^8B Bli 1111 1111 ""■■••'•' Bgjfir HI ■Ml ■Ab^s i Hi HSU -.; ; : S : s § ■ ' E 1 : gggl '. ; g - i § §£ ■ aiSKsseliwH ?, s*»< m ■■bEBbH * Class Book__ __ Copyright N? Gs COPYRIGHT DEPOSIT A TEXT BOOK ON URIC ACID AND ITS CONGENERS WITH SPECIAL REFERENCE TO ITS PHYSICAL AND CHEMICAL PROPERTIES, ITS METABOLISM AND ACCUMULATION IN THE ORGANISM TOGETHER WITH THE DISEASE PROCESSES ARISING THEREFROM AND THEIR .ETIOLOGICAL THERAPY FOR MEDICAL STUDENTS AND PRACTITIONERS BY GEORGE ABNER GILBERT, M. D. Member of Local, County and State Medical Societies of Connecticut; Physician to the Danbury Hospital, etc.; Once Fellow of the New York Academy of Medicine. FIRST EDITION 1907 THE DANBURY MEDICAL PRINTING COMPANY DANBURY, CONNECTICUT, U. S. A. LIBRARY Of CONGRFSSl Two Cooles Received i OCT 24 I90f . Copyright Ertrv CLASS' 4 XKc, No, COPY B. Entered according to Act of Congress, in the year 1907, by The Danbury Medical Printing Co., in the Office of the Librarian of Congress. All rights reserved. PREFACE. This volume is offered as a means of enabling physicians and students to better acquaint themselves with the fundamental principles of uric acid and its accumulation in the organism: a subject which every doctor is supposed to be somewhat familiar with, though one which is barely touched upon in any of our standard text-books. The need of such a work at the present time is almost imperative, not only on account of the vital bearing of the subject upon the ills of human kind, but in order that applicants for license to practice medicine may possess some medium for acquiring the specific information so often demanded of them. For instance, atone of the exami- nations, held not long ago by the New York State Medical Examining Board, among other interesting questions propounded in the Physiology paper occurred the following: " How is uric acid 'developed in the human system? What class of foods increases the development of uric acid?" A few years ago, physiologists would have been obliged to give quite different answers to these two questions than are given to-day. Yet the physician is supposed so keep himself fully abreast of the times and explain such mooted points satisfactorily. To do so, however, he must, perforce, seek assistance from various rare sources outside his library. He must have access to scores of foreign and domestic scientific medical journals, which have been issued from time to time during the past four or five years. Scattered throughout their numerous pages, he may, iv PREFACE. if sufficiently patient and persevering, find some highly instructive papers on the subject, written by profes- sional chemists and other experts. But he must be able to sift the "wheat" from the "chaff" — the "truth" from the "poetry." Many of the older chemical theories have been exploded; therefore, it is only by extensive and painstaking research through this form of literature that a proper understanding of the present status of the uric acid question can be formed. It is partly to fill thismanifest want that the present work has been published. In it have been brought together from all available sources the results of the experimental work of competent Swedish, French, German, Russian, English and American investiga- tors, the deductions from whose findings are presented as far as may be in a simple straightforward manner and from the most practical viewpoint. Few vital questions before the medical profes- sion to-day possess greater interest than does this of uric acid; and it has therefore been the aim here to furnish needed information along such lines as will enable the physician or student to better comprehend the subject and apply his added knowledge to some practical use. G. A. G. 179 Main St., Danbury, Conn. TABLE OF CONTENTS. CHAPTER I. Its Place in Nature. page As a Nitrogenous Excrement 7 As a Plant Food 8 Anabolism vs. Catabolism 8 Location in Vegetable Food 9 Location in Flesh Foods 10 Its Cumulative Action 10 Its Power for Good or Evil 11 CHAPTER II. Historical Review. Discovery of Uric Acid (1776) 13 Early Chemical Findings (1 793-1848) 13 The Early Medical Theory (1 797-1870) 14 Garrod's Discovery (1848-1854) 16 Garrod's Theory 17 Early Xanthin Findings (1851-1889) 17 Early Theory Exploded (1868-1893) 18 Recent Findings (1 895-1905) 20 CHAPTER III. Physical Characteristics. Isolation of Uric Acid 21 Its Appearance 21 Reaction 21 Solubility 2 r Crystallization and Precipitation 23 Attraction 25 Ionic Dissociation 26 CHAPTER IV. Chemical Properties. Composition of Uric Acid 27 Its Acid Behavior 27 Its Purin Structure 28 Nuclein Cleavage 29 Uric Acid Decomposition 31 Synthetic Formation 33 CHAPTER V. Physiological Processes. Endogenous Origin 37 Exogenous Origin 38 Catabolism 38 Decomposition 39 Catalysis 4° Circulation 41 Excretion 43 Egestion vs. Ingestion 44 Purin Bases in Faeces 45 Importance of the Subject 4° The Four Oxidases ., 47 2 TABLE OF CONTENTS. CHAPTER VI. Purin Metabolism. page Definition 48 Unbound Purins — Exogenous 48 Bound Purins — Exogenous 49 Fate of all Food Purins 50 Pharmacologic Action 51 Comparative Metabolism 53 CHAPTER VII. Evolutionary Development. The "Special Creation" Theory 57 The "Spencerian" Theory 58 Transitional Stage 59 The Decimal Decrease 62 An Intermediate Product 64 Muscle Metabolism 66 Vis Inertice 67 CHAPTER VIII. Accumulation in the Organism. Purin Removal 68 Normal Finding of Uric Acid 68 Its Presence a Menace 69 Toxicity of the Purins 69 Why Not Urea? 70 Uric Acid Excess 70 Purin Foods 72 Tables of Exogenous Purins 73 Meats 73, 74 Vegetables , 74 Beverages 74 Miscellaneous 75 White vs. Dark Meats 75 CHAPTER IX. Accumulation in the Organism {Continued). Blood Alkalescence 77 Urinary Acidity "... 78 Weakened Reaction of Blood 79 Deposition of Urates 80 Effect of Alcohol 82 CHAPTER X. Disease Processes. Purin Excess 84 Its Three Stages 84 (1) Uricacidremic Stage. Names 85 Increased Viscosity 86 Capillary Obstruction 86 Localization of Symptoms 87 Faulty Metabolism 87 (2) Rheumatic Stage. Names 88 Transition Period 88 Localization of Symptoms 89 TABLE OF CONTENTS. 3 (3) Gouty Stage. page Definition 90 Formative Period ^ 90 Localization of Deposits 91 CHAPTER XL (ij Uricacid/emic Manifestations. Pain 95 Headache 96 "Next Morning" Headache 97 Fits of Blues 98 Insomnia 99 Headache Powders 100 The Neuroses 102 Periodicity of Symptoms 102 CHAPTER XII. (2) Rheumatic Manifestations. The Beginning 104 Muscular Stiffness 104 Uric Acid Explosion 106 Sites of the Deposits 108 Leg Cramps no CHAPTER XIII. (3) Gouty Manifestations. Characteristics 113 Genito-Urinary Concretions 113 Concretions in Toe-Joint 115 Other Tissues 116 Objective Signs 116 Experimental Production of Gout 117 Intestinal Lithiasis 119 Frequency of Gout 120 CHAPTER XIV. Sequel.e and Complications. Constipation 122 Hepatic Insufficiency 125 Acid Dyspepsia 126 Renal Inadequacy 127 Urea Retention 129 CHAPTER XV. Urinary Analysis. Ocular Inspection 131 Alkaline Urine 133 Retention of Solids 134 Irritability of Neck of Bladder 135 Hepatic Torpor 137 CHAPTER XVI. Uric Acid Tests. Murexid Test 139 Approximate Test 140 Heat and Acetic Acid Test 140 Heintz' Test 141 Harley's Test 142 Schiff's Test 142 Dimrock and Branson's Method 142 4 TABLE OF CONTENTS. PAGE Microscopic Examination 143 The Complicated Tests 144 The Uricometer 144 Hall's Purinometer 145 A Simple Test 145 CHAPTER XVII. Bright's Disease. Definition 146 Congestion 146 True Bright's 146 Renal Dialyzer 147 Specialization 14S Localization 148 Etiology 149 Experiments upon Rabbits 151 Deductions 152 The Three Stages 154 An Early Sign 155 CHAPTER XVIII. Infants and Children. Uric Acid Infarcts 156 Symptoms 157 A Clinical Picture 158 Uricacidaemic Signs 159 Cyclic Vomiting 162 Hematuria 162 Lithiasis 162 Albuminuria 163 Asthma 164 Rheumatic Signs 164 Chorea 165 Diagnosis 166 CHAPTER XIX. Menstruation, Gestation and Menopause. Normal Menstruation 167 Clinical Deductions 168 Therapeutic Conclusions 1 69 General Toxaemia 1 70 Toxaemia of Pregnancy 171 Morning Sickness 172 Puerperal Eclampsia 1 74 Prophylaxis 176 The Menopause 177 CHAPTER XX. Eye, Nose and Throat. Trend of Opinion 1 79 Ocular Phenomena 1 79 Iritis and Coroiditis 180 Temporary Visual Irregularities 181 Astigmatism 182 Nasal Affections. . . 183 Hay Fever 183 Lithaemic Sore Throat 186 Therapy 1 8fc TABLE OF CONTENTS. 5 CHAPTER XXI. Traumatisms and Surgical Notes. page Joint Injuries 188 The Interpretation , 190 Other Traumatisms 191 Sluggish Ulcers 192 A Surgical Hint 192 A Determining Factor 193 CHAPTER XXII. Some Usually Unrecognized Uric Acid Conditions. Spine and Lower Extremities 197 Symptoms 197 Therapeusis 199 Precaution 199 Growing Pains 199 Etiology 201 Raynaud's Disease 202 Local Signs 203 The Uric Acid Theory 203 Conclusions 205 CHAPTER XXIII. Dental Conditions. The Teeth 207 External Influences 207 Protection 208 Decay 209 Uricacidoemia 21 r Toothache 212 Later Stages 214 CHAPTER XXIV. Haig's Work. His Three Books 217 Their Popularity 217 His Theory 218 Concerning Drug Action 219 Adverse Criticism 220 His Mistake 221 A Singular Contradiction 222 Value to the Clinical Worker 224 CHAPTER XXV. The Food Question. Effect of Environment 226 Vegetarianism 228 Modern Conditions 229 Purin Feeding 230 The Remedy 232 CHAPTER XXVI. Dietetics. General Rules 234 Uricacidaemic Patients 235 Rheumatic Patients 237 Chronic Cases 238 Gouty Stage „ 242 Evils of No-Flesh Diet 243 6 TABLE OF CONTENTS. CHAPTER XXVII. Etiological Therapy. page Definition 245 Exciting Etiological Factor 245 Predisposing Etiological Factors 247 Incidental Etiological Factors 249 Summary 250 CHAPTER XXVIII. Current Therapeutic Methods. Nosological Basis 251 A Source of Therapeutic Error 252 Symptom Therapy 253 Its Limitations 256 CHAPTER XXIX. Effect of Remedies in Common Use. A Frequent Indication 258 Prevailing Custom 258 Temporary Effects 259 111 Effects 260 Action of Drugs Used in Rheumatic Stage 262 Effect of Salicylates 263 Concerning the Alkalies 264 CHAPTER XXX. Concerning Gout Therapy. Status of the Question 266 Prevailing Type of Medication 268 Use of Alkalies 270 Effect on Genito-Urinary Concretions 272 Laxative Effects 272 CHAPTER XXXI. The Alkaline Eliminant. Definition 274 Its Clinical Purpose 274 The Objective Effect 270 Its Solvent Effects 278 Methods of Administration 280 CHAPTER XXXII. Lithium. Solvent Properties 283 Combined with a Laxative 284 Sodio-Lithium 285 Its Chemical Action 286 CHAPTER XXXIII. Final Word. Autotoxemia Due to a Non-toxic Factor, 289; The Uric Acid Diathesis, 290; Extent of Investigation, 290; Uric Acid Destruction, 291; Experiments Extra Corpus, 291; Croftan on the Rationale of the Alkaline Treatment, 292; Minkowski and von Noorden on Treatment, 293; Prof. Mendel's Discovery, 294; Classification into Three Stages, 294; Uric Acid an Intermediate Product, 295; Urea the End Product of Purin Catabolism, 295. URIC ACID AND ITS CONGENERS. CHAPTER I ITS PLACE IN NATURE. As a Nitrogenous Excrement. — Nitrogenous metab- olism is recognized to be one of the most important of life's vital processes, of which, in the animal kingdom, uric acid is one of the two essential end products. Though man and many other vertebrate animals give off their urinary nitrogen principally in the form of urea (86 per cent.), birds, insects and reptiles excrete theirs almost entirely as uric acid. Why uric acid should be the end product of tissue metamorphosis in some animals, and not in others, has long remained a mystery to the physiologist. It would seem only rational, however, in the light of modern evo- lutionary science, to conclude that the excretions of animals must necessarily correspond with the individual structural environments of such excretions — i. e., their respective anatomical organs. The mammal, with its kidneys and accessory genital organs, has reached an anatomical evolutionary development which necessitates its nitrog- enous waste being presented in a more soluble form — i. e., urea. In other words, a morphological structure like the 8 URIC ACID AND ITS CONGENERS. kidney, and a physiological excretion like urea, necessarily go hand in hand— evolve pari passu. The fowl and serpent, and other oviparous animals (those that spawn or lay eggs), have never been evolved to the stage requiring a special urinary apparatus, there- fore there is no necessity of their nitrogenous excreta being presented in the more highly oxidized form of urea; for, inasmuch as the ureters end in a common cloaca with the rectum, it may pass out with the feces in the less solu- ble form of uric acid. It has been noted, too, that the red blood corpuscles of all oviparous animals contain nuclei — not observed in the red globules of mammals. As a Plant Food. — The complementary and anti- thetical relationship existing between the metabolic pro- cesses of the animal and vegetable kingdoms is often very strikingly illustrated. The animal, for instance, exhales carbon dioxid, and inhales oxygen: the plant absorbs the former and gives off the latter. One furnishes what the other needs. In a similar manner the fruits of plants serve as a food for animals, while the excrement of animals serves as a food for plants. For years, guano has been used by the agri- culturist as a fertilizer. The guano of commerce is obtained from the islands off the coast of Peru, to which large flocks of sea-birds resort. It is chiefly composed of their excrement in a decomposed state and consists principally of uric acid in the form of ammonium urate. Anabolism vs. Catabolism. — The nitrogen, or ammonium content (NH 4 ), of uric acid (probably nitrate of ammonium), is utilized bv the plant as a food-essential which either is combined with, or is instrumental in the combining of other elements, to form and elaborate tissue ITS PLACE IN NATURE. 9 structure. It is a singular fact that plants have the power of building up or forming from the simple inorganic ele- ments in Nature, the complex organic structures of which they are composed and which serve as food for animals. In short, their metabolic process is chiefly a synthetic process. Animals do not possess this power. On the contrary, they take the complex substances already built up by plants, which, in becoming a part of the animal organism (i. e., digested, absorbed and assimilated), are decomposed into their original elementary parts. The metabolic pro- cess in animals is chiefly an analytical process. The plant, as may be seen, utilizes uricacid as a food constituent; while the animal excretes it as useless waste. In this way, this substance has become an important factor in the cycle of life: in the anabolism of vegetable tissue and the catabolism of animal tissue. Location in Vegetable Food. — Uric acid does not, of course, occur, as such, in plants. It is synthesized to an allied form of purin or xanthin. It is located where we would naturally expect: in the vitalizing or fecundating organs of the plant, i. e., in the germinating seeds, ovules and leaves — as in coffee and tea, peas and beans. In short, it is found in the parts analogous to the secreting organs of animals — the vegetative or reproductive parts: where it appears, in one, an active source of metabolism, and in the other as a passive result. The uric acid or ammonia derivative, in plants, exists as an "alkaloid"; as theobromin (from cacao beans and seeds of theobroma cacao); caffein or theophyllin (from seeds of the coffee tree or from tea leaves) ; morphin ; codein; narcotin; quinin; strychnin; veratrin; atropin; etc. In animals, the analogous bases from which uric 10 URIC ACID AND ITS CONGENERS. acid is metabolized, are guanin, xanthin, hypoxanthin, adenin, etc. Location in Flesh Foods. — By "flesh food," we mean the flesh or meat of dead animals. The blood and tissue-juices of these dead animals contain the waste debris salts (uric acid, xanthins, etc.), which the animal was about to excrete, and would have excreted as useless had it not been killed. This waste, therefore, cannot be considered as a food proper, since it has already been cast off from the disintegrating or dying cells of the animal. Again, the nuclein of the cellular tissues of the animal (composing muscle-fibers and glands) must also be decom- posed after ingestion, into its cleavage products, the xan- thins, thus serving as another food-source for uric acid. In one case, the xanthins already exist as free bases in the tissue-juices of the dead animal; in the other, they are organically combined with the nucleinic acid of the nuclein, but are, of course, set free during the analytic process of digestion. Like the alkaloids of the plant (which are often taken in the form of drugs), these flesh xanthins or purins can only serve to stimulate or irritate temporarily, by causing extra effort on the part of the meta- bolic organs to oxidize them (into uric acid or urea) and effect their removal from the system. Its Cumulative Action. — From what has been said, it will be seen that uric acid is obtained from the foods of the vegetable kingdom, as an alkaloid, xanthin, purin, or extractive of plants; and from foods of the animal king- dom, as an alkaloid, xanthin, purin, or extractive of meat. When introduced into the system, by ingestion of flesh food or of vegetable food of the character described, it acts much like any other alkaloid, in the form of a drug: not as a food ITS PLACE IN NATURE. 11 proper. Like morphin and certain other alkaloids, it has a cumulative action, so that the person who has been accustomed to eating flesh, drinking coffee, etc., may be- come suddenly and unexpectedly poisoned from an "ex- plosion" of its effects, and he will also, probably, become an habitue — that is, his sympathetic nervous system will crave its accustomed irritant or stimulant. It is, therefore, a difficult matter, or perhaps impossible, for the meat eater to turn at once into a vegetarian. It is like giving up the "drink" habit or "drug" habit. Its Power for Good or Evil. — Of course, the human organism is obliged to rid itself of the uric acid resulting from the breaking down of its own bodily cells, as well as of that of the cleavage products derived from the nuclein of flesh ingested as food; so that the metabolic and excretory organs are made sufficiently active in per- forming their essential duty, without introducing gratui- tously more work of a similar character by means of free xanthins, ready formed, which can serve no useful purpose as. food. We are prone to ingest substances into the organism, in this way, which are quite unnecessary and superflous, thus causing extra eliminative effort to get rid of them — as in the case of alcohol, drugs, tobacco, etc. The power of uric acid for good or evil probably resides chiefly in its nitrogen or ammonia content, which will be beneficial to the plant and injurious to the animal. An analogous power is inherent in carbon dioxid, which the animal exhales as poisonous and the plant absorbs as a nutrient. It will be seen, then, that, though uric acid has an important place in Nature, this place is not as a food for man. On the contrary, like carbon dioxid, and like am- 12 URIC ACID AND ITS CONGENERS. monia in other combinations than that of the ureids proper, it is excreted from the animal body as useless waste, which becomes harmful if retained. In fact, it may be decom- posed into carbon dioxid, ammonia and glycocoll. Its true office, then, is to serve as an excrement for animals and a fertilizer for the reproduction and growth of plants. It is a nitrogenous ash, thrown off by the analytical processes (catabolic) of animal life, to be taken up and utilized by the synthetic processes (anabolic) of vegetable life. In conclusion, it may be stated that the excreta of plants are altogether of gases, so that waste substances resulting from the cell life of the plant must remain in its tissues. Such products are always removed to parts in which they cannot interfere with the vital activities of the plant; so that such "extractives" are found in the bark of plants, skins of seeds, etc. CHAPTER II. HISTORICAL REVIEW. Discovery of Uric Acid (1776).— Though the his- tory of uric acid, during its 130 years' ups and downs* contains (until very recently) but few American names of note, the year that marks its beginning has a distinct American sound. In 1776, two years after his discovery of oxygen, Karl Wilhelm Scheele discovered uric acid in a concrement; and, in the same year, Prof. T. Olof Bergman found the substance in a cystitic calculus. Both were well-known Swedish chemists, whose names have become famous for their important discoveries in chemical science. The collected works of the latter were published in 1779-84; those of the former, in 1793. Early Chemical Findings, (1 793-1848). — For a number of years after this discovery of uric acid, chemical experts were interested in its study, and it was soon found to be a normal constituent of human urine. In the same year that Scheele published his volumi- nous work, (1793), Comte de Fourcroy, a well-known French chemist, found urea to be one of the decompo- sition products of uric acid; and, four years later (1797), William Hyde Wollaston, the celebrated English chemist and physicist (who afterward discovered the ultraviolet rays of light), found uric acid in the form of its insoluble salts in the concretions of gout. The next two names to be connected with these earlier uric acid studies are familiarly known to physicians and students in every part of the civilized world; viz., Prof. 14 URIC ACID AND ITS CONGENERS. Friedrich Wohler and Baron Justus von Liebig, the two illustrious German chemists, who associated themselves together for scientific research in the early part of the 19th century. Wohler, who is generally recognized as the "Father of Organic Chemistry," demonstrated, in 1828, the possibility of forming a product of the living organism (i. e., urea) from inorganic material (ammonium cyanate). Liebig was professor of chemistry at Giessen, where he established his laboratory for researches in organic chemis- try, and afterwards published his famous "Dictionary of Chemistry." In 1838, these two scientists, by their com- bined investigations, were enabled to point out conclu- sively the singularly close relationship borne by uric acid toward urea, allantoin and alloxan. Ten years later (1848), it was shown by Wohler and Frerichs that when uric acid was introduced as such into the organism, some of it was transformed into urea, on excretion. The Early Medical Theory (1 797-1 870). — The knowledge gained concerning uric acid and its intimate relationship to urea, soon set medical men to speculating on the probable similarity of origin of the two substances and their probably analogous mode of formation in the body. As urea was known to be the end product of albu- min metabolism, as well as an oxidation product of uric acid, it was reasonable to suppose that the latter was also derived from albumin and represented an intermediate stage in the process. For many years it was believed by medical men, and was so taught by physiologists (and even many physicians today have not learned to the contrary) that normally all albumin passes through a uric acid stage in being oxidized into urea. HISTORICAL REVIEW. 15 From this, it was only a step further to believe that any increase of uric acid must result from faulty albumin metabolism, the process being interrupted at the uric acid stage owing to insufficient oxygenation. Anything which interfered with the normal oxidizing processes of the body, such as disturbances of the circulation or of respiration, was considered responsible for the increase of uric acid. This theory obtained so firm a foothold that experi- mental investigators were, as a rule, prone to make the mistake of looking only for such clinical evidence as seemed to be confirmatory. In other words, facts were made to harmonize with the theory, rather than vice versa. In support of this suboxidation theory, Virchow, in 1847, directed notice to the abnormal amount of uric acid in leukaemia. Six years later, Lehmann's popular i Text- book of Physiological Chemistry" appeared, in which it was taught that uric acid is a half-way stage in the oxi- dation of albumin into urea. In Vol. I, of the German Archives of Clinical Medicine, published in 1866, Bartels advanced his famous hypothesis of the "relative" insuffi- ciency of oxygen as in pneumonia and certain fevers to account for the increase of uric acid, known to be present in these conditions. About this time, numerous feeding experiments by different investigators corroborated Wohler's finding that uric acid, when fed to dogs and man, is given off in the urine largely as urea. This experimental finding was con- sidered convincing proof of the correctness of the albumin- metabolism theory. The fact did not seem to be appre- ciated then, as it is now, that though the experiment proved that uric acid may be burned into urea, this does not neces- sarily mean that all uric acid is thus burned, or that all 16 URIC ACID AND ITS CONGENERS. urea is thus derived. As a matter of fact, it is known that only a small proportion of urea represents burned up uric acid, and only a certain proportion of uric acid is burned into urea. Garrod's Discovery (1848-1854). — The uric acid finding, to which we have now come, is one which has profoundly influenced all subsequent studies and investi- gations of the subject. Though, as already mentioned, Wollaston had discovered uric acid salts in the concretions of gout, fifty years previously, the connection between uric acid and gout was not worked out. To Sir Arthur Garrod, the palm must be awarded for showing the relationship between the two. In 1848, in a paper on "The Blood and Urine in Gout, Rheumatism, and Bright's Disease," read before the Medico-Chirurgical Society of London, Garrod demon- strated that the blood of gouty patients contains urate salts in excess. In determining the presence of an excess of uric acid in the blood, he introduced his famous "thread test"; to wit: — A little blood is collected in a watch crystal and some dilute acetic acid added; in this mixture a linen thread is immersed and the whole set aside to stand for twenty-four hours, evaporation being prevented. At the end of this time, if there is an excess, crystals of uric acid are thrown out, adhere to the thread, and can be easily recognized under the microscope. By the application of this test, it was shown by Garrod that the blood of gouty patients contains uric acid in an abnormally large amount. His findings were subsequently confirmed by several well-known investigators (Ranke, Charcot, Bence-Jones, Salomon, and others) and more recently by Klemperer and Strauss, who used the more HISTORICAL REVIEW. 17 accurate Ludwig-Salkowski method, for determining uric acid in the blood by gravimetric analysis. Garrod's Theory. — Though the knowledge of the mode of formation of uric acid in the body was still incom- plete and faulty at the time of Garrod's discovery, yet the theory he formed concerning the aetiology and pathology of gout is accepted by many authorities even today. He con- sidered that the gouty nodes and tophi are derived pri- marily from an excess of uric acid in the blood, and that the tissue lesions in the affected parts are caused by the deposition of urates. He held that, in gout, there is deficient elimination on the part of the kidneys, the alka- linity of the blood plasma is lessened, and consequently the blood is no longer able to hold the uric acid combination in solution. The latter, in the form of the biurates, is suddenly deposited in and about the joints, where an in- flammatory action of the contiguous soft tissues is effected. Early Xanthin Findings (1851-1889). — As early as 1 85 1, Scherer published his findings of hypoxanthin in the .spleen and in the blood of leukaemic subjects; and, during the next four or five years, experts began to recog- nize the chemical resemblance between uric acid and the xanthins. In 1858, Ranke suggested that inasmuch as uric acid and hypoxanthin were both present in splenic juice and were increased in amount in leukaemia, the two substances possibly had a similar origin, hypoxanthin being an earlier stage than uric acid in the metabolic pro- cess. In 1 87 1, the expert, Salkowski, put forth strong argu- ments against the albumin-metabolism theory and offered in its stead the hypothesis that uric acid is derived from xanthin bases and the spleen; but the time was not yet ripe for the acceptance of this new doctrine. 18 URIC ACID AND ITS CONGENERS. Pure chemists now began those remarkable experi- ments with nucleins and their cleavage products. In 1874, Miescher isolated nucleinic acid from the sperm of salmon and showed that xanthin bases resulted as decomposition products. Again, in 1879, Kossel obtained xanthin, hypo- xanthin, adenin and guanin from nuclein; showing, more- over, that they are not present in nuclein as free bases, but organically combined with the nucleinic acid. Two years later he suggested that these bases were probably fore- stages of uric acid; and, the following year, he offered as an argument that the muscles of birds and reptiles (whose chief metabolic end product is known to be uric acid) are much richer in hypoxanthin than are the muscles of mam- mals. It will be seen that these studies were gradually lead- ing up to the discovery of the fact that uric acid is derived from the nucleins and xanthin bases, as demonstrated by Horbaczewski in 1889, when he performed his classic experiment of squeezing spleen pulp, mixing with it defibrinated blood, passing air through it and finding large amounts of uric acid formed. He believed that he was warranted in declaring that uric acid was an oxidation product of nuclein (only of leucocytes, he thought) through its xanthin cleavage products. This was an important finding, inasmuch as it led to the discovery of the true origin and mode of formation of uric acid in the body. Early Theory Exploded (1 868-1 893). — Little at- tention was at first paid to those experimental findings which threatened in any way to disprove the theory that albumin, in being metabolized in the body, passes through a uric acid stage, and that the latter is increased whenever there is deficient oxidation. Increase of uric acid excretion HISTORICAL REVIEW. 19 following the ingestion of meat, pointed to a nitrogenous origin; and, until certain chemical discoveries were made, that origin was naturally thought to be albumin. As early as 1868, Senator cast some doubt on the sub- oxidation theory, by showing that permanently constricting the thorax of animals, thus limiting their oxygen intake, did not increase the uric acid excretion. In short, inter- ference with respiration did not necessarily mean uric acid increase, though it did mean deficient oxygenation. Again, it was shown by other investigators that anaemia, produced experimentally, did not cause increased uric acid excretion; and, furthermore, that there was no evidence of the oxi- dizing processes being diminished in leukaemia. It was also shown by Minkowski and others that the feeding of pure albumin foods had no direct relation to- ward uric acid increase. The death-knell to the albumin theory was not sounded, however, until Kossel (1893) demonstrated that meat increased uric acid excretion owing to the abundance of free xanthins it contained. In other words, it finally became understood that uric acid was not derived from the albumin of meat, but, as shown by Kossel, Burian and Schur, and others, from the nuclein and free xanthin bases, especially of glandular meats (sweetbread, liver, etc.). Horbaczewski had been the first to point out, by his feeding experiments, that nuclein produced an increase of uric acid excretion within two hours after its ingestion. Professional chemists now abandoned the albumin theory — they recognized the fact that uric acid metabolism and albumin metabolism were carried out along two entirely different lines; but it took medical men some time to learn that the old established theory had been exploded. 20 URIC ACID AND ITS CONGENERS. Recent Findings (1895-1905). — During the last decade many important discoveries have been made con- cerning the origin, destruction, and mode of formation of uric acid in the body, under normal conditions. It has also been shown how the metabolism of uric acid becomes changed under certain pathological conditions and thus gives rise to disease. These various findings, relating to the precipitation of urates out of solution, their faulty ex- cretion, retention and accumulation in the organism, will be considered in detail under their proper headings in the body of this work. CHAPTER III. PHYSICAL CHARACTERISTICS. Isolation of Uric Acid. — The most convenient way of isolating uric acid in its purity, is to submit the excre- ment of snakes to a simple chemical process, the details of which may be found described in any text-book of phy- siological chemistry. It can also be separated from human urine by the employment of a somewhat more complicated though similar analytic method — i. e., by concentration and addition of hydrochloric acid. It was first prepared synthetically by Horbaczewski, in 1882, by treating a mixture of glycocoll and urea at a high temperature. It has also been obtained synthetically by heating a mixture of urea and trichlorlactic acid. Its Appearance. — Pure uric acid is tasteless and inodorous. It is a glistening, snow-white, crystalline powder, which, under the microscope, appears to consist of minute (though regular) transparent, colorless crystals, in the form of rhombic plates, with rounded angles, and often united in pretty rosettes. They may be whetstone, dumb-bell, paddle, and spiculated shaped, and of a reddish or yellow-brown color, due to the accompanying pigment (usually purpurine). They may be seen by the naked eye in the urine, as "sand," " gravel, " "brick-dust," and "red pepper grains." Reaction. — Uric acid slightly reddens blue litmus, as it is a tasteless, weak acid. Solubility. — Uric acid itself is less soluble than most of its salts. It is practically insoluble in dilute acids, 22 URIC ACID AND ITS CONGENERS. alcohol, ether water, or strong solutions of alkaline car- bonates. It dissolves in i : 40,000 parts, cold water, and in 1 : 1,800 parts, boiling water. It is soluble in weak alkaline solutions: therefore, alkaline urine and blood hold uric acid in solution. In a solution containing both uric acid and the soda phosphates (as in the urine and blood), the uric acid is precipitated by the acid phosphates, and held in solution by the basic or neutral phosphates. Uric acid does not occur, as such, in the normal urine, but rather in the form of its more soluble salts or urates — principally with the alkali metals, sodium and potassium. Being a dibasic acid, it is capable of forming two series of these salts — neutral urates and acid urates, the former being more soluble than the latter. The urates, therefore, that we see precipitated from urine, passed in normal quantity, are the acid urates. Uric acid may be precipitated in the form of its characteristic crystals, owing to its liberation from union with sodium or potassium, during the period of the so- called "acid fermentation," when the urine reaches its. greatest acidity (i. e., a few hours after voidance). The neutral urates may also, at the same time, be converted into acid urates and thus precipitated. Even in fresh urine, if the urates are excessive in amount, or if the urine be too acid or too small in quantity to hold the urates in solution, the latter will be deposited in the form of sedi- ment. Under the same conditions, they may be precipi- tated in the bladder before voidance, thus being passed as. gravel. Heat dissolves the urates; cold precipitates them. Thus being more soluble in warm than in cold solutions, PHYSICAL CHARACTERISTICS. 23 the urine may be clear on voiding, but deposit quite a sediment on cooling. This precipitate will be dissolved by heating the urine, which will serve to differentiate it from other precipitates. The urinary urates are usually spoken of as the " amorphous," or " acid," or " mixed " urates. They rarely appear in crystalline form, though small needles are some- times found. As one author says: "The usual form is a rather dense, sandy deposit, cream-colored, yellow, pink or rose-colored, or even brown, depending on the color of the urine. Under the microscope, small sandy particles are seen, usually yellowish or brownish, with now and then a crystal of uric acid. A drop of caustic soda or potash added to the sediment on the slide, will cause it to dissolve immediately. On the other hand, a drop of hydrochloric acid added to the sediment will in two or three minutes produce very small colorless crystals of uric acid." Crystallization and Precipitation. — One of the most significant of the physical characteristics of uric acid is «its strong tendency, when in solution or suspension, to crystallize out on contact with any solid substance, as may be noted on the bottom and sides of the vessel containing it. This characteristic has been observed often enough, so far as trie urine is concerned; but it is so common a phenomenon that its significance has been generally over- looked or disregarded. Garrod discovered this same tendency on the part of uric acid, when in solution or suspension in the blood, to crystallize out and become attached to a solid substance introduced — as witness his "thread test." The precipi- tation of the crystalline urates in the joints of the toe, where the circulation is sluggish, is probably due in some measure 24 URIC ACID AND ITS CONGENERS. to this same factor. The same principle holds good, too, as applied to other solid tissue-structures, where the urates show a predilection to become deposited. In gouty concretions, the uric acid crystals have been formed from the insoluble acid urate or biurate of soda — more correctly called "mononatrium (or monosodic) urate." Laboratory experiments have demonstrated the fact, that, if a solution of sodium hydrate (NaOH) be added to a liquid holding uric acid in solution or sus- pension, the mononatrium urate (acid urate or biurate of soda) will be thrown down as a precipitate; and that, after all the uric acid in the liquid has been thus united with the soda, the mononatrium urate is itself transformed, by the further action of NaOH, into the dinatrium urate (neutral urate of soda), and as this is soluble, it is at once dissolved. Now, from this solution of neutral urate, if acid of any kind be added, the uric acid will fall out as a precipitate — as it does in the gouty joint, where the tissue-juices are subject to sudden variations in their alkalinity. It has been shown in these studies, that the monona- trium urate precipitate (biurate), first thrown down as above described, occurs in the form of transparent amor- phous spheres, which, on standing, are gradually trans- formed into needle-shaped crystals — this being simply an alteration in physical form and not a change in chemical composition. "These amorphous spheres," as one author states, "yield with water certain opalescent (or even clear) false solutions — the so-called colloidal solutions; such colloidal solutions may contain an enormous quantity of urates, far more than can be dissolved in the same quantity of water to make a genuine solution. On standing, the colloidal solutions gradually give rise to saturated genuine PHYSICAL CHARACTERISTICS. 25 solutions, and the excess of urates present then falls out in the form of the crystalline salt." — (Jour. A. M. A., Mar. II, 1905.) The significance of these findings as applied to uratic deposits in certain pathologic conditions, can hardly be overestimated. It is probable that the colloidal urates in the blood pass through a similar process, prior to their precipitation in crystalline form; for it is observed that they are thrown out in those localities where the capillary circulation is most sluggish or where stasis exists, and where the blood and its contents are brought into direct contact with the surrounding solid tissue-structures. Attraction. — Another so-called peculiarity, ob- served in studying the physical chemistry of uric acid, is the tendency of its crystals to attract other urate crystals. So far as we know, Haig was the first to direct attention to this phenomenon and give it practical application, al- though we presume that the crystals of most other salts act in a similar manner toward their sister crystals. ."By throwing a little powdered uric acid on a filter,' ' says Haig, "and pouring a urine (acid in reaction) twice quickly through it, it is possible to abstract almost every particle of uric acid from that urine — which remains in combination with the solid uric acid on the filter." On the other hand, if sufficient alkali be added to the urine to make its reaction alkaline, before pouring it on, instead of giving up its uric acid, it absorbs to itself all the solid uric acid that was on the filter. The importance of this finding or discovery may be utilized in practical therapeutics. For instance, the uratic deposits or concretions in the tissues may be likened to the filter, with its powdered uric acid, in the experiment; 26 URIC ACID AND ITS CONGENERS. while the blood is substituted for the urine. If, now, we can succeed in increasing the alkalinity of the blood suffi- ciently, which bathes the parts containing the deposits, it may be possible to absorb some of the solid uric acid from this so-called filter. Ionic Dissociation. — A further possibility of, at least, partially absorbing these solid precipitates has recently been suggested to us by the exhaustive studies of Paul and His, Jr., into the physical chemistry of uric acid. They have shown that when an aqueous solution of uric acid is being formed, the two available hydrogen atoms of the molecule of uric acid are dissociated in some such anal- ogous manner as when its salts with the alkali metals are formed. Either one or two hydrogen ions are formed (especially the former), as well as the resulting univalent or bivalent molecular anions. The more dilute the solution, the greater the degree of this dissociation. It was found that the number of undissociated mole- cules in the solution is proportional to the number of free hydrogen ions; and, as the former are very insoluble, they are thrown down as a precipitate. The number of hydro- gen ions are, of course, increased by the addition of an acid, (as HCl), which means also a greater number of un- dissociated molecules and their consequent precipitation. To aid the solubility of uric acid, therefore, our aim is not only to increase the alkalinity of the solution, but to de- crease the number of hydrogen ions: and this may be accomplished by means of the introduction into the solution (the blood) of such hydroxyl radicles (OH) as will take up the former to make H 2 0, thus resulting in the formation and excretion of water, with diuresis, and its accompanying molecules of uric acid in solution. CHAPTER IV. CHEMICAL PROPERTIES. Composition of Uric Acid. — Uric (or lithic) acid is composed of the four chief elements in nature — carbon, hydrogen, nitrogen and oxygen — whose atoms are com- bined in the following ratio to form the molecule, C 5 H 4 N 4 3 . Uric acid is, therefore, composed of 31.8 per cent, nitrogen, by weight. Its Acid Behavior. — It has been found to be one of the chief chemical characteristics of this substance to act as an organic acid base — i. e., being capable of readily combining with the alkali monometals to form salts. In short, it is a dibasic acid with the formula H 2 (C 5 H 2 N 4 3 ). It will be seen that it has two H atoms, which may be exchanged for two monometal elements. These two available hydrogen atoms of pure uric acid are usually replaced by one or the other of the alkali metals, sodium or potassium, or it may be by ammonium. With lithium, its most soluble salt (dilithium urate) is formed. The two H atoms may be saturated with two atoms of sodium, forming dinatrium urate (neutral urate of soda), Na 2 (C 5 H 2 N 4 3 ). Or, the monometal may displace but one atom of the H, forming mononatrium urate (biurate of soda), NaH (C 5 H 2 N 4 0,)y In his famous lectures ori the chemistry of uric acid, published at London, in 1892, Sir W. Roberts makes the claim that a monometal may take but one of the four dis- placeable H atoms, in two molecules of uric acid, forming heminatrium urate (what he calls "quadriurate" of soda) 28 URIC ACID AND ITS CONGENERS. NaH(C 5 H 2 N 4 3 ),H 2 (C 5 H 2 N 4 3 ). He is of the opin- ion that it is in this form of the "quadriurate" (which is very soluble) that uric acid circulates in the blood. But, according to the more recent findings of two competent chemical experts, TuniclifFe and Rosenheim, (Cf. Lancet, LXXVIII, 1900, p. 1708) this is only a hypothetical salt and probably has no actual existence. They suggest that Roberts may have been dealing with variable mixtures of uric acid and mononatrium urate. Its Purin Structure. — Structurally, uric acid may be regarded as a purin derivative. The word "purin" is applied to various nitrogenous substances, which are derived from animal and vegetable cells, and which contain the hypothetical chemical molecule, C 5 H 4 N 4 , a sub- stance discovered by Emil Fischer, who made it synthet- ically and called it "purin" (purum uricum), since by the replacement of its various hydrogen atoms by the radicles, hydroxyl (OH), or amino (NH 2 ), or alkyl (CH 3 ), etc., a large number of important derivatives are obtained, such as the various nuclein (alloxuric, xanthin or . purin) "bases," uric acid, caffein, theobromin, theophyllin, etc. All of these purin bodies contain the group, C 5 N 4 , the so-called "purin nucleus." The atoms in this group are arranged thus: N 1 C 6 I I C 2 C 5 N 7 X (purin nucleus) N 3 C 4 N 9 , C 8 It will be seen from the rational formula (given below) of uric acid, that it consists of the purin nucleus, with one CHEMICAL PROPERTIES. 29 hydrogen to each nitrogen atom (forming "purin"), and three oxygen atoms attached to three of the carbons, one to the second atom, one to the sixth atom and one to the eighth atom, thus suggesting the chemical name, "2, 6, 8-trioxypurin," with the formula: HN CO I I CO C NH\ (Uric Acid) I II CO HN C NH/ Hypoxanthin (C 5 H 4 N 4 0), xanthin (C 5 H 4 N 4 2 ), and uric acid (C 5 H 4 N 4 3 ), are known respectively as mono-, di- and tri-oxypurin; while adenin andguaninare called amino- and amino oxy-purin;andcaffein and theobromin known as trimethyl- and dimethyl xanthin. It will be observed that uric acid is a purin derivative, oxidized a step furtherthan xanthin or hypoxanthin, containing one more oxygen atom than the former and two more than the latter. This fact is further shown by the laboratory experiments of Kossel and Salomon, who have demonstrated that uric acid is produced when the nuclein of* yeast or of leucocytes is heated in the presence of air; but, if the air is excluded, the xanthin bodies are produced instead. Furthermore, it is known to physio-chemists, that venous blood generally contains a small proportion of xanthins, while arterial blood contains uric acid and scarcely[any xanthins. Nuclein Cleavage. — These various xanthin bases, or extractives, may exist either as "free" substances in partial solution (as in meat juice or gravy), or may be "bound" together with the other constituents of the nuclei of cell protoplasm (as in the nucleins or nucleo- 30 URIC ACID AND ITS CONGENERS. proteids of glandular tissue), from which they may be readily obtained as cleavage products. The nucleins (or nucleo-proteids) contain albumin and nucleinic acid, the latter of which, on hydrolysis, is oxidized into xanthin bases and thyminic acid (the latter yielding phosphoric acid and a carbohydrate complex). For example, on digestion with pepsin-hydrochloric acid, the nucleo-proteids yield protein (albumin) and an in- soluble residue of true nucleins, which, on further cleavage with dilute mineral acids, yield proteins (albumins) and nucleinic acids, which may undergo further splitting into xanthin (or alloxuric) bases and thyminic acid. These relations are shown in the following schema: Nucleo-proteid /\ Albumin Nuclein /\ Albumin Nucleinic Acid / \ Xanthin Thyminic bases acid The common xanthin or purin derivatives of nucleinic acids are xanthin, hypoxanthin, guanin, and adenin. From these, in turn, may be derived heteroxanthin, paraxanthin, theophyllin, theobromin, caffein, epiguanin, and carnin. But three of the latter (heteroxanthin, paraxanthin and epi- guanin) have thus far been found in the urine. Caffein, theobromin, and theophyllin, occur only in the vegetable world. The remaining members of the group are common constituents of both animal and vegetable cells. Collec- CHEMICAL PROPERTIES. 31 tively they are termed "purin," "xanthin," or'^alloxuric' bases. They are all closely related to each other and to uric acid — which is a further oxidized nitrogenous end product; for, of the total purin nitrogen (0.265 grammes) normally excreted in the urine, by far the greater portion (o.22lTgrammes) is in the form of uric acid, the remainder being xanthin base nitrogen. Uric Acid Decomposition. — Thus far, it has been shown that the purin nitrogen, excreted in the urine as uric acid, is oxidized either directly from the free xanthin bases, or indirectly from the nucleins or nucleo-proteids. But not all of the uric acid thus derived and formed in the bodv becomes excreted in the urine : some of it undergoes further decomposition before excretion, and appears in the urine in the form of urea principally, and to a slight extent in the form of one or more of the urea derivatives. In short, so far, we have considered that portion of uric acid, derived as a decomposition product from the purins, which is eliminated from the body as uric acid without further change: now, we will consider it as a decomposition product of the purins, just as before, but devote our attention to that considerable portion (50 per cent.) which undergoes further change, and is excreted from the bodv in the form of urea, or one of its derivatives. In the former sense, uric acid is considered simply a " purin" body; in the latter it is not only a purin, but a "ureid," and is so classed. The ureids are nitrogenous, crystallizable bodies, which, on hydrolytic decomposition alone, or on simul- taneous oxidation, yield urea. Hence they are derivatives of urea. Their chemical resemblance to the xanthins is shown, when uric acid is treated with an oxidizing agent in 32 URIC ACID AND ITS CONGENERS. the presence of water, when it gives rise to the same pro- ducts as do the xanthins; to wit: (i) C 5 H 4 N 4 3 +0+H 2 0=C 4 H 2 N 2 4 +CH 4 N 2 uric acid alloxan urea (2) C 1 H 2 N 2 4 +2H 2 0=C 3 H 2 3 +CH 4 N 2 alloxan mesoxalic urea acid The relationship of uric acid and other ureids to the xanthins is further shown by decomposing both with hydrochloric acid or hydriodic acid under high pressure. The same products are obtained in each instance, viz: ammonia, carbon dioxid and glycocoll. On decomposition, the ureids yield either urea and a non-nitrogenous acid (containing three carbon atoms) directly, or they give rise to urea and a less complex ureid, which is then further decomposed as in the first instance. They are all related to each other and, as we have seen, to the nucleinic or xanthin bases from which they are in part derived. The mono-ureids (i) are alloxan, dialuric acid, hydantoin, parabanic acid, oxaluric acid, etc. The di- ureids (2) are uric acid, purpurate of ammonia (murexid), allantoin, hydurilic acid, etc. The former generally con- tain two nitrogen atoms in the molecule; the latter, four. With hydrochloric acid, under special conditions, uric acid yields glycocoll, carbon dioxid and ammonia. With nitric acid, it yields first alloxan, and later parabanic acid and carbon dioxid; the parabanic acid then goes on to oxaluric acid and later still to oxalic acid and urea. With permanganate of potash, uric acid in neutral solution at moderate temperature, is split to allantoin and CHEMICAL PROPERTIES. 33 carbon dioxid; and the allantoin, on oxidation, yields urea and oxalic acid; to wit: (i) C 5 H 4 N 4 3 +H 2 0+0=C 4 H 6 N 4 3 +C0 2 uric acid allantoin (2) C 4 H 6 N 4 3 +2H 2 0+0=C 2 H 2 4 +2 CH 4 N 2 allantoin oxalic acid urea The presence in the animal body of urea, glycocoll, oxalic acid, and allantoin, has often been demonstrated. ^Synthetic Formation. — The preparation of uric acid in vitro, through the union of two of its decomposition products, glycocoll and urea, has often been accomplished in the laboratory during the last five or six years; and, as a consequence, it has been suggested by chemists that this, or some similar synthetic process, may take place inside the animal body. As an outcome of his experiments to determine the method of formation of uric acid in the liver of birds, Wiener has come to the conclusion that a small proportion of the uric acid, normally produced in the human organism, is formed synthetically in the liver by the union of tartronic acid (C 3 H 4 5 ) with two urea radicles and the intermediate formation of dialuric acid (as in the laboratory experiment) — the tartronic acid itself being derived from lactic acid by oxidation. E. Schmoll has advanced a similar theory. While the postulating of such a synthetic reduction process to account for the hypothetical formation of uric acid by synthesis in the body, may prove satisfactory to the chemical expert; yet, to us, it seems contrary to Nature's plan that a catabolic waste product should be built up in this way, before excretion, out of its own decomposition U URIC ACID AND ITS CONGENERS. products, or, in fact, out of any other oxidation products. Then, again, we can see no necessity for erecting such an fhypothesis, since all of the uric acid normally excreted as a result of cellular metabolism can be accounted for in the msual manner, — by oxidation of the purins. The catabolic products, which represent disintegra- tion and death of tissue cells in the animal kingdom (i. e., •change from living to non-living matter), are the result of a tearing down process, not a " building up " process. There- fore, if we are to consider uric acid in the light of a nitrog- enous waste product, as the ash of "burned up" material iresulting from oxidation, it is evident that it will be ex- creted from the body as such, or as still further oxidized into urea or its derivatives. It seems strange that Nature should reverse the usual order of things, and take the un- necessary pains of forming a waste substance out of its own decomposition products. Furthermore, the liver (where this synthetic formation is said to take place) is known to furnish an oxidase which decomposes uric acid into urea — exactly vice versa. Some physio-chemists, it is true, accept Wiener's suggestion of a uric acid formation in the liver by syn- thesis; but they cannot consistently consider the uric acid thus formed to have been produced normally as a catabolic waste tissue product. It seems a bit singular that physiol- ogists should accuse the liver of decomposing uric acid into urea and its derivatives, and, at the same time, of recom- posing urea and its derivatives into uric acid — i. e., as part and parcel of a like metabolic process. In the higher ■orders of the animal kingdom it is not the plan of nature to '"build" her cast-off tissue material, — such excrement is Heft for the plant to synthesize. CHEMICAL PROPERTIES. 35 While, therefore, we cannot believe that that con- siderable portion of uric acid which results from cellular decomposition and expenditure of energy in the body, and is excreted in that sense as a nitrogenous waste product of tissue catabolism, is ever formed synthetically in the liver; yet, it is possible, of course, that some may be thus formed directly out of certain chemical derivatives introduced into the stomach, — though the purins, and uric acid itself, when thus introduced, are usually chiefly oxidized by the liver into urea. We know, however, that the liver actually does perform both oxidations and syntheses; but the latter process is usually done to keep toxic substances from enter- ing the general circulation and reaching the body tissues — substances which have been brought to the liver by the portal vein from the stomach and upper intestine. In his experiments with hens and mammals, Wiener fed them urea derivatives and a dibasic non-nitrogenous acid (containing three carbon atoms), and observed an increase of uric acid excretion, (especially in the case of the hens), thus concluding that uric acid, in this case, was formed synthetically out of its decomposition products. This may be true; but the uric acid thus formed is not representative of nitrogenous catabolism, nor of any other ordinary normal catabolic process. On the contrary, it represents the crowning act of a special digestive process which the liver is sometimes called upon to perform in its ca- pacity as a sentinel, to prevent toxic substances from en- tering the general circulation — i.e., substances which have inadvertently, or for experimental purposes, been intro- duced into the stomach. Should these same decomposi- tion products be thrown from the tissues into the circula- tion, owing to some unknown pathogenic condition, they 36 URIC ACID AND ITS CONGENERS. would probably be carried to the liver and synthesized in this same way; but this, of course is not physiological — it is pathological. CHAPTER V. PHYSIOLOGICAL PROCESSES. Endogenous Origin. — From the convincing feeding experiments of Mares, in 1892, and from those of Burian and Schur, Hall and others, more recently, it has been shown that a considerable proportion (probably one-half), of the purin nitrogen excreted in the urine as uric acid and xanthins, is normally produced in the organism from muscle metabolism and the catabolic destruction of the nuclear cellular tissues throughout the body. Owing to Horbaczewski's teachings, it was first thought that only the nucleins of the leucocytes were thus catabolized; but it is now known that the purin bodies are derived from the broken down nuclei of all body cells. It has been demonstrated by O. Lowi that, in mam- mals, the nuclear uric acid, under physiological conditions, is derived principally from the cells of those organs or tissues which undergo most active chemical changes — as the secretory organs. The blood of children contains a greater number of leucocytes than that of adults, con- sequently more uric acid is formed and excreted by children proportionate to their body weight. That the nuclein of cells is not the only source of endogenous uric acid, will at once be seen when remember- ing that the six or eight grains of the latter contained in the twenty-four hours' urine (and an equal amount destroyed in the body) would necessitate the destruction of fully six ounces of nuclein — an enormous daily cell destruction. Burian has recently shown that a great portion of the 38 URIC ACID AND ITS CONGENERS. endogenous uric acid excreted in the urine arises from the oxidation of hypoxanthin, which is a constant product of muscle metabolism. Exogenous Origin. — The uric acid derived from the nucleins and xanthins ingested with food, drink and drugs,, is considered to be of exogenous origin. Like that which results from disintegration and death of the cells within the body, the uric acid derived from foods is obtained in great- est amount from the nucleins of glandular organs — as sweetbread, liver, etc., and from the so-called "extractives" or juices of meat, which contain "free" xanthin bases in considerable amount. More is derived from thymus and liver than from brains and kidneys. Of the 0.06 per cent, of the purin bodies present in meat, no less than 0.045 P er cent - is in a free state — mostly hypoxanthin. It was found by Minkowski that fifty per cent, of the hypoxanthin contained in muscle, liver and spleen, and twenty-five per cent, of that in thymus, (and a smaller per cent, of the adenin) when fed to man, was excreted as uric acid. Many of the vegetable alkaloids are chemically allied xanthins, which likewise serve as a source of uric acid. For instance, when coffee is ingested, one-third of its caffein (trimethylxanthin) is excreted as a purin body. Catabolism. — Physiologists are now generally of the opinion that uric acid is evolved not only in the liver, but in the various other organs and nuclear tissues of the body, as in muscles, kidneys, spleen and blood. Spitzer, Kowalew- ski, and others, have pointed out that the xanthins are found in these several localities, and that uric acid is doubt- less formed there. But this only means that cell destruc- tion goes on everywhere, and that the xanthin cleavage pro- PHYSIOLOGICAL PROCESSES. 39 ducts resulting from such destruction are oxidized still further into uric acid before removal from the immediate neighborhood of the cell destroyed. In short, it simply means a continuation of the disintegrating process — a further change from living to non-living matter. Not all of this purin waste, however, is metabolized in this way into uric acid before removal into the general venous circulation; for, it is known that venous blood con- tains xanthins, whereas arterial blood contains little or none. It would seem, then, that at least some of the cata- bolic xanthins are not transformed into uric acid at the place of cell death, (owing, says Burian, to "poverty of oxygen"), but enter the circulation to become metabolized elsewhere into uric acid. This doubtless takes place chiefly in the liver; for we know that the xanthins ingested into the stomach are carried by the portal vein to the liver and there changed into uric acid or urea. It has been proven that the liver not only metabolizes into uric acid the xan- thins derived from the breaking down of its own cells, but also, the xanthins brought to it from other sources. It is doubtful if the other organs and tissues possess this extra- metabolic function. Decomposition. — Reasoning by analogy and judging from the experiments of Ascoli, Croftan, and one or two others, to determine this point, it is thought that that portion (40 to 60 per cent.) of uric acid which is known to be decomposed in the body and excreted in the urine in the form of urea or its derivatives, is destroyed in the same organs and tissues where it has already been metabolized from the xanthins. But if this be true, it can be true only of endogenous uric acid; since that which is derived from the food and then destroyed, is destroyed in the liver, being 40 URIC ACID AND ITS CONGENERS. brought to the latter by the portal vein from the stomach and small intestine. This latter assumption would seem to be true when it is considered that most of the uric acid, ingested as such into the stomach, is excreted in a very short time as urea. It is further corroborated by the careful and exhaustive investigations carried on conjointly by Soetbeer and Ibrahim, who have demonstrated by their experiments (Cf. Hoppe-Seyler's Zeitschnft fur physiol. Chemie, March 20, 1902), that, when uric acid is injected subcutaneously, much of it is eliminated as uric acid. This indicates that the general tissues do not oxidize exogenous uric acid into urea — a power possessed chiefly by the liver. In short, transformation of exogenous xanthins into uric acid, and of exogenous uric acid into urea, is doubt- less a digestive process, not a catabolic process; therefore, such process takes place in the principal digestive organ, the liver, — perhaps to some extent also in the spleen- Catalysis. — It has been shown that various tissue extracts, particularly those of the liver and spleen, con- tain an oxidase capable of bringing about the conversion of xanthin and hypoxanthin into uric acid. R. Burian has studied also the action of the hypoxanthin-oxidase of muscles, in changing the products of their metabolic activity, and broken down tissue cells into uric acid. He has found that the conversion takes place, not in the muscles themselves, but just as the hypoxanthin is passing from the muscle-fibre into the surrounding lymph. The production of hypoxanthin is increased when the muscle is at work; therefore, the hypoxanthin and uric acid, leaving the muscle, are likewise increased in amount. That some of the hypoxanthin leaves the muscle in this PHYSIOLOGICAL PROCESSES. 41 way, without being changed into uric acid, is probably due, as Burian says, to the fact that the hypoxanthin- oxidase cannot act efficiently on account of lack of oxygen. Doubtless the same thing occurs in other organs and tissues; though sufficient oxygen will soon be furnished the blood, in its passage through the lungs, to enable the oxidation process (into uric acid or urea) to be completed before final excretion. It is now generally claimed by physio-chemists, and on good grounds, that the oxidase of the liver is capable of transforming uric acid into urea or allantoin, or both. It should be remembered, therefore, that not all of the urea present in the urine represents albumin-metabolism, but that some of it is the result of purin-metabolism. Of course, it will be understood that urea is a product of nitrogenous metabolism in both instances. Circulation. — Professional opinions are many and divergent concerning the physical and chemical form in which uric acid circulates through the body. All agree, however, that uric acid does not occur, as such, in the blood, but in combination with something else, as in the form of a salt. It is contended by Schmoll and a few other observers, that, normally, the majority of it is combined with thy- minic acid, or in loose union with some organic atom complex, and, therefore, that it is unrecognizable in that form by any of our present qualitative tests: only when separated from this combination, as in certain diseased conditions (gout, etc.), can it be detected, in which form it may be precipitated out of solution. Others accept Roberts' teaching, that under normal conditions uric acid occurs in the blood as a "quadri- 42 URIC ACID AND ITS CONGENERS. urate," — the heminatrium urate, which is readily soluble. Still others think that it is held in the blood in imperfect solution or suspension with the sodium salt, in the form of mononatrium urate, having combined with the sodium of the carbonates or phosphates present in the blood. We believe that Haig has reached an adumbration of the truth, when he describes uric acid in solution in the normal phosphates of the blood stream, in which there are also probably present some alkaline salts of soda or potash; and that, under certain conditions, this uric acid combination circulates in the form of a colloid or gelat- inous material. This latter idea was suggested to him by watching, day after day, 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. It occurred to him that the capil- laries of the body might be said to resemble the interstices of the filter and that uric acid might be present in the blood in some similar gelatinous form, which would ex- plain a number of clinical phenomena not otherwise accounted for. As stated in a previous chapter, when treating of the subject of "Crystallization and Precipitation," we know from laboratory experiments, that a liquid holding uric acid, when added to a solution of sodium, (as the blood), gives rise to the formation of amorphous spheres of mon- onatrium urate, which yield with water a so-called "col- loidal" solution, in which a greater quantity of uric acid may be held than in a saturated genuine solution. It is not improbable, therefore, that when the uric acid is metabolized and brought in direct contact with the al- kaline carbonates of the lymph and blood plasma, a com- PHYSIOLOGICAL PROCESSES. 43 bination with the sodium takes place in some such manner as above described, thus resulting in its circulation in the body, (through the capillaries, at least, where the journey is first begun and the current is most sluggish), in this peculiar colloid form. Excretion. — Normal urine (excretion in the 24 hours) contains from 0.2 to 0.8 grammes of uric acid, and one- tenth as much of the xanthins. That a much greater quantity of uric acid would appear in the urine if it were not changed into urea by the liver, is shown by the fact that a greatly increased elimination of it occurs (nine times as much, according to Hahn and Nencki) when the blood of the portal vein is prevented from flowing through the liver by establishing a so-called Eck fistula between this and the inferior vena cava, and when the hepatic artery is at the same time ligated. "In this manner, the blood of the spleen and the extensive lymph districts of the intestinal tract," says Simon, "is carried directly into the general circulation and- the combined xanthin bases and uric acid find their way into the urine without being subjected to the action of the oxidases of the liver. We may hence conclude, " says he, "that the appearance of these bodies in the urine is under normal conditions owing to the fact that not all of the blood of the body reaches the liver before being carried to the kidneys." The latter organs simply act as a physiological filter or dialyzer through which pass the urates which are brought thence for final excretion. The urates are always held in solution in fresh, nor- mal urine, but, upon cooling, or after standing a few hours, they may be deposited owing to a reaction between the mononatrium urates and mononatrium phosphate of 44 URIC ACID AND ITS CONGENERS. the urine, resulting in the formation of dinatrium phos- phate and free uric acid. The solubility of uric acid and urates in the urine is dependent on their relations to the neutral or dinatrium phosphates present. The latter possess the power of pre- venting the decomposition of urates into free uric acid, while the tendency of mononatrium phosphate is to cause their decomposition. It is ineffective, however, as long as a sufficient amount of the dinatrium phosphate is present along with it. Egestion vs. Ingestion. — It has been shown by the elaborate feeding experiments of I. Walker Hall, of England, that the addition of foods (containing known quantities of purin bodies) to a purin-free diet, results in an increased egestion of urinary purin, but that the latter is not equal to the quantity ingested. A considerable proportion (40 to 60 per cent.) is not accounted for. To account for this balance, physiologists are now generally agreed that the ingested purin is first oxidized to trioxy- purin (uric acid), and that a portion of this is later de- composed by the liver and finally excreted as urea. L6wi> Neumeister, and other experimenters, have arrived at this same conclusion, demonstrating that the liver of car- nivorous animals and of man possesses the power of oxi- dizing exogenous uric acid — the former into allantoin, the latter into urea — by means of a ferment, or "oxidase." It is further assumed that not all of the purin of en- dogenous origin (i. e., from cellular catabolism) is ex- creted as such, but that a proportion is oxidized by the liver, in the manner above stated, into urea. Ascoli dis- covered the uric acid destroying power of the liver as follows: He mixed blood with uric acid or with lithium PHYSIOLOGICAL PROCESSES. 45 urate and first determined that blood alone did not possess the power of destroying uric acid if kept at body tempera- ture for several days. He then passed a mixture of blood and uric acid through a fresh dog's liver that was kept at body temperature and discovered that a considerable loss of uric acid occurred. At the same time he discovered a great increase of a urea-like substance. In a series of carefully conducted experiments, E. W. Rockwood, (Cf. Amer. Jour, of Physiol., Sept. I, 1904) has shown that the endogenous output of uric acid is variable for different individuals, but constant in quantity for the same person — more constant, in fact, than the elimination of either nitrogen or phosphoric acid. Purin Bases in F^ces. — Though the amount is small and variable, it is, nevertheless, true (as shown by both Hall and Schittenhelm), that the normal feces of man always contains purin bodies. If the dry fecal resi- due is considerable, the amount of purin bodies is rela- tively high. Their presence is evidently due in part to desquamation of the epithelial cells of the intestinal walls. They are also derived from food rich in nuclein, such as thymus, which always increases the quantity of fecal purin. Though generally found in meconium, uric acid itself is seldom found to any great extent in the feces of extra-uterine life. (This is contradicted by Galdi, who shows by recent experiments that the feces of man normal- ly contains about 25 mg. uric acid excreted daily). The purin bases in the feces are chiefly present in the free state, though a small percentage is combined with nuclein. While the purin bases occur regularly in the pancre- atic secretion, they are rarely found in bile, unless the 46 URIC ACID AND ITS CONGENERS. biliary passages are inflamed. Adenin and guanin are abundant in the walls of the intestines, together with smaller amounts of xanthin and hypoxanthin, and it is probably from this source that a considerable percentage of the purin bases in feces is derived. The balance doubt- less represents the unabsorbed purins contained in the nucleins of ingested food. It has been observed that, when exposed to the action of putrefactive organisms, adenin is transformed into hypoxanthin, and guanin into xanthin, so that these two are only found in decomposed material. Importance of the Subject. — As recently pointed out by Prof. R. H. Chittenden, of Yale, in an address delivered before the Massachusetts Medical Society, June 13, 1905, (Cf. Boston Medical and Surgical Journal, Aug. 17, 1905), we know more about the intermediary pro- cesses and products of purin metabolism in the animal economy, than of any other of the metabolic functions. Nucleoproteids are conspicuous in all cells of the body and in all tissues, — glands, muscles, etc. Their wide- spread distribution indicates their great physiological im- portance; and, in consequence, their metabolism must of necessity be a conspicuous feature in the changes taking place in all glandular organs. The importance of the study of uric acid formation and decomposition at once be- comes manifest. In other words, it is easy to see, as Chit- tenden says, " how perversion or inhibition of intermediary metabolism of uric acid may be engendered by causes which act primarily upon the cells where the enzymes (ox- idases) have their origin, or by influences which may bring about changes in the environment surrounding the intra- cellular ferment. " PHYSIOLOGICAL PROCESSES. 47 The Four Oxidases. — In summing up, it is made quite clear how various intra-cellular enzymes, working one after the other, are able gradually to evolve uric acid from tissue nucleo-proteids; to wit: I. Under the influence of a nuclease, nucleic acid is split up with liberation of the free nuclein bases. 2. Then by the action of a deamidizing enzyme, guanase or ade- nase, guanin and adenin are transformed into xanthin and hypoxanthin, respectively. 3. Further, by the action of xanthin-oxidase (Burian), hypoxanthin is oxidized to xanthin, and the latter is converted into uric acid. 4. Finally, it is to be noted that there is another tissue oxi- dase, contained, so far as is known at present, in the liver, kidneys, muscle, and, perhaps, the marrow of bones (Schittenhelm), which has the power of oxidizing and thus destroying uric acid, i. e., decomposing it into urea or its derivatives. This is known as the uricolytic ferment (Mendel). "Here, then," says Chittenden, "we have four dis- tinct enzymes or intra-cellular ferments, more or less responsible agents for the production and presence of uric acid in the body." CHAPTER VI. PURIN METABOLISM. Definition. — The term "metabolism" has been applied to the assemblage of transformations which a constituent of the organism undergoes in its passage through the body. By the term "purin metabolism" we mean (i) the various chemical changes which purin-con- taining substances undergo within the body from the time of their ingestion as food or drink until their egestion from the body as waste; and (2) the physiological processes by which purin waste is derived from destructive metamor- phosis, or the "wear and tear" of the nuclear tissue ele- ments themselves. Unbound Purins — Exogenous. — By " unbound ' or "free" exogenous purins, is meant those oxypurins, aminopurins or methylxanthins (xanthin, hypoxanthin, guanin, adenin, caffein, theophyllin, etc.) which occur as such in food, drink or drugs, not combined with the other constituents (phosphoric acid, albumin, etc.) that go to make up the nuclein of the cell nucleus, or the proteid of the cell protoplasm. From the careful analyses made by many investigators, it has been shown that the purin- content of beef, veal, ham, chicken and other flesh meats, occurs chiefly (75 per cent.) in the unbound or uncombined form; and that, though an equal amount of free purins also occurs in glandular organs (liver, thymus, sweet- bread, etc.), yet the percentage is reversed, there being three times as much of the bound purins, instead of one- third as much. In vegetable foods the unbound purins PURIN METABOLISM. 49 are rarely found. In certain drugs, however, such as caffein, the purins have been extracted from their proteid holding in a chemically pure form, and are, therefore, "free." Ordinarily, owing to the process of cooking, and action of heat, the unbound purins of meat are largely extracted in solution, in the form of gravy, soup, or in that of "beef extract," the remaining fibrous or muscular portion containing the bound purins. If the steak or "bake" be only medium done or rare, a considerable portion of the free purins still remain behind in the tissue- juices. It will be seen that the unbound purins of uncooked meat represent that catabolized or decomposed portion of the nucleo-proteids which the animal was about to ex- crete as useless waste from the system at the time it was butchered; and, therefore, are necessarily found in the blood and tissue-juices of the meat. Most of these free purins are the oxypurins (hypoxanthin and xanthin), though a small quantity of the amino-purins may be found in glandular tissue, — adenin in the pancreas, and guanin in the thymus gland of young veal. Bound Purins — Exogenous. — In the nuclear cellular tissue of glands, the "bound" purins of food substance occur in greatest abundance, the purin ring being bound to- gether with the nucleic acid to form the nuclein or nucleo- proteid. As will be readily understood, the bound purins, in this form, comprised part of the living proteid tissue of the muscles and glands of the animal at the moment of its death; they had not yet become catabolized into purin waste, or "free" purins. Immediately after death, how- ever, and before the tissues can be utilized as food, autoly- 50 URIC ACID AND ITS CONGENERS. sis or auto-digestion takes place (especially in glandular tissue), and certain of the already partially catabolized nucleins undergo further decomposition into free purins. The "free" adenin and guanin present in the living gland, are almost entirely decomposed into hypo-xanthin and xanthin respectively, immediately after the animal's death. For this reason the amino-purins are usually found only bound together in the nuclein molecule of food substances. The methyl-xanthins (cafFein, theophyllin, etc.), are found chiefly in the vegetable world. Fate of All Food Purins. — It should be well under- stood at the outset that the purins ingested in food or beverage pass through the body in a few hours without having served any useful purpose. They are not assimi- lated into the tissues, are not utilized for the production of cell nuclein, exert no direct influence on either carbohy- drate or nitrogenous metabolism — "they indirectly in- voke an output of metabolic energy to insure their early removal from the body." (Hall). In short, they are simply further oxidized, decomposed and excreted. As the "free" purins (with the possible exception of guanin) are readily dissolved in the intestinal juices, they are absorbed unchanged (mostly as hypoxanthin and xan- thin) into the portal circulation and carried to the liver, where they are oxidized into uric acid (40 to 60 per cent.) and urea (40 to 60 per cent.), and thus conveyed through the general circulation to the kidneys and- excreted. A very small portion escapes this oxidation and is excreted in the urine as xanthin. The uric acid portion, above mentioned, is excreted within eight hours after ingestion of the purin, and the smaller xanthin portion within four hours. This would PURIN METABOLISM. 51 seem to indicate that "free" purin metabolism, in the healthy organism, is by no means sluggish. It should be stated in this connection that a considerable portion of the ingested guanin (probably 50 per cent.) passes un- changed through the intestine and is excreted in the feces. When " bound" purins are ingested, a small percent- age is decomposed in the intestine into "free" purins, and appear partly as such in the feces and are partly absorbed; but the greater part of the nuclein is directly absorbed as such into the circulation and undergoes decomposition and final oxidation into uric acid and urea, in the same manner and proportion as already described: the only difference being that, in this case, the phosphoric acid and albumin radicals which are split off from the purin ring of the nuclein molecule, doubtless become utilized in the process of cell construction. In the case of the " bound" purins, the uric acid ap- pears in the urine within a day or two after ingestion of the food, depending on the activity of the circulatory and metabolic organs. According to the carefully conducted feeding experiments of Hall, the system excretes in urine, within forty-eight hours, one-half of the fish, fowl and beef purin in food. It was found, in some instances, that the purin of beans is excreted the same day as eaten. From the foregoing findings, it will be seen that the " bound" purins of food require a more prolonged meta- bolic effort than do the "free" purins, to insure their oxi- dation, decomposition and excretion from the body; thus being contra-indicated in all cases in which the digestion is weak and faulty, especially in children. Pharmacologic Action. — The fact that the purins pass through the body in so short a time, would seem to 52 URIC ACID AND ITS CONGENERS. show that the danger arising from their ingestion may not be due so much to the direct irritation caused by their actual presence at this time, as to the fact that they may become only imperfectly excreted, — in short, that the principal danger is from their retention and accumulation. It should be understood, however, that adenin and guanin (owing to their amino radical )are directly irritating to the mucous lining of the gastro-intestinal tract, and may give rise to inflammation. Adenin is a violent poison, and, whenever retained in the glandular tissue, invariably gives rise to histological changes of grave importance. To a lesser degree, the same is true of the oxypurins, though a longer time is required to produce the results. Among the principal effects noted, when the chemi- cally pure xanthins are ingested, may be mentioned the following: i. The salivary secretions and gastric juice are increased in amount (more watery), though the fer- ments themselves are not correspondingly increased. 2. The methylxanthins, in large doses, tend to induce reflex irritability and muscular contraction or rigidity (due to the nitrogen group, same as in ammonia compounds), and slight diuresis. 3. The amino-purins are directly irritant. 4. Uric acid, itself, in single large doses, daily, will, in three or four days, produce a condition simulating malaria. Kochmann has recently fed several dogs on ox-flesh alone for six to ten weeks. In all of them the liver showed cloudy swelling and fatty infiltration. Fatty degeneration and parenchymatous inflammation of the kidneys were also observed. His conclusions indicate that excessive flesh food may (like alcohol and lead) cause deficient liver metabolism, kidney degeneration, and the consequent alterations in the excretion of uric acid. PURIN METABOLISM. 53 "At present," says Hall, (The Purin Bodies in Food Stuffs, page 78), "there is a tendency to disregard the action of the oxypurins upon the tissues but it must be remembered that when they are in excess they probably form unusual combinations and that such products may act as irritants. When Kochmann added carbohydrate food to the meat diet, his dogs presented fewer post-mor- tem pathological changes. Up to the present date, I have made a large number of personal experiments, and when I have taken large doses of purin bodies — such as 8 grains of hypoxanthin, 15 grains of guanin, 8 to 15 grains of uric acid, — apparently associated symptoms of general mal- aise and irritability have frequently appeared." Comparative Metabolism. — Experiments upon dif- ferent animals have given findings that would seem to indicate (if we have properly interpreted their meaning), that, as we rise in the mammalian scale, the metabolic activity of the intracellular ferments and glandular oxi- dases is correspondingly increased. This is shown to some extent in the action of the general tissues, but more particularly in that of the liver, — the chief metabolic organ or oxidizing depot. In cats and dogs, the liver has reached a certain stage of development in oxidizing or destroying uric acid, — an oxidizing stage in purin metabolism that is one round lower than that of which the human liver is capable. In- travenous injections of lithium urate in the cat leads to much excretion of allantoin, a ureid intermediate between uric acid and urea. Similar experiments upon dogs show that their liver is capable of oxidizing uric acid into allan- toin; while, under the same conditions, the human liver continues the oxidation a stage further, — to urea. 54 URIC ACID AND ITS CONGENERS. If sulfonal be given to cats and dogs, at the time of the above mentioned experiments, thus interfering with the oxidizing power of the liver, the process stops short of the allantoin stage, and uric acid is excreted instead; while, in man, the process stops short of the urea stage, and evi- dences of allantoin appear in the urine. The presence of allantoin instead of urea, in the urine of cats and dogs under special conditions, indicates a lower stage of metabolic evolution than that reached by man. Reasoning from analogy, it would appear that the presence in the human urine of uric acid at all, is due to incomplete decomposition of the purin ring, and indicates that the time may come when the human liver, aided by the then more highly specialized tissues, will be enabled to change all nitrogenous substances (purin as well as albumin) into urea. Uric acid is certainly an intermediate product, formed during the oxidation of the purin radical, which has been split off from the nuclein molecule of cellular tissue, — the end product of which is urea. The more active the hepatic function, the greater the normal per- centage of urea excreted; therefore, excessive uric acid excretion in the urine of man is due, in some measure, to faulty action of the liver, — less uric acid being destroyed (oxidized into urea) than the perfectly healthy liver is capable of. In the human species, the possibilities of a given organ evolving to a higher stage, is seen in the greater number of convolutions in the highly intellectual brain as compared with the brain of persons in a lower stage of civilization. The one is capable of greater work than the other. As we add to the sum of our knowledge concerning the influ- ence upon the liver of certain foods ingested, we may PURIN METABOLISM. 55 eventually learn to eat such substances (both as to quan- tity and quality) as tend to develop and aid the hepatic function, rather than those that injure this important metabolic process. An equally beneficial effect upon the other tissues will naturally follow. Future generations of man, there may be in existence, whose metabolic power (like brain power) will have be- come developed to such a degree that all nitrogenous waste will be fully oxidized into its end product, urea; and such intermediary products as uric acid and allantoin will disappear from the urine entirely. Such an improve- ment, at all events, would be in the line of evolutionary growth and development. If human flesh were to be utilized as food, it is evident that uric acid itself, as well as the "free" xanthins, would be found in the blood and tissue juices of the meat and glandular organs thus ingested. In the carnivorous and omnivorous flesh food now eaten, such as fish and pork, as well as in all herbivorous flesh food, we obtain only the purins oxidized to a stage short of uric acid; thus demon- strating the fact that the intracellular ferments of these animals have not yet reached the more fully evolved form of those present in human cells, which are capable of further oxidizing these "free" purins, not only into uric acid, but, in some instances, into urea itself. It is a mooted question, and open to wide speculation and theorizing, as to the exact chemical form in which uric^acid would be found in healthy human flesh food, i. e., in the blood and extra vascular fluids; whether as a salt or in loose combination with some organic atom com- plex, and in what physical form. But, doubtless, much would depend on the particular locality in which it was 56 URIC ACID AND ITS CONGENERS. found. If in the lymph spaces before combining with the soda salts of the blood, it would perhaps be in a form like other "free purins"; if in the capillary blood, it would probably be in the form of a colloid urate of soda; and if in the general circulation, it might be less colloid but still in the form of a urate. In short, its chemical and physical form would probably vary in a similar manner to that of the glycocholic acid and glycocholate of soda contained in bile, which has also occasionally been found in the urine, as a sodium salt. CHAPTER VII. EVOLUTIONARY DEVELOPMENT. The "Special Creation" Theory. — To account for the various animal forms about us, the "special crea- tion" theory has long offered to the superficial observer the only satisfactory explanation. The human mind, in its partially developed stage of enlightenment, pictured an epoch when the earth was devoid of animal life; when, suddenly, by the fiat of a Great Personal Architect, myriads of denizens of the air, land, and sea, sprang into existence in completed form and shape as we see them today. The crude thinker seems to be incapable of conceiv- ing of a thing created, unless it be done instantaneously (or comparatively so), after human methods, — e. g., as a tin soldier is created by a toy-maker. By such a mind the Deity is thought of as a personality, of the masculine gender, who once created living images of himself, and is now resting somewhere from the toils of his handiwork, — after the manner of the carpenter or sculptor. But how lowly a conception is this! Is it any less repellent to the pure religious instinct, to conceive of an intangible (spiritual) Power, immanent in every atom of the cosmos — the Soul of things — which is as active and potent today as of yore, in causing an increase in complexity of structure and function, to keep pace with the corres- ponding changes in the environment, in the great struggle for existence ? Do we in any way detract from the lofty attributes of Omnipotence, in believing that all physical and psychi- 58 URIC ACID AND ITS CONGENERS. cal phenomena are a manifestation of this Omnipotent Power, from whence these forces emanated in the begin- ning, and are equally pregnant still in gradually giving birth to newer from older forms, until we reach the en- lightened human being of the present, who is still evolv- ing slowly, but surely, to a higher intellectual and ethical plane, — i. e., to a mental or spiritual state in which he is capable of more nearly appreciating the inherent nature of the Creator and the methods of creation ? At all events, they conceive of a mere finite Power, who believe that man in his present condition represents the climax of his Maker's skill. A higher religious faith is that which con- strains us to believe that the human mind (rather than the human body) is in the likeness of its Maker — the Uni- versal Mind, towards the meeting and knowing of Which, It is gradually evolving ours. The "Spencerian" Theory. — Modern biologists and morphologists, who have studied deeply into the nature and changes of tissue structure and the correspond- ing increase in the complexity of function in the animal economy, have been obliged to reject the old "special creation'' theory which was clung to so religiously by our ancestors; and, in its stead, have accepted the more ra- tional belief in a gradual evolutionary development from simple to more complex organic forms. The universal principle or law of evolution, whose working is so plainly seen in the gradual growth and development out of barbarism of the modern social life, — ever tending to a more complete sociologic organization, — is the same, when studied from a biologic viewpoint, in its application to individual organic forms. In short, man in his present physical, moral and intellectual state and EVOLUTIONARY DEVELOPMENT. 59 form, is not an act of special creation, but, like our modern civilization, is a complex product of slow growth, evolved from simpler pre-existing forms, seriatim ad infinitum, — similar in plan to the development of the human foetus from the parent germ cell: the gradual growth and de- velopment of which in the mother's womb represents, on a small scale, the various stages of human evolution during the past ages. Evolution of every kind, whether mental, ethical, social or physical, is an increase of complexity of structure and function, accompanied by a dissipation of motion or energy and integration of matter or substance: "A change," says Spencer, "from an indefinite incoherent homogeneity to a definite coherent heterogeneity." As the organism, (of whatsoever nature) grows as a whole, its component parts necessarily develop pari passu, during which process there is always a survival of the fittest. Transitional Stage. — Every man who accepts the Spencerian theory of evolution, in its application to physi- cal, intellectual, moral and social progress, will readily appreciate the fact that the human organism is still in a transitional stage of growth and development, — i. e., has not yet reached organic perfection. Man is recognized as the highest form of animal life in existence, chiefly because of his superior intellectual capacity, — his power to mold the environment to his will. His high position, as compared with the other members of the mammalian species, depends not so much on general physical attributes, as on the rapidity with which he is evolving along psychical lines. We note the same in- tellectual superiority of the civilized man over the savage and we find that the complexity of structure correspond- 60 URIC ACID AND ITS CONGENERS. ing to this increase in mental function, consists in the multiplication of cerebral convolutions as well as in the greater mass of cerebral tissue. It would seem evident enough to the thoughtful observer that the tendency of human evolution is to minim- ize or reduce the expenditure of muscular energy, (nec- essarily utilized by animals for the purposes of mere existence), thus leaving a reserve force to expend toward intellectual growth and development. For example, in- stead of wasting so much energy in muscular effort to procure sufficient food for the body needs, as was the custom of yore, the enlightened man of modern times is supplied with food with little or no expenditure of muscu- lar force on his part, thus affording him opportunity to utilize the equivalence of this force in the form of cerebral activity. Moreover, food is now prepared in such form (owing to the art of cooking, etc.), as to require much less ex- penditure of energy on the part of the organism to masticate, digest and assimilate it for the body needs, thus again leaving a reserve force to be utilized for intellectual pur- poses. In short, man is evolving along intellectual lines, and the cerebral organ and its accessories necessarily evolve pan passu. As man becomes more intellectual, he may so appor- tion out the work to his vegetative organs and involuntary tissues that the minimum waste of energy will result. He will, at least, see that no unnecessary work is put upon them. As he learns that certain so-called food substances furnish no nutriment to the organism through which latent energy is supplied, but, on the contrary, that they require the expenditure of potential energy to insure their EVOLUTIONARY DEVELOPMENT. 61 removal from the system, he will no longer admit their ingestion. He will finally learn that no waste should be presented to the kidneys for excretion, except only that which results from the expenditure of energy essential to the needs of the organism, and represents some physiologi- cal work performed, — the normal wear and tear of body cells. The time is near at hand when the highly intellectual man will learn to eat only just enough for his needs, and just the kind of food he needs. When he has evolved to this desirable stage, much unnecessary metabolic work which is now being performed by his liver and other tissues will be a remembrance of the past. The cells will be given an opportunity to become more highly specialized and perform their now lighter metabolic duty more satis- factorily. In short, under such circumstances, enzymatic oxidation will be more thoroughly performed, and inter- mediate products of catabolism will gradually disappear from the urine. In a human organism evolved to the stage under dis- cussion, only urea will be excreted as the true end product of nitrogenous waste. Uric acid and its congeners (the xanthins) will be known only as vestigial curiosities, — i. e., so far as the urine is concerned. This fact is well illustrated in studying the structure and function of the metabolic and excretory organs of oviparous animals, as compared with those of mammals. In birds, serpents and fowls (whose nitrogenous end product is uric acid), in- stead of a fully developed genito-urinary apparatus, with kidneys and accessory organs, we see a crude analogue of the kidney, (composed of tissue scarcely more highly specialized than muscle), from whence lead ureters, end- 62 URIC ACID AND ITS CONGENERS. ing in a common cloaca with the rectum, through which are excreted both urine and feces. As might be expected, the function of tissue structures, evolved only to this inter- mediate stage, is correspondingly intermediate in its character, — only partially developed, and, instead of the completely oxidized, soluble end product of nitrogenous catabolism, urea, (which has been evolved pari passu with the fully developed kidney of mammals), we find the less soluble intermediate waste product, uric acid. In other words, the metabolic and excretory organs of oviparous animals have not been evolved to that stage of complexity of structure, which necessitates corresponding complexity of function, in the way of complete enzymatic oxidation. The Decimal Decrease. — That the uric acid and less completely oxidized purins, which are still found in comparatively small amount in the urine of carnivorous and omnivorous mammals, may be considered as evi- dences of a transitional stage in the catabolism of nitrog- enous molecules in the animal economy, will be better understood when studying the proportional quantities of nitrogen contained in these several intermediate products, as compared with that in urea. At least, the gradual decrease observed, on a regular decimal scale, would seem to possess a peculiar metabolic significance. It is well known, for instance, that of the total amount of nitrogen normally excreted from the body in the urine of man, nine-tenths is contained in urea. Of the remaining portion, nine-tenths is contained in uric acid. Of the portion which still remains, nine-tenths is contained in the other oxypurins, of which nine-tenths is in the form of xanthin and one-tenth hypoxanthin. It will be seen, also, that the nitrogen contained in the two oxypurins (con- EVOLUTIONARY DEVELOPMENT. 63 sidered together) bears the same decimal ratio to the less amount contained in the aminopurins, i. e., nine-tenths to one-tenth. The point which chiefly attracts attention here is that the lessened ratio of nitrogen excretion corresponds with the lessened oxidation of the product containing it, as repre- sented in urea, uric acid, xanthin, hypoxanthin, etc. In short, the more highly oxidized products are excreted in greatest amount and contain the most nitrogen. From which it would seem fair to infer that the human organism is evolving gradually and by regular steps to a more perfect stage, in which urea, the complete end product of proteid and nuclein metabolism, will be the only excreted waste molecule containing the used up nitrogen of the system. The aminopurins, xanthins and uric acid appear to be slowly disappearing (and in that order), from the urine and, eventually, they will be found only in the solids and fluids of the interior of the body, where they, of course, are formed temporarily during the primary and intermediary stages of enzymatic oxidation. As the tissues become more highly specialized, the work of oxidation will be more thoroughly performed, and only the completed end pro- duct (urea) will be presented to the kidneys for final ex- cretion. That such a desirable stage of cellular metabolism is in the line of structural and functional evolution is made abundantly manifest from the study of comparative mor- phology and physiology in the animal kingdom. As the man of the future learns better how he ought to "eat to live," cutting out unnecessary purin extractives, etc., from his dietary, and curtailing all useless metabolic effort, his intracellular ferments will be enabled to perform their 64 URIC ACID AND ITS CONGENERS. lessened work more thoroughly, and enzymatic oxidation will be carried to completion. An Intermediate Product. — When it was first discovered a few years ago that uric acid was not a product of pure albumin-metabolism, — i. e., not a half-way stage in the formation of urea during albumin-metabolism, — many physicians jumped to the erroneous conclusion that uric acid, therefore, was not oxidized into urea. Even many pure chemists, when they found that uric acid was a product of nuclein and muscle-metabolism instead of albumin-metabolism, and that these two metabolic pro- cesses were carried out along two entirely different lines, at once concluded that uric acid was the complete end product of nuclein-metabolism, just as urea was the com- plete end product of albumin-metabolism. This, however, is found to be untrue. It is now well known that at least fifty per cent, of the uric acid derived from nuclein metabolism is normally oxidized into urea before being excreted. One of our most prominent physio-chemists is of the opinion that all of the uric acid would be thus further oxidized, if the blood containing it passed through the liver. He says: "We may hence con- clude that the appearance of these bodies (uric acid and xanthin bases) in the urine is under normal conditions owing to the fact that not all of the blood of the body reaches the liver before being carried to the kidneys." (Cf. Simon's Physiological Chemistry, page 254.) The enzymes or ferments of the general tissues, in the present stage of evolution of the human organism, are chiefly the nuclease, guanase, adenase, xanthin-oxidase ? etc., whose special function is to hydrolyze or oxidize the purin radicals during the first stages of nuclein cleavage EVOLUTIONARY DEVELOPMENT. 65 and break-down, carrying on the process seriatim to the uric acid stage and, in some instances, to the urea stage, — i. e., in those tissues which have become somewhat more highly specialized, such as that of which the glandular organs are composed. The general tissues themselves have not yet been evolved to the complexity of structure and function observed in the liver, whose glandular cells have become so much more highly specialized as to secrete a ferment which possesses a higher oxidizing power than the others mentioned, being able to carry out the purin (nitrogen- ous) metabolism to completion, — as represented in the urea molecule. Doubtless the time will come, however, when there will be intracellular ferments of similar en- zymatic power, and the oxidation of the nitrogenous mole- cules, resulting from nuclear destruction in their immedi- ate vicinity, will be carried to the end stage (without the essential aid of the liver ferment), when there will then be excreted from the body only the fully oxidized waste pro- duct of all nitrogenous metabolism (both nuclear and al- buminous) in the soluble form of urea. Such intermediate and partially oxidized nitrogenous products, as the purins and ureids — which are more difficultly dialyzed than urea by the delicate and highly evolved rodded epithelial cells of the renal tubules — will eventually disappear from the urine of man, except- ing under abnormal conditions. While this is a mere theory, yet, even now, we know that fully one-half of the uric acid normally excreted may be made to disappear simply by putting our knowledge into practical use, in the selection of purin-free food substances. We know, too, that much more purin waste will be oxidized into urea 66 URIC ACID AND ITS CONGENERS. if we do not cripple the action of the liver oxidase by ingesting alcohol, or otherwise injuring the hepatic func- tion. Muscle Metabolism. — Until very recently, it has been thought that the endogenous purins were derived principally from the nuclein of the disintegrating tissue cells of the body. But it is shown from the highly inter- esting experiments of Burian that this can hardly be true, that much of the uric acid normally excreted is, in fact, derived from the hypoxanthin which is being constantly formed by muscle metabolism. Whether muscle is in a state of rest or activity, hypoxanthin is formed to a greater or less extent, and this is transformed by the hypoxanthin- oxidase of muscle into uric acid and some of the latter is further oxidized into urea by the oxidases of the liver. As muscular activity results in an increase of the pro- duction of muscle-hypoxanthin, and consequently of uric acid, it will be seen that more uric acid is now developed in the human organism than will be the case in the more highly evolved and intellectual individual of the future, of whom less muscular energy will be required for the body needs. This is but another of the indications that point toward the gradual disappearance of uric acid and its congeners from human urine, — i. e., as judged from the evolutionary standpoint. Without these findings of Burian, however, it ought to have been known a priori that only a part of the endog- enous uric acid, formed in the body, could possibly be derived from the destruction of tissue cells. The six or eight grains of endogenous purin contained in the twenty- four hours' urine, indicate the actual formation in the body of twice that quantity, or fifteen grains, — since fifty per EVOLUTIONARY DEVELOPMENT. 67 cent, was doubtless oxidized into urea. For such an amount as this, at least six ounces of nuclein would have to undergo destruction and this, as may readily be under- stood, is an enormous daily cell destruction. " Cells are too valuable to the organism," as one author correctly says, "to be so lavishly destroyed." It is now becoming the generally accepted belief among physiologists, that the endogenous purins excreted from the body are derived principally from muscle meta- bolism, rather than from cellular catabolism (or nuclein break-down). Such, indeed, is the opinion of such well- known investigators as Burian, Chittenden, Mendel, Macleod, and others. Vis Inertice. — It is well known that the proteids of the tissue and nucleins of the cells, which are so essential to the structure of the human organism and to all animal life, differ from the other molecular compounds because of the nitrogen contained in the former, which is peculiar to all albuminous matter. It is also known that these proteid and nuclein mole- cules are very unstable and constantly being broken down (giving off heat, motion, electric force, etc.), and the nitrogen discharged from the body in the simpler molecules of CHNO, which compose urea, uric acid and the purin bases. In health, therefore, a certain amount of nitrogen (three drams, by weight) is being eliminated daily by way of the urine : now combined in a molecular com- bination in which there is no " explosive" action, the latter being lost when heat and energy were liberated at the moment of the breaking up of the proteid or nuclein molecule — just as the nitrogen of gunpowder, or the nitro- glycerine of the bomb shell, has lost activity after the "explosion" has taken place. CHAPTER VIII. ACCUMULATION IN THE ORGANISM. Purin Removal. — Unlike fat and the glycogen of carbohydrates, nitrogenous extractives are not stored up for future use in the body. Especially is this true of the purin intermediary and end products. As the ash of burned up tissue material, they can serve no further possible purpose in the animal economy; consequently, the sooner they are removed the better. Their retention, as such, in the human organism, is anomalous: they belong to the non-living part of the material world, to which they are to be restored, there to be taken up into vegetable tissue, and reorganized into a form of potential energy through the kinetic force of the sun's rays. Normal Findings of Uric Acid. — A certain amount of uric acid is necessarily always present in the body, owing to the constant breaking down and death of worn out tissue cells, and the ingestion of purin containing foods from which it is derived; but it should never remain at rest in any particular locality,— normally, it is always moving. In the healthy human organism, therefore, uric acid will be found either (i) in the lymph or blood plasma, bathing a given tissue or organ, where it is just leaving the dying cell and starting out on its journey of exit from the body; or, (2) at some point in the general circulation where it is proceeding on its way out. From the moment of its birth, it has but one legitimate object in view, and that is to reach the outer world and rid the organism of its ACCUMULATION IN THE ORGANISM. 69 presence; for it can be of no further use in the schema of life until it reaches the non-organized world. Its Presence a Menace. — The presence of uric acid in the animal body (even physiologically speaking) is a constant menace, for three reasons; viz.: I. It draws upon an essential salt constituent of the blood (sodium) to enable it to be moved along in that menstruum. 2. Much of it, (especially the exogenous portion), calls for the expenditure of energy on the part of an important organ (the liver) to oxidize it into a more soluble end product (urea), and thus further its passage through the blood and present nitrogenous waste to the kidney in a more suitable form for final excretion. 3. Like any foreign colloid, it is liable to get in the way and serve as an impediment. Toxicity of the Purins. — The question may well be asked, that, if uric acid is so much of a menace, why does nature go to the trouble of forming it from the xan- thins ? Why not let the xanthins remain as the unoxidized end product of nuclein metabolism ? Perhaps the answer is to be found in the fact that, though the xanthins may not be troublesome for the reasons given above, they are even a greater menace than uric acid itself, and for an entirely different reason, — i. e., some of them are distinctly toxic. It has been demonstrated that the daily injection of hypoxanthin into rabbits for two months, results in the appearance of distinct degenerative changes in the liver and alterations in the constituents of the bone marrow- From the reports of several competent experimenters, notably those of Gaucher, Tandler, Kolisch, Dostal and Croftan, it has been shown that lesions of the renal cells and arterioles have been produced by the injection of purin bodies into the tissues of animals. In short, we have 70 URIC ACID AND ITS CONGENERS. learned that the xanthins are capable of producing patho- logic changes and giving rise to clinical symptoms similar to those of poisoning by ammonia. It is well known to chemists that uric acid is a substance more difficult to decompose than are the xanthins. Therefore, in the form of uric acid, the nitrogen or ammonia, which the body wishes to excrete, is less likely to be liberated from its holding and set free in the organism. As an end (or inter- mediary) product of purin metabolism, it will be seen that the nitrogen is held more firmly in place in the stable uric acid molecule than in that of the more soluble, but less stable, xanthins. Why Not Urea ? — Again, it may be asked, why is not all of the uric acid decomposed into urea ?— thus> avoiding the constant menace due to the presence of the former substance. Perhaps it would be thus decomposed if all of it passed through the healthy liver. In our present stage of evolutionary development, the individual tissues are not sufficiently specialized, as yet, to perform this oxidizing function, except in part. Some time in the distant future, there may be members of the mammalian species in existence, who will know of uric acid and look back upon it only as a vestigial curiosity. The fact that it withdraws an essential alkaline constituent from the blood (sodium) to enable it to be removed from the body, shows the need of evolutionary improvement. Uric Acid Excess. — The frequent accumulation of uric acid in the body is a well-established fact. To explain this phenomenon, theories galore have been offered by different investigators. Reasoning a priori, the presence of an excessive amount of uric acid in the body at any time might be attributed to one of several causes, or to the action of two or more of such causes combined, to wit: ACCUMULATION IN THE ORGANISM. 71 1. To hyperactivity of cellular energy throughout the body, or in some certain locality, leading to greater cell destruction and consequent increased nuclein metabolism, thus resulting in increased production of uric acid from oxidation of the superabundant xanthin cleavage products. 2. To inability on the part of the kidneys to eliminate the quantity of urates ordinarily brought to them for excretion, thus resulting in a direct retention of uric acid in the system. 3. Owing to deficient oxygenation, or for some other reason, the individual tissues, and particularly the liver, may fail to decompose their accustomed quota of uric acid into urea, thus leading to an abnormal quantity of unoxi- dized uric acid being left in the circulation on its journey of exit. 4. To some change or changes in the character or composition of the blood, due to internal or external causes, which tends to prevent uric acid from forming its usual soluble combination to enable it to be moved along on its journey, of exit, thus causing its precipitation out of the blood and deposition in the tissues, where it accumulates owing to the mutual attraction of its crystals. 5. To sudden and prolonged exposure of the bodily surface to the influence of cold, as in cold baths, leading to temporary accumulation of leucocytes in the cutaneous circulation, as well as the precipitation of urates in that locality, thus causing blocking up of the capillaries and consequent retention of uric acid. 6. To excessive ingestion of purin-containing sub- stances, (especially if combined with alcohol), leading to oxidation by the liver of less urea, consequently leaving more uric acid than can circulate in solution or suspension, 72 URIC ACID AND ITS CONGENERS. thus resulting in the f tiling out of a portion, and its deposition around some solid tissue, where it is retained for a longer or shorter time. 7. To long continued failure of the bowel, from one cause or another, to eliminate its share of purin waste, ultimately resulting in the absorption of the latter into the blood, thus (after its oxidation by the liver) increasing the amount of circulating uric acid to that extent. 8. To prolonged violent muscular effort and conse- quent overproduction of hypoxanthin, with resulting in- crease of uric acid, — more than the kidneys can excrete, if long continued. In short, it will be seen that the accumulation of uric acid in the organism may be due either to increased pro- duction, to retention, or to lessened destruction. But, in the first and last of these three cases, the quantity of uric acid, though greater than normal, may for a time be ex- creted by increased effort on the part of the kidneys, aided, perhaps, by vicarious action on the part of the skin and bowels. Purin Foods. — From the feeding experiments of Siven, Chittenden, Hall, Taylor and others, it has been found that the principal uric acid containing foods are tea, coffee, beef-tea, meat juice, meat extracts, liver, thymus, kidneys, sweetbread, fish roe, brain, butcher's meat, her- ring, peas, beans, asparagus, etc. With a normal diet, on which the excretion of uric acid was 0.364 grammes, Taylor found that the addition of three cups of coffee led to an average excretion of 0.826 grammes of uric acid per day, i. e., the output of uric acid was more than doubled under the influence ofthecaffein of the coffee. ACCUMULATION IN THE ORGANISM. 73 Siven's experiments made with diets, from which nucleins and free xanthins were practically absent, showed very strikingly how variations in the character of the diet will change the amount of uric acid. Thus, for a period of seventeen days, with a daily diet of potatoes, bread, butter, cheese, eggs, milk and apples, the daily output of uric acid averaged 0.433 grammes but, when meat was added to the diet, the excretion of uric acid amounted to 1.009 grammes per day. It will thus be seen that the continued ingestion of food rich in a purin content, may ultimately lead to over- exertion on the part of the kidneys, and faulty excretion of uric acid, with its consequent retention in the organism. Tables of Exogenous Purins. — We submit below a conspectus of the tables of food purins, given in the "Sixty-eighth Report of the Scientific Grants Committee of the British Medical Association," as furnished by I. Walker Hall, M.B., Assistant Lecturer in Pathology, Owens College, Manchester, England: MEATS. Undried purins Grains per lb. Cod 4 . 08 Plai ce 5-57 Halibut 7 • x 4 Salmon 8.16 Tripe 4.01 Mutton 6.76 Veal 8.14 Pork (Loin) 8-49 Pork (Neck) 3.50 Ham (Fat) 8.06 Beef (Ribs) 7 . 99 74 URIC ACID AND ITS CONGENERS. MEATS. Un dried pur ins Grains per lb. Beef (Sirloin) 9 Beef (Steak) 14 Liver 19 Sweetbread (Thymus) 70 Chicken 9 Turkey 8 Rabbit 6 46 27 43 °7 82 3 1 VEGETABLES. Bread (White) o . oo Oatmeal 3 • 46 Rice ' o . 00 Peameal 2.54 Beans (Haricot) 4 • x 7 Potatoes 0.14 Onions o . 06 Tapioca o . oo Cabbage (Green) Lettuce „ o . 00 Cauliflower „ Asparagus (Cooked) 1.51 BEVERAGES. Grains per pint. Lager Beer 1 . 10 Pale Ale 1 .27 Porter 1 . 36 Claret Volnay Sherry [ Port t The points which will attract attention in these tables are the somewhat high alloxur percentages discovered in ACCUMULATION IN THE ORGANISM. 75 beans, oatmeal, peas, asparagus and beers. The presence of purin bodies in beer is doubtless due to the "yeasting" and the processes of manufacture. Vegetables, other than those mentioned, and wines, are found to be free from purins. The purin contents of meat extract, coffee and tea are not given, but are, of course, known to be much higher than any other beverage, or than beefsteak itself; to wit: Uric acid and Xanthins Grains per lb Herring (Loch Erne, kippered) 6.40 Herring (bloater) 2 . 20 Meat juice 49-7° Meat extract 63 . 00 Tea 175-00 Coffee 70 . 00 Cocoa 59-0° It is perhaps well to bear in mind that the blood and tissue juices of very young veal ("bob-calves"), like that of children, contain a ^higher percentage of uric acid than older ones, owing to the greater number of leucocytes, and to the lesser decomposition of uric acid — -i. e., into urea. This is probably owing to the relatively lower degree of alkalescence of the Wood,] (and higher urinary acidity), caused by an exclusive albuminous or animal diet (milk). White vs. Dark Meats. — Concerning the popular opinion that white meats are more suitable for the sick, owing to their greater digestibility and the supposed pres- ence of less uric acid and nitrogenous extractives, it may be said that this belief is shaken by the analyses made by Opper and Rosenquist, which show that while white meats, such as poultry and fish, do in certain cases con- tain less purin extractives, yet the average amount does 76 URIC ACID AND ITS CONGENERS. not appreciably differ in dark and white meats, such as poultry, veal, beef, pork, mutton, etc., to make either pref- erable. They point out that the only way of limiting the ingestion of these deleterious uric acid derivatives is by diminishing the amount of meat taken, rather than for- bidding dark meats. CHAPTER IX. ACCUMULATION IN THE ORGANISM. Continued. Blood Alkalescence. — It is a physiological truth, the significance of which cannot be overestimated, that the vital processes of animal life require for their consum- mation a proper alkaline environment. In other words, the chemic, physiologic, ionic or electric manifestations of force, which we call "the vital processes," are essen- tially connected with a certain degree of alkalinity on the part of their surroundings, (i. e., the presence of K, Na ? etc., "ions"): if this alkalescence be lowered or weak- ened to any extent, a condition results favorable to the neutralizing action of toxins and other chemic manifesta- tions or, "symptoms," which we recognize as disease. It is well understood, for instance, that the tissue juices and solutions within the body are normally alka- line, — the acid gastric juice, perspiration and urine being, strictly speaking, excretions, and outside of the true in- terior of the body. The alkaline reaction of the blood is found to be owing to the presence of mononatrium (or alkaline) carbonate and dinatrium (or neutral) phos- phate; and, so important has the question of maintaining a certain degree of alkalinity come to be considered, in its relation to the metabolic processes, that investigators are now impelled to believe that any factor which pro- duces chemic changes in the composition of the blood and body juices, lowering their alkalinity, is one of the primal causes and starting points of disease. 78 URIC ACID AND ITS CONGENERS. It is claimed that many of the lower animals (espe- cially herbivorae) are more rarely the subjects of infec- tious diseases, as compared with man, owing to a higher degree of alkalinity of the blood. Von Fodor has demon- strated (Cf. Centbl. f. Bakt . u. Prasitkd., 1 894) that the organism of rabbits injected with an alkali, manifests a greater bactericidal action toward anthrax, and that life was preserved longer than in the case of the control ani- mals — those not so treated. Burian and other observers have found a lessened degree of alkalinity of the blood in such affections as cirrhosis of the liver, chronic nephritis, chronic rheumatism, gout, malaria, diabetes, tubercu- losis, etc. The same holds especially true of leukaemia, where the increased production and destruction of the leucocytes of the blood are characteristic. Urinary Acidity. — The question may well be asked: How shall the daily observed phenomenon of an acid water flowing from an alkaline reservoir be accounted for, — i. e., acid urine from alkaline blood ? Is it a uni- versal law that the watery excretion from the blood of animals, and containing the worn out ashes and clinkers of the system, shall become acid the moment it becomes urine ? Evidently not: for it is a well-known fact that only the urine of carnivorous and most omnivorous animals is acid, while that of all herbivorae is alkaline. It is known, too, that an omnivorous animal, like man, may so regulate his diet (by partaking principally of vegetable foods) as to cause an alkaline or neutral urine. The acidity of human urine, then, depends upon the presence in the blood of some substance resulting from the disintegration of animal foods ingested, — evidently, chiefly the nucleins, whose cleavage products are xanthins ACCUMULATION IN THE ORGANISM. 79 and phosphoric acid; for it is known that the acid reac- tion of urine is due to the acid phosphate of soda (which exists as a neutral phosphate in the blood). When this salt is submitted to dialysis, a larger amount of phosphoric acid is found on the outside than on the inside of the dialyzer, showing that the acid of the salt diffuses faster than its base. As a result, acid phosphate appears out- side of the renal dialyzer and renders the urine acid, — and in this way we get an acid water flowing from alka- line blood. Weakened Reaction of Blood. — It has been seen that the acidity of the urine in a given case depends in great measure upon the carnivorous proclivities of the individual, especially upon the amount of nucleins in- gested with animal foods, the decomposition of which within the body results first, in a superabundance of xan- thin cleavage products in the blood, and then of uric acid, the latter being insoluble in proportion to the degree of acidity of the solution. As might be expected, a high degree of urinary acidity, a weakened reaction of the blood, an'd the presence in the latter of an increased amount of uric acid, go hand in hand. All three of these conditions have been found to follow excessive nuclein feeding. That the alkalescence of the blood becomes dimin- ished, is doubtless owing to the neutralizing of the alkaline carbonates, a part of whose sodium is extracted to unite with the uric acid present, to form urates. "As a consequence of this transformation, " says Simon (Physio- logical Chemistry, 230), "the alkalinity of the blood must diminish. But as such a change would give rise to serious disturbances, and as there is a strong tendency on the part 80 URIC ACID AND ITS CONGENERS. of the body to maintain the composition of the blood con- stant, particularly its alkalinity, — a loss of alkali is guarded against by subjecting the various neutral salts to the specific activity of the renal epithelial cells;" i. e., as a result of the renal dialysis, previously described, that portion of the sodium base (of the neutral phosphates) left behind, — after the acid part has escaped through the dialyzer (renal epithelial cells) into the urine, — is trans- formed into alkaline sodium carbonate, which is returned to the blood, thus tending to preserve its alkalescence. While it is true, therefore, that Nature is constantly striving to prevent a weakened reaction on the part of the blood, and that, under ordinary circumstances, she will doubtless succeed, nevertheless, it can be seen that exces- sive nuclein feeding, plus increased nuclear tissue destruc- tion throughout the body, and, perhaps, faulty destruction of uric acid into urea, may not only lead to urinary hyper- acidity, but to subalkalinity of the blood, caused partly by abstraction of sodium from the economy in the form of urinary urates and phosphates (of sodium), and partly by extraction of the alkaline carbonates in the blood itself to form sodium urate. In other words, though Nature's efforts to preserve an equilibrium may generally prove successful; yet, at times, under a stress, they may become inadequate, — when a weakened reaction of the blood en- sues. Deposition of Urates. — As the blood, even with its normal alkalinity, is no more than able to just hold the urates in solution or suspension, — sufficient to insure their transit in circulation, — it is obvious that, during those periods of "weakened reaction" referred to, the urates are likely to fall out as a deposit, thus resulting in their tem- porary accumulation. ACCUMULATION IN THE ORGANISM. 81 The manner in which such deposition may occur is probably similar to that already described in a previous chapter, when considering the "precipitation" of uric acid crystals as observed in vitro. In the form of a "colloidal" solution, it is with difficulty that the passage through the capillaries is effected, so that partial or complete stasis often exists; and a slight reduction in the alkalinity of the solution occurring at such times, the urates will doubtless crystallize out (as in the laboratory) and become attached to the nearest solid tissue structure. Especially will this be true, if exposure of the surface vessels to cold happen at this time, which, of course, tends to hasten crystallization and precipitation. Such temporary deposits will be reabsorbed into solution, (as in vitro), upon restoral of the proper degree of alkalescence to the blood; and the urates may be conducted to another locality and there again be deposited, under similar conditions: and so on, time after time, the process may be repeated. Again, it is well known that strain or activity of muscle fibers, as during prolonged muscular effort, causes increased cell destruction, with production of xanthin cleavage products and consequent uric acid; also reduced alkalinity of the lymph and blood plasma in that neighbor- hood. As may be foreseen, a deposition of urates, as above described, will probably occur in this locality under these circumstances. From what has been said, it will be understood that any factor which tends to reduce the normal alkalescence of the blood stream is likely to cause precipitation of the urates and their deposition and accumulation, especially at such points where the circulation is most sluggish (as 82 URIC ACID AND ITS CONGENERS. through the capillaries) and where most exposed to in- fluences of cold, or where increased work and cell destruc- tion is going on and where the uric acid itself is increased in consequence. Even in constipation, where absorption of acid juices from the retained fecal mass lowers the blood's reaction; or, in dyspepsia, with acid fermentation of un- digested food and consequent absorption, — the same tendency occurs for the urates to become deposited at some point in direct contact with the solid tissue structures where the conditions above mentioned are most favorable, and where the deposit is likely to accumulate owing to the stronger attraction of the crystals en masse. Effect of Alcohol. — Some very significant experi- ments concerning the effect of alcohol in interfering with the oxidation of uric acid derived from its precursors in the food, have recently been performed by Beebe and others, and reported in the Amer. Jour, of Physiol., Sept. I, 1904, The authors of the experiments have shown that a greatly increased quantity of uric acid in circulation follows the ingestion of alcohol taken with purin foods; which in- crease is attributed to the impaired oxidative powers of the liver. In short, it has been demonstrated that alcohol does not hasten the excretion of urates already present in the blood, but that it interferes with purin metabolism, (oxi- dation of uric acid into urea), by its toxic action upon the liver, thus resulting in an increased quantity of unoxidized uric acid in the circulation, — which necessitates extra excretory work on the part of the kidneys. No accumulation would occur under these circum- stances, provided the kidneys were always equal to the emergency of properly excreting the increased quantity of urates; but, if the ingestion of alcohol be continued, the ACCUMULATION IN THE ORGANISM. 83 extra eliminative efforts will finally result in renal inade- quacy and consequent retention. In fact, von Noorden blames alcohol with causing uric acid to be eliminated with difficulty, resulting in retention; and he advises in favor of aiding uric acid elimination. In conclusion, it may be said that, though alcohol is, perhaps, a food, in the sense that when used in small quantity the energy from its oxidation may be utilized for some of the body needs, yet, at the same time, as it inter- feres with the normal activities of a most important organ, the liver, its food value is counterbalanced by its toxic effect; and, as a result, a considerable amount of uric acid is left behind in the circulation, unoxidized, — not decom- posed into urea in the proportion (50 per cent.) it should be. CHAPTER X. DISEASE PROCESSES. Purin Excess. — The accumulation of an excess of uric acid and its congeners in the system, no matter from what one or more of the several causes previously mentioned, almost invariably gives rise to certain well-recognized subjective and clinical signs, which may vary, of course, according to the nature of the accumulation and its locality. Owing to a faulty nosology, our present text-hooks are burdened with as many different "names" of disease as there are tissues affected ; but from an aetiological viewpoint, the disease processes arising from an accumulation of the nitrogenous purins and ureids in the system, may all be classed under the general head of "Purin Excess." By this term, we mean to embrace all disorders resulting from the presence in the human economy of an abnormal quan- tity (or quality) of uric acid and its derivatives, whether suspended in the blood and extra-vascular fluids, or de- posited in the various tissue structures of the body. Its Three Stages. — Like syphilis, which is arbi- trarily divided, as to point of time and location of tissues involved, into a primary, secondary and tertiary stage, so may uric acid or purin excess be divided into three similar stages, viz.: I. Uricacidaemic; 2. Rheumatic; 3. Gouty. In the first stage, the urates are still confined to the blood; in the second they are deposited in the skin, mucosa, or stroma of muscular and glandular tissue, chiefly yet in colloid form; in the third, the deposits have reached DISEASE PROCESSES. 85 the deeper, less vascular structures, where they have be- come crystalline. The line of demarcation is not always sharply drawn here, any more than in syphilis, or in pneumonia (con- gestion, inflammation, hepatization), where one stage may merge into another, or, perhaps, one of them be apparently slighted or skipped over. But, as a rule, in a typical case of uric acid accumulation, we observe first the symptoms due to its presence in excess in the blood, (headache, in- somnia, etc.) ; then, of its deposition from the blood into the surrounding tissues, where it may be reabsorbed and re- moved to some other locality, (muscular pains, etc.); and finally, of its retention and crystallization in the terminal joints, or deeper structures of low vascularity, (concre- tions, etc.). Of course, like syphilis, the disease process may never reach the third stage, and possibly not the second; but, if permitted to go on, the tendency of uricacidaemia is to develop into a rheumatic condition and finally gout. On the other hand, the symptoms of the primary or secondary stage may themselves be overlooked or disregarded, and the first complaint to the doctor be made at the gouty stage. (i) URICACIDtEMIC stage. Names. — The terms " uricacid-aemia," " purin-aemia," "uric-aemia" and "lith-aemia," as suggested by their com- mon Greek derivative ending ("aemia," or blood), mean respectively uric acid blood, purin blood, uric blood, and lithic blood. In short, they are equivalent terms used to designate the primary stage of "Purin Excess," in which the circulation at some point contains so much uric acid, 86 URIC ACID AND ITS CONGENERS. or uric acid in such form, that it cannot be properly con- veyed along on its journey of exit from the body. Increased Viscosity. — The investigations of Rom- berg have taught us that the blood-stream may vary fully ten per cent, in viscosity, by changes in its reaction: being rendered less viscous when the alkalinity is raised by the administration of an alkaline agent like potassium iodide; and more viscous when the alkalinity is diminished in any way, as by the administration of an acid. As we know from clinical experience that one of the chief symptoms of the uricacidaemic stage is a sluggish flow of blood through the capillaries, and that the alkalinity of the blood is diminished at such times, as shown by the accompanying urinary hyperacidity, it is fair to infer that the viscosity of the blood has also been materially increased by the pres- ence of an excess of urates in colloid form. Capillary Obstruction. — The clinician knows that the principal trouble arising from an accumulation of the urates at any point, is owing to its serving as a mechanical impediment to a free capillary circulation. He has learned from experience that blocking up of the capillaries is characteristic of uricacidaemia, and that one of the chief objective signs is a scant, high-colored, strongly acid urine of high specific gravity, which is, in itself, indicative of an impeded capillary flow through the renal epithelial cells. The capillaries, of course, serve the double purpose of supply tubes and waste pipes. In the latter capacity they are obliged to conduct away from a given tissue, the purin waste products resulting from cellular activity and cell destruction. If the conduits be obstructed, as in the uricacidaemic stage, the inevitable result is stasis, con- gestion, and, perhaps, inflammation of the particular tissue or organ where such stasis occurs. DISEASE PROCESSES. 87 Localization of Symptoms. — It will readily be understood that the capillary obstruction, with its result- ing congestion in these cases, is most likely to occur in those organs or tissues which are called upon to do un- usual service, thus throwing an extra amount of labor on the capillaries in that vicinity, which, as supply tubes, must bring the added nutriment required, and, as waste pipes, remove the increased debris (xanthin and uric acid) which necessarily results. The part to be affected, therefore, when the circula- tion is impeded with colloid urates, will vary in different individuals, depending on their vocation, — i. e., which part of the organism, in a given case, is called upon for special effort. The man who uses his brain, or whose cerebral capillaries are required to do extra work, will be subject to headache, depression of spirits, "fits of blues," sleeplessness, inaptitude for mental effort, loss of mem- ory, etc. The man of brawn, or he whose muscles are constantly engaged, will complain of sluggishness, muscu- lar inertia, that "tired feeling," inaptitude for physical exertion, etc. In both of these cases the sensory manifes- tations, or "symptoms," are doubtless due, in part, to the mechanical pressure of the distended venules and arter- ioles on the accompanying nerve-fibrillae and their end- ings; and, in part, to the direct chemical action or toxae- mic effects of the alloxuric bases. Faulty Metabolism. — In nearly all cases, in the uricacidaemic stage, the liver becomes more or less affected, since this organ is actively engaged in every individual; and, if its capillary supply or waste be blocked, its func- tional activity will be correspondingly lessened or interfered with. While it is true that all of the tissue cells of the 88 URIC ACID AND ITS CONGENERS. animal economy take part in the general metabolic pro- cess, yet, inasmuch as the liver is the largest and most complex organ of the body, containing the greatest con- glomeration of such cells, it is not surprising that the greatest stress should be laid upon its action, and that stasis in its immediate vicinity should finally result in so-called hepatic "torpor" and its disagreeable general consequences, — i. e., faulty metabolism throughout the en- tire organism. Capillary obstruction, in this way, may eventuate in an "ill burning" fire, in which the purin ashes of nitrog- enous combustion (xanthin and uric acid) are retained, and accumulate to cause further obstruction, — thus tend- ing to form a circulus vttiosus. (2) RHEUMATIC STAGE. Names. — As may be observed from its Greek de- rivatives, the term "rheum-atism," (meaning liability to "rheum," or "flux"), was applied originally to a humoral malady. In more recent times the term has been used synonymously with "arthritism," although the fact has generally been recognized that other tissues than the joints may be affected. The term "rheumatic," as used by us, is meant to designate the second stage of " Purin Excess," in which the urates at one or more points have been thrown out of solution and deposited in the sur- rounding tissues. Transition Period. — The change from the uric- acidaemic to the rheumatic stage may be gradual or abrupt. At any given point, where the capillary flow is more or less impeded by accumulation of urates, the deposition into the adjacent tissues will be hastened if the latter undergo DISEASE PROCESSES. 89 a sudden strain, or be called upon for work, or if exposed to cold, — in all of which cases the alkalinity of the solu- tion at that point is lowered, and the urates precipitated in consequence. In like manner, the deposition into the tissues may be hastened by the sudden absorption into the circulation of lactic, butyric, et al., acids, caused by gastro-intestinal fermentation. The same effect may be produced in the uricacidaemic patient, at will, by administering drugs which diminish the alkalescence of the blood, such as acid phosphate, morphin, antifebrin, etc. Every physician, long in practice, has doubtless observed "rheumatic" symptoms follow the use of some antipyretic or analgesic agent, which was given by him to relieve a severe head- ache; or from the use of a hypnotic, such as sulfonal, to relieve insomnia. Localization of Symptoms. — Like the sensory manifestations of the uricacidaemic stage, the subjective and objective signs of the rheumatic stage, in so far as their character and localization are concerned, will depend upon the particular tissues that may be involved, which, in turn, will depend in great measure upon the vocation of the individual. For instance, the man whose muscles are exposed to strain, or to influence of cold, will be subject to the muscular stiffness or aches and pains caused by deposition of the urates in the stroma or between the fibers of the muscles so engaged or exposed. Again, if the deposits are in the nerve sheaths, neural- gic twinges will appear; if in the mucous membranes, catarrhal conditions will supervene; if in the skin, some form of eczematous eruption; if in the stroma, or con- nective tissue of glands, cirrhosis of the organ, par- 90 URIC ACID AND ITS CONGENERS. enchymatous, or, perhaps, interstitial inflammation; .if in the fibrous tissue of the cardiac valves, endo-carditis or mitral insufficiency; if in the supporting structures of the larger joints, arthritis; if in the intestinal coat, colicky pains or sluggish peristalsis; if in the alveolar tissue or gums, gingivitis, etc. The uratic deposits, in these cases, are probably still in the colloid, amorphous, or semi-crystalline form, and may be reabsorbed from time to time, to be conveyed to some other locality or excreted from the body entirely. In the latter eventuality, coincidently with disappearance of the symptoms, an increased elimination of urates occurs, as may be observed by examination of the urine. (3) GOUTY STAGE. Definition. — Gout is the third and last stage of 'Purin Excess. " In the two conditions already described, the urates have merely reached the colloid form, remaining (1) in the blood as such, or (2) precipitated temporarily out into the tissues. In gout, however, the deposits (as in the small joints) have finally become crystalline, where they oftentimes remain to cause irritation and set up in- flammation. Formative Period. — Like the tertiary stage of syphilis, the gouty stage of "Purin Excess" may be long in making its appearance; or, it may fail to appear at all, for Nature will endeavor to prevent her waste deposits remaining long in the system. It is only when her efforts to preserve an equilibrium have been weakened by con- stant demand or neutralized by sudden unusual require- ments, that the conditions become favorable for the forma- DISEASE PROCESSES. 91 tion of crystalline deposits; and, even then, only certain localities are eligible sites for the tophi. Repeated slight fluctuations (from lower to normal) in the reaction of the body fluids, incident to the accumu- lation and removal of uratic waste, may be considered a fair measure of the strain that has been put upon the renal dialyzer, — to whose proper working the blood looks for the restoral of alkali on one side and the elimination of urates on the other. Constant use and frequent abuse, in this way, may ultimately weaken the selective and dialyz- ing function of the renal epithelial cells to such an extent as to result in lowered alkalescence of the blood and re- tention of urates, — the latter even being precipitated at times in the kidneys themselves. As may be seen, the chief exciting ^etiological factors during the formative period are those which favor the accumulation of uric acid, as an excessive ingestion of purin containing foods with alcohol, and faulty elimina- tion. Localization of Deposits. — While the circulation of the entire organism becomes thus tainted to a greater or less extent on occasions, it is only in distal parts, poorly vascularized, where the removal of deposits is delayed and where the environing conditions are favorable to the pre- cipitation and crystallization of uric acid, that the tophi or concretions are formed. We know from laboratory ex- periments, as referred to in our previous section on "Crys- tallization, " and from the recent investigations of Prof. Klemperer (Cf. Therapie d. Gegenwart, May, 1904) that a very weak alkaline solution of inorganic salts will dissolve uratic deposits, while the urates in the same solution, when slightly acidulated, will, on the contrary, be abstracted 92 URIC ACID AND ITS CONGENERS. from the solution to become deposited in crystalline form on some contiguous solid substance. The four factors which conduce toward the crystalli- zation in the organism of uric acid, when its urates are present in a saturated or nearly saturated solution with other salts, are: I. Repeated sudden dealkalizations of the solution due to the fluctuating changes in the quantity of its contained alkaline salts; 2. Stasis (complete or almost complete) for ten or twelve hours; 3. Low tem- perature; 4. An adjacent solid. These conditions are not met with in the circulating blood: nor in the blood at all, until it is removed from the body, acidulated, and allowed to stand and cool, when a solid substance introduced becomes the site of crystalline formation, — as in Garrod's " thread test." Nor are they met with in the urine itself, until it is outside of the dialyzer, at rest in the renal pelvis or bladder, and some foreign particle presents as a nidus for the formation of calculi. The four favoring factors are present, however, in certain regions of the body far removed from the cardiac- center, exposed to cold (freezing easily), as in the helix of the ear and the septum of the nose, and where pressure or constriction is put upon the return circulation, as in the bursae of certain joints and toward the end of the great toe. In this metatarsophalangeal joint, the synovial fluid is practically at a standstill, especially when the shoe is on. It has been shown by Frerichs that the synovial fluid of an animal at rest contains twenty per cent, more of the alkaline salts than when in exercise, thus causing sudden lowering of alkalinity on motion of the parts, favoring the precipitation and crystallization of its contained urates, dialyzed from the surrounding capillaries in which the colloid urates are present in excess. DISEASE PROCESSES. 93 So long as a blood, rich in urates, is brought to the spot., the tophus steadily grows by attracting other urates to it. Doubtless there will be alternate precipitations and absorptions, keeping pace with the fluctuations in the reaction of the synovial fluid. Especially will this be observed at night, in the wintry season, after removal of the shoe and restoral of the circulation, with rest of the parts from motion and warming of the toe in bed. On such occasions, either (i) the mechanical irritation of the crystals, as withdrawn in part from their site and re- absorbed into the now highly alkaline synovia, or (2) the chemical effect produced by the change from one form to the other,- — may set up congestion and inflammation of the surrounding tissues, thus giving rise to an acute "gouty attack." To account for the well-known predilection of the urates for the joint of the great toe, Wakefield, (Cf. Ameri- can Medicine, March 25, 1905), offers the following ex- planation: "Having already referred to the predisposition of subkatabolism for certain joints, it only remains to explain here why gout predisposes to the metatarsophalangeal articulation, and analyze the attack: 1. The great toe is the one of greatest strain when walking, and being the farthest removed from the heart, and hence most affected by splanchnic venous stasis, as well as all of the vascular obstructions, arterial and venous, of the intermediate tissues, the oxygenation is poorest. 2. The involved areas, by flaccid expansion and gelatinous spongy consistence becomes extremely prone to impregnation with liberated bases. 3. During the period of greatest subkatabolism in the twenty-four hours ; during the equilibrium of blood distri- 94 URIC ACID AND ITS CONGENERS. bution, namely, the very early morning hours, uric acid salts are taken into solution by the blood and are carried to the seat of greatest subkatabolism, there to be englobed by jellified tissue. The fact that throughout the vascular system the urates are colloidated so completely with colloid food and tissue detritus floating in the blood current, suggests a possible affinity between the two/' CHAPTER XL (i). URICACIDiEMIC MANIFESTATIONS. Pain. — The intelligence immanent throughout the cosmos is nowhere more strikingly manifested than in those retributive acts of justice, observed in the human organism, (as "remorse") when the subjective center is made to suffer for wrongs inflicted on the helpless, in- voluntary tissues, — i. e., when notice is given that some- thing is wrong in a certain locality, as evidenced by the exaggerated sensory impression or perception, which we pain. The essence of this disagreeable sensation lies in the intensity of the stimulus, in the disturbance of the organi- zation of the nerve at some point in its course, or in the excitability of the sensorium. In either case it is an indi- cation that a law of Nature has been violated; and, in order that a similar offense may not occur again, a punish- ment is inflicted which will tend to deter the subject from repeating it. The sensation of "fatigue" is only a lesser degree of pain. It is localized in, or referred to a certain muscle or set of muscles, after prolonged or violent exercise of the same. Why ? Doubtless because of the abnormal amount of waste present, resulting from the increased disinte- gration and death of the cells engaged in furnishing the requisite energy; for we know that the sensation gradually disappears as the purin waste products are removed by the capillaries. In short, we see that the presence of organic non-living matter, in excess of the normal, operates like 96 URIC ACID AND ITS CONGENERS. any other foreign body; and notice is given of its presence and the necessity for its removal. "Pain," in other words, is often but a notification to the center of volition of the presence of some abnormal material (or normal material in abnormal amount) in con- tact with nerve tissue, which, either by mere physical pressure, or by some chemical change induced, gives rise to the subjective feeling. In all cases, it is an unmistakable notice given to the subject that something in that locality is present that ought to be removed, whether a mote in the eye, a thorn in the flesh, a stone in the bladder, a tight shoe, a distended gut or bloodvessel, or what not. As intelligent beings, capable of molding our environment, we are sup- posed to learn from personal experience, or from the experience of others, the nature and cause of the " law- breaking " in each instance, — i. e., learn not only how to avoid infringement in the future, but how to apply the present remedy. Headache. — One of the commonest manifestations of the accumulation of purin waste — its presence in excess in the circulating medium, resulting in capillary ob- struction — is the cerebral pain, called "headache" or "migraine," due to distension of the cerebral veinlets and arterioles, causing pressure on the surrounding nerve tissue. The conservative headache of menstruation is closely connected with uric acid accumulation. We know that two or three days prior to the menstrual discharge, there is a marked diminution of the urinary excretion of urates, which is not accounted for by the presence of an increased amount of purin nitrogen in the urine in other forms, for the latter remains unchanged, or even diminished. We URICACID^EMIC MANIFESTATIONS. 97 know positively that uric acid is retained in the circulation until the second or third day of the flow, when it is excreted in greatly increased amount, at the same time of the dis- appearance of the headache. The relation of cause and effect here, is too close and constant to be disregarded. It should be understood that the above is what hap- pens in normal conditions, when the organs of elimination are active and perform their added duty on such occasions properly, — the only symptoms indicative of this temporary retention being a slight headache and depression of spirits at the beginning of the periods. But, if elimination is im- perfect, (as is so often the case), uric acid remains to accumulate, and we have all the disagreeable symptoms characteristic of migraine. As in menstruation, so it is in the regular paroxysmal headache of migraine, the greatest excretion of uric acid occurs two to four hours after the height of the attack, — i. e., occurs as the headache is passing off. One or two investigators, notably Lichty, some five or six years ago, advanced the idea that this was a proof that uric acid is the result of the headache, not the cause. But it would be just as rational to say that the excreted uratic calculus or gravel is the result of the renal or ureteral colic, instead of the cause. "Next Morning" Headache. — One of the charac- teristic headaches of purin excess, is that which ensues "next morning," after an alcoholic debauch. As already stated in a previous chapter, the effect of toxic doses of alcohol is to interfere with the oxidative function of the liver — i. e., inhibit the catalytic action of its ferment in decomposing uric acid into urea, thus leaving an abnormal amount of unoxidized uric acid in the circulation. Until 98 URIC ACID AND ITS CONGENERS. the organs of elimination succeed in removing this excess, the effects of its presence will be felt, especially a few hours after ingestion of the alcohol, — at the height of the " alka- line tide," during the morning hours, when the uratic waste is en route through the organism. Previously, as the immediate effect of the alcohol, the blood's alkalescence is lowered and the urates precipitated out into the tissues, thus leaving the capillary vessels tem- porarily open and free, causing a sudden blaze of the meta- bolic fires, with the concomitant stimulation and feeling of buoyancy. But on the restoral of its normal degree of alka- line reaction, the blood reabsorbs from the tissues the deposited urates en masse, and we get the disagreeable manifestations of their presence, until Nature's conserva- tive "explosion" occurs, when, figuratively speaking, both the headache and the urates are carried off in the urine, as shown by urinalysis. Fits of Blues. — As the dark cloud presages the near approach of a summer shower, so do the "blues" give evidence of a coming "uric acid storm." In one instance, the air about us is electrically charged, in the other, the blood within us is uratically charged; and a feeling of weight or depression precedes the "explosion" in both cases. A fit of the blues is felt just as the storm is brewing, just as the accumulation is beginning to impede the capil- lary flow, which will soon reach the stage of congestion and distension with the accompanying pressure and headache. It will be seen, then, that "depression of spirits" is usually a precursor of the headache, while both precede the explosion of urates from the circulation, either (i) out of the body entirely, by way of the urine, which is the normal URICACID^MIC MANIFESTATIONS. 99 way, or, (2) out into the tissues (when elimination is im- perfect), which is the "rheumatic" way. Insomnia. — It is a well-known physiological fact that the amount of energy expended in the organism may be considered a fair index of the amount of cell destruction initiated and the consequent purin waste produced. Mental energy, in particular, necessitates cellular com- bustion. Both the mental and physical energy expended during the waking hours are chiefly of the voluntary character, and represent catabolic changes, — change from living to non-living matter. On the other hand, the little energy expended during the sleeping hours is entirely of the involuntary character, representing (1) anabolic changes, — change from non-living to living matter, as in cell re- establishment; and (2) continuation of catabolic changes, — removal of the non-living matter by the capillaries, into the general circulation, to be excreted by the kidneys. These latter two processes are a vegetative function, per- formed without any effort of volition, thus permitting of Nature's sweet restorer, "sleep," so long as voluntary action is not required. But, if an excessive amount of waste be present, from whatever cause, and blocks the cerebral capillaries, so that the distension causes even the slightest pressure on the surrounding brain tissue (especially the voluntary centers), the same effect is produced in making the subject restless, as from the pressure of a fly tickling the nerves of the skin, or of noises impinging on the drum of the ear, or strong light on the eyelids, etc. Any stimulus, which sends an impression to the centers of volition, excites an effort at voluntary action; but, as such action can only be performed when the subject is awake, the tendency is to arouse him from his sleep. 100 URIC ACID AND ITS CONGENERS. In this indirect way, uratic excess, causing capillary obstruction and pressure, often results in insomnia, — especially if the pressure happens to be in the cerebellar region, in which the voluntary centers are chiefly situated. Headache Powders. — It has become well known to the laity that certain powders will relieve a headache; and, as a consequence, the indiscriminate sale of such powders has become enormous. They are usually composed of some antipyretic alkaloid in mechanical combination with caf- fein. The temporary relief afforded may be best explained by citing the action of cafTein, which is typical of all the rest, to wit: The crude material, which serves as a commercial source of cafTein, is tea, or "tea sweepings." At the great warehouses of New York and London, sales are made of waste and damaged tea. It not infrequently happens that whole cargoes of tea are damaged by moisture, being mouldy and unfit for the market. Such goes to the manu- facturing chemist, who extracts the cafTein. An infusion is made by extracting the tea with boiling water, and from this infusion the most of the organic matter is precipitated by a simple process. This vegetable xanthin (trimethyl-xanthin), like other alkaloids, and like the animal purins (as uric acid, itself), when first administered, lowers the alkaline reaction of the blood and clears out the urates by precipitating them into the tissues (often resulting in "rheumatic" symptoms), thus causing freedom of the capillaries and consequent diuresis. It operates, in this way, as a temporary stimu- lant, much like alcohol or opium, causing mental exhilara- tion and a feeling of well-being, — an effect which is due to the free flow of blood through the capillaries. URICACID^EMIC MANIFESTATIONS. 101 Later, however, when alkalescence is restored, as it must be when all of the drug is absorbed, an excess of uric acid proportional to the amount of cafFein introduced, passes again into the blood; and, unless by some means it is speedily eliminated from the body, we get a return of the characteristic manifestations of uricacidaemia, — i. e., obstructed capillaries, scanty urine, defective secretions, loss of appetite, headache, etc. When cafFein is taken into the system, one-third of it appears in the urine as a purin body. Like xanthin, hypoxanthin, guanin, etc., cafFein is physiologically and pathologically identical with uric acid. For all intents and purposes its administration is equivalent to the ad- ministration of uric acid, and produces precisely the same physiological effects. Taken in the form of coffee, tea, headache powders, etc., it has become one of the great introducers of uric acid into the system. It is true, therefore, that headache is temporarily re- lieved by introducing more uric acid into the system, or substances from which it is derived, meat juice, beefsteak, sweetbread, coffee, etc. The efFect is similar to that experienced by the opium habitue, when taking another dose of the toxin which was responsible for the disagree- able symptoms which it now temporarily relieves. The action of sulfonal in relieving insomnia, is only temporary in efFect, and for a similar reason. The true remedial agent in these cases, is the one which tends to cure, by eliminating the offending substance from the system entirely, — not driving it temporarily into the tissues, where it either accumulates to cause "rheu- matic" signs, or is reabsorbed and gives rise to an aggra- vation of the original trouble and a demand for more of 102 URIC ACID AND ITS CONGENERS. the same remedy, and so on, until serious consequences develop. The Neuroses. — As the elimination of a calculus is coincident with the disappearance of the pain which preceded it, we conclude that the calculus was the cause of the symptoms. Girls, during menstruation, often experience relief from pain on the elimination of a blood clot: a woman certainly does, after confinement, when the foetus is delivered. In both cases, the material elimi- nated was the cause of the symptoms complained of. We see the same thing in hepatic colic, on passage of the concretion and often in intestinal colic, on passage of the fecal mass. Reasoning by analogy, we conclude that the excess of urates, excreted immediately after the height of a neurotic attack, must have been the cause of the symptoms, — more especially as there was retention of the same, pre- ceding and at the beginning of the attack. In short, relief ensues upon their elimination. This finding is observed after various paroxysmal neuroses, such as hysteria, epilepsy, spasmodic asthma, chorea, "convul- sions " and " day terrors " of children, etc., and to a similar extent after the milder neuroses, as headache, that "tired feeling," the blues, etc. There would seem to be but one inference. Periodicity of Symptoms.— While uricacidaemic manifestations are not necessarily "explosive" or paroxys- mal to the degree noted in many of the neuroses, nev- ertheless there is always some periodicity to be observed. This is doubtless due to the natural periodic fluctua- tions in the reaction of the blood caused by the ingestion of three meals at regular hours each day, and to the cus- URICACID^MIC MANIFESTATIONS. 103 torn of sleeping at a certain period every twenty-four hours. The periodic changes in the blood's alkalescence thus caused, lead to corresponding changes in the capil- lary flow, when urates are present in excess, which nec- essarily give rise to symptoms more or less periodic in character. There is a wave in all of Nature's phenomena, — physiologic as well as pathologic. In short, though excess of urates in a given case may be present at all times, the manifestations of such excess are likely to be only periodical, — as observed in the intermittent feelings of mental and physical "torpor," capricious appetite, lapses of memory, fits of depression, etc. The periodical changes in the amount of urinary water excreted and its contained urates, will be coincident with these subjective signs of "collaemia" or uricacidaemia. CHAPTER XII. (2) RHEUMATIC MANIFESTATIONS. The Beginning. — Just where the uricacidaemic stage leaves off and the rheumatic stage begins is not always easy to determine; yet it is, perhaps, most con- venient to consider that the rheumatic stage is ushered in when the urates of the obstructed capillaries in any given locality are no longer capable of being held in solution or suspension in the blood stream, but, owing to some excit- ing factor, (as exposure to cold, muscle-strain, etc.) are suddenly thrown down as a deposit on the adjacent tissue structures, where they may temporarily remain until restoral of the blood's alkalescence at that point causes their reabsorption into the circulation, to be conveyed en route to the kidneys for excretion, unless again thrown down as a deposit in some other locality. Muscular Stiffness. — Some idea of the manner in which " rheumatic" pains and aches are commonly caused by deposition of urates, and their infiltration between muscle fibres, may be gained from a physiological study of the stiffness or lameness which results from prolonged or violent muscular work of an unusual character. For instance, it sometimes happens, (as in the case of a pro- fessional man playing a game of base-ball), that the in- creased metabolism and augmented disintegration of nuclear muscle-cells and consequent purin cleavage, give rise to the formation of more waste of the uric acid type than can at once be taken up and removed by the lymph channels and capillaries in that locality, unaccustomed RHEUMATIC MANIFESTATIONS. 105 as they are to such stress. Under these circumstances the excess of uric acid remains as a foreign body to clog muscular action, and we observe the stiffness which usually follows. The length of time during which such " stiff- ness" may remain, will depend chiefly on the activity of the eliminative organs in a given case, and the consequent cleaning out of the capillaries. Again, the increased nuclear destruction and greater metabolism may give rise to more purin cleavage and hypoxanthin than the xanthin-oxidase is capable of de- composing into uric acid, in which case the presence of xanthin or hypoxanthin in excess may serve to produce (perhaps through liberation of ammonia) some toxic or chemical change in the way of inflammatory action, — as observed in the heat and swelling of the overstrained tissues. We know, too, that the leucocytes will soon be increased in amount at such points, and it is possible that their disintegration produces purin cleavage in excess of the normal strength of the oxidase to form into uric acid. At this stage, even though the latter be formed satisfactor- ily, its considerable amount would probably be greater than could be taken up by the capillaries, and a temporary local deposit would result. The destruction of the nucleins, and the consequent change from guanin to xanthin, and adenin to hypoxan- thin, is best shown by the following schema, in which it will be observed that ammonia is liberated in both in- stances; to wit: C 5 H 5 N 5 0+H 2 0=C 5 H4N 4 2 +NH 3 Guanin Xanthin Ammonia 3 C 5 H5N5+H 2 0=C 5 H4N 4 0+NH : Adenin Hypo Ammo- xanthin nia 106 URIC ACID AND ITS CONGENERS. The further conversion of xanthin into uric acid is purely a process of oxidation brought about by a typical intracellular oxidase, the reaction being shown to its full extent by use of their respective constitutional formulae; to wit: HN — CO HN — CO II II CO C — NH\ CO C — NH\ | | CH+O --= | || CO HN — C— N/ HN — C — NH/ Xanthin Uric Acid These several changes of cell disintegration, from the splitting off of the purin bases to the oxidation of uric acid, take place seriatim', and, under normal conditions, the quantity formed is no more than can be taken care of by the venules and thus satisfactorily removed. But under the extraordinary conditions we are considering (pro- longed and violent muscular work), the removal does not keep pace with the increased supply, and blocking up of the capillaries in that vicinity results. Especially will this be true if the circulation at that point already contains an excess of uratic waste, as is often the case with a pro- fessional man. Uric Acid Explosion. — By an "explosion" of uric acid is meant that phenomenon of Nature, so often ob- served, when she is attempting to rid the circulation of an excess of urates. On such occasions, if the eliminative organs are active and equal to the emergency suddenly put upon them, the obnoxious urates will be expelled by way of the urine and feces; and the only subjective mani- festations of the explosion will be the depression of spirits, headache, etc., preceding the increased excretion. RHEUMATIC MANIFESTATIONS. 107 But, on the other hand, if the patient be constipated, or the secretions otherwise locked up, the urates will be "exploded" out of the circulation into the tissues, and a "rheumatic" attack ensues, either of skin, mucosa, muscles, glandular organs, or in the joints themselves. Such "explosions" only occur, of course, after a prior retention of uric acid and consequent blocking up of the capillaries. In short, it is one of Nature's sudden changes from the uricacidaemic to the rheumatic stage of "Purin Excess." The objective signs, preceding an "explosion," and at the beginning of the headache, will be a scant, high- colored, over-acid urine, with high specific gravity, often- times extremely foetid. On some occasions, scalding during micturition will be observed. The liability to precipitation of calculi in the bladder is increased at such times, owing to the increased per cent, of urates in a given sample of urine; though the total quantity excreted during the twenty-four hours will be diminished. When the "explosion" occurs, (i. e., after the height of the headache attack), the quantity of urinary water is augmented and contains urates in excess of the normal; i. e., the daily excretion will be in excess. Urinalysis, before and during the decadence of the attack, will in- dicate first retention and then increased elimination, both of water and of urates. A sample of the scant, high-colored urine contains more urates than the same quantity of urine immediately after the headache; but less is elimina- ted during the twenty-four hours, at first. It should be understood, however, that the above holds good only when the eliminative organs are active and equal to the emergency at the time of the "explosion." 108 URIC ACID AND ITS CONGENERS. In many cases, the retention and accumulation have so often been repeated, that the time comes when the excre- tory organs fail to meet the emergency, and the urates, being withheld, are driven into the tissues, and we get a "rheumatic attack." On such occasions, after the period of the headache, though the urinary water is increased in amount, as before, the excess of urates does not appear, — they have been driven elsewhere. In both cases, the diuresis is due to the freeing of the capillaries, when the urates are removed from the circulation. In the first instance, Nature has succeeded (by means of the " explosion") in ridding the system entirely of the excess; in the second, she has succeeded in relieving the circulation at the expense of the tissues, and " rheu- matics" supervene. The latter is usually the outcome whenever exposure to cold or muscular strain occurs just prior to the "explosion," thus lowering the alkalinity of the blood and tending to hasten precipitation of the urates be- fore they can be eliminated. Sites of the Deposits. — The muscles are oftener the seat of the deposits and infiltrations than other tissues, though the skin and mucous membranes receive their quota. Tissues subject to exposure and strain seem to be those for which the urates have the greatest predilection, doubtless because of the frequent lowering of alkalinity at these points, caused by such exposure and strain. The fibrous tissues of such joints as are most commonly sub- jected to strain, are also frequently affected. The efforts of the skin to serve as a vicarious avenue of elimination probably tends in some measure to stimulate the circulation of the surface vessels, at the time of an attempted "explosion," especially if the main excretory RHEUMATIC MANIFESTATIONS. 109 organs are themselves inadequate; but, the great exposure of the bodily surface to influences of cold, tends to cause fluctuations in the alkalescence of the blood at that point and the consequent deposition of the urates, which pre- vents free elimination through the pores, resulting in checked excretion and such affections as a dry, scaly skin, eczema, psoriasis, etc. In fact, it is now the generally accepted opinion among dermatologists that many affec- tions of the skin which they are called upon to treat, are simply the manifestations of imperfect excretory function due to the presence of uratic deposits, and that local treat- ment alone will prove insufficient to effect a cure. Similar effects are observed in the mucous membrane, lining the respiratory tract, exposed to sudden and frequent changes of temperature through inspired draughts of air, as in the nasal passages, pharynx and bronchi, where such affections as coryza, nasal catarrh, hay fever, tonsillitis, bronchitis and spasmodic asthma are most common. In some cases of uric acid "explosion," in which the kidneys and bowels have proven unequal to the emergency, we witness the effects of retention of urates in this wise: 1st., by their deposition from the surface vessels and the consequent irritation of skin or mucosa (as in eczema or tonsillitis); 2nd., by their deposition from the deeper ves- sels into the fibrous tissues of muscles or joints (as in muscular or articular rheumatism). The skin eruption or tonsillitis usually precedes the so-called "rheumatism" in these cases, although, strictly speaking, both are alike manifestations of the "rheumatic" stage of purin excess. One is not the cause of the other; both are due to a com- mon cause. They may alternate with each other or occur together in the same case. The same phenomenon is often 110 URIC ACID AND ITS CONGENERS. observed in asthma or hay fever and rheumatism; but the latter trouble is simply a later manifestation of a "stage" common to both. Recent advocates of the bacterial origin of rheumatism offer in support of the germ theory the argument that ton- sillitis, preceding rheumatism doubtless means that the tonsils are a port of entry by which the germs gain access into the organism. But it would be just as rational to suggest that the skin is a port of entry, as observed in the eruption which often precedes the rheumatic attack. From the viewpoint we have taken, however, instead of their being "ports of entry/' to admit some external in- fectious agent, the mucosa and skin, in both instances, are attempting to serve as "ports of departure" for the exit of an internal autoinfectious agent. The twinges and lancinating pains, commonly des- cribed as "neuralgic," would seem to be caused when the deposit occurs in the sheathe of the affected nerve, at some point in its course, as observed in sciatica. Leg Cramps. — The cramps of the lower extremities are probably due to deposits in the muscles themselves, especiallv in the gastrocnemii and solei of the leg and plantar region of the foot. This region is particularly liable to deposits owing to the sluggish vascular flow here, explained on purely mechanical principles. Cold feet are similarly caused, as well as the varicose veins and chronic ulcerations common to this localitv. In the opinion of Macdonald (Cf. Northwestern Lan- cet, August 15, 1900): "The circulation in the leg has not only to overcome the force of gravity, but that of mechani- cal pressure from above as well; man, in fact, being the only animal in which the weight of the whole column of RHEUMATIC MANIFESTATIONS. Ill blood contained in the vena cava presses directly upon the veins of the lower limbs. Unlike other veins, the cava is not supplied with valves; and it will at once be seen, in recalling the action of the hydraulic press, what a powerful effect the weight of its column of blood must have. This defect in the structure of our vascular system, — i. e., the cessation of valves at just the point where they would be of the most use in the erect posture, — is only another of the manv significant proofs in favor of the evolutionary theory of growth and development. The indication is that man has assumed his present upright position within so com- paratively recent a period that the body is not yet perfectly adapted for it; for, in other animals, of course, the cava lies in a horizontal position in which valves are not es- sential. " "It will be observed that persons subject to cramps are worse at night, after a day in which the body has been forced to assume the erect position, as in standing con- stantly at work at a bench. The mechanical effect upon the veins of the lower limbs, preventing the return venous flow, may be seen, too, in the results which follow after having been seated for some time in the well-known " cross- legged" position, — when severe cramps in the leg so crossed (usually the left) will often be the consequence. "The same effect is often observed in chronic consti- pation. The colon, containing an accumulation of feces, presses on the iliac veins (more particularly on the left side when partial impaction of the sigmoid flexure occurs) causing congestion of the leg veins, producing cramps, cold feet, etc. This is especially the case in elderly people, who are usually constipated, and in whom the walls of the colon are partially atonied. It has been said that "washing 112 URIC ACID AND ITS CONGENERS. out the colon," has often been resorted to as an effective cure for cold feet. Cramps and cold feet, too, are troublesome at times to the pregnant woman, owing, probably, to the pressure exerted on the iliac veins by the gravid uterus." "It will be seen, from what has been said, that an obstructed or sluggish circulation in the lower limbs, result- ing in defective nutrition of the muscles of that locality, is a constant predisposing cause of cramps, and that in any rational treatment of the same, this fact should be borne in mind. The products of metabolism and tissue waste, which should be immediately removed from the body, are allowed, owing to obstruction to venous return, to remain behind to vitiate the surrounding structures. Especially is this the case in persons of the gouty diathesis, who are notoriously subject to cramps. Uric acid, a product of purin metabolism, is, in these people, deposited in the form of urate salts in the muscles surrounding the congested veins of the leg and foot, interfering with nutrition and serving mechanically as an irritant and direct cause of spasmodic contractions." CHAPTER XIII. (3) GOUTY MANIFESTATIONS. Characteristics. — It is a common error to consider that gout is restricted to the foot or toe. While it is true that the phalangeal joint of the big toe is one of the most favorable localities for the formation of uratic concretions, it is by no means the only one. In whatever part of the body the physical and chemical environment is such that the precipitation and crystallization of urates may take place, gouty manifestations in that locality may result; but such environing conditions are very rarely met with except in two or three distal positions, unless under very unusual circumstances. Gout is characterized by the formation of crystalline urates or concretions, whose presence generally gives rise to disturbances accompanied with great pain. The gouty patient is not so much of an invalid, except from the pain he suffers and t-he enforced quiet he must observe, no matter whether the concretion be in the metatarsophalan- geal joint, in the renal tubules or pelvis, the ureters or the bladder. Genito-urinary Concretions. — One portion of the organism in which there is a strong tendency for the urates to precipitate themselves in crystalline form, is in the genito-urinary tract, — the renal tubules, pelvis, or the bladder. In each of these, localities, the crystallization is most likely to occur when the urine is scant and concen- trated, and some solid substance is present around which the crystals may group themselves. 114 URIC ACID AND ITS CONGENERS. According to Prof. Byron Robinson, of Chicago, who has made a special study of the aetiology of uric acid cal- culus: "The maintaining of uric acid in suspension, non- precipitated, not in concretions, is supposed to be due to the colloidal properties of the urine aided by its coloring material, — pigments. For example, the darker colored che urine, the more uric acid it holds in suspension. The more concentrated the urine, the more liability to precipitation of uric acid. If there is a small, weak stream, uric acid calculus forms with facility, and is liable to lodge as a con- crement. The maximum concentrated solution of urine tends to crystallize with vastly more facility and frequency than dilute urine. Single crystals are rapidly floated through the ureter by diuresis, while in small quantities of urine with a weak stream, the crystals tend to lodge and increase in dimension." It will be seen that oliguria is the best condition for the multiplication of uric acid calculus. Cardiac disease, with resulting partial stasis and congestion is frequently the precursor of ureteral colic and haematuria, — i. e., calculus rapidly forms. Human urine contains usually about one part uric acid (commonly urate of sodium) to one thousand. When the sodium urate exceeds one to one thousand parts of urine, it is frequently deposited as a sediment in the ex- creted urine, either immediately, or shortly on standing. The deposit of uratic crystals, so often seen in urine in the form of sand, gravel, brick-dust or red pepper grains, can be regarded as pathologic only when the precipitation occurs within four to six hours subsequent to the evacuation of the urine. Excessive and rapid uric acid crystallization subsequent to urination indicates that the crystallization GOUTY MANIFESTATIONS. 115 may occur previous to the voiding of the urine, endanger- ing the precipitation of uric acid and the formation of calculus. Concretions in Toe Joints. — The excruciating pain caused by the presence of a concretion in the genito- urinary tract has been supposed to be due to the pressure produced on adjacent sensitive tissues, which would like- wise result from the presence of any other solid foreign body of irregular contour. The pain in the toe joint is probably due to the same mechanical cause to a great extent; but, in this location, as the concretion cannot escape and steadily increases in size, inflammatory dis- turbances, with swelling of the tissues, add to the pressure and pain. It has already been explained, in a previous chapter, why the circulating blood itself, though it may contain an overplus of urates, is not an eligible site for the formation of concretions. To the several reasons therein given may be added the two, referred to by Prof. Robinson as being operative in the case of the urine: i. e., (i) its colloidal properties, and (2) the presence of a pigment, — both of which are more pronounced in the blood than in the urine. The feeble flow of the current, mentioned by him as a factor favorable to the precipitation of urates in the urine, is even better illustrated in the case of the toe joint, where the lymph stream is practically motionless at the time the shoe is worn. Then, too, the lymph and synovia lack the pigment and colloidal character of the blood, rendering either of the former a favorable medium for crystalliza- tion of the urates as soon as dialyzed from the capillaries, — as in the case of the tubules and pelvis of the kidney as soon as the urine is dialyzed from the blood. 116 URIC ACID AND ITS CONGENERS. Other Tissues. — Urates are occasionally precipi- tated in crystalline form in parts poorly vascularized on the bodily surface, as at certain points in the skin, in the bursa of the elbow, and in the helix of the ear. In the latter situation, true concretions are found and sometimes in the skin, though usually laminae or scales are found here. The nasal septum is frequently a site, and rhinologists are now inclined to attribute many cases of hay fever and chronic nasal catarrh to this irritant factor; though, as a rule, patients with these disorders are still in the "rheumatic" stage. The microscopic deposits which occur in the coats of cerebral arteries, in men of advanced age, who have been subject to years of constant and severe mental strain, are sometimes of the minute crystalline form, and indirectly lead to the brittleness of the parts and final rupture at the moment of some sudden distension of the vessels, e. g., as observed in apoplexy. Occasionally, too, the deposits in the cardiac valves become crystalline, and similar sudden fatalities result, — as in so-called "heart failure." In all of these instances, the person affected is as much a "gouty subject" as he who has the classical concretions in the metatarsophalangeal joint of the great toe. The victim of atheromatous arteries, or of endocarditis (mitral stenosis) or of hay fever in its chronic form, or of kidney stones, or even of "gravel" in its later manifestations, may be said to have reached the "gouty stage" of purin excess; and he has generally passed through the same "uricacidaemic" and "rheumatic" experiences as the man with the typical gouty foot. Objective Signs. — As in the primary and secondary stages, the urine, prior to an acute attack or "explosion" GOUTY MANIFESTATIONS. 117 in gout, is scant and concentrated. t ]iough less urates than normal are excreted during the twenty-four hours. From the moment of the height of the attack, during the sub- sidence of the pain and other symptoms, the urine begins to increase in amount, both as to water and urates, until the excretion becomes greatly in excess of the normal. In short, previous retention and subsequent elimination are as characteristic of the gouty explosion as of the rheumatic explosion. Experimental Production of Gout. — In the Berliner Klinische Wochenschrift, No. I, page 7, 1900, H. Kionka reports some interesting facts respecting the pro- duction of experimental gout in domestic fowls. The fowls were kept in cages and fed exclusively on hashed horse meat, which had been previously stripped of sinew and fat. As much water as they wished to drink was al- lowed. The fowls took to the new diet very rapidly, and at the start it seemed to agree with them very well. But, after some time, ordinarily in from three to five months, they began to show 'signs of disorders presenting all the characteristics of gout. The disease assumed different forms. In one variety, in which the symptoms appeared at an early date and ran a rapid course, the first change observed in the fowls was that their gait became uncertain, and that they fell to the ground after hopping ofT their perch. The weakness in their legs went on increasing, and, on certain days, when probably the pains were felt with more severity, they re- mained lying down, with their legs drawn under them, and took no food. Their joints were manifestly swollen. These attacks lasted a few days, after which the swelling 118 URIC ACID AND ITS CONGENERS. of the joints disappeared? and the fowls again began to eat and walk about. After some time, the attacks became more and more frequent; appetite disappeared; the fowls became thin and died. In this form of the disease, slightly marked deposits of urates were found around the joints when examined post mortem. The tophi were well developed in a second variety of the disease, which was not attended with real attacks of gout, as in the first mentioned cases, but which presented only a simple, temporary aggrava- tion of the accidents of gout, i. e., an uncertain gait and pain in walking. In these cases, when examined post mortem, the tophi, which were well marked, were found in the joints and between the sheaths of the tendons of the legs and claws. The third variety of gout affected the viscera, with deposits of urates on the serous membranes, and infarcts of uric acid in the kidneys. In all these varieties of gout the kidneys of the fowls, when examined post mortem, were found to be affected with gouty neph- ritis. Another experimenter, whose researches have at- tracted wide attention, is Freudweiler. In order to decide the question whether the deposits of urates in the tophi form the primary lesion, or whether they are (according to Ebstein) secondarily deposited in the injured necrotic tissue, he made numerous injections of sodium biurate. He could demonstrate that the deposit used, acts injurious- ly on the tissue, leading to an extensive reactionary in- flammation. The inflammatory foci, thus produced ex- perimentally, differ histologically in no way from the tophi of gout. Based on these results, Freudweiler does not believe it probable that the uric acid deposition is preceded GOUTY MANIFESTATIONS. 119 by a tissue necrosis; he agrees with the explanation first given by Garrod, that the tissue lesions are caused by the deposition of urates. In 1884, Gaucher discovered that the injection into the body of a healthy animal of small quantities of xanthin and hypoxanthin produced marked changes in the excre- ting cells of the kidney parenchyma {nephrite epithehale), similar to the lesions found in gout. Kolisch and Tandler observed the same. More recently, Croftan observed by similar investigations that granular atrophy of the kidneys was produced identical with this nephrite epithelialet which is a constant precursor of gout. In Croftan's "Experiment IX," a guinea pig received daily injections hypodermically of a 0.5 per cent, watery solution of xanthin for a period of seventy days. After four weeks, albumin was found in the urine. The animal was killed at the expiration of the seventieth day and the kidney parenchyma submitted to microscopic examina- tion. A granular degeneration of the epithelial cells lining the tubuli contorti and a proliferation of the endothelium of the intertubular capillaries were found. The picture corresponded in every way with the form of nephritis observed in the formative period of true gout. Intestinal Lithiasis. — Concretions are not only found in the tubules of the kidneys as above described, but in the intestinal canal. In the Revue de Therapeutique, Vol. LXVIII, 397, Vibert discusses the occurrence of this gouty manifestation under two forms: 1. Those forms of concretions which do not originate within the canal it- self, such as pancreatic or biliary calculi. 2. Those origina- ting in the canal, existing either in the form of intestinal sand or as well matured calculi. Colic is the most pressing 120 URIC ACID AND ITS CONGENERS. symptom calling for relief here, as in the case of renal concretions and of phalangeal gout. Frequency of Gout. — Futcher considers the oc- currence of the disease throughout the country, and sum- marizes his views as follows: "(i). Gout in the United States is undoubtedly more common than is generally supposed. (2) Out of 13,400 medical cases admitted to Dr. Osier's wards in the Johns Hopkins Hospital during a period of thirteen years, there were thirty-five gout cases, or 0.24 per cent, of the total number of patients. For the same number of years at St. Bartholomew's Hospital there were 116 gout cases out of a total of 31,100 medical admissions, or 0.37 per cent, of the cases. Thus, among hospital patients gout is only about one-third more frequent in London than in Balti- more. (3) All of the thirty-six cases were white males. The largest number of cases occurred in the fifth decade. Twenty-seven of the patients were native-born Americans. (4) The majority of cases appear to have earned rather than inherited their gout. Alcohol and lead seemed to be the most potent predisposing aetiological factors. (5) Thirty-three of the thirty-six cases had reached the chronic stage before they came under observation. In seventeen of the cases tophi were present. (6) Among the more interesting complications, may be mentioned three cases of gouty bursitis; one case of parotitis; one of pericardi- tis; one of retrocedent gout, with symptoms simulating intestinal obstruction. (7) There was evidence of disease of the kidneys in the majority of the cases. Albuminuria occurred in twenty-seven, and hyaline and granular casts in twenty-three instances. (8) Arteriosclerosis was present in twenty-three cases, and a mitral systolic murmur in GOUTY MANIFESTATIONS. 121 five. (9) Many gout cases are mistaken for rheumatism. Four of the cases were repeatedly diagnosed as such on the early admissions, the appearance of tophi later revealing their true nature. (10) The series illustrates the great im- portance of examining the ears and the vicinity of the joints for the presence of tophi in all cases of multiple arthritis." CHAPTER XIV. SEQUELAE AND COMPLICATIONS. Constipation. — Mathews says: "First try and ascertain what is the cause of the constipation. In this con- nection, I wish to state that after an examination and observation of these cases extending over twenty years, I am forced to believe that the majority of them have as a basis a constitutional derangement. In trying to solve the problem, it was observed that many of these patients were of a rheumatic or gouty diathesis. Acting upon this hypoth- esis, I have treated them by combating this special trouble and have found that in many cases the constipation would take care of itself. My theory is that in the rheu- matic or gouty subject, the intestines are brought under the same conditions that the disease or diseases are made man- ifest in other portions of the body. The muscular coat of the intestine is particularly afTected by the gouty con- dition, and in consequence loses its contractile power." In any effort to explain the ^etiological relationship which is known to exist between certain cases of consti- pation and uric acid retention, the following three facts must be borne in mind, viz.: i. The alimentary tract is practically outside of the true interior of the body; its mucous membrane is, in reality, a continuation of the skin, and before any substance can enter the system proper, it must be absorbed or osmosed through this gastro-intestinal lining. 2. The intestinal lining is supplied with capillary vessels and their attendant nerves in a similar manner to the skin, and they are subject to the same chemico_ sequels: and complications. 123 mechanical influences, — e. g. , heat and cold, alkalies and acids, pressure, etc. 3. When waste material from the food introduced has reached the "fecal reservoir" (especially the sigmoid and rectum) it is a foreign body, containing nothing than can benefit the system and much that is actually harmful and should therefore be removed from contact with its surroundings as soon as possible. If this "foreign body" is not removed, but remains to accumulate with others of a like character until the walls of the intestine are distended with pressure: What is the mechanical effect upon the capillaries ? Their flow is necessarily impeded. The returning veins below that point, especially the rectal veins, are congested, and hemorrhoids result. Moreover, if uric acid is present in excess in the circulation, it will eventually be deposited at this point and a nidus of urates be formed as in any other portion of the bodily surface where the circulation is im- peded by strain or pressure, as in the toe joint owing to pressure of the shoe. The fibrous coats of the colon and rectal walls being thus infiltrated with urates of soda, intes- tinal gout arises, muscular contractions are more or less impeded and loss of peristalsis follows; while the circu- lation being impeded at the same time, the parts are illy supplied with nutritive material, and atony results. That the "colic" and constipation following the steady introduction of lead and iron into the system are due to deposits in the fibrous tissues, producing a gouty con- dition of the bowels resembling that caused by the soda biurates, is a fact now becoming recognized by some of our most careful investigators. It has been shown that lead and iron (like zinc, mercury and other metals) form in- soluble compounds with uric acid, which are precipitated 124 URIC ACID AND ITS CONGENERS. out of the blood into the connective tissues at those points where the conditions are especially favorable, as in the fibrous coating of the intestinal tract. It is well known that lead colic can be successfully treated by the same thera- peutic agency that has been found efficacious in typical gouty conditions, and that the colic, constipation, etc., are produced by the irritant effects of urate of lead in the intestinal walls in the same manner as above described in the case of the urate of soda. Moreover, that the same aetiological factors which are usually mentioned as being instrumental in the production of gout, or the "gouty" tendency, may also, eventually, cause constipation, will be readily understood when remembering that both are often due to the same chemico- mechanical influences; i. e., an obstructed circulation in the parts affected, and deposition or formation of uratic salts (of soda, of lead, of iron, of zinc, etc.) at that point. Of course the additional effect produced by a lack of biliary secretion in cases of hepatic insufficiency, leading up to the loss of peristalsis owing to distinctly chemical reasons, is a matter outside of the uric acid field in consti- pation, except in so far (and this is important) as an excess of uric acid may serve to obstruct the capillary flow in the liver cells and thus interfere with the quantity of bile secreted. The pancreatic and intestinal glandular se- cretions may also be rendered scant in amount for the same reason, (i. e., a general "collaemia") and the bowel con- tents become more difficult to expel owing to the lack of the proper semi-fluid consistence. Again, owing partly to the absorption into the general circulation of toxic material from the contents of the "fecal reservoir/' partly to the impeded capillary flow throughout SEQUELS AND COMPLICATIONS. 125 the intestinal walls, giving rise to impaired nutrition, and partly to the lowered alkalescence of the blood (from intestinal absorption), causing sufficient change of solubil- ities for uric acid in that fluid as to result in the precipi- tation of the latter in colloid form into the capillaries throughout the body, thus obstructing their flow, — a train of evils results such as usually accompanies or follows con- stipation: headache, dizziness, lassitude, mental hebetude, irritability, loss of appetite, etc., including yarious other functional disturbances brought on as the direct or indirect result of this abnormal condition. In other words, "collaemia" will be produced in all cases wherever an excess of uric acid exists at the time of the constipation; and if the latter should be permitted to become chronic, the uric acid excess will subsequently become increased as the result of a lowered general metabolism. In this way, a "circulus vitiosus"is established. Hepatic Insufficiency. — As one writer graphically says: "The liver has sometimes been called the 'human grate.' It is all of this; for it not only stands guard over the burnt up material of the system, sifting out the cinders and ashes of combustion from the general circulation, but also serves as a barrier against the entrance of undesirable or overplus fuel from the bowel by way of the portal circu- lation. This intimate relation existing between the liver and the bowel is a sufficient reason why hepatic disorders usually follow or accompany digestive or intestinal dis- turbances. A blockade in the rectum means a disturbance of the portal circulation and the loading of a heavy burden upon the liver. As the most important centre of the ab- dominal venous system, the blood supply to this organ is enormous; and it will at once be seen that if the bowel exit 126 URIC ACID AND ITS CONGENERS. be choked with waste, much will be absorbed and carried to the human grate which must itself become 'clogged' in the endeavor to unload the burden." Whenever the liver fails to remove the burnt up tissue waste, the circulation becomes charged with ashes and clinkers. In short, the "grate" of the system has become clogged and the fire is being deadened with the products of its own combustion. The blood abounds with deleterious matters choking up the smaller vessels, which interferes with the nutrition of every important organ and tissue of the body. Bilious congestion and stasis exist, which may result in an increase of connective tissue growth and partial fatty degeneration of cells. Hyperemia of other glandular organs ensues, their secretory and excretory functions are both imperfectly performed and the system necessarily becomes loaded with toxic waste — of which catabolic products of the uric acid type are the most com- mon. The typical symptoms of hepatic insufficiency, due to obstruction of its capillaries with an excess of urates, are such that we know something is wrong with the liver; to wit: "bad taste" in the mouth, heavily yellow-coated tongue, nausea, thirst, anorexia, epigastric fullness, flatu- lency, headache, vertigo, constipation, yellowish con- junctiva, languor, debility, countenance sallow and worn, urine scanty and high colored, containing "brick dust" deposits and bile pigments. Acid Dyspepsia. — The failure of the liver to perform its normal oxidizing function, owing to capillary obstruc- tion from urates, often results in a scanty secretion of bile into the duodenum and consequent decomposition of food from lack of this essential antiseptic. As is well known, food decomposition is one of the most conspicuous evi- sequels: and complications. 127 dences of intestinal indigestion, resulting in sour eructa- tions and the so-called "acid dyspepsia." If an examina- tion of the urine at such times, points toward uricacid- aemia, that method of treatment will prove most effective which aims at the elimination of urates from the system, — much more effective than if attention is directed simply toward the local gastro-intestinal symptoms. In other words, a uric acid solvent and eliminant will give more satisfactory results than a purely digestive agent, such as pepsin, pancreatin, etc. Renal Inadequacy. — The intimate relation of cause and effect, as observed between kidney disease and uric acid retention and accumulation, or vice versa, has long been recognized; and such expressions as "gouty kidney," "lithaemic nephritis," etc., are commonly found in most of our text-books on medical practice. Garrod's theory that, in gout, the alkalinity of the blood is lessened and the amount of uric acid in circulation increased owing to deficient power of elimination on the part of the kidneys, is now quite generally accepted as true. According to Futcher: 'The most probable ex- planation for the increase is that it is due to a diminished excretion of uric acid by the kidneys with consequent retention in the circulating blood. Minkowski, who has comparatively recently reviewed the evidence, supports this theory. Hans, Vogt and Reach have shown that the output of uric acid after the ingestion of nuclein-containing food is much less marked in the gouty than in the healthy individual. Garrod was of the opinion that the excess of uric acid in the blood was due to the nephritis present. It is a well-known fact that in chronic gout, serious organic disease of the kidneys occurs. It has been suggested that 128 URIC ACID AND ITS CONGENERS. even before any organic disease of these organs develops, there may be a 'functional' disturbance of the secretory elements. " Minkowski and His, Jr. have advanced the view that the uric acid in gouty individuals circulates in the blood in a different organic combination than in the blood of healthy persons, and that consequently the kidneys are functionally incapable of eliminating the acid in the same way they do in normal metabolism. Whatever the true explanation of the phenomenon may be, the fact is recog- nized that a diminished excretion of uric acid by the kidneys occurs in gout. The recent investigations of Mac- alester corroborate this. When we consider the constancy and rapidity of tissue change, the large mass of new material to undergo construction, and of waste material to be disposed of and that the kidney is at once the avenue for the removal of the most complex forms of tissue waste, and the by-path along which the absorbed products of intestinal decom- position are removed; that it is also subject to marked and frequent variances in the quantity of the excretory mater- ials delivered to it,— then it is not surprising that the selective function of the renal filter should occasionally become disordered, and elimination by that channel be imperfectly performed. Furthermore, in such an atmospheric medium as we live, where sudden exposures to chills occur, the function of the skin is depressed and an undue share of the work of elimination is again thrown upon the kidneys. But it is not altogether, in this case, simply an excess of work that the kidneys are called upon to do, for, as is well known, suppression of the perspiration is followed by increased SEQUELAE AND COMPLICATIONS. 129 acidity of the urine, and from this we may infer diminished alkalinity of the blood, leading to the accumulation of uric acid in the circulation, and the deposition of its salts in the various tissues of the body, including the canaliculi of the kidney itself. In summing up, therefore, it may be said that pre- ceding the stage usually denominated "Bright's disease," an auto-intoxication process has been going on, resulting in a vitiated circulation and the diseased condition known as "uricacidaemia," among the more direct causes of which may be enumerated the following, to wit: I. Excessive nitrogenous or purin waste from "high living" (or from certain fevers). 2. Increase of the raw material from which uric acid is formed, i. e., the excessive use of nitrog- enous foods, or foods rich in nucleins. 3. Gastrointes- tinal indigestion and fermentation, from overfeeding, etc., 4. Absorption of the products of retained fecal matter in constipation. 5. Any factor causing functional disturb- ance of the liver, — the great urea-forming organ of the body, — resulting in the presence of an excess of uric acid unoxidized. 6. Frequent chilling of the bodily surface, which checks perspiration from the skin, resulting in sub- alkalinity of the blood, the retention in excess of uric acid in the circulation and subsequent deposition in the various connective tissues of the body. Urea Retention. — In the more advanced stage of the disease process, after constant irritation of the tubules has resulted in anatomical or histological changes in the kidney and impairment of its excretory function, it has: been seen that certain of the urinary constituents are re- tained in the circulation, the most important of which is urea, a waste product constantly produced in the metabo- 130 URIC ACID AND ITS CONGENERS. lism of every organism wherever there are changes in proteid matter. The daily average production of urea, in man, has very little variation, the human organism elim- inating about one ounce in twenty-four hours. Its re- tention gives rise to a violent toxicosis, having many of the clinical aspects of poisoning from strychnia. The human economy generates enough in eight hours to render life extinct. It is, therefore, upon the elimination of this waste that life may depend; and the non-elimination of it presents many clinical conditions, from a dizzy head- ache to uraemic coma and fatal eclampsia. From this it will be seen that defective elimination of proteid waste, i. e., urea, rather than abnormal loss of the proteid itself, i. e., albumin, is what demands our chief attention in Bright's disease. CHAPTER XV. URINARY ANALYSIS. Ocular Inspection. — The general practitioner may gain much valuable knowledge of his patient's faulty metabolic condition, from a mere physical examination of the urine from time to time. If he suspect uric acid ac- cumulation from the general symptoms, he may feel more certain of his diagnosis if certain urinary signs are present. Inasmuch as Nature constantly strives to rid the organism of an excess of such waste, there will doubtless be times when she succeeds in the effort, and the urine will give evidence of the fact. If the urates are about to be excreted in excess of the normal (or an attempt at such excessive excretion is being made), ocular inspection at that time will show a high- colored urine, in which brick dust deposits are thrown down in greater or less, amount within three or four hours after voidance, attaching themselves in a few hours to the bottom and sides of the container, often requiring the application of hot water and sapolio and a vigorous scrub- bing to effect their removal. The twenty-four hours' quantity of urine in these cases may be less than normal, specific gravity high and the reaction overacid. Even, therefore, though the pre- cipitation apparently be due to excessive acidity and a lessened amount of water, it is safe to infer that Nature is struggling to eliminate uratic waste from the system, not- withstanding that the reduced alkalinity of the blood (as thus indicated) tends to further its retention and accumu- 132 URIC ACID AND ITS CONGENERS. lation. In either case, it is pointed out to the physician that eliminative aid should be furnished. Such attempted uratic explosions will be observed either in acute cases, or at the time of exacerbations in chronic cases, — during the attack at its height and as it is passing off. Had the urine been inspected during the few days preceding the attack in acute cases, or during the inter- vals between attacks in chronic cases, it would have been found more copious and less highly colored, with little or no signs of precipitation. It is, in fact, at these times that the excreted urates are subnormal in amount, and re- tention occurs. If ocular inspection has shown a scant, high-colored urine, with tendency to precipitation of urates, as above described, the physician should remember that the same tendency to precipitation at such times also holds true in the bladder and kidneys, where calculi will be formed. As already quoted from Prof. Byron Robinson : " If there is a small, weak stream, uric acid calculus forms with facility and is liable to lodge as a concrement. The concentrated urine tends to crystallize with vastly more facility and frequency than dilute urine. Single crystals are rapidly floated through the ureter by diuresis, while in small quantities of urine with a weak stream, the crystals tend to lodge and increase in dimension." (Cf. American Medicine, Aug. 26, 1905, p. 366.) It will thus be seen that a mere physical examination of the urine often furnishes the physician with sufficient evidence to warrant him in adopting the akaline elimina- tive treatment to effectually combat the two-fold danger which threatens his patient; viz: 1. The tendency to retention and accumulation of urates (as shown by at- URINARY ANALYSIS. 133 tempted "explosions")- 2. The tendency to irritation of the kidnevs and bladder, and the formation of calculi. Alkaline Urine. — The irritation of the mucous lin- ing of the bladder, caused by the presence of urate crystals in abundance, in a strongly acid urine of the character above described, leads oftentimes to a certain well-known urinary phenomenon of positive diagnostic significance. It will be observed, for example, if the excreted urine remains scant and over-acid for some time, that, eventually symptoms referable to the bladder will be complained of, and the urine becomes ammoniacal in odor and alka- line in reaction. How is this to be accounted for ? The explanation is simple enough. The urine which passes through the ureters into the bladder, being hyper- acid and loaded with urate crystals, causes, by means of this two-fold irritation, a congestion or catarrhal inflamma- tion of the bladder surface, which results in the production of mucus, pus, or other inflammatory products. The latter, when admixed with the bladder urine, produces ammoniacal decomposition or alkaline fermentation, — the same as is observed in all urines when exposed to the air, a few hours after voidance. As a result, in the cases we are considering, therefore, the urine is alkaline when voided; notwithstanding that at the moment of its entering the bladder from the ureters it was strongly acid. From this it will be seen that if the urine is alkaline when first voided, cystitic trouble is probably existent. If this alkalinity be found to be due to a volatile alkali (ammonium), then we may be sure that ammoniacal decomposition has taken place in the bladder owing to the presence of catarrhal or purulent inflammatory products. It should be understood, of course, that alkaline urine is sometimes caused by the presence of the fixed alkalies 134 URIC ACID AND ITS CONGENERS. (sodium, potassium, lithium), such as occurs when the alkaline remedies are being taken. To determine beyond doubt whether the alkalinity be due to a volatile or to a fixed alkali, the following simple plan is recommended; to wit: The litmus which has been turned to blue is ex- posed to the air until it has become thoroughly dry. If the blue color remains, it was due to a fixed alkali; if not, to a volatile alkali. In the latter eventuality, we know that the bladder is more or less inflamed; we immediately suspect uric acid irritation and employ the alkaline elimin- ative treatment. It seems unnecessary, after what has been said, to point out that the mineral acids are contraindicated in the class of cases under discussion. Retention of Solids. — It is well known that the daily expenditure of energy and "wear and tear" of the animal cells result in the corresponding excretion of a certain amount of waste solids in the urine; that, as a rule, about seven and one-half grains of these solids are excreted for every pound of body weight, so that a man in the prime of life, weighing 160 pounds, normally excretes 1200 grains of urinary solids every twenty-four hours. Of this amount, one-half is composed of urea. It often happens, in the later stages of Bright's disease and in serious hepatic disorders, that urea is not being properly eliminated; while uric acid has been only partially eliminated for some time previous, giving rise to various symptoms indicative of retention and accumula- tion. Though, of course, quantitative estimations are essential to an understanding of the exact amount of these waste products which is being eliminated; nevertheless, for ordinary practical purposes, the approximate total URINARY ANALYSIS. 135 amount of solids excreted may first be ascertained, from which it is readily determined whether urea and the urates are being retained to any great extent — even judging very fairly of the total amount of the former waste product. At all events, if retention of solids be discovered, especially when symptoms of toxaemia coexist, no further evidence is required to demonstrate the need of employing the alka- line eliminative treatment as an effective aid to the meta- bolic and excretory organs during this emergency. In determining the approximate amount of solids excreted in the urine daily, the "Haines-Bulkley Rule" is doubtless the method most extensively utilized in actual practice today; to wit: "Multiply the last two figures of the specific gravity by the total number of ounces of the twenty-four hours' urine, and add to this product one-tenth of itself." For example, if the specific gravity is 1,015 and total number of ounces 40, then 15 X 40 = 600, + 60 = 660 grains of solids (or 330 grains, urea). In this supposititious case, 500 grains of waste solids (or more than 200 grains of urea) were retained on that particular day, i. e., if the patient were an adult, weighing from 150 to 160 pounds. Women excrete absolutely less than men; but not relatively, proportionate to their weight. It will readily be understood that in such a case as above described, efforts should at once be made to assist the organism in ridding itself of this burden of retained waste, and insure this desirable outcome by way of every possible channel of exit — kidneys, skin, liver and bowels. Irritability of Neck of Bladder. — It should not be forgotten that incontinence of urine, near the two ex- tremes of life, may often be due to irritation of the neck 136 URIC ACID AND ITS CONGENERS. of the bladder, owing to the passage of a strongly acid urine loaded with urate crystals. In babes, of course, the urine is voided at any and all times, owing to the fact that the sphincter muscle at the neck of the bladder is yet undeveloped. At the stage of youth, however, this muscle, like the sphincter ani, has grown to sufficient strength, in the way of contractile power, to prevent the involuntary emptying of the bladder; though, of course, the previous "habit" of submitting to urinary pressure must gradually be overcome by a system of education. Nature will succeed in these cases, pro- vided there is no extraneous influence to prevent. Un- fortunately, such a hindrance to normal action is often seen in the constant irritation produced by the passage of minute irregularly formed crystals of uric acid in an over- acid urine. To determine, in a given case, whether the incon- tinence (or frequent urination) be due to irritation of this character, a brief examination of the urine will usually suffice. If the latter is over-acid and contains urate crystals in abundance, as shown by the characteristic "brick-dust" deposits, the diagnosis is readily established and the proper alkaline treatment may be instituted. Again, in advanced life, the sphincter muscle becomes more or less weakened, from years of constant usage; and, though incontinence may not result from this acid irri- tation, we usually observe that frequent urination becomes necessary to prevent the otherwise involuntary emptying of the bladder. The diagnosis is readily made from an examination of the urine, as already described. It should be remembered, however, that enlarged prostate is a frequent accompaniment of this condition, in elderly URINARY ANALYSIS. 137 males. Nevertheless, the alkaline eliminative treatment will generally prove beneficial. Hepatic Torpor. — The characteristic brick-dust deposits in over-acid urine, is indicative of an attempted excessive excretion and is almost always just prior to an "explosion," — i. e., the effort on the part of Nature to rid the system of previously retained urates, — though this is not invariably true, for the excess excreted may be due to faulty metabolism: that is, an increased quantity of urates may be carried to the kidneys for excretion, owing to the failure of the liver to oxidize its normal proportion of uric acid (50 per cent.) into urea. The excess, in other words, is composed largely of uric acid that, under normal con- ditions, should be oxidized into urea by the oxidases of the liver. The ill effects of this form of hepatic insufficiency are most commonly met with in those who lead an indolent, luxurious life, or in those whose occupation keeps them within doors and subjects them to more or less mental strain and worry. There is generally present great de- pression of spirits and a general sense of weariness and inaptitude for effort of any kind. The sleep is sometimes restless, and on awakening in the morning the victim feels as tired and listless as on retiring the previous night. Familiar to every practitioner is the countenance of the "bilious" individual, his sallow, yellowish skin, dull eye, sodden tongue covered with a thick yellowish fur, offensive breath and complaints of nausea, lack of appetite, constipation, alternating with attacks of diarrhoea. All these clinical phenomena are doubtless due to inactivity of the liver, accompanied with an excess of unoxidized uric acid in circulation. 138 URIC ACID AND ITS CONGENERS. Many people suffer periodically with the symptoms above enumerated and yet do not consider themselves sufficiently ill to consult a physician. They consider it as a matter of course that nature ordained they should not enjoy good health and spirits only at occasional intervals. Instead of presenting the matter to a physician, thus enabling him to treat their condition in a rational and scientific manner, the majority of these people proceed to treat themselves. Physic is resorted to every few days (which, at first, benefits them temporarily), and eventually the vicious "pill habit" is formed. Not until the urgent symptoms arise which force these patients to seek pro- fessional advice, do they finally realize the fact that they are not well, but actually ill. Should the urinary signs, above described, accompany the constitutional signs of hepatic insufficiency, the physi- cian may feel assured that the diagnosis of the uricacid- aemic stage of purin excess is well established, and that he is justified in recommending the proper treatment for that condition. CHAPTER XVI URIC ACID TESTS. r, Murexid Test. — To determine the presence of uric acid in the urine, by chemical means, the murexid test is probably the simplest, and is one of extreme beauty, to wit: A small portion of the urinary sediment, or the residue obtained by evaporating to dryness at a low heat over an alcohol lamp a few drops of urine in a watch crystal, is placed on a porcelain plate, a drop or two of nitric acid added to dissolve it, and the solution carefully evaporated to dryness over a spirit-lamp flame: a red residue remains. A drop or two of liquor ammoniae is added to this, when there promptly appears a beautiful purple color, which will gradually diffuse itself as the ammonia spreads. This in- dicates uric acid or the urates. The above method sometimes proves unsatisfactory owing to tardy results and a pink (instead of purple) color produced. It will be found by experience, too, that a slight excess of ammonia destroys the beautiful purple color. One of the most important precautions to be ob- served in performing this experiment, is to drop the ammonia upon the plate without at first allowing it to come into direct contact with the residue. Prof. Samuel E. Earp, of Indianapolis, recommends that a volatile salt of ammonia be used instead of a solution. The salt is placed on a metal plate and covered with the evaporating dish. The heat from the flame which is then applied underneath the plate, causes quick volatilization; and it will be found that the purple red (purpurate of 140 URIC ACID AND ITS CONGENERS. ammonia) color covers the evaporating dish completely on its inner surface. Approximate Test. — For ordinary practical pur- poses the approximate amount of urates present may be determined as follows: Strongly acidulate some urine in a test-tube with hydrochloric acid and set aside for twenty-four hours. An examination, then, will reveal crystals of uric acid collected in the bottom of the container, also some on the sides and some floating on the surface of the urine. By testing the urine in question against a companion tube holding an equal quantity of normal urine and treated in the same manner, an approximate comparison may be made which will be accurate enough for ordinary purposes. "^J In the foregoing experiment, it should be understood that nearly the whole, if not all, of the uric acid thus made evident, is obtained from the decomposition of the urates with the consequent liberation of the acid. Heat and Acetic Acid Test.— The detection of an excess of uric acid in the urine/according to the following plan, is very simple: The testis best done by filling a test tube nearly full of urine and bringing the upper stratum to the boiling point; then add a few drops of four per cent, solution of acetic acid, boil again and set the test tube aside in a cool place. The crystals of uric acid will begin to form directly under the surface layer of the urine. The amount formed will give the relative quantity excreted, thus indicating the over production. When the amount of uric acid in the urine is normal, no precipitation of the acid can be effected by this method. While the above is not an absolute quantitative method for estimating the uric acid, it is one that is practical URIC ACID TESTS. 141 and shows very quickly that there is overproduction, also the relative amount of overproduction from day to day. It can be made accurately quantitative by collecting the uric acid crystals on a weighted filter and reweighing, which will give the exact percentage of uric acid in excess of the normal amount. In this manner, and in a few hours, the exact quantity of uric acid can be estimated. Of course, when there is no excess of uric acid in the sample, it requires the use of a considerable quantity of one of the stronger mineral acids — sufficient to decompose the normal urates and thus set free the uric acid otherwise held in combination with the sodium — before the presence of the crystals is demonstrated. By applying this so-called "heat and acetic acid test" from day to day, or from week to week, as the importance of the case may indicate, it is very easy to determine with accuracy the perfection of enzymatic oxidation, or whether there is an increase or decrease in the perfection. , Heintz' Test. — A few years ago it was the common practice in the laboratory to employ Heintz' test for the quantitative estimation of uric acid, but it has since become the custom to resort to the more accurate (though more complicated) method of Hopkins or Folin./ The "gravi- metric method" recommended by Heintz is usually applied as follows : Take 200 cubic centimeters (nearly half a pint) of urine, and add to it twenty cubic centimeters (six fluid drachms) of hydrochloric or nitric acid. Set aside in a cool place, as a cellar, for twenty-four hours (better forty-eight hours), at the end of which time the highly colored uric acid crystals will be found adhering to the sides and at the bot- tom of the beaker glass. Collect these precipitated uric 142 URIC ACID AND ITS CONGENERS. acid crystals on a previously weighted filter and wash thoroughly with cold distilled water. Dry the filter and crystals in any hot place, as in a desiccator, at a tempera- ture of 212° F.; and then weigh. The weight of the two, minus the weight of the filter, will be the weight of the uric acid in 200 cubic centimeters of urine — excepting, of course, the small portion retained in the acid and washings. In employing this method, if albumin be present, it should first be removed. Moreover, the urine should always be filtered before applying the test, for otherwise subsequent filtration is very difficult. Harley's Test. — This is a very delicate qualitative test^and is most conveniently applied as follows: In a solution of sodium or potassium carbonate dis- solve a portion of the suspected uric acid precipitate, and place a drop or two of the resulting solution on paper. Add to this a solution of silver nitrate. If a distinct gray stain promptly occurs it is positive evidence of the presence of uric acid or urates. ^ Schiff's Test. — This is very similar to the foregoing test, and is best employed as follows: p— A piece of filter paper is moistened with a solution of nitrate of silver, and a drop of a solution of the suspected uric acid deposit in sodium carbonate is added. Owing to the reduction of the oxide of silver, a brownish black color develops, which is a certain indication of the presence of uric acid. If there is only 0.002 milligramme of uric acid present, a yellow color is obtained instead. Dimmock and Branson's Method.— For the rapid quantitative estimation of uric acid, the following method devised by Dimmock and Branson is considered quite satisfactory: URIC ACID TESTS. 143 To ioo cubic centimeters (3J fluid ounces) of urine is added one gramme (16 grains) of lithium carbonate (Li 2 C0 3 ). After boiling, for about three minutes, in a con- ical flask (Erlenmeyer) of about 100 cubic centimeters capacity, the liquid is filtered while hot to remove the precipitated earthy phosphates, etc., which are washed with a little distilled water until the filtrate measures ex- actly 100 c.c. To 50 c.c. of the filtrate, which contains uric acid as lithium urate, 5 grammes of ammonium chloride are added, shaking the liquid, until dissolved. After three minutes, the contents of the flask are warmed to 120 F., so as to secure a uniform aggregation of the precipitated ammonium urate. The whole is now poured into a tube, graduated in parts per thousand of uric acid, and deposition allowed to take place, the reading being taken after four hours have elapsed. Microscopic Examination. — Without entering into details, it may be said that the presence of uric acid as such is generally easily recognized by the microscopic peculiar- ities of its crystals, which in their commonest form may be said to be "lozenge-shaped." It should be remembered, too, that the crystals are always colored yellowish red, being with their salts the only urinary deposits thus stained. Therefore, when a sediment is examined, the crystals of which are thus colored, it may, without hesitation, be con- sidered as composed of uric acid or its combinations. Should a crystalline deposit, examined under the microscope, still remain of doubtful character, it can be shown to be uric acid, whenever it will respond as follows : (a) Insoluble in cold or hot water, but readily dis- solves in the alkalies — soda, potash, or ammonia; then, if the alkaline solution thus produced, be treated with an 144 URIC ACID AND ITS CONGENERS. excess of acetic acid, the typical "lozenge-shaped" forms will crystallize out in a few hours. (b) The sediment placed on a glass slide responds to the murexid test. Occasionally we meet with "dumb-bell" crystals of uric acid which have the characteristic shape of oxalate of lime crystals. They may be distinguished from the latter, however, by their larger size, their darker color, and their solubility in alkalies. The Complicated Tests. — The three tests for the quantitative estimation of uric acid, which are doubtless the most exact, are the Hopkins' Method, the Folin's Method, and the Ludwig-Salkowski Method. One or the other of these is now employed in expert laboratory work; but it is practically impossible for the physician to utilize any of them. The details of each method may be found published in full in special treatises on urinary analysis. The Hopkins' Method furnishes results which are as accurate as those obtained with the older method of Lud- wig-Salkowski, and has the advantage of greater simplicity. " It is based upon the fact," says Simon, " that uric acid can be completely precipitated from the urine by the addition of certain ammonium salts. Insoluble acid ammonium urate thus results, which is transformed into the free acid, and this estimated either gravimetrically or by titration with a solution of potassium permanganate of known strength." Folin's Method is a recent modification of the above and is being adopted by the majority of chemical investi- gators; it is sometimes spoken of as the "Folin-Hopkins Method," or "Folin's Modification of Hopkins' Method." The Uricometer. — A glass instrument has been devised by Ruhemann, of Germany, for the ready deter- URIC ACID TESTS. 145 mination of the quantity of uric acid in a given sample of urine. He explains his method as being simple, quick and practical, as follows: At the bottom of the instrument sulphuric acid is placed, to which is added a solution of iodine, 1.5 gm., with which has been titrated potassium iodide, 1.5 gm., alcohol, 15 gm., and distilled water, 185 gm. Urine is then dropped, one drop at a time, shaking after each addition, until the solution is pale pink. This, upon the last shaking, becomes milk white. With each instrument, detailed explanations of the above reaction are given. The sides of the uricometer are marked, the level of the mixture showing the percentage of uric acid in the sample examined. Hall's Purinometer. — I. Walker Hall, M.D., of Manchester, England, has invented a glass instrument (simpler in construction than Doremus's ureameter) for the purpose of estimating the amount of purins in the urine, or elsewhere. It consists essentially of three parts, viz.: (1) A closed, graduated tube; (2) A stop-cock with a bore of the same diameter as the upper tube; (3) A small glass reservoir of known cubical capacity. Printed directions for its intelligent use accompany each instrument. The "purinometer" was made for Hall by Goetze, of Leipsic, and may be obtained from Messrs. Gallenkamp, Sun Street, Finsbury, England. A Simple Test. — Quantitative estimation of uric acid may be performed by adding a teaspoonful of con- centrated hydrochloric acid to three fluid ounces of urine and allowing it to stand for forty-eight hours in the dark. The uric acid deposits are then dried and weighed. CHAPTER XVII. bright's disease. Definition. — The term " Bright's disease" has been applied, since 1827, to renal disorders characterized by various histological changes in the kidney substance, which give rise to the three classic symptoms described by Bright — albuminuria, dropsy and uraemia. It has sometimes been defined as a disease characterized by degeneration of the kidneys, whereby the excretory function is so im- paired that urea and the urates are not satisfactorily elimi- nated from the blood. Congestion. — As the kidney is composed of delicate tissue highly vascularized, it is naturally subject to the same sudden external influences that cause congestion of other internal organs and specialized tissues, and which may develop an inflammation. Therefore, congestion, or acute inflammation of the kidney may occur as in any other highly vascularized tissue, brought on by exposure of the body to cold and dampness, thus causing contracted surface capillaries and a flux of blood to the deeper organs — to the kidney for instance, after lying prone on the back on damp ground. True Bright's.— Though a congestion or inflam- mation, such as we have just described, may render the kidney more liable to Bright's disease thereafter; yet, in itself, it can hardly be classed as true Bright's, since any of the mucous or serous membranes as well as other gland- ular organs may become affected in this way by such accidental causes. By true Bright's is meant those tissue BRIGHT'S DISEASE. 147 degenerations or histological changes, to which the kidney alone is rendered liable, owing to its anatomical position and physiological duty as an excretory organ. In this latter capacity, the kidney is subject to insidious vascular influences which interfere with its work as a dialyzer and eventually give rise to anatomical changes in its tissue. It will be seen, then, that the disabled or crippled kidney in "true Bright's," is the indirect result of the delicate and dangerous task it has to perform in elimi- nating waste tissue products and accidental toxins from the blood. Being a process of change, slow in its develop- ment, Bright's disease is usually "chronic"; though, of course, under specially aggravating circumstances, it may be subacute or even acute. Renal Dialyzer. — By means of the glomeruli of the Malpighian body and the epithelium lining the tubules, the kidney serves as a renal dialyzer. From the blood brought to it, it dialyzes in aqueous solution (the urine) the greater part of the excretory products of the human organism, resulting from the wear and tear of the body cells, the chief and most important of which are (i) the intermediary and end products of nitrogenous metabo- lism and (2) the soluble mineral salts. It also dialyzes the overplus products of digestion, not utilized by the organism; the various extraneous matters introduced occasionally, such as poisons, drugs, etc.; and the ptomaines and other products of decom- position or fermentation, absorbed into the circulation from the intestinal tract. Of the total amount of water thrown off daily by the human organism, at least fifty per cent, is excreted by the kidneys in the form of urine, which contains in solution or suspension the various substances alluded to. 148 URIC ACID AND ITS CONGENERS. Specialization. — It has been discovered that the renal dialyzer, in its entirety, is so constructed that it acts differently than a mere mechanical apparatus; though, of course, the epithelial membrane is subject to the same mechanical influences in the way of pressure, etc., (due to arterial tension) as any other dialyzing membrane would be. The epithelial cells lining the tubules not only serve as a mechanical filter, but, like the nucleated cells of the secretory organs, they possess the power of apparent selection. For instance, it has been found that organic substances such as uric acid are eliminated by the rodded epithelium of the tubules, while the glomeruli chiefly separate the water and inorganic salts normally present in the urine. This specialization in the work of the cells, however, is probably due to the known difference in their structure, one form of cell permitting certain substances to dialyze or filter through, while the other form does not. Localization. — It will at once be seen that these delicate cells in their dialyzing capacity will become differently affected, according to their special duty; one, in its work of osmosing water and its contained salts, the other in its work of osmosing organic substances. Inasmuch as the glomeruli are minute vessels belong- ing to the vascular system, they will naturally be chiefly affected by circulatory influences in the way of pressure or lack of pressure, and will suffer in sympathy with the heart and its vessels — i. e., becoming disturbed coinci- dently with cardiac troubles, arterio-sclerosis, etc. On the other hand, any trouble with the epithelium of the tubules must be ascribed to the irritation arising from its work in eliminating the organic toxins — either from over- work, or from the necessity of eliminating imperfectly BRIGHT'S DISEASE 149 catabolized toxins which are dialyzed with greater diffi- culty. In chronic Bright's disease, according to Bate (Cf. The Lancet-Clinic, Oct., 1905, p. 412), "the glomeruli long remain normal after the rodded epithelium of the tubules have undergone changes, thus showing that the organic toxins (uric acid, etc.), eliminated by these rodded epithelial cells, give rise to the tubular changes prior to the vascular changes. Therefore, not only must the cause of this metabolic hindrance be removed, but the toxins al- ready in the system must be eliminated in some non-ir- ritative form." ^Etiology. — Various substances, accidentally intro- duced into the organism, will, of course, in their passage through the dialyzing cells, irritate the renal epithelium or glomeruli and may produce inflammation and degenera- tive changes characteristic of Bright's — drugs like can- tharides and lead, for instance. But in the common forms of Bright's disease, the irritation is more gradual and, in the great majority of cases, is caused by the overplus ex- cretion of organic products of nitrogenous catabolism — - generally imperfectly oxidized. Or, it may be due in some instances, of course, to absorption of toxins from the intestinal tract. Minkowski found that 0.5 gramme of adenin, ad- ministered daily to dogs, produced malaise, vomiting, and, after five or six days, death. Before death, the urine of these animals contained albumin, casts, and epithelial cells; and, after death, the kidneys showed inflammatory changes and uric acid deposits. Though this is, of course, a much more rapid process than that which is noted in Bright's disease, nevertheless it serves to illustrate how 150 URIC ACID AND ITS CONGENERS. irritating to the epithelial cells are the suboxidized pro- ducts of purin metabolism. According to Schmiedeberg, the effects of the purin derivatives, in considerable dosage, is to increase reflex irritability, and, ultimately, to cause complete tetanus or even paralysis. The muscles may become permanently contracted, passing into a condition of coagulation similar to that produced by heat and cold; while the action on the kidney is seen in the marked diuresis. Vaughan, in his "Cellular Toxins" (page 346), states that hypoxanthin and most of the other purins coagulate muscle, and that their diuretic action parallels this effect. He believes that the increased reflex irritability which they cause is due to the nitrogen groups (as with ammonia compounds), but that the action upon muscles and kidneys is peculiar to the purin molecule. This same author (page 344) again states: 'The actual amount of uric acid eliminated may be considera- bly less than that actually carried to the kidneys to be elimi- nated, since the kidney may be incapable of effecting the complete excretion. In this case, deposits of uric acid will occur either in the joints (as in rheumatism), or in the kidneys, as in adenin poisoning or in the infarcts of the new-born (Spiegelberg)." He also believes that "the purin bases may be looked upon as undergoing changes similar to those of uric acid." Rachford, in "Neurotic Disorders of Childhood" (p. 79), attributes kidney disease to the irritant action of the purin bodies. He further says (p. 83) : 'The gastro- intestinal canal is probably the most important channel through which the purin bodies may be eliminated, when there is defective excretion through the kidneys; this fact BRIGHT'S DISEASE. 151 is quite empirical and is based on the accumulated testi- mony of the medical profession for many years. The value of laxative medication in these cases, however, is probably not entirely due to the fact that in this way the absorption of exogenous or intestinal purins into the circulation may be largely prevented, but it is also probably due to the fact that the intestinal canal, by proper cathartic medica- tion, may be stimulated to the more rapid excretion of endogenous purins and other poisons circulating in the body media." Croftan, after numerous experiments, has come to the conclusion that the purin bases are capable of pro- ducing cardio-vascular changes in those forms of nephritis in which retention of excrementitious substances precedes the lesions of the heart and arteries. He believes that the purin bases are the primary factor in the causation of "gouty" kidney. In the "lead" form of interstitial nephritis, the toxic action of this metal is either the same as that of the purin bases, or it can cause changes in the organism which lead to the formation of these bases. The same toxins may simultaneously produce both nephritis and arteriosclerosis. From his investigations, this author concludes that the purin bases play an important role in the production of the cardio-vascular changes observed in all forms of nephritis, excepting the chronic indurative form sometimes seen as the result of senile arteriosclerosis. Experiments Upon Rabbits. — To determine the effect of continued daily injections of purin bodies in rabbits, I. Walker Hall, of England, performed a very interesting experiment. Four young rabbits were kept under observation for fifty days. In two of the rabbits, daily injections of a solution of hypoxanthin were given 152 URIC ACID AND ITS CONGENERS. during this time, and, in the other two, a solution of guanin. At the death of the animals, post-mortem in the first two showed the cortex of the kidneys to be very pale, with little distinction between the two zones. In both of the other animals, the kidneys showed degenerative changes in the cells of the tubules, marked hyperaemia, and a com- mencing proliferation of the intima of the smallest arter- ioles; but no interstitial nephritis, and no glomerular changes, — as yet. Deductions. — If we have properly interpreted the findings brought to light from the many experiments held by different investigators, it would seem to have been con- clusively demonstrated that the rodded epithelium of the renal tubules is the first tissue to be affected in a beginning degeneration of the kidneys, due to suboxidized metabolic products — which, of course, is not recognized as Bright's disease, until the process has become sufficiently advanced to give rise to the well-known objective signs. It is im- portant, therefore, that we should know what causes this first injury, and thus be enabled to remove such cause before the kidney becomes seriously damaged. In short, our attention should be directed toward certain symptoms, which precede those indicative of an advanced stage of some renal disorder. As the rodded epithelium of the tubules is known to be specially engaged in dialyzing from the blood the organic substances present in the urine : — the products of nitrog- enous catabolism — it is evident that the primary trouble is some fault of metabolism, and that the irritant is either a purin or ureid (or both), or urea itself. It can hardly be urea, since this product continues to be dialyzed (i. e., does not become retained) until the epithelium of the tu- BRIGHT'S DISEASE. 153 bules has become degenerated to an alarming extent and has involved the surrounding tissues, so that even water is imperfectly osmosed. Urea is evidently the complete end product of nitrogenous catabolism; and it is the best form which Nature has yet succeeded in evolving, for the purpose of being easily dialyzed (without causing irrita- tion) by the delicate epithelium lining the convoluted tubules. It is evident, therefore, that the irritation of the epithe- lial cells, at the outstart, is not due to the osmosis of urea, but to the more difficult osmosis of the ureids, which the oxidase of the liver and the intracellular ferments of the tissues have failed to oxidize into urea, thus leaving a con- siderable quantity of unoxidized nitrogenous waste, in the form of uric acid, to be dialyzed by the kidney epithelium. It is much like asking the gastro-intestinal membrane to absorb food products that have been imperfectly digested, or the stomach to digest food particles that have been im- perfectly masticated: irritation results in both instances. A certain proportion of ureids, in the form of uric acid is capable of being dialyzed through the tubularepithelium without apparent harm (just as a small proportion of im- perfectly masticated food may be digested); but, if the proportion be increased beyond this certain point, or if ureids in some unusual form (allantoin, for instance) be present, it will sooner or later result in irritation. This fact, indeed, is shown in the experiments upon animals, when purins introduced in considerable amount lead to the formation of more uric acid than can be excreted, resulting in inflammation of the tubular epithelium and deposits of urates in the canaliculi and elsewhere. It is known that continued ingestion of alcohol inter- feres with the oxidative function of the liver and results in 154 URIC ACID AND ITS CONGENERS. an excess of unoxidized uric acid in circulation — especially if purin-containing food substances be eaten freely at the same time. At first, under such circumstances, the kidneys succeed in eliminating the excess of uric acid, as may be observed by urinalysis; but, eventually, if the abuse be kept up, the irritation of the epithelium leads to degener- ation of the renal epithelial cells and they become unable to dialyze the urates brought to them, and finally the urea itself. The same results obtain whenever the liver fails to perform its metabolic function (oxidation into urea) properly, from whatsoever cause. The ultimate conse- quence is likely to be Bright's disease. The Three Stages. — It will be seen that the kidney of chronic Bright's disease, as well as the "gouty" kidney, presents evidence of passing through the three stages of purin excess. In the "uricacidaemic" stage, the kidney is simply embarrassed in its work, owing to the obstruction of the capillaries and the consequent variation in the mechanical pressure upon the dialyzing membrane. We have a "torpid" kidney as well as "torpid" liver. In both the rheumatic and uricacidaemic stages, the kidney is subjected to its greatest irritation during an "explosion" of the urates, when the dialyzing capacity of the rodded epithelium of the tubules is strained to its ut- most. Not many such "explosions" should be allowed to occur, before proper measures be taken to prevent the in- evitable damage thus threatened. Indeed, we should not wait for any further evidence of a possible Bright's disease. The third, or gouty stage, is that in which the urates can no longer be dialyzed, except very imperfectly; are retained and become deposited, either in the body else- where or in the kidney itself, finally becoming crystalline. BRIGHT'S DISEASE. 155 The kidneys of uricacidaemic and rheumatic patients become more or less injured at the time of every "ex- plosion" of the urates by way of the urine; though, in many instances, the kidneys will escape for a time, owing to the explosions taking place in the joints or elsewhere. The tendency of nature, however, is to rid the system of the excess if possible ; and, if she be left unaided at such times, a heavy burden is likely to be put upon the kidneys — one that may prove disastrous to the delicate epithelial cells. It is right here that the physician is given oppor- tunity to prove the worth of his calling, by apportioning out the work of excretion, giving the bowels -a due share, and lightening the work of the kidneys by presenting the urates in greater dilution and in non-irritative form. At the same time, efforts should be made to aid the liver in its work and stimulate a more active body metabolism, thus leading to a fuller oxidation of the products of nitrogenous catabolism — i. e., into the end product, urea. Overin- dulgence in purin-containing foods and drinks, should of course, be prohibited. • An Early Sign. — In the opinion of Hobart Amory Hare, as expressed in his " Practical Diagnosis, or The Use of Symptoms in the Diagnosis of Disease" (p. 408): "Often an excess of uric acid in the urine antedates the development of chronic contracted kidney." The moral to be derived from this study is, that appro- priate eliminative treatment should be begun at the pri- mary stage when "uratic explosions" are common — thus preventing further damage to the renal dialyzer and a probable Blight's disease which may ensue. CHAPTER XVIII. INFANTS AND CHILDREN. Uric Acid Infarcts. — The earliest stage in life, in which disordered conditions of the system due to uric acid are manifest, is in the newly-born infant with uric acid in- farcts of the kidney. Though these infarctions, according to Koplik (Diseases of Infancy and Childhood, 619), "are found in the kidneys of over one-half of the infants who die in the first weeks afterbirth," — and, probably, also occur in the majority of all new-born infants; yet, in the opinion of most authorities, the serious symptoms resulting from pathologic changes in the kidneys, are principally met with in those cases in which a "gouty" ancestry can be traced. In discussing the appearance of these infarcts, Fen- wick and Lewis (Disorders of Digestion in Infancy and Childhood, 17) state that, when the kidney is examined under the microscope, "the straight tubules are found to be blocked by opaque granular cylinders, which, under a high power, are seen to be composed of a vast number of spheroidal crystals." Considerable discussion has taken place concerning the exact composition of these crys- talline deposits: Virchow maintaining that they consist of urate of ammonium, while other authorities (Parrot, West) consider them to be either uric acid or urate of sodium. The presence of these infarcts is generally attributed to the sudden alteration in the blood circulation of the newly born and the consequent plus excretion of nitrog- enous metabolic waste products in the kidneys. Inas- much as little water is consumed during the first few days INFANTS AND CHILDREN. 157 of extra uterine life, these products are not flushed out; but, on the contrary, tend to settle in the pyramidal portion of the kidney in the straight lining tubules. In the words of Virchow: "It is quite common to see reddish or yellow- ish deposits, or even brownish streaks, which microscopical examination shows to be uric acid crystals blocking the straight urinary tubules." (Cf. Keating's "Cyclopaedia of the Diseases of Children," Vol. I, p. 70). Concerning this point, we note the following in Graetzer's "Practical Pediatrics," page 34, (translated from the German by Sheffield, 1905): "Post mortem transverse section reveals here a yellowish-red streak. This uric acid infarct usually disappears after the child has consumed more fluid, and is entirely eliminated after two or three weeks. At times, however, it is of longer duration: uric acid and ammonium urate crystals are retained in the lumen of the tubules, of the papillae and renal pelvis as small reddish-yellow granules, which, after having produced certain disturbances, become visible in cloudy urine." Symptoms. — "The urine of the first few days of life," says Holt (The Diseases of Infancy and Childhood, 639) "often shows a deposit of urates or uric acid in the form of a reddish-yellow stain upon the napkin. The reaction of the urine at this time is usually strongly acid." If the young nursling is restless while urinating, cries aloud, strains hard and passes but little urine, uric acid infarct must always be thought of. The wet portions of the diapers are generally found to be darker in color than usual: it is sometimes observed that the margins of these spots have a reddish shade and are covered with reddish granules. Not until these are found is the diagnosis 158 URIC ACID AND ITS CONGENERS. certain, as the other symptoms may be caused also by cystitis for instance. Uric acid infarct may also give rise to redness of the prepuce or the internal surface of the labia as a result of irritation. In older children these symptoms usually do not indicate the presence of a uric acid infarct, but of the existence of newly formed uric acid concretions, which are undoubtedly formed in their development by residues of the former. Uric acid infarcts also give rise to nephritis. "It is therefore advisable," says Graetzer, "to aid the elimination of persistent uric acid infarcts as soon as pos- sible by means of large quantities of water." A Clinical Picture. — E. J. Lorenze, of New York, reports a typical case of uric acid infarcts, in an apparently healthy child, born of a young Irish woman, which, at the end of the first week after birth, began to cry too much. At the end of twenty-four hours (the crying having continued almost constantly), fever developed and slight gastric disturbances, consisting of occasional vomiting. At this time, pink stains appeared on the child's napkins. At every act of micturition, the napkin had a salmon-colored stain, sometimes small and sometimes rather large. This stain was at once recognized as the "brick-dust deposit," and plenty of water was immediately ordered to be ingested as recommended above by Graetzer, by Holt, and by other pediatric authorities. The infant received all the water it could hold. It soon became evident, however, that the treatment would have no effect. The child became worse; temperature rose to 104 F.; the face was anxious in ex- pression at all times. The legs were flexed, and often the thighs were flexed on the abdomen. The abdomen was usually hard, but no special tenderness on pressure was INFANTS AND CHILDREN. 159 noticed. Urine continued to show the brick dust stains. After a week of suffering the child died. About fifteen months later, Lorenze delivered this same woman of another child, which resembled the former in almost every respect. In about five days, the infant began with brick dust deposits on its napkin, and suffered symptoms similar in all respects to the other child. In addition to the water in this case, the alkaline lithia salt, elsewhere described in this work, was administered. The mother received a teaspoonful in a glassful of hot water three times a day, and ten grains were administered to the infant three times a day — the child nursing at the mother's breast. "In two days," says Lorenze, "all stains dis- appeared from the napkins, and the child developed and remained normal in every respect." . The unfortunate outcome of the treatment in the first case, and the speedy and satisfactory results obtained from the use of an alkali in this second case, indicate that the trouble in both instances was doubtless due to the presence of uric acid infarcts, and that the kidneys not only needed to be flushed out with water, but required assistance in the way of an alkaline solvent and eliminant. Uricacid^mic Signs. — In children, whose youthful organisms become burdened with an accumulation of urates in excess, symptoms referable to the uricacidaemic stage are those which are most commonly observed. The reason for this preponderance of uricacidaemic over rheu- matic or gouty signs is easily explicable. The difference between a child and an adult, in the ability to quickly rid the system of uric acid by way of the proper channels, is readily understood. Owing to the active bodily metab- olism and rapidity of oxidation in children, due to their 160 URIC ACID AND ITS CONGENERS. play out of doors, and with their eliminative functions un- checked by faulty kidney action (as is so often the case with adults), it will at once be seen that the excess of waste products of the uric acid type do not remain long in the body. On the contrary, they simply produce their tran- sient effects while en route through the blood, and are then excreted. Generally, there is no storing up of urates in the organs and tissues as is the case later in life. During infancy, uricacidaemia is not of frequent occur- rence due, of course, to the purin free diet; but, later in childhood, when meat soups, coffee and tea are given free- ly, we begin to get first diseases of the uricacidaemic type, and later those of the rheumatic. Chief among the dis- orders of the first class, due to the presence of urates in the blood of children, may be mentioned, according to Wheeler {Brooklyn Medical Journal, ]une, 1905): "migraine, con- vulsions, epilepsy, mental sluggishness, albuminuria and asthma." In the opinion of this author, girls suffer more than boys from these disorders, owing to their comparative lack of physical exercise. He believes, too, that the children of the rich develop these disorders much more than the chil- dren of the poor because of their being reared in luxury and allowed too much strong coffee, tea, rich soups and an excessive amount of meat. They are housed too much. Music, French, and German lessons keep them indoors when they should be playing in the open air. "As a type of such disorders," says he, "a child will be found anaemic; subject to headaches (of the persistent or migrainous type); capricious in appetite; perhaps over weight for its age, but with flabby flesh, circulation poor, extremities cold, nervous in speech and manner, and some- INFANTS AND CHILDREN. 161 times showing choreiform movements: this, too, in a class of cases, which, although anaemic, bear iron badly." The urine, says Holt, is scanty, frequently pale, and in many cases contains an excess of uric acid. Drummond, in the Lancet, 1897, describes an aggra- vated condition of uricacidaemia in the young. "In some cases," he says, "there is a persistent headache in the frontal or vertical region, loss of appetite, constipation, anaemia and loss of flesh. The temperature of the body is low, and for several weeks at a time may remain below normal. The heart action varies. It is sometimes rapid, but more often slow. It is not uncommon to have a pulse of forty or fifty, although the patient is nervous in manner. The pulse tension is raised. The hands and feet are gener- ally cold. In some cases, sudden attacks of giddiness oc- cur which are difficult to distinguish from slight epilepti- form seizures. The knee-jerk, as a rule, is distinctly lessened and may be absent. A sluggish habit of mind and body may be noted along with other character traits foreign to the patient." The so-called "night-terrors" of children is another condition due to uricacidaemia, in the opinion of Wheeler, and may be classed with the paroxysmal neuroses, mi- graine and petit mal. This condition, he thinks, often alternates with migraine in the same patient, and like most other diseases under discussion is found in children who are nervous and excitable and come of rheumatic parents, — parents who have also produced weak-minded or epi- leptic children. In children of susceptible nervous systems, "convulsions" may take the place of an attack of mi- graine; in fact, this may be said to be the rule in very young children. %r- 162 URIC ACID AND ITS CONGENERS. Cyclic Vomiting. — That nausea and vomiting is a frequent indication of infantile uricacidaemia (as it often is of this same stage in the adult), may be noted in the two cases of uric acid infarcts, with brick dust stains on the napkins, reported by Lorenze, in which this symptom was one of the first to appear and remained constant. The importance of examining the urine, in cases of cyclic vomiting, is shown by Holt (p. 328), who states that the following interesting observation upon the uric acid ex- cretion in one of his patients, was made by Dr. C. A. Herter — all the results being based upon the twenty-four hours' urine; to wit: Urea Uric Acid Ratio of Uric Grammes Grammes Acid to Urea Time Taken Before the attack (normal) 13.606 0.251 1 to 54 First Day ! 7*249 0.110 1 to 157 Second Day 12.023 0.091 1 to 132 Third Day ll -7 1 3 °- 2 34 J to 5° Several weeks after- ward (normal) I 5-°4° 0.283 1 to 53 Hematuria. — In the opinion of Holt (p. 104), the blood carried from the kidney, in these cases, is some- times due to the irritation of uric acid infarctions, and may have nothing to do with the general hemorrhagic disease. Lithiasis. — The authoritative statement is made in the American Text Book of the Diseases of Children, 970 (edited by Louis Starr, M.D., Philadelphia) that urine loaded with uric acid, urates, oxalates and phosphates, may cause an incontinence as well as irritable bladder; hence the urine in such cases should always be examined. INFANTS AND CHILDREN. 163 The following significant statement is also made (p. 978): "Lithiasis is the deposition of certain solids of the urine in the urinary tract, any portion of which, from its beginning in a Malpighian capsule to its terminal ex- pansion (the bladder), may be the seat of such deposits. The sediments thus precipitated include uric acid and its compounds as the most common ingredients. They may be so minute as to be barely visible to the naked eye, con- stituting sand or gravel; or they may be a couple of inches or more in diameter, when they are spoken of in common language as stones in the kidney or bladder. The uric acid sediments are often found in the shape of red sand in the very first urinary discharges of the new-born infant. If, on examination, the urine is found highly acid in re- action, depositing uric acid sediments, the treatment is principally by alkalies." "It is admitted/' says Keating in his work (I-597), "that the urine of infants is richer in uric acid than that of adults. The uric acid infarctions of Virchow, the urates of sodium and ammonium, constituting the grit found in the kidney tubules, the brown dust on the napkins, which is shown by the microscope to be mostly formed of uric acid, all point to a congenital or inherited tendency to pro- duce this substance in excess. This excess may be positive or relative — positive in proportion to all other ingredients; and relative, in that other ingredients may be deficient. " Albuminuria. — Albuminuria may be a symptom due to uricacidaemia. With a more careful examination of the urine in children of late, we find albuminuria a more common condition than was formerly thought. It is very common at puberty. It very often follows an attack of migraine, and is due to the increased blood pressure incident to the collaemia. 164 URIC ACID AND ITS CONGENERS. Asthma. — "Again," says Wheeler, "asthma is a con- dition which is comparable to an attack of migraine in the suddenness of its onset. In children asthma runs a some- what different course than in the adult. It never occurs as an independent condition, but may precede, accompany or follow a bronchial catarrh." A rheumatic parentage can also usually be traced in these cases. Rheumatic Signs. — While diseases of the uricaci- daemic stage are by far the most common in children; nevertheless, if the rules of dietary are violated day after day, or metabolism reduced by some intercurrent disease (as scarlet fever), then we may get a storing up of uric acid with development of diseases of the rheumatic type. Principally among the latter, says Wheeler, " are rheuma- tism, gout (rarely), adenoids, nasal-pharyngeal catarrh, chronic bronchitis and eczema." "Though there is a tendency in some quarters," says this author, "to class rheumatism among the germ diseases, nevertheless, I think we cannot rule out uric acid as a predisposing cause. Exposure to cold throws down the excess of urates in the blood into the joints and tendon sheaths, then with a lessened resistance of the tonsils, or naso-pharyngeal mucous membrane, a port of entry is given to a micrococcus which may be normally present and harmless in the oral cavity, but which becomes active in the blood with the production of toxins causing symp- toms of chills, fever and inflammation of the joints. In childhood, the joints are bathed in a more liberal amount of alkaline fluid than is the case in the adult, and even though the alkalinity may be so greatly reduced and the circulation of blood become so sluggish through cold as to cause a temporary deposit of uric acid or the acid INFANTS AND CHILDREN. 165 urates, yet with the activity of metabolism these would be quickly redissolved and pass again into the blood to be excreted." For this reason, true gout is a disease almost unknown in childhood, though occasionally an isolated case is reported. Adenoids, naso-pharyngeal catarrh and chronic bronchitis are other diseases of childhood depending in part, if not wholly, on the uric acid tendency. Concerning the first mentioned, Mackie, of Nottingham, England, says: "I scarcely see a case of adenoids but where there is an arthritic or migrainous parentage." The frequency of pharyngitis, laryngitis and bronchi- tis in rheumatic adults, has frequently been noted. 'These same conditions," says Wheeler, "occur in child- hood, but are not so constant an accompaniment as in later life. Its cause is supposed to be due to a deposit of uric acid in the fibrous structures of the naso-pharynx, larynx and bronchi — this deposit acting as a local irritant in the same manner that it does in a joint." One of the most freq'uent manifestations of the "rheu- matic" or "gouty" tendency in infancy and early child- hood, is eczema. Some writers call eczema a "gout of the skin.' Uric acid is an ^etiological factor in only a certain proportion of cases, however, the rest depending upon other diathetic conditions. Chorea. — Chorea is another disease of childhood which is now generally recognized to be of uric acid origin. Concerning the relationship between chorea and rheuma- tism, Holt, from personal observations, has noted in over fifty per cent, of his cases a rheumatic parentage, and further states : " If cases of chorea are followed for several years, it is surprising to note how the evidences of the rheu- 166 URIC ACID AND ITS CONGENERS. matic diathesis develop the longer the cases are followed. " Again, Herter and Smith, who have made a study of the urine in chorea, found that in very many cases there was an excessive elimination of uric acid frequently (Holt, 721). Diagnosis. — In the majority of instances, it will be found that children, suffering from disorders due to uric acid accumulation, have a hard, tense pulse, some anaemia, and a sluggish capillary circulation accompanied by fre- quent excesses of urates in the urine. The urine is generally high-colored, scant, hyperacid and of high specific gravity. Frequent uric acid "explo- sions" occur, when the quantity of urates excreted is greatly in excess of the normal — three times greater in some cases. In discussing cases in which uric acid is thrown down in the form of crystals in the urine, or in that of the well known brick-dust deposit, Holt says: "This condition is one in which the solvent power of the urine for uric acid is much reduced. Such urine, as a rule, is highly colored, strongly acid, and may have a high specific gravity. This condition is dependent upon a disturbance of nutri- tion, and one which is most frequently associated with the gouty diathesis. It is not very common in children, except in those of gouty antecedents. " CHAPTER XIX. MENSTRUATION, GESTATION AND MENOPAUSE. Normal Menstruation. — It is a fact of considera- able interest to note, that, in the experimental study of the menstrual function, physiologists have discovered the same phenomenon that the pathologist has observed in connection with an attack of gout, and that is, that both are preceded and attended (at first) by a distinct fall in the output of nitrogen in urine and feces, notwithstanding that the amount of nitrogen ingested with the food in each case remains unchanged. It is further observed that, two or three days prior to the menstrual flow, as before the gout attack, there is marked retention of uric acid, as shown by the diminished excretion in the urine; while, during and immediately following the flux in both in- stances, the amount of urates excreted in the urine is in excess of normal. The nitrogen retention of menstruation is attributed by Schrader (Cf. von Noorden's Beitrage zur Lehre vom Stoffwechsel, II, 132) to a decreased formation of urea. This is doubtless true and would seem to indicate that at least part of the excess of urates, excreted during the menstrual flux, represents that portion of uric acid which was not oxidized into urea as normally, thus resulting in more of the former and less of the latter. But not all of this plus excretion of uric acid can be due to this cause: some of it, probably, represents that other and legitimate portion which had been previously retained, for it has been shown that two or three days prior to the flow, the urine 168 URIC ACID AND ITS CONGENERS. contains less of the urates than normally, the excess not appearing until the flow is established, and continuing a day or two afterward. Two other objective signs, connected with the physi- ology of menstruation, are enlarged thyroidea and in~ creased blood pressure, both of which are doubtless caused by temporary demands for increased function. While the thyroid gland does not always appear to enlarge, yet every general practitioner has noticed its increase in size in many women at this time, only to return to its normal dimensions at the end of the flow. Concerning the in- creased demands made upon the heart, to overcome the effect of capillary obstruction due to the presence of urates in excess, Oliver {Brit. Med. Jour., I, 1375) has demon- strated conclusively, by means of the arteriometer, that there is high blood pressure in menstruation. Clinical Deductions. — During normal menstrua- tion, the retention of urates in the capillaries, just before and at the beginning of the flow, necessarily produces the customary uricacidaemic symptoms, such as depression, headache, loss of appetite, etc., these of course disap- pearing as the urates themselves disappear, as shown by an examination of the urine. This is what occurs each month, and this is all: that is, if the female is in good health, her organs of "defense" and excretion being equal to the demands made upon them for this temporary ex- ercise of increased function. But, in those cases (all too common), in which the or- ganism is already overburdened with uratic waste, or the secretions locked up from constipation or some other cause — the sluggish eliminative organs or those of defense being unable to perform their added duties promptly and satis- MENSTRUATION, GESTATION, ETC. 169 factorily — then, as a result, we get classic symptoms of the uricacidaemic stage due to retention, ranging all the way from a severe headache to the most alarming neurotic attacks — migraine and nausea, and even violent hysteria or epileptiform seizures. The high blood pressure of menstruation will, of course, become aggravated under the circumstances mentioned above, thus indirectly tending to produce cardiac troubles eventually, and perhaps nutritive dis- turbances in the walls of the bloodvessels themselves, resulting in atony. As to the thyroid gland, it is now understood that it acts as an "organ of defense"; that its internal secretion or ferment, like those of the liver, aids in the decomposition or oxidation of cellular waste products (among which is uric acid), thus, when such waste is increased as in men- struation, the gland becomes temporarily congested or hypertrophied at the time of performing its added function. As this occurs regularly from month to month, it is highly probable that in some uricacidaemic patients, the exag- gerated function and consequent enlargement may grad- ually become greater until eventually the permanent en- largement results, known as Graves' disease. Probably the other ductless glands are temporarily congested in this way each month, and, perhaps, may become permanent- ly enlarged under similar circumstances. Therapeutic Conclusions. — From these clinical findings, deduced from the experimental study of men- struation, we are forced to the conclusion that to prevent or relieve the various disorders incident to this important function, the best results will be obtained by directing attention to the chief organs of defense and elimination — 170 URIC ACID AND ITS CONGENERS. especially to liver, kidneys and bowels. Previously stored up uratic waste, if there be such (and there generally will be) , should be thoroughly removed before the expected day of menstruation, and in this way lighten the duties of elimi- nation which are known to be physiologically increased at this time. In short, the same rational methods should be employed here as have been found to be effectual in other similar uricacidaemic conditions. The reason for this physiological retention of nitrogen previous to and at the beginning of the flow, and of the plus excretion of purin nitrogen afterwards, has never yet been satisfactorily explained. But, as the same phenomenon has been noted in migraine, chorea, epilepsy, gout, and other uric acid explosions, we judge that it is simply one of Nature's laws to thus herald the approach of some essential strain on the part of the organism to rid itself in this rhythmical manner of the uratic waste products result- ing from sexual energy. "Those who have written on the subject," says Sted- man (Med. Rec, Oct. 7, 1905), "have agreed that the men- strual act exerts a well-marked influence on the various bodily functions, and that this depends on chemical pro- cesses. A stimulus which proceeds periodically from the genital system, gives rise to an increased metabolism, which in turn manifests its effects on blood pressure, temperature, etc. These superflous metabolic products are then believed to find their way back to the genital system, there to be eliminated until the physiological balance is again restored. " General Toxemia. — From the classic investi- gations of Bouchard, we know that toxic material is being constantly reabsorbed into the blood and eliminated from MENSTRUATION, GESTATION, ETC. 171 it, consisting, in part, of that which is ingested directly with the food, but chiefly of the waste products of cell activity within the body — i. e., the precursors of urea and the urates. The organism, in health, rids itself of the toxic mater- ial partly by elimination and partly by chemical destruction or decomposition into non-toxic or less toxic substances. Elimination takes place chiefly by way of kidneys and bowels, while chemical decomposition takes place prin- cipally in the liver and thyroidea. It will readily be under- stood, therefore, that a condition of toxaemia results when- ever either the introduction of toxic material into the blood is excessive, or its elimination or chemical decomposition becomes insufficient. Toxemia of Pregnancy. — It will be seen that the three possible causes of the development of a toxaemic condition are commonly present in pregnancy, and that, consequently, a certain degree of toxaemia appears to be almost physiological for that state. First, the greater in- gestion of toxic material in the food is noticed in the un- natural longings of the pregnant woman for indigestible articles of diet. Second, excessive introduction into the blood occurs when the end products of fetal metabolism are resorbed into the maternal blood, which thus receives toxic material from both mother and fetus. Third, the pressure of the gravid uterus upon kidneys, liver and bowels, and partial compression of arteries and veins regulating their blood supply, may serve to interfere with the activity of both the organs of defense and elimination. In short, it must be admitted that during pregnancy, not only does a large amount of toxic material reach the blood, but the work of elimination and chemic destruction is hampered to some extent. 172 URIC ACID AND ITS CONGENERS. It must not be forgotten that the metabolic and excre- tory organs of the pregnant woman are called upon to do extra duty: that another individual is springing into existence whose need for nutriment and elimination of waste increases with each day and hour of its growth. The mother must not only prepare and furnish the necessary building material in proper form, but she must remove the debris which results from the new construction. She must become the scavenger of, as well as serve as the outlet for, the child's excreta. Through the renal channel of the parent must be discharged the metabolites of both mother and fetus. In verification of this fact, we have only to point to the increased toxicity of the urine of the healthy woman during pregnancy. As soon as the equilibrium between importation and elimination of toxins is disturbed, the symptoms of auto- intoxication appear, and these are identical (or, atleast correspond closely) with those of the uricacidaemic stage in purin excess. They first become manifest in form of disturbances in the digestive and nervous system. Nausea and vomiting, probably the first symptoms of a pregnancy toxaemia, are characteristic of almost every form of intoxication. If the toxaemic condition becomes aggravated, if the patient is possibly especially susceptible (e. g., if uricacidaemia already exists), the vomiting may become very obstinate, it may develop into hyperemesis, into uncontrollable vomiting. There is increased reflex irritability, a symptom quite common for certain intoxi- cations in the non-pregnant state, as also after the inges- tion of poisons. Morning Sickness. — To explain the occurrence of toxaemic symptoms very early in pregnancy, Ehrenfest MENSTRUATION, GESTATION, ETC. 173 (St. Louis Courier of Medicine, 1905, p. 200) presents a novel idea. "As long," he says, "as we had to regard fetal metabolism as the only source for toxic material, it seemed impossible to explain nausea or i morning sickness' on the ground of toxaemia. To-day, we can do so, because we know that just in the earliest stages of preg- nancy, chorionic tissue in form of the trophoblast shows a very marked tendency to penetrate into maternal tissue." In other words, this author advances the theory that the chorionic cover of the placenta is a most important source of toxic material. Inasmuch as the fetal tissue originates from this source, which is subsequently carried into the maternal system, he thinks that it is in the mater- nal blood that it becomes partly dissolved, causing the destruction of red blood cells. "In this way," says he, "syncytiolysins and syncytiotoxins are formed, which on the other hand, cause the reactive formation of the cor- responding antitoxic substances," — according to the Ehr- lich theory of immunization and its application by Veit to the phenomenon of deportation of fetal tissue into the maternal system. He believes that it is thus explained why we may expect to see toxaemic symptoms so early in pregnancy — i. e., before fetal metabolism can serve as a factor. It is evident, however, that the "morning sickness" may not be due entirely to this cause, that, in fact, neither the chorionic nor fetal tissue may be chiefly responsible; though, of course, there is little doubt that the symptom is mainly one of toxaemia. Inasmuch as it is during the first weeks of pregnancy that the "sickness" occurs, it would seem that the toxic material, which causes it, may prob- ably be the same as that which passes off each month with 174 URIC ACID AND ITS CONGENERS. the menses, and which would have done so in this instance had not conception supervened and checked the menstrual flow. In other words, there is retention of the metabolic waste which is periodically eliminated from the genital system in the catamenial discharges. The physiological balance is temporarily interrupted; and, until the organ- ism succeeds in restoring this equilibrium, we observe the uricacidaemic symptoms (common to menstruation) thus aggravated during the first stage of pregnancy. Like the disorders of menstruation, it will be seen that the toxaemic symptoms of pregnancy will doubtless be most severe in those cases in which the eliminative organs are already handicapped, owing to the presence of an excess of urates in the circulation. That the flow through the capillaries is often impeded at this time in this way, may be seen in the almost immediate appearance of vari- cose veins in the lower extremities of many pregnant women, before the gravid uterus has become sufficiently enlarged to exert any pressure on the iliac veins. Puerperal Eclampsia. — It is obvious that the high toxicity of the blood during pregnancy, combined with the necessity of increased function on the part of the organs of defense and elimination, must exert a harmful effect upon these organs that may result in histologic alterations in their tissues, that under normal conditions would be con- sidered pathologic. Degenerative changes in the paren- chyma of both liver and kidneys are likely to occur; and, if a certain limit in such alterations be transgressed, the functions of these organs necessarily become interfered with, and toxic waste is retained. In this way a dangerous circulus vitiosus is formed, especially in those cases in MENSTRUATION, GESTATION, ETC. 175 which the capillaries are obstructed with urates at the time of impregnation. But it is upon the liver that the work is primarily thrown of arresting and transforming the toxic principles added to the maternal circulation. This organ (aided by the thyroidea), during pregnancy, is engaged in a constant fight against a threatened toxicosis. If it fails in the defense, toxalbumins remain in the blood and fall upon the kidney whose finer structures soon become injured in the effort to remove the undesirable waste from the body. From this excess of duty, both liver and kidneys are apt to succumb and cease to eliminate the morbid products only partially. But, with Pinard, we believe that the kidney has only this secondary relation to eclampsia, and that albuminuria is a sign of hepatic insufficiency. In other words, we believe that the theory of autointoxication, which is now so steadily gaining ground, will ultimately be considered the only rational one in discussing the aetiology of eclamp- sia. The fact will soon be recognized that convincing proof has been furnished by Ehrenfest and others for their contention, "that nausea, morning sickness, hypere- mesis, or headache, albuminuria, increased patellar re- flexes and eclamptic convulsions, are not different dis- eases, but only different symptoms of various degrees of pregnancy toxaemia." It is, then, the intermediate products of nitrogenous metabolism chiefly — which the liver has failed to arrest and transform — that remain in the circulation to cause the autoinfection manifested by headache, vertigo, digestive disturbances, visual irregularities, insomnia, and various other uricacidaemic signs, which usually precede and 176 URIC ACID AND ITS CONGENERS. usher in the "convulsive seizures." One of the great dan- ger signals, therefore, which may be looked for in lieu of albuminuria, is the absence of a normal amount of urea (the end product of nitrogenous metabolism) in the urine. For, it must be remembered that although albumin may be absent (which is supposed to be an indication of safety), yet the amount of urea eliminated may be far below nor- mal; in which case our prophylactic measures against eclampsia should at once be instituted. Prophylaxis. — The fact that European clinics show a mortality of twenty per cent, in eclampsia, would seem to indicate that there is still much to be desired in the way of rational treatment. Procrastination has always been the principal trouble. The perfunctory examinations of the urine for albumin, during the latter months of preg- nancy, are not sufficient. A far better plan would be to determine the amount of urea excreted. But even this is not enough; for instead of waiting until the organism has become sufficiently crippled to give this damaging evidence, it should be the aim to furnish aid that will pre- vent the necessity of such testimony. The direction which our prophylactic as well as thera- peutic efforts should take, may be learned from studying the good effects following venesection or uterine hemor- rhages, accompanied with enemeta of salt solution. By bleeding a quart, not only is considerable blood pressure removed, but the circulation is at once freed of twenty- five per cent, of its waste toxins, while the addition of the salt solution decreases their relative proportion. It mav thus be understood that the treatment of this condition should be eliminative. Liver, kidneys and bowels should be aided from the beginning. Waste should MENSTRUATION, GESTATION, ETC. 177 not be permitted to accumulate until the urea or album- inuria sign shows the imminent danger of eclampsia. On the contrary, attention should be given to the first uric- acidaemic signs that appear — even in the first days of preg- nancy. Uricacidaemic signs, when occurring in the pregnant state, are much more significant than at any other time, and demand from the physician the exercise of his closest care and keenest judgment. The remedy which he has found to be most effectual in ridding the system of uratic waste in the non-pregnant state should be prescribed with- out hesitation at the earliest moment. Or, if the case should not be seen thus early, if premonitory symptoms of the dreaded convulsions are already manifest, even under these circumstances, elimination is still indicated and will give the best results. The Menopause. — The severity of the untoward symptoms which so often occur at the climacteric period, will depend in great measure upon the ability of the ex- cretory organs to shoulder the extra responsibility of re- moving from the system such waste as may still be thrown into the circulation periodically, and which has hitherto been removed to a great extent by means of the menstrual flow. For thirty years, or more, the organism has been accustomed, each month, to rid itself of certain catabolic products of (and by way of) the genital system, and it is somewhat of a shock to change all this at once. Fitful efforts to continue the long established function will be made for a time, and if the resulting waste is properly re- moved by way of the regular channels of excretion, no serious results will follow. But, on the other hand, if the capillaries are already obstructed and the circulation overcharged with uratic 178 URIC ACID AND ITS CONGENERS. waste, thus rendering the organs of defense and elimina- tion illy prepared to perform this added duty, then the usual disorders, common to the uricacidaemic or rheuma- tic stage of purin excess, will doubtless appear. The toxaemic condition, in such cases, is similar in many respects to that of suppressed menstruation or of the. be- ginning of pregnancy, and the indications for eliminative treatment are practically the same. It will be found an excellent plan, therefore, to thoroughly flush out the uratic sewage some time prior to the anticipated period, thus reducing materially the work of elimination which is known to be physiologically increased at this time. CHAPTER XX. EYE, NOSE AND THROAT. Trend of Opinion. — Not only is the general prac- titioner beginning to recognize and appreciate the im- portance of eye, of nose, or of throat symptoms, when endeavoring to arrive at a rational diagnosis of certain systemic disorders, but the ophthalmologist, the rhinolo- gist, and the laryngologist, too, now appreciate the neces- sity of constitutional treatment in the management of many pathologic conditions found in the eye, nose or throat. Though, in the past, specialists were prone to attribute many general disturbances to the influence of the local disorder (which had been referred to them for treatment), the trend of modern opinion is to reverse this finding, and consider the local disorder, in many instances, as one of the manifestations of some constitutional dyscrasia. Ocular Phenomena. — The attention of the oculist is now being directed to the fact that many morbid con- ditions of the eye, which interfere with distinct vision, are more than mere optical disturbances : that there exists, in other words, an underlying constitutional dyscrasia, of which the eye symptoms are simply local manifestations. One of the first systemic disorders to be connected with ocular phenomena, was Bright's disease, and, today, the oculist as well as the physician in general practice, recognizes such visual disorders as "albuminuria retini- tis," "uremic amaurosis," "retinal apoplexy," etc., as indices of some unsuspected renal disease — thus serving as a means of early diagnosis. It has, in fact, become a com- 180 URIC ACID AND ITS CONGENERS. mon practice for the specialist to refer certain eye patients to the general practitioner for urinalysis — provided the eyes of such patients fail to present apparent local cause for the visual disturbances complained of. The fact that Bright's disease is so often connected with uric acid retention, soon led to the discovery that such retention is in itself a frequent cause of optical pheno- mena. As early as 1890, Sanford Morton reports in the Ophthalmic Review, for March, of that year: "I saw stasis or thrombosis in the vessels of the retina, in one or two cases, taking place during an attack of megrim, and there is every probability that these troubles were due to uric acid." Prof. G. E. de Sweinitz, of the University of Penn- sylvania, in a paper read before the Philadelphia County Medical Society, November, 1902, on the subject of "Ocular Manifestations of Chronic Bright's Disease," which he considers so often a direct manifestation of uric acid accumulation, names such conditions as "albumin- uric retinitis or neuro-retinitis; alterations in the caliber of retinal vessels from sclerosis in chronic cases, with hemorrhage when general arteriosclerosis coexists; paresis or paralysis, chiefly of the external rectus and superior oblique muscles;" and especially to "recurring subcon- junctival hemorrhage," which latter symptom, he urges, has not received the attention its significance demands. (Cf. Tyson's " Bright's Disease and Diabetes. ") Iritis and Choroiditis. — The fact has for some time been recognized, by both the specialist and general prac- titioner, that congestion or inflammation of the iris is a frequent accompaniment of the rheumatic stage of purin excess, and the term "rheumatic iritis" has become quite EYE, NOSE AND THROAT. 181 common in medical literature. Theobald (Reference Handbook of the Medical Sciences, Vol. IV) distinctly recognizes iritis to be of gouty and rheumatic origin. In a paper, read before the Fourth Annual Meeting of the Western Ophthalmologic Association, Feb. 10, 1899, Bronson treated somewhat at length the subject of "Uric Acid as a Factor in the Causation of Choroiditis. " "If," says he, "we will bear in mind the close anatomic relation- ship between the choroid and the iris, we will not be sur- prised to know that if uric acid causes a disturbance in the latter (rheumatic iritis), it will also in the former." Dr. Bronson refers to the fact that the capillary network of the choroid is the finest in the body and that in consequence of the law that the velocity of a current is inversely to its lumen, the velocity of the capillary current here must be very many times less than that of the posterior ciliary artery. It is well known that in the chronic toxaemias produced by uric acid, the earliest manifestations of necro- biotic changes are found in the arterioles and capillaries, and inasmuch as the blood current in the structure of the choroid is slower than elsewhere, the blood, charged with toxic substances, is in contact with its minute vessels much longer than in the larger arteries and veins. Temporary Visual Irregularities. — It not in- frequently happens to the oculist that it is almost impossi- ble for him to refract satisfactorily a case presenting some apparent anomaly of the eye, and which, perhaps, after a few days, or a week, can be corrected with very little difficulty. In some of these instances, when the patient presents himself, he can barely see the test chart. The eyes are red and irritated; lids swollen; there is strong intoler- ance to light, and rapid dilation and contraction of the 182 URIC ACID AND ITS CONGENERS. pupil. Sometimes the eyes are bulged and staring, suffused with tears. Other uricacidaemic signs are almost invariably present in these cases. The urine is very scant, dark colored, overacid and loaded with urates. The patient often admits that he is just convalescing from a protracted alcoholic debauch. The usual alkaline eliminative treat- ment quickly relieves the more urgent symptoms; and, after a few days, no trouble will be experienced in correct- ing any visual irregularity, — or, the patient may now con- clude that glasses are not needed. These cases would seem to be similar to those de- scribed by Campbell, in his "Auto-Intoxication in Diseases of the Eye." After defining auto-toxaemia and a lithaemic condition, he says: "It has been conclusively shown that almost, or quite all the tissues of the body suffer inflam- matory reaction in the event of auto-intoxication by the cellular waste products above indicated. The various effects upon the lids, upon the conjunctiva and cornea, have been gone over again and again/' Astigmatism. — In the International Clinics (Jan., 1900), Vol. IV, p. 173, in an article entitled "A Few Thoughts Indicating a Causative Connection Between the Uric Acid Diathesis and Astigmatism," Louis J. Lauten- bach, M. D., Ph.D. (Surgeon in charge of the Phila- delphia Eye, Nose and Throat Institute), states that for several years he has been suspicious that the phenomena attendant upon cases in which astigmatism was present, were in some way connected with an increase in the quan- tity of uric acid retained in the system; and it is only recently that the conviction forced itself upon him that the connection is too constant to be accidental, and that some EYE, NOSE AND THROAT. 183 causative relation must exist between the two conditions. Of forty-two cases of astigmatism examined by him, uri- nalysis revealed in every instance, urine typical of the lithaemic condition, — being overacid, of high specific gravity, developing an excess of uric acid elements. After the employment of the alkaline eliminative treatment in these cases, assisted by the use of proper glasses, the astig- matism invariably disappeared. Uratic deposits in con- junctivae and skin also disappeared, the latter organ be- coming softer and moister, losing that dry, scaly appear- ance and the itching so characteristic of the uric acid dyscrasia. Nasal Affections. — It is now quite generally agreed upon by rhinologists that polypoid degeneration of the ethmoidal bodies, in part or in whole, is in many cases the result of repeated uric acid irritation of these bodies. Study of certain cases, supplemented by extended obser- vation in a number of others, makes clear what might be expected — removal of nasal polypi no more cures asthma than would the removal of tophi about the joints of the fingers cure gout. Results have proven, in both cases, that the anti-uric regime is most effective. Freudenthal describes a condition of inflammation of the turbinates, in connection with rheumatic arthritis else- where; and reports several cases, a number of which he has seen. He thinks many cases of what are called simple "coryza" may be rheumatic, and sees no reason why the nose should not be affected, even though the articulations there do not happen to be as typical as those in other parts of the body. Hay Fever. — Although other theories have been suggested from time to time, but one can be said to have 184 URIC ACID AND ITS CONGENERS. stood the test of clinical experience; and, today, there is a general consensus of opinion among the best informed, that the following are the essential ^etiological factors in the production of hay fever; to wit: I. An external irritant. 2. A sensitive local surface, due (a) to uric acid ob- struction, or (b) to anatomical abnormalities of the naso- pharynx. That something besides an "external irritant" is neces- sary to produce this complaint is evidenced from the immu- nity enjoyed by country people, who are, as one writer sug- gests, "surrounded by a pollen-laden atmosphere during the whole period of vegetation, while the dust in the roads is often several inches deep during the dry weather of the summer, and passing teams raise clouds of dust that float in the air for several minutes. The natives of these rural localities are not free from the irritant pollens that cause hay fever in city dwellers, for the ever present ragweed grows in luxuriance, and the golden rod blooms by every roadside and their pollens float on every breeze." The fact that victims of hay fever are found among those of sedentary habits; among professional and busi- ness men of the populous centers, with whom ingestion of food is out of proportion to physical exercise; among the inhabitants of cities who indulge most freely in the meats and sweets of the table; and especially among the "gouty" inclined, — is a strong indication of its autotoxic or purin origin. It is a well-known fact, too, that hay fever never oc- curs in an individual with perfectly healthy nasal passages; the capillaries of the latter being obstructed, turgescence of the mucous membrane, with frequent swelling of the tissues, is an inevitable consequence, and a sensitive sur- EYE, NOSE AND THROAT. 185 face is exposed to the external irritant. The important function of the nasal mucosae of purifying the inspired air and neutralizing countless germs, is illy performed; and doubtless, ptomaines from the decomposed secretion not only serve as a local poison, but may enter the general circulation. Other uricacidaemic or rheumatic signs are commonly present; while the urine is concentrated, heavy, and loaded with lithates. The clinical picture is typical of uric acid excess, with obstruction of the nasal capillaries; and the results ob- tained from the alkaline eliminative treatment have thus far proven most satisfactory. Concerning the nature and cause of the suddenness of the attack or paroxysm, in many cases, Bishop (Dis- eases of Nose, Throat and Ear, p. 39) offers the following explanation: u As a tumor or hypertrophied bone may give rise to convulsive seizures in epilepsy, and as its re- moval may be followed by relief when no other structural cause exists, so in hay fever, where new growths and other lesions of the nasal mucous membrane are present, the attack may be started by the accumulation and the sud- denly setting free of uric acid. This precipitates the par- oxysm by its irritant action, which finds expression in the group of symptoms characteristic of nervous catarrh or asthma, instead of one of the other allied diseases. The particular form of manifestation may be determined by the growth or seat of irritation, located in the nasal cavi- ties. Where this is the only determining factor of the nature of the morbid symptoms (no other organic disease having resulted from the long-standing trouble) the re- moval of such a peripheral source of irritation may give relief from these symptoms, but it may not prevent the 186 URIC ACID AND ITS CONGENERS. uricacidaemia from switching of? into other kindred lines of disturbances, if not corrected. The uric acid theory makes clear the reasons why some persons suffer from at- tacks of nervous coryza under certain favorable conditions in winter as well as in summer months. It also unifies all the various forms of hay fever. " Lith^mic Sore Throat. — The resemblance of the nasal mucosae of hay fever sufferers to the "lithaemic sore throat," described by Sir Morell MacKenzie (Journal of Laryngology and Rhinology, Vol. Ill, No. 8), is suffi- ciently striking to augur a similar causation. "The lithaemic throat," says this eminent author, "is usually uniformly red, the tonsils are slightly swollen, the uvula elongated and thickened, and all these parts bathed with a considerable amount of mucous secretions. The urine is heavy, small in quantity and loaded with urates. One peculiarity of the lithaemic throat," says he, (and this is also true of the nasal passages in hay fever), "is the fact that the applications of a stimulant or an as- tringent nature, instead of affording relief to the patient are apt to cause additional distress." MacKenzie's theory of the causation of the underlying constitutional trouble, is that of subalkalescence of the blood and sub- oxidation — uric acid and its congeners being the chief resultant products. Frequent attacks of tonsillitis (the so-called rheu- matic tonsillitis), alternating with the customary uricaci- daemic or rheumatic signs of purin excess, is a very com- mon indication of the lithaemic throat. Therapy. — The character of the general treatment, in these stubborn complaints, differs in no wise from that which is indicated in other uricacidaemic or rheumatic EYE, NOSE AND THROAT. 187 conditions. "The irritable throat of lithaemia," Mao Kenzie states, "is sometimes amenable to abstention from wine and too much nitrogenous food, with the ad- ditional aid of a brisk purgative." For the relief of lithaemic affections of the skin and mucous membranes, Piffard mentions one or two objects which should constantly be kept in view. i. The depur- ation of the blood. 2. The increased oxidation of ali- mentary substances. "The first object should be attained," he says, "by the use of alkaline diuretics, by laxatives, and by increasing elimination by way of the skin." The second object is attained "by stimulating the action of the liver and increasing metabolism." In short, the alka- line eliminative treatment is indicated here, as elsewhere. CHAPTER XXL TRAUMATISMS AND SURGICAL NOTES. Joint Injuries. — The cause of the protracted and painful convalescence, often following some trifling in- jury to the joint, has of late been a subject of fruitful dis- cussion among many eminent clinicians and surgeons. The unsatisfactory outcome of a purely local treatment, in the handling of certain cases of lame and partially stiffened joints, due originally to strain or injury, has led to the belief that some underlying constitutional factor must be held responsible. After a careful study of the question from a clinical standpoint, watching results from different lines of treat- ment in an extensive series of cases, Prof. William H. Porter, of New York, in an article, "To What Extent Does Rheumatic and Gouty Diathesis Enter into Trau- matic Joints, i. e., Sprains and Bruises ?" read before the Massachusetts Medical Society, at Boston, June 13, 1900 (Cf. Medical Record, Sept. 22, 1900), has this to say: "The relationship of the so-called gouty and rheumatic condition of the system should always be taken into con- sideration in connection with every traumatism that impli- cates the joints. If such a state of the system is found to be present, it must be given due consideration in the general management of the case; otherwise, recovery will be greatly retarded/' Practically the same conclusion was arrived at by the late Prof. Thomas H. Manley, of New York. In a paper on the "Constitutional Treatment in Joint Injuries" (Cf. TRAUMATISMS AND SURGICAL NOTES. 189 New York Lancet, Jan., 1901), he states: "When there- fore, we meet with severe arthritis after joint injury, and this fails to respond to ordinary therapeutic measures, we should carefully investigate into the environment of the patient, his habits, his antecedent history, and examine well into his general condition. The most common com- plication is rheumatic. We must resort to the therapeutic test; in other words, treat the patient as well as his injury. In order to reach the system, and eradicate the cause, when rheumatism is present, internal medicine should be simultaneously given in all cases." Similar advice is given by the late Prof. A. M. Phelps, of New York. In considering the subject of hip-joint disease, he refers particularly to the rheumatic joint, pre- ceded by an injury, in which cases constitutional treat- ment is always required in addition to the mechanical and operative. {Peoria Medical Journal, Dec, 1898.) A good illustration of the value of such advice, in the class of traumatisms under discussion, is seen in a brief published report of the experience of Dr. W. T. Tilney, of Crawfordsville, Ind., which will doubtless recall to the minds of many physicians similar cases that have been met with in their practice. The doctor states that he suffered for two years with a stiff-knee joint, which he had sprained. All local treatments had failed, and he had about given up hope of getting any relief. It finally occurred to him that the trouble might be rheumatic, and he at once instituted the alkaline eliminative treatment with success- ful results. In a short time the lameness entirely dis- appeared; and six months afterwards (Sept. 20, 1901) he reports that the joint still remained in its normal condition. 190 URIC ACID AND ITS CONGENERS. Another similar case, though one more serious and of much longer duration, is reported by Smith, in the St. Louis Medical and Surgical "Journal, March, 1901. In this case, the doctor suffered for six years, before instituting the proper treatment. His trouble, also, was in the knee- joint, — i. e., synovitis, following an injury, which confined him to the house for several weeks, and from which he recovered with permanent slight stiffness. Three years afterwards, the knee began to enlarge, gradually increas- ing in size until nearly twice as large as normal. He was forced to give up his work, and for three months sat in a wheeled chair. He went into a sanitarium and was treated with baths, electricity, massage, etc., but with little benefit. He remained in this unsatisfactory and prac- tically helpless state, until the summer of 1899 — nearly three years. At this time — other joints having, in the meantime, become somewhat affected, and noting urate deposits in quantity in the urine — he began the alkaline eliminative treatment for rheumatism. In a few days, the joint began to decrease in size and the general health to improve. In September of that year, after a short visit to the Catskills (where he had continued treatment), the doctor returned home and re-entered into practice. Eigh- teen months afterward (March, 1901) he reports that he is a "new man;" that, with the exception of occasional "slight stiffness" of the knee, he is as well as ever, weighing within five pounds as much as he did before the attack. The Interpretation. — Judging from the symptoms and clinical history of many cases, it would seem that, though a swollen and inflamed joint may be traced to an injury and apparently be entirely due to the latter, never- theless deposits of urates may immediately center at that TRAUMATISMS AND SURGICAL NOTES. 191 point and serve as a further source of irritation and hind- rance to natural recovery. Especially is this likely to be true, if the patient chance to be suffering already from an excess of urates in the circulation at the time of the injury. Owing to the local congestion following upon a trau- matism of the joint, the urates as well as leucocytes are brought to this point in increased quantity; and, as the surrounding lymph and synovia become reduced in alka- linity, the conditions are favorable for the precipitation of the urates, which become attached to the contiguous solid fibrous tissues. The urate salts have a well-marked tendency to seek out the fibro-serous structures (or white tissues) con- nected with the locomotor apparatus — those subject to strain; and, as acid is produced as a result of contraction, precipitation occurs at this point and becomes a nidus or center for the attraction of further deposits. The mechani- cal or chemical irritation, resulting from the presence of these crystals, may usher in an attack of arthritis resem- bling that of acute gout. It will be readily understood that, until the removal of such deposits, either through phagocytic action or the return of the blood's alkalescence normally produced, or through increased solvency of the blood produced medi- cinally, the case is likely to prove stubborn and conval- escence protracted. Other Traumatisms. — Of the various other joint lesions, in which may develop severe and harassing rheu- matoid pains, may be mentioned those following contu- sions, fractures and dislocations. Indeed, the after pains, in many cases, are even more troublesome than the original injury, which they usually follow within a fortnight or a 192 URIC ACID AND ITS CONGENERS. month. In some cases, the subsequent pain is out of all proportion to the injury; it lasts a long time and is rebel- lious to local treatment. As to internal treatment, the same advice is offered here as in that of sprains, and the resultant swelling and stiffness, already considered. The same explanation is also given as to the cause. Sluggish Ulcers. — Abrasions or contusions of the surface of the lower extremity, especially in the tibial region where the circulation is naturally sluggish, may de- velop into unhealthy sores or varicose ulcers, which resist all local forms of treatment. This untoward result is more likely to happen if the capillaries in that vicinity are obstructed with urates (as shown by cramps and cold feet), thus preventing a free flow to the injured surface and growth of healthy granulations. In these cases, in conjunction with the local methods usually employed, the alkaline eliminative treatment is indicated as in the joint injuries previously described, and for the same reason. If uricacidaemic signs already exist, or have previously existed, no further doubt is to be enter- tained that the sluggish action of the part is due to ob- struction of the circulation from urates; and the proper measures should be taken accordingly. A Surgical Hint. — In a recently published article in the International Medical Magazine, Montgomery (Professor of Gynecology, Jefferson Medical College) has voiced the sentiment of the great body of modern surgical operators, in the statement that the highest success in sur- gical procedures is attained when all factors, which are likely to disturb the subsequent convalescence, are, so far as possible, recognized and eliminated. He believes that in surgical operations, the eliminating powers of the TRAUMATISMS AND SURGICAL NOTES. 193 patient should be restored to their most effective condi- tion, and that any condition which is likely to clog the metabolic processes or those of oxidation, should be cor- rected. He says that one of the most important disturb- ances of this function, whose baneful influences are too frequently underestimated, is uricacidaemia; that patients affected with this condition do not bear surgical operations well. The convalescence is complicated by defective elimination through the kidneys, etc. The lessened re- sistance induced by uratic obstruction favors the occur- rence of localized congestions and inflammations, which may frequently be the cause which favors the develop- ment of sepsis. "Every operator," says Montgomery, "has witnessed the development of untoward manifestations where the slight extent of the operation, the apparent good health of the patient, and the scrupulous care exercised during operation, justified him in anticipating the most favorable results. A careful scrutiny in many cases demonstrates the uric acid condition under consideration to have been the factor which has turned the scale in the wrong direction. " The fact is becoming better recognized every day that it is particularly important to establish a normal function- ating activity of the liver, kidneys and bowels, prior to surgical procedures; for, if the excretory organs be inac- tive or impaired from any cause, the normal reparative ener- gies of the body will become so weakened after an operation that recovery is doubtful. Not only is it considered neces- sary to examine the urine for evidences of casts, sugar or albumin, but for the presence of an excess of urates, or of lack of urea. A Determining Factor. — The fact that the victim of purin excess, whether in the uricacidaemic or rheumatic 194 URIC ACID AND ITS CONGENERS. stage, is notoriously deficient in excretory powers, has led to the conviction that among the determining factors which prevent proper recovery from surgical operations, by choking the capillaries and impeding normal repara- tive processes, must be reckoned the purin or ureid bodies, of which uric acid is the type and chief representative. It is doubtful if any other of the metabolic waste products are so commonly retained and produce so much trouble, by interfering with the processes of nutrition and' elimina- tion, as does this retrograde cellular tissue product under discussion. It was the generally accepted belief among the mem- bers of the profession, that had President McKinley (at the time of the wound and operation which proved so disastrous) been in the prime and vigor of health, with organs of secretion and excretion equal to the full per- formance of their duty, the wound and operation might not have proven fatal. It is believed that the impairment of the metabolic functions and gradual accumulation of toxic waste products within the system served to paralyze reparative energy when the occasion demanded. The necessity of immediate operation rendered it impossible in this instance to rid the organism of purin waste in the manner recommended in such cases. The local irritation of tissue observed in the diabetic patient, when injured or operated upon, is well known to the surgeon. The frequent association of gout and dia- betes has caused much speculation as to the probable similarity of origin of these two complaints — though one represents faulty metabolism of nitrogenous products and the other of the carbo-hydrates; and much food for reflec- tion is afforded the thoughtful physician in such cases as TRAUMATISMS AND SURGICAL NOTES. 195 that of the lamented McKinley. Was he suffering from purin excess (or the so-called "gouty diathesis"), and were retrograde tissue products present in such quantity as to serve as a disturbing factor ? We know that when the normal interchange between blood and tissue is interrupted, the latter dies for lack of nutriment. We know that gangrene, or death of cells, is the result of nutritive failure, i. e., either no nutriment is brought to the cell (capillary circulation being obstructed) or else the toxic waste products of cell disintegration are allowed to accumulate and choke absorption — and the cell languishes in the midst of its own excreta. The necessity of freeing the capillaries of such obstruction, before an important surgical operation, at once becomes manifest; and it is largely for this purpose that eliminative remedies are now recommended as a precautionary measure to such procedures. It is now becoming better understood and appre- ciated that anything which interferes with the functional activity of the excretory organs and prevents the free elimination of cellular waste, not only causes the blood to become loaded with deleterious matter that renders it less able to take up the further retrograde products of cell activity, but that the blood (thus overloaded) less readily conveys the nutrient material which is absolutely necessary to the life and health of the cells; and, furthermore, the accumulating toxins not only inhibit the activity of the cells, but lessen their power to recognize and combat mal- eficent agents. We begin to realize to how great an ex- tent the welfare of the body depends on the consentaneous activity of the cells, the blood and the excretory organs; and, also, to appreciate the importance of autointoxica- 196 URIC ACID AND ITS CONGENERS. tion as an important factor in the production of a dis- turbed condition unfavorable to the growth and repair of tissue — always so essential after surgical operation. In short, the patient operated upon (with unsatis- factory results) may have suffered no infectious nor con- tagious disorder; he may not have been exposed to an en- vironment which his system was unable to cope with — i. e., he may have had no poison introduced into his body from without; he had simply neglected to rid himself of the poisons generated within. An important point, then, to be observed before operation, is to devote (whenever possible) a few days to the preparation of the patient — i. e., shake down the grate and clean out the ashes and clinkers: remove the slag. Prof. Augustin H. Goelet, of New York, in discussing this subject of preparation of the patient, especially for abdominal operations, recommends that from one to three weeks, at least, should be consumed in getting the patient in condition. He gives careful atten- tion to the diet, and prescribes such eliminative agents as will best stimulate the action of the kidneys, liver and bowels. He believes that the alkaline eliminative treat- ment, employed in this way as a preparatory measure, will enable the surgeon to do "better work in a shorter time and will materially lessen the mortality following abdom- inal operations." (Cf. Charlotte Medical Journal, Dec, 1898.) CHAPTER XXII. SOME USUALLY UNRECOGNIZED URIC ACID CONDITIONS. Spine and Lower Extremities. — In a paper en- titled "Manifestations of Lithaemia in the Spine and Lower Extremities, Simulating Orthopedic Conditions," read at the meeting of the Buffalo Academy of Medicine, May 2, 1905 (Cf. American Medicine, Sept. 30, 1905), Le Breton calls attention to a class of cases not described as such in text books. He excited no little interest in re- porting a series of nine of these cases, which had been re- ferred to him by general practitioners in different portions of the state during the past two years, for orthopedic treat- ment; but in which such treatment was shown by him to be of minor importance, as compared with the constitu- tional measures he employed to eliminate from the system the true aetiological factor, and thus relieve the underlying condition — the so-called "lithaemia," "irregular gout," "a rheumatic tendency," etc.; or, as he says: "A condi- tion in which nutrition is at fault, oxidation imperfect, and organs functionally deranged." Symptoms. — Of the nine cases reported by Le Breton, eight were females ranging in age from twenty to thirty. The chief symptom always complained of, was either backache or pain in the feet, of such a character as to lead to the diagnosis of flat-foot or of some spinal condition requiring support. Questioning usually elicited acknowledgement of the following symptoms: — Indigestion, with excess of gas; pain after eating, and sour eructations; constipation; a 198 URIC ACID AND ITS CONGENERS. general lack of energy and of strength; a tendency to dizzi- ness, fainting and cardiac palpitation; general nervous- ness, insomnia and paresthesias. Goitre occasionally present. Urinalysis usually revealed a hyperacid urine, of high specific gravity, the quantity being less than a quart in twenty-four hours. Or, again, less frequently, it might be alkaline, of low specific gravity, the quantity being abnor- mally high for the twenty-four hours. Rarely is a normal urine found. "When backache is the major symptom, it is apt to be localized between the shoulders or in the lumbar region. Two or three spinous processes are found to be tender on pressure. The ribs and surrounding muscles are often sore to the touch. Tender points are sometimes dis- covered over various peripheral nerves, especially the sciatic nerves. Motions of the spinal column may cause pain. When motion produces pain, an advantageous ad- junct in the treatment is to have the patient wear for a few months a light jacket. When pain in the feet is the chief complaint, the site of the pain may be widespread, as, for example, through- out both feet and in both calves; or it may be localized in the ball of the foot, or in the heel, or some particular tarsal joint. Pressure reveals deep tenderness in the ball of the foot, or over the plantar fascia, or dorsum of the foot. Pressure over the sciatic nerves very often finds typic tender points over both nerves and over the roots of these nerves in the lower part of the back. Occasionally wide- spread tenderness is present over all the muscular tissues of the lower extremities. It is a noticeable fact that until these patients have had general treatment, they are utterly UNRECOGNIZED URIC ACID CONDITIONS. 199 unable to endure the pressure of plates or a lift in the shoes, even if there is a flat-foot." Therapeusis. — "The curative treatment," says Le Breton, "is one directed at the diathesis; for support by jacket or flat-foot plate may be only secondarily indi- cated." In every instance, successful results were ob- tained by ordering regular hours, proper exercise and diet, plenty of water, and an alkaline eliminant remedy. Im- provement is usually manifest at once, unless the neuras- thenic element is strongly developed. In some instances, local treatment may consist of static electricity, massage or the mechanical vibrator. Later, Blaud's pills and general tonics may be indicated. Precaution. — Ordinarily, these well-known signs of uricacidaemic or rheumatic stages of purin excess are easily recognized and the proper treatment instituted; but, in the class of cases under discussion, the underlying condition is so masked by one or the other of the two prominent symptoms mentioned, that a wrong diagnosis is apt to be made. A complete cure, however, may usually be looked for, if the true condition is recognized and the proper alkaline eliminant treatment employed. It is evi- dent that the urates in these cases are deposited chiefly in the neighborhood of the rigid articulations of the spine and tarsus, rather than in the more flexible joints and muscles at other portions of the body, as is commonly the case. For this reason, the pains in the back and feet overshadow the other general symptoms, which differ in no wise from the usual uricacidaemic or rheumatic signs. Growing Pains. — Another conspicuous symptom of purin excess, the true nature of which is generally unrecognized or overlooked, is that manifestation of the 200 URIC ACID AND ITS CONGENERS. rheumatic stage popularly known as "growing pains. " The rational treatment indicated in these cases is often withheld by the physician, owing to the mistaken idea that nothing abnormal exists, that the pains are simply evidence of the rapid growth of a healthy physical organism. Though pediatrists have frequently called attention to the rheumatic character of the symptoms, the popular fallacy has become so firmly rooted that little heed is given to such warnings. Sixteen years ago, in his Therapeutics of Infancy and Childhood (Cf. Archives of Pediatrics VI, 6, p. 355), Jacobi sounded a note of warning on the subject, in the following significant paragraph: "The large majority of attacks of 'growing pains,'" says he, "means rheumatism; it is the failure to appreciate this fact that gives rise con- stantly to mistakes in diagnosis, and the neglect in the administration of both preventive and curative measures. " Again, more recently, in a magazine article, (N. T. Med. Jour, and Phila. Med. Jour.. Sept. 30, 1905), Satterlee, in concluding his discussion of "Rheumatic Poison and Its Treatment," has this brief admonition to offer: "In closing, I would earnestly call attention to the importance of recognizing and treating all rheumatic con- ditions in children, like the so-called 'growing pains' and frequent attacks of follicular amygdalitis, etc., especially where they have an hereditary history of any of the diseases of rheumatic poison in parents or grandparents." Another notice, given along these same lines, is that of Barbour (Amer. Practitioner and News, March, 1905) in "Some English Views on Rheumatism," in which he says: "In England, as well as here, the fact that rheuma- tism is more frequent and more serious in childhood than in UNRECOGNIZED URIC ACID CONDITIONS. 201 adult life is not appreciated, and authors of text-books still write fatuously of its frequency in early adult life, and of its rarity in children. Such errors die hard, and, un- fortunately, carry in their train numberless mistakes in diagnosis, and unnumbered pains, illnesses and deaths. Until the profession at large recognizes that 'growing pains' are rheumatic in origin and a frequent cause of organic heart lesions, the work of education must be kept up." 'The English pediatricians," continues this author, ''are doing yeoman service in arousing trie profession to a knowledge of all the varied manifestations of rheumatism and to an appreciation of its importance. As one of the most eminent of their pediatrists said to me: 'Twenty- five per cent, of all cases in the children's hospitals suffer from rheumatism in one form or another.' The large in- cidence of rheumatism in London would seem to follow on the excessive dampness and the overcrowding; and the older men still recognize the importance of these factors, as predisposing causes, probably by lowering the resist- ing power of the organism." ^Etiology. — -As referred to in the foregoing remarks, "dampness and overcrowding" may probably serve to some extent as predisposing factors, in the aetiology of the rheumatic condition in London children; to which, we may add, that dampness and cold serve also as exciting causes, not only in London but in America. "Growing pains," muscular pains, etc., must all be grouped together as characteristic signs of the rheumatic stage of purin ex- cess, all of which are indicative of the deposition of urates chiefly in the white tissues (sheathes of muscles, aponeuroses, bursas, capsular ligaments, pericardium, en- docardium, or in the joints) : such deposits often being pre- 202 URIC ACID AND ITS CONGENERS. cipitated through reduced alkalinity of the lymph or blood, caused by the exposure of the surface vessels to cold and dampness — especially after violent exercise. The apparent greater liability of boys and girls ap- proaching puberty, to these transient deposits, thus giving rise to "growing pains," is probably due in considerable measure to the suddenly increased cellular metabolism of the genital system, incidental to the transformation of the hitherto latent sexual energy into functional activity, and the consequent necessity of increased elimination of purin waste. The exposure of the body to inclement weather at this time, serves as an exciting factor to cause deposition of urates, even though the latter be but little in excess of the normal. The rheumatic signs produced will usually be temporary in these cases, owing to the activity of the excretory organs and abundant oxygen supply in the youthful organism. The danger, however, of the deposi- tion occurring in the endo- or pericardial tissues, should urge the adoption of preventive or curative measures in the way of alkaline treatment, precisely of the same char- acter as that recommended in the rheumatic stage of purin excess in the adult cases. Raynaud's Disease. — This disorder, commonly discussed under the head of "symmetrical gangrene," was first described by Raynaud, in 1862; who found that it occurred most frequently in convalescence from exhaust- ing illness, and in chlorotic, nervous individuals in early adult life. The disease is usually described in text-books as "a neurosis characterized by an exaggeration of the excito-motor power of the cord in presiding over the vaso- motor centers, as shown by vascular spasm, venous or arterial, in symmetrical parts of the body." UNRECOGNIZED URIC ACID CONDITIONS. 203 In his "Thesis" (p. 166), Raynaud says: "The ex- tremities are most often affected because these are the por- tions of the body which have most surface in proportion to bulk, and therefore most likely to lose their heat by con- duction and radiation, and most early become cooled down below the point at which the life of the tissues can be con- tinued." The foregoing is significant in showing what great importance Raynaud attached to the causative influence of exposure to cold. Local Signs. — The phalanges are the parts most commonly affected, especially of the fingers; also the tip of the nose and external ear. At first, the surface is cold, white and bloodless (without feeling dead) ; the skin be- comes wrinkled and shrunken; the ends of the fingers, thin and conical. Afterward, there is itching and severe pain, followed by a bluish skin and finally gangrene. The local asphyxia may be partial, producing merely a temporary ischaemia, cyanosis, or erythema, in which case there is likely to be frequent recurrences of the trouble, or the asphyxia may be so complete and continued as to produce absolute gangrene. Treatment has usually been of no avail. The Uric Actd Theory.— Haig was the first to point out the probable uric acid origin of this affection; having been led to the discovery by the slowness of capil- lary reflux on the surface of the extremities (observed after slight digital pressure), in all cases of uric acid excess in the circulation. He at once concluded that the aspyhxia of the part in Raynaud's disease might be caused bv uric acid collaemia, which he defines as a condition of obstruc- tion in the capillaries through a thickened or viscid state 204 URIC ACID AND ITS CONGENERS. of blood, producing stasis, subnutrition, and finally gan grene. This stasis in the surfaces, especially at the ex- tremities, as he very properly avers, will be still further hastened by the action of cold. In support of Haig's theory, Rosewater recently pre- sented the report of "A Case of Lithaemic Gangrene,'' in a paper read before the Clinical and Pathological Section of the Academy of Medicine, Cleveland, Ohio, 1905, and demonstrates very clearly that the so-called Raynaud's disease, from which his patient was said to be suffering, was simply one of a series of symptoms due to uric acid toxaemia, which yielded readily enough to the proper die- tetic and medicinal treatment. The following is a brief summary of the case; to wit: "A man, sixty-four years old, emphysematous, rheu- matic for thirty-five years (for the past eight years suffer- ing with asthma and bronchitis) with a history of previous superficial gangrene, is treated for gangrene of the anterior right tibial surface by elevation, antisepsis, heat, andalac- tocereal diet. Discharged cured in six weeks. Advised to continue the diet (antilithaemic) and soon reports that his asthmatic difficulty is decidedly relieved; six weeks later, while on this diet, but three hours after eating a beefsteak, a violent pruritus develops. Relief and cure follow return to the lactocereal diet; but after two months, he develops, February, 1902, a superficial gangrene of all toes but the third of the right foot. He had observed the diet, except that for fully one month he had twice daily a cup of beef tea. The flesh sloughed off, but reformed on the indicated treatment and diet. Seven months later, he complains of loss of memory and mental unbalance. His diet was kept up, except that UNRECOGNIZED URIC ACID CONDITIONS. 205 he was daily drinking tea and coffee. On strict observance of the diet, he has remained well now for over seventeen months. The history of this case : lithaemic stigmata, deviation from normal each time uric acid or purin food was added (each time only one incriminating article), and the patient's return to and maintenance of normal health, when strictlv on the diet, is as diagnostic of lithaemia and as justifiable, as would be potassium iodide and mercury for lues. The gangrene was superficial and accompanied by a relative stasis of the blood stream, and not by a toxic con- traction of arterioles; due likely, as Haig states, to uric acid viscosity, as apparently corroborated bv Romberg, who found that the blood stream might vary fully ten per cent, in viscosity, which, in arteriosclerosis and other con- ditions, must be extremely injurious, especially in the cap- illaries and to the heart." Conclusion. — The case reported by Rosewater, together with several others cited by Haig, fairly demon- strates the fact that occlusion of the capillaries (generally at the venous end) by urates, may prevent the return flow of blood from the poorly vascularized extremities, and give rise to the production of the same series of objective symptoms, as would follow from a ligature of the part. The normal interchange between blood and tissue cell is interrupted; and, if the obstruction is complete and per- mitted to remain long enough, the cell languishes and dies in the midst of its own excreta — i. e., gangrene results. But, if the obstruction is only partial, we get the usual signs of temporary ischaemia, cyanosis, erythema, etc. The fact that other uricacidaemic signs are invariably present; that ingestion of purin foods and drinks speedily 206 URIC ACID AND ITS CONGENERS. aggravates the local condition; and that withholding further introduction into the system of such foods and drinks, taken in conjunction with the employment of anti- uric-acid treatment affords speedy relief, — would seem to furnish satisfactory clinical evidence of the uratic origin of this affection. Indeed, from a theoretical viewpoint as well, the established physico-chemical facts are sufficiently abundant to warrant the classification of Raynaud's dis- ease among "some usually unrecognized uric acid con- ditions. " CHAPTER XXIII. DENTAL CONDITIONS. The Teeth. — The three anatomical divisions of the tooth, with which, from a uric acid standpoint, we are particularly interested, are (i) the peridental membrane, (2) the tooth-pulp, and (3) the dentine. The surrounding alveolar tissue and gums are usually affected secondarily. The peridental membrane, which envelopes the root of the tooth, in its alveolar socket, may be considered in the light of a periosteum, upon which the tooth as a whole like other bones of the body, depends for nourishment and protection. The tooth-pulp, like bone-marrow, is generously equipped with a vascular and nerve supply which enables it, in turn, to feed and nourish the mineral constituency of its surrounding bony encasement — the dentine. It is a very highly sentient organ; and, morphologically speak- ing, may quite properly be considered an analogue of bone- marrow. The dentine, or bony substance of the tooth, is per- meated throughout its matrix with fibrils leading from the tooth-pulp, by means of which it is vitalized and kept in good repair. External Influences. — The teeth are greatly ex- posed to external irritant factors, which serve as exciting causes in the production of pathological conditions. Especially will this be true when the vitality of the tooth- pulp or dentine has become lowered by any constitutional dyscrasia. 203 URIC ACID AND ITS CONGENERS. In no other part of the body do we find the organs subjected to such extreme thermal and chemical changes as in the oral cavity, where the teeth are exposed by direct contact to sweet and salt substances, to hot and cold liquids, acids, alkalies, etc. Protection. — Ordinarily, when the organism is in its normally healthy condition, and the teeth are in good repair, the lime (phosphate and carbonate) and other in- organic salts, which chiefly compose the dentine, are in such proportion to its organic constituents (7 to 3) that adequate protection is afforded the delicate internal tis- sues of the tooth against these deleterious external in- fluences — for, of course, only the dentine and its enamel are exposed by direct contact. Under these circumstances, the healthy dentine, for instance, owing to its peculiar composition, is a poor thermal conductor, and prevents the transmission of hot and cold waves to the pulp and, in this way, saves it from such forms of irritation. The same may be said concern- ing the effect of sweet and salt substances, acids, etc. But, on the other hand, should the proper kind and amount of nutriment to the dentine (from the general blood supply) be withheld or interfered with in any way, thereby changing the normal proportion of its mineral and organic constituents, it will at once be seen that its degree of con- ductivity may be altered in such manner as to permit trans- mission of thermal, chemical or mechanical impulses, and by such means seriously injure the delicate and sentient tissue of the pulp. The importance of this kind of protection is often made manifest to us when improper filling is used in a carious cavity. For example, if a metal filling (such as DENTAL CONDITIONS. 209 gold) be fitted, the pulp often becomes irritated from these external influences, as evidenced by the violent pain and ache of the part — for metallic substances serve as a good conductor. But, if such filling be removed and a poor conductor substituted, such as gutta percha or oxyphos- phate cement, the pain immediately ceases, as has frequent- ly been demonstrated in actual practice. So long as a liv- ing pulp exists in a carious tooth, it should be protected by such filling-device as corresponds most closely to the composition of normal dentine. Decay. — A further point to be considered in the cases above described, in which the dentine is illy nourished, — is its susceptibility to decay. If its supply of nutriment from the general circulation (through the medium of the pulp arterioles) be inadequate or vitiated, the phosphates and carbonates, as well as the organic matter, both of which are so essential to the stability of bone structure, will be- come deteriorated in quality or quantity — and disinte- gration eventually ensues from the effect of exposure to heat, pressure, acids, etc. In this way, by the softening and breaking down of the substance of dentine, a carious cavity develops and finally disorganization of the tooth- pulp itself, which has now become more or less exposed to the deleterious external influences from which it has been previously protected. In short, tooth-decay often origin- ates primarily from some systemic disorder. In an elaborate article, on the "Constitutional Causes of Tooth Decay," read by Prof. Eugene S. Talbot, of Chicago, before the Fourth International Dental Congress, Aug. 30, 1904, reference is made to several cases ob- served in actual practice, wherein some systemic disturb- ance was the obvious aetiological factor in the production of decay, among which we note the following, to wit: 210 URIC ACID AND ITS CONGENERS. (i) "A woman, twenty-two years old, a lifelong patient, became pregnant. Her teeth, which had been in fine condition up to this period, decayed rapidly thereafter. Caries appeared around new fillings and many new cavi- ties occurred within twelve months." (2) "A man, forty-six years of age, a broker, had sound, healthy teeth, with few fillings, until an attack of nervous prostration consequent on business strain oc- curred, when his teeth decayed rapidly, softening so that the enamel could be removed like leather." (3) "A minister, thirty-eight years of age, with a fine set of teeth, broke down from overwork. After three years absence in France, he returned to America with every tooth decayed, twenty-one of his teeth having to be crowned." (4) "A woman of forty-six years had two sons and a daughter. The daughter, at eighteen, was attacked with peritonitis and died within a week, thereby plunging her mother into deep depression. The mother's teeth, pre- viously in good condition, presented in eight months many cavities." (5) "Miller (Cf. Dental Cosmos, March, 1904) mentions the case of a man forty-five years of age, who was in fair health with the exception of asthma and a rheumatic tendency, and who was the subject of a well- marked case of erosion." Many such cases might be cited, but the point to which we wish to direct attention here is the significant clinical fact that tooth-decay is often but the local ex- pression of the existence of some constitutional disturbance, during the progress of which the substance of dentine is rendered liable to disintegration (caries) owing to its fail- DENTAL CONDITIONS. 211 ure to receive an adequate supply of bone nutriment to keep it in good repair and in a condition to resist external influ- ences, to which it is ever exposed. UricacidjEMIA. — Among the various systemic fac- tors, which are instrumental in checking the flow of blood through the vessels of the pulp, thereby preventing the conveyance of nutriment to the surrounding dentine (thus contributing to its death and decay), none is more common than that stage of purin excess which we have designated " uricacidaemic." In discussing this phase of the subject, it should not be forgotten that the teeth, as an integral part of the mam- malian organism, are dependent (like any other animal tissue) on the general circulation for a supply of nutriment. For this purpose, the tooth-pulp is furnished with its minute arterioles and nerves which branch off from the larger dental and alveolar vessels and pass through the foramen to each pulp. From these pulp-arterioles and nerves, in turn, myriads of microscopic filaments are given off to and permeate the matrix of the surrounding dentine. It was once thought that the pulp was simply a for- mative organ and that its mission ended with the for- mation of the tooth; but it is now known that it is a true vital organ and continues to nourish the dentine by means of its bloodvessels and nerves. The dentine, too, is known to be a living tissue, subject to all the changes which vitality gives to an organ — such as nutrition and recuper- ation. From all this, it will be seen that the tissues of the tooth must suffer from the consequences of capillary obstruction in that immediate neighborhood; and, like other bodily tissue, will be subject to deterioration of 212 URIC ACID AND ITS CONGENERS. structure from lack of nutriment, owing to such ob- struction. That these end vessels of the teeth often contain their full quota of waste matter, which the system is attempting to eliminate, may be seen in the deleterious local effects produced when the salts of lead, iodine, or mercury have been introduced and are retained in the circulation. The "lead line" on the gums, "mercurialization," loosening of the teeth, local pain and tenderness, noted under these circumstances, are too well known to require further com- ment. Moreover, it is almost unnecessary to state in this connection, that the urate salts are also known to accumu- late in this locality and give rise to the accustomed effects. Stomatologists are now generally agreed that the urates have as strong a predilection for the gomphosis articu- lation and connective tissues of the teeth as for any other joint or tissue of the body. It should be understood, how- ever, that the effects produced from their presence in excess in the condition we are considering (i. e., the uric- acidaemic stage) are simply such as may arise from obstruction of the flow of blood in the vessels of the pulp. Toothache. — The first symptom complained of in the uricacidaemic stage of these dental conditions, is tooth- ache. Like the distension of the cerebral vessels causing headache, the pressure of the vessels (distended with urates) against the surrounding highly sentient pulp-tissue causes toothache. Owing, too, to the firm bony encase- ment in which the pulp is inclosed, there is little or no opportunity for expansion, and the resulting pain is cor- respondingly severe — the so-called "throbbing" tooth- ache, initiated suddenly from bodily exposure on a cold, windy day. DENTAL CONDITIONS. 213 Inasmuch as in this primary stage, the dentine has not been deprived of its proper nutriment sufficiently long to cause disintegration of its tissue-structure, there may as yet be no evidence of erosion or caries, — no signs of begin- ning decay; consequently, the toothache sufferer points out to the doctor or dentist an apparently perfectly sound tooth as the source of his trouble. This sometimes leads to ludicrous mistakes on the part of the surgeon. He and the patient disagree as to which tooth is the real "acher" but the former is so positive that some other adjacent carious tooth is the cause of the disturbance that he ex- tracts the latter, only to learn afterwards that the patient was probably correct — for the "toothache" continues. Whenever an apparently sound tooth is pointed out in this way as being the "acher," it is a good plan to strengthen one's diagnosis by looking for other uricacidaemic signs elsewhere — as a scant, high-colored, overacid urine, and, instead of extracting this or some other guiltless member, the proper eliminative measures should be employed to clean out the obstructed capillaries, as in headache, back- ache, or any other lithaemic "ache" occurring elsewhere in the body. It sometimes happens that this form of uricacidaemic toothache will suddenly disappear the moment the nervous victim approaches the portals of the (to him) chamber of torture. His pain is gone and, oftentimes, he returns home without entering the surgeon's office. How is this phenomenon to be accounted for, in the cases we are considering ? Simply, that strong emotion, or fear, through vaso-motor control, causes the sudden emptying of the surface capillaries of face and head — as in the s ud- den pallor often seen in persons overcome with such 214 URIC ACID AND ITS CONGENERS. emotions. The force with which these vessels are emptied may be sufficient to drive the uratic obstruction back through the foramen into the larger alveolar vessels, and thus temporarily relieve the distensive pressure and ache of the pulp, due to' such obstruction. It is, of course, likely to return as soon as the capillary circulation is restored and the urates again enter or attempt to enter, the pulp artery through the foramen. While the foregoing explanation is based largely on theoretical deductions, yet we know from an extended clinical experience that very many uricacidaemic patients complain of "toothache" as one of the troublesome sub- jective symptoms, and that the alkaline eliminative treat- ment affords the most satisfactory results. It is almost invariably accompanied with other subjective and object- ive signs of lithaemia, which likewise disappear under the treatment. For all practical purposes, therefore, it would seem wise to class this so-called "nervous," "functional," or "neuralgic" toothache under the same category as the other "aches" characteristic of uricacidaemia, and employ the same therapeutic resources. As these cases are often submitted for first aid to the physician, rather than to the dentist, opportunity is given for systemic treatment, where local measures can be of little avail, except to afford tem- porary relief of the pain. Later Stages. — Retention of urates in the pulp- arterioles, if long continued, results in the gradual dis- organization and decay of all the tissue-structures of which the tooth proper is composed. This is partly due to lack of an adequate supply of proper nutriment and finally to the direct irritation of the uratic deposits themselves. The illy-nourished dentine loses its proportion of calcium and DENTAL CONDITIONS. 215 organic material, so essential to bone structure, and is thus more easily affected by external irritants: a cavity de- velops. The pulp, from lack of this bony protection, be- comes injured and is eventually inflamed and destroyed: the latter effect being due in great measure to the presence of deposits of urates, which in the later stages are thrown down. The inflammation also extends to the soft tissues, and such conditions as gingivitis, and, perhaps, alveolar abscess may supervene. In the words of the stomatologist, we have all the clinical signs characteristic of "gouty pericementitis." In the American Text-Book of Operative Dentistry (515-531), in the chapter on "Pyorrhea Alveolaris of Constitutional Origin," written by Prof. C. N. Peirce, of Philadelphia, the views of modern stomatologists concern- ing the influence of uric acid retention in the system in the production of many disorders of the teeth and gums, is given somewhat in detail; from which we note the follow- ing paragraph, on the effects of the uratic deposits in pyorrhea : "The deposit is the source of irritation which in most cases is followed by inflammation, leading to inflammatory degeneration and probably coagulation necrosis of the cellular elements. The alveolar walls melt down particle by particle, the pericementum disappears, the diseased area usually becomes infected by pyogenic organisms, and the process of suppuration is an additional factor leading to the exfoliation of the teeth. As in necrotic areas of other parts, calcareous deposits occur, which cover and almost entirely obscure the primary deposit of urates. * * * By the continued irritation of uratic deposition and the co- operation of micro-organisms, the inflammatory process 216 URIC ACID AND ITS CONGENERS. extends until the membrane is destroyed to such an extent that it is no longer capable of nourishing and supporting the teeth. " The alkaline treatment (eliminative in character), in conjunction with the usual local measures, is recommended by this well-known authority. CHAPTER XXIV. haig's work. His Three Books. — To the writings of Alexander Haig, M.A., M.D. (Oxon.), F.R.C.P., of London, England, the profession is chiefly indebted for having brought the uric acid subject into the deserved promi- nence it holds. Aside from the numerous articles from his pen, which have appeared from time to time in English and American medical journals during the past few years, are the following three books, which have been read ex- tensively on both sides of the Atlantic; to wit: i. "Uric Acid as a Factor in the Causation of Dis- ease' ' — his main work: a cloth bound volume of 816 pages, containing seventy-five cuts, which has now reached its seventh edition. 2. "UricAcid: An Epitome of the Sub- ject'' — a condensed statement of the main facts as they occur in his former work, and contains 158 pages. 3. "Diet and Food" — a little book of 138 pages, devoted entirely to purin-free foods in relation to " Strength and Power of Endurance, Training and Athletics." Their Popularity. — Haig's views, concerning the influence of uric acid in the causation of disease, have been adopted by the great body of practitioners who have read his main work. The popularity of this book is due in great measure to the evident deep sincerity of its author, to its general lack of technicalities, and its mass of con- vincing clinical experiments. Few medical works of recent times have appeared in which the subjects treated of have been presented in a 218 URIC ACID AND ITS CONGENERS. more readable form. The language is plain, and the thoughts of the author are made so clear that a tyro could readily grasp his meaning. His strong convictions are patent in every page; every paragraph; every sentence. The fact, too, that he has himself been the subject of many of his experiments gives added weight to his inter- pretation of the findings. For many years, he was the victim of severe headaches and it is to his studies into the causes of these headaches and their treatment that he was led to the discovery of the most important facts concerning uric acid. One discovery led to another, until finally, he reached the conclusions which he now so convincingly brings out in his main work. His theories, indeed, are argued with such inherent faith, that they appear more in the nature of established facts. / His Theory. — Haig is of the opinion that if the raw material (nucleins and purins), from which exogenous uric acid is derived, be entirely cut off from the food which we ingest, the body will have no trouble in taking care of that other portion of uric acid (endogenous), which is derived from muscle metabolism and the breaking down of the tissue cells within the organism. He firmly believes that the various uric acid troubles which afflict mankind are due to the introduction of "food poisons"; and, that, if care be taken to ingest purin-free foods only, the organism will be enabled to eventually rid itself of the accumulation of stored-up urates in the tissues, and remain in a healthy condition thereafterward — i. e., so far as uric acid is con- cerned, and provided no more "raw material" is ingested. He has consequently become a strict vegetarian, himself,, and strongly advises all of his uric acid patients (and their number is by no means small) to follow his example. He HAIG'S WORK. 219 claims that, by this means, his own sufferings have been made to disappear, as well as the sufferings of hundreds of others. Concerning Drug Action. — Haig classifies all uric acid disorders under two heads; viz.: I. Collaemic. 2. Arthritic. In disorders of the former class, the urates are still in the blood, and the symptoms are caused by the blocking up of the capillaries with uric acid in a colloid, gluey, or semi-gelatinous form. In those of the latter class, the urates have been precipitated out into the tissues, there- fore the blood is temporarily freed of uric acid. He classes uric acid remedies under two heads; viz.: I. Solvents (heat and alkalies). 2. Precipitants (cold and acids). By means of the "precipitant" remedy, disorders of the "collaemic" class (headaches, etc.) are relieved, owing to the driving out of uric acid from the blood into the tissues. By means of the "solvent" remedy, disorders of the "arthritic" class -(rheumatism, etc.) are relieved, owing to the resorption of uric acid from the tissues into the blood. He says: "There is thus a law that all local precipi- tation diseases are relieved by solvents, and that all col- laemic diseases are relieved by precipitants; in other words, by those things which clear uric acid out of the blood and drive it into the fibrous tissues — these being but two sides of the same process. More than this, by the ad- ministration of solvents or precipitants, we can produce at pleasure a member, either of the collaemic or of the arthri- tic group, and change the one for the other at will. Indeed I very frequently ask patients which they prefer to have, as 220 URIC ACID AND ITS CONGENERS. I know that in curing the one I must produce the other. In serious cases, there is, of course, no choice — one must choose that which is least deadly to life, and that is gener- ally a member of the arthritic group." — (Uric Acid: An Epitome of the Subject, iio-iii). Adverse Criticism. — It will be seen that Haig uses drugs for their temporary effects only. He places his reli- ance chiefly on rigid dietary rules. But we must strongly and adversely criticize his statement: — "J know that in curing the one I must produce the other." It is true, that when the solvent remedv is used in the treatment of rheumatism, — collaemic symptoms (such as headache) will be temporarily produced while the urates are passing en route through the blood. But if this sol- vent remedy be at the same time an el'iminant remedy, the urates, instead of remaining in the blood, are excreted from the body by way of kidneys and bowels. The col- laemic, as well as arthritic symptoms, therefore, will dis- appear when the excess of urates is thus removed. By this method of treatment, we not only drive the urates out of the tissues into the blood, but out of the body entirely. This has been clinically demonstrated to the satisfaction of hundreds of physicians and their patients. Again, Haig is decidedly wrong, in recommending "precipitant" remedies at all. The idea that uric acid headaches can be cured only by driving the urates out of the blood into the tissues, thus producing rheumatism, is an extremely narrow view to take. On the contrary, in- stead of precipitating the urates out of partial solution or suspension, our object should be to render them even more soluble, and, at the same time, aid the excretory organs in their function of elimination. That is, bv means of a HAIG'S WORK. 221 remedy, which increases the alkalinity of the blood, we also render the latter less viscous and the colloid or gelatinous urates, which block up the capillaries, are changed thereby into a more soluble, aqueous form, and may be convey- ed in this way, in solution, to the kidneys and excreted in the urine, which has itself been made less acid and a better solvent of urates in consequence. Thus, we not only remove the cause of the headaches (as Haig does), but we avoid producing the rheumatism (which Haig does not). As physicians, we should not become blinded to the fact, that a person may stop ingesting "food poisons" and yet suffer from the ill effects of these same "food poisons" which he has previously ingested. It would be irrational to claim, that the only way to cure a case of opium poison- ing is to withhold the further introduction of opium. We are not yet willing to admit that there is no therapeutic efficacy in prescribing an "antidote" in such cases. On the other hand, it must be admitted by Haig that it is not always possible, in actual practice, to prevent the ingestion of purin-containing foods. Are we then, in truth, per- forced to accept his dictum: "I know that in curing the one I must produce the other ?" " Must" (in some cases) "produce the other" (temporarily), he might better have said. His Mistake. — In demonstrating so clearly to the medical world the influence of uric acid as a factor in the causation of disease, Haig has accomplished a work that will cause posterity to enroll his name in a list with such men as Liebig, Virchow, Niemeyer, Pasteur, Koch, and other discoverers of some fact or phenomenon of medical importance. But, like the discoverers of a hitherto un- 222 URIC ACID AND ITS CONGENERS. known continent, he has fallen into the temptation of at- tempting too much: he has made an impossible effort to sound all channels, scale every mountain peak, find the source and delta of every stream, look into every inlet and harbor for a safe anchorage, etc. His mistake is in setting out personally upon more ex- ploring expeditions than any single individual could possi- bly complete in a satisfactory manner and which should have been left for others who were not thus handicapped, and who were better situated or more thoroughly equipped to perform the work properly. Haig is not a chemist. Some of his subsidiary theo- ries, based upon far-fetched chemical speculations, are distinctly amusing, or would be, if such credence were not given to his every opinion by the general practitioner. It is owing to some of the crude chemical methods he em- ploys, and the remarkable therapeutic conclusions derived from them, that his entire work has been derided by the physio-chemist and other specialists. They have summed up the whole by judging of some of the unessential parts. This is unfortunate, as well as unfair, for it has led to a much underestimated opinion in certain scientific quarters, of the value of Haig's work. A Singular Contradiction. — In his effort to dis- cover some chemical fact that would fit in with one of his subsidiary therapeutic theories, Haig not only makes an inexcusable physiological blunder, but contradicts himself in a most remarkable manner. He is trying to explain how lithia relieves arthritis, and yet, at the same time, combines in the body with the phosphates, thus causing retention and a lessened excretion of uric acid in the urine. He refers to an ancient chemical treatise, (Rose), in * which he found it stated that, in the laboratory, lithia HAIG'S WORK. 223 " forms a nearly insoluble triple phosphate with hypophos- phate of soda, or with the triple phosphate of ammonia and soda — salts generally present in animal fluids." He jumps to the conclusion that lithia, when introduced into the circulation, probably forms a chemical combination in the nature of these "triple phosphates" and "thus puts out of use" a certain amount of soda phosphate, which normally holds uric acid in solution in the blood. He forgets that these so-called triple phosphates, "in animal fluids," are those of magnesium and ammonia which are found in the urine after voidance and after decomposition has taken place, when the "earthy" phosphates (magne- sium and calcium) are formed, which, being insoluble, are thrown down as a precipitate. It will thus be seen how far-fetched is the chemical fact which he found that would apparently satisfy the demands of his therapeutic theory. But, still more surprising is the following statement which he makes: "Lithia, then, relieves arthritis by clear- ing the blood of uric acid, but not, as was supposed, by eliminating uric acid from the body. We now see that it clears the blood, but retains uric acid in the body." (Uric Acid as a Factor in the Causation of Disease, Fifth edition, p- 58)- Relieves arthritis, by driving uric acid out of the blood into the tissues! He here stultifies himself and contra- dicts his main theory, which appears repeatedly through- out this same work. His chief contention is, and has always been, that any drug, which clears the blood of uric acid by driving it into the tissues, causes arthritis. In this, he is doubtless correct. It would appear, that in order to bolster his unimportant notion regarding the therapeutic action of lithia, he flatly contradicts himself. It is largely 224 URIC ACID AND ITS CONGENERS. owing to these chemical idiosyncrasies, which he has al- lowed to creep into his work, that Haig's reputation as a scientist has been made to suffer from the unfriendly pens of numerous writers. Notwithstanding these minor faults, it is doubtful if any scientific medical work of modern times contains so many important practical truths, or points out so many significant clinical facts, as does this remarkable work of Haig. Value to the Clinical Worker. — While Haig's well-known "vegetarian" views will probably never be- come generally accepted, nor his rigid dietary treatment followed out to the letter, yet much practical good will result from his having attracted so much attention to the subject. The beneficial results he has obtained, by cutting off entirely the food source of exogenous uric acid, can only serve to emphasize in the physician's mind the im- portance of interdicting certain well-known purin-foods in the dietary which he allows his patient. But it should not be forgotten that even the amount of endogenous uric acid normally formed within the body may become excessive, if not properly eliminated, or if the liver becomes tempor- arily disabled and fails to oxidize into urea its due propor- tion (50 per cent.) of uric acid formed from day to day, Nor should we forget that some undue muscular effort or exposure of the surface of the body to a sudden chill, may cause precipitation of the urates in a given locality thus exposed, even though uric acid be present in but slight excess over the normal amount. One great value of Haig's work lies in the clearness and thoroughness with which he has demonstrated how uric acid, by obstructing the capillary circulation, thus HAIG'S WORK. 225 slowing the capillary reflux and causing increased blood- pressure, may become the exciting factor in the production of so many circulatory diseases. That it does so impede the flow of blood, he has proven conclusively. Prof. Haig's experiments upon himself, and others, whereby he has clinically demonstrated by means of "pre- cipitant" and "solvent" remedies that he can actually produce one or the other class of uric acid disorders, at will, are exceedingly interesting and instructive. In other words, he has shown that simply by "clearing the blood" of uric acid by precipitating the same into the tissues, and vice versa, he can reproduce the very diseases that occur in the natural course of events : thus pointing out the fact that the things in Nature which act as precipitants (cold and acids), serve to lessen the blood's alkalescence and cause the precipitation of urates, resulting in rheumatic symp- toms; while, on the other hand, those that act as solvents (heat and alkalies) serve to increase the blood's alkales- cence and cause the resorption of urates from the tissues, relieving the rheumatic symptoms and producing those of the uricacidaemic type, unless the urates are removed from the circulation by way of the excretory organs. It is in aiding the performance of this latter function that the work of the physician may appear in evidence. CHAPTER XXV. THE FOOD QUESTION. Effect of Environment. — In the never-ending struggle for existence, all organic living forms, whether of the animal or vegetable kingdom, are constantly reacting with, and adapting themselves to, their environment, upon which they are dependent for sustenance. This environ- ment may be limited to a square foot of soil, as in the case of the plant, or extended to a square mile or more, as in the case of many animals and some of the human kind, or may include a greater part of the earth's surface, as in the case of the most enlightened modern peoples with international facilities. But, owing to the trouble and expense incurred in obtaining food-substances from a dis- tance, the great mass of human beings look to their more immediate environment for sustenance. As such environ- ment varies in different zones of the earth, so does the character of the food vary among the different nations. Moreover, it will be observed that the fauna and flora, from which sustenance is derived, are always appropriate to the peculiar needs of the organism (in its struggle for existence) in that particular locality. For example, the climatic environment of the Esquimau requires him to avail himself of the adipose-producing (heat-retaining) hydrocarbon elements in food, which he finds ready to hand in the lower cryptogams, and oil and blubber-bearing piscatorial denizens of that region. The indolent dwellers in torrid regions, on the other hand, find in the fruits of their luxuriant flora the carbo-hydrate element ready THE FOOD QUESTION. 227 prepared, requiring little exertion on theirpart to obtain it, thus obviating the necessity of so much nitrogenous (energy- producing) food in the struggle for existence. Owing to the character of their environment (there being a meager fauna) the nations of the East have been forced to obtain the nitrogenous element in food chiefly from the vegetable kingdom (rice); though the palates of the wealthier class are pampered with purin-delicacies, obtained from both the animal and vegetable world, — as the roe of the sturgeon and the alkaloid of the tea-plant, so highly prized by the Chinese. The purin-alkaloid of the coffee bean is used in a similar manner by other vege- tarian peoples. The highly civilized peoples of the temperate zones of the earth still hold largely to the nitrogenous foods of animal origin, entailed as a legacy from their ancestors. The settlers of England and America, during the first century or two, were confronted with an environment that required hard work and they found a rich fauna, which furnished the nitrogenous food-elements essential to the performance of such work. It was natural, right and proper that our ancestors should avail themselves of "the goods the gods provided," and thereby, in their hard strug- gle for existence, obtain essential nitrogenous fuel at the minimum expenditure of energy: in this way, not only ridding the forest of these troublesome and dangerous denizens, but gaining strength whereby to clear away the forest itself and pave the way for future fertile acres, as well as populous cities and towns. From what has been said, it will be seen that what serves as adequate sustenance for the people of one zone may not be sufficient for those of another. The Japanese 228 URIC ACID AND ITS CONGENERS. have proved that foods derived from the vegetable world, when coupled with temperate habits of eating and drinking, tend to produce a hardy and vigorous race but this does not necessarily mean that such vegetable-feeding is the best for the Englishman or the American, whose progenitors for ages have been accustomed to a quite different mode of living. While the Englishman or the American may, doubtless, with advantage, cut down his purin-luxuries to the level of the Japanese, it would be a dangerous experi- ment for either of the former to attempt to deprive himself, all at once, of the nitrogenous food of animal origin to which his digestive apparatus has become so completely adjusted. It would seem, therefore, that man assimilates from his environment that which is obtained along the lines of least resistance, so that different geographical groups of people thrive best on their own particular foods, to which their organs of digestion and assimilation have attuned themselves. This is similar in a general way to what we see in contrasting the foods of the different animal species — the bulkv herbivorous mammal thriving on vegetable matter that the little rodent would starve upon. Vegetarianism. — The facts above mentioned have been referred to here in order to point out one of the rea- sons why the English speaking peoples, as a rule, have carnivorous proclivities — i. e., through the force of en- vironment as well as hereditary descent. Enough has been said to indicate that it would be unphysiological to attempt to change all this in a day: that is, for the entire nation to suddenly become "vegetarians," as some misguided enthusiasts suggest, for, as may be seen, our nutritious needs and digestive capacity have been molded into their THE FOOD QUESTION. 229 present shape as an inevitable result of the reaction of the parent organism with the environment. Though " meat-eating" has borne so conspicuous a part in the development of our people, we cannot be accused of selecting the flesh of carnivorous animals for food, as do some of the vegetarian peoples when desiring a "delicacy." With the exception of fish (and possibly pork), the Anglo-Saxon restricts his choice to vegetable- feeding animals. And even though the vegetarian Chinese eat ypung cats and dogs, as delicacies, yet the animals are quickly fattened on a vegetable food — rice. The natives of Hawaii serve baked dog as a table luxury, but, here, too, the animal is fattened on a vegetable tuber, taro, in the form of "poi." The result, in both cases, is a tender and toothsome meat, much like pork. Modern Conditions. — The environment of our ancestors of a hundred years ago, was quite different from that to which the organism must adapt itself today, es- pecially in the more populous centers. While our sturdy forefathers had a restricted environment, from which they selected the muscle-fuel most needed in their struggle for existence, we have an almost unlimited environment which furnishes fuel of every kind to meet the varied re- quirements of modern life. Moreover, it must be remembered that evolutionary change has been going on, not only in our sociological development, where men are engaged in entirely different pursuits, mental and physical, but in the physiological needs of our organism, which must undergo corresponding change. A century or more ago, men struggled along very nearly the same lines, and their food requirements were very much alike. Today, the inhabitants of a single state 230 URIC ACID AND ITS CONGENERS. are so differently conditioned in the struggle, that it would not be a stretch of the imagination to class them under different species — from a physiological standpoint. Their conditions in life may be so widely different, that two men residing in the same American city may be further apart in their food-requirements, than is the average American from the Chinaman. While, therefore, it will be seen that "what was good enough for father, is good enough for me," is hardly a safe guide for correct eating, neither is it practicable to lay down any specific feeding-rule (such as "vegetarianism") that all can follow. Our environment, which has grown so enormously in its complexity, necessitates a corresponding growth in the ability of the reacting agents to adapt them- selves to this changed condition and he, who would not fall by the wayside, must train his organism to meet these varied requirements. In a general way, a mixed regi- men is essential, but, owing to the division of labor in highly civilized communities, the amount and relative proportion of the ingredients will vary, according to men- tal and physical requirements, — the nitrogenous element (of animal origin) predominating in one case and that of vegetable origin in another, carbo-hydrate material in an- other, much of the inorganic salts in another, fat in an- other, etc. In short, no single menu will answer the pur- pose for all, nor for the same individual at all times. Purin Feeding. — While our parents necessarily in- gested a certain proportion of purin-substances with their meat-eating, it is doubtful if they introduced into their system in this way much more waste extractive than do the vegetarian peoples, with their purin tea, coffee, etc., and, even if they did, their physical activity and out-of- THE FOOD QUESTION. 231 door life served to keep open the avenues of escape and prevent accumulation. Meat was eaten for sustenance: for the strength-giving properties of its muscular tissue. The sweetbreads, fries, and other glandular organs were thrown away. What are now considered purin-delicacies were then deemed unfit to eat. The great packing houses of the "beef trust," today, make up into "food" every portion of the animal, from the tip of his nose to the heel of his hoof, and all this is "pre- served" or "canned" and sent broadcast throughout the land. Nothing is wasted, not even the blood. It is said that the only part of the pig which is not turned into account, is his "squeal"! And there is a constantly growing demand for all these so-called "purin-delicacies." The chefs of the great city hotels, restaurants, rathskellers, and private palaces, have become very expert in concocting animal refuse into "toothsome" dishes to tickle the palate of the after- theater and other midnight patrons, who are out in quest, not of food, but something in the way of a "fourth meal" that can be washed down with a relish. Why is this ? Simply because there are so many supernumerary individuals born today whose struggle for existence consists in the mere search for something to pander to an appetite that has become depraved through the lack of necessity to perform any legitimate object in life. But the stern laws of Nature will eventually rid the earth of such incumbrances. This will be done through disease. The man who overloads his blood with fuel that cannot be utilized, must sooner or later bank the fire and much more so he who shovels in ashes and clinkers at the same time. 232 URIC ACID AND ITS CONGENERS. If these pleasure-seeking supernumeraries were the only people to thus destroy themselves, no harm would be done but, unfortunately, the enormous quantity of purin- stuff in the market and the success of modern cookery in preparing animal refuse in palatable form, has resulted in establishing the pernicious purin-eating habit. Many people indulge in these dishes under the mistaken notion that they are ingesting nitrogenous nutriment in concen- trated form. By thus loading the system with animal purins in food-stuff, and vegetable purins in table-drinks (tea and coffee), taken in conjunction with over-feeding and a sedentary life, it is not surprising that gout, rheuma- tism, and other metabolic disorders are becoming so prev- alent. The Remedy. — Instead of committing the people to "vegetarianism" exclusively, the physiological remedy lies in the direction of a purin-free mixed diet. Man, as the highest of the mammalian scale — surrounded with the most complex environment and having the most com- plex organism by which to adapt himself — is not meant to become an herbivorous animal nor to feed on fruits and nuts, like the frugivorous or granivorous rodent, nor on flesh food, like the carnivora: — He is capable of living on all and is entitled to the best of all. If the same care and skill that has been shown by the "beef trust" and expert chefs in utilizing all animal refuse for food, were given toward removing all purin-waste from meat that is to be eaten, a kind of sustenance would re- main, not only capable of easy digestion but furnishing nitrogenous food-elements in the most acceptable form. Of course, the proportion of flesh-food of this kind which should be combined with the nitrogen and carbo-hydrates THE FOOD QUESTION. 233 of the vegetable kingdom to make up the proper mixed regimen, would depend on the needs of the organism of each individual — i. e., whether his nerve-force or muscle- energy needed replenishing chiefly; and this would de- pend largely on his vocation and manner of living. A system of food-education is needed. The govern- ment should see that all foods manufactured or prepared for public use should be free not only from so-called "poisons" but from so-called "purins," which are almost equally poisonous or, at least, almost equally toxaemic. Chefs should be required to educate themselves along the lines of proper food preparation, just as the druggist is required to understand the compounding of medicines — using the "poison" or "danger" label on goods that call for it. The people, themselves, should be instructed in the public-school course, learning the composition of food substances, so as to be enabled to determine the propor- tion of each element in a mixed regimen, which may be physiologically indicated in a given case. While all this may seem visionary; yet, as evolution- ary progress points toward the desirability of such know- ledge, we can see no reason why it may not come to pass sometime in the distant future. At all events, the neces- sity for self-defense becomes more urgent as the competition in the struggle for existence grows keener, from day to day; and the time approaches when the minority will be de- feated, — i. e., they who fight for personal wealth at the expense of the public health. CHAPTER XXVI. DIETETICS. General Rules. — In the dietetic treatment of "purin excess," the general practitioner seldom finds two patients thus afflicted who require exactly the same regi- men but he will find many cases wherein certain food- substances should always be interdicted and in which certain general rules will always apply, for example: i. No exogenous purins should be needlessly intro- duced into the organism. 2. No article of food nor drink should be ingested that causes gastro-intestinal fermentation, flatulence, epigas- tric distress, constipation, or insomnia, in a given case. 3. The daily quantity of food ingested should never exceed the digestive capacity of the patient; while the quantity digested should never be in excess of the daily physiologic needs of the organism. 4. A mixed regimen (both animal and vegetable) is usually indicated. 5. The proportion of flesh food allowed should de- pend on muscular requirements. 6. No acid food nor drink should be allowed, nor any food, drink, medicine, etc., which lowers the blood's al- kalescence or increases the acidity of the urine. 7. With the above exceptions, the dietary should correspond in a general way with that to which the patient has long been accustomed. If it be true that the symptoms complained of in a given case are due primarily to the failure of the organism. DIETETICS. 235 from one cause or another, to free itself of purin-waste properly, so as to prevent capillary obstruction or con- sequent uratic depostion, then it is obviously the duty of the physician to see that his patient does not introduce purin food-products unnecessarily into the system; for it is manifest that our medicinal means will prove more effective in aiding the organism to rid itself of an excess, provided such excess is not increased by an extraneous supply. As carbo-hydrate feeding is contraindicated in dia- betes, so are purin-containing foods contraindicated in purin excess. In one case, we wish to cut off the supply of raw material from which sugar is manufactured within the system; in the other the raw material from which uric acid is obtained. Practical experience has shown that bread, potatoes, other starchy foods and sweet materials, aggravate the diabetic symptoms; while, it has been like- wise demonstrated that fried meats, meat soups, extracts, gravies, coffee, tea, acid foods and drinks, aggravate the uricacidaemic, rheumatic, or gouty symptoms. In one case, the trouble appears to be due to faulty carbo-hydrate metabolism; whereas, in the other, purin catabolism and elimination seem to be at fault. Uricacid^mic Patients. — Inasmuch as the symp- toms in the primary stage are often transient in character, being those caused chiefly by an impeded flow of the blood- current through the capillaries, resulting in local pain from distension and pressure, and in sluggish action in the tissue cells from accumulation of waste, — it will be seen that the principal therapeutic indication is to remove the obstruction at once by conveying it away in the circulation. This uratic impediment, being as yet in non-crystalline 236 URIC ACID AND ITS CONGENERS. form, can usually be taken up and removed in a short time. The patient, therefore, may well afford to deny himself of certain table-luxuries, or even what he con- siders table-necessities for a few days, if he is assured of obtaining more speedy relief of the symptoms thereby. The less the amount of nutrient material introduced into the blood-stream at this time (during the few days referred to) — i. e., the less solid or semi-solid matter to be conveyed by the circulating medium through the capillar- ies — the more dilute will be the blood and consequently a better solvent by which to take up the obstruction and remove it. In short, the freer the circulation of food products (even though the latter be assimilable) the greater the opportunity for purging itself; in other words, the blood should never be overloaded with chylous nutriment at these times. From this it will be seen that the diet of the uricacid- aemic patient, during the treatment of the acute symptoms, as an attack of migraine, should not only be comparatively free from purin-containing substances but considerably restricted in the daily quantity of other foods allowed, especially tissue-making material — nitrogenous foods. Such carbo-hydrate materials as contain the alkaline salts or organic acid bases which are known to combine with the carbonates of the blood and form alkaline salts, are in- dicated — such as the citrates in many garden fruits. Foods containing starch and sugar should not be eaten in sufficient quantity to cause gastric fermentation. In order that the alkalies contained in them may combine as bases with the free uric acid in the urine, such vegetables as cabbage, cauliflower, turnips, spinach, etc., may be eaten by patients subject to gravel or calculi. Alkaline drinks, DIETETICS. 237 (vichy, soda) or lime juice and water should be recom- mended, as well as plenty of plain water. A very good menu may be selected from the following articles, for breakfast: — cornmeal mush, oatmeal gruel, gluten cakes, soft-boiled egg, stewed prunes (sweetened with saccharine, dissolved in water before preserving), "poi" cocktail. For dinner or luncheon: — raw oysters, little neck clams, ripe olives, vermicelli soup, vegetable soup with rice, boiled brook fish, roasted fowl, baked potato, squash, turnip, carrots, new corn, lettuce, spinach, custards, tapioca. It is, of course, understood that the patient is to indulge sparingly and that any idiosyncrasy is to be respected. Rheumatic Patients. — In the secondary stage of purin excess, the circulation becomes, from time to time, comparatively free from uratic waste owing to its precipi- tation out of solution and consequent deposition into the tissues; but, as the blood speedily regains its normal al- kalinity after such temporary withdrawal of urates, the latter are resorbed into the circulation which again be- comes subalkaline and the urates are once more thrown out of solution and deposited in the tissues at some other locality: and thus the process continues (deposition, re- sorption; deposition, resorption) until Nature, herself, succeeds unaided in eliminating the urates from the sys- tem via the urine (i. e., by repeated "explosions"), or until aid is furnished by means of a rational dietetic and medicinal treatment. It will be seen, therefore, that the same general plan of feeding may be recommended for the relief of acute attacks, or exacerbations, here, as has already been sug- 238 URIC ACID AND ITS CONGENERS. gested for the removal of capillary obstruction in the primary stage. That is, the blood-stream should be bur- dened with as little chylous nutriment as possible under the circumstances, and, as far as practicable, should be fur- nished with no exogenous purins nor other material that tends to acidulate. The rules regarding the quality and quantity of foods ingested, are equally applicable in both cases — i. e., during the two or three days', or a week's treatment. Chronic Cases. — While the above-recommended re- stricted diet (or one even much more restricted) may be insisted upon for a brief period, and directions will usually be religiously observed by the patient, during the few days essential to the handling of his case until subsidence of the acute symptoms, yet it will be found that in the pro- phylactic treatment of such cases, as well as in the more prolonged treatment of chronic cases, that a somewhat different feeding-plan must be adopted. Physicians will readily recognize that the rheumatic stage of purin excess furnishes more chronic cases, ob- stinate to treatment, than all other disease-processes com- bined. The patient has usually reached an age when habits have become firmly rooted, and which, in the great majority of instances, cannot be suddenly uprooted nor radically altered without injury. Immediate denial of many or all of the accustomed table-viands may be found necessary to the treatment indicated at the time of an exacerbation of the symptoms and will generally prove satisfactory in results, but it would be impracticable and, perhaps, disastrous, to attempt the same thing in those cases in which we wish to establish a more prolonged, possibly, permanent dietary. DIETETICS. 239 In the cases under discussion, the patient is not us- ually bed-ridden, but is enabled to be up and around and, probably, to attend to business. We refer to the so-called " office patient," in whose case the trouble may have ex- isted for one year, ten years or more. "Stiffness" in muscle or joint, "aches and pains" in various localities, constipation, "biliousness," etc., are some of the symp- toms commonly complained of. In our efforts to afford substantial relief in these cases, we may greatly aid the therapeutic measures employed by combining the same with a rational dietary. If the patient always gained an intelligent comprehension of his physi- cian's wishes in this matter, and a feeding-plan were sug- gested that could be followed out in a given case and ob- servations made that directions were being obeyed, — the question of "diet" would no longer remain relegated to the position of neglect it now occupies in the clinical hand- ling of these "chronic" cases of the rheumatic stage. One of the most significant modifications that can be made with profit in the. dietary of most of these patients is a reduction in the daily quantity of food ingested. In a paper, on "The Importance of a Study of Nutrition," read before the New York Academy of Medicine, Oct. 9, 1905, Prof. R. H. Chittenden, of Yale, says: 'There is a great tendency to an overaccumulation of reserve material in the blood. It is easy, in enriching the blood by food, to overenrich it, to cause, through oversupply of food mater- ial too much chyle and other material to enter the blood. My own observations in this direction, continued now for several years, lead me to believe that there is much of value to be learned in a study of the minimal quantities of food required to maintain health and strength. The real needs 240 URIC ACID AND ITS CONGENERS. of the body for food are unquestionably much below the amounts ordinarily consumed and, this being true, one may well ask the question, does not this excess of food, for which the body has no physiologic need, in the long run imperil the health of the individual, diminish the ordinary powers of resistance, and so pave the way for various forms of disordered nutrition, which we speak of as dis- ease?" (Cf. American Medicine, Nov. II, 1905, p. 818). From his elaborate feeding experiments, which have so attracted the attention of the scientific world, Prof. Chittenden has proven that but little more than one-half the total amount of nitrogen hitherto deemed absolutely essential to physiologic needs, is required to maintain health and strength to the highest degree. However, we have long felt positive that one of the principal aetiological factors to be reckoned with, in accounting for the chronic- ity of the rheumatic stage of purin excess, is not altogether the ingestion of raw material from which uric acid is formed, but also (and to no inconsiderable degree) the ingestion of too much nitrogenous food (both animal and vegetable) as well as all other food-essentials. In short, our patients are inclined to overeat and do overeat. In fixing upon a regimen for any given case, the quantity allowed will depend to some extent on the pre- vious habits of the patient in that respect. If always a heavy eater, he may require for a time more than the average individual but less than he has been accustomed to. The proportion of nitrogenous food, essential to the needs of the organism, will be greater in the case of the individual who uses up muscular energy, than he who expends brain force but, in nine cases out of ten, the laboring man greatly exceeds physiologic requirements, as does his sedentary neighbor. \ DIETETICS. 241 From the animal kingdom, milk and eggs furnish abundant nitrogen and are purin free. The man of brawn will probably demand his meat, and with good reason; but he may be instructed in the manner of cooking it, so that the unbound purins will be removed. He should be made to understand that the glandular meats and meat extracts furnish little or no nutriment, but on the contrary are exceedingly rich in both bound and unbound purins. In short, the patient should have it fully explained to him why certain materials are not foods at all: that they only serve to aggravate his condition. Many sedentary patients require only a relatively small proportion of animal food and, even such as should be considered essential in a given case, may be either purin- free (as milk and eggs), or cooked in such manner (boiled) as to be comparatively free of unbound purins. In any instance, where a radical change in the diet be considered advisable, the change should be madegradually: introducing the new articles of food after some lapse of time, without producing" digestive disturbances. Further- more, it must be understood that no food substance of whatsoever nature be allowed, which the patient has learned from past experience is likely to disagree. Peas, beans and lentils, when ripe or dried, likewise peanuts and mush- rooms, are some of the articles that ought to be prohib- ited, not only because of the purin raw material which they contain but because of their indigestibility . Meat soups of all kinds, being strong solutions of uric acid (xanthins), should be absolutely forbidden. Adult meat is preferable to young meat (veal, etc.), and should be boiled or roasted — never fried. Fish, poultry and game birds are better than butcher's meat. 242 URIC ACID AND ITS CONGENERS. Gouty Stage. — In this, the third and last stage of purin excess, although the dietetic treatment resembles in a general way that which has already been suggested, yet, in one important particular, the gouty individual must be much more careful, and that is in regard to the restriction of such food-material as tends to add to the dialyzing work of the kidneys — especially the epithelial cells lining the renal tubules. The many attempts to rid the system of purin waste (most of it needlessly introduced) have been so long and so oft repeated, that the epithelium of the renal tubules (by means of which such waste is dialyzed) has finally become injured, so that not only are nitrogenous molecules in the intermediately oxidized form of uric acid, imperfectly ex- creted, but also nitrogenous molecules in the completely oxidized form of urea. In those cases, which we recognize as "gout," "Bright's disease," "renal colic," "calculi," etc., the kidneys have become not only incapable of excreting an excess of uric acid or of urea, but incapable of excreting a normal quantity of each — -i. e., that resulting from tissue catabolism. The constant overwork forced upon the dial- yzing cells of the tubular epithelium has resulted in weak- ening them to a degree that even an average amount of work is illy performed so that eventually urea itself, as well as uric acid is retained. It is evident that the kidneys, in these cases, will have enough to do in eliminating (by aid of our medicinal treatment) the nitrogenous waste already retained in the system, without having their work increased by adding nitrogen from without. In short, the dietary of gout, es- pecially in the advanced stages, should consist of as little DIETETICS. 243 nitrogen as is compatible with the health of that particular individual. Fried meat, meat and bean soups, glandular organs, foods and drinks that acidulate the blood, are absolute "poisons" in these cases. Inasmuch as the majority of these patients expend but little muscular energy, the pro- portion of nitrogen allowed in their dietary (during the eliminative treatment) should be cut down to at least one- fourth of the amount to which they have been accustomed. In fact, we believe that a strict dietary, like Haig's (but with less albumin), would prove advantageous in these particular cases. Evils of No-Flesh Diet. — -In an address, delivered Feb. 17, 1906, at the Harvard Medical School (Cf. St. Louis Med. Rev., March 10, 1906), BaronTakaki, Surgeon General of the Imperial Japanese Navy, shows very clearly that the dread disease "beri-beri," which has so long been a scourge to vegetarian peoples, is caused largely by errors of diet, especially to the lack of a proper proportion of flesh food. In 1884, a new regulation was issued by the Japanese Medical Corps, which allotted to the men of the navy a con- siderable increase in bread and meat ration. Previously to this time, they received thirty-six ounces of rice and only five ounces of meat or fowl daily. Under the new regulation, a twelve ounce meat ration is allowed. The death rate of beri-beri per thousand used to be very heavy; whereas, now, there have been only three cases in the last five years in the navy. This disappearance of beri-beri has been accom- panied with the disappearance also of certain intestinal diseases from which they used to suffer. " Before the new diet was established," says Baron Takaki, "the men of the Japanese navy could not stand the winters. Now they are able to stand them as well as the men 244 URIC ACID AND ITS CONGENERS. of any other nation. In addition to the usual supply of rice the men now are given barley, a food which they did not have before; as well as more meat. The ration is rice, twenty- four ounces; barley, eight ounces; and meat, one pound, in the navy. The army tried the experiment of giving more meat and no barley; but comparative observations showed that the death rate was not lowered under this treatment." From these experiences, above reported, we learn something of the value of a mixed diet for men engaged in active pursuits. Not only is an average quantity of flesh food indicated, but vegetable proteid in more than one form or combination. The original ration of rice alone (with in- sufficient flesh allowance) furnished 1152 grains vegetable proteid while the new ration of rice and barley furnished but little more — 1224 grains. We judge, therefore, that it is not so much the increased quantity of proteid that is bene- ficial, as the different form in which it occurs. Further- more, the increased amount of vegetable proteid in the new diet requires but thirty-two ounces of vegetable food, whereas thirty-four ounces were ingested before. In short, it is decreased quantity plus improved quality of the food that has proved beneficial. It will be seen that a no-flesh diet is contraindicated under normal conditions; yet, of course, it may be resorted to temporarily in certain diseased conditions, more espec- ially in the gouty stage of purin excess where the work of the kidneys, in dialyzing nitrogenous waste molecules, should be rendered as easy as possible. Indeed, in these cases, a no-proteid diet is indicated, temporarily; for the kidneys should be given no additional nitrogenous work to perform during the interval in which we are attempting to aid the system in eliminating stored-up nitrogen by way of the various channels of exit. CHAPTER XXVII. ETIOLOGICAL THERAPY. Definition. — Though the mere coupling of the two words is, probably, in itself, enough to suggest the meaning of the term, "^Etiological Therapy," nevertheless, it is so essential to our purpose that there should be an intelligent comprehension of the idea we wish to convey by thus using the expression, that we have taken the liberty of coining a special definition of our own; to wit: As therapy means "the treatment of disease," and aetiology, "ascertainment of the cause," then the term "iEtio- logical Therapy," may well be defined as Treatment of Disease by Removal of the Cause; or, at least, by ascertain- ing the cause and attempting to remove it. Exciting ^Etiological Factor. — In the preceding pages, it has been shown that the symptoms and physical signs of the various disturbances, classed under the general head of "Purin Excess," are due to a common cause — i. e., the presence, at some point in the circulation or tissues, of an excess of nitrogenous uratic waste in either amorphous or crystalline form. We have seen that, floating in the blood-current throughout the vascular system, the urates in the arterioles are intermixed with colloid food-material, and in the ven- ules with colloid tissue-detritus, tending in this way to ob- struct the capillary flow — as in the "uricacidaemic" stage; and, whenever the reaction of the blood at such points of obstruction becomes suddenly lowered, from exposure of the part to influences of cold, absorption of acid material, 246 URIC ACID AND ITS CONGENERS. or from muscular activity, the urates are precipitated out of solution and deposited in the adjacent tissue-structures — as in the "rheumatic" stage; and, if such deposition, oft repeated, takes place in the poorly oxygenated distal small joints, subject to strain, pressure, and sudden dealkaliza- tions of the surrounding synovia, crystallization occurs and concretions are formed — as in the "gouty" stage. In each case, it is obvious that the subjective symptoms may be traced directly and ascribed almost entirely to the mechani- cal irritation or interference of a mass of urates, either in the way of pressure against nerve-tissue or by preventing ingress or egress of blood by way of the capillaries; though, of course, it may be said, that the nerve-disturbance and metabolic-inactivity could possibly be due in part to some chemical action, such as may be produced by ammonia, which is known to be liberated during the process of purin catabolism. The objective signs, such as discoloration of the skin and conjunctivae, or a scant, high-colored urine, etc., are due to the same mechanical factor which, by impeding the capillary flow, restrains glandular action (especially of liver and kidneys), and consequently the blood and urine con- tain subcatabolized products and pigments which cause discoloration. In short, it will be seen that the exciting aetiological factor, in all of the abnormal conditions we are considering, is the presence of an excess of nitrogenous waste in the form of urates — usually "stationary at some point. From all this, it is manifest that one of the first require- ments of our "^Etiological Therapy" is to institute such measures as will best succeed in freeing the blood and tissues, at any point or points, of uratic excess, whether in ^ETIOLOGICAL THERAPY. 247 the colloid state or in crystalline form; and to remove it from the body entirely. But that is not all; for such removal is effective for only the time being. The same condition of affairs (presence of uratic excess) may be repeated, unless, in addition, some more radical means are taken to prevent. In other words, it is necessary to ascertain the predisposing causes and attempt their removal also. Predisposing ^Etiological Factors — Any agency of whatsoever nature, to whose direct or remote influence the presence of an excess of urates can be shown to be due, may properly be considered a "predisposing aetiological factor" in the cases under discussion. For instance, overeating leads to the introduction into the blood- stream of more chylous nutriment than can be utilized by the tissues, so that the returning capillaries contain over- plus fuel in addition to the normal uratic waste, which, together, may choke the flow, the uratic portion being likely to become precipitated; that is, by "stoking up" the human furnace with more fuel than can be burned, we are likely to "bank the fire," especially if the grate is allowed to become choked with the ashes and clinkers of uratic combustion. Persistent neglect in giving heed to Nature's notifi- cation, that the fecal reservoir is full and needs attention, often leads indirectly to the production of urates in excess and their deposition at some point. The retained fecal mass is constantly losing by osmosis much of the absorb- able portion that would otherwise be excreted with the egesta. This absorbed material not only acidulates the blood, lowering its reaction and tending to cause precipi- tation of the urates; but it must, of course, be eliminated 248 URIC ACID AND ITS CONGENERS. chiefly by way of the kidneys, increasing the amount of work performed by the renal epithelium, which work, being of an unusual character, may injure the delicate cells in their dialyzing capacity and eventually cause retention of the urates. The liver, too, is burdened with the ad- ditional duty of metabolizing this absorbed material into forms less toxic, and may itself become injured in the work, eventually losing the power to oxidize into urea its normal proportion (50 per cent.) of uric acid, thus leaving the latter in excess in the circulation. Again, owing to the pressure of the distended colon against the iliac veins, the return venous flow of the lower extremities is partially checked, thereby causing stasis favorable to the deposition of urates in those parts. It will be seen, therefore, that constipation is one of the important "predisposing aetiological factors" which must be taken into account, if our aetiological therapy is to prove successful. It is not alone the "errors of omission" (such as neglect to keep open the sewers) that may serve to injure the liver and kidneys in this way; but also "errors of com- mission." For instance, the introduction of certain sub- stances into the system by way of food, drink, or drugs, may lead to the evil consequences we wish to avert. Over- plus food material, useless food material (especially the purins), certain beverages (as coffee, alcohol, acid drinks, etc.), and many toxic drugs (morphine, coal-tar antipy- retics and analgesics, etc.), may eventually so cripple the hepatic and renal functions, that increased uric acid pro- duction added to deficient uric acid elimination gives rise to an accumulation of urates in the system sufficient in amount to produce serious consequences. In fact, the "gouty" stage itself, may be reached, through these in- ^ETIOLOGICAL THERAPY. 240 dulgences or "errors of commission, " in a very short period of time. Alcoholic excess, in conjunction with the "purin-eating" habit, is probably one of the most common exciting causes of hepatic and renal insufficiency, which in turn are predisposing aetiological factors to be reckoned with in our aetiological therapy. From what has been said, it will be seen that three of the predisposing causes to be removed in the treatment of purin excess, are overeating, constipation, and hepatic- renal insufficiency. As overeating and constipation, how- ever, are themselves often responsible for the faulty action of liver and kidneys, it would, perhaps, be more practicable to limit our therapeutic study to the consideration of such measures as will succeed best in restoring the normal function of liver, kidneys and bowels, or, at least, aid them in the performance of such natural function. iNCiDENTALiETiOLOGiCAL Factors. — Under this head, we mean to include such causative agencies as are likely to be operative only at occasional intervals, produc- ing effects which are usually sudden and transient in char- acter: that is, effects which are more or less immediate, and in which the causes themselves suddenly disappear. In these cases, the aetiological factor being already withdrawn at the time the patient presents himself for relief, we cannot, of course, remove it as in the other instances described: we can only treat the effects and caution the patient to hereafter avoid exposure to like influences. Under this class of "incidental aetiological factors/' we may mention here two or three of those which are thought to be the most common, and with which it would be well for the physician to make his "purin excess" 250 URIC ACID AND ITS CONGENERS. patients thoroughly acquainted; to wit: (i) Exposure of a part or of the entire surface of the body to cold, or to cold and dampness combined; (2) Violent or unusual mus- cular efforts; (3) Holding the body or one of its mem- bers in a constrained or awkward position or attitude for some time, causing pressure upon the veins at some point, thus serving to prevent the return venous flow below, which is likely to result in capillary stasis or obstruction,, and uratic deposition — as when sitting in the well-known "cross-legged" position. In the particular instance last mentioned, the evil con- sequences are likely to be precipitation of the urates into the gastrocnemii of the calf, producing night cramps of the foot or leg, or, possibly, initiating an attack of podagra. Summary. — In summing up the subject, it will be seen that our "aetiological therapy" may be conveniently grouped or studied under three principal headings; viz.: 1. The use of effective medicinal or other means to remove from the circulation or tissues the exciting aetio- logical factor itself. 2. The adoption of such measures, hygienic, dietetic and therapeutic, as will tend to prevent or relieve the evil influences of predisposing aetiological factors, especially in the way of aiding or restoring the normal function of liver,, kidneys and bowels. 3. To caution against exposure to certain incidental aetiological factors, at the same time treating symptomati- cally the ill effects already produced by them. CHAPTER XXVIII. CURRENT THERAPEUTIC METHODS. Nosological Basis. — Before studying, in its clinical details, the treatment of purin excess based on a rational "aetiological therapy," as briefly outlined in the last chapter, we will first consider the methods now in vogue, based on an entirely different and irrational nosological therapy. Our medical nomenclature is altogether an arbitrary affair, such a scheme of name-grouping or classification being resorted to, not only in pathology, but in botany, chemistry, and other sciences, for convenience of study. But this simple fact has long been lost sight of and it is now the custom to treat the names of disease rather than the abnormal condition itself. That is to say, our text-books recommend a certain line of treatment for all disorders bearing the same name, notwithstanding that they may be and possibly are, in many instances, due to quite different aetiological factors, which are still in active operation, and instrumental in keeping up the chronicity of the given trouble. Or again, and what is much worse, we turn to volume one, two, or three, of any system of medical prac- tice, which volume may be devoted especially, for instance, to diseases of the respiratory tract, and there find grouped under their respective headings, such disease-names as, "chronic nasal catarrh," "chronic bronchitis," "bronchial asthma," "hay fever," etc., with a similar treatment rec- ommended for all of the same name, but a different treat- ment for those of different names, notwithstanding the fact 252 URIC ACID AND ITS CONGENERS. that the latter (though differently named according to the anatomical character and locale of the tissues affected) may be due to precisely the same cause, which is still present and in active operation. In short, the arbitrary method of classifying and naming diseases according to the anatomical tissues affected, has led to the irrational plan of treating alike those diseases bearing the same name, while those of unlike names are differently treated. For example, we are taught to treat bronchial asthma along certain definite lines, and lumbago along certain other definite lines. Because differently named, they are considered to be two distinct and separate diseases, requiring different medicinal treat- ment. But it should be understood at the outstart, that it is not the name that ought to decide the line of treatment. We know, that, oftentimes, the same medicinal treatment will prove effective in both bronchial asthma and muscular rheumatism (notwithstanding their different names) since they are frequently due to a common aetiological factor — a factor which may be removed in both cases by the same effective medicinal means. A Source of Therapeutic Error. — If diseases bear- ing different names were always, or even generally, caused by different aetiological factors, no great harm would arise from the fact that different lines of medicinal treatment are recommended in our current text-books in such cases; but, as a matter of truth, widely different tissues from an anatomical as well as histological standpoint are subjected to the same systemic aetiological factor, and the same internal treatment will be required to remove that irritant factor (mechanical or chemical) and effect a cure of the diseased condition in each case. For illustration, the tissues of the CURRENT THERAPEUTIC METHODS. 253 phalangeal joints of the metacarpus or metatarsus, as well as the tissues of the glandular organs will both be affected in their peculiar way whenever the circulation is impeded at either point, thus interfering with the supply of nutrition and removal of waste. The treatment should be the same (i. e., eliminative) in both cases, notwithstanding the widely different character and locality of the tissues involved and the different disease-names usually applied. Under the irrational plan of therapy now in vogue, no one would think of treating a disorder of the finger or toe joints by the same medicinal means as used in the case of the glandular organs. And yet, we know that the "gouty" toe joint and "gouty" liver or kidney often go hand in hand. Symptom Therapy. — There must, of course, be some definite plan or system observed in the naming of disease and, while our present system is not the best, it has become thoroughly established and doubtless will remain for many years to come. But it must not be forgotten that the disease-titles now in use, are simply descriptive of the principal symptoms or of some physical aspect presented. In fact, the name represents or portrays the outward effects or manifestations of the disease rather than its inherent nature or causation. For instance, such signs as heat, swelling, color and pain (inflammation) suggested the adoption of the Greek termination itis, added to the anatomical name of the tissue thus affected, as in the terms, "bronchitis," "peritonitis," "tonsillitis," "cellulitis," "pleuritis," "pneumonitis," "urethritis," "meningitis," "otitis," "pharyngitis," "appendicitis," "nephritis," etc., etc. Sometimes the Latin term was used instead, as in pneumonia, diphtheria, hysteria, etc. Again, the Latin suffix, meaning "to flow," was added to the word-root '254 URIC ACID AND ITS CONGENERS. indicating whether the flow was checked or increased, as amenorrhea, leucorrhea, otorrhea, etc. In case of pain, a similar term was used to suggest that symptom, as neuralgia (nerve pain) myalgia (muscle pain), odontalgia (tooth-pain), etc. The word "fever" is often added to some physical characteristic of the complaint, as scarlet fever, typhoid fever, malarial fever, spotted fever, etc. Again, a descriptive term of some physical peculiarity of the disease is adopted, as smallpox, measles, chickenpox, whooping cough, croup, etc. It will be seen that in recommending the same treat- ment for diseases of the same name, our text-books are simply teaching us to treat similar symptoms alike. We know that this is unscientific, for the same symptoms are oftentimes quite differently caused and require different medicinal treatment to remove such cause. It is not the effect, but the cause that demands our chief attention, if we expect to attain a complete cure and afford permanent relief. We know, for example, that the symptom, "inflam- mation," which is the one most commonly adopted in naming diseases under our present system, may be caused by a hundred different irritant factors, and it is unreason- able to expect that these different etiological factors can all be removed by the same medical treatment. Or, on the other hand, many different symptoms may be caused by the same irritant factor, the symptomatic evidence depend- ing on the anatomic character and location of the par- ticular tissue involved. For instance, an obstruction of the blood-current may cause headache, or insomnia, or both, when occurring in the cerebral capillaries; leg or foot cramps, if in the vessels of the lower extremity; "bilious- CURRENT THERAPEUTIC METHODS. 255 ness," if in the hepatic or portal vessels; hemorrhoids, if in the rectal veins; scanty urine, if in the renal vessels, and so on. According to our modern nosological or sympto- matic therapy, these different manifestations would call for quite different medicinal treatment; but, according to the rational aetiological therapy, suggested in our previous chapter, the same medicinal measures should be employed in each instance, i.e., when due to a common cause. In the "uricacidaemic" stage of purin excess, we have such different disease-names or symptoms, as migraine, neurasthenia, hypochondria, insomnia, coryza, anaemia, odontalgia, neuralgia, etc. According to the present plan of therapy, these conditions are treated differently; but, if our plan of "aetiological therapy," as suggested in the last chapter, be followed out, they will oftener than not be treated alike. Under the old regime, when fever and pain are prominent symptoms, analgesics or antipy- retics are given; for anaemia, a tonic; for insomnia, an hypnotic; for neurasthenia, hysteria or hypochondria, a sedative; for coryza, an antipyretic, analgesic, antiphlo- gistic or alterative, either singly or combined. Such treat- ment relieves temporarily, simply because it masks or neutralizes the symptoms. The cause itself is allowed to remain. In the "rheumatic" stage, we have scores of differ- ently named diseases, according to the locality affected and the predominence of one or more signs, as arthritis, myal- gia, lumbago, sciatica, bronchitis, tonsillitis, etc. But, as may be seen, these are only symptomatic titles, given according to the locality and anatomic character of the tissues affected. Under our "aetiological therapy," w hen similarly caused they would all be treated substantially 25 6 URIC ACID AND ITS CONGENERS. alike, so far as internal medication is concerned. Though the symptoms of the rheumatic stage may vary, therefore, according to the histologic nature of the tissue-structures where the precipitate occurs, thus leading to different manifestations and their corresponding different disease- titles, yet the aetiologic factor itself (i. e., the uratic deposit) is practically the same and calls for the same solvent or eliminant measures to effect its removal from the given location. This does not mean that the eliminant agent is used in the sense of a "cure all," for, on the contrary, it is indicated only for a single purpose. Notwithstanding the various manifestations that are made to disappear, only a single cause is removed. Again, in the last, or "gouty" stage, we are confronted with such symptomatic disease-titles, as podagra, rheu- matoid arthritis or arthritis deformans, endarteritis, atheromata, nephritis or Bright's disease, renal colic, calculi, etc. As in the previous stages, a rational aetiologi- cal therapy in these cases, calls for a similar line of treat- ment. In short, we should not permit the arbitrary naming or classification of diseases now in vogue (based on the physical effects produced) to blind us to the fact that the masking or neutralizing of such effect, does not, by any means, remove the cause and cure the complaint. Its Limitations. — It is not meant to convey the impression here that we consider the present symptomatic therapy to be entirely useless or futile. On the contrary, we think that it is very often advantageous to mask or neutralize acute symptoms, especially those of a painful character. But this is only for a temporary purpose. Immediate relief is demanded in certain cases, and we administer the sedative, hypnotic, analgesic, etc., to afford CURRENT THERAPEUTIC METHODS. 257 such instant relief; but our curative measures aim to eliminate the cause, and when this object is attained the "effects" will often take care of themselves. Of course, in many conditions, as in "inflammation," we direct at- tention to the local (anatomical) trouble and endeavor to ameliorate the particular symptoms of the same; but, at the same time, we should not forget to look for the irritant factor which is responsible for the given inflammation, and adopt such means as will tend to remove it from the system. CHAPTER XXIX. EFFECT OF REMEDIES IN COMMON USE. A Frequent Indication. — Among the many symp- toms, effects, manifestations, or so-called " diseases, " which may properly be classed under the head of purin excess, those of the first or uricacidaemic stage are probably the most commonly met with in general practice and most frequently require prompt medicinal aid. The majority of such cases are of a subacute character, in which the partially precipitated amorphous urates in the colloidal or so-called " Kugelurate" form, choke the capillaries at one or more points and give rise to the customary glandular insufficiency due to an impeded circulation, and to the various local disturbances caused by pressure of the dis- tended vessels. If the absorbability of a given mass of these amor- phous urates is such that it can be taken up in the circu- lation and removed elsewhere, as indicated by the fitful and transitory character of the pains, occurring first at one point and then at another, we have pretty good evidence that our "^etiological therapy," if adopted, will prove successful; that is, it would seem that by slightly increasing the alkalinity and consequent solubility of the blood, the latter would be enabled to hold the urates in solution long enough to reach the kidneys, from whence they would be eliminated from the body entirely. Prevailing Custom. — But, instead of directing at- tention to the elimination of these threatened deposits, the general practice is to prescribe some effective agent to EFFECT OF REMEDIES IN COMMON USE. 259 ameliorate the symptoms which they produce. In other words, something is given to relieve the subjective sen- sations complained of. If the most troublesome mani- festation should chance to be a headache, toothache, mental and physical inertia, or wandering pains, accom- panied possibly with a slightly rising temperature, the patient is almost invariably given an antipyretic or anal- gesic medicine — usually one of the coal tar products. Antifebrin, phenacetin, morphin, quinin, and remedies of this class are the favorites, the object being to afford immediate relief. The patient generally appears satisfied with this make-shift mode of treatment, until constantly recurring attacks or exacerbations point out to him the necessity of having more radical measures employed, for which pur- pose he is forced to seek other professional advice. In ninety per cent, of such cases, however, the new attendant pursues a like plan of symptomatic treatment, and the primary disorder either becomes stubbornly chronic, or the rheumatic stage is speedily reached. Temporary Effects. — Though the drugs above mentioned will probably produce satisfactory results so far as the immediate neutralization of the symptoms is con- cerned, nevertheless their effect is but temporary. This cannot well be otherwise, for all of these agents are pre- cipitants. They tend to further acidulate the blood (already subalkaline), causing the urates and other waste salts to be thrown down as a precipitate and deposited in the tissues, thus freeing the circulation, increasing gland- ular and cellular activity for a time, relieving the capillary stasis and consequent pressure and pain. In short, the urates are simply precipitated out of solution into the sur- 260 URIC ACID AND ITS CONGENERS. rounding connective-tissue structures and, as soon as the remedy is withheld and the blood regains its former degree of reaction and lessened viscosity, the deposits are re- absorbed into the circulation where they may again serve to impede the capillary flow and reproduce all of the previous effects due to such impediment. These precipitant remedies, as will be seen, produce almost immediate relief of the symptoms owing to the temporary removal of the urates out of the capillaries into the tissues, which permits the ready flow of blood to the glandular organs and other parts — i. e., so long as such obstruction remains absent. But the causative factor is not removed from the system; it is still present and will be heard from again as soon as the effect of the remedy is gone. Furthermore, by driving the deposits in this way into the tissues, a rheumatic attack may be initiated, as is sometimes seen when prescribing an analgesic or antipy- retic drug for the relief of headache, vague pains, a threatened corvza, eczema, etc. III Effects. — Inasmuch as these patients are already suffering from the effects of acidosis (i. e., decreased alka- lescence of the blood and extra vascular fluids) it is evi- dently irrational and unscientific to increase such acidosis by introducing precipitant remedies into the system. The urine in these cases is scant, high-colored and overacid, which would seem to point out the necessity of an alkaline remedy rather than an acid remedy. The effect of these latter drugs in acidulating the blood is practically the same as that produced by uric acid itself, which is known to temporarily relieve the symptoms by causing precipitation of the retained urates. The evil hour is simply postponed and the danger from accumulation constantly increases. EFFECT OF REMEDIES IN COMMON USE. 201 It is like the stimulating effect of opium on the habitue, who craves more of the poison to relieve the ill effects already produced by the drug. In both instances, the action is cumulative. For the temporary relief of insomnia, sulphonal or some similar agent is given; but the therapeutic action in this case is like that of the analgesic in relieving headache. The pressure from the distended cerebral vessels is relieved momentarily by driving the uratic obstruction into the tissues. On the following night, however, the same tactics must be repeated, and so on indefinitely. The aetiological factor is not removed from the system. Furthermore, repeated doses of sulphonal are known to interfere with the oxidizing function of the liver, i. e., less than the normal proportion (50 per cent.) of uric acid is transformed into urea. The inevitable result is an increased amount of uric acid left in circulation, which tends further to obstruct the capillaries and aggravate the insomnia. If the latter dis- order be due to an obstruction of the cerebral capillaries it is evident that a cure will not be effected until such obstruction is entirely removed from the system. If it be granted that cellular inactivity or glandular insufficiency and faulty metabolism, accompanied with depression of spirits, languor, vague pains, malaise, etc., be due in a given case to retention of nitrogenous waste, which accumulates at some point in the capillaries and impedes the circulation there, very little argument would seem to be required to convince the practitioner of the folly of prescribing any drug that tends in the least to prevent the elimination of such waste by the natural channels of exit. It is fully as essential to the burning organism that the ashes and clinkers of combustion be 262 URIC ACID AND ITS CONGENERS. removed as that a sufficient amount of the proper kind of fuel be introduced. Waste and repair go hand in hand, and it is certainly a mistaken therapy on the part of the physician to oppose Nature's efforts to remove such waste. But the precipitant remedy does just this in the cases we are considering, for it has been convincingly shown by clinical experiment that antipyretic and analgesic drugs acidulate the blood and urine and check the elimination of uratic waste. Action of Drugs Used in Rheumatic Stage. — For the relief of the symptoms resulting from the irritating presence of deposits in the tissues or joints, many different drugs are employed, varying according to the histologic nature of the tissues involved and their anatomical position. If the mucous membranes chance to be the seat of the deposits, as in bronchial asthma, hay fever, tonsil- litis, etc., local applications are, of course, indicated in many instances to remedy the ill effects of congestion or inflammation; and, during the acute attacks, as in spas- modic asthma, to relieve the dyspnoea, inhalation of such volatile substances as nitrite of amyl, or the fumes from burning stramonium leaves or nitre paper may be em- ployed. This form of treatment is essential to tide over an existing attack by influencing, through direct means, the dilation of the surface arterioles, thus permitting the temporary passage of the urates to the deeper and larger vessels; while, between attacks, such curative agents as hydriodic acid, iodide of potash and other well-known alteratives are generally used. The latter remedies are rationally indicated and pro- duce good results in these cases, -provided the exciting aetiological factor (the deposit) is alone responsible for the EFFECT OF REMEDIES IN COMMON USE. 263 given manifestation. But, in the majority of instances, predisposing causes, such as hepatic insufficiency and con- stipation are responsible for the oft-recurring attacks, and it is impossible to effect a cure so long as these disturbing factors remain, which are not removed by the iodide treat- ment. Notwithstanding the fact, therefore, that potassium iodide is known to lessen the viscosity of the blood and decrease acidosis, thereby aiding in the solution of the urates and their probable resorption into the circulation, the patient remains liable to further attacks, until the proper means are taken to restore the natural functions of liver and bowels and prevent the continued accumulation of urates from faulty oxidation and elimination. Effects of Salicylates. — In rheumatism proper, especially articular rheumatism, the salicylic acid prepar- ations have been used most extensively in recent years. It has been shown by laboratory experiment as well as by clinical investigation that the initial doses of salicylic acid increase the excretion of urates. This increased urinary excretion is attributed by different authors to different causes. In the opinion of Weidner, Levison, and others, the acid simply increases the number of leucocytes, the increased excretion of urates being the result of the in- creased leucocytosis. Haig and others believe, on the contrary, that the drug acts like the alkalies, and "flushes out" the uric acid. The question is still a moot one. Whatever the precise nature of this observed action on the part of the salicylates, we know that the urgent symptoms of articular rheumatism are ameliorated by thus increasing temporarily the excretion of urates. In cases of this description, where treatment is only given for a few hours to relieve acute manifestations, the therapeutic effect 264 URIC ACID AND ITS CONGENERS. of the salicylates is usually satisfactory. But if more pro- longed medication is indicated, this remedy will prove a failure. Its deleterious action on the stomach, and, later, on the kidneys, tends to prevent the free elimination of urates, and its continued administration proves harmful. In cases of so-called "muscular rheumatism," chronic arthritis, sciatica, lumbago, etc., the transient effect of the salicylates, in increasing uratic excretion, falls short of the true therapeutic requirements. Not only is it necessary in these instances to neutralize acidosis and effect the re- sorption and removal of the local deposits bv more pro- longed treatment; but, like the cases of bronchial asthma, hay fever, etc., already described, it is essential that some effective means be taken to insure oxidation of purin waste and prevent further accumulation, by stimulating and aiding the function of liver, kidneys and bowels. Concerning the Alkalies.— The salts of the alkali metals, sodium, potassium, lithium, etc., have proved beneficial in the treatment of both the uricacidaemic and the rheumatic stage of purin excess. From chemical urin- alysis, we know that these agents, when introduced into the system, can be made to neutralize the acidity of the urine — changing the reaction to alkaline in some instances. This certainly ought to convince the most skeptical that the alkalescence of the blood is raised at the same time. But, owing to certain titration experiments with solutions (in vitro) analogous in character to the blood, the pure chemist says otherwise. According to the theoretical- experimental deductions of the laboratory expert, the alkalinity of the blood is not affected by the introduction of alkalies. It would seem that nothing will neutralize the acidosis, in these cases, according to the pessimistic views EFFECT OF REMEDIES IN COMMON USE. 265 of the professional chemist. Indeed, the latter has become a therapeutic nihilist. But the general practitioner knows that some of these alkaline agents will neutralize acidity. Clinicians of wide experience, such as Jacobi, have demonstrated to their satisfaction, that alkaline waters do possess solvent power over the urates to a limited extent. The amount of alkali, however, contained in the natural waters is too slight, according to this eminent authority, to produce much therapeutic effect. He believes that those artificially prepared are much to be preferred. The same objection holds against the majority of tablets and effervescent salts and mixtures; not enough alkali is absorbed into the blood to produce the solvent effect desired; i. e., too large doses are required to hold the urine at the neutral point a sufficient length of time. CHAPTER XXX. CONCERNING GOUT THERAPY. Status of the Ouestion. — In "The Practical Medi- cine Series of Year Books," for 1905, the author, Frank Billings, of Chicago, declares in his introductory note that his volume contains a review of the best literature of medi- cine for the year. Under the head of " Metabolic Diseases," gout occupies the first place, concerning the treatment of which we note the following: "The keynote to the treat- ment lies in (1) limiting all toxic influences and formation of toxins, particularly in the alimentary canal, in order to minimize the retrograde metamorphosis of the body nn- cleins, (2) in preventing the absorption of all toxic mater- ial, or (3) in promoting the elimination of the products of toxic agents. Immediatelv following the foregoing paragraph, in a parenthetic note commenting on the use of salicylates in the treatment of gout, the associate editor, Dr. j. H. Salisbury, of Chicago, a well-known writer on the uric acid problem, calls attention to the fact that the increase of uric acid ex- cretion seen after the administration of salicyl compounds may be due to the excitation of a digestive leucocytosis as shown by Schreiber and Zaudy. He says: "The action of these remedies on the kidney should be borne in mind, as the researches of Luthje have shown a direct injurious influence from doses similar to those used for therapeutic purposes. The long-continued use of such a remedy, in patients predisposed, as gouty patients are, to disease of the kidney, is not advisable." CONCERNING GOUT THERAPY. 267 From the preceding two paragraphs, the reader gleans the substance of practically all that can be learned on gout therapy, from the most careful study of the published utter- ances of our modern authorities appearing in the various foreign and domestic journals and text-books issued during the past ten years. The tendency of modern scientists is to point out how little is positively known concerning the pathogenesis of gout, and at the same time to demonstrate the futility of attempting a cure by means of any known form of internal medication. It is claimed by a few laboratory experts that gouty concretions are unaffected by alkalies extra corpus, conse- quently the alkaline treatment must prove ineffective; but nothing better, or, rather, nothing at all, is suggested in its stead. The physician and his patient are left practi- cally helpless. Again, while fanciful theories galore have been offered concerning the relation of uric acid to gout, yet, from the therapeutic standpoint of the chemist, the anti-uric-acid regime is deemed inoperative. In his recent work on "Uric Acid," McCrudden in- dorses the opinion of Rosenfeld that alkalies have no in- fluence on the solvent power of the urine for uric acid; and furthermore, that the alkalescence of the blood is unaffected by drugs. Another laboratory experimenter (Joulie), goes so far as to claim the discovery of a new method of deter- mining the acidity of a given solution, which proves that the blood, instead of being alkaline as we have always been taught, is in reality neutral or acid, notwithstanding its reaction to litmus. To such extremities is the closet stu- dent brought by limiting his investigations to chemical findings in vitro. 268 URIC ACID AND ITS CONGENERS. As a result of the conflicting views of the chemist and clinician, concerning the inherent nature of gout and the effect of medication, the existing literature on the subject we are discussing is very unsatisfactory. The majority of those other investigators, however, who have happily had experience along the lines of clinical observation as well as laboratory study — such well-known authors as Chittenden Futcher, Burmin, Pfeiffer, Aronsohn, von Noorden, Men- del, and others — are inclined to accept the original teachings of Garrod, as briefly alluded to in a previous chapter. It is now quite generally agreed by these authors, that the alkalescence of the blood is reduced in gout; that the circulation is overcharged with urates at the beginning of and a few days prior to the attacks; that the urine contains an excess of urates at the height of an attack and as it is passing off; that the gouty subject excretes exogenous purins but poorly; that the accumulation in the system is chiefly owing to retention, because of insufficient kidney elimination from disease of that organ; that the acute joint symptoms are probably due to variations in the reaction of the synovia (dealkalization followed by hyperalkalization) causing sudden dissolution of the previously inert crystal- line formations; that the alkaline eliminative treatment is theoretically, rationallv and experientially indicated. I am pleased to state at this point that clinical experience enables me to heartily indorse these latter views of the subject. Prevailing Type of Medication. — Most modern clinicians will doubtless acknowledge the force of the state- ment made by Billings, that the "keynote to the treatment" of the gouty stage of purin excess (as in the two previous stages) is to limit all toxic influences which tend in any way CONCERNING GOUT THERAPY. 269 to inhibit the retrograde metamorphosis of the body nu- cleins, striving, at the same time, to prevent the absorption of toxic material and to promote the elimination of the pro- ducts of toxic agents, particularly from the alimentary canal. In short, the experience of the general practitioner has taught him the therapeutic value of drugs that stimulate the action of the organs of defense (especially the liver) and aid in cleaning out the intestinal tract, thus preventing the absorption or introduction into the circulation of such waste material as tends to acidulate the blood and extra- vascular fluids. Alkaline diuretics are also commonly pre- scribed to further elimination by way of the kidneys. Concerning the particular medicinal agents to be em- ployed for the foregoing purposes, authorities differ. Per- sonally, I have come to agree with Salisbury, Pfeiffer, and others, that the prolonged use of the salicylates is exceed- ingly detrimental. While they do increase the excretion of urates temporarily, and in acute cases may be employed two or three days for that purpose, (as in acute articular rheumatism) yet, as* the ultimate effect on stomach and kidneys is such as to lead to absolute injury and reten- tion, their administration in chronic cases or for prophy- lactic purposes is to be strongly condemned. The same objection holds against the use of the colchi- cum preparations. Continued ingestion of this drug in effective doses almost invariably causes congestion of the delicate epithelium of the renal tubules; and the patient, eventually, is done more harm than good. Moreover, neither of these two agents produces the effect on liver and bowels so much to be desired; nor do they possess that essential solvent power, to render them beneficial in cases of gravel and calculi. 270 URIC ACID AND ITS CONGENERS. Use of Alkalies. — Notwithstanding the recently published statement of McCrudden (Cf. "Uric Acid," p. 243) that the bulk of laboratory evidence, so far as he has examined into the matter, " seems to indicate that alkalies neither decrease nor increase the excretion of uric acid"; nevertheless, the bed-side evidence reported by the general practitioner must be taken as conclusive that the alkalies very often do increase such excretion — i. e., in cases in which excess actually exists in the blood, as in gout. Chemists, themselves, disagree on this point; but there is little doubt in the minds of physicians. Physicians do disagree, however, as to which is the most effective alkali to be employed. The most popular agents of this class are the salts of sodium, potassium and lithium. The bicarbonate of sodium, iodide of potassium and citrate of lithium have been perhaps most extensively used until within the past two years. When one of these agents is given in such form and in such considerable dosage as to "saturate" the system, it is known to produce effects which are desirable in a rational gout therapy; to wit: — 1. To neutralize the urine. 2. To lessen the viscosity of the blood. 3. To increase temporarily the excretion of purin nitrogen. 4. To cause diuresis. Unfortunately, in practical therapeutics, it is very diffi- cult to insure the absorption of a sufficient quantity of the given alkali to produce the above effects. For example, four hundred grains of the bicarbonate salt, given daily, have been found necessary to hold the urine constantly at the alkaline point of reaction to litmus; consequently, in the pharma- ceutical form in which these alkalies are usually presented to us (tablets, effervescent salts, mineral waters, etc.), it is impracticable to administer them in adequate dosage. As CONCERNING GOUT THERAPY. 271 ordinarily prescribed, not enough of the alkali becomes absorbed to produce but the most evanescent effects — cer- tainly not enough to insure the solution of gouty concre- tions. In the chemical combination in which the sodium salt is commonly administered, the greater portion passes through the intestinal canal and is expelled with the egesta in the form of sodium hydrogen sulphide, thus serving as a laxative. The phosphate of sodium is most frequently utilized for this purpose. If the alkali be given singly, therefore, in simple molecular combination (as a base with an acid), little effect is observed, so far as increasing the ex- cretion of urates is concerned. In fact, most of the absorba- ble portion is oxidized in the body to carbonate, which eventually adds to the crystallization of sodium acid urate. A similar effect is said to take place when a potassium or lithium salt is given singly, in the chemical combination of acid and base (though to a lesser extent in the case of lithium) ; they are transformed to carbonates after absorp- tion, and though at first a slight increase of uric acid excre- tion is observed, a decrease is afterward shown; but this, in some instances, is probably due to the fact that the origi- nal retention was slight, and the excess within the system has been eliminated. (Cf. C. Clar, in Centralblatt fur die Medicin Wissen, Vol. XXVI, 466.) It will thus be seen that, while the single salts of the alkali metals, as ordinarily prescribed, can hardly be ex- pected to remove the crystalline biurates from the system, nor cause dissolution of gouty tophi, they may and do pro- duce some beneficial effects, temporarily, by eliminating loose semi-crystalline ureids and serving, to a certain ex- tent, as a material aid to the normal excretory functions, by 272 URIC ACID AND ITS CONGENERS. neutralizing the urine and increasing its flow, thereby enabling the latter to hold a greater quantity of purin waste salts in solution. Much greater therapeutic effects may, of course, be expected when the alkaline agent is ingested in such chemi- cal combination that the base may be absorbed and set free to unite with the uric acid, while the acid radical is taken up with some other base requiring elimination, both be- ing removed. Effect on Genito-urinary Concretions. — Though the simple alkaline salts, prescribed singly or in conjunc- tion with other simple alkaline salts, do not in the ordinary dosage become absorbed in sufficient amount or in such chemical form as to materially affect the dissolution of the crystalline formations in joints and other connective tissues within the body, as in the so-called " regular gout," they do neutralize the reaction of the urine to such an extent that the latter may hold the urates in more perfect solution or suspension, and in this way prevent the irritation of the genito-urinary mucous lining from the passage of small concretions or gravel. As remedies in cystitis, therefore, or for the purpose of allaying the kidney irritation due to the imperfect solution of minute irregular urate crystals, or gravel, the administra- tion of the simple alkaline salts has been found to produce fairly satisfactory results. For this purpose, the citrates have become quite popular, being especially indicated whenever the urine is concentrated and overacid. Laxative Effects. — Again, for their laxative effects, the alkaline cholagogues prove beneficial in the gouty stage. By initiating an increased flow of bile and by stimulating the action of the liver, these agents tend to prevent the ab- CONCERNING GOUT THERAPY. 273 sorption of toxic material from the alimentary canal and promote the elimination of the products of toxic agents: two important therapeutic effects, which are essential to the "keynote of the treatment," as laid down in the recent works of Billings and others. CHAPTER XXXI. THE ALKALINE-ELIMINANT. Definition. — In its therapeutic application, the term " alkaline-eliminant," is used here to designate any remedial agent, that, prescribed in ordinary medicinal dosage, is known to alkalinize an overacid urine and aid in the elim- ination of urate salts in cases of purin excess. Its Clinical Purpose. — The main object in prescrib- ing a remedy of this character is to effect the removal from the system of the "exciting aetiological factor/' as described in our previous chapter on " ^Etiological Therapy." At the same time, if such remedy prove effective in causing the removal of the chief " Predisposing ^Etiological Factor," described in the aforementioned chapter, its therapeutic value would be enhanced tenfold. The action of the alkaline-eliminant in increasing the excretion of urates is to be observed, of course, only so long as an excess of uric acid remains in the blood or tissues, capable of being removed. When such excess has actually been removed, knowledge of the fact will be apparent from the disappearance of certain characteristic subjective and objective symptoms, and from the gradual decrease in the urinary excretion of urates observed, until, finally, the normal, or less than the normal per cent, is reached. Unlike the precipitant agent, — which reduces the amount of uric acid excreted to the normal, or lower, by driving the excess out of the circulation into the tissues — the alkaline-eliminant merely hastens the hour when the minimum excretion is reached, by stimulating the hepatic THE ALKALINE-ELIMINANT. 275 function and aiding in the more complete oxidation of the purins (40 to 60 per cent.) to the end stage (urea), thereby decreasing the amount of uric acid left in circulation and lessening the total amount to be excreted. In other words, inasmuch as in uricacidaemic patients much of the excess of uratic waste in circulation is owing to the failure of the "torpid" liver to oxidize its due share (50 per cent.) of uric acid to urea, as in health, it is evident that when the hepatic function becomes more active as a result of the administra- tion of the alkaline-eliminant, less uric acid and more of the urea will be carried to the kidneys for excretion, thus limit- ing the work of elimination to the removal of the previously accumulated uratic excess. It will be seen that the final decrease in the urinary excretion of urates, observed after taking the alkaline-elim- inant a few days, may be attributed chiefly to two causes ; viz. : 1 . The removal of all, or a part of the accumulated excess in the system. 2. The reduction in the amount of uric acid formed from day to day. This action is quite different from that of quinic acid. The latter, according to the claims of its German supporters (Weiss, Schlayer, and others), is said to decrease the excretion of urates by preventing the synthesis of uric acid from glycocoll and urea on reaching the kidneys. But the theory on which this supposed action is based has been shown to be unsound. No such synthesis occurs. Some experimenters (His, Foerster, Nicolaer, and others), have been unable to detect any variation in the excretion of urates after the ingestion of quinic acid; but, like tannic acid and other astringents found in the rind of certain fruits, skins of seeds, and bark of certain plants, it doubtless does produce such an effect, even in health — its action in that respect, probably, being much like that of the ordinary acid precipitant. 276 URIC ACID AND ITS CONGENERS. The Objective Effect. — The objective effect ob- served from the use of the alkaline-eliminant is exactly the opposite of that from quinic acid. Concerning this latter agent, Ulrici has shown {Arch. f. experimen. Path. u. Pharm., XLVI, 321) that the ultimate effect is to actually increase above the normal the quantity of uric acid elimi- nated, after the withdrawal of the drug. He has demons- trated that the lessened excretion is only temporary; that the formation of uric acid in the system is in nowise af- fected; but that it becomes temporarily deposited in the tissues, or "locked up." In the opinion of many observers, such astringent principles, as the quinates, interfere with the absorption of food containing them; and the immediate decrease ob- served in the amount of uric acid eliminated in the twenty- four hours, means either a disturbance in the digestive tract, or a retention of the toxin in the body. The precipi- tant action of tannin on albuminous substances would seem to give some color to this assertion. "It is possible, moreover/' as one writer suggests, ''that in introducing quinic acid, its equivalent alkaloid, or one of its salts, into the stomach, we are gratuitously furnishing the system an extra amount of purin material to be metabolized and eliminated at some future time, since it is known that the small amount of vegetable purins ingested as food is contained in the bark, rind, and peel. Like other vegetable alkaloids or extractives (e. g., as the xanthins and tannin of tea and coffee) quinic acid may tend to subalka- lize the blood and tissue juices and cause a precipitation of urates in the various connective tissues of the body, thus causing their disappearance temporarily from the urine, only to reappear in added amount when the normal blood reaction is restored. " THE ALKALINE-ELIMINANT. 277 The fact will be readily appreciated that the objective effect of the alkaline-eliminant is just the reverse of all this. Instead of immediately lessening the amount of uric acid excreted in the urine, the effect during the first few days of its administration is to increase the elimination. Both bowels and kidneys are first " flushed out" in order to re- move the accumulated waste, soon after which a gradual reduction in the amount of urates excreted in the urine and feces will be observed. The stimulating effect on the meta- bolic function of the liver may be seen in the increased urea formation. In short, an agent is furnished which aids this much-abused organ in oxidizing the nitrogenous (purin) waste molecule into its normal end product. Furthermore, the alkalescence of the blood and tissue juices is increased instead of diminished, as may be seen from the lessened acidity of the urine — which may even become alkaline in reaction. An agent is thus given whose objective effect is to eliminate the existing "aetiological factor" from the sys- tem; not cause its retention. Two other important objective effects which should follow the use of the alkaline-eliminant, are (i) diuresis and (2) laxation. Victims of purin excess, in whatsoever stage, almost always suffer from the ill effects of retained sewage, both liquid and solid. The two channels of exit have become choked with cast-off material which cannot long be retained without causing toxaemic symptoms from the absorption of urinous (ammoniacal) exhalations and fecal sewer gas. While the choking up of the capillaries with uratic waste and colloid food detritus may be considered partially responsible for the inaction of kidneys and bowels, it should not be forgotten, that, at the same time, the chok- ing up of the two channels of exit react upon the capillaries 278 URIC ACID AND ITS CONGENERS. themselves by interfering with the removal of their uratic obstruction, thus setting up a circulus vitiosus, which the true eliminant destroys by loosening up at both ends of the line. The need of such diuretic and laxative action is indicated by the concentrated, high-colored, odoriferous urine, and the still more concentrated malodorous material in the fecal reservoir, observed in the majority of cases of purin excess. By thus aiding the normal excretory functions of the organism, in the disordered condition which we have de- scribed elsewhere under the head of "hepatic-renal insuffi- ciency," any anti-uric-acid agent of the character under discussion becomes instrumental in removing the chief "predisposing aetiological factor" in cases of purin excess, which removal is essential to success in the treatment, especially in the last or "gouty" stage. Its Solvent Effects. — Notwithstanding the pro- nounced pessimistic views of the pure chemist, concerning the doubtful utility of introducing anything into the system with the object of increasing the alkalescence of the blood and its consequent greater solvency for the urates, we can- not blind ourselves to the well-established clinical fact, that, after the ingestion of the alkaline-eliminant, as well as many of the single alkaline salts (i. e., when taken in considerable dosage) as mentioned in the preceding chapter, strongly acid urine may be changed to a neutral, or even alkaline reaction. This means, if it means any- thing, that the blood brought to the kidneys, from which this urine is dialyzed, has suddenly become more alkaline than before. We know, too, that the urine of herbivorous animals is alkaline, and that their blood is consequently more THE ALKALINE-ELIMINANT. 279 strongly alkaline in reaction to litmus than is the blood of carnivorous animals or of omnivorous man, with his acid urine. Again, we know that when the urates are not being excreted in normal amount in the urine during the twenty- four hours, the latter is overacid and that when an "ex- plosion "of urates occurs in a given case, the urine becomes temporarily more copious and less acid, or perhaps neutral. It is evident, therefore, that the reduction of urinary acidity is accompanied by a corresponding change in the degree of the reaction of the blood — i. e., it becomes more alkaline (there is less tendency toward acidulation). We cannot doubt that like other weak alkaline solutions whose alkalinity has been increased, such blood has also become a better solvent of the urates. At all events, clinical testi- mony supports this view, for the symptoms due to accu- mulation of urates at a given point speedily disappear, while the urine itself shows an increased excretion at the same time — just as an "explosion" of urates occurs as an attack is passing off. Still further, it has been repeatedly shown that even the crystalline biurates in the joints may be partially or wholly absorbed into the lymph and carried into the circu- lation, which has become a better diluent after administra- tion of the alkali. The same may be said concerning the solution of renal and cystitic concretions, in a urine made alkaline by the same means. Of course, the amorphous urates, which still remain in the blood in the capillaries in the form of a colloidal solution, are much more sensitive to this change in the blood's alkalescence and are removed more speedily and with less difficulty, as may be observed in the greater ease with which we afford relief to patients in the uricacidaemic 280 URIC ACID AND ITS CONGENERS. stage. It is well known to chemists, that while the amor- phous and the crystalline forms of the acid urate have the same chemical composition, yet that the former have a far higher solubility. In fact when the amorphous urates are held in water or blood serum they form colloidal solutions which usually become supersaturated; and, under these circumstances, the crystalline form is readily precipitated out of solution. It has been demonstrated by Baumgarten that as soon as the amorphous form is washed free from impurities, further washing changes it to the crystalline form. This phenomenon has since been confirmed by the two eminent chemical authorities, TuniclifFe and Rosen- heim (Cf. Lancet, 1900, 1, 1708). Again, the solvent effects, or, rather, the oxidizing effects, of the alkaline-eliminant, is further observed in the increased cellular activity produced throughout the body. Owing to the raised alkalinity (or lessened acidity) of their environment, the individual tissue cells themselves possess greater enzymatic power. The hydrolytic enzymes or ferments secreted by the cells require a certain degree of alkalinity (or O H. ions) in their surroundings to become normally effective in metabolizing nitrogenous waste. The increased activity observed in this respect is partly due to the freer circulation through the capillaries, and partly to the greater solvency of the lymph and blood, both of which have become better diluents. Indirectly, there- fore, solvent effects are obtained by insuring a more com- plete cellular oxidation of purin waste, which being less colloidal, renders the blood less viscous and consequently a better solvent — at least, a better medium for conveying amorphous urates to the kidneys for final excretion. Methods of Administration. — Various methods of prescribing eliminants are in vogue. In the words of THE ALKALINE-ELIMINANT. 281 von Noorden (Diseases of Metabolism: Saline Therapy, Part V, jS): "We know of a number of drugs, and we know of many measures, that are capable of increasing the uric acid of the urine for the time being, or of decreasing it. This means that by employing these remedies or measures we are able to 'wash out' the uric acid or cause its retention. We have every reason to include uric acid retention in the pathology of gout, and to welcome every measure that is capable of removing an excess of uric acid from the blood." Prof, von Noorden recommends saline mineral waters (as Homburg and Kissingen) for the above purpose. But, as stated by Prof. Jacobi and other eminent clinicians, the natural mineral waters have been found to be too poor in their alkaline ingredients to ever become very effective as uric acid eliminants. They are beneficial to a certain ex- tent, but enormous quantities must be ingested. The increased quantity of water excreted by this means serves a good purpose in some cases. As reported on a previous page, Jacobi recommends alkaline waters artificially pre- pared. In more recent years, the use of the simple alkaline salt, given singly, has been abandoned by the majority of practitioners, as being inferior to other methods. Even yet, however, a physician may have his favorite mode of combining two or more of the simple salts in order to ob- tain the effect of their conjoint chemical action, after ab- sorption. Prescriptions are sent to the local druggist, which call for the mechanical mixture of these salts, to be administered in powder form, or, perhaps, in some liquid combination. Pills and tablets containing the mechanical union of two or more simple salts, are also employed to 282 URIC ACID AND ITS CONGENERS. some extent. It is a common practice, too, to better insure the absorption of these remedies by first cleaning out the intestinal tract with some cathartic agent. While these different methods have proven more or less satisfactory in a limited number of cases; nevertheless, owing to the crude union of the salts and their uncertain chemical action in the organism after absorption (when- ever such absorption really occurs), results, in many chronic cases of the rheumatic and gouty stages, have only been temporarily beneficial — recurrence of the attacks being very common. Evidently, in many instances, the improvement has been due to the establishment of a more active bodily metabolism, without succeeding in actually removing from the system the accumulated excess of urates. Therefore, as von Noorden truly says: "We have good reason to welcome every measure that is capable of removing an excess of uric acid from the blood.'' CHAPTER XXXII LITHIUM. Solvent Properties. — Of the various alkalies that may be employed in therapeutics to aid in the solution of uric acid and insure its elimination from the body by way of the urine, lithium, from the chemist's standpoint, should for various reasons be the most effective; and clinical experience has proven the correctness of this a priori reasoning. Even in average medicinal dosage and in the form of one of its simple alkaline salts (citrate, carbonate, benzoate, etc.), physicians have been enabled to neutralize the reaction of the urine without producing irritation of the stomach or the kidneys. Concerning the purely solvent properties of lithium, the following brief findings reported by professional chemists and pharmaceutical experts may prove some- what interesting; to wit: Gorsky (Centralblatt fur der med. Wissen, 28, 27) (1890) found increased uric acid excretion after LiC0 3 . PfeifFer (Verhandl. des 5/ Kongr. fur innere Medizin, 444,) (1886), found after use of LiC0 3 , that less uric acid is given up to the uric acid filter (in the urine) than before the salt was administered. His finding has since been confirmed by Neumayer. From these results, both investigators have concluded that the dissolving power of the urine for uric acid is increased after ingestion of lithium. In other words, it has been shown that this alkali tends to prevent the deposition of uric acid calculi. 284 URIC ACID AND ITS CONGENERS. W. His (Verhandl. des \%t Kongr. fur inner e Medizin, 425,) (1900), found that the lithium salt shows an espe- cially great tendency to form neutralized solutions, in presence of the colloidal solution of amorphous urates. The fact is well known to chemists that lithium is by far the best solvent of uric acid in the test-tube. In short the dilithium urate (neutral urate of lithium), Li 2 (C 5 H 2 N 4 3 ), is the most soluble of all urate salts. It is im- portant to note that when solutions of uric acid are to be utilized for injection into the body for experimental purposes, a solution of lithium urate is almost invariably employed. In his classical experiment for discovering the uric-acid-destroying power of the liver, Ascoli mixed blood with lithium urate and perfused it through the gland, finding that a considerable loss of uric acid occurred and that urea was correspondingly increased in amount. Prof. J. A. Patton, in considering the pharmacology of alkaline medication, classes the lithium salts among the so-called "indirect" alkalies. They are absorbed and oxidized in the blood and excreted as carbonates, diminish- ing the acidity of the urine and increasing the alkalinity of the blood. This increased alkalinity of the blood, he claims, promotes its oxidizing functions, as shown by the final decrease in the relative amount of the uric acid and an increase of urea eliminated in the urine. He has found that among these indirect alkalies, the lithium salts are much the best uric acid solvents. Combined with a Laxative. — Hutchinson (Jour. A. M. A., Dec. 3, 1904), voices the opinion of the majority of practitioners of America and Great Britain, when he says: "The 'old reliable' remedies in gout — in which great group the alkaline laxatives are most important — LITHIUM. 285 have won their laurels, and enormously relieve the situation, by checking the acid processes of fermentation in the ali- mentary canal and sweeping the putrescent matters out of the system before they have time to give off their toxicant products to the blood. In short, almost every remedy" continues he, "which clinical experience has proved to be of value in gout and the gouty state will be found to prevent the fermentation or absorption of the intestinal toxins or to promote their elimination from the system" As previously stated in our chapter on /Etiological Therapy, that remedy will prove the most effective as an alkaline-eliminant in the treatment of purin excess which best succeeds in relieving the condition designated "hepatic-renal insufficiency," thereby removing the most important of the predisposing aetiological factors. Lithia, with or without some saline laxative, but preferably with it, as in thialion, has been found to be the most efficacious of the alkalies in removing this torpidity of bowels and kidneys, without resort to the drastic purgatives some- times used in such troubles. Sodio-Lithium. — Judging from personal experience and from the published reports of eminent clinicians at home and abroad, the so-called "laxative sodio-lithium salt" has been found to be more satisfactory for the purpose above referred to, than any of the simple lithium salts. This is a complex salt formed by the union of sulphuric and citric radicals (3 to 7) with sodium and lithium bases. In the preparation of this alkaline combination (thialion) it is said that the usual custom in manufacturing the simple alkaline salts is departed from. Instead of segregating the various products as they arise in the 286 URIC ACID AND ITS CONGENERS. analytic process, the lithium base, in this instance, is left in chemical union with one of the residual products (sodium sulphate); thereby resulting in the production of a laxative salt, containing lithium and sodium, in which these two bases are in such relation that vital action is required to part them. Hence, in lieu of a mixture or mechanical combination of sodium and lithium salts, we have a new and complex combination in which the chemi- cal and therapeutic effects are necessarily sui generis. Its Chemical Action. — From the standpoint of the chemist it has been an interesting problem to account for the wide difference observed in the solvent and eliminative effects of this complex sodio-lithium salt, as compared with that following the use of any mixture or mechanical combination of the sodium and lithium salts, or with that of either salt when prescribed singly. Though only partially soluble in cold water, it is freely so in hot water, by which means it forms an artificial alkaline mineral water of unusual potency and solvent properties — thus coinciding with the views of Jacobi, as expressed in a previous chapter. Eminent clinical authorities agree that the solvent effects of this laxative salt are best obtained by administering it in hot aqueous solution in the pro- portion, approximately, of one to ninety (one heaped teaspoonful of the salt to a pint of water). After eight years of clinical demonstration, supple- mented by numerous laboratory tests, the generally accepted opinion concerning the chemical action (in the system) of this salt, as shown by the report of the chemist, is somewhat as follows: — Inasmuch as sodium sulphide is known to be discharged from the bowels, two or three hours after administration, it is evident that a portion of LITHIUM. 287 the sodium must necessarily have been absorbed; which is supposed to have been made possible owing to the sulphuric radical of the salt uniting with both the sodium and lithium — i.e., so far as these bases are present in the proportion requisite for such purpose. That the absorp- tion probably occurs in this form is further indicated by the fact that the lithium, which is known to be eliminated chiefly by way of the kidneys, must also have entered the circulation; and such absorption would be much easier in the form of sodium-lithium sulphate than in the form of lithium citrate. (It should be explained here that chemists doubt if the sodium salt formed by the sulphuric acid is a neutral salt at the beginning; that probably an acid salt is the first member — not Na 2 S0 4 but HNaS0 4 — -in which case the sodium-lithium sulphate may readily be assumed, and in which form the lithium would be absorbed with com- parative ease.) From this, it is supposed that the citric radical then unites with the sodium ,to form sodium citrate, which is very readily absorbed. It will be seen from the foregoing description that eliminative action by way of the urine is two-fold; (i) lithium (a base) is free to unite with uric acid: (2) the citric radical, broken to carbonic acid, is free to unite with any base present in the blood (as waste product), and thus secure its elimination. These effects (produced in the way described) would seem to account for the observed clinical absence of any kidney irritation; though of course, such explanation is based chiefly on theoretical reasoning. While, as intimated elsewhere, the simple lithium salts, as ordinarily prescribed, do neutralize the urine to some extent and do increase temporarily the excretion of urates, nevertheless, the alkali is not absorbed in such 288 URIC ACID AND ITS CONGENERS. form and in sufficient amount as to insure the removal of previously accumulated deposits in the joints and elsewhere, and, furthermore, does not promote the elim- ination of intestinal toxins from the system; but, in the laxative combination, as above described, not only is this latter desirable effect produced, but what is more import- ant still, the lithium is absorbed in toto. CHAPTER XXXIII. FINAL WORD. While it is admitted that there is yet no real consensus of opinion among scientists concerning the pathological importance of uric acid, and that the question of its metab- olism and clinical effects is still sub judice; nevertheless, it can no longer be doubted that the careful researches carried out in recent years point most unmistakably to the fact that it is one of the waste products of the human organism most frequently retained, and responsible for many of the common ills. Some writers do not freely accept this latter con- clusion, on the ground that autotoxaemia cannot properly be attributed to the action of a substance which is in itself non-toxic. This criticism, however, is made by the laboratory expert and not by the practicing physician. The latter knows from experience that any mechanical factor which interferes with the freedom of the capillary circulation, or which impinges as a foreign body upon the surrounding delicate tissues, even though it may be but a lump of innocuous jelly or crystal, will inevitably give rise to local and systemic disturbances, which, if not primarily toxaemic in character, are likely to become such by reason of the chemical and physical (pathological) changes induced. The septicemic condition caused by the presence of an innocuous foreign body in the vermiform appendix may be cited as an analogous case, — i.e., toxaemia due to a non-toxic factor. 290 URIC ACID AND ITS CONGENERS. Some authors ridicule the idea of a "uric acid diathesis " It is true that the term has been used some- what loosely in medical literature, for the majority of physicians in employing this disease-name simply mean to infer that the patient is suffering from symptoms of uric acid retention and accumulation; that is, an acquired condition due to the fault of the individual, not a diathetic condition due to the fault of his construction, with which he was born and to which he has always been especially and peculiarly subject, — such as a strumous diathesis, for instance. Notwithstanding all this, it is by no means impossible that, in some instances, a uric acid diathesis may actu- ally exist. If, for one or more generations, the meta- bolic organs (especially the liver) have been persistently abused, by overeating, alcoholic excesses, sedentary life, etc., a weakened power to metabolize the purins into urea in the normal proportion (50 per cent.) may eventually result, and this weakness may become a family trait, transmitted from one generation to another. In short, the tendency to uric acid retention and accumulation may be handed down like any other physical, moral or intellec- tual tendency, — i.e., transmission of a metabolic weakness as well as a mental weakness. It is probable that no other subject :n physiology has received so great attention at the hands of scientific investigators in the last ten years, as has been devoted to the experimental study of uric acid metabolism. Several excellent original contributions have appeared in both the domestic and foreign medical journals, and not a few special treatises in the form of brief monographs. Some of these are invaluable to the student who wishes to gain a FINAL WORD. 291 comprehensive knowledge of the subject. But the fact cannot be too strongly impressed upon the mind of the beginner, that it is a fault, or oversight, of many able modern writers to devote insufficient space to the con- sideration of one most important topic; viz: the destruc- tion of uric acid formed in the organism; i.e., its oxidation into urea (40 to 60 per cent.) before excretion. Owing to the above neglect, many conscientious physician-editors now entertain the idea (and so state in articles written for their journals) that it has been found that uric acid is not transformed in the body into urea. Knowing that the old theory (of uric acid being a half-way stage in the metabolism of albumin into urea) has been exploded, they are not aware that physiologists have demonstrated beyond cavil that uric acid is a half-way stage in the metabolism of nuclein or purins into urea. The fact is now well established that urea is the end pro- duct of nitrogenous catabolism, both albumin and purin. The significance of this knowledge to physicians becomes at once apparent when considering the subject of treatment. He should know that the liver is the organ chiefly responsible for the oxidation of uric acid into urea, and take such measures as are known to stimulate the performance of its enzymatic function. In other words, he should know that the employment of means to insure the oxidation or destruction of uric acid, is scarcely less important, from the therapeutic standpoint, than that which has to do with its elimination. The discoveries made by chemical experts, of the behavior of uric acid and its salts under various special conditions extra corpus, have led to a much more intelligent appreciation of the probable physiological and pathological 292 URIC ACID AND ITS CONGENERS. purin changes which take place in the system. For exam- ple, it had been doubted by some physicians that uric acid could circulate in the colloid or amorphous form, since colloids were not supposed to dialyze. It has been shown, however, by the experimental investigations of His, Ord, Roberts, and others (Cf. Sir W. Roberts, Croonian Lectures, Lancet, 1892) that the amorphous form of the acid urate readily dialyzes, and that from such colloidal solutions (upon standing) the urates are grad- ually precipitated out in crystalline form. This precipita- tion is most likely to occur, or, rather, occurs most readily, when sodium salts are added to the solution. These chemical experiments point out the probability that uric acid circulates in the amorphous form and that colloid urates are dialyzed from the capillary blood into the lymph spaces or synovial sacs of the joints. As the fluids in these latter situations are oftentimes practically at rest, are rich in sodium salts and lack coloring pigment, the urates may readily become crystalline in these localities. Another chemical discovery of great practical signifi- cance, especially in pointing out the rationale of the alkaline treatment, is that reported by Croftan, who has studied the composition and mode of action of the liver ferment or "oxidase." He states that it consists of a nucleoproteid and albumose, each of which is dependent on the other; but the latter is the special agent in the oxidation process, — i.e., in transforming uric acid into urea. The albumose itself is held in solution by the pres- ence of certain salts. The nucleoproteid content simply acts as a carrier of oxygen, owing to its power of dissociat- ing H 2 2 — giving offO; and oxygen, of course, is essential to the enzymatic action of the albumose. He has found FINAL WORD. 293 that while salts like the nitrates diminish this power of the nucleoproteids to liberate O, other compounds, such as the alkalies, greatly increase it. He suggests, and with much good reason, that the well known efficiency of the alkalies in the treatment of gouty affections may be connected with this action. Minkowski, in referring to the subject of treatment, says that the aims of therapeutics may be divided into three classes: — "i. Treating the primary defects in the metabolism. 2. Influencing especially the metabolism of the uric acid. 3. Treating the individual symptoms in different cases." {Die Gicht, p. 271). As to influencing the metabolism of uric acid, this eminent investigator believes that we should "endeavor to prevent the body from becoming highly charged with uric acid." To effect this desirable object he suggests the following four methods, viz: " (a) By decreasing the formation of uric acid; (b) by furthering the excretion; (c) by hastening the further oxidation; (d) by increasing the solubility of the uric acid in the blood and tissues." Von Noorden (Cf. Verhandl. des 14/ Kongr. fur inner e Med.) (1896) refers to the abnormal tendency, occurring in some cases, to form uric acid concretions. In considering the treatment, he says that we should "(1) give large quantities of water to increase the dissolving power of the urine for uric acid; (2) give such food as gives rise to little uric acid; (3) administer drugs which, after passing through the body, make the urine a better solvent for uric acid; keep out of the food, substances which, after passing through the body, make the urine a poor solvent for uric acid." In the "alkaline-eliminant" mode of treatment recommended in the preceding chapters of this work, it 294 URIC ACID AND ITS CONGENERS. will be seen that the chief aims of therapeutics in gout, as above suggested in the words of Minkowski and von Noorden, have been kept constantly in view. The practical results obtained after several years' experience from the employment of this treatment by the author, urged him to investigate the subject more fully and determine, if possible, the modus operandi of the alkalies and discover whether they were used only empirically with merely accidental good effects, or if there was a scientific basis for such treatment which would prove its rationale. The reader is now left to judge for himself whether such a scientific foundation has been established. The richest single contribution in recent years to the subject of the aetiology of gout, or arthritis urica, is that of Prof. Lafayette B. Mendel, of Yale University, in an address delivered before the Harvey Society, at the New York Academy of Medicine (Cf. 'Journal American Med- ical Association, April 1906). By means of his laboratory experimentation, in conjunction with that of Prof. Chitten- den, it has been shown that after the ingestion of a purin meal (meat), a characteristic rise in the urinary excretion of uric acid in the healthy subject invariably occurs. The curve is especially well marked in those cases in which alcohol was ingested with the meal. In a gouty or rheumatic subject, however, it was observed that this postprandial curve was very much lessened; and, in some cases, did not appear at all. From these experiments, it has been demonstrated by Prof. Mendel, that the exogenous purins are excreted but poorly in cases of gout. The retention of uric acid is evidently a chief factor in the aetiology of this disorder. The various symptomatic ills, classed under the head of "purin excess/' have been considered here as one FINAL WORD. 295 common disease-process, divided into three separate stages. While this is to some extent arbitrary, and is done for the greater convenience of the treatment of the subject and its better understanding; nevertheless, the clinical evidence is of a character that forces upon us the conviction that such a division is warranted, if not actually demanded, by the existing pathological conditions (both physical and chemical) as instigated by the processes of Nature herself. Again, uric acid has been considered in this work as an intermediate nitrogenous molecule, occurring seriatim during the physiological process of catabolizing or oxi- dizing the purins into urea — the true end molecule, which is much more easily dialyzed by the highly evolved epithe- lial cells of the human kidney. Lastly, it is intimated that in the general process of organic evolution, as the human organism becomes more thoroughly adapted to its internal and external environ- ment (the liver, especially, functionating to better effect as the individual learns how to treat it properly, and what quality and quantity of food substances to ingest), uric acid will eventually disappear as a waste product in the urine, except in cases of disease. According to the law of the "survival of the fittest," the more soluble and more highly oxidized nitrogenous end molecule, CH 4 N 2 0, will eventually be the only ureid excreted in health. BIBLIOGRAPHICAL AND GENERAL INDEX. A Acetic acid test for uric acid in urine, 140. Acid, absorbed into circulation from intestines, 89. behavior of pure uric acid, 27. dyspepsia in purin excess, 126. Adenase, a tissue ferment, 47, 64. .Adenin, a violent poison, 52, 53. changed into hypoxanthin and ammonia, 105. in walls of intestine, 46. Adenoids, due to uric acid reten- tion, 165. /Etiological Therapy, definition of, 245. summary of, 250. Albuminuria, in children, 163. in gout, 120. Albuminuric retinitis, 180. Alcohol, a cause of "next morning" headache, 97. effect of on liver, 82. inhibits action of uricolytic fer- ment, 97. its effect on kidneys in Bright's disease, 153, 154. its food value overbalanced by toxic effect, 83. lowers alkalescence of blood, 98. predisposing factor in gout, 120. Alkaline-eliminant, clinical purpose of, 274. consideration of, 274-282. laxative and diuretic effects of, 277, 278. methods of administration of, 280, 281. modus operandi of, 293, 294. objective effects of, 276, 277. stimulant action on liver, 277. solvent effects of, 278. Alkaline remedies, action of, 219. effects of, 264, 265. on genito-urinary concre- tions, 272. used as diuretics, 269. use of in purin excess, 270, 271, treatment in joint injuries, 190. Raynaud's disease, 204. Alkaline remedies, some spinal trou- bles, 199. of tooth disorders, 216. Alkalinity affected by absorption of acid intestinal juices, 82. of blood and tissue juices, 77. after absorption of urates, 91. reduced by exposure to cold, 81. reduced by muscular effort, 81. reduced by antipyretic drugs, 260. reaction, contradicted by Joulie, 267. of urine, due to fermentation in bladder, 133. when first voided, 133. Alkyl, a substitute radicle, 28. Allantoin, a di-ureid, 32. in cats and dogs, 53, 54. possible irritant of kidneys in Bright's disease, 153. Alloxan, a mono-ureid, 32. Alloxuric bases, their properties, 31. percentages in beers, 74. Alveolar abscess, causation of, 215. American Journal of Physiol- ogy, 45, 82. American Medical Association, its journal, 25, 284, 294. American Medicine, 93, 132, 197, 240. American Practitioner and News, 200. American Text-Book of the Diseases of Children, 162. of Operative Dentistry, 215. Amino, a substitute radicle, 28. Amino-oxypurin, chemical name for guanin, 29. Amino-purin, chemical name for adenin, 29. Amino-purins, disappearing from urine of man, 63. Ammonia, liberated during muscular strain, 105. during purin metabolism, 246. Amorphous urates, absorbability of, 258. dissolved in alkaline blood, 279, 280. 298 BIBLIOGRAPHICAL AND GENERAL INDEX. Amorphous urates, readily dialyze, 292. Anaemia, symptoms of uricacidaemic stage in children, 160. Apoplexy, how occasionally caused, 115. Approximate test for uric acid in urine, 140. Arch. f. experiment. Path. u. Pharm., 276. Archives of Pediatrics, 200. Aronsohn, accepts Garrod's teach- ings, 268. Arteriosclerosis, in gout, 120. Arthritis, disorders of, due to uric acid deposition, 219. Ascoli, discovered uric acid destroy- ing power of liver, 44. finds uric acid is oxidized in body into urea, 39. Asthma, a symptom of uric acid re- tention, 183, 184. bronchial, potassium iodide in, 262, 263. in children, 163. precedes rheumatic attack in children, 109, 163. Astigmatism, relation of to uric acid retention, 182. Auto-intoxication, in relation to surgical procedures, 196. Autolysis, or auto-digestion of purins after animals' deaths, 49, 50. Autotoxaemia, due to a non-toxic factor, 289. B Backache, symptom of uric acid ex- cess, 197, 198. Baltimore, frequency of gout in, 120. Barbour, on growing pains of chil- dren, 200. Barley, a food now allowed in Japanese navy, 244. Bartels, his suboxidation theory, 15. Bate, on chronic Bright's disease, 149. Baumgarten, on amorphous urates, 280. Beebe, experiments with alcohol, 82. Beitrage zur Lehre vom Stoffwech- sel, 167. Bence-Jones, confirmed Garrod's findings, 16. Bergman, Prof. T. Olof., found uric acid in a cystitic calculus, 13. Beri-beri, dietetic treatment of, 243. Berliner K lini s c he Wo c hen- schri/t, 117. Beverages, tables of, showing amount of purin content, 74. Biliousness, symptoms of in purin excess, 138. Billings, Frank, on gout treat- ment, 266. Birds, serpents and fowls, uric acid metabolic end product of, 61. Bishop, his Diseases of Nose, Throat and Ear, 185. Bladder, irritability of neck of, 135. Blood, alkalescence of, 77, after taking the alkaline-elimi- nant, 279. reduced by antipyretics, 260. effect of alkalies on, 264, 265. its reaction, 267. its toxicity in normal preg- nancy, 171. pressure increased in menstru- ation, 168. why uric acid concretions do not form in, 115. Blues, fits of, their relation to uric acid retention, 98. Boston Medical and Surgical Jour- nal, 46. Bouchard, on resorption of toxins of body, 170, 171. Breton, Le, on orthopedic conditions, due to uric acid, 197. Brick-dust deposits in urine, 131. Bright's disease and eye affections, 179, 180. causes and treatment of, 146-155. preceded by an auto-intoxication process, 129. British Lancet, on quadriurates, etc., 28, 161, 280, 292. British Medical Journal, 168. Bronchitis, in children, 165. Bronson, on choroiditis, 181. Brooklyn Medical Journal, 160. Burian, R., demonstrates danger of lessened alkalinity of blood, 78. his feeding experiments, 37. his hypoxanthin-oxidase of mus- cles, 40. his theory of poverty of oxy- gen, 39. shows uric acid to be derived from muscle hypoxanthin, 66. shows uric acid to be derived from xanthin bases of meats, 19. BIBLIOGRAPHICAL AND GENERAL INDEX. 299 C Caffein, its physiological effect, ioo. one-third of from coffee excreted as a purin body, 38. Calculi, in urine of infants and chil- dren, 162, 163. Campbell, his Auto-intoxication in Diseases of the Eye, 182. Capillary obstruction with colloid urates, 86. Carbohydrate elements in food of tropical regions, 227. Caries, of teeth, from systemic causes, 210. Cellular Toxins, by Vaughan, 150. Centbl. f. Bakt. u. Prasitkd., 78. Centralblatt fur die Medicin Wissen, 271, 283. Charlotte Medical Journal, 196. Charcot, confirmed Garrod's find- ing, 16. Children, calculi in urine of, 162, 163, growing pains of, 199-201. purin excess in, 156-166. why more susceptible to uric- acidaemic stage, 159. Chinese, purin delicacies of the, 227-229. Chittenden, Prof. R. H., accepts Garrod's teaching, 268. believes uric acid comes largely from muscle metabolism, 67. concerning intermediary purin metabolism, 46. his feeding experiments, 72. on subject of nutrition, 239, 240. on uric acid excretion in gout, 294. Chorea, of uric acid origin, 165. the urine in, 166. Choroiditis, due to uric acid excess, 181. Oar, C, on action of alkalies, 271. Coffee, a cause of increased uric acid excretion, 72. Colchicum, objections to use of, 269. Collaemic disorders of uric acid origin, 219. Colloid urates, in uricacidaemic stage, 87. Concretions, in toe joints, 115. Constipation, a causative factor in uric acid excess, 247, 248. due to retention of uric acid, III. sequela of purin excess, 122. Coryza, due to retention of uric acid, 109. Coryza, may be rheumatic, 183. Croftan, Prof. A., experiments on guinea pigs, 119. on kidney troubles due to purins, 151. on liver oxidase, its composition, 292. shows lesions of renal cells, 69. shows uric acid changed to urea, 39. Croonian Lectures, by Sir William Roberts, 292. Cyclopaedia of Diseases of Children, by Keating, 157. D Dental conditions, in purin excess, 207-215. Congress, Fourth International, 209. Dental Cosmos, 210. Dentine, a poor thermal conductor, 208. how normally nourished, 211. Depression of spirits, preceding head- ache, 98. Diabetes, unfavorable for surgical operations, 194. Dialuric acid, a mono-ureid, 32. Die Gicht, 293. Diet and food, etc., 217. general rules for, 224. no-flesh, evils of a, 243, 244. Dietetics, for uricacidaemic patients, 235, 236. general rules concerning, 234. Dilithium urate, solubility of, 284. Dimethyl xanthin, chemical name for theobromin, 29. Dimmock and Branson's test for uric acid, 142. Dioxypurin, chemical name for xanthin, 29. Diseases of Infancy and Childhood, by Holt, 157. of Metabolism, by von Noorden, 281. Disorders of Digestion in Infancy and Childhood, by Fenwick and Lewis, 156. Di-ureids, contain four N. atoms to the molecule, 32. Dostal, on renal lesions from injec- tion of purin bodies, 69. Drummond, on aggravated uricacid- aemia in children, 161. Dyspepsia, of acid character, 126. 300 BIBLIOGRAPHICAL AND GENERAL INDEX. Earp, Prof. Saml. E., on the murexid test, 139. Ebstein, concerning the tophi of gout, 118. Eclampsia, puerperal, how caused, 174. Eczema, due to checked excretion of uric acid, 109. of children, 165. Ehrenfest, his theory of morning sickness in pregnancy, 172, 173. Elimination, essential before surgical operations, 193. English pediatricians, views of on rheumatism, 201. Environment, its relation to food requirements, 226. of American settlers, restricted, 229. unlimited, of modern times, 229, 230. Enzymes and ferments of tissues, 64. Erlenmeyer, his conical flask, 143. European clinics, statistics of, on eclampsia, 176. Evolution, explains why vena cava lacks valves, ill. theory of, 58. Exciting ^etiological factor of purin excess, 245. Excretory functions, aided by alka- line-eliminant, 278. Eye, disorders of, due to uric acid retention, 179-183. Fatigue, its setiological relationship to pain, 95. Feet, pains of, in rheumatic stage, 198. Fenwick, on uric acid infarcts of infants and children, 156. Ferments, intracellular, of the gen- eral tissues, 64 Fischer, Emil, made purin syn- thetically, 28. Fcerster, concerning quinic acid, 275. Folin, his test for uric acid, 144. Food, a mixed regimen indicated, '230, 232. education, a system of required, 233. for rheumatic stage, 237, 238. for uricacidaemic stage, 235, 236. in its relation to environment, 226 228. Food purins, their ultimate fate in the body, 50. tables of, 73. Formative period, in gouty stage of purin excess, 90. Fourcroy, Comte de, found urea as decomposition product of uric acid, 13. Fowls, gout produced experimentally in, 117. Frerichs, on changes in alkalinity of synovial fluid, 92. showed uric acid to be trans- formed in body into urea, 14. Freudenthal, on coryza and asthma, 183. Freudweiler, on tophi of gout, 118. Futcher, accepts Garrod's teachings on gout, 268. on frequency of gout in the United States, 120. on kidney insufficiency, due to uric acid excess, 127. G Galdi, finds uric acid excreted daily in feces of man, 45. Garrod, Sir Arthur, found uric acid in blood of gouty persons, 16, 17. his thread test, 17. on uric acid excess and nephritis, 127. Gangrene, resulting from capillary stasis, 195. Gaucher, injects xanthin, and hypo- xanthin, 119. shows lesions of renal cells from injection of purin bodies, 69. Genito-urinary concretions, how formed, 113. in concentrated urine, 114. influence of alkalies on, 272, 273. German Archives of Clinical Medi- cine, Vol. I, 15. Glycocholic acid, in bile, 56. Glycocoll, 21, 33. Gcelet, Prof. Augustin PI., on abdom- inal operations, 196. Gcetze, maker of Hall's purinometer, 145. Goiter, how sometimes caused, 169. in some spinal conditions, 198. Gorsky, on action of lithium, 283. Gout, characteristics of, 268. BIBLIOGRAPHICAL AND GENERAL INDEX. 301 Gout, experiments in the production of, 117. excretion of uric acid in, 167. its frequency in United States, 120. therapy of, 266-273. uric acid deposits in, 118. Gouty stage, dietetic treatment of, 242, 243. formation of concretions in, factors favorable to, go, 92. manifestations of, 113. names of symptoms of, 256. of purin excess, 84-90. Gouty-pericementitis, 215. Greetzer, on uric acid infarcts of infants, 157. recommends water in infarcts of infants, 158. Graves' disease, how sometimes caused, 169. Growing pains, symptoms in rheu- matic stage, 199-201. Guanase, a ferment of tissues, 47, 64. Guanin, a direct irritant in intestines, 52, 53- excreted in feces, 51. how changed to hypoxanthin and ammonia, 105. in walls of intestines, 46. Guano, as a fertilizer, 8. H Hahn and Nencki, show uric acid is changed to urea by the liver, 43, Haig, Alexander, believes uric acid circulates in solution with phosphates, 42. criticism of his works, 220. concerning Raynaud's disease, 203. contradicts himself, 222. experiments with drugs, 225. his classification of uric acid disorders, 219. his mistake, 221, 222. his uric acid labors, 217-226. his uric acid theory, 218. his uric acid experiment, 25. on action of salicylates, 263. on drug action, 219. popularity of his works, 217. value of his work to clinicians, 224. Haines-Bulkley Rule for estimating amount of solids in urine, 135. Hall, I. Walker, experiments con- cerning removal of purins from body, 50. experiments on rabbits, 151, 152. found one-half bound purins of flesh food excreted in 48 hrs. , 51. his feeding experiments, 37, 72, his work on Purin Bodies in Food Stuffs, 53. invents the purinometer, 145. shows 40 to 60^ of uric acid to be changed into urea, in body, 44- Hans, on uric acid retention in gouty people, 127. Hare, Prof. Hobart Amory, on uric acid excess in Bright's disease, 155. Harley, his test for uric acid in urine, 142. Harvard Medical School, 243. Hawaii, purin delicacy of the natives of, 229. Hay-fever, due to checked excretion of uric acid, 109, 183-185. Headache, conservative of menstru- ation, 96. "next morning," after alcoholic debauch, 97. of uricacidcemic stage, how caused, 96. powders, their action in system, 100. precedes uric acid explosion, 107. Heart failure, how occasionally caused, 115. Heat and acetic acid test for uric acid in urine, 140. Heintz, his test for uric acid in urine, 141. Hematuria, in children, 162. Hepatic insufficiency, a complication of gout, 125. torpor, its effect on uric acid excess, 137. renal insufficiency, a predispos- ing cause of purin excess, 247, 248. Herter, C. A., on urine in chorea, 166. on urine in cyclic vomiting, 162. His, Jr., W., concerning quinic acid, 275. his studies into physical chemis- try of uric acid,' 26. 302 BIBLIOGRAPHICAL AND GENERAL INDEX. His, Jr., W., on action of lithium, " 284. thinks uric acid circulates in dif- ferent combination in gout, 128. wonderful experiments of, 292. Holt, on urine of children in chorea, 165, 166 on urine of children in cyclic vomiting, 162. on urine of children in uricacid- aemia, 161. on urine of infants, 157. recommends water for uric acid infarcts, 158. Homburg, a natural alkaline water, recommended by von Noor- den, 281. Hopkins, his test for uric acid in urine, 144. Hoppe-Seyler's Zeitschrift fur phy- siol. Chemie, 40. Horbaczewski, obtained uric acid from spleen pulp, 18. showed that nuclein produced increased uric acid excretion in 2 hrs., 19. the first one to prepare uric acid synthetically, 21. thought uric acid was derived only from nuclein of leuco- cytes, 37. Hutchinson, on action of the alka- line laxatives, 284, 285. Hydantoin, a mono-ureid, 32. Hydro-carbon elements, in food, 226. Hydrochloric acid, used to acidulate urine, 141. Hydroxyl radicles. 26. Hydurilic acid, a di-ureid, 32. Hypoxanthin oxidase, cannot act efficiently without O, 41. formed from, muscles, 66. Hysteria, one of the neuroses, 102. Ibrahim, on uric acid injected sub- cutaneously, 40. Incidental ^etiological factors of purin excess, 249. Infarcts of uric acid in kidneys of fowls, 118. in kidneys of infants, 156. symptoms of, 157, 158. Inflammation, as a local symptom, 253. 254. Inflammation, in treatment of, remove the cause, 257. Insomnia, cause of, 99. International Clinics, Vol. IV., 182. Internationa/ Medical Magazine, 192 . Intestinal lithiasis, 119. Intracellular ferments, of general tissues, 65. Ionic dissociation, in uric acid solu- tions, 26. Iritis, due to uric acid retention, 180. J Jacobi, Prof. A., on artificial alkaline waters, 265, 281, 286. on growing pains, 200. Japanese, food requirements of, 227, 228. navy, food now adopted for, 243. Joints, injuries of and convalescence from, 188. treatment of, 190. Joulie, on neutral reaction of blood, 267. Journal of Laryngology and Rhin- ology, Vol. III., 186. Journal of the American Medical Association, 25, 284, 294. K Keating, his Cyclopaedia of Diseases of Children, 157. on character of urine in infants and children, 163. on uric acid infarcts of infants and children, 157. Kidney, as a dialyzer or filter of urine, 79, 80, 147. cause of inflammation of in Bright's disease, 149. congestion of, 146. injured by salicylates, 266, 267. in true Bright's disease, 146, 147. in uricacidaemic and rheumatic stages, 154. its action stimulated before surgical operations, 193. its power of apparent selection, 148. its power of excretion injured by purins, 150. no irritation of, from sodio- lithium, 287. of new-born infants, 156. osmosis of uric acid through epi- thelium of tubules, 148. BIBLIOGRAPHICAL AND GENERAL INDEX. 303 Kidney, troubles of, in purin excess, 127. work of as an excretory organ, 127, 128. work of as an excretory organ to be favored in gouty stage, 242. Kionka, H., his experiments upon fowls, 117. Kissingen, a natural alkaline water, recommended by von Noorden, 281. Klemperer and Strauss, confirmed Garrod's findings, 16. Klemperer, Prof., on weak alkaline solutions of inorganic salts, 91. Kochmann, experiments on dogs with ox-flesh, 52, 53. Kolisch, on lesions of renal cells from injection of purin bodies, 69. on the injection of xanthin and hypoxanthin, 119. Kossel, obtained xanthin, hypoxan- thin, adenin and guanin from nuclein, 18. showed that meat increases uric acid excretion owing to its free xanthins, 19. Kowalewski, found uric acid in all nuclear tissues, 38. Kugelurate form of amorphous urates, 258. L Lancet (British), 28, 161, 280, 292. Lancet-Clinic, The, 149. Lautenbach, Prof. Louis J,, on astigmatism, 182, 183. Laxatives, effects of alkaline salts, 272, 273. in lithaemic sore throat, 187. Le Breton, on orthopedic conditions, 197-199. Leg-cramps, due to uric acid reten- tion, no. Lehmann, his Text-Book of Physio- logical Chemistry, 15. Levison, on action of salicylates, 263. Lewis, on uric acid infarcts of infants and children, 156. Lichty, considered uric acid w T as ex- creted as result of headache, 97. Lithemia, synonymous with uricacid- semia, 85. Lithemic gangrene, or Raynaud's disease, 204. Lithemic sore throat, Sir Morell Mc- Kenzie, 186. Lithiasis, in children, 162. Lithium, alkaline salt of, for uric acid infarcts, 159. combined with a laxative, 284,286. diurate, solubility of, 284. Haig's views concerning its action, 223. properties of, 283-285. salts of, in reducing acidosis, 270, 271. urate of, injected intravenously into animals, 53. Liver, affected by toxic action of alcohol, 82. in uricacidsemic stage, 83. its relation to eclampsia, 175. oxidase of, 292. oxidizing function injured by sulphonal, 261. synthetic formation of uric acid in birds', 34. the human grate, 125, 126. the urea-forming organ, 137. torpid, to be stimulated, 275. Lorenze, E. J., reports case of uric acid infarcts in two infants, 158, 159. Lowi, O., agrees with Hall, 44. believes nuclear uric acid derived chiefly from glandular organs, 37- Ludwig-Salkowski test for uric acid in urine, 144. Luthje. on injurious action of salicy- lates, 266. Lymph, why favorable to uric acid concretions, 115. M Macalester, on uric acid retention in gout, 128. Macdonald, concerning leg-cramps, no. MacKenzie, Sir Morell, on lithemic sore throat, 186. Mackie, on adenoids, 165. Macleod, believes uric acid is derived chiefly from muscle metab- olism, 67. Manley, Prof. Thos., on joint injuries, 188. Mares, his feeding experiments. 37. Mathews, concerning constipation,. 122. 304 BIBLIOGRAPHICAL AND GENERAL INDEX. McCrudden, his book on "Uric Acid," 267, 270. McKinley, Pres., concerning the operation upon, 194. Meat, increases uric acid excretion, 73- soups, solutions of xanthins, 241. tables of, showing purin con- tent, 73, 74. white vs. dark, 75. Medical Record, 170, 188. Mendel, Prof. Lafayette, accepts Garrod's teachings, 268. believes uric acid is derived largely from muscle, 67. his uricolytic ferment, 47. on the checked excretion of uric acid in gout, 294. Menopause, uric acid excess in, 177. Menstruation, experimental study of, 167. retention of uric acid at begin- ning of flow, 97. Menu, for purin excess patients, 237. Metabolism, comparative, in animals, 53- faulty, in uricacidcemic stage, 87. Methylxanthins, cause reflex irritabil- ity, 52. Microscopic examination, for uric acid in urine, 143. Miescher, on xanthin bases as decom- position products of uric acid, 18. Migraine, followed by uric excretion in excess, 97. in children, 160, 161. in menstruation, 169. Miller, on tooth decay in rheumatism, 210. Minkowski, gives adenin to dogs, 149. his feeding experiments with ade- nin and hypoxanthin, 38. on treatment of uric acid excess, 293. shows pure albumin foods do not cause uric acid excess, 19. shows that, in gout, uric acid is in different combination, 128. supports Futcher's view, 127. Mono-oxypurin, chemical name for hypoxanthin, 29. Mono-ureids, two N. atoms to the molecule, 32. Montgomery, Prof., on surgical opera- tions, 192, 193. Morton, Sanford, on eye affections, 180. Mucous membrane, a vicarious avenue for excretion of uric acid, 109. Murexid test for uric acid, 139. Muscle, defective nutrition of, 112. metabolism of uric acid, 40, 64, 66. strain, and blood subalkalinity, 104. when at work, increases hypoxan- thin, 40. Muscular energy minimized in the or- ganic evolutionary process, 60. stiffness, how caused. N Nencki, shows that uric acid is changed by liver to urea, 43. Nephrite epitheliale, a precursor of gout, 119. Neumayer, on action of lithium, 283. Neumeister, agrees with Hall, 44. Neuralgic twinges, in rheumatic stage, 89. Neuroses, due to uric acid retention, 102. Neurotic Disorders of Childhood, by Rachford, 150. New York Academy of Medicine, 239. New York and Philadelphia Medical Journal, 200. New York Lancet, 189. Nicolaer, concerning quinic acid, 275. Night terrors, of children, 161. Nitrogen, loses "explosive" action at moment of nuclein breakdown, 67. retention and excretion in men- struation. 167, 170. Nitrogenous elements in food, 227. excreta, 7. food, excess of ingested, 239, 240. food elements, 227. waste, 55. Nomenclature, modern medical, 251. Northwestern Lancet, no. Nose, disorders of, due to uric acid retention, 183-186. Nosological basis of treatment, 251, 252. Nuclease, a tissue ferment, 47, 64. Nuclein cleavage. 29. most of it absorbed from intes- tines direct into circulation, when fed to man, 51. BIBLIOGRAPHICAL AND GENERAL INDEX. 305 Nucleo-proteids, 30. Nutrition, a study of, 239, 240. O Objective signs of purin excess, how caused, 246. Ocular inspection of urine, 131. phenomena, due to uric acid ex- cess, 179. Oliguria, favors formation of uric acid calculus, 114. Oliver, on high blood pressure in men- struation, 168. Omnipotent power, its impersonality, 58. Operations, surgical, importance of elimination before, 193. Ophthalmic Review, 180. Opper, analysis of white and dark meats, 75. Ord, experimental investigations of, 292. Osier, wards in Johns Hopkins Hos- pital, 120. Overeating, a causative factor of purin excess, 247. Oviparous animals, whose end prod- uct is uric acid, 8. Oxaluric acid, a mono-ureid, 32. Oxidase of liver, its character and function, 41, 292. Oxypurins, of meat, 49. Pain, howcausedinuricacidemicstage, 95- in gout, a characteristic, 113, 115. Parabanic acid, a mono-ureid, 32. Parrot, on composition of uric acid infarcts, 156. Patton, Prof. J. A., on alkaline medi- cation, 284. Paul, on ionic dissociation, as applied to uric acid solutions, 26. Peirce, Prof. C. N., on pyorrhea areo- laris, 215. Peoria Medical Journal, 189. Pericarditis, often present in gout, 120. Peridental membrane, an analogue of bone marrow, 207, 208. Pfeiffer, accepts Garrod's teachings, 268, 269. on action of lithium, 283. Phelps, Prof. A. M., on joint injuries, 189. Phosphates, Haig's views concerning, 223. Piffard, on treatment of lithemic affec- tions of skin, 187. Pinard, on liver in eclampsia, 1 75. • Porter, Prof. W. H., on sprains and bruises, 188. Potassium iodide, in lessening viscos- ity of blood, 262, 263. salts, in lessening acidosis, 270, 271. Practical Diagnosis, or the Use of Symptoms in the Diagnosis of Disease, by Hare, 155. Practical Medicine Series of Year Books (1905), Billings, 266,268. Pediatrics, by Grretzer, 157. Precipitant remedies, their action, 274, 275- resembles quinic acid, 275. Precipitants, their action on urates, 259, 260. therapeutic action, 219, 220. Predisposing factors of purin excess, 247. Pregnancy, morning sickness of, 172. toxaemia, cause of, 171. Prevailing custom of treatment of purin excess, 258, 259. Proteid molecules, unstable, 67. Psoriasis, due to checked excretion of uric acid, 109. Puerperal eclampsia, how caused, 174. its treatment, 176. Purin delicacies, of modern times, 231, 232. excess, an accumulation of uric acid and congeners, 84. feeding of American settlers, 230, 231. foods, 72. tables of, showing contents of, 73- free foods, from animal kingdom, 241. free mixed diet, usually indicated, 232. nucleus, 28. the three stages of "purin excess, " 84. Purinometer, an instrument for de- tecting amount of purin bases, 145. Purins and ureids, difficulty dialyzed by kidneys, 65. comparative metabolism of, 53. 306 BIBLIOGRAPHICAL AND GENERAL INDEX. Purins and ureids, bound, exogenous, 49- decimal decrease of, in urine, 62. free exogenous (excepting gua- nin). dissolved in intestinal juices, 50. pharmacological action of in body, 5- unbound, exogenous, 48. unbound, exogenous, in feces, 45. unbound, exogenous, how re- moved by cooking properly, 241. their removal from system, 63. their toxicity, 69. Purpurine, a pigment of urine, 21. Purpurate of ammonia, a di-ureid like uric acid, 32. in murexid test, 139. Purum uricum, 28. Pyorrhea Alveolaris, of constitutional origin, 215. Q Quinates, action of on the urates in the blood, 276. Quinic acid, its physiological effects, 276, 276. R Rachford, his work on the Disorders of Childhood, 150. Ranke, confirmed Garrod's finding, and suggested that uric acid and hypoxanthin have a similar origin in body, 16. Raynaud, his Thesis, 203. Raynaud's disease, cause of, etc., 202- 206. Reach, on uric acid retention in gouty subjects, 127. Reaction of blood, weakened, 79. Reference Handbook of the Medical Sciences, Vol. IV., 1S1. Remedies in common use, effect of, 258-264. ill effects of, 260. temporary effects of, 259, 260. Renal inadequacy, 127. Retention cf solids in urine, 134. Revue de Therapeutique, 119. Rheumatic attack, from uric acid ex- plosion, 107, 108. joints, 188, 189. iritis, 180, 181. patients, proper food for, 237,238. Rheumatic stage, action of drugs used in, 262. growing pains a symptom of, 199- 201. manifestation of, 104. names of symptoms in, 255. of Purin Excess, 84, 88. signs of, in children, 164. Roberts, Sir W., his quadriurate of soda, 28. investigations of, 292. Robinson, Prof. Byron, on uric acid calculus, 114, 132. Rockwood, E. W., shows endogenous excretion of uric acid differs or varies in different individu- als, 45. Romberg, on viscosity of the blood, 86. Rose, his ancient chemical treatise, 222. Rosenfeld, on action of alkalies, 267. Rosenheim, expert opinion concerning quadriurates, 28. on amorphous urates, 280. Rosenquist, his analysis of white and dark meats, 75. Rosewater, on Raynaud's disease, 203, 204. Ruhemann, invents the uricometer, 144. Salicylates, action of (Salisbury) 266, 267. effect of, on stomach and kidneys, 263, 264. Saline therapy, von Noorden, 281. Salisbury, Prof. J. H., on action of salicylates, 266, 269. Salkowski, his theory that uric acid is derived from xanthin base, 17. with Ludwig, discovers test for uric acid, 144. Salomon, confirms Garrod's finding, 16. Satterlee, on growing pains, 200. Scheele, Karl VVm., the discoverer of uric acid (1776), 13. Scherer, finds hypoxanthin in spleen of leukemic subjects. 17. Schiff, his test for uric acid in urine, 142. Schittenhelm, finds uricolytic ferment in marrow of bones, 47. shows that normal feces contain purin bodies, 46. BIBLIOGRAPHICAL AND GENERAL INDEX. 307 Schlayer, concerning quinicacid, 275. Schmiedeberg, on effects of purin de- rivatives, 150. Schmoll, E., believes uric acid circu- lates in combination with thy- minic acid, 41. Schrader, on nitrogen retention in menstruation, 167. Schreiber, on action of the salicylates, 266. Schiir, feeding experiments of, 37. finds uric acid is derived from xanthin bases, 19. Sciatic nerves, tender points over, 198. Senator, casts doubt on Bartel's sub- oxidation theory, 19. Sheffield, translates Graetzer's book, from the German, 157. Silver nitrate test for uric acid, 142. Simon, Prof. Chas. E., believes all uric acid would be changed to urea, if all blood passed through the liver, 43. his Physiological Chemistry, 64. on blood reaction, 79. Siven, his feeding experiments with uric acid containing foods, 72, 73- Skin, vicarious avenue of uric acid explosion, 108. Smith, L. B., a victim of joint injury, 190. Smith, on urine in cyclic vomiting, 1 66. Sodio- lithium, its action, 285, 286. Sodium, salts of, in reducing acidosis, 270, 271. Soetbeer, injects uric acid subcuta- neously, 40. Solvent effects of the alkaline elimi- nant, 278. properties of lithium, 283, 284. Special Creation theory, 57. Spencerian theory of evolution, 58. Spiegelberg, on uric acid infarctions of the new-born, 150. Spine and lower extremities, uric acid excess in, 197. Spitzer. found uric acid in all nuclear tissues, 38. Starr, Prof. Louis, on urine of chil- dren, 162. Stedman, on N. retention in men- struation, 170. St. Louis Courier of ALedicine, 173. St. Louis Medicaland Surgical Jour- nal, 190. St. Louis Medical Review, 243. Strauss, with Klemperer, confirmed Garrod's finding, 16. Sulfonal, effect on liver of mammals, 54-. injurious action of, on liver, 261. relieves insomnia temporarily, 101. Surgical procedures, how to prepare for, 192-194. Sweinitz de, Prof. G. E., on ocular symptoms in Bright's disease, 180. Symptom therapy, 253, 254. Symptoms, localization of, in rheu- matic stage, 89. localization of, in uricacidaemic stage, 87. periodicity of, 102. Synovia, good locale for uric acid crystallization, 115. Syphilis, three stages of, similar to those of Purin Excess, 84, 85. Takaki, Baron, on foods of Japanese navy, 243. Talbot, Prof. Eugene, on constitu- tional causes of tooth decay, 209. Tandler, on injections of xanthin and hypoxanthin, 119. lesions of renal cells from injec- tion of purin bodies, 69. Tannin, precipitant action of, on al- buminous substances, 276. Taylor, feeding, experiments of, 72. Teeth, alkaline treatment of affections of, 216. anatomical divisions of, 207. decay of the dentine of, 209. disorders of, 207-215. gold filling, a good conductor, 209. urate deposits in, 214. Temporary effects of antipyretic drugs, 259- Theobald, on rheumatic iritis, 1S1. Therapie d. Gegemvart, 91. Therapeutic error, a source of, 252, 253- methods of to-day, 251-258. Thialion, asan alkaline-eliminant,285. Throat, disorders of, due to uric acid retention, 186, 187. Thyroid gland, an organ of defense, 169. 308 BIBLIOGRAPHICAL AND GENERAL INDEX. Thyroid gland, enlarged during men- struation, 168. Tilney, W. T., a victim of joint injury, 189. Tonsillitis, due to checked excretion of uric acid, 109. precedes rheumatic attack, 109. Toothache, symptom of uricacidsemic stage, 212, 213. Toxaemia, of pregnancy, 171. Transitional stage, in human evolu- tion, 59. Transition period, in rheumatic stage, 88. Traumatisms, convalescence from, 191. Treatment, of names of disease, 251- 255. Trimethylxanthin, chemical name for caffein, 29. effect of on blood, 100, 101. Trioxypurin, chemical name for uric acid, 29. Tunicliffe, expert opinion on quadri- urate of soda, 28. expert opinion on amorphous urates, 280. Tyson, his Bright's Disease and Dia- betes, 180. U Ulcers, varicose, uric acid retention in, 192. Ulrici, concerning quinic acid, 276. Uratic deposits, 25, 80. absorbed, en masse, 82. after joint injuries, 191. cause of pain, 95. cause of tissue lesions, 119. from subalkaline blood, 81. in tissues of teeth, 214. localization of in gouty stage, 91. explosion in gout, 116. explosion, possible beginning of Bright's disease, 155. Urates, amorphous, absorbability of, 258. amorphous or acid, 23. deposited in canaliculi of kidney, 129. deposited in growing pains, 202. deposition of, causes muscular stiffness, 104. dilithium, most soluble of all urate salts, 27, 284. dinatrium, 27. Urates, explosion of, 98. explosion of, following migraine, 97- held in solution in normal urine, 43- heminatrium, 28. mononatrium, 27. of heavy metals, 124. of soda in intestinal walls, 123. precipitated in unusual localities, . II5 ' sites of, in rheumatic stage, 108. Urea, end product of albumin meta- bolism, 14. end product of all nitrogenous metabolism, 65, 295. its daily average excretion, 135. its daily average production, 130. retained in the organism, 129. retention of, in eclampsia, 176. retention of, prior to menstrual flow, 167. Ureids, nature of, 21, 32. Uricacidsemic manifestations, 95. patients, proper food for, 235, 236. signs, in diseases of infants and children, 159. .signs in pregnancy, 177. signs in Raynaud's disease, 205, 206. stage and tooth decay, 211. stage of Purin Excess, 84, 85. stage, names of symptoms in, 255. Uric acid, An Epitome of the Subject, by Haig, 217. an intermediate product of purin metabolism, 54, 64, 295. a nitrogenous excrement, 7. a plant food, 8. As a Factor in the Causation of Disease, by Haig, 217. as a factor in choroiditis, 181. as an alkaloid of plants, 9. as a vestigial curiosity, 61. a simple test for, 145. attraction of its crystals, 25. causes first injury in Bright's dis- ease, 152, 153. causes symptoms of malaise, 52. concerning its synthetic forma- tion, 33. conditions usually unrecognized, 197-206. crystallization in gouty stage, 92. crystals of, their color and shape, 143. BIBLIOGRAPHICAL AND GENERAL INDEX. 309 Uric acid, derivation from xanthin bases, 17. diathesis, how caused, 290. disease processes, due to its pres- ence in excess, 82. discoveries concerning, in later days, 291. dissolved, by alkaline eliminant, 278, 279. early theory of origin of exploded, 18. excess and food poisons, 218. excess, causes of, 71, 72. excess, three stages of, 84. excreted in excess as headache disappears, 97. excreted soon after ingestion as such, 50, 51. excretion, consideration of, 43. excretion, following lithium, 283. explosion, 107. formed faster than excreted, 150. free menu card, 237. how it circulates in the body, 41. in amorphous form, 280. in blood, increased in gout, 268. in colloid form, 56. increased by ingestion of alcohol with purin foods, 82. in human flesh food, 55. in its relation to astigmatism, 182. in its relation to growing pains, 201. in its relation to hay-fever, 1.85. in its relation to jointinjuries,i88. in its relation to surgical opera- tions, 193-195. in its relation to the teeth, 2 10-2 16. in relation to varicose veins and ulcers, 192. infarcts in infants, 156. infarcts in infants, symptoms of, 157. in feces, 45. injurious to cells of renal tubules, 152. in Kugelurate form, 258. in meat (stake or bake) done rare, 49- in urine, 21. its acid behavior, 27. its accumulation in the organism, 68. its catabolism, 39. its chemical form in flesh food, 55. Uric acid, its chemical properties, 27. its composition, 27. its crystallization and precipita- tion, 23. its crystallization in urine, 114. its cumulative action, 10. its decimal decrease in urine, 62. its decomposition in the organ- ism, 31. its discovery (1776) by Scheele, 13. its egestion vs. ingestion, 44. its elimination in pregnancy, 171. its endogenous origin, 37. its exogenous origin, 38. its experimental study, 290. its ionic dissociation, 26. its normal finding in the organ- ism, 68. its pathological importance, 289. its power for good or evil, 11. its purin structure, 28. its retention and excretion in menstruation, 167. its retention at the menopause, 177. location of in flesh food, 10. location of in vegetable food, 9. metabolism and albumin meta- bolism, 19. McCrudden's treatise on, 267, 270. of no use in the body, 68. of urine in children, 166. of urine in chorea, 165. of urine in cyclic vomiting, 162. oxidation of, into urea, 50, 291. physical appearance of, 21. produced from xanthins, 106. rational formula of, 29. recent findings concerning, 20. resorbed and eliminated, 125. retention and gangrene, 195. retention in constipation, 123. retention in muscular effort, 105. retention of in gout, 294. retention producing leg cramps, no. solubility of, 21. storms, preceded by depression of spirits, 98. Tables of, 73, 74. tests, Folin-Hopkins' method for expert laboratory work, 144. tests, general, 139-146. the early medical theory concern- ing, 14. 310 BIBLIOGRAPHICAL AND GENERAL INDEX. Uric acid theory, of Raynaud's disease, 203, 204. Uricolytic ferment, 47. Uricometer, instrument for testing for uric acid, 144. Urinalysis, general consideration of, I3I-I39. in cystitis, 133. in hepatic insufficiency, 138. preceding and following head- ache, 107. Urine, alkaline, due to volatile alkali, 133. alkaline, of herbivorous animals, 278, 279. alkaline, sign of cystitis, 133. cause of its acidity, 78. condition of, in uric acid explo- sions, 107. contains one part uric acid to 1000, 114. " incontinence of, 136. in some spinal troubles, 198. its character in gout, 117. its ocular inspection, 131. its physical appearance during an attempted explosion, 131. its toxicity in pregnancy, 172. uric acid crystallization in, 114. V Varicose ulcers, retention of uric acid in, 192. Vaughan, his work on Cellular Toxins, 150. Veal (bob-calves), contains greater percentage of purins, 75. Vegetables, Tables of, showing purin content of, 74. Vegetarianism, why unphysiological, 228, 229. Vegetarian views of Haig, 224. Veit, his theory of immunization, 173. Verhandl. des Kongr. f. innere Medizin, 283, 293. Virchow, finds abnormal amount of uric acid in leukemia, 15. on clinical appearance of uric acid infarcts, 157. on composition or uric acid in- farcts, 156. Viscosity of the blood, 86. Visual irregularities, temporarily caused, 181. Vibert, on intestinal concretions, 119. Vogt, on uric acid retention in gouty subjects, 127. Vomiting, cyclic, of infants and chil- dren, 162. Von Fodor, demonstrates lessened alkalinity of blood, 78. Von Liebig, Baron Justus, investigates with Wohler, 14. Von Noorden accepts Garrod's teach- ings on gout, 268. blames alcohol for causing diffi- cult excretion of uric acid, 83. his Diseases of Metabolism, 281. on subject of treatment, 203. W Wakefield, on causation of gout in toe, 93- Weidner, on action of salicylates, 263. Weiss, concerning quinic acid, 275. West, on composition of uric acid infarcts, 156. Wheeler, on asthma of children, 164. on rheumatism of children, 164, 165. on uricacidsemia of children, 160, 161. Wiener, believes in synthetic forma- tion of uric acid in body, 34. Wohler, Friedrich, on relation ©f uric acid to urea, allantoin, etc., 14, 15. Wollaston, Wm. Hyde, found uric acid in gouty concretions, 13. X Xanthin bases, cause of pathological changes like ammonia, 70. early findings of, 17. effects of in body, 52. how changed to uric acid, 106. solutions of, as meat soups, 241. Xanthin oxidase of muscles, 47, 64. Xanthins, of tea and coffee, like quinic acid, 276. Zaudy, on action of the salicylates, 266. Zeitschrift fur physio I. Chemie, 40, OCT 24 190?