 573-574 ; from the effects of urates on the spleen, 557-558 ; shook or chill during menstruation, 562. diet, efiect on, 561, 571, 885. fevers, of, 558. hot climates, of, 560. malaria and, 558. menstruation and, 561-562. pernicious excess of uric acid in, 552, 568-569. relation to, bilious attacks, 551. ,, development of girls, 556, 561. ,, dyspepsia, 138, 567. ,, melancholia, 3^3. salicylates in treatment of, 518, 571. summary of facts concerning, 563. treatment of, 518, 569, 571. Anderson, the late Dr. J., on intraocular tension and high blood pressure, 223. Aneurysm, 136. Angina, asthma and, 422. 908 INDEX Angina, causation of, 221, 655. ,, glycosuria and, 653. Mays, Prof., on, 655. ,, migraine and epilepsy, resemblance to, 656. ,, morning hours, why worse in, 294, 655. Animal food, efteots of living on, 160, 554, 825. ,, ,, quantity necessary for nutrition, 828. ,, ,, uric acid, quantity contained in, 726, 827, 828. Antimony in migraine, 267, 345. Antipyrin, 68-69, 195, 429 ; action in curing a uric acid headache, 69, 268 ; as a cardiac depressant, 268. Anuria, absence of ursemic phenomena in, 315. Aphasia due to collsemia, 264. ,, Sir W. H.Broadbent on its causation, 264. Apoplexy, pulmonary, case of fatal, 565. Appendicitis, causation of, 454-455, 467. ,, Chinese, rare among, 475. ,, pathology of, 457. ,, plumbism and, 458. ,, surgical treatment of, not always satisfactory, reason why, 475. ,, treatment of, 474-475 ; by salicylates, 466, 474. Apples, value of, in diet, 344, 715. Apsley House, Slough, Bucks, practical instruction in foods at, 837. Argyria, 316, 461. Arterial tension, see pulse tension. Arteries, causation of atheroma and degeneration of, 218-219. -Arterio-solerosis, 205. Arteriometer : lessened range of postural variation in advanced life, 205 ; its explanation, 205. ,, morning and evening readings, 205. ,, posture effects due to gravity, 203. „ sphygmograph and, similar effects of postural change on both, 203, 204. Arteriometer of Dr. Oliver, 202 ; serves to demonstrate the effects of uric acid, 205 ; shows that the higher the blood pressure the more dilated is the radial artery, 204, 216. Arthritis accompanied by nephritis, 614. „ diagnosis of, 703-704, 741, 810. gout, of, 127-128, 692. ,, influence of external causes, 731. „ menstruation and, 141, 550. „ rheumatism, of, 692. ,, salicylates and hot pack produce. Dr. Cowen on, 797. ,, treatment of, 812, 820. uric acid relation to, 161, 556, 574, 741 ; reacts to conditions that affect solubility of uric acid, 694. Artificial plus excretion of urates, 7, 103, 106. , , uratic arthritis resembles rheumatism, 692. Asparagus, xanthine in, 825, 861. Aspirin, 814. Asphyxia a cause of coUsemia and convulsions, 294-295. Asthma : acid fumes, action in, 429. ,, antipyrin, action in, 429. ,, bad air and, 428. ,, causation of, 137, 429. certain hours relation to, 294, 415-416, 422 , , compressed air in treatment of, 426. diet and, 415-416, 423, 429, 430. ,, diuresis following attack of, 416. ,, dust and, 428. dyspepsia and, 423. ,, epilepsy and, 294, 426. ,, gout and, 413, 422. ,, iodides, action in, 428, 429, 430. ,, meals and, 415. INDEX 909 Asthma : nasal troubles and, 426, 428, 433. phthisis and, 424, 425. position, effect on, 423. pregnancy and, 416. skin diseases and, 426. tobacco and lobelia, action in, 429. treatment of, 429. uric acid and, 135, 413-417, 420, 422, 423. Asthenia of coUsemia, 406. Atheroma, 136. Athletes find meat bad for training, and why ? 407. Atropine, action in relieving stomach pain, 469. Attlee, Dr., cases recorded by, 596. Auditbry centre, efieots of collsemia upon, 264. Auerbach, Dr., alkalinity of blood in carnivora, 83-84. Author's researches on excretion and results obtained, 16-18, 78, 82. Autumn and winter correspond to evening and night, 31. Bad temper, the effect of high blood pressure on intracranial circulation, 137. Banks, Sir W. M., on cancer and food, 462. Barker Smith, Mr., on chalk in diabetes, 689. ,, ,, chloride of ammonium as a precipitant of uric acid in blood, 92 ; author's results with his process, 93-99. Barnard, Mr., on the function of the pericardium, 748. Barnes, Dr. , on phthisis and pregnancy, 426. ,, ,, suicide and menstruation, 340. Bastain, Dr., on amnesia, 264. Bathing, syncope during, 213. Becker, Dr., on salicylic acid in pneumonia, 444. Beef, aUoxur bases in, 119. ,, Englishman's, not a source of power or endurance, 870. ,, Liebig's extract of, effect on uric acid excretion, 112, 119. Beef-tea : ansemia, effects in, 542, 543. „ epileptic fits, effect on, 308, 309. „ stimulant action of, 123. „ uric acid in, 542. Beer, acidity of, 714 ; harmless when there are no urates, 766. Belladonna, action of, the ireverse of that of opium, 46, 47, 342. ,, effects common to drugs which increase the excretion of uric acid, 47. ,, epilepsy, in, 287. ,, pulse and blood pressure, efiects on, 47. ,, uric acid excretion, efiects on, 47. Ben Nevis cold, 410-411. Berkhart, Dr., on gouty tophus and sarcoma, 461. Berlioz and Yvon, MM. , relation of uric acid to urea, 3 9. Beyts, Captain, 653. ,, ,, on the treatment of pneumonia, 445. „ „ ,, „ Arthritis, 817, 820. Biernaoki on the causation of hysteria, 290. Bile intoxication, a cause of bradycardia, 211. Bilious attack, 423, 469. ,, headache, 272. Biliousness is collsemia, 253. Birds, presence of uric acid in blood of, 555. '. Black, Dr., on gout of the fibrous tissues, 431, 436. Blackwater fever : chlorate of potash, effects and, 524. ,, ,, hiBmoglobinuria and, 520. ,, ,, quinine and, 521, 523, 525 ; and effects of quinine, 524 ; action of quinine in producing, 525. „ pathology of , 520, 525. Blood, acute rheumatism in, 75. alkalinity of, 39-40, 53, 90-91, 371. ^-'-^ INDEX Blood, alkalinity, cold diminislies, 186. >> ,, diet, relation to, 40. >. „ fevers, relation to, 40, 78, 90-91. .1 11 solubility o£ uric acid depends on, 187-189. ,, „ time o£ greatest, 184. ,, circulation of, efiects of uric acid on, 112, 167, 173. ,, coagulation and tlirombosis, 564 ; Sir J. Fayrer on, 565. ,, decimal : age, influence on, 331. ,, ,, card for practical use, 573. chlorosis, in, 541, 543, 545, 546, 570. , , , , colour card for estimation of, 573. ,, ,, Curves: beef -tea, cafieine, &c., showing effects of, 541, 5i3. ,, ,, ,, case of myxcsdema fed on thyroid, 549. ,, ,, „ hour to hour, 537. ,, ,, index of uric acid excretion, as, 533. ,, ,, ,, uric acid excretion, showing relation to, 9-10, 533, 535, 639. ,, ,, diurnal fluctuations, 539 ; control of, 539-40. ,, ,, examination of, instead of urine, 573. , , , , index of uric acid in Mood, 673, 905. ,, ,, menstruation, relation to, 157-158. ,, ,, method of obtaining, 533. , , , , normal conditions, in, 533. ,, ,, uric acid, relation to, 156, 570. ,, decomposition of, through fatigue, 400. ,, destruction and the spleen, 557 ; and uric acid, 530, 569. ,, diet, efiect on the quality of, 441. ,, diseases of, due to collaeniia, 135-136. ,, epilepsy, of, 297. ,, gout, in, 77, 81, 100. ,, granules : alkalies, effect on, 377-378. „ ,, drugs, effects on, 97. ,, ,, disease, effects on, 81. „ „ index, the quantity of uric acid in blood, 10, 99-100. ,, ,, method of estimation, 92, 95. „ ,, relation to blood pressure, 174. II 11 I, capillary circulation, 10-13. 11 ,1 ,1 uric acid iu urine, 10, 96-97. ,, pressure, age and, 247-249, 328. ,, ,, Brigbt's disease in, 199-200. ,, „ capillary reflux and, 234-236. ,, ,, cardiac disorders due to, 209-210, 393, 394. „ ,, changes in, in treating chorea, 807. ,, ,, coUaemic point, time of, 184. ,, ,, control of, 290. ,, ,, crimes and, 155. ,, ,, deep breathing lowers, 150, 210. „ ,, diet and, 228, 236, 237. ,, ,, disease, relation to, 234, 245. 5. I. diuresis of Bright's disease due to, 199-200. ,, ,, drugs and, 234. ,, ,, fits and, 206, 314. ,, fluids and, 228-229, 262. „ ,, Graves's disease, in, 146, 147 ; as the cause of Graves's disease 142, 144, seg[. ' ,, ,, headache and, 150-161, 271. „ ,, high: causes of, 224, 392. effects of, on the heart, 394 ; on the lungs, 421. eye symptoms and, 223. insomnia and, 324. not due to contraction of arteries, 215-216. pulse tracings of, 213. masturbation and, 154. menstruation, during, 142. mental excitement, delirium and mania in 349 INDEX 911 Blood pressure, mercury and, 194. nioriimg and evening variations in, 169. opium and, 195 ; an opium-eater's experiences, 155. pain, effects on, 391. posture, efieots on, 203-204. prominent eye and, 145, 149, 150-151. radial diameter, relation to, 208. rate of heart's action controlled by, 169. reduction of, 150, 262, 267. results, 247. sexual appetite and, 154-155. temper and, 261. temperature and, 241, 242. temporary insanity and, 154-155. uric acid and, 185-136, 187, 164, 172, 190-192, 217, 224, 302, 899. urine, excretion of, and, 170-171. vascular degeneration and, 218, 221, weather, relation to, 289. serum, behaviour towards uric acid, 179. ,, uric acid in, 10, 18, 21, 36, 73, 88, 92, 94, 95, 156, 162, 169, 178-174, 215, 904 ; measured by difierenoe in temperature of mouth and rectum, 36 ; relation to quantity in urine, 73, 88 ; amount dependent on its solvent power, 124-125. ,, vessels : diseases of, due to ooUaemia, 136. ,, ,, mechanical obstruction of, 187. Bouchard, M., on acids as digestion products, 52. ,, ,, causation of rheumatism, 776. „ „ gout, 457. Bracing climates, 411, 436. Bradycardia : angina, relation to, 212. causation of, 209-210. definition of, 226. fatigue of, 212. menstruation, of, 157. nervous system and, 209, 211. physiological and pathological conditions associated with, Prof. Biegel on, 207, seg^. pneumonia, after, 339. post-febrile, 208-209, 339. strong and robust, in, explanation of, 209, 339. Brain : blood supply of, effects on, of acids and alkalies, 841. opium, 342. „ „ „ „ uric acid, 222, 323. ,, fever of the drama, Mr. Hope Lewis on causation of, 754, s«g. ; indica- tions for salicylates in, 757. ,, softening of, pathology and treatment, 356. Braithwaite, Dr., on salt in diet as a cause of cancer, 463. Brass-workers' ague, 454. Bread-stufis, classes of, 837. ,, nourishing properties ^f different breads, 836. ,, xanthine in, 835, 861. Breathing exercises tend to reduce high blood pressure and obesity, 150. Bright's disease : alkalies, value of, in, 185. alkalinity of blood in, 133. blood decimal in, 624 ; effect of drugs on, 615-616. ,, pressure in, 396. cases of, 692, 605 ; cured, 611, 612, 614 ; where drugs failed, 617. causation of, 388 ; due to poisoned blood, 580. chronic bronchitis and, 421. clothing and climate and, 640. coUsemia, relation to, 135, 205. defective combustion, a name for, 619, 634, 638, 648. diet and, 63S, 639. dyspepsia and, 577; Dr. Tirard on, 577. etiology of, 579, 588. 912 INDEX Bright's disease : exercise and, 639. ,, fevers and, 603, 636. ,, headache as a guide in treatment, 648. ,, heart failure in, 388, 619, 621, 627. ,, increase of, 461. ,, influenza, following, 565. ,, Labadie-Lagrave, Dr., on, 581. ,, Mahomed, late Dr., on, 579 ; pre-albuminuric stage of, 580. ,, meat eating and tea drinking, due to, 639. ,, migraine and, 268, 575, 685, 648. ,, pre-albuminuric stage of, 580. ,, pregnancy and, 621. ,, prevention of, 648. , , previous vrritings of author on, 579. ,, prognosis of, 642. ,, pulse of, 201. ,, purpura and, 506. ,, Semmola, late Prof., on, 580. ,, skin troubles in, 443, 506. ,, suicide and, 333, 340. ,, thirst not felt in, 201. ,, theoretical connections and explanation, 635. , , thrombosis and, 565. ,, treatment of, 635, 643; by diuretics, 645; their real action, 645 ; by mercury and salicylates, 643. ,, uric acid in blood in, 565. ,, urine, excretion of, in, 192-201. Broadbent, Sir W. H., on aphasia, 264. causation of epilepsy, 287. dilatation of heart, 213, 386. insomnia and high tension, 323. mental depression and melancholia, 206, 324. pulse of menstruation, 258, 340. uraemic convulsions, 206. Bromides and alkalies in epilepsy, 313. Bronchi, gout of, 135, 480. ,, „ causation and cure, 843, 844-847. ,, ,, excretion of uric acid before and after, 842. „ ,, gout of intestines alternating vrith, 846. „ ,, symptoms of, 844. Bronchitis, causation of, 421. ,, common cold and, 410. ,, effects of drugs on, 412. „ milk diet in, 435, 437. ,, treatment by salicylates, 434, 442, 443, 444 ; by tar and similar drugs, 198. • Bronzed diabetes, causation of, 666. Brooks, Dr., on salicylates in diabetes, 681. Brovm bread, xanthine in, 861. Browne, Sir J. Criohton, on dreamy mental states, migraine and epilepsy, 310. ,, Dr. Sinclair, on efieots of meat eating, 884. Bruce, Dr., on coUsemia and aouteness of vision, 232. Brunton, Sir T. Lauder, on action of, digitalis, 171-172; erythrophlgsum, 171-172. ,, ,, „ blood pressure and excretion of urine, 171. „ ,, ,, causation of Graves's disease, 145; headache, 259. „ ,, „ kidney circulation, 171. jj „ ,, large spleen and urate calculi, 49. „ „ „ oxalates, production of, 566. Buck, Mr. A. H., on urea in tuberculosis, 439. Buckler, Dr., on "rheumatic leucoinitis," 430; its relief by salicylates, 434- cases where salicylates may fail and author's explanation of, 436. ' Burnett, Dr. G. S., on melancholia, 323. Butter in diet, 839. INDEX 913 Buzzard, Dr., on vertigo, 268, 264. CafEeine aHeots the blood like urio acid, 117. ,, oardiao stimulant, as, 193. ,, chemical composition, 107, 117. ,, equivalent to uric acid, 8-9, 544. ,, headache, should not be used in, 826. ,, swallowing, effect of, 115, 117. ,, xanthine group, a member of, 117. Cairo, diet and disease in, 463, 885. Calcium chloride in Graves' disease, 143 ; treatment of skin troubles, 511. „ diabetes, a cure for, 689. ,, solubility of its urate, 59. „ water in (Dr. G. Thin), a cause of gout, 59. Calculus, causation of, 49, 127, 256, 267, 879. ,, India, in, Freyer, Mr. , on, 881. ,, ,, Homestead, Surgeon-Major T., on, 884. ,, ,, native vegetarians suffer, reason of, 881. ,, ,, Roberts, Captain, on, 880, 882, 888. ,, prevention of, 880. ,, ratio of women to men, 888. ,, relation to gout, 256, 888 ; rice eating, 880, 882 ; wheat eating, 880, 882. ,, treatment of, 880. CaJomel, action of, 343. „ asthma in, 429. ,, cold, use in, 436. „ diabetes, in, 681. „ epilepsy, in, 315. „ excretion of urates, effects in, 66, 364. „ gout of intestines, a cause of, 451-452. ,, headache, during attacks of, 284. „ insomnia, in, 324. Cancer a disease of the vigorous, 463, „ food and, 461, 462 ; Mr. Roger Williams on, 461, 463 ; Sir. W. M. Banks on, 462, 468 ; Sir. W. MacGregor on, 462. „ headache, relation to, 269. „ " highest on record" death-rate and its associations, 461. „ occupations and, 462. „ potatoes a preventive of, 462, 463. „ salt a factor in causation, 463 ; Dr. Braithwaite on, 463. Cannabis indioa, blood pressure lowered by, 199. ,, melancholia cured by, 198. ,, meuorrhagia, in, 199. , , migraine cured by, 198. ,, stimulant action of, 198, 199. „ urio acid, action on, 103, 198. CapiUariea, obstruction of j asthma caused by, 429. ,, ,, coUsemia, by, 175, 184; effects of cold and heat on, 182, 188. ,, ,, drugs no direct relation to, 207. „ ,, mechanism of production, 173-174, 178. ,, ,, results of, 164. ,, ,, varies as uric acid in blood, 138, 134, 171, 207, 384. Capillary circulation, diet effects on, 237. „ ,, drugs, effects of, 162, 238, 240. ,, ,, measurement of, author's attempts, 231, seq. ; instrument for, 233. „ ,, morning and evening, 169-170, 233, 285, 287. ,, ,, Raynaud's observations on, 232-233. „ ,, temperature effects on, 235-236, 241. ,, ,, weather effects on, 288, 239. ,, dynamometer, where obtained and how to use, 903-904. ,, reflux, causes quickening, 246. „ „ children, in, 287, 245. 68 914 INDEX Capillary reflux, constant relation to blood pressure, 234, 235, 236. ,, „ dyspnoea, in, 245. ,, „ fever, in, 243, 245. , , , , index of — circulation of the body, 247 ; nutrition and oom- bustion, 604; uric acid in blood, 446, 447, 700, 899, 904, 905 ; uric acid fluctuations, 573. ,, „ shook, in, 406. Carbuncle, pathology of, 441. Carcinoma, chronic collsemia due to, 256. „ chronic irritation by uric acid and, 461 ; Mr. D'Arcy Power's writings on, 461. Cardiac muscle, effect of diuretin on, 193. Carnivora, alkalinity of blood in, 84 ; chloroform effects on, 395. Carotid, compression of, in convulsions, 315. ,, „ in headache, 262. Cataractous lenses, do they contain uric acid, 81-82. - Catarrh : chlorides and iodides, of, 443. ,, contagious disease and, causation of, 135, 412 ; effects of salicylates in producing immunity, 442. „ liability to its indirect evil effects, 440. ,, liquorice in, 198. „ menstruation and, 141-142. Catarrhal inflammation of fibrous tissues, Dr. Buckler on the characteristics of, 486. Caton, Dr. E. , on the treatment of endocarditis, 815 ; Dr. Fisher's criticism of, 789-790. Cerebral degenerations, 136. ,,. hEemorrhage, 135 ; increase of, 461-462 ; treatment, 318-319, 647. Chambers, the late Dr. King, on vascular tension, 224 ; epilepsy, 286. Chapman, Dr., on causation of cardiac irregularities, 214. j. Charcot on epilepsy and migraine, 293. Charles, the late Dr. Cranstoun, on intermittent albuminuria, 600. Cheadle, Dr., on liability of girls to rheumatism, 556. Child, relation of surface to bulk in, 776. Chinese, appendicitis rare among, 475. „ • food and strength of, 870. „ immunity from chloroform syncope among, 398. ,, urine used medicinally by, 123. Chlorides, 51. Chloroform, ansesthetic, contraindications to use as, 404. ,, parturition, safe in, 397. ,, post-partum, dangerous, 397 ; Dr. Rushton Parker on, 397. ,, syncope, alkaloids in urine and. Prof. Poohl and Sir Lauder Brunton on, 399. .. 1, frequency in Edinburgh, India and London, 398. „ ,, Kirk, Dr., on, 388, 398. .. 1, nitrites produce similar effects, 396 ; may be employed to test the danger of, 399. " ,1 Wilson, Dr., on, 389; author's explanation of one of his cases, 391. ,, why followed by syncope, 388. Chlorosis, blood decimal curves in, 541, 543, 545, 546, 570. „ case after a year on diet, 572. ,, causation of, 551, 556. ,, diet, cured by, 569-671. ,, dyspepsia and bilious attacks, relation to, 551, 662. ,, increase of, and reason of, 564. ,, iodide of mercury, cured by, 646. „ iron, beef-tea and alkalies, effect on, 641. ,, „ ,, „ caffeine „ ,, 643. ,, treatment of, 569-671 ; best way to treat, 671. ,, uric acid, effects on, 545. Chorea : blood pressure, relation to, 806, 807. ,, Churton, Dr. , on, 807. INDEX 915 horea, oollsemia may be a, result of, 135, 498, 805 ; case to illustrate relation to weakness of heart, 806. drugs, effects in, 804. girls, more frequent in, reason, 498, 806. Handford, Dr., on, 803. Kirke, Dr., theory of causation, 805 ; as modified by the author, 805. migraine parallel with, 293, 803. rheumatism, relation to, 803. salicylates, action in, 804. Sturges, the late Dr., on, 808. Cider, acidity of, 714 ; effects on acidity of urine, 714 Circulation, cerebral function and, 121. brain, and high arterial tension, 137, 259 ; effect of drugs on, 267. conditions allowing of subnormal blood pressure, 349. lungs, in, 420. mercury, effect on, 226-227. migraine and, 214-215. prominent eye and obstruction of, 149. relation to time of life, 247-249, urates in the blood and, 10, 135-136, 137, 170, 175, 215, 217. Cirrhosis, 135. Clarke, the late Sir Andrew, on arthritic haemoptysis, 218; phthisis and gout, 424, 436. Climate, gout and, 651. ,, suicide and, 331. „ uric acid precipitation and, 640. Clothing, 851. Clouston, Dr., on meat craving in children, 402. Cocaine, abuse of, how contracted, 335. ,, action of, 63, 343 ; resembles that of morphine, 63, 64. ,, curves showing effects on uric acid, 62. ,, fatigue prevented by, 359. ,, gout of the intestines and, 452, 455. ,, stimulant when meat fails. 111. Cocoa, stimulant action of, 123. Cold, a common, causation of, 410, 412, 421, 434-435 ; effect of a purge oh, 412 ; treatment of, 436. ,, antagonised by low diet, 641. „ arthritis due to, 190, 641, 808. ,, bracing climates and, 411. ,, Ben Nevis and, 410. ,, oollsemia and, 186. ,, morning bath and afternoon depression, 325. ,, origin of, 412. Colic : abdominal, recurrence of, in women, 159. „ pathology of, 468. „ production of, by copper, 454. „ „ „ lead, 56, 451, 453, 454. „• „ „ mercury, 66, 451. „ „ „ zino,"69, 451, 454. ,, treatment by salicylates, 452, 453, 473. Colitis, causation of, 454, 467. CoUsemia: alkalinity of joints, effects on, 775. „ anaemia and, 517. ,, artificial glycosuria in lead colic and, 666. „ ,, production of, 89, 128. „ auditory centre, effects on, 264. ,, arteries, effects on nutrition and structure of, 218-219. „ bradycardia and, 207, seq. „ Bright's disease, effects in, 200-201. „ capillaries, effects on, 126, 133, 207. „ causation of infectious diseases and, 412. „ characteristics of, 136. chorea due to, 145. 916 INDEX Collsemia : ciroulatiou, effects on, 126, 133, 215. ooUsemic point, and the, 176, 184, 274, 294. congestion of liver due to, 651. contagious disease faivours the onset of, 441. definition of, 30 n., 175. diet, effect on, 205. digestive disturbances and, 211. diseases subsidiary to, 135-136. dyspepsia and, 428, 449. epilepsy and, 206, 314. exercise and, 37. fluctuations in, 330. measured by temperatures in mouth and rectum, 36, 308. obesity and, 867. paralysis, case of, due to, 597-600. physiological, 205. piles and pruritus ani due to, 652. post-febrile, 339, 388. prominent eye an index to, 151. precipitation by cold, 175, 186. production of, 125. Eaynaud's disease and, 495, 497. solubility and introduction, a matter of, 125. solution of, by increasing alkalinity, 176, 178, 185-186; rising temperature, 182, 183. stasis and thrombosis due to, 565. suicide and, 325-327. syncope and angina due to, 218, 221. toxicity of urine and, 399-400. uric acid in urine, corresponds with excess of, 125 ; except in nephritis, 125. CoUoid uric acid, see Uric acid in colloid form. Combustion, failure of, 684, 638 ; due to ooUaemia, 634 ; in lead colic, 666. ,, heart muscle, relation to, 672. „ how to test, 206, 671. ,, microbic diseases and, 639. ,, urea and, 670. Conception rate and uric acid, 156. Constipation and diet, 337, 840. Control of uric acid inevitably controls disease, 825, 856. Convulsions : bottle-fed infants, of, 315. ,, causation, 294. ,, coUaemia and, 135. ,, headache and, 294. ,, morphine in, 318. ,, puerperal, 206. ,, ursemio, 206. Cooling tub water prevents salivation by mercury, 644. Copaiba, how it causes diuresis, 102, 197 ; other .drugs which act in the same way, 102, 197. Copper, see Colic. Cowen, Dr., on arthritis produced by salicylates and hot pack, 797. Craig, Dr. M. , on blood pressure in the insane, 349. Cramps, 135, 139. Cretinism and mental depression in the mother, 399. Crime, increase of, 408. Crosse, the late Dr. W. H., on " blaokwater fever," 521. CuUen, his observations the best guide in treatment, 864 ; quoted by Sir A. Garrod in reference to effects of diet and labour in gout, 557, 728. " Curare diabetes " parallel with uric acid acid diabetes, 656. Daily fluctuations of blood decimal curves, Dr. Edgecombe on, 539, 541 ; author's results, 540 ; can be controlled, 641 ; due to uric acid, 540, 541 ; effects of exercise on, 540-541. Davies, Dr., on drugs in skin diseases, 505. INDEX 917 Day terrors in children, 310 ; relation to epilepsy, insanity and hysteria, 310 dyspepsia, 310. De Quinoey on opium in phthisis, 440. " Dead hand," 135, 494. Deep breathing, palpitation relieved by, 210. Degeneration, Max Nordau on, 408. ,, tabes, of the cord in, 356-857. Delirium, relation to blood pressure, 349-351. Dengue, myalgio pains of, their relation to exercise, 753. Development of boys and girls, curve of, 553 ; efiect on formation and excretion of uric acid, 557. Dewey, Dr. , author's results with his treatment, 854 ; author's modification of his treatment and its use, 855 ; on starvation by overfeeding, 856 ; work on diet, 852. Diabetes: Bright's disease and, parallelism between, 685. ,, bronzed, causation of, 666. ,, cures recorded by chalk, 689 ; restricted diet, 690. ,, degenerations associated with, 218. ,, high blood pressure in, case of, 653-654 ; theoretical connections 652. ,, mellitus alternates with gout, 651, 682. ,, ,, cases of, 671 ; severe, 675. ,, ,, efieots in, of acids, 657. „ „ „ antipyrin, 659. „ „ ,, fevers, 659-661. ,1 ij I) opium, 659. ,, ,, ,, salicylates, 658, 681. „ „ ,, surgical operations, 659, 661. ,, ,, ,, water containing sulphates, 657. „ ,, liver conditions in, 650, 651. ,, ,, migraine as the final ending of, 682, 685. „ ,, rheumatism and, 657. „ ,, salicylates diminish sugar not urea, 681. „ ,, treatment of, 686, 877. „ possibility of a urio-aoid-free diet for, 686-687. ,, uranium nitrate in, action of, 688 ; Dr. S. West on, 688. „ what we have to do, 687, 690. Diarrhoea in children, bronchitis and, 412. „ collapse after, 526. • DioMnson, Dr. Lee, case of hsemoglobinuria following muscular exercise, 384, Diet : albumens in, amount necessary, 834, 849. „ alcoholism and, 336-337, 875. ,, animals, in, efiects of, 82. ,, Apsley House home for practical instruction in, 837 n. ,, asthma, in, 430. ,, author, experiences of, 405, 830 ; particulars of diet used by, 834, seq. „ blood, eflfects on, 570, 832, 855, 856. „ bread-stuffs, 836, 837. „ cancer and, 462. ,, chlorosis, a cure for, 569, 570. ,, coUsemio paralysis, case of, cured by, 697-599. ,, convulsions, in, 206. ,, Cullen's observations on, 728. „ difficulties with, and their cause, 849. ,, diabetes, in, 690. ,, endurance and, 405. „ errors in, effects of, 852. „ England, in, 728. English and native armies in India, effects on, 868. ", epilepsy, in, 285, 305, 307, 316. ,, fatigue and, 366. ,, fruit and sugar, 868. „ Germany, in, 728. gout, efieots in, author's experiences, 730. ,, great variety in, 837. „ hay fever, in, 427. 918 INDEX Diet : happiness and enjoyment of life, effects on, 872, 873. headache, in, 253, 262, 270, 271, 291, 570. how to alter, 865. Indian native soldier, of, 881, 882. malaria, in, 527, 529. mental depression, in, 407. morals of the young, effects on, 154, 312, 873. pulse and blood pressure, efieots on, 228, 647, 648, 832. suicide and, 331, 334, 335. training, in, 407. treatment, object of, 160, 825, 827. urate excretion, effects on, 109, 287, .858, 860, 862; erroneous conclusions regarding, 860, 862. uric-aoid-free, 136 ; list of foods, 835 ; warmth of, 851. vegetarian, in pregnancy and parturition, 385. Digestion at a standstill in the uric acid headache, 447. Digestive disturbance, ooUsemio diseases associated with, 2ir. Digitalis : action parallel to that of uric acid, 172. ,, bradycardia due to intoxication by, 211. ,, epilepsy, in, 287. ,, mental depression with high blood pressure, in, 346. Dimethyl-xanthine, 192, 193. Dilatation of the stomach, a point in its pathology, 447 ; relation to collaemia, 448. Dinner, efieots on headache, 110. Discharging sores act as natural setons, 266. Disease incidence on English and native armies in India, 868. Distaste for fluids when water is being retained in the blood by oollsemia, 30. Diuretin, action of, due to the salicylate element not to theobromine, 193. Diuretics, mode of action of, 134, 171, 343, 645. Diuresis, blood pressure and, 200. ,, drugs causing : alkalies, 192. cocaine, 64. copaiba, 102, 198. digitalis, 172. diuretin, 192. erythrophlseum, 172. iodides, 101. lithia, 196. mercury, 66. opium, 61. resinous substances, 198. sheep's thyroid, 117. salicylates, 44, 121, 192. ,, following asthma, 416. „ „ epilepsy, 279-280. „ „ headache, 252, ,, ,, hysteria, 289. ,, ,, Raynaud's disease, 499. „ relation to fever, 603. „ retention of uric acid and, are proportional, 547. Dockrell, Dr. Morgan, on tobacco smoking in alopecia senilis, 345. Dog, alkalinity of blood, 83. ,, urates in blood and organs, 83. ,, uric acid excretion of, effects on, of hyposulphite of soda, 82, 125. „ „ „ meat, 82. ,, ,, ,, „ salicylate of soda, 83. Dogs, excretion in, effects of diet on, 82 ; of drugs, 82-83. ,, uric acid formation in, 83. Dreamy mental states, migraine and epilepsy, Sir J. Crichton Browne ou, 298. Drewitt, Dr. D. , on setons in migraine and epilepsy, 266. Dried fruits, albumen in, 835. Dropsy, causation of, 604 ; due to heart failure, 604. „ chronic Bright's disease, reason of absence in, 603. „ drugs, removed by, 603, 645-646. INDEX 919 Dropsy : fever, effect in removing, 603. ,, headaehe, in, 223. ,, physiological conditions, a mere exaggeration of, 579, 604. „ slow absorption of water from the tissues and, 604. ,, treatment of, 645-646. Drags, action of, due to their effects on uric acid, 162. „ animals, effects in, 82-83. ,, hypothetical action on vessels and nerve centres, 120; the renal epithelium, 121. „ injection of, 842. „ non-absorption of, in epileptic fits, 303 ; and in headache, 804. „ suicide and, 384. ,, urate excretion, that diminish, 51 ; that increase, 39. Drysdale, Dr. C. R., on tobacco smoking, 345. Duckworth, Sir Dyoe, on gout and rheumatoid arthritis, 424 ; on gout, 450, 457. Dukes, Dr., arguments as to causation of albuminuria, 586. ,, cases of albuminuria, 585, 586. ,, fatal fatigue, 384, 386. Dumat, Dr. Aylmer, on the myalgio pains of dengue, 753. Dunn, Dr. J., on hay fever, 428. Dysmenorrhoea, connection with blood pressure and uric acid, 288 ; with rheu- matoid joints, 752. Dyspepsia, alkalinity of blood in, 133. anaemia and, 567 ; pernicious, 562-563, 852. arthritis and, 703. asthma and, 428. causation of, 447. collsemia and, 55, 137, 211, 447, 449, 563, 878. chlorosis and pernicious anaemia and, 562, 852. diagnosis of, due to collsemia, 469. diseases related to, 55, 447, 562. effects of, 447. epilepsy and, 423. gout, of, 703 ; gout of intestines and, 450. .headache and, 106, 42:3, 447. intestinal irritation and, 55. menstruation and, 141-142. mercury, action in, 449. suicide and, 829. treatment of, 469, 472. urine excretion, effect on, 448. Dyspnoea, effect on alkalinity of blood, 90. Earle, Mrs. 0. W., on effects of diet, 892. Ebstein on urate irritation, 160. Eocles, the late Dr. , on causation of rheumatism by exposure to cold and damp after fatigue, 385 n. „ treatment of damaged joints, 887. Eclampsia, a uric acid storm, 595 ; value of morphine in, 606. Eczema, 135, 506, 509. Edigecombe, Dr., on daily fluctuations of blood decimal curves, 539, 541. Edwards, Major W. E., on opium in fatigue of horses, 381 ; training of soldiers, -406-407. Eggs do harm like meat, 272. Egypt, cancer and diet in, 463. Ellis, Mr. Havelock, on sexual climaxes, 155. Eliot, George, suffered from migraine, 278. Endocarditis, 748, 784 ; production of, by drugs, 784 ; temperature charts of, showing effects of drugs, 786, 790 ; why more common than pericarditis, 761. Endurance, powers of, greatly increased by a urio-acid-free diet, 367, 881. Enteritis, 135, 451. Epilepsy, absorption of drugs during, 303. 920 INDEX Epilepsy, accumulating poison, due to, 298. • ,, albuminuria and, 297. ( ,, alkalies in, 185-186 ; produced by alkalies given to a gouty patient, 313. ,, anaemia of brain and, 287 ; ansemia or stasis produced by urates, due to, 288. ,, asthma, parallel with, 416. ' ,, authors quoted on : Ackermann, Dr. , etiology of , 313-314. ' ,, ,, Broadbent, Sir W. H., causation of, 287. ,, ,, „ Browne, Sir J. Orichton, dreamy mental states and, 298, 310. „ „ „ Eskridge, Dr. J. T., results with diet, 287. / ,, „ ,, Ferguson, Dr. J., results with diet, 287. / ,, ,, ,, Gowers, Sir W., comparison with migraine, 292. ,, ,, ,, Herter and Smith, Drs., 'intestinal putrefaction in, 283 ; explanation of their observations, 284, 303, 666. ,, ,, Logan, Dr., results with diet, 286. ,, ,, Mordhorst, Dr., urine of, 313. ,, ,, Moxon, Dr., stoppage of heart in, 287. ,, ,, Raymond, du Bois, causation, 277. ,, ,, Voisin, J., and R. Petit, Drs., case due to heart failure, 296 ; on gastric troubles, 295 ; intoxi- cation, 295 ; toxicity of urine, 296. „ „ Wynne, Dr., intoxication, 292, 295. bilious headache and, 280. blood changes and, 297. brain, ansemia of, and, 287 ; power of, and, 298 ; pressure on the, in, 286. causation of, 287-288, 291, 297, 314 ; Sir W. H. Broadbent on, 287 ; du Bois Raymond's theory, 277 ; Tripier's theory, 287 coUsemia the cause not the result of, 287, 291. convulsions and, 295. day terrors of children and, 310. diagnosis of, 315. diet in, case cured by, 224. ,, drugs and, effects of, 286, 288, 308. „ results with, 286, 287. ,, treatment by, 316-317. ■ dreamy mental states and. Sir J. Crichton Browne on, 298, 310. drugs in, 279, 286, 288, 308 ; excretion of, during and after a fit, 283, 303. dyspepsia and, 138, 279. • fatigue and, 279. fits_ of, excretion of drugs during and after, 283, 303 ; preceded by drowsiness, 285 ; temperature after, 308 ; urine of, 277, seq. gastric troubles and, 295-296. , headache and, 279, 292-294. heart's action in, 394. heaviness and drowsiness and, 285. heredity and, what is inherited, 298. hypersemia of brain and, 261. intestinal putrefaction and, 283-284, 473. kidney circulation during and after paroxysm, 283. mental and moral defects from, 312. menstruation and, 141-142, 279. pregnancy and, 288, 416, 497. pulse of, 206. salicylates in, 283 ; why they may fail, 283, 285. tea and thein& effects on, 308. ~ temperature after fits, 308. treatment of, 315-316 ; by diet, 316-317. uraemia and, 315. urate excretion in, author's results, 277, 300-301 ; results of others 281-282. ' INDEX 921 Epilepsy, uric aoid, oases of, in the urine (Dr. Mordhorst), 313 ; fluctuation of, compared with that of; headache, 277, 279, 303. „ urine of fits, 277, seq. ; difficult to separate, 280, 300. „ vertigo and, 263. „ wounds, repair of, and, 297. Epistaxis, cure of, Mr. J. Hutchinson on, 230 ; by a draught of urine, 123. „ exposure to cold and, 230. „ morning hours and, 230. „ relation to season of year, 230. Erythema, cause of, a possible, 508. „ psoriasis in contrast with, 504. ,, salicylates and, 504, 508. Erythrophlseum, effect on blood pressure and secretion of urine, 171-172 ; effects parallel to those of uric acid, 171-172. Eskridge, Dr., on diet treatment of epilepsy, 287. Evening, brightness in the, explanation of, 363. Ewart, Dr. , on faulty metabolism after excess of nitrogenous food, 736. ,, „ gout and goutiness, 733 ; relation of gout to leucocythasmia, 734 ; nitrogenous food, 735. Exanthemata, pathology of, 440. Excitement, relation to blood pressure, 349-351. Excreta of reptiles as a treatment of phthisis, 123 ; urates a matter of solubility and introduction, 39 ; can be altered at pleasure, 125, 126. Exercise : acidity of urine, effects on, 359. ,, arthritis, seat of, determined by, 161. ,, blood pressure, effects on, 263. , , gout prevented by, 887. „ headache, effects on, 263, 887. ,, massage, partly replaced by, 887-888. ,, meat and tea-takers, in, 408. ,, mental depression, effects on, 887. ,, metabolism, effects on, 887. ,, nitrogen excretion, efieots on, 373. ,, temperature curves, effects on, 37. „ urate excretion, efiects on, 360, 361, 362, 364, 365, 366. ,, urea formation, effects on, 379, 403. Exophthalmic goitre, prominent eye of, 147. Eye, position of normal, 147. „ symptoms of uric aoid headache, 251. „ tension in, and blood pressure, 223. Family periodic paralysis, 386. Fatigue, bradycardia due to, 212. defective circulation in muscles and, 386. diagnosis of, 401. diet and, 166-167, 367, 405. epitome of all defective combustion, 359. fatal. Dr. Dukes on, 384. horses, in, causation, 370 ; treatment by opium, 403. Mahomed, late Dr., on the signs of, 880. pathology of (Prof. Mosso), 400. poison in the blood, is uric acid, 379 ; Prof. M. Foster on, 379. prevention of, by cocaine, 212 ; salicylates, 365 ; in soldiers and sailors, 402. rheumatism and, 385. stiffness and myalgia and, 385. syncope, 384 ; Sir W. H. Broadbent on, 386. training, effects of, on, 367, 403. urea excretion and, 361, 363, 378. uric acid, excretion and, 361, 363, 373 ; in blood, proportional to, 361, 379, 380, 384. urjc-acid-free diet and, 367, 405. Weston the pedestrian, case of, 380. weather changes and, 379, 384. 922 INDEX Pawoett, Dr. J., his results, 104 ; criticisms by the author, 105-106. Payrer, Sir J., on pulmonary thrombosis, 565. Peuwiok, Dr. Saltan, on acute phthisis, 425. Fere, M. Ch., on renal circulation after an epileptic fit, 283 ; pulse in epilepsy, 279 ; epilepsy and migraine, 293. Ferguson, Dr. , on diet treatment of epilepsy, 287. Fever : acidity of urine, relation to, 28, 40, 208, 731. alkalinity of the blood, relation to, 77, 85, 208, 498. causation of, 152. children, has greater effect in, 776. ooll^mia following, 382-383, 339. convalescence, the pulse of, 208. diuresis, 28, 603 ; author's experiences, 660. microbes, an effort of Nature to burn up, 152. pulse of typhoid, Marey on, 213. rheumatism, may produce, 660. salicylates in, 560. skin troubles follovping, 505. urates in blood, effect on, 85, 208, 498. Fevers due to microbes, effect of collsemia in favour of tKem, 152 ; treatment of, by salicylates and diet, 527-528, 637. Fibrous structures, alkalinity of, 748. ,, ,, diseases due to uric acid irritation of, 135, 466. <, ,, heart, of, 748. ,, „ inflammations of, characteristics of, 436. ,, ,, intestine, of, urates in, 455. Fibro-brouchitis, signs of, 431. Fibroid phthisis, 486. Pick and Wislioenus, experiment on the sources of muscular energy, 373, 374 ; result to some extent fallacious, 374-375. Fidgets, pathology of, 803. Fisher, Dr. Theodore, on Dr. Caton's treatment of endocarditis, 789. Fits more common in boys than girls, 503. Fitzgerald, Mr. G. E., on puerperal eclampsia, 318. Flatulence and uric acid, 185. Plea-bites and their results, 509. Fluids in diet, relation to blood pressure, 262, 318. Pood, anaemia and, 578. „ poor, of, hovsr ignorance leads to loss, 873. „ prisons, asylums and poorhouses, of, suggestions as to, 872. Poods, percentage of contained albumen, 835. Formation, excretion and, of urates, general conclusions, 16-17, 124 ; over long periods, 16: ,, urate, must be distinguished from excretion, 39. ,, uric acid, does not vary in relation to urea, 38, 132. Poster, Prof. M,, effects of exercise on reaction of muscles, 747; on the physiology of weariness, 379. Poster, Sir W., lactic acid in diabetes produces rheumatism, 657. Frazer, Mr. J. E. , on iodide of mercury in haemoptysis, 239. Preyer, Mr., on stone in India, 881. Fright a depressant and cause of coUsemia, 123-124. „ chorea, relation to, 128. ,, cure of, by a draught of urine, 128. Prugivora have great powers of endurance, 337. Fruit and vegetables : acidity of urine, effects on, 715, 716, 721. „ „ gout, effects in, 715, 716, 868. ,, ,, harmless apart from meat, 716, 868. ,, ,, water supplied and thirst prevented by, 337. Pullerton, Dr. A., on the action of cocaine, 65. Function dependent on amount of urate in blood, 133. Functional disease must be distinguished from organic, 255, 257. Gairdner, Sir W. T., on iodide of potassium in asthma, 429. Gangrene, symmetrical, case of, 491. INDEX 923 Gardner, Dr. Willougliby, on gout and melancholia, 347. Garratt, Dr., on acidity of the urine and excretion of phosphates, 41. Garrod, Sir A., on alltalinity of joints, 695 ; spleen, 5. „ ,, fluids in tissues and joints, 189. ,, ,, gout, 52, 151, 178, 256; gout of intestines, 450. „ ,, pregnancy and gout, 151. ,, ,, previous work and its great value, 7. ,, ,, urates, distribution of, in the body, 5, 455. „ ,, uric acid in blood, 73, 75, 554 ; excretion, 128. Garrod, Dr. A. E., on alkalies, effect on urine and heart, 761. ,, ,, anaemia of rheumatism, 558. ,, ,, rheumatism, oolchicum in, 760; uric acid causation of, 745. „ ,, urate deposits, 745, 746. Gastralgia, 105 ; salicylates in, 458. Gastro-intestinal irritation as a cause of collEemia, 55, 214-215, 562. Gayford, Dr., case of enlarged glands cured by diet, 768. Gee, Dr., oollsemic paralysis diagnosed as hysteria, 598. ,, gout and chronic headache, on, 268. General paralysis : causation, 355 356. ,, curve of annual incidence, 357. ,, degeneration of nervous tissues in, 357. „ great mental power, relation to, 357. ,, insomnia and, 356. „ migraine and, 355. ,, tabes and, 357. Girls and women : chorea, greater liability to, 806. ,, ,, development in, 552, 553. „ ,, Eaynaud's disease, greater liability to, 556. „ „ rheumatism, greater liability to, 556. ,, ,, uric acid fluctuations in, 331, 332, 553. Glands, enlargement of, 135, 772 ; Dr. Gayford's case, 768. Glaucoma : blood pressure, relation to, 223. ,, pathology of, 223. GlycocoU, chemical formula, 107. „ relation to hippurio acid, 43 ; salicyluric acid, 43 ; uric acid, 43. Glycosuria, ague and, 651. ,, albuminuria and, parallel causation, 665. ,, angina and, 654-655. ,, gout and, 656. ,, granular kidney and, 653. ,, lead colic, can be produced in, 665. ,, relation to time of day, 670. ,, (see also Diabetes mellitus) . Gogarty, Dr., on oedema of eyelids in migraine, 223. Goodhart, Dr., on asthma, 414. „ ,, excess of uric acid in the urine of children, 838. ,, ,, formation of uric acid and sugar, 838. Goodson, Mr. W., on the use of cooling tub water with mercury, 644. Gossage and Coutts, Drs., on convulsions, 294. Gout : air tubes, of, Dr. Buckler on, 430 ; urates found in situ, 431. alkalies in, 738. artificial production of, 161, 692. attack of, explanation of, 704 ; biurate not the cause of, reason, 695. blood pressure and, 226. bodily labour, effects of, 557, 728. Bright's disease, chronic, and, 137. bronchi, of, cure by salicylates, 432, 434 ; author's case, 844. „ relation to arthritis, 431 ; tubercle and phthisis, 431, 434. „ symptoms of, 844. caecum, of, 452. characteristics of, 136, 436. causation of, by arrest of menstruation, 781 ; hemorrhage, 731. chloroform and, 398-399. cider, relieved by, 715. congestion of the liver and, 650. 924 INDEX Gout, dependence on solubility of urates, 692. „ diagnosis of, 737. ,, diet in, 132 ; meat diet, 109; records of cures by diet, 739-740. ,, drugs clearing the blood of uric acid, action in, 335, 709. ,, dyspepsia and, 703, 728. „ fibrous tissues, of, tends to fly from place to place, 469-470, 845 ; spread to adjacent tissues, 846. ,, fibrous tissues of teeth, of, cured by salicylates, 739. „ goutiness and. Dr. Ewart on, 733. ,, hot bath, action in producing, 704. ,, intestines, of, 434, 450, 846. author's personal experiences, 451, 844. causation, 455. diagnosis of, 450, 466-467 ; differential diagnosis, 469. lead colic, similar to, 452-453. Logan, Dr., case of, 464. treatment of, 469. ,, local irritation, Mordhorst's theory of, 189. ,, „ injury, effects of, 161, 730. ,, meat eating in, effects of, 728 ; author's experiences, 110-111 ; pure meat diet in, 713. ,, melancholia and, 105, 347. ,, menopause, relation to, 496. ,, cesophagus, of, 459. ,, pelvic fibrous tissues, of, 455, 469. ,, pharyngitis and. Dr. de Havilland Hall on, 433. ,, phthisis and, 424, 435. ,, rheumatism, differs from, 692 ; identical with, 160, 698 ; may have to be treated as, 738. „ rheumatoid arthritis and, two names for stages of same condition, 160, 782, 783. Scotland, rare in, 338, 728. ,, season and oUmate, effects of, 327, 704, 729-730. „ sedentary work, effects of, 729. skin, of, 506. ,, solvents of uric acid, relieved by, 136, 739. ,, stone and, 256. ,, thrombosis and, 564. „ trachea and bronchi, of, 432, 844. ,, treatment of, 739; by colchicum, 738; by salicylates, 739. ,, uric acid, excretion in cases of, 105, 696. „ ,, the group of diseases due to precipitation of, 135. ,, ,, headache and, 265. Gowers, Sir W., on cancer and argyria, 461. ,, ,, migraine and epilepsy, 292, 293. Grant, Dr. Dundas, chloride of ammonium useful for headache, 548. Grashey, Prof., effects of high arterial tension on cerebral circulation, 259-260. Gravel, see Calculus. Graves' disease, acute rheumatism and, 145. blood pressure and, 142, 144, 146, 147. cases in illustration, 143-145. causation, 144, 145. chorea and, 140. menstruation and, 142. mercury, treatment by, 145. pathology, suggestions as to, 145. prominent eye of, distinguished from that of high blood pressure, 147-148. ,, ,, women, occurrence in, 142. Gravity, effects on the circulation, 208 ; value in clinical work, 204. Great mental power and insanity, 402. Guanine, chemical formula, 107. Guarana : headache, a cure for, 826 ; why it should not be used, 286. ,, stimulant action of, 123. Gull and Sutton, degenerative processes in vessels, 187. INDEX 925 Guthrie, Dr. L. G., on hsematuria, 515, 516. Haemoglobinuria, ansemia and, 516-517. ,, blackwater fever and, 520 52,S. oases of, 513, 5U, 515-516. , , causation of, 529, 530, 531 , 566 ; parallel to hetero- albuminsemia and albuminuria, 576, 595. ,, oollsemia, signs of, in, 513, 530. ,, drugs, produced by, 557. ,, dyspepsia and, 138. , , headache and, 517. ,, kidney irritation caused by, 595. ,, malaria and, 520-523. ,, nephritis and, 595. ,, Qxaluria with, causation of, 566. ,, Koberts, the late Sir W., on, 591. ,, urea formation, control by uric aoid and, 596 ; relation to albumen in, 592. ,, uric aoid storm, a, 514. Hsemoptysis, treatment of, 229 ; Mr. J, E. Fraser on, 229. Hsemorrhage : arteries, from, 229. ,, capillaries or veins, from, 229. ,, cerebral treatment of, 647. ,, gout due to, 731. „ treatment of, 229-230. Haig, Colonel P. de H. , on the diet of the army in India, 868. Hair's asthma cure, 198, 428. Hall, Dr., on purln in oatmeal, 835. ,, ,, absence of purin from white bread, 835. Hall, Dr. de Havilland, on gout and pharyngitis, 483. Handford, Dr. , on chorea, 803. Handsou, Dr. C. P., case of collsemic paralysis cured by diet, 597-599. Harley, Dr. V., on muscular power in morning hours, 362. Harper, Dr. , urea in tuberculosis, 439. Havelock-Ellis, Mr., on annual curve of conception rate, 155. „ ,, curve of incidence of general paralysis, 357. Hawthorne, Dr. C. O., on cirrhosis of liver and pyrexia. 472. Hay fever, causation of, 427. ,, climate, relation to, parallel with catarrh, 411, 427. „ Dunn, Dr. J., on, 428. „ treatment of, 427. Haycraft's process and the estimation of uric acid, 894 ; in tissues, 8, 9, 76. Headache, age, inEuence on, 265, 267. alternation of, with cardiac failure, 143 ; gouty pains, 8-4, 105, 127- 128. altitude, influence of, 271. artificial production of, 254-255. author's immunity and its cause, 258. bilateral, 260. Bright's disease and, 268. cancer and organic disease and, 256, 269. causes producing : acids, 183-184. ,, capillary obstruction, 132-133^ ,, heat and bad air, 53. ,, intracranial pressure, 260, 265. ,, meat eating, 9, 129-130, 254. ,, theory of causation, 254, 256. characteristics of, 320. cold hands and feet in, 156, 167, 269. compression of carotid in treatment, 262, 276. cures of, 183, 184, 266, 270, 275. diagnosis of, 269. diet, effects of, 1, 2, 253-255, 258, 270-272, 573. digestion at a standstill in, 447. 926 INDEX Headache : duration of, 250. „ dyspepsia and, 138. ,, early morning, 184. ,, epilepsy and, parallel between, 292. , , excretion, and absorption of drugs in, 304 ; of urates in, 452-453 ; relation to normal excretion of uric acid, 258-259. ,, exercise, effects of, 263. „ gout and, 253, 256-257, 265. „ heredity and predisposition to, 298. ,, meat produces, 9, 129-130, 254. ,, menstruation and, 146, 250, 258. periodicity of, 250, 257-258. „ position, effects of, 261. „ preceded by well-being, 253, 258. „ prevention of, 270, 276. „ pulse of, 251. „ rheumatism and, 105, 253. ,, sea- sickness, of, 217. ,, setons in the neck in, 266. , , starvation cure of, 275. ,, temperature in mouth and rectum during, 38. ,, treatment of : diet, by, see Diet above. „ „ drugs, by, 183, 184, 270, 272-276. ,, „ indications for, 266, 270, 291-292. ,, ,, setons in the neck, by, 266. ,, . ,, starvation and diminished fluids, by, 267, 273. ,, ,, stomach in, 270. uric acid and, 2, 9, H-12, 13-14; 138, 143-144, 252, 258. „ urine scanty in, 251-252, 269. ,, warmth, effect of, 185, 186. Heart : blood pressure, effects of high, 221, 394. ,, coUsemia, influence in, 353-354. ,, dilatation of, 386. ,, disease of, left chambers, 750-751 ; right chambers, 750. ,, failure, blood pressure in, 212, 213, 406. ,, „ chloroform, after, 388, seg. ; common in carnivora, 395; before and after delivery, 397-398 ; rare in herbivora, 895. ,, „ coUaemia and, 401. „ „ delirium and mania, relation to, 350. ,, ,, nitrites, after, 895. ,, ,, signs of, in Bright's disease, 388. , , fibrous tissues of, 749. ,, prominent eye, an index to strength of, 149. „ strength of, determines the disease, 497-498. ,, valves of, 750 ; liable to injury or strain, 750. ,, weakness of, effects in Raynaud's disease, 489. Heat, as a cause of disease, 404 ; treatment by opium or salicylates, 404. cold and, their efiect : on excretion, 31-33, 52 ; on suicide, 333. effects of, with and without salicylates, 473, 474. endurance and, 367-368. not a depressant for those free from collsemia, 404, 405, 641, 885. production of, 380 ; effects of uric acid on, 380. uric acid headache relieved by, 185, 186. Herringham, Dr., on meat and migraine, 272. Herter, Dr., excretion of uric acid in epilepsy,' 281, 448; intestinal putrefaction, 283, 566. Herz, on degeneration of vessels, 187. Hetero-albuminsemia, 581. Hill, Dr. L., on fluids and blood pressure, 228. Hindus, calculus and rheumatism rare in, 883. History of author's researches, 1. Hofmann, Dr. G., on acids and well-being, 322-323. Hope-Lewis, Mr., brain fever of the drama, 754, seq. ,, ,, ease of poisoning by beef-tea, 735-736. „ ,, salicylates in the skin, irritation produced by morphine 62-63 INDEX 927 Hopkins and Hope, Messrs., effects of thymus freed from nuclein, 120. Horbaczewski, on the formation of uric acid, 128; his results may be due to excretion or introduction, 129. Horder, Dr. E. G., on chloroform among the Chinese, 398. „ ,, diet of the Chinese, 870. Horses, opium given to Indian, 403. „ rheumatism, and, 369-370, 408-404 ; why they suffer, 369-370. Horsley, Mr. V., relief of intracranial pain by trephining, 260. Hubbard, Dr., on convulsions of bottle-fed infants, 315. Huchard, on salicylate of methyl in hepatic colic, 472. Humphry, the late Professor, on diet of the aged, 422, 864-865. Hunger, bradycardia in, 207, 208. Hunter, Dr., on blood destruction and increase of uric acid, 531 ,, ,, causation of pernicious ansemia, 567 ; author's explanation of his facts, 568. ,, ,, spleen, the, in destruction of blood by drugs, 558. „ ,, uric acid and Raynaud's disease, 495. Hunter, John, on the paleness of nausea, 214. Hydrsemia, effects on solution of urate deposits, 708. Hyperaemia, vascular changes and, 223. Hyposulphites, action on acidity, 51. Hypoxanthin: chemical composition, 107. ,, effects of svrallowing, 8, 99, 114. „ effects of feeding animals with, 836. ,, eq^uivalent to uric acid, 8. Hysteria, causation of, 289, 290, 353. ,, eoUaemic paralysis diagnosed as, 598, 600. ,, mental and moral defects from, 312. ,, nutrition in, 289. „ relation to uric acid, 135, 289. Immunity against cold and wet under salicylates, 442 ; relation to solubility of uric acid, 442. Incidence of disease on English and native armies in India, how far the effect of diet, 868. India, army in, eats little meat, 868. ,, natives of : cause of their sufferings, 881-882. ,, ,, cancer among, 463. ,, „ endurance of, 406-407, 889. ,, ,, malaria and diet of, 527. ,, ,, vegetarian : gout, rheumatism and stone in, 370. ,, ' ,, immunity from chloroform syncope, 398. , , opium given to horses in, 408. ,, salicylates in, bad action of, 460. Infection, liability to, 152. Inflammation, blood condition in, 77-78. ,, fibrous tissues of air tubes, of, 431. Influenza, suicide and, 339. Injury, effects of, in: gout, 730; rheumatism, 751-752. Insane diathesis and craving for meat in children, 402. Insanity, increase of, 407. ,, relation to great mental power, 402. , Insect bites, immunity from, in relation to oollaemia, 509. Insomnia : calomel, treated by, 324. , , cured by diet, 356. ,, high blood pressure, relation to, 324. Instruments and methods, 893. Intestinal putrefaction in epilepsy, author's explanation of, 283, 472-473, 566. Intestines, gout of. 484, 447, 450, 457 ; author's experiences, 451, 452, 845 ; effects of salicylate of soda on, 452, 453 ; explanation of lead colic, 451 ; Sir A. Garrod and Sir Dyce Duckworth on, 450. Intoxications, bradycardia and, 208, 211. ,, epilepsy and, 295. Intracranial, circulation, uric acid effects on, 302. 928 INDEX Interoranial pressure, headaolie and, 259-260. Iodide of mercury, effect on urine and blood, 122, 546-S47 how it may fail, 122, 644. ,, potassium, value of, in : asthma, 428-429 : fits, 305. Iodides : acidity of urine, effects on, 197. ,, arterial tension, efiects on, 100-101. ,, asthma treated by, 428. ,, Bright's disease treated by, 643-644. ,, danger of suddenly leaving off, 211. ,, effects on excretion of : urates, 101-102 ; water, 102, 122, 546. , , gout of skin produced by, 506. .#■■ „ haemorrhage treated by, 229. Ipecacuanha, probable action in migraine, 267. Ireland, cancer and diet in, 462. Ireland, Dr. W., suicide and insanity, 407. Iron, causing retention of uric acid, 53-54, 197. „ gout, in, 710. ,, rheumatism and rheumatoid arthritis, in, 55, 768, 818. Jaksch, Prof. R. von, on excess of uric acid, 565. Jandrassick on the action of mercury, 195. Jaundice, 135, 211. Jerome, Dr. W. J. S., on alloxur-holding bodies in food, 119. ,, „ thymus feeding, efiects of, 119. Joints, alkalinity of, 695. ,, removal of urates from, 781. ,, tissues of, in old and young, 695. ,, uric acid stored in, 126, 127. ,, vascularity of, 695. Jones, Dr. Handfield, on the heart in pregnancy, 624, 626. ,, Dr. Lloyd, on the causation of chlorosis, 561. ,, Dr. 0. Clayton, on catching cold, 435. Keith, Dr. George S. : diabetes cured by restricted diet, 690. ,, ,,' diet in uric acid disease, 848. ,, ,, reference to writings of, 848, 849. ,, ,, stimulant action of liquorice, 198. Kidd, Dr. W. , salicylates and fatigue, 366. Kidney, alkalinity of, may control the excretion of uric acid, 74. ,, circulation in, at the end of an epileptic paroxysm, 283 ; Sir Lauder Brunton on, 171 ; effects of uric acid on, 170 ; effects of drugs on 171. , , congestion of, due to bad blood, Mahomed, 580. ,, diseased, can produce normal urine, 583. ,, granular, with good sp. gr. of urine, 782. ,, lesion of, is secondary to hetero-albuminsemia, 580. „ Raynaud's disease, in, 477, 500. „ role of, in uric acid formation, 19-20. ,, water from, 418, 419. Kirk, Dr., behaviour of herbivora and carnivora after chloroform, on, 395. ,, blood |rom case of uraemia, on, 605. ,, blood pressure does not fall after chloroform as the heart slows, 394. ,, chloroform syncope, on, 667. Krainsky on the urine of epilepsy, 278. Kraus, Dr. , rel&tiou of glycosuria to breakfast and time of day, 667. ,, ,, author's explanation of his facts, 669-670. Labadie-Lagrave, Dr., on causation of Bright's disease, 581. Labour : effects on skin and urine, 729-730. ,, gout prevented by (Gullen), 728, 729. Lange, Professor, mental depression and uric acid diathesis, 322, 324. Lea, Dr. Sheridan, xanthine bodies and vegetable alkaloids, 835 n. Lead, appendicitis and, 454, 458. INDEX 929 Load, bradycardia due to, 211. causation of colio, 451, 452. gout in, 710. poisoning by, 55-56 ; salicylate of soda in, 452-453. primary and secondary action of, 55-56, 197, 458, 459. urate of, insoluble, 53. Lecauu, relation of uric acid to urea, 19. Leech, Prof., on the action of nitrites, 72. Leeper, Mr. E. R., action of thyroid extract, 352. • ' i> .> mania, treatment of a case of, 352. Lemon, use of infusion of, in acute rheumatism, 759-760. Lepine, opium in stomach pain, 46iS. Leucocytheemia : arsenic, effects of, in, 517. „ case of, 495, 517. „ coUsemia, relation to, 494. II iron in, 517. ,1 salicylates and acids in, 518, 519. Leucoinitis, 430. Liddell, Dr., excretion of uric acid in a case of gout, 698. Liebermeister, effects of diet in gout, 862. Lime salts, elimination of, 220. Liquorice as a stimulant-, 198 ; explanation of its action, 193. Lithia : acidity of urine, effects on, 196-197. alkalies in contrast with, 197. arthritis, effects in, 58-59. chemical explanation of its action, 68. diuretic, as a, 196. urate very soluble, 58. uric acid excretion diminished by, 59. Liveingj Dr., on epilepsy and migraine, 7, 497. „ headache, work on, 3, 7, 250, 251, 267. Liver : abscess, causation of, 471. „ gout, relation to, 471. „ relief of, by salicylates, 470. acids in congestion of, 659. alkalinity of, determines rate of excretion of ingested uric acid, 470-473 > oollosmia, effects of, 651. congestion of, action of mercury in retaining uric acid and, 5i7. causation of, 471, 593. „ gout, relation to, 650-651. „ piles and pruritus ani, a cause of, 653. „ wines and spirits, how produced by, 471. diabetic, 650. fibrous tissues of, effects of uric acid on, 471. uric acid retention in, 79-80, 125, 126, 127, 177-178, 470-471. Lookwood, Dr. C. E. , case of peri-typhlitis caused by salicylates, ^65. Loewy and Richter, artificially produced fever, 152 , Logan, Dr. , cases quoted, 264-265, 268. London fog may cause bronchitis, 432. Luff, Dr., on absence of uric acid from blood in health, 554. , , altered conditions of renal epithelium as a cause of the accumula- tion of uric acid in gout, 555. „ solubility of sodium biurate, 705. Lungs : atmospheric pressure in, causation of diminished, 420-421. ,, circulations in, 420. ,, congestion of, relation to diminished atmospheric pressure in the chest. 421. ,, water excreted from : author's researches, 418, 419. urine parallel with, 418, 419. Yavein, Dr., researches of, 417 4,19. MHcGreaor. Sir W., on cancer and diet, ^62. -MackeS Dr.. on' meat diet and -aenna 561. Mackie, Dr., catarrh and unc acid, on, 433. 59 930 INDEX Maokie, Dr., hsemoglobinuric fever, 521. „ neuritis and uric acid, 510. ,, treatment of anEemia by diet, 572. Mahomed, the late Dr., on Bright's disease, causation of, 579-580, 582-585. ,, ,, „ high tension and its signs, 380. ,, ,, „ Weston, observations on, 380. Malaria, case of, 528. ,, effects of quinine, 521. ,, parasite of, Dr. G. Thin on, 522. ,, Raynaud's disease and, 522. ,, treatment by diet and salicylates, 524-525, 527. Malarial feVer, action of, in causing haemoglobinuria, 520-523. Malays, urine used medicinally by, 123. Manganese, effects on urate excretion, 59. Man not a carnivore, 84. Mania : blood pressure, relation to, 349-351 ; Dr. Craig on, 849. „ causation' of , 349, 353. „ coUsemia, and, 135. ,, diet change in, 351. ,, melancholia alternating with, explanation of, 350. ,, mental and moral defects from the same cause, 312. „ stupor, changed to, by treatment, explanation of, 353. Man's blood and urine differ from those of carnivora, 83-84. Manson, Dr., on hsemoglobinuric fever, 520. Marey, M., on alcohol, effects on the temperature, 36 ; pulse, 166. lungs and blood pressure, 421. rate of heart's action, 167. signs of high arterial tension, 261, 423. pulse : alcohol effects on, 214. ,, morning and evening, 169. ,, typhoid fever, of, 213. „ vomiting and mal de mer, of, 214, 217. temperature of the surface, 35. Massage, effects in removing urates, 887-888 ; for structures damaged by urates, 887. Massalongo and Silvestri, diuretic eiiocts of diuretin, 193. Masturbation, relation to blood pressure, 154, 155. Mays, Professor T. J., on angina, 655. ,, „ „ consumption, 488. ,, ,, ,, rheumatism and pneumonia, 431. ,, ,, ,, salicylates in phthisis, 230. Meakin, Mr. H. B., on urine as a stimulant, 123. Meat, or meat diet, alkalies cannot be taken with impunity by eaters of, 850, 851. ansemia and, 885. arthritis, in, 713 ; Dr. Armstrong on, 714. asthma, in, 415. cancer and, 461. constipation and. 837, 840. craving for, in children and epileptics, 402. dangers and results of diet of, 110, 111, 120. eaters do well at first, 111 ; badly later on, 111-112. eating leads to taking of stimulants. 111, 387; produces diuresis and thirst, 237. epileptic fits and headache and, 306. extracts, effects of taking, 9, 389, 614. ,, stimulants as, 128. uric acid in, 9. ,, xanthin in, 9. Germans and Scotch eat less than English, 728. gout in, 714. malaria and, 529. Persia, only eaten by rich in, 827. suicide and, 335. stimulant, is a, 336. training, and, 415. INDEX 931 Meat, or meat diet, wio acid headache, and, 253-254. .. ,. wine dinner, effect on excretion of urio aoid, 109-110, 415-416. Melanonoua, alternation with mania, 350. case of, 347-348. gout and, 105. mental depression and,' 323, 324. pulse of, 206. relations to early morning hours, 346. symptoms of, 823. Meningitis, urates in blood in, 125. Menorrhagia, 199. Menstruation, absence of postural changes of blood pressure in (Dr. Oliver) 142. arthritic troubles may be improved by, 142. blood decimal, effects on, 157. bradycardia of, 340. ' catarrh and, 142, 421. oollasmia of, how produced, 141. commencement of, 562. colic and, 159. dyspepsia and, 142. epilepsy and, 142. gout and, 496, 731-732. headache and, 146, 250, 258. mental bias of women and, 341 ; depression and, 142, 341. metabolism and, T. Schrader on, 153 ; author's explanation of his results, 153-154. myxcedema made worse by, 550. Raynaud's disease and, 496. rheumatism and, 141, 142. sexual activity and, parallel with seasonal alterations, 169. skin eruptions and, 139. suicide, a cause of, 332, 340. temperature of, 157 158. thyroid enlargement during, 142, 146. uric acid excretion in. 139-142. Menorrhagia, relation to blood pressure and food poisons, 288. Menopause, gout after, 496. Mental depression, anasmia of the brain, due to, 346. ,, cause of, is central, 322. cold, effect of, 186. ,, diagnosis of, 323. , , disease and, 320 ; mental depression is disease and must be treated as such, 328. ,, digitalis, effects in, 3i6. drugs, effects in, 89, 321. ,, dyspepsia and, 138. ,, early morning hours and, 294, 325, 327, 346. ,, gout and, 333. ,, headache and, 320, 346. ,, high arterial tension and, 206. ,, insidious onset of, 328. ,, melancholia and, 327. ,, menstruation and. 141-142. ,, moral sense, thought, resolution and, 328-329. ,, periodicity a distinguishing mark, 324. ,, pulse of, 206. ,, Punch on, 321. ,, production of, 335. ,, religious bias in women and, 340 341. ,, season, relation to. 33 34, 325, 329. ,, suicide and, 325 326 ; most common age for, 328. ,, symptoms of, 320. ,, temporary insanity, is, 328. ,, terrible realities of, 328. „ treatment of, 335, 402. 932 INDEX Menta depression, uric acid excretion, relation to daily and yearly fluotuationa in, 325, 330, 346. ,, disease, relation to circulation and blood pressure, 401. ,, enjoyment of life, effects of diet on, 873. ,, excitement, blood pressure and, 849-351. ,, prominent eye increased by excitement, 150. „ power, insanity and, 402. Mercury, blood pressure, effects on, 194, 195, 196, 226. ,, Bright's disease, in, 205-206. ,, colic, a cause of, 451. ,, diuresis, a cause of, 66, 68. ,, dyspepsia, acts on the circulation in, 449. „ fatigue, in, 403-404. ,, free capillaries, a, cause of, 66. ,, gout and rheumittism, in, 710. ,, Graves' disease, in, 145. ,, neuralgia, a cause of, 710. ,, solubility of its urates, 66-67. ,, tachycardia, in, 209. ,, urates, retention of, due to, 66 ; cause of, 67-68, 121. ,, urea excretion undet exercise, effect on, 364. ,, uric acid, clears the blood of, 121. Metabolism, children, in, 775 776. cold, effect of, 186. collsemia and, 867. diminished by flooding the blood with uric acid, 89, lll-llS. drugs, effects of, 89 ; explanation of effects of small doses, 162. estimation of rate of, 206. increased by clearing the blood of uric acid, 89, 107, 111. menstruation, effects of, 140-141, 153. nitrogen, phosphorus and sulphur in the albumen molecule, of, 51-52. pregnancy, effects of, 151-152. sexual act, effect of, 153-154. uric acid, effects of, 161-162, 289. xanthin and uric acid, makes short work of the difference between, 115. Microbes and the causation of rheumatism, 772-773, 788. ,, coUsemia and, 135. ,, may be burnt up if circulation is free, 412, 413, 441, 527. ,, r61e of, in disease, 446. ,, protected by oollsemia, 413. ,, uric acid, may be less important than, 10. Microbic diseases, incidence determined by uric acid, 34. Migraine : alternates with rheumatism, 105, 311, 556, 766. ,, better in old age, and why, 267. ,, blood pressure and, 420. ,, brain workers, generally in, 265. ,, Bright's disease and, 26S, 576, 648. ,, causation by animal food, 130, 271, 272. ,, cerebral arteries, dependent on the size of, 265. ,, diabetes and, 685. ,, diseases allied to, 145. „ cured by antipyriu, which weakens the heart, 268 ; diet, 270, 271. „ epilepsy and, 295. ,, gout and, 265. ,, mental and moral defects from, 312. „ nerve centre theories and, 215. ,, pregnancy and, 151. ,, Raynaud's disease and, 497-498. ,, sexual intercourse and, 153-154. ,, tabes dorsalis and, 365. Milk diet, bronchitis, in, 435, 437. „ constipation due to, 840. ,, convulsions, in, 206, 317. INDEX 933 Milk diet, epilepsy, in, 282, 305. Miles, Mr. E. H. : book on diet, 367,407 ; experiences of, 889 ; on diet in training, 407, 890. ,, ,, experiences of, as an atblete, 407; diet experiences, 889, 890. ,, ,, stimulants, on the taking of, 890. ,, ,, waste products on, and the author's reply, 891. Miukuwslii ou alloxur bases, 119. Mitral valves, lesion of, 752 ; how a small lesion becomes a big one, 752. Monkeys, urates in blood and organs, 84. Monro-Grier, Dr., case of diabetes, 682. Moore, Mr. , cancer a disease of the vigorous, 463. Moore, Dr. Norman, on guaiacum in syphilis, 103. ,, ,, liver abscess, 470. Moral degeneracy, 154, 408. Mordhorst, Dr. 0., on calves' thymus, effect ou the excretion of uric acid, 119. ,, „ epilepsy and the excretion of uric acid, 312. „ ,, rheumatism, causation of, 189. ,, „ spherical urate: as a cause of local irritation, 189; as a cause of lymphatic obstruction, 189, 190. „ „ urates and their solubilities, 187-189. Morning cold baths, effect on mental depression, 325. Morphine : action of, 60-61, 194-195, 212. ,, eclampsia, in, 606. ,, habit, 61 ; how contracted, 335 ; danger of suddenly leaving off, 211 ; treatment of, 62 ; use of salicylates, 61-63, 336. ,, puerperal eclampsia, in, 318. ,, stimulant when meat fails, 111. „ tachycardia, in, 209. Morton, Mr. Stanford, thrombosis in retina in migraine, 223, 260. Mosquito bites, 509, 529. Mosso, Professor, pathology of fatigue, 400. Mott, Dr., on the spleen as a centre of blood destruction, 558. Moxon, the late Dr., the heart in epilepsy, 287, 387. Murohison : on plus formation of uric acid, 729. „ vertigo, 263. Murders, seasonal variation in, 329. Murray, Dr., on Graves' disease, 145. ,, mercury effect on the circulation, 227. „ pleurisy caused by cold, 434. Muscle, uric acid contained in, 8-9, 80, 125 ; xanthin contained in, 8. Muscles : acidity of, effects of exercise on, 747-748. ,, coUsemia, effect and after-effect of exercise on, 185. „ nutrition of, effects of high tension on, 223. ,, vascular degeneration, effects of, 223. Mushrooms, 825, 861. Myxoedema, menstruation worse during, 550. ,, pregnancy, better during, 550. ,, thyroid feeding, effects of, 550. ' Naso-pharyngeal congestion, diet cure of, 427 „ ,, pathology of, 427. Nations, diseases of, 409. Natives of India, see India. Natural plus excretion of urates, 21. Nausea, circulation of, 214. „ pulse of, 217. Neale, Dr. E., on urine as a stimulant, 123. Necrosis of tissue, Mordhorst's theory, 189. Nephritis : accompanying arthritis, 614. „ causation of dropsy in, 602. „ chronic collsemia due to, 602, 604. „ excretion of urates in, 125, 602. Nervous system the Jupiter of medicine, 732. Neurasthenia, treatment of, 448. 934 INDEX Neuritis, causation by : alcohol, arsenic and some metals, 510 ; uric acid, 510. ,, relation to retinitis and collsemia, 510. Neuroses, the, of higkand low blood pressure, 310 311. Neurosis, inheritance of, 871 ; does not explain everything, 871 ; the author's. and what he inherited, 265, 871. Newsholme, Dr., on causation of rheumatism, 742, 743. Nitrites : acidity of urine, effects on, 69, 72. ,, diameter of radial artery, effect on, 395. „ Leech, Professor, on the action of, 72. ,, pulse, effects on, 396. ,, sulphurous acid compared with, 70-71. Nitrogen, deficient supply of, no cure for uric acid disease, 831 ; effects Qu nutrition, 831. „ output during menstruation, 153 ; after exercise, 873-375. ,, physiological quantity, no reason for not taking, 837, 840. ,, reasons for not taking too much, 842. Nocturnal urination : Bright's disease, a symptom of, 200. „ high tension, a result of, 200. Nordau, Max, on degeneration, 408. North, experiments on diet and the excretion of nitrogen, 373. Nuchalalgia, 323. Nuclein and uric acid, 119-120, 128-129. Nutrition : circulation, effect of impeded, on, 223. „ cold, effect of, 186. ,, hysteria, in, 289. „ sexual act, effect of, 153-154. „ urate in blood, dependent on amount of, 86, 111-112. Nuts as a source of food, 835, 839. O'Gonnell, Col. M. D., ague cases reported by, 530. Oatmeal, purin in, 835. Obesity, blood pressure and, 150. , , how to avoid, 867. ., pathology and treatment, 867. , , tendency to, diminished by deep breathing, 150. GJidema of the eyelids in migraine, 228. CEsophagus, gout of, 459. Oil in diet, 839. Oliver, Dr. G., arteriometer of, 202-205. ,, ,, blood pressure of menstruation, on, 298. „ ,, epilepsy and pregnancy, on, 293. Oliver, Professor, off lead poisoning, 458. Opium action compared with that of belladonna,- 45-47 ; dependent on thei alkalinity of the blood, 121. ,, Bright's disease, in, 201-202. ,, chronic rheumatic arthritis, in, 818. ,, diminished effect in vegetarians, 343. ,, exercise, effects of, counteracted by, 359-360. habit, 211, 335. ,, Indian horses, given to, 403. ,, intravenous injection of, 342. ,, morphine effects on excretion of uric acid and, 60-61. phthisis, in, 440. physiological effects of, 61, 120-121, 155, 504. ,, preventive of disease, as, 151, 155, 404; parallel with pregnancy, 1S6. ,, pulse, effect on the, 195-196. ,, sexual appetite and, 154-155. „ skin wounds and, 297. ,, stomach pain, in, 468-469. „ wasting diseases, in, 257. Oppenheim, Dr., on tabes and migraine, 355. Ord, Dr., case of glycosuria with angina, 653. Organic disease, relation to headache, 269. Osier, Professor, cases of cirrhosis of liver, 667, Ovaritis. 135. INDEX 935 Oxalates, paroxysmal hsemoglpbiuuria, in, throw light on its oauaation, 567. ,1 urine, in, how produced, 566. Oxidation, 90 ; efieot of deficient, 52, 90. Pain : effects on blood pressure, 391. ,, severe, causing bradycardia, 212. Pakes, Dr. W. C. C, on " blackwater " fever, 521. Palpitation; case of, alternating with headache, 143 ; relief of, 210. Paralysis, 135 ; of cranial nerves accompanying migraine, 260. Parker, Dr. Eushton, on chloroform in parturition and afterwards, 39T. Parkes on urea and exercise, 373. Paroxysmal hsemoglobinuria, see haemoglobiuuria. Parturition : chloroform during and after, 397. ,, uric acid effects on, 153. Pathology, importance of urates in, 90-91. Peiper, Dr., alkalinity of blood in fevers, 39-40, 52, 338. Pelvic fibrous tissues, gout of, 469. Pericarditis and dilatation of heart, Mr. Barnard on, 749. Pericardium, inflammation of, 750; why less frequently affected than endo- cardium, 751. Periostitis, 135. Peritoneum, inflammation of fibrous tissues of, 135. Perspiration, acidity of, 52. ,, albumen in, 600. „ effects of, in meat and tea takers, 408 ; effect of arrest of, Sir A. Garrod on, 52. „ not weakening apart from collaemia, 381. Petitj Dr. , on the causation of epilepsy, 295. Pfeiffer, Dr. B., on irritation produced by urates, 764-765. Pharynx, inflammation of, pathology of, 433. ,, „ podagra alternating with, 433. ,, „ relation to gout and rheumatism, 433, 434. „ „ treatment of, 433. Phosphate of soda, 41-42, 179 ; action hindered by acids, 45, 175-176 ; acts best with alkalies, 45, 176 ; effect on uric acid excretion, 193-194. Phthisis, destruction of gastric mucous membrane and, 425. „ dyspepsia and, 425, 436. gout and; 424, 435-436, 440. „ Mays, Professor, treatment, 488 ; author's modification, 488. „ meat diet, effects of, 430, 439. ,, metabolism, effects of injury and depression of, 430. ,, open-air treatment, explanation of success, 662. ,, pregnancy and parturition, relation to, 436. „ rheumatic pneumonia, relation to, 431 ; author's suggestions, 431-432. ,, spring time and, 34, 435. „ treatment, by diet and drugs, 123, 198, 199, 437, 439 ; treatment of stomach in, 425. Pigeon's dung as a stimulant, 123. Piles, 136 ; and pruritus ani, Mr. Maitland Thompson on causation of, 652. Piperazidin, 45-46. Plasmon, its use, 866. Pleurisy, ;35, 434. Plumbism, see Lead colic. Pneumonia : case treated by salicylate, 560. causation of post-febrile bradycardia, 209, 339. post-febrile albumin aria and, 339. rheumatism and, 431. treatment by salicylates, 444-446. urates in blood in, 78, 125, 559. Poehl, Prof., when dangerous to give chloroform, 399. Population, excess of, relative to diet, not absolute, 369. Post-febrile temperatures, 558, 559 ; effects of drugs on them, 560. Potash, chlorate of, poisoning by, 526. Potatoes, value of, in diet, 344, 362, 372, 850. 936 INDEX Power, Mr. D'Aroy : case of Raynaud's disease, 499. ,, ,, irritation in the causation of cancer, 461. Precipitants, result of curing chlorosis by, 574. Precipitation of uric acid, diseases due to, 134-135. Pregnancy, chloroform syncope and, 397. cold and fevers, relation to, 151. effects of, on : asthma, 151, 416. ,, epilepsy, 497. , , excretion of urates, 496. ,, migraine, 151, 497. ,, myxoedema, 550. ,, Raynaud's disease, 496, 497. ,, suicide, 333. normal effects of, 151 ; abnormal, 152. opium, parallel effects with, 151. value of non-meat diet in, 288, 385, 627. Prentice, Dr. G. , on "blaokwater" fever, 520. Pressure and strain, arterial degeneration due to, 218-219, 221. Prominent eye, age of patients with, 149. „ blood pressure a cause of, 146. ,, facial conditions accompanying, 148-150. „ Graves' disease, of, distinguished from that of other condi- tions, 147. ,, stages of, 148. Prostatic troubles, high blood pressure and meat eating, 652 ; cure by diet, 652. Protene, use of, 866. Pruritus ani, 136, 652. „ vulvffi, 136, 653. Psoriasis, cured by salicylates, 507 ; different effects on covered and uncovered parts, 50'7. „ gout and, 507. ,, parallelism with uric acid diseases, 135, 506-507. ,, relation to salicylates and heat, 507. „ skin, a gout of, 508. ,, treatment of, 511. Ptomaines, 107. Puerperal convulsions, 206. ,, eclampsia treated by morphine, 318. Pulex irritans, 509. Pulse : alkaline tide, of, 169. antipyrin well-being, of, 195, 196. blood pressure, relation to, 396. Bright's disease, of, slow, 201 ; altered by drugs, 201. convalescence of, the effect of the fever, 208, 213. epilepsy, of, 206, 287. evening hours, of, 169. faltering, 213. fever, of, 208. intermittent, 213. irregular, 498. lead colic, of, 458. Marey's law of, rate, 167, 207, 394, 395. mental depression and melancholia, of, 206. menstruation, effects of, 157-158, 258, 340. mercury, low tension produced by, 194, 195.' opium, well being of, 195, 196 ; rebound, 195. Raynaud's disease of, 486-487, 498. temperature in mouth and rectum, relation to, 170. tension, see also Blood pressure. acidity of urine, relation to, 168. alkalies do not directly affect, 344. arteriometer and, 202. daily variations of, 169. high, effects on arteries, 216, 208. brain, 222. INDEX 937 Pulse : tension, high, effects on eye, 223. )i ,, ,, ,, kidneys, 223. >. ,, ,, ,, liver, 228. ,) ,, ,, ,, muscles, 218, 228. » ,) ,, ,, nutrition, 218. >. ,, ,, ,, skin, 223. ,, ,, ,, general effects of , 168. „ „ ,, signs of, 167, 202. 1, ,, ,, treatment by diet and drugs, 226, 228. ,, ,, method of demonstraticg, 202. ,, ,, sphygmograph, what it tells us, 230. ,, „ urates in blood, relation to, 13, 102, 167, 207. ,, tobacco smoking, effect of, 345. ,, uric acid headache, of, 251. Pulses, the : how they were found out, 257. „ result of eating, 219, 221. „ xanthine in, 870, 835, 857. Punch, case illustrating mental depression, 321. Purdon, Dr. H. S. , psoriasis and diet, 511. Purin in oatmeal, 835. ,, what it is, 8. Purpura, Bright's disease and, 506. ,, causation, 506. ' „ colloid uric acid, possible connection with, 506. ,, uric acid may explain its relation to many diseases, 506. Quinine, action of, in causing hsemoglobinuria, 526-527 ; in malaria, 524-525 ; in small and large doses, 49-51. ,, haemoglobinuria, an occasional cause of, 49, 521, 523. , , headache produced by, 49. ,, malarial fever, in, 521, 523. ,, plus excretion of urate caused by, 48. ,, Kanke, observations of, and their explanation, 49-50. ,, spleen, effects on the, in disease, 49. Badcliffe, Dr., on bromides and alkalies in epilepsy, 318. ,, „ epilepsy and migraine, 29.8. Kadial artery, blood pressure, relation to, 203. ,, posture, effects of, 203-205. Raynaud's disease, ague, relation to, 498, 520. ,, blood pressure, relation to, 420 ,, capillary circulation in the skin in, 232-283. ,, cases of, 477-485, 487, s«2. ,, causation of, 222, 476, 526. „ colloid uric acid and, 222, 486, 493, 504. ,, dyspepsia and, 138. ,, epilepsy parallel with, 293. ,, etiology of, 493. ,, extremities and surfaces, why limited to, 222, 493. ,, fevers, relation to, 498, 520. ,, girls and women, why more frequent in, 489, 498, 503. ,, haemoglobinuria, why associated with, 567, 577. ,, menstruation and, 496, 550. ,, migraine and, 496 ; parallel with, 293. ,, opium, use of, in, 508-504. „ pregnancy and, 416, 496-497, 550. ,, prevention by drugs, 511. ,, salicylates in treatment, 484-485, 519. ,, spasm, can it produce death of tissues, 222, 494, 506. ,, treatment of, 511. ,, uraemia associated with, Dr. Aitken's case, 501. ,, ,, urate excretion in, 477. Reigel, Professor, on bradycardia, 207, 208, 339. 938 INDEX Eenal epithelium, supposed action of drugs on, is often absurd, 121. „ vessels, contraction of, effects on flow of urine, 17C-171. Resins, action on uric acid, 103, 19S. Respiratory disease, a cause of bradycardia, 208, 211. Retention of uric acid, its meoBanism, 177, seq. Retinitis, 135, 510, 646. Reymond, Professor du Bois, on causation of headache, 259. „ ,, epilepsy, 277. Rheumatism, alkalies in, 742, 761. „ alternates with migraine 105, 311, 766. ,, artificial production of, 161. ,, oases of, 777, 784. causation of, 432, 758-759, 823-824; Mordhorst'a theories, 189; Dr. Newsholme on, 742 ; by cold and damp after fatigue, 385, 759, 802 : the late Dr. A. S. Bccles on, 759. „ chorea, relation to, 803, 808 ; observed relations, possible explana- tion, 806 ; Dr. Ghurton on, 807 ; to chorea and migraine, 766, 803. „ colohicum for, 760. ,, diagnosed gout, found, 778. ,, diet disease, a, 772, 773-775. „ dysmenorrhoea, connection with, 752. ,, Ecoles, the late Dr. A. S., on causajiion by cold and damp after fatigue, 759. ,, fatigue, relation to, 385. „ fever, effect of, in producing, 385, 742. ,, girls specially liable to, reason, 556, 753. „ gout : diagnosed, found, 778. ,, „ difference between, and, 745. ,, ,, often only a name for, 781. ,, ,, resemblance to, 759. ,, Graves' disease and, 145 ,, horses, amoug, 369-370 ;^its relation to fatigue, 335. ,, infective disease, as, 742, sej. „ is gout, 693. ,, iron effects in, 768. , , lemon cure for, 759-760. ,, local injury, effects of, 748, 751, 752. ,, menstruation and, 141-142. ,, Newsholme, Dr., on causation, 742. ,, origin, uric acid not microbes, 744-745, 772-773, 788. pelvic organs and fascia, of, 747. ,, pneumonia and, 431. ,, prevention in children, 783. ,, production by uric acid, 741, 744; explains action of diet and drugs, 742. ,, relapse and its cause, 792. „ salicylates in, 12, 45, 460, 741 ; non-effect of, in warm climates, 460 ; or with hot pack, 797 ,, sex and age, influence of, 556, 753. ,, specific febrile diseases, relation to, 743. , , solubility of urates explains it, 256. „ temperature in acute, 759. „ tonsillitis and fatigue, 766-767. ,, treatment of, 818, seg. ; 823. „ Turkish bath, effects of, 801. ,, urates, excretion by salicylates in, 741, 744; why they may be absent from joints after daath, 256, 746; solubility of, ex- plains the disease, 256. „ vegetarians in India, among, 372. Rheumatoid arthritis, confusion of ideas on, 781. >, ,, opium in, 818. >> ,. relation to migraine in women, 766 ; to megrim, 782. 11 ,, urates found after death, 781. Rhubarb, stimulant action of, 198. Rice, albumen in, 836. INDEX 939 Binger, Dr., ou zino and coppei: colic, 454. Roberts, Captain, on calculus in India, 880, 882 883 Boberts, the late Sir W., on : alkaline tide, the, 6, 168. „ Bright's disease, 185, 588. ,, efieots of fever on acidity of urine, 40 „ haemoglobinuria, 691. ,, solubility of the biurate, 706. ,, urate elimination, 6. V-- .1 1. uric acid excretion, 6. fiobertson, Dr. W. Ford, nitrogenous foods and paralysis, 358. ^Ueston, the late Professor, on relation of body surface to bulk, 776. Hoss, the late Dr., on well-being preceding fits, 278. Eoy, Professor, experiments on circulation of brain, 341, 342. .Salicln, 45. Salicylates, action of, in ansemia, 518, 571, 877. „ chorea, 804. „ common cold, 436. „ convulsions, 315. „ diabetes and glycosuria, 649. „ epilepsy, 285. fever, 527, 560, 637. ,, intestinal pain, 452, 465. „ lead colic, 459. morphine habit, 61-63, 336. „ psoriasis, 507. ,, respiratory troubles, 434. „ rheumatism, 12-13, 432, 744, 813; effects due to elimination of urates, 744. ,. „ ,, skin diseases, 507.. ,, alkalies hinder and acids aid their action on urates, 43 45 182 460 793. ..... ,, arthritis, fail to cure, in India, and reason, 796. ,, oases in which they fail, Dr. Buckler's experiences, 434 ; author's 792, 845 ; Dr. Osburn Cowen's, 797. „ cure psoriasis, 507. „ heat and cold, effects on their action of, 442, 507, 796, 817-818. „ immunity from cold while taking, 468. „ mode of using, to remove urate deposits, 707. „ rheumatism, do harm in, in certain conditions, 45, 792, 797. „ rules for administration of, in catarrh and pneumonia, 444-445. „ urate excretion under, in acute rheumatism, 45, 762. Salicylic acid and its compounds, 42. ,. ,, ,, cause plus excretion, not plus formation, 43-44. ,, ,, ,, opium and, in phthisis, 440. ,, ,, ,, plus excretion under, not accompanied by any headache, 193. Salicyluric acid : chemical explanation of clinical facts, 43. „ composition, 43. „ solubility, 42-43, 460. Saliva, albumen in, 600. Salivary glands, 138. Salol, 45. Salt in diet, 463, 841. Sambon, Dr., ou "blackwater" fever, 520. Sander, Dr. W., on migraine and general paralysis of the insane, 355. Saul, Mr. J. E., on action of lithia on excretion of uric acid, 58. ,, ,, estimation of urates when the urine contains iodides, 897. „ „ solubility of urates of mercury, 66-67 ; colloid uric acid, 175. Saundby, Dr., on albuminuria in Bright's disease, 586. Sayill, Dr. : cases of chronic articular rheumatism, 777. ,, skin troubles treated by calcium chloride, 511. Scarlatinal nephritis., prevention of, by salicylates, 637. Scarlet fever, prevention of sequelee by salicylate treatment, 637. 940 INDEX Soars, precipitation o£ urates on, 751, 752. Schrader, diminished output of nitrogen m menstruation, 15.3. Sohreiber, Dr. E., uric aoid infarcts, 80. Scotch freedom from gout, explanation, 728. Sea sickness, high blood pressure and headache of, 217. Season, effects of, on causation of disease, 34. ,, ,, depresssion and suicide, 331, 333. ,j ,, excretion of urates, 31-32. „ ,, gout production, 729. Sedentary occupations and suicide, 332. Semmola, the late Prof. ; Bright's disease, atrophy of skin in, 581-582; theory of, 581. „ ,, facts of, 580-581. ,_ ,, milk diet, on, 437. Setons, probable action of, in migraine and epilepsy, 266. Sex and suicide, 331-332. Sexual act, effect on blood pressure, 154-155. ,, appetite and blood pressure, 154-155. Sherrington, Prof., experiments on brain circulation, 341. Shock, pathology of, 406. Sibbald, Sir John, suicide rate and time of year, 325-326. Silver: efiects in epilepsy, 68, 316. ,, solubility of its urate, 68. ,, tonic efiects, 68. Skin, atrophy of, in^Bright's disease, 156, 585. ,, condition of, in headache, 156 ; menstruation, 142 ; with prominent eye, 148. ,, deficient circulation in, Mordhorst on, 191. ,, diseases of, 135, 136, 506. ,, ,, asthma, relation to, 426. ,, ,, iodides and bromides, produced by, 443. ,, ,, post-febrile, 505. ,, ,, treatment, 505. ,, ,, urio acid, relation to, 139, 504. ,, drugs, effects of, 122, 511. ,, fevers, effects of, 505. ,, menstruation and eruptions of, 139, 141-142. Sleeplessness, action of mercury in relieving, 324; explanation of connection. with high blood pressure, 324. Smith, Dr. B. E., excretion of uric acid in epilepsy, 281, 448. Smith, Dr. W. G-., on leucocythaemia, 495. Smith, Mr. Kellet, on hsemoglobinuria, 520. Solly, Dr., on climate in Brights disease, 641 ; gout, 730 ; hay fever, 427. ,, effects of cold, 411. Solubility of urates as a guide to the action of drugs, 87-88. ,, ,, effects on excretion, law of, 88. ,, ,, exceptions, as lithia, 58. ,, ,, explains action of mercury, 67-68. Southey, Dr., case of symmetrical gangrene, 491. Spender, Dr. Kent, opium in arthritis, 818. Sphygmograph, Dudgeon's, 902 ; Mr. Symons' pen for, 902. Sphygmometer, 233, 903 ; where obtained and how to use, 903. Spleen : blood destruction, a centre of, 558. ,, leucocythaemia, in, 495. „ uric acid stored in, 48, 76, 79, 127, 177-178. Splenic leucocythaemia, explanation of large urate excretion in, 76, 79, 126-127 ; if stores are reduced excretion falls, 127. Spratling, Dr. E. J., on epilepsy, 317. ,, ,, urticaria, 508. Spring and summer correspond to morning. 34 ; excretion of uric aoid in, 330. Stammering, periodic, pathology of, 264-265. Starvation and headache, 273, 275. Steavenson, the late Dr. W. E., on asthma and meat diet, 415, 416. Stevenson, Brigade-Surg. Lieut.-Ool., cases recorded by, 393. Stewart, the late Sir T. Grainger, case of myxcedema fed with thyroid, 550. INDEX 941 Still, Dr., on day terrors in children, 310. Stimulants and foods contrasted, 875, 878. Stimulation is always wrong, 336-337, 876. Stomach : aches, 463, 464. „ epilepsy, in, 279, 283. „ pathology of dilatation,_447. „ treatmant of, in headache, 273. Stone alternating with gout, 256. Structure modified by urate in blood, 551. Strychnia, action of, 69 ; on consumption, 438 ; on uric acid, 197. Sufficient urea without unnecessary uric acid, 160, 827. Sugar in glycosuria parallels excretion of uric acid, 662-663 ; may do no harm in gout apart from meat, 868. Suicide : age and nutrition, relation to, 328, 332. Bright's disease and, 333, 340. ,, daily and yearly fluctuations correspond with those of uric acid, 329. , , diet, as a result of error in, 334, 335. ,, drugs, relation to, 833. „ fever, relation to, 329, 332. ,, fluctuations in collsemia and, 325, 329, 330. „ increase of, 326, 334, 407. „ influenza and, 339. ,, menstruation, in relation to, 340. ,, moral failure and, 328. ,, occupation, relation to, 332. ,, physical conditions, efiect of, 327. ,, pregnancy and, 333. ,, sex, relation to, 331-332. ,, time of day in relation to uric acid and, 331 ; time of year, 325, 327, 329, 331, 333. ,, weather and, 333. Sulphates : action on phosphates, 45. „ causing retention of urates, 51. ,, waters containing, use in diabetes, 657-658 ; in gout, 712. Sulphuretted hydrogen action on urates. 566. Sulphurous acid : alkalinity of blood, effects on, 71. ,, ,, nitrites, similar action to, 71. ,, ,, preservative of vegetables, 71 ; of wines, 71. Summer months, efiect of, on : causation of gout, 327, 730 ; excretion of uric acid, 32. Sunstroke, causation of, 212. Surgical operation, efiect on urea and sugar, 565, 661, 662. Sutherland, Dr. G. A., inflammation of vermiform appendix, 464. Sydenham, on the efiect of sedentary work on gout, 729 ; gout as a winter disease, 729. Sympathetic nerves versus uric acid, 215-221. Sympson, Dr. Mansel, salicylates in diabetes, 681. Syncope: bathing, causation by, 213. chloroform, after : connection with alkaloids in urine, 399 ; with diet, " „ 398 ; with gout, 398. " Horder, Dr. E. Q-., experience among the Chinese, ", " 398. Kirk, Dr., on, 388. ] ,, suggested causation of, 401. „ fatigue, causation by, 386, 387. „ kneeling posture, due to, 395. Syphilis and Baynaud's disease, 502. Tabes, relation to, blood pressure, 354, 356. ,, general paralysis, 357. ,, ,, migraine, 355. Tachycardia, 209-210. Tar, bronchitis, asthma, and phthisis, use in, 198. ,, stimulant, as a, acts like an acid, 198. 942 INDEX Tar, uric acid, action on, 103. Tea drinking, is uric acid taking, 836. epileptic fits, effect on, 307, 808, 309. ,, stimulant action of, 123. ,, suicide and, 335. Teeth troubles, relation to gout, 739 ; treatment by salicylates, 739. Teething and catarrh, 412. Temperature : collsemia, a guide to the severity of, 36-38. „ curves in rheumatism and gout, 758. ,, menstruation, efiect of, 1S7-1S8. ,, metabolism, as a guide to, 610. mouth and rectum, in, effects on, of disease, 36, 37, 38. drugs, 36,38. exercise, 37. ,, ,, ,, Marey's observations, 35. ,, subnormal, in headache, 2S1. Test meal to estimate activity of metabolism, 588. Theatres and hot rooms : alkalinity of blood, effect on, 53. ,, ,, headaches dueto, 53. ,, ,, urates in blood, effects on, 63. Thein, 107, 307. Theobromine equivalent to uric acid, 8, 94, 107, 193. Thin, Dr. G. , on lime in water as a cause of gout, 69. „ ,, parasite of malaria, 522. Thirst : absence of, in Bright's disease, 201 ; Etbsenee of, and distaste for fluids in collsemia and hydrsemia, 30. „ goes vfith absence of uric acid from blood and diuresis, 30. ,, meat eating and, 874. „ sign of want of water in blood, 201. Thompson, Mr. Maitland, on causation of pruritus ani, 652. Thrombosis : Bright's disease in, 666. ,, causation by uric acid, 565. ,, diabetes and, 564. ,, Payrer, Sir J., on, 565. „ gout and, 564. ,, heat, damp and surgical operations, efiect of, 565. Thymus feeding causes increased excretion of uric acid, Dr. Mordhorst on, 119. Thyroid extract as a stimulant, 128. feeding causing ansmia, 550. ,, ,, asthma, 551. ,, „ migraine, 118, 119. ,, myalgia and asthma following, 117-118. gland, effect of, due to nitrogenous extractives, 118 ; effect Of swallowing, 116, 117, 118. „ ,, enlargement of, during menstruation, 142, 146. Time of day, relation to blood pressure in mania and melancholia, 351. Tobacco : irritability and mental depression, effects on, 345. ,, mental power diminished by, 845. ,, migraine, probable action in, 267. , , pulse tension lowered by, 845. ,, smoke, efiects on alkalinity of blood, 429. Todd, the late Dr., cold bath and depression, 325. Tomson, Dr., case of paroxysmal albuminuria, 572. Tonsillitis, case of recurrent, cured by taking urine, 124. ,, enlargement of cervical glands and, 769. ,, rheumatism, relation to, 768. Tooth, Dr. , case of dropsy removed by fever, 608. „ treatment of epilepsy by salicylates, 285. Trachea and bronchi, gout of, 135, 433, 844 ; treatment by salicylates, 433, 845. Treatment, general remarks on, 825. Treves, Sir F., causation of typhlitis, &c., 467. Turks, endurance and vitality of, 368, 405. Turkish bath, effects of, 704, 801. Turpentine, 103. Typhlitis : causation, 467. INDEX 943 Typhlitis : treatment by salicylates, 453. Typhoid fever, pulse of, 213. Tyson, Dr. W. T., on Vichy water and migraine, 274, 813. T^son, Professor, on salicylates in gout, 877. Uraemia, case of, showing causation, 605 ; urates and granules in blood, 607 „ classification of, 135. ,, diuretin in, 193. ,, evil eHects of too much fluid, 318. „ fits of, 206, 605. „ gout, ending in an attack of, 879. ,, headache of, 605. ,, opium, use of, in, 606. „ pulse of, 605. „ Raynaud's disease, in associiation with, 501. ,, symptoms of, often due to uric acid, 603; parellel to those of col- Isemia, 605. ,, treatment of, 318, 606. „ urates in blood of, 605. ,, urea, low, on days of attack, 501 ; not due to defective elimination, 501. Uranium nitrate, mode of action in diabetes, 688. Urate, the needle (Mordhorst), 187 ; spherical (Mordhorst), 187. Urates: absence from joints after death no proof that thev have not been there 182, 256, 746. acids add alkalies, action of, 175-176, 178, 182, 183. acute rheumatism, excess in urine of, comes from the joints, 762 ; not found in joiots in, 746. attracted by certain organs and tissues, 105, 125, 265. causing functional disease, 165. efiects of swallowing known quantities, 107-108. greater formation per lb. in the young, 775-776. irritate surroundiDg tissues, 160, 693, 762. precipitation on scars, 752. pregnancy, increased in, 496. solubility of. Dr. Luff and the late Sir W. Roberts on, 705, 706. solution and removal from joints in gout, 708, 781. Urea, administration of, effects of, 439, 578. amount of, relatively to uric acid, 16-19, 26, 27, 277-27«, 281. diminished formation of, in Bright's disease, 581, 592. estimation of, 893. excretion the guide in diet, 834, 857. fall in excretion of, in fatigue, 205, 361 ; its meaning, 379. formation of, as a test of nutrition and of Bright's disease, 588-589 ; relation to albuminuria, 592, '612; effect of exercise on, 360-362, 379. fluctuations, 289. increase of, by surgical operation, 661. large excretion of, in the cure of Bright's disease and its meaning, 612-618. physiological level of, 160, 871, 827. tuberculosis in, 489. Uric acid: acidity of urine, raised by, 40, 110-111. ,, annual variations in relation to disease, 38. „ arthritis of, general law of causation, 743. ,, artificial plus excretion, 39. „ attracts uric acid, 163, 177-179. ,, blood, in, 73, 76-79, 124-126, 184, 186, 190, 442, 547, 554. I, „ amount deduced from amount in urine and relation to urea, 21, 898. ,, ,, amount may be estimated by the microscope, 92, 655, 899. ,, ,, animals, and viscera of, 82-83. „ "„ birds, of, 19 n,, 656; Dr. Watson on, 656. ,, ,, daily variations in, 1.68-169. ,, blood destruction and. Dr. Hunter on, 531, 567. ,, chemical composition of, 107. -944 INDEX Urio acid: causes disease through its effect on the circulation, 132-133. coUsemia, absolute freedom from, 408. colloid form and the causation of : Raynaud's disease, 222, 48b, 4Jd " thrombosis, 564-565 ; possible mechanical obstruction of capil- laries by, 173, 175, 215. control of, inevitably controls diseases due to it, 864. ■ ,, daily excretion, 23, 25. deficient combustion, a cause not a result of, 153. ,' direct absorption of, from food, 7, 109. discovery of pov?er to alter excretion, 3, 6, 20, 39, 105. , characteristic of, 401. classification of, 131-136. diet causation, 833, 871, excess of nitrogen, may be due to, 841. possible on any diet, 843. result of folly in diet, 888. dissolved by salicylate, 429. diurnal effect on temperature of skin, 35-36. diurnal variations in relation to disease, 31, 34. effect of taking, depends on alkalinity of blood, 108-119. effects of taking Liebig's extract of meat, 112 ; xanthine, 114-116. effects on : blood pressure, 183. excretion of : diet, 109-113, 227, 832. caffeine, 115, 117. ,, hypoxanthin, 114. meat dinner, 110. ,, sheep's thyroid, 116, 117-119, 550. ,, tea. Dr. Morton's experiments, 830. metabolism, 90, 104, 107-108, 378. ,, tissue circulation, 133. enormous pov?er over circulation and so over physiology and path- ology, 39. epilepsy, relation to, 287-288, 814. estimation of, 231, 894 ; advantages of Haycraft's process, 897 j from the hourly excretion of vpater, 898 : in tissues and organs, 898 ; why begun, 2. excess due to previous failure of excretion, 20, 132. excessive formation, Murchison, 729. excretion, adults and old people, in, 17-19, 248. ,, blood decimal and, 9-10, 535. „ control of, 132. ,, dog under hyposulphite of soda, 82 ; under salicylates, 83. „ dogs, in, 82. „ drugs, effects of. 38, 192, sec[. „ epilepsy, in, 279, 291, 299. fever and inflammation, in, 28, 208, 389, 659-601. ,, large, in spring, 33, 491. ,, menstruation during, 139, 140, 141, 142, 158. ,, parallel with sugar in glycosuria, 661. ,, results of author, 14, 16-17 ; of others, 19. ,, salt, effect of, on, 841. ,, seasonal alteration of; 156, 159. „ sodium, under bicarbonate and salicylate of, 793. „ wasting disease, in, 18-19, 256. factor in causation of disease, as a, 165, 527. filter experiments, 178, seq. formation, 17, 128-129, 131, 192 ; in dogs, 83 ; relation to urea con- stant, 181-182, 160. fluctuations, 325-829, 573. free diet, why so called, 875 ; and the curve of blood decimal, 570. Garrod, Sir A., theories of formation and excretion, 5, 13, 19. general conclusions about formation and excretion, 124. granules in the bltfbd of birds, 556 ; man under complete control, 556. headache : alkalies, cured by, 183. ,, drugs relieving, 195, 196. ,, epitome of a wide field in pathology, 247. INDEX 945 Uric acid : headache : eye symptoms of, 251. „ production of, by vinegar and acids, 183, 184. „ slow capillary reflvix between attacks, 270. „ treatment of, by starvation, 273, 275 hetero-albuminaemia and albuminuria, a cause of, 585 hospital beef tea, in, 480, 542, 543. increased by quinine, 525 ; introduction or elimination mistalien for mcr^eased formation, 39, 128-129, 862; formation, no proof of, infarcts in kidney, 80-81, 125. interferes with its own solubility, 190. inverse relation to urinary water, 22, 27, 111, 191-192 kidneys, in, 74, 79, 104, 125. large excretion not a sign of large formation, 864 metabolism and, 161-162. microbes plus, diseases produced by, 135. natural plus excretion, 21, 22. oatmeal, in, 835. percentage of, in various food substances, 826. plus excretion : under alkalies, 39. „ belladonna, 46-47. ,, phosphate of sodium, 41-42, 45. ,, quinine, 48-51. ,, salicylate of sodium, 43-44. wasting disease, in, 257. „ pneumonia, in, 78, 125. „ poisoning by, diagnosed as hysteria, 598, 600. „ precipitated by chloride of ammonium, 548. ,, pulse tension relation to, 167. „ quantity : blood, in, in various diseases, 125. 1. 1, foods, in, how to estimate, 826. )) ,, introduced with food, 110. » „ various tissues, in, 125. „ removal of, 165. ,, retention produced by acids, 50-51, 178, 182-183. j> ,) „ alkalies with salicylates, 182. » ,, ,, antipyrin, 68, 69. )) I, „ cocaine, 62, 68-64. » „ „ iodides, 100, 102. » 1, ,, iron, 63-54. » ,. ,, lead, 53, 54. „ ,, „ lithia, 57-58 ; explanation of, 58. ,1 ,, ,, mercury, 66-68. „ „ ,, morphine, 60-61. ,, „ „ nitrites, 71-72. „ „ „ silver, 68. „ solubility and excretion, 39, 88, 104-105, 178, 192. ,, sources of excreted, 181. spleen in, 76, 79, 104, 125, 471. „ stimulant, as a, 123. „ taken by mouth, 7, 123, 124, 130, 163-164, 225, 358, 376. „ time of life, relation to, 247-249. „ tissues other than spleen and kidneys, in, 74, 79, 80, 104, 125. „ warmth and, 851. „ yearly excretion, 81-32. Uricacidaemia, see CoUsemia. Urinary diseases and bradycardia, 208, 211. pigments in lead coUc, 666 ; their meaning, 666. water : asthma attack, relation to, 416. ,, blood pressure, relation to, 170. „ day and night hours of, 27, 29, 170. ,, excretion controlled by controlling uric acid, 170. „ inverse relation to uric acid, 22, 27-30, 103, 133-134, 191-192, 197. „ lithia, effects of, 196. 60 946 INDEX Urinary water : profuse after headache, 252 ; from excess of water- in blood, 27 ; in fever and dropsy, 28. ,, ,, relation to other excretions, 419. „ ,, soda and potash, effects of, 197. „ „ , scantiness not due to digestion, 30, 194. „ ,, scanty before and after breakfast, 194; during headache, 251- 252 ; from obstruction of circulation, 27, 195, 200 ; from want of water in blood, 28, 30, 200 ; during epileptic fits, 302. „ ,, water from lungs, relation to, 418. Urine, acidity of, 16, 26. alkalinity of blood, relation to, 21, 89. estimation of, 898. excretion of uric acid, relation to, 23-24, 26, 39, 104-106, 168. headache and, 257. iodides, effects of, 197. lithia, effects of, 196, 197. menstruation, in, 258. oxidaMon, relation to, 52. time of lowest, 184. urea, relation to, 16, 25-26, 51-52, 546. „ fits of, 206, 802. ,, index of blood condition, as, 96, 104, 291. , , in treatment of : epistaxis, 123 ; recurrent sore throat, 124. ,, lead colic, of, 458. ,, poisons in : bad subjects for chloroform, 399 ; epilepsy, 278, 299, sej., 566 ; pernicious ansemia, 567. ■ Z^ ,, sp. gr. may be high in granular kidney, owing to large excretion of urates, 782. „ stimulant and tonic, as, 123. „ toxicity of, 399-400 ; parallel with excretion of urio acid, 399. Urticaria : acute rheumatism, relation to, 504. ,, uric acid, a main factor of, 508. Vascular degeneration : blood pressure and, 218. ,, „ urates, due to, 222. ,, „ vegetarianism and, 218-221. Vasomotor system : albuminuria, and, 588. ,, „ deficient circulation and the, 214-216. Vegetable alkaloids, 107, 117. ,, ashes in gout, Dr. Luff on, 724 ; criticisms by author, 725. Vegetarian diet : alcoholism in, 336. colds and, 440. endurance and, 366-367. epilepsy and, 286. India, in, 527. pregnancy, in, 385-386. Vegetarianism : advocates of, 891-892. ,, old age and, the late Prof. Humphrey on, 422. Venesection effects on chlorosis, 159. Vertigo, causation of, 263-264 ; Dr. Buzzard on, 263-264. Vichy water in migraine, 274, 313. Vomiting : circulation in, 214. „ pulse of, 217. Voisin, Dr. , on causation of epilepsy, 295. Von Jaksch, Professor, author's explanation of his results, 84, 90. „ „ salicylates in fever, on, 637. ), „ nricacidsemia, on, 84. Wade, Sir W. F. : on immunity of pregnant women from infectious disease, 151 i> I, menstruation, effects in chlorosis, 159. i< „ venesection, effects of, 159. Warren, the late Dr. Pelham, on the treatment of epilepsy, 286.' INDEX 947 Wasting disease, urates in blood in, 125 ; excessive excretion of urates in, 18-19, 256 ; explanation of, 708. Water : drinking in uric acid diseases, 886-887. „ excretion from lungs, 417-419 ; relation to urinary water, 417-419 ; how estimated, 417, 901. Watson, Dr. J., case of gouty gastritis cured by salicylates, 465-466. Watson, Dr. Chalmers : excretion of uric acid in a case of gout, 698. „ „ uric acid in blood of birds, 555. Well-being, what it is, 321 ; relation to : angina, 655 ; headache, 257, 258 ; fits, 258. West, Dr. S., treatment of diabetes by uranium nitrate, 688. Weston, signs of fatigue in, 381. Wheaton, Dr., on blaokwater fever, 520. ,, blood in Raynaud's disease and hsamoglobinuria, 479, 482, 486, 520. „ specimen of uric acid infarct in kidney, 80. Whisky, gout not produced by, 338 ; acidity of, 728. Wholemeal bread, xanthiu in, 861. Wiesbaden gout water, 312, 314. Williams, Dr. Ethel M. N., circulation disturbances and mental conditions, 312. WUliams, Dr. 0. P., compressed air in asthma, 426. WUliams, Dr. Koger, on cancer and food, 461. Wilson, Mr. A., on chloroform syncope, 389-390, 392. Wilson, Dr. T., on headache, 183. Wiudle, Professor, on fatigue and rheumatism after it, 367, 369. Wines, acidity of, 716. Winter and summer, effects on excretion of urates, 32. Women and men, relative liability to diseases, 353, 354. ,, „ exophthalmic goitre, 147. „ „ gout, ratio between, 883. ,, ,, Graves' disease, 142. „ „ stone, ratio between, 883. Work, nitrogen output and, 373, 374-375. Wynne, Dr., on causation of epilepsy, 292, 295. Xanthine and its compounds, equivalent to uric acid, 8, 107, 225. „ chemical composition and relations, 107. ,, human blood in, 556. ,, metabolism in the body, 115. ,, physiological effects, 106, 114-115. Xanthines : asparagus, in, 861. „ breads, in, 835, 836. „ method of estimating quantity in any food, 9, 115-116. universal throughout the vegetable kingdom, 835. ,, urea, how they cause a rise of, 124. Yavein, Dr., on excretion of water from skin and lungs, 414, iYl. Young, Dr. W., oases illustrating efiect of non-meat diet, 271-272, 874. effect of surgical operation on the excretion of urea, fabl-bbJ. Yvon and Berlioz, MM., relation of uric acid to urea, 19. Zinc, colic due to, 451, 452. ,, solubility of its urate, 68. „ tonic effects, 68-69. Zuelzer, Semiologie des Harns, 41 n.