The Address on Medicine. BY E. L. SHURLY, M.D., OF DETROIT, MICH. Delivered at the Forty-second Annual Meeting of the American Medi- cal Association, held at Washington, D. C., May, 189/. Reprinted from " The Journal of the American Medical Association," May 23, 1891. CHICAGO : Printed at the Office of the Association. 1891 THE ADDRESS ON MEDICINE. Mr. President and Members:-As it would be improper on this occasion to attempt even a men- tion of the vast number of interesting and in- structive ideas and observations connected with the science and practice of medicine, which has been evolved during the past year, I shall present for your attention only some points bearing on THE RELATION OF MICROORGANISMS AND TOX- INES TO THE SO CALLED ZYMOTIC OR INFECTIOUS DISEASES, and as this subject in its various ramifications is too vast for a detailed consideration, I must of necessity confine myself, in great measure, to a generalization upon the biological and chemical features involved. While laboratory work has done perhaps more than any other branch of sci- ence toward clearing up many vexed questions about physiological and pathological activities, yet to be of lasting value and guidance it must agree with general and clinical observations. While this has been the case more often than otherwise, yet there are instances where labora- tory observations and clinical data have crossed swords! Before proceeding to an examination of the topics mentioned, it will be necessary for us to keep in mind the fact, that the organized animal body is composed of, and is under, the operation 2 (the same as other bodies) of the three elements of the Universe, Ether, Energy and Matter, under various forms and methods of combination; to which maybe added what is known as "Vital Force," which some scientists regard as " energy of position" from the combustion of food. Also that this fact applies to a condition of disease as well as health ! For in Somatic death, even, i. e., death of the whole body, there are certain ele- mental tissues which die first, such as the blood and parenchymatous tissue, while certain other tissues, such as the epithelial, resist for a time, at least, the destructive or resolving power of Kinetic Chemical energy. In fact, the only difference between life and death from a physical point of view, consists of changes in the molecular or atomic arrangements under the direction of chem- ical, calorific, or electric energies. For matterand energy axe indestructible! As Shelley says, "I change, but I cannot die." To understand at all, the range of pathology and pathological chemistry,-to which we must undoubtedly look for the solution of many of the problems of the present day, it will be proper to take a brief survey of physiology and animal chemistry, which may be considered the founda- tion stones of our art. To sum them up according to Mills, Foster and Kirk, we have The Proximate Principles, which are: Nitrogenous -Proteids. Non-nitrog- enous Organic Certain Crystalline bodies. Sugars (Carbo-hydrates), Fats (Hydro-carbons). The Inorganic Mineral salts. Water. The proteids are the chief constituents of liv- ing tissues, including the blood and lymph. 3 The molecule is highly complex, consisting of a great number of atoms, and is formed of the ele- ments C.H.N.O.S. and P., although some chem- ists think that we are still in ignorance of its exact molecular constitution. The proteids are amorphous and non-diffusible, excepting the pep- tones. They are soluble in strong acids and al- kalies with change of properties and constitu- tion. In general, they are coagulated by alcohol, ether and heat. They may be classified into: Native Albumins: Egg-albumin, serum-albu- min. Derived Albumins (albuminates): Acid-albu- min, alkali-albumin, including syntonin (from muscle), para-peptone, and casein. Globulins: Globulin, paraglobulin, fibrinogen, myosin, vitellin, globin. Fibrin: Coagulated proteids. Peptones: By the decomposition of proteids (albumin) by digestion with pepsin we obtain: Antialbumose, anti-peptone ; and with trypsin, hemi-albumose, hemi-peptone, leucin andtyrosin. By decomposition with acids, we get with hy- drochloric acid: antialbumate, antialbumid, hemi- albumose and hemipeptone. And with sulphuric acid we get antialbumid, hemialbumose, hemipeptone, leucin and tyrosin, and lardacein (an amyloid substance). The nitrogenous, non-crystalline bodies allied to proteids are: mucin, chondrin, gelatin (or glu- ten), elastin, keratin, nuclein, chitin. Carbo-hydrates (Sugars): Dextrose, maltose, lactose, inosit, dextrin, glycogen, tunicin. Fats, Fatty Acids, etc.: Formic acid, propionic acid, acetic acid, butyric acid, valerianic acid, ca- proic acid, capric acid, caprylic acid, laurostearic acid, myristic acid, palmitic acid, stearic acid. The Oleic (Acrylic) Acid Series : Oleic acid. 4 The Neutral Fats: Glycerin. The Glycocholic Acid Series: Glycol, The Lactic Acids: Bibasic Acids ( Oxalic Acid Series') : Oxalic acid, succinic acid. The complex nitrogenous fats (which are ob- tained from nerve tissues) such as lecithin, gly- cerin, phosphoric acid, protagon, neurin, cerebrin. The Series of Bile Acids, etc.: Cholic (or cho- lalic) acid, glycocholic acid, taurocholic acid, and cholesterin; which has been said to be the only free alcohol formed in the body. The Bile Pigments: Bilirubin, biliverdin, cho- letelin, hydrobilirubin. The Pigments of Urine: Urobilin, uroerythrin. The Indigo Series: Indican, indigo, indol, skatol. The Nitrogenous Metabolites: Urea, urea ni- trate, uric acid, creatin, creatinin, allantoin, hy- poxanthin (sarkine), xanthin, carmin, guanin, kynurenic acid, glycin, taurin, leucin, asparagin, amido succinamic acid, aspartic acid, glutaminic acid and cystin (an amido-acid). The Acids of the Benzine, oi Aromatic Series: Benzoic acid, hippuric acid, phenol, tyrosin. In addition, we must include the leucomaines, for the discovery of which we are chiefly indebted to Gautier. According to Vaughn and Novy there are three groups, which they classify as follows : The uric acid group, in which they enumerate ten bases. The creatinin group, consisting of seven bases, and a third, undetermined group. Besides these Brieger, Gautier, Hoppe Seyler and others, have isolated from animal and vege- table organisms in various states of decomposi- tion, about forty substances called ptomaines, some of which exist, and are formed, at times, in 5 the human economy-especially in the intestinal canal. Now, when we contemplate this vast array of physiological and pathological chemical prod- ucts of the laboratory of the animal body, some of which are so noxious if retained in certain situations or are deflected from certain courses, we ought not to be surprised at the ease with which that equilibrium of the functions-called Health-may be upset; especially as the so-called civilized human being is not only an artificial animal with artificial impulses, and a great range of volitional power; but is assailed on every side by enemies of a parasitic nature, which, if suc- cessful in the ' ' universal struggle, ' ' may greatly hinder the molecular and chemical coordination. Many thinkers have maintained that the biologi- cal were not distinctive from the chemical pro- cesses in Nature; but, although intimately con- nected, we must recognize the difference between the peculiarly vital character of molecular and blastic changes concerned in cellular movement, growth and development, such as Karyokenesis; and those changes which, from time to time, take place in the composition of the proximate princi- ples in the nature of fermentation or oxidation, which are strictly chemical. We know that certain irritations of a chemi- cal, mechanical, electrical or calorific nature may be transmitted to vessels, so as to pro- duce stasis and inflammation, or, directly to leucocytes, or other cellular elements, so as to induce other changes-degenerations-such as the albuminous, amyloid, waxy, lardaceous, caseous or hyaline. We also recognize that there are various degrees of susceptibility and resistance belonging to different tissues, and at different times under equal provocation, so that the blood, leucocytes, and other cells which under the influ- 6 ence of the nervous system, are the most impor- tant agents in carrying on the oxidation and nutri- tion of the body, may become the agents of tissue destruction. As Armory says, speaking in a gen- eral way of the nutrition and formation of healthy tissue: " We may classify these under two prin- cipal heads. That of metabolism, which com- prises the whole range of transformation under the influence of chemical processes, and by means of which proteid substances undergo their many changes; and that of cell proliferation, by means of which the cells are multiplied." These meta- bolisms, whether of the constructive or destruc- tive character, are chiefly performed by function- ally active cells. Although the question of independent trophic nerve action is still unsettled, we know that the influence of the vaso-motor system over the blood and nutrition is very great; for strong external stimuli, such as shock, etc., will produce changes of a physical character in the blood. Wertheim found that the blood of animals which had suffered severely from extensive burns showed afterwards the presence of foreign bodies-yellowish gran- ules, besides increased fluidity, and disintegra- tion of the red blood corpuscles. Concerning animal chemistry there is but com- paratively little known! However, we have seen from the immense variety of chemical substan- ces already discovered to be results of fermenta- tion, or chemical action and reaction, what the probable changes are ! Laboratory experiments by Kolb, Munk, Peterson of New York, Shaw and others show that electrical energy is capable of producing great chemical transformation and de- composition in organic substances, outside the body. They show also that similar changes, either primarily or secondarily, may be produced 7 in living tissue. These observers have thus car- ried into the system such substances as iodine, strychnia and quinia, in proof of which, these substances were found in the urine in twelve hours or so afterwards. Zinselli has demonstrated be- yond doubt, physiological, chemical, and calorific effects upon living tissues by electrical energy- electrical osmosis-as he called it. Protoplasm, composed of carbon, hydrogen, oxygen, nitrogen, sulphur and phosphorus, ar- ranged into a very complex molecule, which is "the physical basis of life,'' as Huxley says, and which is the main substance of all animal and vegetable cells, seems capable of the widest de- gree of change; by "its universal and constant waste; and its repair by interstitial formation of new matter similar to the old.'' "Its power to give rise to new forms similar to the parent ones by a process of division. Its manifestations of periodic change in constitution developing decay and death.'' Mills, Foster and other physiologists state that protoplasm is not a single proteid substance, but a mixture of such. It contains often also starch, fat, chlorophyl, etc. The cell is composed of proto- plasm, nuclein, plasmine and chromatine as Dr. McCallum, of Toronto (who has been investiga- ting nutrition), calls the coloring matter of ani- mal cells. Protoplasm under nerve influence con- structs a certain substance which is antecedent to another final product, which is called a ferment. According to Vonjaksch, when fibrin or other proteids are acted upon by pepsin and hydro- chloric acid at a proper temperature, etc., the proteid passes through several stages before being finally converted into peptone. The proteid molecule seems to be split up and the albumoses are the first bodies formed. Kuhne 8 describes a proto-albumose, hetero-albumose, and deutero-albumose. Passing to the blood, which is such an important tissue both in health and disease, and so involved in any consideration of protoplasm, we find its chemical composition to be water, proteids, salines, fats, and extractives. The proteids being known as para-globulin, globulin, serum-albumin and fibrinogen; the principal extractives: urea, creatin, and allied bodies, sugar and lactic acid-the serum contain- ing the alkaline salts. The different corpuscles make up from one-third to one-half the weight of the blood, and of this, the red corpuscles may be said to constitute a greater part. The colorless cells are known to contain, besides protoplasm, peculiar granules, fats, glycogen, lecithin, pro- tagon, and other extractives. One especial inter- est attaches to the red corpuscles, on account of their containing, organically or intimately com- bined, iron. There have been very many interesting studies in relation to the blood and nutrition, of late, which wre have not the time to notice. Physiolo- gists have, however, found different actions of globulins, para-globulins and fibrinogen in serum. The behavior of coagulation, and the action of so-called fibrin fermentation is not without inter- est from a pathological point of view, for we shall probably find, in the future, that in many of the general diseases, characterized by parenchyma- tous inflammation, such as lobar pneumonia, the disease may be due to this vital process-includ- ing chemical changes of local origin and influ- ence; for it must strike every one who gives thought to it, that some of these diseases, at least, affecting organs are not essentially inflammations, but are diseases of the blood, as has been found by my colleague, Dr. Gibbes, in some investiga- 9 tions now being made upon pneumonia. What Virchow terms parenchymatous inflammation, that is, cloudy swelling or parenchymatous de- generation, met with in many febrile diseases,- especially the infectious fevers and septicaemia, and after poisoning by arsenic, phosphorus or strong mineral acids is, probably, due initially to some local change in the blood and cells of the part. Dr. W. C. .Glasgow, of St. Louis, pointed out a similar pathological condition in connection with some forms of acute pulmonary diseases a few years ago. Payne considers the granular degeneration so often accompanying febrile or inflammatory in- fections as a passive and not an active process, re- sulting from the action on the epithelium or parenchymatous elements of a part, of some in- jury, which, acting on the vessels and connective tissues, produces hyperaemia-exudation and cell- diapedesis. Another supposition is, that these molecular changes are the consequence of the high temperature to which the tissues are sub- jected during febrile conditions. Concerning the typical physiological ferments contained in the saliva, gastric juice, pancreatic juice and bile, we ought to say a word. Saliva is composed of proteids, mucous and salts. Its principal function is in reducing starchy matters of food to sugar. It produces besides dextrose and maltose, acrhrodextrine. This takes place in an alkaline solution; but a feeble acid added will be sufficient to stop the action. The active ferment of this fluid is ptyalin. The activity of gastric juice is due to the ferment, pepsin. The exact nature of the process by which proteid is changed to peptone is not known. This proteo- lytic action is possessed by some vegetable organ- isms which are said to form a para-peptone. 10 Bile.-In the composition of human bile we have bile salts, soap and fats, cholesterin, lecithin and glycocholates, and taurocholates, also waste products, such as hemoglobin and cholesterin. The digestive action of bile consists mainly of re- solving mucous into a proteid and an animal gum; it also assists pancreatic fluids in the emul- sifying process, and thus allows of more ready osmosis. Pancreatic Juice.-The organic constituents are alkali albumin, peptone, leucin, tyrosin, fats and soaps, and indol. It is amylolytic, proteolytic, and steaptic. These powers are attributed to three ferments, amylopsin, trypsin, and steapsin. Proteid digestion is carried still farther than by the gastric juice, and we have a quantity of the non-crystalline nitrogen compounds formed, leu- cin, one of the amido groups in the fatty acid series, and tyrosin, one of the aromatic series. Now with all this biological, chemical, molecular, and fermentative action going on in the human body, forming a great number of simple and com- plex organic substances, not only inocuous but poisonous, being ranked as tissue, as well as functional poisons, may we not find abundant cause for disease? Peptones injected into the blood of a healthy animal, according to Brunton, will cause death. Even the healthy blood of one species of animal injected into that of another, will cause death from non-adaptability, accord- ing to Mills. The experiments and observations of Dr. Stockton, of Buffalo, showing the deleterious effects produced by the entrance of the Portal blood into the systemic circulation is highly in- structive as bearing on this point. Microorganisms and many enzymes injected into the blood are readily destroyed, as pointed 11 out by Mitchell, Prudden, and others. Although there is a parasite (the filaria sanguinis hominis) which is known to inhabit the blood. Many ob- servers believe that certain febrile states are caused by the absorption into the blood of pep- tones, which have gone through and not been split up by the liver into globulin. It is not improb- able that absorption of ptomaines from the intes- tinal canal (which always contains some) may account for many of the so called "malarial at- tacks'' which so often serve as mantles of relief to our bewildered diagnostic sense. The proof of which may be assumed from the prompt relief which ensues from a brisk cathartic oftentimes. That dangerous condition known as ammonsemia and acetonsemia is more likely due to the absorp- tion of ammoniae toxines (the result of perverse chemical action) than to the presence in the blood of a special micrococcus. However, it is argued by those who have found microbes in urine, freshly voided, in that diseased condition called bacteruria, that the microorganisms are the essential cause. It is known to physiologists that after severe exercise the alkalinity of muscle juice is changed to acid, due to the presence of sarco-lactic acid. May we not see here the possibility of a combination with some organic base, so as to constitute a poison, the absorption of which determines disease. The chemical examination of sputum in various dis- eased states of the respiratory apparatus, shows, according to Kossell, Hoppe-Seyler, Salomon, Vonjaksch, Filehue, Stonikow, and others, the presence of peptone, serum-albumin, cholesterin, acetone, acetic, butyric, and caproic acids. Gly- cogen, and ferments resembling pancreatic fer- ments, besides a large number of different bac- teria. Bitter and Rietsch have shown that cholera mi- 12 crobes contain and elaborate a peptonizing fer- ment, and Hueppe has shown by experiment that the so-called cholera bacillus produces a toxine, the peculiar properties of which he has demonstrated on healthy animals. The researches of Kossell show that among the decomposition products of nuclein are found guainine, which occurs in plants and vegetables. The tissue of some animals contain adenine, hy- poxanthine and xanthine. Guainine and creatine are said by Vaughan and Novy to mutually re- place one another. Creatine is considered by Hoppe-Seyler as an intermediate product in the formation of urea. The cholesterine, found in the body is capable of many chemical substi- tution products. An analysis of the thyroid gland by Bubnow gave hypoxanthine, paralactic acid, and a proteid substance which he named thry eoprotein. Nothnagel found that the bile acids taken up into the circulation interfered with nutrition, producing fatty degeneration of organs or lymph glands. Among other poisons called by Brieger toxines, may be mentioned the so called cadaveric alkaloids, such as neuridine, cadavarine, saprine, mydaleine, putrescine, muscarine, choline, and pepto-toxines. We obtain also, from the putre- faction of albuminous matters, formic, acetic, butyric, valerianic, palmitic, acrulic, acrotomic, glycolic, lactic, valero-lactic, oxalic, glutaminic, and aspartic acids, and various ammonias, besides numerous amine bases, such as propylamine, tri- methlamine, etc., also the fixed alkaloidal bases, some of which are given above. Martin and Wolfenden, by their experiments, show that the poisonous property of jequirity or abrin resides in a globulin and an albumose. They also show that peptic albumose is poisonous to dogs. They 13 give an interesting table of comparison of these with snake poisons. Poisonous alkaloids from articles of food have been separated by Brieger and others, in some instances, and are now recog- nized as probable causes of disease. The ques- tion of fermentation as set up by microorganisms and the production of enzymes and toxines by them, is a leading one, and as yet unsettled. We have seen that these processes go on in na- ture in all instances of decomposition and putre- action. The chemical effects may be typically illustrated by the action of toruli and other yeast fungi, which, by fermentation, produce alcohols, acetic acid, etc., from saccharine substances. Parvinski has published the clinical history of a case of asthma in a young person in which the urine contained a large quantity of acetone dur- ing the paroxysms. A similar process of fer- mentation has been pointed out by Brieger, Hueppe, Vonjaksch„and others in relation to the cholera bacillus, as shown by the poisonous ef- fects on animals, by the introduction of the tox- ine which they had separated from the bacillus culture, and which they believe to have been pro- duced by the bacillus. Klebs and Loeffler have also discovered that the diphtheria bacteria pro- duces a ptomaine which may be the cause of the general infection, the microorganism being only local in its operation, a theory advocated years ago by Oertel. Loeffler could not find the bacillus in the blood, and believes that it always resides outside the body .while the toxine is the real poison. Brieger and C. Fraenkel have shown that diphtheria bacteria produces two poisons, one of which acts toxically, while the other secures im- munity. Zuegler claims to have isolated a poi- sonous crystalline alkaloid from tubercle, which he believes capable of producing the disease. 14 Herman Scholl, of Prague, confirms the con- clusions of Brieger and Fraenkel that both an- aerobic and aerobic bacteria produce poisons (toxines) or enzymes. The former more than the latter. Dr. F. Tydston, of Chicago, has shown that the evolution of venereal disease is not due to a coccus, but a ptomaine which inhabits the vagina, proving this by experiment. Many ob- servers, however, claim to have found the coccus of gonorrhoea in the joints. There is much doubt as to the exact part played by the bacillus of ty- phoid fever, and without giving the controversy between Klebs, Bberth, Koch, Meyer, Fried- lander, Gaftky, and others, it is probably as Beu- mer and Peiper say, not really pathogenic, and that the disease is produced, as Brieger suggests, by a toxine. Dr. Gibbes and myself found that sterilized watery extract of tubercle would kill a newly hatched white-fish in fifty-five seconds, completely permeating the .protoplasmic mass, while an alkaline extract would do so in about sixty-five seconds. Mice afterwards injected with the fish show no signs of septicaemia or other dis- ease, but die if injected with the same extract. Thus showing a peculiar affinity between proto- plasm and tubercle toxines. To discuss in a special manner the saphrophy- tic and pathogenic bacteria concerned in a full biological study would take so much time that I can only, as it were, allude to them. In Bisenberg's tables of known bacteria for laboratory use one hundred and sixteen species are enumerated, etc. We have found that when guinea-pigs were in- jected subcutaneously with the extracts made from the lungs of monkeys dead of (their) ordin- ary phthisis pulmonalis (which is characterized by marked emphysema) the only effects were 15 fever with catarrhal symptoms, lasting about two weeks. On the other hand, when in- jected with an extract made from tuberculous lungs from the human being, general tuberculosis followed. The morbid anatomy of the monkey lung is identical, from an ordinary view, with that of human phthisis pulmonalis. This prob- ably illustrates the condition which all patholo- gists recognize now as pseudo-tuberczdosis. I am aware that it is generally accepted that bacteria or their spores are the essential cause of most, if not all of the infective diseases. And the results of bacteriological investigation during the last few years would seem to support such a doctrine, for the following reasons, viz.: That they can be isolated by color reaction and thus directly con- nected with the diseased body where found. Moreover, they require a certain time for develop- ment, thus corresponding to the period of incu- bation of such diseases; many of them being ecto- genic and saprogenic, anaerobic, or aerobic, can thus live until the opportunity for invasion offers. Being endowed with life and multiplying enor- mously, they can strenuously resist destruction. Being protoplasmic (composed of albuminous material) and microscopic they can more readily affiliate with animal fluids, cells and tissues. Ex- isting in a passive or quiescent state as well as an active one, they can behave like vegetable seeds and spores, and preserve a long period of latency. For these, as well as other reasons which could be adduced, we are led to believe that bacteria must be the cause in some way or other of the zymotic or infectious diseases. But the question arises, how do they accom- plish this? By mere local growth for a parasitic life, by a secretion of material from themselves, in other words, are they secreting cells ? or, by 16 inducing at once chemical changes or fermenta- tion of a destructive character with the formation of new substances-poisons ? If we examine carefully into the basis on which certain forms of organisms stand as the materies morbi of a given disease, we shall find that those who are so strong in their faith in the essential microbic origin of disease have not in some in- stances looked fairly into the status of affairs. For instance, take the case of the comma bacillus of Koch, Fraenkel, in his text-book of bacteri- ology, third edition, says: No case of genuine cholera has as yet been reported in which the comma bacillus has been absent. From the context, he probably means in the intestines. This has been undoubtedly disproved! This illustrates again what was said at the outset, that all of these questions should be looked at without bias as far as possible, without regard to nation- ality, and from the stand point of clinical as well as laboratory experience. In whatever manner their life history is exem- plified certain effects have been observed connected with them, as a class. Their career ad interim from one animal to another is not well known (excepting perhaps the bacillus of anthrax). Some people supposing that they may be sapro- genic at first, and thence transformed to pathogen- ic. In the case of many of them, their spores have either never been really demonstrated to exist, or their behavior formulated. Most species, if not all, are destroyed by the healthy fluids or tissues, and hence their destiny depends upon a favorable nidus or pabulum, which means disease. It is ob- vious that their artificial culture in media outside the body or in the lower animals can only ap- proximately reflect their real natural growth and development, for in no instance is it possible to 17 transfer the artificially cultivated microorganism to an animal with the absolute certainty that nothing else accompanies the bacterium. Take, for instance, tubercle bacilli, the study of which has given the most satisfactory results. We are being inoculated day by day with tubercle bacilli from the air. Why do any escape ? Because some are so healthy that they are immune. But how is it that every guinea-pig inoculated gets tuber- culosis ? The radical believers in microbiosis say, because they are all susceptible. But the probable explanation is (like that of diphtheria), that the materies morbi is introduced and carried away by the lymphatics and sets up a general chemical change. There is also local change, abscess, at the situation of the inoculation from which are furnished spores which may flourish in the blood or lymph fluid afterward, where they will now find suitable pabulum for development, thus showing the fact that certain bacteria, at least, develope or act under certain conditions only, and upon a particular nidus. Their chem- ical composition is unknown during a state of ac- tivity. That certain species only appear to be pathogenic, would imply a state of specialization analogous to living nucleated cells. That their action is local, primarily, in all cases, may be assumed, because their behavior in no way shows that they themselves invade or maintain their ex- istence in the blood or lymph fluids, because the blood would destroy them. For there are but few instances recorded of any one having found bac- teria in the blood, unless we except the anthrax bacilli. Therefore it is probable that pathogenic bacteria develope only where some previous dis- ease or abnormal state of the body suitable to them exists. That having found such, they take root, as it were, and there by catalytic action 18 primarily, and secondarily, give rise to a particu- lar toxine or poison which in turn acts selectively as a tissue poison ! The various facts stated of a toxine connected with diphtheria, typhoid fever, cholera, suppura- tion and abscess (which has been shown to be in- dependent of bacteria), croupous pneumonia, scarlatina, phthisis pulmonalis, syphilis, tetanus, gonorrhoea, cobra and other snake poisons, etc., together with the well known (chemical) noxious products forming constantly in the body, are suffi- cient, it seems to me, to show that the etiological agency of bacteria are mediate and not immediate! This catalytic action coincides with clinical ob- servations in many directions, as, for instance, the action of snake poisons, as shown by Weir, Mitchell, and the British India Sanitary Reports. From the cobra (one of the most deadly of ser- pents) an alkaloid as the active principle has been separated, but how far its virulence has been test- ed we do not know. There are formed in certain plants, as we know, very poisonous alkaloids and glucosides, many of them corresponding in chemical character and physical behavior to animal alkaloids and col- loids; solanine, for instance, is a basic glucoside which under the influence of dilute acids splits up into solanidine and sugar. Both of these active principles are blood poisons belonging to the group of sapro-toxines. I would say that the experiments of Dr. Gibbes and myself, point to the same thing as to the na- ture and behavior of tubercle when cultures or extracts are introduced subcutaneously. We have also observed that the insufflation of sun- dried sputum (tubercular) will produce phthisis pulmonalis, while the inoculation of sputum (phthisis) which has been long dry from age will 19 not produce tuberculosis. This seems to have been confirmed by some recent experiments made by Dr. Stone in the Harvard Laboratory, who inoculated guinea pigs, with negative results, with sputum which had been long dried, and which was probably from a case of phthisis pul- monalis. We are now carrying on an investigation to ascertain the effects of inoculating guinea pigs with sputum from phthisical patients, which spu- tum has been dried in the sun in Southern Cali- fornia, under the supervision of Dr. Norman Bridge, of Chicago. The investigation has not proceeded far enough to show just what effects it will have in the production of tuberculosis, but one remarkable result has already been ob- tained. Six guinea pigs were inoculated, and within thirty-six hours after the operation two died of septicaemia, showing that this effect, which is a frequent result of inoculation with sputum taken directly from patients, is probably not caused by any organsim, and thus coinciding per- fectly with observations which Payne gives in bis text-book relating to the occurrence of septicae- mia without microorganisms having been discov- ered in connection therewith. Concerning the tubercle bacilli, the bacilli immediately produced in the several diseases known as tubercular, why would any previously prepared nidus be necessary ? If they, or their spores (which have not as yet been satisfactorily demonstrated) are constantly invading us (which is undoubtedly true), they must at once be de- stroyed, or, if gaining access to the fluids of the body, would set up mechanically or otherwise, inflammation and peculiar effects as any other foreign body would. But as such microorgan- isms must find just the proper conditions for de- velopment or not develop, we may assume that 20 such conditions imply previous disease, such as caseation, whether tuberculous or not. We have already seen what complex and delicate processes attend the changes of proteids, and how easy, by radical or atomic substitution, one may be changed into the other ; we can therefore see how probable it is that these microorganisms op- erate by a peculiar property which enables them to decompose or exercise a catalytic action on certain states and kinds of proteids. The sub- ject of immunity and susceptibility of course cannot be discussed here-suffice it to say that the ideas and experiments of Trudeau of New York, and McLaughlin of Texas, in this direc- tion, are worthy of careful attention, and apply not only to microbes but to chemical substances connected with them. To say nothing of the chemical action and products normally evolved, as already explained, Abelous has obtained sixteen species of microbes from the empty stomach by lavage ; seven of these were well known varieties, ten of these attacked and changed albumin, twelve fibrin, and nine gluten, ten caused transfor- mations of lactose into lactic acid; thirteen formed a variable quantity of glucose from starch; rapid and energetic decomposition with evolution of gas, leucin, tyrosin, indol, skatol and ammonia compounds took place in presence of saliva. I do not know that all of these observations have been confirmed. But we have confirmed his ex- periments regarding albumin, which is readily transformed by saliva in the presence of microor- ganisms outside the body. Experiments with invertin, a ferment found in the intestinal canal, have shown some interesting results in relation to microbe metamorphosis, which are still, however, sub judici. Jaccoud finds the pneumococcus, be- sides several other forms of bacteria, in diphthe- 21 ria. He believes that individual reaction is what determines the disease. What application can be made therapeutically of the facts obtained ? It is manifest that the dis- eases in question are caused in some way by the presence or entrance of microorganisms. There- fore the main therapeutic indication is to attack them, or neutralize their operation. We have seen that bacteria either produce for themselves or from the organic substances which they attack, a poison, or enzyme, and that this can be cultivated outside the body in some instances. Pathological chem- istry has not demonstrated with exactness the na- ture of all of these poisons, or classified them, but it is fair to believe that such will surely take place in the near future. Although it is gener- ally supposed that the inorganic chemicals are not tissue poisons, but act only upon the functions through the nervous system, yet we believe that such is not the case when we observe the tissue changes produced by iodine, bromine, phospho- rus, arsenic, the silver, gold, platinum and cupric salts, besides some of the vegetable alkaloids. Dr. Gibbes and myself have been able to neutral- ize the toxic effect of tubercle by admixture with chlorine iodine. Chloride of gold combined with glycerine, salts of platinum and glycerine and peroxide of manganese, outside the body, and with the chlorine, iodine, and gold and sodium chloride in inoculated animals. That certain chemicals have a selective action on tissues can- not be doubted; take, for example, the hypoder- mic injection of cantharidin used a few years ago by Cornil and Ranvier, resulting in the pro- duction of inflammation of the air passages; also the work lately of Liebreich in injecting canthar- adate of potassium for the cure of phthisis pul- monalis and tuberculosis, which he believes pro- 22 duces exudation, as when applied to the skin. Also the selective action of strychnia and atropia, the latter acting on the secretory cells of the sali- vary glands, stopping secretion notwithstanding the induction of hyperaemia. Arecoline, a vol- atile liquid alkaloid from the areca nut, has a selective action on the heart and is excreted unchanged. Harnack probably states the truth in saying that the action of drugs is molecu- lar and fermentative. On account of the changes which remedies are apt to undergo in the stomach and intestines, by being oxidized or other- wise changed before absorption into the system, the rational way, it seems to me, is to introduce the agent hypodermically; in this way it is pos- sible to get effects which cannot be accomplished otherwise. Dr. Lauderer has obtained beneficial effects in phthisis from hypodermic injection of balsam Peru, which he says goes at once to the diseased part, thus simulating animal fluids or cultures, as exemplified by the effects of Koch's lymph and similar cultures used before by Pas- teur, Grancher, Martin, Rengi, Gibbes and oth- ers. Dr. Behring has lately found that a number of chemical substances used hypodermically, such as aurochloride of sodium, naphthaline, and tri- chloride of iodine, were capable of neutralizing the poison of diphtheria in guinea pigs, but the most active of all was the trichloride of iodine. He also practiced, in diphtheria the plan of vac cinating the animals with bacilli cultures. Prof. Merzolski reports much better effects from bro- mide of gold used hypodermically (in and y2 gr. doses), than by the usual way of administra- tion of bromides. The prompt effects of Samm- ter's treatment of erysipelas by carbolic acid in- jections, are well known. The superior effects of the treatment of syphilis, by hypodermic in- 23 j ection of cyanide and bichloride of mercury and chloride of gold and sodium are striking, as we all know. Dr. Zumbali, of Rome, found hypo- dermic injections of chlorodyne in profuse diar- rhoea particularly superior to its administration by the mouth. The hypodermic injection of ergot for the relief of haemoptysis is another example. This agent, administered in considerable quantity by the mouth, will often fail* whereas one, or at most two, hypodermic injections of or | gr. of ergotin will generally stop a severe attack. Dig- italis also acts upon the cells and vascular sys- tem more certainly when so administered. I may also mention the beneficial effects of strych- nia used hypodermically, in typhoid conditions. That animal poisons can be neutralized in the body, I believe, will soon be more generally dem- onstrated. The experience of Tyndall, of New York, in the vaccination process for the cure of tuberculosis, promises well. Hemmeter has stopped the course of diphtheria by the vaccina- tion of the patient with an erysipelas toxine ; and Prof. Grancher states that persons suffering from tenia tonsurans are immune from diphtheria. This would seem toshow that there must be a sort of antagonism or isomerism between animal and chemical poisons ; and why may not more universal application be made of this principle, with a view of obtaining more specific therapeutic agents and effects? The ethereal oils, on account of their diffusable antiseptic properties, are un- doubtedly applicable to the neutralization of dis- ease when used hypodermically, and may prove yet of great value in the zymotic diseases. We are now engaged in using some of them in this way, and find that they actually provoke the li- quefaction of effused products. We are also ex- perimenting with members of the benzoin and 24 formic acid series, and the toluidines, in an en- deavor to learn their action on metabolism and disease poisons. Dr. Emil Schutz believes that drugs act topically on the secretions by precipi- tating albumin. He also demonstrated, by cases, that tannic acid may produce urticaria by exter- nal application alone. Galezowski, of Paris, has lately discovered a new bacteriacide, by the de- composition of an *aniline dye, which has the same properties as pyoktania on the tissues. In this direction we may look for brilliants re- sults, on account of the action of these substances on albuminates. My chief object is to awaken a more general interest in physiological and pa- thological chemistry, to the end that we may as speedily as possible acquire a scientific chemical therapy, and thus release her from the dungeon of empiricism, where she has been imprisoned with so little light these many years.